JP2020117509A - Conjugates for treating diseases - Google Patents

Abstract

To provide conjugates of PBD prodrugs.SOLUTION: Conjugates comprising B-(AA)-L-(L)-(AA)-(L)-(L)-D-L-D, B-(AA)-L-D, B-(AA)-L-D-L-D-L-(AA)-B or B-L-AA-L-AA-L-L-(L)-(L)-(AA)-(L)-D-L-D[In the formula, B is formula I, AA is an amino acid, L-Leach denote a linker, Dis a PBD prodrug, Dis a DNA-binding substance, z1-12 each denote an integer of 0-5].SELECTED DRAWING: None

Description

The present invention relates to pyrrolobenzodiazepine (PBD) prodrugs and conjugates thereof. The present invention also relates to pharmaceutical compositions of the conjugates described herein, methods of making and using the same.

The mammalian immune system provides a means for recognition and elimination of pathogenic cells such as tumor cells and other invasive foreign pathogens. Although the immune system usually provides a strong line of defense, there are many cases in which pathogenic cells such as cancer cells and other infectious agents evade the host immune response and grow or persist with the associated host pathogenicity. Chemotherapeutic agents and radiotherapy have been developed, for example, to eliminate replicating tumors. However, currently available chemotherapeutic and radiotherapy regimens have deleterious side effects due to lack of sufficient selectivity to preferentially destroy pathogenic cells, and thus normal hematopoietic systems like the hematopoietic system. It can also harm host cells and other non-pathogenic cells. The deleterious side effects of these anti-cancer agents highlight the need for the development of novel therapies that are selective for pathogenic cell populations and have reduced host toxicity.

Researchers are developing therapeutic protocols to destroy cytotoxic compounds by targeting them to pathogenic cells. Many of these protocols utilize toxin conjugated to antibodies that bind to pathogenic cell-specific or overexpressed antigens to minimize delivery of the toxin to normal cells. Using this approach, a specific immunotoxin has been developed, consisting of antibodies directed against specific antigens on pathogenic cells, antibodies bound to toxins such as ricin, Pseudomonas exotoxin, diphtheria toxin and tumor necrosis factor. Has been done. These immunotoxins target pathogenic cells, such as tumor cells, that carry specific antigens recognized by antibodies (Olsnes, S., Immunol. Today, 10, pp. 291-295, 1989; Melby. , EL, Cancer Res., 53(8), pp. 1755-1760, 1993; Better, MD, PCT publication number WO 91/07418, published May 30, 1991).

Another approach to targeting a population of pathogenic cells, such as cancer cells or foreign pathogens, within the host is to avoid pathogenic cells to avoid the need for administration of compounds that may also exhibit unrelated host toxicity. It is to enhance the host immune response. One strategy reported for immunotherapy involves the binding of antibodies, such as genetically modified polyvalent antibodies, to the surface of tumor cells which display the constant region of the antibody on the cell surface, where various processes mediated by the immune system. To induce tumor cell death (De Vita, VT, Biologic Therapy of cancer, 2d ed. Philadelphia, Lippincott, 1995; Soulillou, JP, US Pat. No. 5,672,486). However, these approaches are complicated by difficulties in defining tumor-specific antigens.

Folic acid plays an important role in nucleotide biosynthesis and cell division, intracellular activity that occurs in both malignant cells and certain normal cells. The folate receptor has a high affinity for folate, and binding of the folate receptor affects the cell cycle in dividing cells. As a result, folate receptors have been associated with a variety of cancers that have been shown to have elevated folate receptor expression, such as ovarian cancer, endometrial cancer, lung cancer and breast cancer. In contrast, folate receptor expression in normal tissues (eg kidney, liver, intestine and placenta) is limited. This differential expression of the folate receptor in neoplastic and normal tissues makes the folate receptor an ideal target for small molecule drug development. The development of folate conjugates represents a route for the discovery of novel treatments that utilize the differential expression of folate receptors. There is a great need for the development of folate conjugates, methods of identifying folate receptor positive cancers and methods of treating patients with folate receptor positive cancers.

In one aspect, the invention has the formula:
^{_{B- (AA) z1 -L 2 -}} (L 3) z2 - (AA) z3 - (L 1) z4 - (L 4) z5 -D 1 -L 5 -D 2,
^{_{B- (AA) z10 -L 2 -D}} 2,
^{_{B- (AA) z11 -L 2 -D}} 1 -L 5 -D 1 -L 2 - (AA) z12 -B or ^{B-L 1 -AA-L 1} -AA-L 1 -L 2 - (L 3 _{^{) z6 - (L 4) z7}} - (AA) z8 - (L 4) z9 -D 1 -L 5 -D 2
[In the formula,
B, AA, L ¹ , L ² , L ³ , L ⁴ , L ⁵ , D ¹ , D ² , z1, z2, z3, z4, z5, z6, z7, z8, z9, z10, z11 and z12, respectively. Is defined as described herein)
Alternatively, a conjugate is provided that comprises a binding ligand having a pharmaceutically acceptable salt thereof, a linker and a drug.

In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a conjugate described herein or a pharmaceutically acceptable salt thereof, and at least one excipient.

In another aspect, the invention provides a method of treating abnormal cell growth in a mammal, including a human, comprising administering to the mammal any of the conjugates or compositions described herein. provide.

The conjugates of the invention may be described as embodiments in any of the sections listed below. It is understood that any aspect described herein may be used in connection with any other aspect described herein, as long as the aspects are not in conflict with each other.

（式中、
各場合において、Ｒ^１およびＲ^２は独立してＨ、Ｄ、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、−ＯＲ^７、−ＳＲ^７および−ＮＲ^７Ｒ^７’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニルおよびＣ_２〜Ｃ_６アルキニルにおける各水素原子は、独立して、場合により、ハロゲン、−ＯＲ^８、−ＳＲ^８、−ＮＲ^８Ｒ^８’、−Ｃ（Ｏ）Ｒ^８、−Ｃ（Ｏ）ＯＲ^８または−Ｃ（Ｏ）ＮＲ^８Ｒ^８’により置換されていてよく；
Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は、それぞれ独立してＨ、Ｄ、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、−ＣＮ、−ＮＯ_２、−ＮＣＯ、−ＯＲ^９、−ＳＲ^９、−ＮＲ^９Ｒ^９’、−Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＯＲ^９および−Ｃ（Ｏ）ＮＲ^９Ｒ^９’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニルおよびＣ_２〜Ｃ_６アルキニルにおける各水素原子は、独立して、場合により、ハロゲン、−ＯＲ^１０、−ＳＲ^１０、−ＮＲ^１０Ｒ^１０’、−Ｃ（Ｏ）Ｒ^１０、−Ｃ（Ｏ）ＯＲ^１０または−Ｃ（Ｏ）ＮＲ^１０Ｒ^１０’により置換されていてよく；
Ｒ^７、Ｒ^７’、Ｒ^８、Ｒ^８’、Ｒ^９、Ｒ^９’、Ｒ^１０およびＲ^１０’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニルまたはＣ_２〜Ｃ_６アルキニルであり；
Ｘ^１は−ＮＲ^１１−、＝Ｎ−、−Ｎ＝、−Ｃ（Ｒ^１１）＝または＝Ｃ（Ｒ^１１）−であり；
Ｘ^２は−ＮＲ^１１’−または＝Ｎ−であり；
Ｘ^３は−ＮＲ^１１’’−、−Ｎ＝または−Ｃ（Ｒ^１１’）＝であり；
Ｘ^４は−Ｎ＝または−Ｃ＝であり；
Ｘ^５はＮＲ^１２またはＣＲ^１２Ｒ^１２’であり；
Ｘ^１が−Ｎ＝もしくは−Ｃ（Ｒ^１１）＝のとき、Ｙ^１はＨ、Ｄ、−ＯＲ^１３、−ＳＲ^１３もしくは−ＮＲ^１３Ｒ^１３’であり、またはＸ^１が−ＮＲ^１１−、＝Ｎ−もしくは＝Ｃ（Ｒ^１１）−のとき、Ｙ^１は＝Ｏであり；
Ｘ^４が−Ｃ＝のとき、Ｙ^２はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、−Ｃ（Ｏ）Ｒ^１４、−Ｃ（Ｏ）ＯＲ^１４、−Ｃ（Ｏ）ＮＲ^１４Ｒ^１４’であり、またはＸ^４が−Ｎ＝のとき、Ｙ^２は存在せず；
Ｒ^１１、Ｒ^１１’、Ｒ^１１’’、Ｒ^１２、Ｒ^１２’、Ｒ^１３、Ｒ^１３’、Ｒ^１４およびＲ^１４’はそれぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、−Ｃ（Ｏ）Ｒ^１５、−Ｃ（Ｏ）ＯＲ^１５および−Ｃ（Ｏ）ＮＲ^１５Ｒ^１５’から成る群から選択され；
Ｒ^１５およびＲ^１５’は、それぞれ独立してＨまたはＣ_１〜Ｃ_６アルキルであり；
ｍは１、２、３または４である）
のものであり、 1. Formula ^{_{B- (AA) z1 -L 2 -}} (L 3) z2 - (AA) z3 - (L 1) z4 - (L 4) z5 -D 1 -L 5 -D 2,
^{_{B- (AA) z10 -L 2 -D}} 2,
^{_{B- (AA) z11 -L 2 -D}} 1 -L 5 -D 1 -L 2 - (AA) z12 -B or ^{B-L 1 -AA-L 1} -AA-L 1 -L 2 - (L 3 _{^{) z6 - (L 4) z7}} - (AA) z8 - (L 4) z9 -D 1 -L 5 -D 2
[In the formula,
z1, z10, z11 and z12 are each independently 2, 3, 4 or 5;
z2 is 0, 1 or 2;
z3 is 0, 1, 2, 3 or 4;
z4 is 0, 1 or 2; and z5 is 0, 1 or 2 and z6 is 0, 1 or 2;
z7 is 0, 1 or 2;
z8 is 0, 1, 2, 3 or 4;
z9 is 0, 1 or 2;
B is the formula I

(In the formula,
In each case, R ¹ and R ² are independently H, D, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, —OR ⁷ , —SR ⁷ and —NR. ⁷ R ^7′ selected from the group consisting of, wherein each hydrogen atom in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl is, independently, optionally halogen, —OR ^{8, -SR 8, -NR 8 R} 8 may be substituted by ^{', -C (O) R 8} , -C (O) oR 8 or ^{-C (O) NR 8 R 8} ';
R ^{3, R} 4, ^{R 5} and ^{R 6,} H independently, D, _halogen, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl, -CN, -NO ₂ , selection ^{-NCO, -OR 9, -SR 9,} -NR 9 R 9 from a group consisting of ^{', -C (O) R 9} , -C (O) oR 9 and ^{-C (O) NR 9 R 9} ' Where each hydrogen atom in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl is independently, optionally, halogen, —OR ¹⁰ , —SR ¹⁰ , —NR ^{10. R 10 ', -C (O)} R 10, -C (O) oR 10 or ^{-C (O) NR 10 R 10} ' may be substituted by;
^{R 7, R 7 ', R} 8, R 8', R 9, R 9 ', R 10 and ^{R 10'} is, H _{independently, D,} C 1 ~C _{6 alkyl,} C 2 -C ₆ alkenyl Or C ₂ -C ₆ alkynyl;
X ¹ is ^{-NR 11 -, = N -,} - N =, - C (R 11) = or = C ^{(R 11)} - a and;
X ² is -NR ^{11 '-} or = a N-;
X ³ is ^{-NR 11 '' -, - N} = or -C ^{(R 11 ')} = a and;
X ⁴ is -N= or -C=;
X ⁵ is NR ¹² or CR ¹² R ^12′ ;
When X ¹ is -N= or -C(R ¹¹ )=, Y ¹ is H, D, -OR ¹³ , -SR ¹³ or -NR ¹³ R ^13' , or X ¹ is -NR ¹¹ -, When =N- or =C(R ¹¹ )-, Y ¹ is =O;
When X ⁴ is -C = a, ^{Y 2} is _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C ₆ ^{alkenyl, -C (O) R 14,} -C (O) OR 14, -C (O ) a ^{NR 14 R} 14 ^', or when ^{X 4} is -N =, ^{Y 2} is absent;
R ¹¹ , R ^11′ , R ^11″ , R ¹² , R ^12′ , R ¹³ , R ^13′ , R ¹⁴ and R ^14′ are each independently H, D, C ₁ -C ₆ alkyl or —C. ^(O) R 15, is selected from the group consisting of -C (O) ^{oR 15} and ^{-C (O) NR 15 R 15} ';
R ¹⁵ and R ^15′ are each independently H or C ₁ -C ₆ alkyl;
m is 1, 2, 3 or 4)
Of the

（式中、
Ｒ^１６はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、−Ｃ（Ｏ）Ｒ^１９、−Ｃ（Ｏ）ＯＲ^１９および−Ｃ（Ｏ）ＮＲ^１９Ｒ^１９’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニルおよびＣ_２〜Ｃ_６アルキニルにおける水素は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、およびＣ_２〜Ｃ_６アルキニル、−ＯＲ^２０、−ＯＣ（Ｏ）Ｒ^２０、−ＯＣ（Ｏ）ＮＲ^２０Ｒ^２０’、−ＯＳ（Ｏ）Ｒ^２０、−ＯＳ（Ｏ）_２Ｒ^２０、−ＳＲ^２０、−Ｓ（Ｏ）Ｒ^２０、−Ｓ（Ｏ）_２Ｒ^２０、−Ｓ（Ｏ）ＮＲ^２０Ｒ^２０’、−Ｓ（Ｏ）_２ＮＲ^２０Ｒ^２０’、−ＯＳ（Ｏ）ＮＲ^２０Ｒ^２０’、−ＯＳ（Ｏ）_２ＮＲ^２０Ｒ^２０’、−ＮＲ^２０Ｒ^２０’、−ＮＲ^２０Ｃ（Ｏ）Ｒ^２１、−ＮＲ^２０Ｃ（Ｏ）ＯＲ^２１、−ＮＲ^２０Ｃ（Ｏ）ＮＲ^２１Ｒ^２１’、−ＮＲ^２０Ｓ（Ｏ）Ｒ^２１、−ＮＲ^２０Ｓ（Ｏ）_２Ｒ^２１、−ＮＲ^２０Ｓ（Ｏ）ＮＲ^２１Ｒ^２１’、−ＮＲ^２０Ｓ（Ｏ）_２ＮＲ^２１Ｒ^２１’、−Ｃ（Ｏ）Ｒ^２０、−Ｃ（Ｏ）ＯＲ^２０または−Ｃ（Ｏ）ＮＲ^２０Ｒ^２０’により置換されていてよく；
Ｒ^１７およびＲ^１７’は、それぞれ独立してＨ、Ｄ、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^２２、−ＯＣ（Ｏ）Ｒ^２２、−ＯＣ（Ｏ）ＮＲ^２２Ｒ^２２’、−ＯＳ（Ｏ）Ｒ^２２、−ＯＳ（Ｏ）_２Ｒ^２２、−ＳＲ^２２、−Ｓ（Ｏ）Ｒ^２２、−Ｓ（Ｏ）_２Ｒ^２２、−Ｓ（Ｏ）ＮＲ^２２Ｒ^２２’、−Ｓ（Ｏ）_２ＮＲ^２２Ｒ^２２’、−ＯＳ（Ｏ）ＮＲ^２２Ｒ^２２’、−ＯＳ（Ｏ）_２ＮＲ^２２Ｒ^２２’、−ＮＲ^２２Ｒ^２２’、−ＮＲ^２２Ｃ（Ｏ）Ｒ^２３、−ＮＲ^２２Ｃ（Ｏ）ＯＲ^２３、−ＮＲ^２２Ｃ（Ｏ）ＮＲ^２３Ｒ^２３’、−ＮＲ^２２Ｓ（Ｏ）Ｒ^２３、−ＮＲ^２２Ｓ（Ｏ）_２Ｒ^２３、−ＮＲ^２２Ｓ（Ｏ）ＮＲ^２３Ｒ^２３’、−ＮＲ^２２Ｓ（Ｏ）_２ＮＲ^２３Ｒ^２３’、−Ｃ（Ｏ）Ｒ^２２、−Ｃ（Ｏ）ＯＲ^２２および−Ｃ（Ｏ）ＮＲ^２２Ｒ^２２’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、−ＯＲ^２４、−ＯＣ（Ｏ）Ｒ^２４、−ＯＣ（Ｏ）ＮＲ^２４Ｒ^２４’、−ＯＳ（Ｏ）Ｒ^２４、−ＯＳ（Ｏ）_２Ｒ^２４、−ＳＲ^２４、−Ｓ（Ｏ）Ｒ^２４、−Ｓ（Ｏ）_２Ｒ^２４、−Ｓ（Ｏ）ＮＲ^２４Ｒ^２４’、−Ｓ（Ｏ）_２ＮＲ^２４Ｒ^２４’、−ＯＳ（Ｏ）ＮＲ^２４Ｒ^２４’、−ＯＳ（Ｏ）_２ＮＲ^２４Ｒ^２４’、−ＮＲ^２４Ｒ^２４’、−ＮＲ^２４Ｃ（Ｏ）Ｒ^２５、−ＮＲ^２４Ｃ（Ｏ）ＯＲ^２５、−ＮＲ^２４Ｃ（Ｏ）ＮＲ^２５Ｒ^２５’、−ＮＲ^２４Ｓ（Ｏ）Ｒ^２５、−ＮＲ^２４Ｓ（Ｏ）_２Ｒ^２５、−ＮＲ^２４Ｓ（Ｏ）ＮＲ^２５Ｒ^２５’、−ＮＲ^２４Ｓ（Ｏ）_２ＮＲ^２５Ｒ^２５’、−Ｃ（Ｏ）Ｒ^２４、−Ｃ（Ｏ）ＯＲ^２４または−Ｃ（Ｏ）ＮＲ^２４Ｒ^２４’により置換されていてよく；
またはＲ^１７およびＲ^１７’は結合してＣ_４〜Ｃ_６シクロアルキルまたは４〜６員環ヘテロ環を形成してよく、ここでＣ_４〜Ｃ_６シクロアルキルまたは４〜６員環ヘテロ環における各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^２４、−ＯＣ（Ｏ）Ｒ^２４、−ＯＣ（Ｏ）ＮＲ^２４Ｒ^２４’、−ＯＳ（Ｏ）Ｒ^２４、−ＯＳ（Ｏ）_２Ｒ^２４、−ＳＲ^２４、−Ｓ（Ｏ）Ｒ^２４、−Ｓ（Ｏ）_２Ｒ^２４、−Ｓ（Ｏ）ＮＲ^２４Ｒ^２４’、−Ｓ（Ｏ）_２ＮＲ^２４Ｒ^２４’、−ＯＳ（Ｏ）ＮＲ^２４Ｒ^２４、−ＯＳ（Ｏ）_２ＮＲ^２４Ｒ^２４’、−ＮＲ^２４Ｒ^２４’、−ＮＲ^２４Ｃ（Ｏ）Ｒ^２５、−ＮＲ^２４Ｃ（Ｏ）ＯＲ^２５、−ＮＲ^２４Ｃ（Ｏ）ＮＲ^２５Ｒ^２５’、−ＮＲ^２４Ｓ（Ｏ）Ｒ^２５、−ＮＲ^２４Ｓ（Ｏ）_２Ｒ^２５、−ＮＲ^２４Ｓ（Ｏ）ＮＲ^２５Ｒ^２５’、−ＮＲ^２４Ｓ（Ｏ）_２ＮＲ^２５Ｒ^２５’、−Ｃ（Ｏ）Ｒ^２４、−Ｃ（Ｏ）ＯＲ^２４または−Ｃ（Ｏ）ＮＲ^２４Ｒ^２４’により置換されていてよく；
Ｒ^１８は、Ｈ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３−Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^２６、−ＯＣ（Ｏ）Ｒ^２６、−ＯＣ（Ｏ）ＮＲ^２６Ｒ^２６’、−ＯＳ（Ｏ）Ｒ^２６、−ＯＳ（Ｏ）_２Ｒ^２６、−ＳＲ^２６、−Ｓ（Ｏ）Ｒ^２６、−Ｓ（Ｏ）_２Ｒ^２６、−Ｓ（Ｏ）ＮＲ^２６Ｒ^２６’、−Ｓ（Ｏ）_２ＮＲ^２６Ｒ^２６’、−ＯＳ（Ｏ）ＮＲ^２６Ｒ^２６’、−ＯＳ（Ｏ）_２ＮＲ^２６Ｒ^２６’、−ＮＲ^２６Ｒ^２６’、−ＮＲ^２６Ｃ（Ｏ）Ｒ^２７、−ＮＲ^２６Ｃ（Ｏ）ＯＲ^２７、−ＮＲ^２６Ｃ（Ｏ）ＮＲ^２７Ｒ^２７’、−ＮＲ^２６Ｃ（＝ＮＲ^２６’’）ＮＲ^２７Ｒ^２７’、−ＮＲ^２６Ｓ（Ｏ）Ｒ^２７、−ＮＲ^２６Ｓ（Ｏ）_２Ｒ^２７、−ＮＲ^２６Ｓ（Ｏ）ＮＲ^２７Ｒ^２７’、−ＮＲ^２６Ｓ（Ｏ）_２ＮＲ^２７Ｒ^２７’、−Ｃ（Ｏ）Ｒ^２６、−Ｃ（Ｏ）ＯＲ^２６および−Ｃ（Ｏ）ＮＲ^２６Ｒ^２６’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、−（ＣＨ_２）_ｐＯＲ^２８、−（ＣＨ_２）_ｐ（ＯＣＨ_２）_ｑＯＲ^２８、−（ＣＨ_２）_ｐ（ＯＣＨ_２ＣＨ_２）_ｑＯＲ^２８、−ＯＲ^２９、−ＯＣ（Ｏ）Ｒ^２９、−ＯＣ（Ｏ）ＮＲ^２９Ｒ^２９’、−ＯＳ（Ｏ）Ｒ^２９、−ＯＳ（Ｏ）_２Ｒ^２９、−（ＣＨ_２）_ｐＯＳ（Ｏ）_２ＯＲ^２９、−ＯＳ（Ｏ）_２ＯＲ^２９、−ＳＲ^２９、−Ｓ（Ｏ）Ｒ^２９、−Ｓ（Ｏ）_２Ｒ^２９、−Ｓ（Ｏ）ＮＲ^２９Ｒ^２９’、−Ｓ（Ｏ）_２ＮＲ^２９Ｒ^２９’、−ＯＳ（Ｏ）ＮＲ^２９Ｒ^２９’、−ＯＳ（Ｏ）_２ＮＲ^２９Ｒ^２９’、−ＮＲ^２９Ｒ^２９’、−ＮＲ^２９Ｃ（Ｏ）Ｒ^３０、−ＮＲ^２９Ｃ（Ｏ）ＯＲ^３０、−ＮＲ^２９Ｃ（Ｏ）ＮＲ^３０Ｒ^３０’、−ＮＲ^２９Ｓ（Ｏ）Ｒ^３０、−ＮＲ^２９Ｓ（Ｏ）_２Ｒ^３０、−ＮＲ^２９Ｓ（Ｏ）ＮＲ^３０Ｒ^３０’、−ＮＲ^２９Ｓ（Ｏ）_２ＮＲ^３０Ｒ^３０’、−Ｃ（Ｏ）Ｒ^２９、−Ｃ（Ｏ）ＯＲ^２９または−Ｃ（Ｏ）ＮＲ^２９Ｒ^２９’により置換されていてよく；
Ｒ^１９、Ｒ^１９’、Ｒ^２０、Ｒ^２０’、Ｒ^２１、Ｒ^２１’、Ｒ^２２、Ｒ^２２’、Ｒ^２３、Ｒ^２３’、Ｒ^２４、Ｒ^２４’、Ｒ^２５、Ｒ^２５’、Ｒ^２６、Ｒ^２６’、Ｒ^２６’’、Ｒ^２９、Ｒ^２９’、Ｒ^３０およびＲ^３０’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され、ここでＣ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、ハロゲン、−ＯＨ、−ＳＨ、−ＮＨ_２または−ＣＯ_２Ｈにより置換されていてよく；
Ｒ^２７およびＲ^２７’は、それぞれ独立してＨ、Ｃ_１〜Ｃ_９アルキル、Ｃ_２〜Ｃ_９アルケニル、Ｃ_２〜Ｃ_９アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、−（ＣＨ_２）_ｐ（糖）、−（ＣＨ_２）_ｐ（ＯＣＨ_２ＣＨ_２）_ｑ−（糖）および−（ＣＨ_２）_ｐ（ＯＣＨ_２ＣＨ_２ＣＨ_２）_ｑ（糖）から成る群から選択され；
Ｒ^２８はＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリールまたは糖であり；
ｎは１、２、３、４または５であり；
ｐは１、２、３、４または５であり；
ｑは１、２、３、４または５である）
のリンカーであり、 AA is an amino acid,
L ¹ is the formula II

(In the formula,
R ¹⁶ is H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, —C(O)R ¹⁹ , —C(O)OR ¹⁹ and —C(O)NR. Hydrogens in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl selected from the group consisting of ¹⁹ R ^19′ , independently, optionally halogen, C ₁ -C. _{6 alkyl,} C 2 -C ₆ alkenyl, and _C 2 -C ₆ ^{alkynyl, -OR 20, -OC (O)} R 20, -OC (O) NR 20 R 20 ', -OS (O) R 20, - _{^{OS (O) 2 R 20,}} -SR 20, -S (O) R 20, -S (O) 2 R 20, -S (O) NR 20 R 20 ', -S (O) 2 NR 20 R 20 ^{', -OS (O) NR 20} R 20', -OS (O) 2 NR 20 R 20 ', -NR 20 R 20', -NR 20 C (O) R 21, -NR 20 C (O) OR ^{21, -NR 20 C (O)} NR 21 R 21 ', -NR 20 S (O) R 21, -NR 20 S (O) 2 R 21, -NR 20 S (O) NR 21 R 21', - _{^{NR 20 S (O) 2 NR}} 21 R 21 may be substituted by ^{', -C (O) R 20} , -C (O) oR 20 or ^{-C (O) NR 20 R 20} ';
R ¹⁷ and ^{R 17 'is,} H independently, D, _halogen, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 22, -OC (O)} R 22, -OC (O) NR 22 R 22 ', -OS (O) R _{^{22, -OS (O) 2 R}} 22, -SR 22, -S (O) R 22, -S (O) 2 R 22, -S (O) NR 22 R 22 ', -S (O) 2 NR ^{22 R 22 ', -OS (O} ) NR 22 R 22', -OS (O) 2 NR 22 R 22 ', -NR 22 R 22', -NR 22 C (O) R 23, -NR 22 C ( ^{O) OR 23, -NR 22 C} (O) NR 23 R 23 ', -NR 22 S (O) R 23, -NR 22 S (O) 2 R 23, -NR 22 S (O) NR 23 R 23 _{^{', -NR 22 S (O)}} 2 NR 23 R 23', are selected from the group consisting of ^{-C (O) R 22, -C} (O) oR 22 and ^{-C (O) NR 22 R 22} ', wherein in _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5- to 7-membered each hydrogen atom in the ring heteroaryl is independently optionally _halogen, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ ^{alkynyl, -OR 24, -OC (O)} R 24 , -OC(O)NR ²⁴ R ^24' , -OS(O)R ²⁴ , -OS(O) ₂ R ²⁴ , -SR ²⁴ , -S(O)R ²⁴ , -S(O) ₂ R ²⁴ , ^{-S (O) NR 24 R 24} ', -S (O) 2 NR 24 R 24', -OS (O) NR 24 R 24 ', -OS (O) 2 NR 24 R 24', -NR 24 R ^{24 ', -NR 24 C (O} ) R 25, -NR 24 C (O) OR 25, -NR 24 C (O) NR 25 R 25', -NR 24 S (O) R 25, -NR 24 S (O) ₂ R ²⁵ , -NR ²⁴ S(O)NR ^{25 _{R 25 ', -NR 24 S (}} O) 2 NR 25 R 25', -C (O) R 24, may be replaced by -C (O) ^{OR 24} or ^{-C (O) NR 24 R 24} ';
Alternatively, R ¹⁷ and R ^17′ may be joined to form a C ₄ -C ₆ cycloalkyl or 4-6 membered heterocycle, wherein in the C ₄ -C ₆ cycloalkyl or 4-6 membered heterocycle. Each hydrogen atom is, independently, optionally halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocyclo. _alkyl, C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 24, -OC (O)} R 24, -OC (O) NR 24 R 24 ', -OS (O) R 24, -OS _{^{(O) 2 R 24, -SR}} 24, -S (O) R 24, -S (O) 2 R 24, -S (O) NR 24 R 24 ', -S (O) 2 NR 24 R 24' , -OS(O)NR ²⁴ R ²⁴ , -OS(O) ₂ NR ²⁴ R ^24' , -NR ²⁴ R ^24' , -NR ²⁴ C(O)R ²⁵ , -NR ²⁴ C(O)OR ²⁵ , ^{-NR 24 C (O) NR 25} R 25 ', -NR 24 S (O) R 25, -NR 24 S (O) 2 R 25, -NR 24 S (O) NR 25 R 25', -NR 24 _{^{S (O) 2 NR 25 R}} 25 ', -C (O) R 24, -C (O) oR 24 or ^{-C (O) NR 24 R 24} ' may be substituted by;
R ¹⁸ _{is, H, D, C 1 ~C} 6 _alkyl, C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl, C} 3- _{C 6} cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 -C ₁₀ aryl, 5-7 membered ^{heteroaryl, -OR 26, -OC (O)} R 26, -OC (O) NR 26 R 26 ', -OS (O) R 26, -OS (O) 2 R 26 _{^{, -SR 26, -S (O)}} R 26, -S (O) 2 R 26, -S (O) NR 26 R 26 ', -S (O) 2 NR 26 R 26', -OS (O) _{^{NR 26 R 26 ', -OS (}} O) 2 NR 26 R 26', -NR 26 R 26 ', -NR 26 C (O) R 27, -NR 26 C (O) OR 27, -NR 26 C ( ^{O) NR 27 R 27 ',} -NR 26 C (= NR 26'') NR 27 R 27', -NR 26 S (O) R 27, -NR 26 S (O) 2 R 27, -NR 26 S From (O)NR ²⁷ R ^27′ , —NR ²⁶ S(O) ₂ NR ²⁷ R ^27′ , —C(O)R ²⁶ , —C(O)OR ²⁶ and —C(O)NR ²⁶ R ^26′. is selected from the group consisting of, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 -C Each hydrogen atom in the ₁₀ aryl and the 5-7 membered heteroaryl is, independently, optionally halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, —(CH ₂ ) _p OR ²⁸ , —( _{CH 2) p (OCH 2)} q OR 28, - (CH 2) p (OCH 2 CH 2) q OR 28, -OR 29, -OC (O) R 29, -OC (O) NR 29 R 29 ' _{^{, -OS (O) R 29,}} -OS (O) 2 R 29, - (CH 2) p OS (O) 2 OR 29, -OS (O) 2 OR 29, -SR 29, -S (O) _{^{R 29, -S (O) 2}} R 29, -S (O) NR 29 R 29 ', -S (O) 2 NR 29 R 29', -OS (O) NR 29 R 29 ', -OS (O ) ₂ NR ²⁹ R ^{29 ′} , —NR ^{29 R 29 ', -NR 29 C (} O) R 30, -NR 29 C (O) OR 30, -NR 29 C (O) NR 30 R 30', -NR 29 S (O) R 30, -NR 29 _{^{S (O) 2 R 30,}} -NR 29 S (O) NR 30 R 30 ', -NR 29 S (O) 2 NR 30 R 30', -C (O) R 29, -C (O) OR 29 Or optionally substituted by -C(O)NR ²⁹ R ^29' ;
R ¹⁹ , R ^19′ , R ²⁰ , R ^20′ , R ²¹ , R ^21′ , R ²² , R ^22′ , R ²³ , R ^23′ , R ²⁴ , R ^24′ , R ²⁵ , R ^25′ , R ²⁶ , R ^26′ , R ^26″ , R ²⁹ , R ^29′ , R ³⁰ and R ^30′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ To C ₇ alkynyl, C _{3 to} C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl and 5 to 7 membered heteroaryl, where C _{1 to} C _{7 are selected. alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} each hydrogen in aryl and 5-7 membered heteroaryl atoms are independently optionally halogen, -OH, -SH, it may be substituted by -NH ₂ or -CO ₂ H;
R ²⁷ and R ^27′ are each independently H, C ₁ -C ₉ alkyl, C ₂ -C ₉ alkenyl, C ₂ -C ₉ alkynyl, C ₃ -C ₆ cycloalkyl, —(CH ₂ ) _p ( _{sugar), - (CH 2) p} (OCH 2 CH 2) q - ( sugar) and _{- (CH 2) p (OCH} 2 CH 2 CH 2) is selected from the group consisting of _q (sugars);
R ²⁸ is H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C _10. Aryl, 5-7 membered heteroaryl or sugar;
n is 1, 2, 3, 4 or 5;
p is 1, 2, 3, 4 or 5;
q is 1, 2, 3, 4 or 5)
Is a linker of

L ² is a releasable linker;
L ³ is _C 1 -C ₆ ^{alkyl, - (CR 39 R 39 '} ) r C (O) -, - (CR 39 R 39') r OC (O) -, - NR 39 R 39 'C (O) _{^{(CR 39 R 39 ') r}} -, - (CH 2) r NR 39 -, - (OCR 39 R 39' CR 39 R 39 ') r C (O) -, and ^{- (OCR 39 R 39' CR} 39 ^{R 39 'CR 39 R 39'} ) - r C (O) - is selected from the group consisting of,
Here, R ³⁹ and R ^39′ are each independently H, D, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -OR ⁴⁰ , -OC(O)R ⁴⁰ , -OC(O)NR ⁴⁰ R ^40' , -OS( _{^{O) R 40, -OS (O}} ) 2 R 40, -SR 40, -S (O) R 40, -S (O) 2 R 40, -S (O) NR 40 R 40 ', -S (O _{^{) 2 NR 40 R 40 ',}} -OS (O) NR 40 R 40', -OS (O) 2 NR 40 R 40 ', -NR 40 R 40', -NR 40 C (O) R 41, -NR ⁴⁰ C(O)OR ⁴¹ , -NR ⁴⁰ C(O)NR ⁴¹ R ^41' , -NR ⁴⁰ S(O)R ⁴¹ , -NR ⁴⁰ S(O) ₂ R ⁴¹ , -NR ⁴⁰ S(O)NR. ⁴¹ R ^41' , -NR ⁴⁰ S(O) ₂ NR ⁴¹ R ^41' , -C(O)R ⁴⁰ , -C(O)OR ⁴⁰ and -C(O)NR ⁴⁰ R ^40'. Done;
R ⁴⁰ , R ^40′ , R ⁴¹ and R ^41′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. Alkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, and 5-7 membered heteroaryl; and in each case r is 1, 2, 3, 4, or 5 And
L ⁴ represents ^{-C (O) (CR 44 R} 44 ') t -, - NR 42 CR 43 R 43' CR 43 R 43 '(OCR 44 R 44' CR 44 R 44 ') t -, - NR 42 CR ^{43 R 43 'CR 43 R 43} ' (OCR 44 R 44 'CR 44 R 44') t -, - NR 42 CR 43 R 43 'CR 43 R 43' (OCR 44 R 44 'CR 44 R 44') t ^{C (O) -, - NR} 42 CR 43 R 43 'CR 43 R 43' (CR 44 = CR 44 ') t -, and ^-NR 42 _C 6 _{~C 10} aryl _(C 1 -C ₆ alkyl) OC ( O)-selected from the group consisting of;
here,
R ⁴² is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, wherein C ₁ -C ₆ alkyl. each hydrogen atom in _C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl , _C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 45, -OC (O)} R ⁴⁵ , -OC(O)NR ⁴⁵ R ^45' , -OS(O)R ⁴⁵ , -OS(O) ₂ R ⁴⁵ , -SR ⁴⁵ , -S(O)R ⁴⁵ , -S(O) ₂ R ^45. , -S(O)NR ⁴⁵ R ^45' , -S(O) ₂ NR ⁴⁵ R ^45' , -OS(O)NR ⁴⁵ R ^45' , -OS(O) ₂ NR ⁴⁵ R ^45' , -NR ^{45. R 45 ', -NR 45 C (} O) R 46, -NR 45 C (O) OR 46, -NR 45 C (O) NR 46 R 46', -NR 45 S (O) R 46, -NR 45 _{^{S (O) 2 R 46,}} -NR 45 S (O) NR 46 R 46 ', -NR 45 S (O) 2 NR 46 R 46', -C (O) R 45, -C (O) OR 45 Or optionally substituted by -C(O)NR ⁴⁵ R ^45' ,

R ^{43, R 43 ', R 44} and ^{R 44} are each independently _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl Each hydrogen atom in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl is independently, optionally, selected from the group consisting of: _halogen, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 47, -OC (O)} R 47, -OC (O) NR 47 R 47 ', -OS (O) R 47, -OS (O) 2 R 47, -SR 47, - S(O)R ⁴⁷ , -S(O) ₂ R ⁴⁷ , -S(O)NR ⁴⁷ R ^47' , -S(O) ₂ NR ⁴⁷ R ^47' , -OS(O)NR ⁴⁷ R ^47' , _{^{-OS (O) 2 NR 47 R}} 47 ', -NR 47 R 47', -NR 47 C (O) R 48, -NR 47 C (O) OR 48, -NR 47 C (O) NR 48 R 48 ^{', -NR 47 S (O)} R 48, -NR 47 S (O) 2 R 48, -NR 47 S (O) NR 48 R 48', -NR 47 S (O) 2 NR 48 R 48 ', Optionally substituted by -C(O)R ⁴⁷ , -C(O)OR ⁴⁷ or -C(O)NR ⁴⁷ R ^47' ;
R ⁴⁵ , R ^45′ , R ⁴⁶ , R ^46′ , R ⁴⁷ , R ^47′ , R ⁴⁸ and R ^48′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl. is selected from the group consisting of _C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl;
In each case t is 1, 2, 3, 4 or 5;
L ⁵ represents _C 1 _{-C 10} ^{alkyl, - (CR 49 = CR 49} ') u -, - (CR 49 R 49') u C (O) -, - CH 2 CH 2 (OCR 49 R 49 'CR 49 _{^{R 49 ') u -, -}} CH 2 CH 2 CH 2 (OCR 49 R 49' CR 49 R 49 'CR 49 R 49') u -, - CH 2 CH 2 (OCR 49 R 49 'CR 49 R 49' ) _u C (O) - and _{^{-CH 2 CH 2 (OCR 49 R}} 49 'CR 49 R 49' CR 49 R 49 ') u C (O) - is selected from the group consisting of wherein ^{R 49} and ^{R 49 Are} each independently selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, wherein C _{1 is} -C _{6 alkyl,} C 2 -C _{6 alkenyl,} each hydrogen atom in the C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C ₆ alkyl, _{C 2} -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, -OR 50, -OC ^{(O) R 50, -OC (} O) NR 50 R 50 ', -OS (O) R 50, -OS (O) 2 R 50, -SR 50, -S (O) R 50, -S (O _{^{) 2 R 50, -S (O}} ) NR 50 R 50 ', -S (O) 2 NR 50 R 50', -OS (O) NR 50 R 50 ', -OS (O) 2 NR 50 R 50' ^{, -NR 50 R 50 ', -NR} 50 C (O) R 51, -NR 50 C (O) OR 51, -NR 50 C (O) NR 51 R 51', -NR 50 S (O) R 51 _{^{, -NR 50 S (O) 2}} R 51, -NR 50 S (O) NR 51 R 51 ', -NR 50 S (O) 2 NR 51 R 51', -C (O) R 50, -C ( O) may be substituted by ^{oR 50} or ^{-C (O) NR 50 R 50} ';
^{R 50, R 50 ', R} 51 and ^{R 51'} is, H _{independently, D,} C 1 ~C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl alkyl is selected from the group consisting of 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl;
In each case u is 0, 1, 2, 3, 4 or 5;
D ¹ is a PBD prodrug; and D ² is a DNA binding agent]
A conjugate or a pharmaceutically acceptable salt thereof comprising a binding ligand, a linker, and a drug having the following formula.

〔式中、
Ｒ^１ａ、Ｒ^２ａ、Ｒ^３ａおよびＲ^４ａは、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｃ（Ｏ）Ｒ^１１ａ、−Ｃ（Ｏ）ＯＲ^１１ａおよび−Ｃ（Ｏ）ＮＲ^１１ａＲ^１１ａ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１１ａ、−ＯＣ（Ｏ）Ｒ^１１ａ、−ＯＣ（Ｏ）ＮＲ^１１ａＲ^１１ａ’、−ＯＳ（Ｏ）Ｒ^１１ａ、−ＯＳ（Ｏ）_２Ｒ^１１ａ、−ＳＲ^１１ａ、−Ｓ（Ｏ）Ｒ^１１ａ、−Ｓ（Ｏ）_２Ｒ^１１ａ、−Ｓ（Ｏ）ＮＲ^１１ａＲ^１１ａ’、−Ｓ（Ｏ）_２ＮＲ^１１ａＲ^１１ａ’、−ＯＳ（Ｏ）ＮＲ^１１ａＲ^１１ａ’、−ＯＳ（Ｏ）_２ＮＲ^１１ａＲ^１１ａ’、−ＮＲ^１１ａＲ^１１ａ’、−ＮＲ^１１ａＣ（Ｏ）Ｒ^１２ａ、−ＮＲ^１１ａＣ（Ｏ）ＯＲ^１２ａ、−ＮＲ^１１ａＣ（Ｏ）ＮＲ^１２ａＲ^１２ａ’、−ＮＲ^１１ａＳ（Ｏ）Ｒ^１２ａ、−ＮＲ^１１ａＳ（Ｏ）_２Ｒ^１２ａ、−ＮＲ^１１ａＳ（Ｏ）ＮＲ^１２ａＲ^１２ａ’、−ＮＲ^１１ａＳ（Ｏ）_２ＮＲ^１２ａＲ^１２ａ’、−Ｃ（Ｏ）Ｒ^１１ａ、−Ｃ（Ｏ）ＯＲ^１１ａまたは−Ｃ（Ｏ）ＮＲ^１１ａＲ^１１ａ’により置換されていてよく；またはＲ^１ａは結合であり；またはＲ^４ａは結合であり；
Ｒ^５ａ、Ｒ^６ａおよびＲ^７ａは、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｃ（Ｏ）Ｒ^１３ａ、−Ｃ（Ｏ）ＯＲ^１３ａおよび−Ｃ（Ｏ）ＮＲ^１３ａＲ^１３ａ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１４ａ、−ＯＣ（Ｏ）Ｒ^１４ａ、−ＯＣ（Ｏ）ＮＲ^１４ａＲ^１４ａ’、−ＯＳ（Ｏ）Ｒ^１４ａ、−ＯＳ（Ｏ）_２Ｒ^１４ａ、−ＳＲ^１４ａ、−Ｓ（Ｏ）Ｒ^１４ａ、−Ｓ（Ｏ）_２Ｒ^１４ａ、−Ｓ（Ｏ）ＮＲ^１４ａＲ^１４ａ’、−Ｓ（Ｏ）_２ＮＲ^１４ａＲ^１４ａ’、−ＯＳ（Ｏ）ＮＲ^１４ａＲ^１４ａ’、−ＯＳ（Ｏ）_２ＮＲ^１４ａＲ^１４ａ’、−ＮＲ^１４ａＲ^１４ａ’、−ＮＲ^１４ａＣ（Ｏ）Ｒ^１５ａ、−ＮＲ^１４ａＣ（Ｏ）ＯＲ^１５ａ、−ＮＲ^１４ａＣ（Ｏ）ＮＲ^１５ａＲ^１５ａ’、−ＮＲ^１４ａＳ（Ｏ）Ｒ^１５ａ、−ＮＲ^１４ａＳ（Ｏ）_２Ｒ^１５ａ、−ＮＲ^１４ａＳ（Ｏ）ＮＲ^１５ａＲ^１５ａ’、−ＮＲ^１４ａＳ（Ｏ）_２ＮＲ^１５ａＲ^１５ａ’、−Ｃ（Ｏ）Ｒ^１４ａ、−Ｃ（Ｏ）ＯＲ^１４ａまたは−Ｃ（Ｏ）ＮＲ^１４ａＲ^１４ａ’により置換されていてよく；
ここで、
Ｒ^６ａおよびＲ^７ａは、それらが結合する原子と一緒になって、場合により結合して３〜７員環ヘテロシクロアルキルを形成するか、またはＲ^５ａおよびＲ^６ａは、それらが結合する原子と一緒になって、場合により結合して３〜７員環ヘテロシクロアルキルまたは５〜７員環ヘテロアリールを形成し、ここで３〜７員環ヘテロシクロアルキルまたは５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１６ａ、−ＯＣ（Ｏ）Ｒ^１６ａ、−ＯＣ（Ｏ）ＮＲ^１６ａＲ^１６ａ’、−ＯＳ（Ｏ）Ｒ^１６ａ、−ＯＳ（Ｏ）_２Ｒ^１６ａ、−ＳＲ^１６ａ、−Ｓ（Ｏ）Ｒ^１６ａ、−Ｓ（Ｏ）_２Ｒ^１６ａ、−Ｓ（Ｏ）ＮＲ^１６ａＲ^１６ａ’、−Ｓ（Ｏ）_２ＮＲ^１６ａＲ^１６ａ’、−ＯＳ（Ｏ）ＮＲ^１６ａＲ^１６ａ’、−ＯＳ（Ｏ）_２ＮＲ^１６ａＲ^１６ａ’、−ＮＲ^１６ａＲ^１６ａ’、−ＮＲ^１６ａＣ（Ｏ）Ｒ^１７ａ、−ＮＲ^１６ａＣ（Ｏ）ＣＨ_２ＣＨ_２−、−ＮＲ^１６ａＣ（Ｏ）ＯＲ^１７ａ、−ＮＲ^１６ａＣ（Ｏ）ＮＲ^１７ａＲ^１７ａ’、−ＮＲ^１６ａＳ（Ｏ）Ｒ^１７ａ、−ＮＲ^１６ａＳ（Ｏ）_２Ｒ^１７ａ、−ＮＲ^１６ａＳ（Ｏ）ＮＲ^１７ａＲ^１７ａ’、−ＮＲ^１６ａＳ（Ｏ）_２ＮＲ^１７ａＲ^１７ａ’、−Ｃ（Ｏ）Ｒ^１６ａ、−Ｃ（Ｏ）ＯＲ^１６ａまたは−Ｃ（Ｏ）ＮＲ^１６ａＲ^１６ａ’により置換されていてよく、そしてここで、５〜７員環ヘテロアリールにおける１個の水素は、場合により結合であり、またはＲ^５ａは結合であり； 2. D ¹ is the formula III

[In the formula,
R ^1a , R ^2a , R ^3a and R ^4a are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -C(O)R ^11a , -C(O)OR ^11a and -C(O)NR ^11a R ^11a'. Selected from the group consisting of: C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -. Each hydrogen atom in C ₁₀ aryl and 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C _6. cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 11a, -OC (O)} R 11a, -OC (O) NR 11a R 11a ', -OS(O)R ^11a , -OS(O) ₂ R ^11a , -SR ^11a , -S(O)R ^11a , -S(O) ₂ R ^11a , -S(O)NR ^11a R ^11a' , -. _{^{S (O) 2 NR 11a R}} 11a ', -OS (O) NR 11a R 11a', -OS (O) 2 NR 11a R 11a ', -NR 11a R 11a', -NR 11a C (O) R 12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a R ^12a' , -NR ^11a S(O)R ^12a , -NR ^11a S(O) ₂ R ^12a , -NR ^11a S(. ^{O) NR 12a R} 12a substituted _{^{', -NR 11a S (O)}} 2 NR 12a R 12a', -C (O) R 11a, -C (O) oR 11a or ^{-C (O) NR 11a R 11a} ' R ^1a is a bond; or R ^4a is a bond;
R ^{5a, R 6a} and ^{R 7a} are, H independently, _D, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, the group consisting of -C (O) R 13a, -C (O) oR 13a , and ^{-C (O) NR 13a R 13a} ' Selected from where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl. And each hydrogen atom in the 5-7 membered heteroaryl optionally represents C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered. _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 14a, -OC (O)} R 14a, -OC (O) NR 14a R 14a ', -OS (O) R 14a _{^{, -OS (O) 2 R 14a}} , -SR 14a, -S (O) R 14a, -S (O) 2 R 14a, -S (O) NR 14a R 14a ', -S (O) 2 NR 14a ^{R 14a ', -OS (O)} NR 14a R 14a', -OS (O) 2 NR 14a R 14a ', -NR 14a R 14a', -NR 14a C (O) R 15a, -NR 14a C (O ) OR ^15a , -NR ^14a C(O)NR ^15a R ^15a' , -NR ^14a S(O)R ^15a , -NR ^14a S(O) ₂ R ^15a , -NR ^14a S(O)NR ^15a R ^15a'. , -NR ^14a S(O) ₂ NR ^15a R ^15a' , -C(O)R ^14a , -C(O)OR ^14a or -C(O)NR ^14a R ^14a' ;
here,
R ^6a and R ^7a , together with the atom to which they are attached, optionally combine to form a 3-7 membered heterocycloalkyl, or R ^5a and R ^6a are the same as the atom to which they are attached. Together, they are optionally joined to form a 3-7 membered heterocycloalkyl or a 5-7 membered heteroaryl, wherein each in a 3-7 membered heterocycloalkyl or a 5-7 membered heteroaryl. The hydrogen atoms are, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-7 membered ^{heteroaryl, -OR 16a, -OC (O)} R 16a, -OC (O) NR 16a R 16a ', -OS (O) R 16a, -OS (O) _{^{2 R 16a, -SR 16a, -S}} (O) R 16a, -S (O) 2 R 16a, -S (O) NR 16a R 16a ', -S (O) 2 NR 16a R 16a', -OS ^{(O) NR 16a R 16a '} , -OS (O) 2 NR 16a R 16a', -NR 16a R 16a ', -NR 16a C (O) R 17a, -NR 16a C (O) CH 2 CH 2 - , -NR ^16a C(O)OR ^17a , -NR ^16a C(O)NR ^17a R ^17a' , -NR ^16a S(O)R ^17a , -NR ^16a S(O) ₂ R ^17a , -NR ^16a S(. ^{O) NR 17a R} 17a substituted _{^{', -NR 16a S (O)}} 2 NR 17a R 17a', -C (O) R 16a, -C (O) oR 16a or ^{-C (O) NR 16a R 16a} ' And one hydrogen in the 5-7 membered heteroaryl is optionally a bond or R ^5a is a bond;

R ^8a and R ^9a are each independently H, D, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 member. _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered _{^{heteroaryl, -CN, -NO 2, -NCO,}} -OR 18a -OC (O) R 18a, -OC (O) NR 18a R 18a _{^{', -OS (O) R 18a}} , -OS (O) 2 R 18a, -SR 18a, -S (O) R 18a, -S (O) 2 R 18a, -S (O) NR 18a R 18a' ^{_{, -S (O) 2 NR 18a}} R 18a ', -OS (O) NR 18a R 18a', -OS (O) 2 NR 18a R 18a ', -NR 18a R 18a', -NR 18a C (O) R ^19a , -NR ^18a C(O)OR ^19a , -NR ^18a C(O)NR ^19a R ^19a' , -NR ^18a S(O)R ^19a , -NR ^18a S(O) ₂ R ^19a , -NR ^18a. S(O)NR ^19a R ^19a' , -NR ^18a S(O) ₂ NR ^19a R ^19a' , -C(O)R ^18a , -C(O)OR ^18a and -C(O)NR ^18a R ^18a'. Selected from the group consisting of: C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -. Each hydrogen atom in C ₁₀ aryl and 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C _6. Cycloalkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -OR ^20a , -OC(O)R ^20a , -OC(O)NR ^20a R ^20a' , _{^{-OS (O) R 20a, -OS}} (O) 2 R 20a, -SR 20a, -S (O) R 20a, -S (O) 2 R 20a, -S (O) NR 20a R 20a ', - _{^{S (O) 2 NR 20a R}} 20a ', -OS (O) NR 20a R 20a', -OS (O) 2 NR 20a R 20a ', - NR ^20a R ^20a' , -NR ^20a C(O)R ^21a , -NR ^20a C(O)OR ^21a , -NR ^20a C(O)NR ^21a R ^21a' , -NR ^20a S(O)R ^21a , -. NR ^20a S(O) ₂ R ^21a , -NR ^20a S(O)NR ^21a R ^21a' , -NR ^20a S(O) ₂ NR ^21a R ^21a' , -C(O)R ^20a , -C(O). OR ^20a or -C(O)NR ^20a R ^20a' may be substituted;
R ^10a is _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} Aryl, 5- to 7-membered heteroaryl, -OR ^22a , -OC(O)R ^22a , -OC(O)NR ^22a R ^22a' , -OS(O)R ^22a , -OS(O) ₂ R ^22a , -SR ^22a , -S(O)R ^22a , -S(O) ₂ R ^22a , -S(O)NR ^22a R ^22a' , -S(O) ₂ NR ^22a R ^22a' , -OS(O)NR. _{^{22a R 22a ', -OS (O}} ) 2 NR 22a R 22a', -NR 22a R 22a ', -NR 22a C (O) R 23a, -NR 22a C (O) OR 23a, -NR 22a C (O ^{) NR 23a R 23a ', -NR} 22a S (O) R 23a, -NR 22a S (O) 2 R 23a, -NR 22a S (O) NR 23a R 23a', -NR 22a S (O) 2 NR ^{23a R 23a, -C (O)} R 22a, is selected from the group consisting of -C ^{(O) oR 23a,} and ^{-C (O) NR 22a R 22a} ', wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} each hydrogen atom in the C 6 _{-C 10} aryl and 5- to 7-membered ring heteroaryl is independently , Optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 To 7-membered ring heteroaryl, -OR ^24a , -OC(O)R ^24a , -OC(O)NR ^24a R ^24a' , -OS(O)R ^24a , -OS(O) ₂ R ^24a , -SR ^24a. , -S(O)R ^24a , -S(O) ₂ R ^24a , -S(O)NR ^24a R ^24a' , -S(O) ₂ NR ^24a R ^24a' , -OS(O)NR ^24a R ^{24a. _{', -OS (O) 2 NR}} 24a R 24a', -NR 24a R 24a ', -NR 24a C (O) R 25a, -N R ^24a C(O)OR ^25a , -NR ^24a C(O)NR ^25a R ^25a' , -NR ^24a S(O)R ^25a , -NR ^24a S(O) ₂ R ^25a , -NR ^24a S(O). NR ^25a R ^25a′ , —NR ^24a S(O) ₂ NR ^25a R ^25a′ , —C(O)R ^24a , —C(O)OR ^24a or —C(O)NR ^24a R ^24a′. And R ^11a , R ^11a′ , R ^12a , R ^12a′ , R ^13a , R ^13a′ , R ^14a , R ^14a′ , R ^15a , R ^15a′ , R ^16a , R ^16a′ , R ^17a , R. ^17a' , ^R18a , ^R18a' , ^R19a , ^R19a' , ^R20a , ^R20a' , ^R21a , ^R21a' , ^R22a , ^R22a' , ^R23a , ^R23a' , ^R24a , ^{R24a. ', R 25a} and ^{R 25a'} are, H independently, _D, C 1 -C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 _{-C 13} cycloalkyl, 3-7 Selected from the group consisting of membered heterocycloalkyl, C ₆ -C ₁₀ aryl, and 5-7 membered heteroaryl;
Provided that at least two of R ^1a , R ^4a and R ^5a are a bond, or R ^5a and R ^6a together with the atom to which they are attached, optionally combined, are a 3-7 membered ring heterocycle. When forming a cycloalkyl or a 5-7 membered heteroaryl, one hydrogen in the 5-7 membered heteroaryl is a bond and one of R ^1a or R ^4a is a bond]
The conjugate of claim 1, which is: or a pharmaceutically acceptable salt thereof.

3. Item 3. The conjugate or a pharmaceutically acceptable salt thereof according to Item 1 or 2, wherein D ² is a minor groove-binding drug.

〔式中、
Ｒ^１ｂ、Ｒ^２ｂ、Ｒ^３ｂおよびＲ^４ｂは、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｃ（Ｏ）Ｒ^１３ｂ、−Ｃ（Ｏ）ＯＲ^１３ｂ、および−Ｃ（Ｏ）ＮＲ^１３ｂＲ^１３ｂ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１３ｂ、−ＯＣ（Ｏ）Ｒ^１３ｂ、−ＯＣ（Ｏ）ＮＲ^１３ｂＲ^１３ｂ’、−ＯＳ（Ｏ）Ｒ^１３ｂ、−ＯＳ（Ｏ）_２Ｒ^１３ｂ、−ＳＲ^１３ｂ、−Ｓ（Ｏ）Ｒ^１３ｂ、−Ｓ（Ｏ）_２Ｒ^１３ｂ、−Ｓ（Ｏ）ＮＲ^１３ｂＲ^１３ｂ’、−Ｓ（Ｏ）_２ＮＲ^１３ｂＲ^１３ｂ’、−ＯＳ（Ｏ）ＮＲ^１３ｂＲ^１３ｂ’、−ＯＳ（Ｏ）_２ＮＲ^１３ｂＲ^１３ｂ’、−ＮＲ^１３ｂＲ^１３ｂ’、−ＮＲ^１３ｂＣ（Ｏ）Ｒ^１４ｂ、−ＮＲ^１３ｂＣ（Ｏ）ＯＲ^１４ｂ、−ＮＲ^１３ｂＣ（Ｏ）ＮＲ^１４ｂＲ^１４ｂ’、−ＮＲ^１３ｂＳ（Ｏ）Ｒ^１４ｂ、−ＮＲ^１３ｂＳ（Ｏ）_２Ｒ^１４ｂ、−ＮＲ^１３ｂＳ（Ｏ）ＮＲ^１４ｂＲ^１４ｂ’、−ＮＲ^１３ｂＳ（Ｏ）_２ＮＲ^１４ｂＲ^１４ｂ’、−Ｃ（Ｏ）Ｒ^１３ｂ、−Ｃ（Ｏ）ＯＲ^１３ｂまたは−Ｃ（Ｏ）ＮＲ^１３ｂＲ^１３ｂ’により置換されていてよく；またはＲ^１ｂ、Ｒ^２ｂ、Ｒ^３ｂおよびＲ^４ｂのいずれか１つは結合であり；
Ｒ^５ｂ、Ｒ^６ｂおよびＲ^７ｂは、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３−Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｃ（Ｏ）Ｒ^１５ｂ、−Ｃ（Ｏ）ＯＲ^１５ｂ、および−Ｃ（Ｏ）ＮＲ^１５ｂＲ^１５ｂ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｌ^４Ｈ、−Ｌ^３Ｈ、−ＯＲ^１５ｂ、−ＯＣ（Ｏ）Ｒ^１５ｂ、−ＯＣ（Ｏ）ＮＲ^１５ｂＲ^１５ｂ’、−ＯＳ（Ｏ）Ｒ^１５ｂ、−ＯＳ（Ｏ）_２Ｒ^１５ｂ、−ＳＲ^１５ｂ、−Ｓ（Ｏ）Ｒ^１５ｂ、−Ｓ（Ｏ）_２Ｒ^１５ｂ、−Ｓ（Ｏ）ＮＲ^１５ｂＲ^１５ｂ’、−Ｓ（Ｏ）_２ＮＲ^１５ｂＲ^１５ｂ’、−ＯＳ（Ｏ）ＮＲ^１５ｂＲ^１５ｂ’、−ＯＳ（Ｏ）_２ＮＲ^１５ｂＲ^１５ｂ’、−ＮＲ^１５ｂＲ^１５ｂ’、−ＮＲ^１５ｂＣ（Ｏ）Ｒ^１６ｂ、−ＮＲ^１５ｂＣ（Ｏ）ＯＲ^１６ｂ、−ＮＲ^１５ｂＣ（Ｏ）ＮＲ^１６ｂＲ^１６ｂ’、−ＮＲ^１５ｂＳ（Ｏ）Ｒ^１６ｂ、−ＮＲ^１５ｂＳ（Ｏ）_２Ｒ^１６ｂ、−ＮＲ^１５ｂＳ（Ｏ）ＮＲ^１６ｂＲ^１６ｂ’、−ＮＲ^１５ｂＳ（Ｏ）_２ＮＲ^１６ｂＲ^１６ｂ’、−Ｃ（Ｏ）Ｒ^１５ｂ、−Ｃ（Ｏ）ＯＲ^１５ｂまたは−Ｃ（Ｏ）ＮＲ^１５ｂＲ^１５ｂ’により置換されていてよく；
ここで、
Ｒ^６ｂおよびＲ^７ｂは、それらが結合する原子と一緒になって、場合により結合して３〜７員環ヘテロシクロアルキルを形成するか、またはＲ^５ｂおよびＲ^６ｂは、それらが結合する原子と一緒になって、結合して場合により３〜７員環ヘテロシクロアルキルまたは５〜７員環ヘテロアリールを形成し、ここで３〜７員環ヘテロシクロアルキルおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１７ｂ、−ＯＣ（Ｏ）Ｒ^１７ｂ、−ＯＣ（Ｏ）ＮＲ^１７ｂＲ^１７ｂ’、−ＯＳ（Ｏ）Ｒ^１７ｂ、−ＯＳ（Ｏ）_２Ｒ^１７ｂ、−ＳＲ^１７ｂ、−Ｓ（Ｏ）Ｒ^１７ｂ、−Ｓ（Ｏ）_２Ｒ^１７ｂ、−Ｓ（Ｏ）ＮＲ^１７ｂＲ^１７ｂ’、−Ｓ（Ｏ）_２ＮＲ^１７ｂＲ^１７ｂ’、−ＯＳ（Ｏ）ＮＲ^１７ｂＲ^１７ｂ’、−ＯＳ（Ｏ）_２ＮＲ^１７ｂＲ^１７ｂ’、−ＮＲ^１７ｂＲ^１７ｂ’、−ＮＲ^１７ｂＣ（Ｏ）Ｒ^１８ｂ、−ＮＲ^１７ｂＣ（Ｏ）ＯＲ^１８ｂ、−ＮＲ^１７ｂＣ（Ｏ）ＮＲ^１８ｂＲ^１８ｂ’、−ＮＲ^１７ｂＳ（Ｏ）Ｒ^１８ｂ、−ＮＲ^１７ｂＳ（Ｏ）_２Ｒ^１８ｂ、−ＮＲ^１７ｂＳ（Ｏ）ＮＲ^１８ｂＲ^１８ｂ’、−ＮＲ^１７ｂＳ（Ｏ）_２ＮＲ^１８ｂＲ^１８ｂ’、−Ｃ（Ｏ）Ｒ^１７ｂ、−Ｃ（Ｏ）ＯＲ^１７ｂまたは−Ｃ（Ｏ）ＮＲ^１７ｂＲ^１７ｂにより置換されていてよく；またはＲ^５ｂ、Ｒ^６ｂもしくはＲ^７ｂのいずれか１つは結合であり； 4. The formula of D ² is

[In the formula,
R ^1b , R ^2b , R ^3b and R ^4b are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered ring heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered ring heteroaryl, -C(O)R ^13b , -C(O)OR ^13b , and -C(O)NR ^13b R ^{13b. '} Wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ Each hydrogen atom in -C ₁₀ aryl and 5-7 membered heteroaryl is independently, optionally, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C. ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 13b, -OC (O)} R 13b, -OC (O) NR 13b R 13b ' , -OS(O)R ^13b , -OS(O) ₂ R ^13b , -SR ^13b , -S(O)R ^13b , -S(O) ₂ R ^13b , -S(O)NR ^13b R ^13b' , _{^{-S (O) 2 NR 13b R}} 13b ', -OS (O) NR 13b R 13b', -OS (O) 2 NR 13b R 13b ', -NR 13b R 13b', -NR 13b C (O) R ^14b , -NR ^13b C(O)OR ^14b , -NR ^13b C(O)NR ^14b R ^14b' , -NR ^13b S(O)R ^14b , -NR ^13b S(O) ₂ R ^14b , -NR ^13b S. (O)NR ^14b R ^14b′ , —NR ^13b S(O) ₂ NR ^14b R ^14b′ , —C(O)R ^13b , —C(O)OR ^13b or —C(O)NR ^13b R ^13b′. It may be substituted; or any one of R ^1b , R ^2b , R ^3b and R ^4b is a bond;
R ^{5b, R 6b} and ^{R 7b} is, H independently, _D, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl, C} 3- _{C 6} cycloalkyl, 3-7 Membered ring heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-7 membered heteroaryl, —C(O)R ^15b , —C(O)OR ^15b , and —C(O)NR ^15b R ^15b′. is selected from the group, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} Each hydrogen atom in aryl and 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl. 3 to 7 membered ring heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered ring heteroaryl, -L ⁴ H, -L ³ H, -OR ^15b , -OC(O)R ^15b , -OC( ^{O) NR 15b R 15b ',} -OS (O) R 15b, -OS (O) 2 R 15b, -SR 15b, -S (O) R 15b, -S (O) 2 R 15b, -S (O _{^{) NR 15b R 15b ', -S}} (O) 2 NR 15b R 15b', -OS (O) NR 15b R 15b ', -OS (O) 2 NR 15b R 15b', -NR 15b R 15b ', - NR ^15b C(O)R ^16b , -NR ^15b C(O)OR ^16b , -NR ^15b C(O)NR ^16b R ^16b' , -NR ^15b S(O)R ^16b , -NR ^15b S(O) ₂ ^{R 16b, -NR 15b S (O} ) NR 16b R 16b ', -NR 15b S (O) 2 NR 16b R 16b', -C (O) R 15b, -C (O) oR 15b or -C (O ) Optionally substituted by NR ^15b R ^15b′ ;
here,
R ^6b and R ^7b , together with the atom to which they are attached, optionally combine to form a 3 to 7 membered heterocycloalkyl, or R ^5b and R ^6b are the same as the atom to which they are attached. Together, they combine to optionally form a 3-7 membered heterocycloalkyl or a 5-7 membered heteroaryl, wherein each of the 3-7 membered heterocycloalkyl and the 5-7 membered heteroaryl. The hydrogen atoms are, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-7 membered ^{heteroaryl, -OR 17b, -OC (O)} R 17b, -OC (O) NR 17b R 17b ', -OS (O) R 17b, -OS (O) ₂ R ^17b , -SR ^17b , -S(O)R ^17b , -S(O) ₂ R ^17b , -S(O)NR ^17b R ^17b' , -S(O) ₂ NR ^17b R ^17b' , -OS. (O)NR ^17b R ^17b' , -OS(O) ₂ NR ^17b R ^17b' , -NR ^17b R ^17b' , -NR ^17b C(O)R ^18b , -NR ^17b C(O)OR ^18b , -NR. ^17b C(O)NR ^18b R ^18b' , -NR ^17b S(O)R ^18b , -NR ^17b S(O) ₂ R ^18b , -NR ^17b S(O)NR ^18b R ^18b' , -NR ^17b S( _{^{O) 2 NR 18b R 18b '}} , -C (O) R 17b, -C (O) oR 17b or ^{-C (O)} NR ^17b may be substituted by ^{R 17b;} or ^{R 5b, R 6b} or ^{R 7b} One of is a bond;

R ^8b and R ^9b are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. _cycloalkyl, C 6 _{-C 10} aryl, 5-7 membered _{^{heteroaryl, -CN, -NO 2, -NCO,}} -OR 19b, -OC (O) R 19b, -OC (O) NR 19b R 19b ' , -OS(O)R ^19b , -OS(O) ₂ R ^19b , -SR ^19b , -S(O)R ^19b , -S(O) ₂ R ^19b , -S(O)NR ^19b R ^19b' , _{^{-S (O) 2 NR 19b R}} 19b ', -OS (O) NR 19b R 19b', -OS (O) 2 NR 19b R 19b ', -NR 19b R 19b', -NR 19b C (O) R ^20b , -NR ^19b C(O)OR ^20b , -NR ^19b C(O)NR ^20b R ^20b' , -NR ^19b S(O)R ^20b , -NR ^19b S(O) ₂ R ^20b , -NR ^19b S. From (O)NR ^20b R ^20b' , -NR ^19b S(O) ₂ NR ^20b R ^20b' , -C(O)R ^19b , -C(O)OR ^19b and -C(O)NR ^19b R ^19b'. is selected from the group consisting of, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 -C Each hydrogen atom in the ₁₀ aryl and the 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cyclo. Alkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -OR ^21b , -OC(O)R ^21b , -OC(O)NR ^21b R ^21b' , -. OS(O)R ^21b , -OS(O) ₂ R ^21b , -SR ^21b , -S(O)R ^21b , -S(O) ₂ R ^21b , -S(O)NR ^21b R ^21b' , -S. (O) ₂ NR ^21b R ^21b' , -OS(O)NR ^21b R ^21b' , -OS(O) ₂ NR ^21b R ^21b' , -NR ^{2 1b} R ^21b' , -NR ^21b C(O)R ^22b , -NR ^21b C(O)OR ^22b , -NR ^21b C(O)NR ^22b R ^22b' , -NR ^21b S(O)R ^22b , -NR. ^21b S(O) ₂ R ^22b , -NR ^21b S(O)NR ^22b R ^22b' , -NR ^21b S(O) ₂ NR ^22b R ^22b' , -C(O)R ^21b , -C(O)OR. ^21b or -C(O)NR ^21b R ^21b may be substituted;
R ^{10b, R 11b} and ^{R 12b} are, H independently, _D, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 23b, -OC (O)} R 23b, -OC (O) NR 23b R 23b ', -OS (O) R _{^{23b, -OS (O) 2 R}} 23b, -SR 23b, -S (O) R 23b, -S (O) 2 R 23b, -S (O) NR 23b R 23b ', -S (O) 2 NR ^{23b R 23b ', -OS (O} ) NR 23b R 23b', -OS (O) 2 NR 23b R 23b ', -NR 23b R 23b', -NR 23b C (O) R 24b, -NR 23b C ( O)OR ^24b , -NR ^23b C(O)NR ^24b R ^24b' , -NR ^23b S(O)R ^24b , -NR ^23b S(O) ₂ R ^24b , -NR ^23b S(O)NR ^24b R ^{24b. _{', -NR 23b S (O)}} 2 NR 24b R 24b', is selected from the group consisting of ^{-C (O) R 23b, -C} (O) oR 23b and ^{-C (O) NR 23b R 23b} ', wherein in _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5- to 7-membered Each hydrogen atom in a ring heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring. _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 25b, -OC (O)} R 25b, -OC (O) NR 25b R 25b ', -OS (O) R 25b, _{^{-OS (O) 2 R 25b,}} -SR 25b, -S (O) R 25b, -S (O) 2 R 25b, -S (O) NR 25b R 25b ', -S (O) 2 NR 25b R ^25b' , -OS(O)NR ^25b R ^25b' , -OS(O) ₂ NR ^25b R ^25b' , -NR ^25b R ^{25. b'} , -NR ^25b C(O)R ^26b , -NR ^25b C(O)OR ^26b , -NR ^25b C(O)NR ^26b R ^26b' , -NR ^25b S(O)R ^26b , -NR ^25b S. _{^{(O) 2 R 26b, -NR}} 25b S (O) NR 26b R 26b ', -NR 25b S (O) 2 NR 26b R 26b', -C (O) R 25b, -C (O) oR 25b or —C(O)NR ^25b R ^25b may be substituted, or R ^10b and R ^11b , together with the carbon atom to which they are attached, are optionally joined to form a C ₆ -C ₁₀ aryl. Or R ^11b and R ^12b , together with the carbon atom to which they are attached, optionally combine to form exo-methylene; or R ^12b is absent;
R ^13b , R ^13b' , R ^14b , R ^14b' , R ^15b , R ^15b' , R ^16b , R ^16b' , R ^17b , R ^17b' , R ^18b , R ^18b' , R ^19b , R ^19b' , R. ^20b , R ^20b' , R ^21b , R ^21b' , R ^22b , R ^22b' , R ^23b , R ^23b' , R ^24b , R ^24b' , R ^25b , R ^25b' , R ^26b and R ^26b' are respectively. independently _{H, D,} C 1 ~C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 _{-C 13} cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} Selected from the group consisting of aryl, C ₁ -C ₆ alkyl (C ₆ -C ₁₀ aryl) and 5-7 membered heteroaryl, wherein C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkyl (C ₆ -aryl). Each hydrogen atom in C ₁₀ aryl) and a 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C. ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered _{heteroaryl, -CN, -NO 2, -NCO,} -OH, -SH, -NH 2, -SO ₃ H, -C (O) OH and -C (O) may be substituted by NH _2;

Provided that one of R ^1b , R ^2b , R ^3b , R ^4b , R ^5b , R ^6b and R ^7b is a bond;
R ^1c , R ^2c and R ^5c are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7. membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, the group consisting of -C (O) R 6c, -C (O) oR 6c and ^{-C (O) NR 6c R 6c} ' Selected from where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl. And each hydrogen atom in the 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered ring heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered ring heteroaryl, -OR ^7c , -OC(O)R ^7c , -OC(O)NR ^7c R ^7c' , -OS( _{^{O) R 7c, -OS (O}} ) 2 R 7c, -SR 7c, -S (O) R 7c, -S (O) 2 R 7c, -S (O) 2 OR 7c, -S (O) NR _{^{7c R 7c ', -S (O}} ) 2 NR 7c R 7c', -OS (O) NR 7c R 7c ', -OS (O) 2 NR 7c R 7c', -NR 7c R 7c ', -NR 7c C(O)R ^8c , -NR ^7c C(O)OR ^8c , -NR ^7c C(O)NR ^8c R ^8c' , -NR ^7c S(O)R ^8c , -NR ^7c S(O) ₂ R ^8c. , -NR ^7c S(O)NR ^8c R ^8c' , -NR ^7c S(O) ₂ NR ^8c R ^8c' , -C(O)R ^7c , -C(O)OR ^7c or -C(O)NR. ^7c R ^7c′ may be substituted; or when J is —CR ^13c =, R ^5c is absent; provided that one of R ^1c or R ^2c is a bond;
R ^3c and R ^4c are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. _cycloalkyl, C 6 _{-C 10} aryl, 5-7 membered _{^{heteroaryl, -CN, -NO 2, -NCO,}} -OR 9c, -OC (O) R 9c, -OC (O) NR 9c R 9c ' , -OS(O)R ^9c , -OS(O) ₂ R ^9c , -SR ^9c , -S(O)R ^9c , -S(O) ₂ R ^9c , -S(O)NR ^9c R ^9c' , _{^{-S (O) 2 NR 9c R}} 9c ', -OS (O) NR 9c R 9c', -OS (O) 2 NR 9c R 9c ', -NR 9c R 9c', -NR 9c C (O) R ^10c , -NR ^9c C(O)OR ^10c , -NR ^9c C(O)NR ^10c R ^10c' , -NR ^9c S(O)R ^10c , -NR ^9c S(O) ₂ R ^10c , -NR ^9c S. ^{(O) NR 10c R 10c '} , -NR 9c S (O) 2 NR 10c R 10c', -C (O) R 9c, the -C (O) ^{oR 9c} and ^{-C (O) NR 9c R 9c} ' is selected from the group consisting of, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 -C Each hydrogen atom in the ₁₀ aryl and the 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cyclo. Alkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -OR ^11c , -OC(O)R ^11c , -OC(O)NR ^11c R ^11c' , -. OS(O)R ^11c , -OS(O) ₂ R ^11c , -SR ^11c , -S(O)R ^11c , -S(O) ₂ R ^11c , -S(O)NR ^11c R ^11c' , -S. (O) ₂ NR ^11c R ^11c' , -OS(O)NR ^11c R ^11c' , -OS(O) ₂ NR ^11c R ^11c' , -NR ^11c R ^11c' , -NR ^11c C(O)R ^12c , -NR ^11c C(O)OR ^12c , -NR ^11c C(O)NR ^12c R ^12c' , -NR ^11c S(O)R ^12c , -NR ^11c S(O) ₂ R ^12c , -NR ^11c S(O). ^{) NR 12c R 12c ', -NR} 11c S (O) 2 NR 12c R 12c', -C (O) R 11c, substituted by -C ^{(O) oR 11c} or ^{-C (O)} NR ^{11c R 11c} You may;
J is ^{-C (O) -, - CR} 13c = , or ^{- (CR 13c R 13c ')} - a and,
^R6c , ^R6c' , ^R7c , ^R7c' , ^R8c , ^R8c' , ^R9c , ^R9c' , ^R10c , ^R10c' , ^R11c , ^R11c' , ^R12c , ^R12c' , R. ^13c and R ^13c′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. Selected from the group consisting of cycloalkyl, C ₆ -C ₁₀ aryl and 5-7 membered heteroaryl;

R ^1d is H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ Aryl, 5-7 membered heteroaryl, —OR ^2d , —SR ^2d and —NR ^2d R ^2d′ selected from the group consisting of:
R ^2d and R ^2d′ are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring. It is selected from the group consisting of _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl, _{C 3} -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} each hydrogen atom in the C 6 _{-C 10} aryl and 5- to 7-membered ring heteroaryl, ^optionally, -OR 3d, ^{-SR 3d} and ^{-NR 3d, Optionally} substituted by R ^3d′ ;
R ^3d and R ^3d′ are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring. is selected from the group consisting of _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl;
R ^1e is H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ It is selected from the group consisting of aryl and 5-7 membered heteroaryl, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 each hydrogen atom in membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5- to 7-membered ring heteroaryl is independently _optionally, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl, C} 2 ~ C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 2e, -OC (O)} R 2e, -OC ^{(O) NR 2e R 2e '} , -OS (O) R 2e, -OS (O) 2 R 2e, -SR 2e, -S (O) R 2e, -S (O) 2 R 2e, -S ( ^{O) NR 2e R 2e ',} -S (O) 2 NR 2e R 2e', -OS (O) NR 2e R 2e ', -OS (O) 2 NR 2e R 2e', -NR 2e R 2e ', ^{-NR 2e C (O) R 3e} , -NR 2e C (O) OR 3e, -NR 2e C (O) NR 3e R 3e ', -NR 2e S (O) R 3e, -NR 2e S (O) _{^{2 R 3e, -NR 2e S (}} O) NR 2e R 2e ', -NR 2e S (O) 2 NR 3e R 3e', -C (O) R 2e, -C (O) oR 2e or -C ( O) optionally substituted by NR ^2e R ^2e ;
R ^2e , R ^2e′ , R ^3e and R ^3e′ are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl, wherein _C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl, _{C 2} -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} each hydrogen atom in the C 6 _{-C 10} aryl and 5- to 7-membered ring heteroaryl, optionally, ^{-OR 4e,} - ^Optionally substituted by SR ^4e or —NR ^4e R ^4e′ ;
R ^4e and R ^4e′ are independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. Selected from the group consisting of cycloalkyl, C ₆ -C ₁₀ aryl and 5-7 membered heteroaryl;
v is 1, 2 or 3; and * is a covalent bond]
Item 4. The conjugate according to any one of Items 1 to 3, which is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

5. Each AA independently represents L-lysine, L-asparagine, L-threonine, L-serine, L-isoleucine, L-methionine, L-proline, L-histidine, L-glutamine, L-arginine, L-glycine. , L-aspartic acid, L-glutamic acid, L-alanine, L-valine, L-phenylalanine, L-leucine, L-tyrosine, L-cysteine, L-tryptophan, L-phosphoserine, L-sulfo-cysteine, L- Arginosuccinic acid, L-hydroxyproline, L-phosphoethanolamine, L-sarcosine, L-taurine, L-carnosine, L-citrulline, L-anserin, L-1,3-methyl-histidine, L-α-amino- Adipic acid, D-lysine, D-asparagine, D-threonine, D-serine, D-isoleucine, D-methionine, D-proline, D-histidine, D-glutamine, D-arginine, D-glycine, D-asparagine. A term selected from the group consisting of acid, D-glutamic acid, D-alanine, D-valine, D-phenylalanine, D-leucine, D-tyrosine, D-cysteine, D-tryptophan, D-citrulline and D-carnosine. The conjugate according to any one of 1 to 4 or a pharmaceutically acceptable salt thereof.

6. Item 6. The conjugate according to any one of Items 1 to 5, wherein R ¹⁶ is H, or a pharmaceutically acceptable salt thereof.

7. R ¹⁷ and R ^17′ are each independently selected from the group consisting of H, C ₁ -C ₆ alkyl and —OR ²² , wherein each hydrogen atom in C ₁ -C ₆ alkyl is independently, if the may be substituted by ^{-OR 24;} or ^{R 17} and ^{R 17 'may} form a _C 4 -C ₆ cycloalkyl or 4-6 membered heterocyclic ring bonded, wherein _C 4 -C Each hydrogen atom in a _6- cycloalkyl or 4- to 6-membered heterocycle may be independently substituted, optionally with halogen, C ₁ -C ₆ alkyl or —OR ²⁴ ;
Item 7. A conjugate or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 6.

8. R ¹⁸ is _C 1 -C ₆ alkyl, 5-7 membered ^{heteroaryl, -OR 26, -NR 26 C (} O) R 27, -NR 26 C (O) NR 27 R 27 ', -NR 26 C ( ═NR ^26″ )NR ²⁷ R ^27′ and —C(O)NR ²⁶ R ^26′ , wherein each hydrogen atom in C ₁ -C ₆ alkyl and 5-7 membered heteroaryl is , independently, _optionally, C 1 -C _{6 ^{alkyl, -OR 29, - (CH 2}} ) p OS (O) 2 oR 29, -OS (O) 2 oR 29 or -C (O) ^{NR 29,} Optionally substituted by R ^29′ ;
R ²⁶ , R ^26′ , R ^26″ , R ²⁹ and R ^29′ are each independently H or C ₁ -C ₇ alkyl, wherein each hydrogen atom in C ₁ -C ₇ alkyl is independently and, optionally, halogen, -OH, -SH, may be substituted by -NH ₂ or -CO ₂ H;
R ²⁷ and ^{R 27 'are} each independently _H, C 1 _{~C 9 alkyl,} C 2 -C _{9 alkenyl,} C 2 -C _{9 alkynyl,} C 3 -C ₆ cycloalkyl, - _{(CH 2) p} (sugar _{), - (CH 2) p} (OCH 2 CH 2) q - ( sugar) and _{- (CH 2) p (OCH} 2 CH 2 CH 2) is selected from the group consisting of _q (sugars);
n is 2, 3, 4 or 5;
p is 1, 2, 3, 4 or 5;
q is 1, 2, 3, 4 or 5;
Item 8. The conjugate according to any one of Items 1 to 7 or a pharmaceutically acceptable salt thereof.

〔式中、
Ｒ^１６はＨであり、そして＊は共有結合である〕
から成る群から選択される、項１〜８のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 9. L ¹ is

[In the formula,
R ¹⁶ is H and * is a covalent bond]
Item 9. A conjugate or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 8, which is selected from the group consisting of:

10. In each case R ¹ and R ² are H;
R ^{3, R} 4, ^{R 5} and ^{R 6} is H; ^{X 1} is ^{-NR 11} - a and; ^{X 2} is = a N-; ^{X 3} is -N =; ^{X 4} is -N = X ⁵ is NR ¹² ; Y ¹ is ═O; Y ² is absent; R ¹¹ and R ¹² are H; m is 1, 2, 3 or 4; and * Is a covalent bond;
Item 10. The conjugate according to any one of Items 1 to 9 or a pharmaceutically acceptable salt thereof.

を有する、項１〜１０のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 11. formula

11. The conjugate or a pharmaceutically acceptable salt thereof according to any one of items 1 to 10, which comprises:

を有する、項１〜１１のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 12. formula

Item 12. A conjugate or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 11, which comprises:

13. - _{(AA) 4} - salt sequence is -Asp-Arg-Asp-Asp-, are conjugate or a pharmaceutically acceptable according to any one of claims 1-12.

14. The conjugate or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 13, wherein the sequence of —(AA) ₂ — is Val-CIT.

〔式中、
Ｒ^３１はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３２、−ＯＣ（Ｏ）Ｒ^３２、−ＯＣ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）Ｒ^３２、−ＯＳ（Ｏ）_２Ｒ^３２、−ＳＲ^３２、−Ｓ（Ｏ）Ｒ^３２、−Ｓ（Ｏ）_２Ｒ^３２、−Ｓ（Ｏ）ＮＲ^３２Ｒ^３２’、−Ｓ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｃ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｃ（Ｏ）ＯＲ^３３、−ＮＲ^３２Ｃ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）_２Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）_２ＮＲ^３３Ｒ^３３’、−Ｃ（Ｏ）Ｒ^３２、−Ｃ（Ｏ）ＯＲ^３２または−Ｃ（Ｏ）ＮＲ^３２Ｒ^３２’により置換されていてよく；
Ｘ^６はＣ_１〜Ｃ_６アルキルまたはＣ_６〜Ｃ_１０アリール（Ｃ_１〜Ｃ_６アルキル）であり、ここでＣ_１〜Ｃ_６アルキルおよびＣ_６〜Ｃ_１０アリール（Ｃ_１〜Ｃ_６アルキル）における各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３４、−ＯＣ（Ｏ）Ｒ^３４、−ＯＣ（Ｏ）ＮＲ^３４Ｒ^３４’、−ＯＳ（Ｏ）Ｒ^３４、−ＯＳ（Ｏ）_２Ｒ^３４、−ＳＲ^３４、−Ｓ（Ｏ）Ｒ^３４、−Ｓ（Ｏ）_２Ｒ^３４、−Ｓ（Ｏ）ＮＲ^３４Ｒ^３４’、−Ｓ（Ｏ）_２ＮＲ^３４Ｒ^３４’、−ＯＳ（Ｏ）ＮＲ^３４Ｒ^３４’、−ＯＳ（Ｏ）_２ＮＲ^３４Ｒ^３４’、−ＮＲ^３４Ｒ^３４’、−ＮＲ^３４Ｃ（Ｏ）Ｒ^３５、−ＮＲ^３４Ｃ（Ｏ）ＯＲ^３５、−ＮＲ^３４Ｃ（Ｏ）ＮＲ^３５Ｒ^３５’、−ＮＲ^３４Ｓ（Ｏ）Ｒ^３５、−ＮＲ^３４Ｓ（Ｏ）_２Ｒ^３５、−ＮＲ^３４Ｓ（Ｏ）ＮＲ^３５Ｒ^３５’、−ＮＲ^３４Ｓ（Ｏ）_２ＮＲ^３５Ｒ^３５’、−Ｃ（Ｏ）Ｒ^３４、−Ｃ（Ｏ）ＯＲ^３４または−Ｃ（Ｏ）ＮＲ^３４Ｒ^３４’により置換されていてよく；
Ｒ^３２、Ｒ^３２’、Ｒ^３３、Ｒ^３３’、Ｒ^３４、Ｒ^３４’、Ｒ^３５およびＲ^３５’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；
Ｒ^３６は独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３７、−ＯＣ（Ｏ）Ｒ^３７、−ＯＣ（Ｏ）ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）Ｒ^３７、−ＯＳ（Ｏ）_２Ｒ^３７、−ＳＲ^３７、−Ｓ（Ｏ）Ｒ^３７、−Ｓ（Ｏ）_２Ｒ^３７、−Ｓ（Ｏ）ＮＲ^３７Ｒ^３７’、−Ｓ（Ｏ）_２ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）_２ＮＲ^３７Ｒ^３７’、−ＮＲ^３７Ｒ^３７’、−ＮＲ^３７Ｃ（Ｏ）Ｒ^３８、−ＮＲ^３７Ｃ（Ｏ）ＯＲ^３８、−ＮＲ^３７Ｃ（Ｏ）ＮＲ^３８Ｒ^３８’、−ＮＲ^３７Ｓ（Ｏ）Ｒ^３８、−ＮＲ^３７Ｓ（Ｏ）_２Ｒ^３８、−ＮＲ^３７Ｓ（Ｏ）ＮＲ^３８Ｒ^３８’、−ＮＲ^３７Ｓ（Ｏ）_２ＮＲ^３８Ｒ^３８’、−Ｃ（Ｏ）Ｒ^３７、−Ｃ（Ｏ）ＯＲ^３７または−Ｃ（Ｏ）ＮＲ^３７Ｒ^３７’により置換されていてよく；
Ｒ^３７、Ｒ^３７’、Ｒ^３８およびＲ^３８’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
から成る群から選択される、項１〜１４のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 15. L ² is

[In the formula,
R ³¹ is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₁ -C ₆ alkyl. each hydrogen atom in _C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl , _C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 32, -OC (O)} R ³² , -OC(O)NR ³² R ^32' , -OS(O)R ³² , -OS(O) ₂ R ³² , -SR ³² , -S(O)R ³² , -S(O) ₂ R ^32. , -S(O)NR ³² R ^32' , -S(O) ₂ NR ³² R ^32' , -OS(O)NR ³² R ^32' , -OS(O) ₂ NR ³² R ^32' , -NR ^{32. R 32 ', -NR 32 C (} O) R 33, -NR 32 C (O) OR 33, -NR 32 C (O) NR 33 R 33', -NR 32 S (O) R 33, -NR 32 _{^{S (O) 2 R 33,}} -NR 32 S (O) NR 33 R 33 ', -NR 32 S (O) 2 NR 33 R 33', -C (O) R 32, -C (O) OR 32 Or optionally substituted by -C(O)NR ³² R ^32' ;
X ⁶ is C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl), wherein C ₁ -C ₆ alkyl and C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl). Each hydrogen atom in is optionally halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. _cycloalkyl, C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 34, -OC (O)} R 34, -OC (O) NR 34 R 34 ', -OS (O) R 34, - _{^{OS (O) 2 R 34,}} -SR 34, -S (O) R 34, -S (O) 2 R 34, -S (O) NR 34 R 34 ', -S (O) 2 NR 34 R 34 ^{', -OS (O) NR 34} R 34', -OS (O) 2 NR 34 R 34 ', -NR 34 R 34', -NR 34 C (O) R 35, -NR 34 C (O) OR ^{35, -NR 34 C (O)} NR 35 R 35 ', -NR 34 S (O) R 35, -NR 34 S (O) 2 R 35, -NR 34 S (O) NR 35 R 35', - _{^{NR 34 S (O) 2 NR}} 35 R 35 may be substituted by ^{', -C (O) R 34} , -C (O) oR 34 or ^{-C (O) NR 34 R 34} ';
^{R 32, R 32 ', R} 33, R 33', R 34, R 34 ', R 35 and ^{R 35'} is, H _{independently, D,} C 1 ~C _{7 alkyl,} C 2 -C ₇ alkenyl is selected from the group consisting of _C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl;
R ³⁶ is independently selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₁ -. C _{6 alkyl,} C 2 -C _{6 alkenyl,} each hydrogen atom in the C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl, C} 2 ~ C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, -OR 37, -OC ( ^{O) R 37, -OC (O} ) NR 37 R 37 ', -OS (O) R 37, -OS (O) 2 R 37, -SR 37, -S (O) R 37, -S (O) _{^{2 R 37, -S (O)}} NR 37 R 37 ', -S (O) 2 NR 37 R 37', -OS (O) NR 37 R 37 ', -OS (O) 2 NR 37 R 37', ^{-NR 37 R 37 ', -NR 37} C (O) R 38, -NR 37 C (O) OR 38, -NR 37 C (O) NR 38 R 38', -NR 37 S (O) R 38, -NR ³⁷ S(O) ₂ R ³⁸ , -NR ³⁷ S(O)NR ³⁸ R ^38' , -NR ³⁷ S(O) ₂ NR ³⁸ R ^38' , -C(O)R ³⁷ , -C(O ) OR ³⁷ or -C(O)NR ³⁷ R ^{37' which} may be substituted;
R ³⁷ , R ^37′ , R ³⁸ and R ^38′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a covalent bond]
15. The conjugate or a pharmaceutically acceptable salt thereof according to any one of items 1 to 14, which is selected from the group consisting of:

〔式中、
Ｒ^３１はＨであり；そして
Ｘ^６はＣ_１〜Ｃ_６アルキルである〕
のものである、項１〜１５のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 16. L ² is an expression

[In the formula,
R ³¹ is H; and X ⁶ is C ₁ -C ₆ alkyl]
Item 16. The conjugate according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof, which is

〔式中、
Ｒ^３１はＨであり；そして
Ｘ^６はＣ_６〜Ｃ_１０アリール（Ｃ_１〜Ｃ_６アルキル）である〕
のものである、項１〜１５のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 17. L ² is an expression

[In the formula,
R ³¹ is H; and X ⁶ is C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl)]
Item 16. The conjugate according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof, which is

〔式中、
Ｒ^３６は独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３７、−ＯＣ（Ｏ）Ｒ^３７、−ＯＣ（Ｏ）ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）Ｒ^３７、−ＯＳ（Ｏ）_２Ｒ^３７、−ＳＲ^３７、−Ｓ（Ｏ）Ｒ^３７、−Ｓ（Ｏ）_２Ｒ^３７、−Ｓ（Ｏ）ＮＲ^３７Ｒ^３７’、−Ｓ（Ｏ）_２ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）_２ＮＲ^３７Ｒ^３７’、−ＮＲ^３７Ｒ^３７’、−ＮＲ^３７Ｃ（Ｏ）Ｒ^３８、−ＮＲ^３７Ｃ（Ｏ）ＯＲ^３８、−ＮＲ^３７Ｃ（Ｏ）ＮＲ^３８Ｒ^３８’、−ＮＲ^３７Ｓ（Ｏ）Ｒ^３８、−ＮＲ^３７Ｓ（Ｏ）_２Ｒ^３８、−ＮＲ^３７Ｓ（Ｏ）ＮＲ^３８Ｒ^３８’、−ＮＲ^３７Ｓ（Ｏ）_２ＮＲ^３８Ｒ^３８’、−Ｃ（Ｏ）Ｒ^３７、−Ｃ（Ｏ）ＯＲ^３７または−Ｃ（Ｏ）ＮＲ^３７Ｒ^３７’により置換されていてよく；
Ｒ^３７、Ｒ^３７’、Ｒ^３８およびＲ^３８’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
のものである、項１〜１５のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 18. L ² is an expression

[In the formula,
R ³⁶ is independently selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₁ -. C _{6 alkyl,} C 2 -C _{6 alkenyl,} each hydrogen atom in the C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl, C} 2 ~ C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, -OR 37, -OC ( ^{O) R 37, -OC (O} ) NR 37 R 37 ', -OS (O) R 37, -OS (O) 2 R 37, -SR 37, -S (O) R 37, -S (O) _{^{2 R 37, -S (O)}} NR 37 R 37 ', -S (O) 2 NR 37 R 37', -OS (O) NR 37 R 37 ', -OS (O) 2 NR 37 R 37', ^{-NR 37 R 37 ', -NR 37} C (O) R 38, -NR 37 C (O) OR 38, -NR 37 C (O) NR 38 R 38', -NR 37 S (O) R 38, -NR ³⁷ S(O) ₂ R ³⁸ , -NR ³⁷ S(O)NR ³⁸ R ^38' , -NR ³⁷ S(O) ₂ NR ³⁸ R ^38' , -C(O)R ³⁷ , -C(O ) OR ³⁷ or -C(O)NR ³⁷ R ^{37' which} may be substituted;
R ³⁷ , R ^37′ , R ³⁸ and R ^38′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a covalent bond]
Item 16. The conjugate according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof, which is

19. Item 16. The conjugate or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 15, wherein R ³⁶ is H.

〔式中、
＊は結合である〕
のものである、項１〜１５、１８または１９のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 20. Linker is an expression

[In the formula,
* Is a bond]
Item 20. The conjugate according to any one of Items 1 to 15, 18 or 19 or a pharmaceutically acceptable salt thereof, which is

〔式中、
＊は結合である〕
のものである、項１〜１５、１８または１９のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 21. Linker is an expression

[In the formula,
* Is a bond]
Item 20. The conjugate according to any one of Items 1 to 15, 18 or 19 or a pharmaceutically acceptable salt thereof, which is

〔式中、
＊は結合である〕
のものである、項１〜１６のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 22. Linker is an expression

[In the formula,
* Is a bond]
Item 17. The conjugate according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof, which is

〔式中、
＊は結合である〕
のものである、項１〜１６のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 23. Linker is an expression

[In the formula,
* Is a bond]
Item 17. The conjugate according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof, which is

〔式中、
＊は結合である〕
のものである、項１〜１５または１６のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 24. Linker is an expression

[In the formula,
* Is a bond]
Item 17. A conjugate or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 15 or 16, which is

〔式中、
＊は結合である〕
のものである、項１〜１５、１８または１９のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 25. Linker is an expression

[In the formula,
* Is a bond]
Item 20. The conjugate according to any one of Items 1 to 15, 18 or 19 or a pharmaceutically acceptable salt thereof, which is

〔式中、
＊は結合である〕
のものである、項１〜１５、１８または１９のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 26. Linker is an expression

[In the formula,
* Is a bond]
Item 20. The conjugate according to any one of Items 1 to 15, 18 or 19 or a pharmaceutically acceptable salt thereof, which is

〔式中、
＊は結合である〕
のものである、項１〜１５、１８または１９のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 27. Linker is an expression

[In the formula,
* Is a bond]
Item 20. The conjugate according to any one of Items 1 to 15, 18 or 19 or a pharmaceutically acceptable salt thereof, which is

〔式中、
＊は結合である〕
のものである、項１〜１５、１８または１９のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 28. Linker is an expression

[In the formula,
* Is a bond]
Item 20. The conjugate according to any one of Items 1 to 15, 18 or 19 or a pharmaceutically acceptable salt thereof, which is

〔式中、
Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｂ、Ｒ^３ｂ、Ｒ^４ｂ、Ｒ^８ｂおよびＲ^９ｂはＨである〕
のものである、項１〜２８のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 29. -D ¹ -L ⁵ -D ² has the formula

[In the formula,
R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a , R ^2b , R ^3b , R ^4b , R ^8b and R ^9b are H]
Item 29. The conjugate or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 28, which is

30. R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a , R ^2b , R ^3b , R ^4b , R ^8b and R ^9b are H, L ⁵ is C ₁ -C ₁₀ alkyl or -(CR ⁴⁹ R ^49′ ) _u C(O)—, R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3 or 4, Or a pharmaceutically acceptable salt thereof.

〔式中、
Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^６ａ、Ｒ^７ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｃ、Ｒ^３ｃ、Ｒ^４ｃ、Ｒ^５ｃはＨである〕
のものである、項１〜２８のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 31. -D ¹ -L ⁵ -D ² has the formula

[In the formula,
R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^2c , R ^3c , R ^4c and R ^5c are H]
Item 29. The conjugate or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 28, which is

32. L ⁵ is C ₁ -C ₁₀ alkyl or —(CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3, Item 32. The conjugate according to any one of Item 31, which is 4 or 5, or a pharmaceutically acceptable salt thereof.

〔式中、
Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^６ａ、Ｒ^７ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａはＨである〕
のものである、項１〜２８のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 33. -D ¹ -L ⁵ -D ² has the formula

[In the formula,
R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a and R ^10a are H]
Item 29. The conjugate or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 28, which is

34. L ⁵ is C ₁ -C ₁₀ alkyl or —(CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3, Item 34. The conjugate according to Item 33, which is 4 or 5, or a pharmaceutically acceptable salt thereof.

〔式中、
Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^６ａ、Ｒ^７ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅはＨである〕
のものである、項１〜２８のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 35. -D ¹ -L ⁵ -D ² has the formula

[In the formula,
R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a and R ^1e are H]
Item 29. The conjugate or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 28, which is

36. L ⁵ is C ₁ -C ₁₀ alkyl or —(CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3, Item 34. The conjugate according to Item 35, which is 4 or 5, or a pharmaceutically acceptable salt thereof.

〔式中、
Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^６ａ、Ｒ^７ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^１ｄはＨである〕
のものである、項１〜２８のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 37. -D ¹ -L ⁵ -D ² has the formula

[In the formula,
R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a and R ^1d are H]
Item 29. The conjugate or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 28, which is

38. L ⁵ is C ₁ -C ₁₀ alkyl or —(CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3, Item 38. The conjugate according to Item 37, which is 4 or 5, or a pharmaceutically acceptable salt thereof.

〔式中、
Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^６ａ、Ｒ^７ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａはＨである〕
のものである、項１〜２８のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 39. -D ¹ -L ⁵ -D ² has the formula

[In the formula,
R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a and R ^10a are H]
Item 29. The conjugate or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 28, which is

40. L ⁵ is C ₁ -C ₁₀ alkyl or —(CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3, 40. The conjugate according to Item 39, which is 4 or 5, or a pharmaceutically acceptable salt thereof.

〔式中、
Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^６ａ、Ｒ^７ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａはＨである〕
のものである、項１〜２８のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 41. -D ¹ -L ⁵ -D ² has the formula

[In the formula,
R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a and R ^10a are H]
Item 29. The conjugate or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 28, which is

42. L ⁵ is C ₁ -C ₁₀ alkyl or —(CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3, Item 42. The conjugate according to Item 41, which is 4 or 5, or a pharmaceutically acceptable salt thereof.

〔式中、
Ｒ^２ａ、Ｒ^３ａ、Ｒ^５ａ、Ｒ^６ａ、Ｒ^７ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｂ、Ｒ^３ｂ、Ｒ^４ｂ、Ｒ^５ｂ、Ｒ^６ｂ、Ｒ^７ｂ、Ｒ^８ｂ、Ｒ^９ｂ、Ｒ^１０ｂ、Ｒ^１１ｂおよびＲ^１２ｂはＨである〕
のものである、項１〜２８のいずれか一項に記載のコンジュゲートまたはその薬学的に許容される塩。 43. -D ¹ -L ⁵ -D ² has the formula

[In the formula,
R ^2a , R ^3a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^2b , R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^8b , R ^9b , R ^10b. , R ^11b and R ^12b are H]
Item 29. The conjugate or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 28, which is

44. L ⁵ is C ₁ -C ₁₀ alkyl or —(CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3, The conjugate of claim 43 or a pharmaceutically acceptable salt thereof, which is 4 or 5.

のコンジュゲートまたはその薬学的に許容される塩。 45. formula

Or a pharmaceutically acceptable salt thereof.

46. 46. A pharmaceutical composition comprising a therapeutically effective amount of the conjugate of any one of paragraphs 1-45 or a pharmaceutically acceptable salt thereof, and at least one excipient.

47. 46. A method of treating abnormal cell proliferation in a mammal, including a human, comprising administering to the mammal the conjugate of any one of paragraphs 1-45.

48. Item 48. The method according to Item 47, wherein the abnormal cell proliferation is cancer.

49. Cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous melanoma or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, egg Ductal cancer, endometrial cancer, endocervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, Prostate cancer, chronic or acute leukemia, lymphoid lymphoma, bladder cancer, renal or ureteral cancer, renal cell carcinoma, renal pelvic cancer, central nervous system (CNS) tumor, primary CNS lymphoma, spinal axis tumor, brain stem glioma 49. The method of paragraph 48, which is a pituitary adenoma, or a combination of one or more ongoing cancers. In another embodiment of said method, said abnormal cell growth is a benign proliferative disease, including but not limited to psoriasis, prostatic hypertrophy or restenosis.

50. Use of the conjugate according to any one of paragraphs 1-45 in the manufacture of a medicament for the treatment of cancer.

FIG. 1 shows that EC1629 (♦) administered at 2 μmol/kg TIW for 2 weeks reduces KB tumors in test animals compared to untreated controls (●). The dotted line indicates the final administration date. FIG. 2 shows that EC1744 (■) administered at 2 μmol/kg TIW for 2 weeks reduces KB tumors in test animals compared to untreated controls (●). In addition, FIG. 2 also shows that EC1788 (▲) administered at 0.2 μmol/kg TIW for 2 weeks reduces KB tumors in test animals compared to untreated controls (●), and EC1788 is completely intact. Indicates that you have given a response. The dotted line indicates the final administration date. FIG. 3 shows that EC1884 (d) administered for 2 weeks at 2 μmol/kg TIW reduces KB tumors in test animals compared to untreated controls (a). Furthermore, FIG. 3 also shows that EC1879 (c) administered at 2 μmol/kg TIW for 1 week reduces KB tumors in test animals compared to untreated controls (a), and EC1879 has a partial response. Indicates that you have given. Furthermore, FIG. 3 also shows that EC1788 (b) administered at 0.4 μmol/kg BIW for 2 weeks reduces KB tumors in test animals as compared to untreated subjects (a), as well as complete EC1788. Demonstrate success and cure. The dotted line indicates the final administration date. FIG. 4 shows that EC1879 (▲) administered at 2 μmol/kg TIW for 2 weeks reduces KB tumors in test animals compared to untreated controls (■), and C1879 5/5 test animals. Shows a complete response in and in 5/5 test animals a cure. The dotted line indicates the final administration date. FIG. 5 shows that EC1744 (■) administered at 2 μmol/kg TIW for 2 weeks reduced MDA-MB-231 tumors in test animals compared to untreated controls (■), and EC1744 was 5/. 5 shows a complete response in 5 test animals and a cure in 4/5 test animals. The dotted line indicates the final administration date.

Definitions As used herein, the term "alkyl" includes carbon atoms that are optionally branched, and includes 1 to 20 carbon atoms. In certain embodiments, alkyl is advantageously C ₁ -C ₁₂ , C ₁ -C ₁₀ , C ₁ -C ₉ , C ₁ -C ₈ , C ₁ -C ₇ , C ₁ -C ₆ and C ₁ -C _4. It should be understood that it can be of limited length, including. _{Specifically, C 1 ~C 8, C 1} ~C 7, C 1 ~C 6 and including _C 1 -C _4, alkyl group such particularly limited length, "lower alkyl" Can be called. Specific alkyl groups are not limited, but include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, Including octyl etc. The alkyl may be substituted or unsubstituted. Common substituents are cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, oxo (=O), thiocarbonyl, O-. Carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, C-carboxy, O-carboxy, nitro and amino, or a substitution described in the various embodiments provided herein. Including a group. It is understood that "alkyl" can be combined with other substituents as provided above to form a functionalized alkyl. By way of example, a combination of "alkyl" and "carboxy" groups described herein may be referred to as a "carboxyalkyl" group. Other non-limiting examples include hydroxyalkyl, aminoalkyl and the like.

As used herein, the term "alkenyl" includes chains of carbon atoms, which are optionally branched, and contains 2 to 20 carbon atoms, and also at least one carbon-carbon double bond (ie C=C) is included. In some embodiments, the alkenyl is preferably _{includes C 2 ~C 12, C 2 ~C} 9, C 2 ~C 8, C 2 ~C 7, C 2 ~C 6 and _C 2 -C _4, were limited It is understood that you get by the length. _{Specifically,} including _{C 2 ~C 8, C 2 ~C} 7, C 2 ~C 6 and _C 2 -C _4, alkenyl groups such particularly limited length can be referred to as lower alkenyl. The alkenyl may be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Specific alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl or 3-butenyl and the like.

The term "alkynyl" as used herein includes a chain of carbon atoms, which is optionally branched, and contains 2 to 20 carbon atoms, and also at least one carbon-carbon triple bond (ie C ≡ C) is included. In certain embodiments, the alkynyl is advantageously _{comprises C 2 ~C 12, C 2 ~C} 9, C 2 ~C 8, C 2 ~C 7, C 2 ~C 6 and _C 2 -C _4, were limited It is understood that it can be of length. _{Specifically, C 2 ~C 8, C 2} ~C 7, C 2 ~C 6, and a _C 2 -C _4, alkynyl groups such particularly limited length can be referred to as lower alkynyl .. The alkenyl may be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Specific alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.

The term “aryl” as used herein refers to an all carbon monocyclic or fused ring polycyclic group of 6 to 12 carbon atoms having a fully conjugated π electron system. In some embodiments, aryl is advantageously understood to be of limited size, such as C ₆ -C ₁₀ aryl. Specific aryl groups include, but are not limited to, phenyl, naphthalenyl and anthracenyl. Aryl groups can be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein.

The term "cycloalkyl" as used herein is a 3- to 15-membered, all-carbon monocyclic ring, all-carbon 5-membered/6-membered or 6-membered/6-membered ring. Fused Bicyclic or Polycyclic Fused Rings of a Ring ("Fused" ring system means that each ring in the system shares a pair of adjacent carbon atoms with each other ring in the system. , And one or more rings may contain one or more double bonds, but cycloalkyl does not contain a fully conjugated pi-electron system. In some embodiments, the cycloalkyl is _{advantageously} understood to be of _{C 3 ~C 13, C 3 ~C} 6, C 3 ~C 6 and _C 4 -C limited magnitude, such as _6. The cycloalkyl may be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Specific cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, norbornyl, norbornenyl, 9H-fluoren-9-yl and the like. Including.

The term “heterocycloalkyl” as used herein refers to 3 to 12 ring atoms in which at least one ring atom is a heteroatom such as nitrogen, oxygen or sulfur and the remaining ring atoms are carbon atoms. Refers to a monocyclic or fused ring group having ring atoms. Heterocycloalkyl may optionally contain 1, 2, 3, or 4 heteroatoms. Heterocycloalkyl may also have one or more double bonds, including double bonds with nitrogen (eg, C=N or N=N), but does not include a fully conjugated pi-electron system. In some embodiments, heterocycloalkyl is preferably understood to be of limited size, such as 3-7 membered heterocycloalkyl, 5-7 membered heterocycloalkyl, and the like. Heterocycloalkyl may be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Specific heterocycloalkyl groups include, but are not limited to, oxiranyl, thianaryl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, oxepanyl. , 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2,3,4-tetrahydropyridinyl and the like.

The term "heteroaryl", as used herein, is 1, 2, 3 or 4 ring heteroatoms, carbon atoms selected from 5 to 12 ring atom nitrogen, oxygen and sulfur. Refers to a monocyclic or fused ring system containing the remaining atoms and also having a fully conjugated pi-electron system. In some embodiments, heteroaryl is preferably understood to be of limited size, such as 3-7 membered heteroaryl, 5-7 membered heteroaryl, and the like. Heteroaryl may be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Specific heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl, pyrazinyl, tetrazinyl, quinazolinyl, quinoxanyl, thienyl, It includes isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl and carbazoloxy.

“Hydroxy” or “hydroxyl” as used herein refers to an OH group.

As used herein, "alkoxy" refers to both an -O-(alkyl) group or an -O-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

As used herein, “aryloxy” refers to an —O-aryl group or an —O-heteroaryl group. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy and the like.

As used herein, "mercapto" refers to the -SH group.

As used herein, "alkylthio" refers to a -S-(alkyl) group or a -S-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.

As used herein, "arylthio" refers to a -S-aryl group or a -S-heteroaryl group. Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like.

As used herein, "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

As used herein, "trihalomethyl" refers to a methyl group that has three halo substituents, such as a trifluoromethyl group.

“Cyano” as used herein refers to a —CN group.

As used herein, a "Sulfinyl" is -S, wherein R" can be any R group described in the various embodiments provided herein, or R" can be a hydroxyl group. (O) refers to a R″ group.

As used herein, a "sulfonyl" is -S, wherein R" is any R group described in the various embodiments provided herein, or R" can be a hydroxyl group. (O) ₂ R″ group.

As used herein, “S-sulfonamido” is —S(O) ₂ NR″R, where R″ is any R group described in the various embodiments provided herein. '' refers to a group.

As used herein, “N-sulfonamido” is —NR″S(O) ₂ R, where R″ is any R group described in the various embodiments provided herein. '' refers to a group.

As used herein, “O-carbamyl” is —OC(O)NR″R″, wherein R″ is any R group described in the various embodiments provided herein. Refers to the group.

As used herein, "N-carbamyl" is R"OC(O)NR"-, where R" is any R group described in the various embodiments provided herein. Refers to the group.

As used herein, "O-thiocarbamyl" is -OC(S)NR"R", where R" is any R group described in the various embodiments provided herein. Refers to the group.

As used herein, “N-thiocarbamyl” refers to a R′OC(S)NR″— group, where R″ is any R group described in the various embodiments provided herein. Refers to.

As used herein, "amino" refers to a -NR"R" group, wherein R" is any R group described in various aspects provided herein.

As used herein, “C-amido” is —C(O)NR″R″, where R″ is any R group described in the various embodiments provided herein. Refers to the group.

As used herein, "N-amido" is R"C(O)NR"-, where R" is any R group described in the various embodiments provided herein. Refers to the group.

“Nitro” as used herein refers to a —NO ₂ group.

As used herein, "bond" refers to a covalent bond.

As used herein, “optional” or “optionally” means that the event or circumstance described below may, but need not, occur, and the description is Including cases where the event or situation occurs and cases where it does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may, but need not, be present and the description states that the heterocyclic group is substituted with an alkyl group. And the situation in which the heterocyclic group is not substituted with an alkyl group.

As used herein, "independently" means that the events or circumstances described later are to be interpreted as is with respect to other similar events or circumstances. For example, the use of "independently, optionally," in the context where several equivalents of a hydrogen group may be optionally replaced by another group, means that each hydrogen atom is replaced by another, identical or different, substituent. It means that the hydrogen atom on the case group may be replaced. Or, for example, where there is more than one group for every group that can be selected from the set of possibilities, the use of “independently” means that each group can be selected from the set of possibilities separately from any other group. It means a group, and the groups selected in that context may be the same or different.

The term "pharmaceutically acceptable salt" as used herein refers to those salts that are counterions that can be used in medicine. Salts like this:
(1) The free base of the parent conjugate and an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid and perchloric acid, or acetic acid, oxalic acid, (D) malic acid or (L) malic acid, Or an acid addition salt obtainable by reaction with an organic acid such as maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid; or (2 ) The acidic protons present in the parent conjugate are replaced by metal ions, for example alkali metal ions, alkaline earth ions or aluminum ions; or ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine, etc. And salts formed upon coordination with organic bases such as Pharmaceutically acceptable salts are well known to those of skill in the art, and any such pharmaceutically acceptable salt may be contemplated in connection with the embodiments described herein.

〔式中、
Ｒ’は側鎖であり、そしてΦは少なくとも３個の炭素原子を含む〕
の１つを有する分子を含み得る。
「アミノ酸」は立体異性体Ｄ−アミノ酸およびＬ−アミノ酸形態のような立体異性体を含む。具体的なアミノ酸は、限定されないが、２０個の内在性ヒトアミノ酸およびそれらの誘導体、例えばリシン（Ｌｙｓ）、アスパラギン（Ａｓｎ）、スレオニン（Ｔｈｒ）、セリン（Ｓｅｒ）、イソロイシン（Ｉｌｅ）、メチオニン（Ｍｅｔ）、プロリン（Ｐｒｏ）、ヒスチジン（Ｈｉｓ）、グルタミン（Ｇｌｎ）、アルギニン（Ａｒｇ）、グリシン（Ｇｌｙ）、アスパラギン酸（Ａｓｐ）、グルタミン酸（Ｇｌｕ）、アラニン（Ａｌａ）、バリン（Ｖａｌ）、フェニルアラニン（Ｐｈｅ）、ロイシン（Ｌｅｕ）、チロシン（Ｔｙｒ）、システイン（Ｃｙｓ）、トリプトファン（Ｔｒｐ）、ホスホセリン（ＰＳＥＲ）、スルホ−システイン、アルギノコハク酸（ＡＳＡ）、ヒドロキシプロリン、ホスホエタノールアミン（ＰＥＡ）、サルコシン（ＳＡＲＣ）、タウリン（ＴＡＵ）、カルノシン（ＣＡＲＮ）、シトルリン（ＣＩＴ）、アンセリン（ＡＮＳ）、１，３−メチル−ヒスチジン（ＭＥ−ＨＩＳ）、α−アミノ−アジピン酸（ＡＡＡ）、β−アラニン（ＢＡＬＡ）、エタノールアミン（ＥＴＮ）、γ−アミノ−酪酸（ＧＡＢＡ）、β−アミノ−イソ酪酸（ＢＡＩＡ）、α−アミノ−酪酸（ＢＡＢＡ）、Ｌ−ａｌｌｏ−シスタチオニン（シスタチオニン−Ａ；ＣＹＳＴＡ−Ａ）、Ｌ−シスタチオニン（シスタチオニン−Ｂ；ＣＹＳＴＡ−Ｂ）、シスチン、ａｌｌｏ−イソロイシン（ＡＬＬＯ−ＩＬＥ）、ＤＬ−ヒドロキシリシン（ヒドロキシリシン（Ｉ））、ＤＬ−ａｌｌｏ−ヒドロキシリシン（ヒドロキシリシン（２））、オルニチン（ＯＲＮ）、ホモシスチン（ＨＣＹ）およびそれらの誘導体を含む。これらの各例はまた、本発明に関する、上で示したＤ−配置を企図する。特に、例えば、Ｄ−リシン（Ｄ−Ｌｙｓ）、Ｄ−アスパラギン（Ｄ−Ａｓｎ）、Ｄ−スレオニン（Ｄ−Ｔｈｒ）、Ｄ−セリン（Ｄ−Ｓｅｒ）、Ｄ−イソロイシン（Ｄ−Ｉｌｅ）、Ｄ−メチオニン（Ｄ−Ｍｅｔ）、Ｄ−プロリン（Ｄ−Ｐｒｏ）、Ｄ−ヒスチジン（Ｄ−Ｈｉｓ）、Ｄ−グルタミン（Ｄ−Ｇｌｎ）、Ｄ−アルギニン（Ｄ−Ａｒｇ）、Ｄ−グリシン（Ｄ−Ｇｌｙ）、Ｄ−アスパラギン酸（Ｄ−Ａｓｐ）、Ｄ−グルタミン酸（Ｄ−Ｇｌｕ）、Ｄ−アラニン（Ｄ−Ａｌａ）、Ｄ−バリン（Ｄ−Ｖａｌ）、Ｄ−フェニルアラニン（Ｄ−Ｐｈｅ）、Ｄ−ロイシン（Ｄ−Ｌｅｕ）、Ｄ−チロシン（Ｄ−Ｔｙｒ）、Ｄ−システイン（Ｄ−Ｃｙｓ）、Ｄ−トリプトファン（Ｄ−Ｔｒｐ）、Ｄ−シトルリン（Ｄ−ＣＩＴ）、Ｄ−カルノシン（Ｄ−ＣＡＲＮ）である。本明細書に記載の態様に関して、アミノ酸はそれらのα−アミノおよびカルボキシ官能基を介して（すなわちペプチド結合形態で）、またはそれらの側鎖官能基（例えばグルタミン酸における側鎖カルボキシ基）を介して、およびそれらのα−アミノまたはカルボキシ官能基のいずれか一方を介して、本明細書に記載のコンジュゲートの他の部分と共有結合できる。本明細書に記載のコンジュゲートに関して使用されるとき、アミノ酸は、それらが包含されるコンジュゲート中で双性イオンとして存在し得ると解される。 As used herein, "amino acid" (also referred to as "AA") means any molecule containing an α-carbon atom covalently bound to an amino group and an acid group. The acid group may include a carboxyl group. "Amino acid" has the formula:

[In the formula,
R'is a side chain, and Φ contains at least 3 carbon atoms]
A molecule having one of:
"Amino acid" includes stereoisomers such as stereoisomer D-amino acid and L-amino acid forms. Specific amino acids include, but are not limited to, 20 endogenous human amino acids and their derivatives such as lysine (Lys), asparagine (Asn), threonine (Thr), serine (Ser), isoleucine (Ile), methionine ( Met), proline (Pro), histidine (His), glutamine (Gln), arginine (Arg), glycine (Gly), aspartic acid (Asp), glutamic acid (Glu), alanine (Ala), valine (Val), phenylalanine. (Phe), leucine (Leu), tyrosine (Tyr), cysteine (Cys), tryptophan (Trp), phosphoserine (PSER), sulfo-cysteine, arginosuccinic acid (ASA), hydroxyproline, phosphoethanolamine (PEA), sarcosine. (SARC), taurine (TAU), carnosine (CARN), citrulline (CIT), anserine (ANS), 1,3-methyl-histidine (ME-HIS), α-amino-adipic acid (AAA), β-alanine. (BALA), ethanolamine (ETN), γ-amino-butyric acid (GABA), β-amino-isobutyric acid (BAIA), α-amino-butyric acid (BABA), L-allo-cystathionine (cystathionine-A; CYSTA-). A), L-cystathionine (cystathionine-B; CYSTA-B), cystine, allo-isoleucine (ALLO-ILE), DL-hydroxylysine (hydroxylysine (I)), DL-allo-hydroxylysine (hydroxylysine (2 )), ornithine (ORN), homocystine (HCY) and their derivatives. Each of these examples also contemplates the D-configuration shown above for the present invention. In particular, for example, D-lysine (D-Lys), D-asparagine (D-Asn), D-threonine (D-Thr), D-serine (D-Ser), D-isoleucine (D-Ile), D -Methionine (D-Met), D-proline (D-Pro), D-histidine (D-His), D-glutamine (D-Gln), D-arginine (D-Arg), D-glycine (D-). Gly), D-aspartic acid (D-Asp), D-glutamic acid (D-Glu), D-alanine (D-Ala), D-valine (D-Val), D-phenylalanine (D-Phe), D -Leucine (D-Leu), D-tyrosine (D-Tyr), D-cysteine (D-Cys), D-tryptophan (D-Trp), D-citrulline (D-CIT), D-carnosine (D-). CARN). For the embodiments described herein, the amino acids are either through their α-amino and carboxy functional groups (ie, in peptide-bonded form) or through their side chain functional groups (eg, side chain carboxy groups in glutamic acid). , And their covalent bonds to other moieties of the conjugates described herein via either one of their α-amino or carboxy functional groups. It is understood that when used with respect to the conjugates described herein, the amino acids can exist as zwitterions in the conjugates in which they are included.

を含む。 As used herein, "sugar" refers to a hydrocarbon such as a monosaccharide, disaccharide or oligosaccharide. Monosaccharides are preferred for the present invention. Non-limiting examples of sugars include erythrose, threlose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, galactose, ribulose, fructose, sorbose, tagarose and the like. The sugars used in the context of the present invention are understood to include the cyclic isomers of amino sugars, deoxy sugars, acidic sugars and combinations thereof. Non-limiting examples of such sugars include galactosamine, glucosamine, deoxyribose, fucose, rhamnose, glucuronic acid, ascorbic acid and the like. In some embodiments, the sugar for use with the present invention is

including.

As used herein, a "prodrug" can be administered to a subject in a pharmacologically inactive form that can then be converted to the active form through normal metabolic processes, such as hydrolysis of oxazolidine. Refers to a compound. It is understood that the metabolic processes by which a prodrug can be converted to an active drug include, but are not limited to, one or more spontaneous chemical reactions, enzyme-catalyzed chemical reactions and/or other metabolic chemical reactions and combinations thereof. It is understood that many metabolic processes are known in the art and the metabolic processes by which the prodrugs described herein are converted to the active drug are not limiting. A prodrug can be a precursor or compound of a drug that has a therapeutic effect on the subject.

The term “therapeutically effective amount” as used herein includes, but is not limited to, treatment in a subject (ie, a tissue system, animal or human) being examined by a researcher, veterinarian, doctor or other clinician. Refers to the amount of a drug or drug substance that elicits a biological or pharmaceutical response, including alleviation of the symptoms of the disease or disorder in which it is present. In one aspect, therapeutically effective amount is an amount of active agent that can alleviate the disease or symptoms of the disease with a reasonable benefit/risk ratio applicable to any medical procedure. In another aspect, a therapeutically effective amount is an amount of an inactive prodrug that, when converted through normal metabolic processes, produces an amount of active drug that can elicit the sought biological or pharmaceutical response in a subject. Is.

Regardless of monotherapy or combination therapy, the dose is also to be advantageously selected with reference to any toxic or other undesired side effects that may occur during the administration of one or more of the conjugates described herein. To be done. Furthermore, the co-therapy described herein allows the administration of conjugates that exhibit such toxicity or other undesirable side effects in low doses, which are below the threshold of toxicity, or It is understood to be in a lower therapeutic window than would otherwise be administered in the absence of co-therapy.

As used herein, “administration” includes, but is not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, intraocular, sublingual. , Vaginal, rectal, etc., and all methods for introducing the conjugates and compositions described herein into a host animal. The conjugates and compositions described herein may be administered in unit dosage forms and/or formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and/or solvents.

As used herein, "pharmaceutical composition" or "composition" refers to one or more conjugates described herein or pharmaceutically acceptable salts, solvates, hydrates, It refers to a mixture with other chemical components such as acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the conjugate to a subject. Pharmaceutical compositions suitable for delivery of the described conjugates and methods of making them are readily apparent to those of ordinary skill in the art. Such compositions and methods for their manufacture are found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).

"Pharmaceutically acceptable excipient" refers to an inert substance, such as a diluent or carrier, that is added to pharmaceutical compositions to further facilitate administration.

Detailed Description In each of the above and each of the following embodiments, the formula includes and represents not only all pharmaceutically acceptable salts of the conjugate, but also any and all hydrates of the conjugate formula and/or Also includes solvates. It is understood that certain functional groups such as hydroxy, amino, etc. form complexes and/or coordination conjugates with water and/or different solvents in different physical forms of the conjugate. Therefore, the above formulas should be understood to include and represent the various hydrate and/or solvate formulas. It should also be understood that the conjugated non-hydrates and/or unsolvates are represented by such formulas, and the conjugated hydrates and/or solvates are also the same. ..

The conjugates described herein can be represented by the general notation B, L and a drug (Drug), where B is a cell surface receptor binding ligand (aka "binding ligand") and L is a linker that may include a releasable moiety. (Ie a releasable linker) and L may be represented by one or more of the groups defined herein, AA, L ¹ , L ² , L ³ , L ⁴ or L ⁵ , and the drug (Drug) is Represents one or more drugs (eg, D ¹ and D ² ) covalently attached to a conjugate.

Conjugates described herein include, but are not limited to, the formula ^{_{B- (AA) z1 -L 2 -}} (L 3) z2 - (AA) z3 - (L 1) z4 - (L 4) z5 -D 1 -L ⁵ -D ^{2
B-L 1 -AA-L 1} -AA-L 1 -L 2 - (L 3) z6 - (L 4) z7 - (AA) z8 - (L 4) z9 -D 1 -L 5 -D 2
^{_{B- (AA) z10 -L 2 -D}} 2
^{_{B- (AA) z11 -L 2 -D}} 1 -L 5 -D 1 -L 2 - (AA) z12 -B
^{_{B- (AA) 4 -L 2 -D}} 1 -L 5 -D 2
^{_{B- (AA) 4 -L 2 -L}} 3 -AA-L 1 -L 4 -D 1 -L 5 -D 2
^{_{B- (AA) 4 -L 2 -L}} 3 - (AA) 2 -D 1 -L 5 -D 2
^{_{B- (AA) 4 -L 2 -D}} 2
^{_{B- (AA) 4 -L 2 -D}} 1 -L 5 -D 1 -L 2 - (AA) 4 -B
^{B-L 1 -AA-L 1} -AA-L 1 -L 2 -D 1 -L 5 -D 2
^{B-L 1 -AA-L 1} -AA-L 1 -L 2 -L 3 - (AA) 2 -L 4 -D 1 -L 5 -D 2
^{B-L 1 -AA-L 1} -AA-L 1 -L 2 -L 3 -L 4 - (AA) 2 -L 4 -D 1 -L 5 -D 2
^{B-L 1 -AA-L 1} -AA-L 1 -L 2 -L 3 -L 4 -D 1 -L 5 -D 2
^{B-L 1 -AA-L 1} -AA-L 1 -L 2 -L 3 - (AA) 2 -D 1 -L 5 -D 2
^{B-L 1 -AA-L 1} -AA-L 1 -L 2 -L 3 -D 1 -L 5 -D 2
[In the formula,
B, AA, L ¹ , L ² , L ³ , L ⁴ , L ⁵ , D ¹ and D ² are defined by various embodiments described herein, and z 1 is 2, 3, 4 or 5. ;
z2 is 0, 1 or 2;
z3 is 0, 1, 2, 3 or 4;
z4 is 0, 1 or 2;
z5 is 0, 1 or 2;
y1 is 0, 1 or 2; y2 is 0, 1 or 2; y3 is 0, 1, 2, 3 or 4; and y4 is 0, 1 or 2]
Can be defined according to various aspects including.

As used herein, the term cell surface receptor binding ligand (also known as "binding ligand") refers to a receptor commonly found on cell surfaces, particularly those found on the surface of pathogenic cells, overexpressed and/or predominantly. Refers to compounds that bind and/or target specifically expressed receptors. Specific ligands include, but are not limited to, vitamins and vitamin receptor binding compounds.

Specific vitamin moieties include carnitine, inositol, lipoic acid, pyridoxal, ascorbic acid, niacin, pantothenic acid, folic acid, riboflavin, thiamine, biotin, vitamin B ₁₂ and fat-soluble vitamins A, D, E and K. These vitamins and their receptor binding analogs and derivatives constitute targeting agents that are covalently attached to a linker. Specific biotin analogs that bind to the biotin receptor include, but are not limited to, biotin, biotin sulfoxide, oxybiotin, and the like.

〔式中、
各場合において、Ｒ^１およびＲ^２は、独立してＨ、Ｄ、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、−ＯＲ^７、−ＳＲ^７および−ＮＲ^７Ｒ^７’から成る群から選択され、ここで水素原子Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニルおよびＣ_２〜Ｃ_６アルキニルにおける各水素原子は、独立して、場合により、ハロゲン、−ＯＲ^８、−ＳＲ^８、−ＮＲ^８Ｒ^８’、−Ｃ（Ｏ）Ｒ^８、−Ｃ（Ｏ）ＯＲ^８または−Ｃ（Ｏ）ＮＲ^８Ｒ^８’により置換されていてよく；
Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は、それぞれ独立してＨ、Ｄ、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、−ＣＮ、−ＮＯ_２、−ＮＣＯ、−ＯＲ^９、−ＳＲ^９、−ＮＲ^９Ｒ^９’、−Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＯＲ^９および−Ｃ（Ｏ）ＮＲ^９Ｒ^９’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニルおよびＣ_２〜Ｃ_６アルキニルにおける各水素原子は、独立して、場合により、ハロゲン、−ＯＲ^１０、−ＳＲ^１０、−ＮＲ^１０Ｒ^１０’、−Ｃ（Ｏ）Ｒ^１０、−Ｃ（Ｏ）ＯＲ^１０または−Ｃ（Ｏ）ＮＲ^１０Ｒ^１０’により置換されていてよく；
Ｒ^７、Ｒ^７’、Ｒ^８、Ｒ^８’、Ｒ^９、Ｒ^９’、Ｒ^１０およびＲ^１０’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニルまたはＣ_２〜Ｃ_６アルキニルであり；
Ｘ^１は−ＮＲ^１１−、＝Ｎ−、−Ｎ＝、−Ｃ（Ｒ^１１）＝または＝Ｃ（Ｒ^１１）−であり；
Ｘ^２は−ＮＲ^１１’−または＝Ｎ−であり；
Ｘ^３は−ＮＲ^１１’’−、−Ｎ＝または−Ｃ（Ｒ^１１’）＝であり；
Ｘ^４は−Ｎ＝または−Ｃ＝であり；
Ｘ^５はＮＲ^１２またはＣＲ^１２Ｒ^１２’であり；
Ｘ^１が−Ｎ＝または−Ｃ（Ｒ^１１）＝のとき、Ｙ^１はＨ、Ｄ、−ＯＲ^１３、−ＳＲ^１３または−ＮＲ^１３Ｒ^１３’であり、または
Ｘ^１が−ＮＲ^１１−、＝Ｎ−または＝Ｃ（Ｒ^１１）−のとき、Ｙ^１は＝Ｏであり；
Ｘ^４が−Ｃ＝のとき、Ｙ^２はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、−Ｃ（Ｏ）Ｒ^１４、−Ｃ（Ｏ）ＯＲ^１４、−Ｃ（Ｏ）ＮＲ^１４Ｒ^１４’であり、または
Ｘ^４が−Ｎ＝のとき、Ｙ^２は存在せず；
Ｒ^１１、Ｒ^１１’、Ｒ^１１’’、Ｒ^１２、Ｒ^１２’、Ｒ^１３、Ｒ^１３’、Ｒ^１４およびＲ^１４’はそれぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、−Ｃ（Ｏ）Ｒ^１５、−Ｃ（Ｏ）ＯＲ^１５および−Ｃ（Ｏ）ＮＲ^１５Ｒ^１５’から成る群から選択され；
Ｒ^１５およびＲ^１５’は、それぞれ独立してＨまたはＣ_１〜Ｃ_６アルキルであり；
ｍは１、２、３または４であり；そして
＊は共有結合である〕
のものである。 In some embodiments B is folic acid or a derivative thereof. In some embodiments, B is of formula I

[In the formula,
In each case R ¹ and R ² are independently H, D, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, —OR ⁷ , —SR ⁷ and —. Each hydrogen atom in a hydrogen atom C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl selected from the group consisting of NR ⁷ R ^7′ , independently, optionally halogen; ^{, -OR 8, -SR 8, -NR} 8 R 8 may be substituted by ^{', -C (O) R 8} , -C (O) oR 8 or ^{-C (O) NR 8 R 8} ';
R ^{3, R} 4, ^{R 5} and ^{R 6,} H independently, D, _halogen, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl, -CN, -NO ₂ , selection ^{-NCO, -OR 9, -SR 9,} -NR 9 R 9 from a group consisting of ^{', -C (O) R 9} , -C (O) oR 9 and ^{-C (O) NR 9 R 9} ' Where each hydrogen atom in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl is independently, optionally, halogen, —OR ¹⁰ , —SR ¹⁰ , —NR ^{10. R 10 ', -C (O)} R 10, -C (O) oR 10 or ^{-C (O) NR 10 R 10} ' may be substituted by;
^{R 7, R 7 ', R} 8, R 8', R 9, R 9 ', R 10 and ^{R 10'} is, H _{independently, D,} C 1 ~C _{6 alkyl,} C 2 -C ₆ alkenyl Or C ₂ -C ₆ alkynyl;
X ¹ is ^{-NR 11 -, = N -,} - N =, - C (R 11) = or = C ^{(R 11)} - a and;
X ² is -NR ^{11 '-} or = a N-;
X ³ is ^{-NR 11 '' -, - N} = or -C ^{(R 11 ')} = a and;
X ⁴ is -N= or -C=;
X ⁵ is NR ¹² or CR ¹² R ^12′ ;
When X ¹ is -N= or -C(R ¹¹ )=, Y ¹ is H, D, -OR ¹³ , -SR ¹³ or -NR ¹³ R ^13' , or X ¹ is -NR ¹¹ -, When =N- or =C(R< ¹¹ >)-, Y< ¹ > is =O;
When X ⁴ is -C = a, ^{Y 2} is _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C ₆ ^{alkenyl, -C (O) R 14,} -C (O) OR 14, -C (O ) a ^{NR 14 R} 14 ^', or when ^{X 4} is -N =, ^{Y 2} is absent;
R ¹¹ , R ^11′ , R ^11″ , R ¹² , R ^12′ , R ¹³ , R ^13′ , R ¹⁴ and R ^14′ are each independently H, D, C ₁ -C ₆ alkyl or —C. ^(O) R 15, is selected from the group consisting of -C (O) ^{oR 15} and ^{-C (O) NR 15 R 15} ';
R ¹⁵ and R ^15′ are each independently H or C ₁ -C ₆ alkyl;
m is 1, 2, 3 or 4; and * is a covalent bond]
belongs to.

またはＩｂ

〔式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｙ^１、Ｙ^２、Ｘ^１、Ｘ^２、Ｘ^３、Ｘ^４、Ｘ^５、ｍおよび＊の各々は、式Ｉについて定義されている通りである〕
のものである。 When B is represented according to formula I, it is understood that both D and L forms are contemplated. In some embodiments, B has the formula Ia

Or Ib

[In the formula,
Each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y ¹ , Y ² , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , m and * is defined for formula I. It is as it is done]
belongs to.

〔式中、
＊は式Ｉについて定義されている通りである〕
のものである。 In some embodiments described herein, R ¹ and R ² are H. In some aspects described herein, m is 1. In some embodiments described herein, R ³ is H. In some embodiments described herein, R ⁴ is H. In some embodiments described herein, R ⁵ is H. In some embodiments described herein, R ⁶ is H. In some embodiments described herein, R ³ , R ⁴ , R ⁵ and R ⁶ are H. In some embodiments described herein, X ¹ is -NR ¹¹ and R ¹¹ is H. In some embodiments described herein, X ² is = a N-. In some embodiments described herein, X ³ is -N =. In some embodiments described herein, X ⁴ is -N =. In some embodiments described herein, X ¹ is -NR ¹¹ and R ¹¹ is H; X ² is =N-; X ³ is -N=; and X ⁴ Is -N=. In some embodiments described herein, X ⁵ is NR ¹² and R ¹² is H. In some embodiments, Y ¹ is =0. In some embodiments, Y ² is absent. In some embodiments, B has the formula Ic

[In the formula,
* Is as defined for formula I]
belongs to.

〔式中、
＊は式Ｉについて定義されている通りである〕
のものである。 In some embodiments, B has the formula Id

[In the formula,
* Is as defined for formula I]
belongs to.

またはその薬学的に許容される塩であると理解される。 In some embodiments, the conjugates described herein have an exemplary formula

Alternatively, it is understood to be a pharmaceutically acceptable salt thereof.

The linker for B and the drug (Drug) attached in the conjugates described herein may be represented by the groups AA, L ¹ , L ² , L ³ , L ⁴ or L ⁵ .

AA is an amino acid as defined herein. In some embodiments, AA is a naturally occurring amino acid. In some embodiments, AA is L-type. In some embodiments, AA is type D. It is understood that in certain embodiments, the conjugates described herein include one or more amino acids as part of the linker, the amino acids can be the same or different, and can be selected from the group of amino acids. It is understood that in some embodiments, the conjugates described herein include one or more amino acids as part of a linker, the amino acids can be the same or different, and can be selected from the group of D or L amino acids. To be done. In some embodiments, each AA is independently L-lysine, L-asparagine, L-threonine, L-serine, L-isoleucine, L-methionine, L-proline, L-histidine, L-glutamine, L -Arginine, L-glycine, L-aspartic acid, L-glutamic acid, L-alanine, L-valine, L-phenylalanine, L-leucine, L-tyrosine, L-cysteine, L-tryptophan, L-phosphoserine, L- Sulfo-cysteine, L-arginosuccinic acid, L-hydroxyproline, L-phosphoethanolamine, L-sarcosine, L-taurine, L-carnosine, L-citrulline, L-anserine, L-1,3-methyl-histidine, L-α-amino-adipic acid, D-lysine, D-asparagine, D-threonine, D-serine, D-isoleucine, D-methionine, D-proline, D-histidine, D-glutamine, D-arginine, D -A group consisting of glycine, D-aspartic acid, D-glutamic acid, D-alanine, D-valine, D-phenylalanine, D-leucine, D-tyrosine, D-cysteine, D-tryptophan, D-citrulline and D-carnosine. Selected from.

In some embodiments, each AA is independently L-asparagine, L-arginine, L-glycine, L-aspartic acid, L-glutamic acid, L-glutamine, L-cysteine, L-alanine, L-valine, L-leucine, L-isoleucine, L-citrulline, D-asparagine, D-arginine, D-glycine, D-aspartic acid, D-glutamic acid, D-glutamine, D-cysteine, D-alanine, D-valine, D Selected from the group consisting of leucine, D-isoleucine and D-citrulline. In some embodiments, each AA is independently selected from the group consisting of Asp, Arg, Val, Ala, Cys and CIT. In some embodiments, each AA is independently selected from the group consisting of Asp, Arg, Val, Ala, D-Cys and CIT. In some embodiments, each AA is independently selected from the group consisting of Asp, Arg, Val, Ala and CIT. In some embodiments, z1 is 4 and the sequence of AA therein is -Asp-Arg-Asp-Asp-. In some embodiments, z3 is 2 and the sequence of AA therein is Val-Ala. In some embodiments, z3 is 2 and the sequence of AA therein is Val-CIT. In some embodiments, z1 is 4, the sequence of AA therein is -Asp-Arg-Asp-Asp-, and z3 is 2 and the sequence of AA therein is Val-Ala. .. In some embodiments, z1 is 4 and the sequence of AA therein is -Asp-Arg-Asp-Asp-, and z3 is 2 and the sequence of AA therein is Val-CIT.

In some embodiments, z8 is 3. In some embodiments, z8 is 2. In some embodiments, z8 is 2 and the sequence of AA therein is Val-Ala. In some embodiments, z10 is 5. In some embodiments, z10 is 4. In some embodiments, z10 is 3. In some embodiments, z10 is 4 and the sequence of AA therein is -Asp-Arg-Asp-Asp-. In some embodiments, z11 is 5. In some embodiments, z11 is 4. In some embodiments, z11 is 3. In some embodiments, z11 is 4 and the sequence of AA therein is -Asp-Arg-Asp-Asp-. In some embodiments, z12 is 5. In some embodiments, z12 is 4. In some embodiments, z12 is 3. In some embodiments, z12 is 4 and the sequence of AA therein is -Asp-Asp-Arg-Asp-. In some embodiments, z11 is 4 and z12 is 4. In some embodiments, z11 is 4 and the sequence of AA therein is -Asp-Arg-Asp-Asp- and z12 is 4 and the sequence of AA therein is -Asp-Asp-. Arg-Asp-. In some embodiments, z8 is 2 and the sequence of AA is -Glu-Glu-, where the amino acids are ar covalently linked at their α-amino functional group and side chain carboxylic acid.

〔式中、
Ｒ^１６はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、−Ｃ（Ｏ）Ｒ^１９、−Ｃ（Ｏ）ＯＲ^１９および−Ｃ（Ｏ）ＮＲ^１９Ｒ^１９’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニルおよびＣ_２〜Ｃ_６アルキニルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、およびＣ_２〜Ｃ_６アルキニル、−ＯＲ^２０、−ＯＣ（Ｏ）Ｒ^２０、−ＯＣ（Ｏ）ＮＲ^２０Ｒ^２０’、−ＯＳ（Ｏ）Ｒ^２０、−ＯＳ（Ｏ）_２Ｒ^２０、−ＳＲ^２０、−Ｓ（Ｏ）Ｒ^２０、−Ｓ（Ｏ）_２Ｒ^２０、−Ｓ（Ｏ）ＮＲ^２０Ｒ^２０’、−Ｓ（Ｏ）_２ＮＲ^２０Ｒ^２０’、−ＯＳ（Ｏ）ＮＲ^２０Ｒ^２０’、−ＯＳ（Ｏ）_２ＮＲ^２０Ｒ^２０’、−ＮＲ^２０Ｒ^２０’、−ＮＲ^２０Ｃ（Ｏ）Ｒ^２１、−ＮＲ^２０Ｃ（Ｏ）ＯＲ^２１、−ＮＲ^２０Ｃ（Ｏ）ＮＲ^２１Ｒ^２１’、−ＮＲ^２０Ｓ（Ｏ）Ｒ^２１、−ＮＲ^２０Ｓ（Ｏ）_２Ｒ^２１、−ＮＲ^２０Ｓ（Ｏ）ＮＲ^２１Ｒ^２１’、−ＮＲ^２０Ｓ（Ｏ）_２ＮＲ^２１Ｒ^２１’、−Ｃ（Ｏ）Ｒ^２０、−Ｃ（Ｏ）ＯＲ^２０または−Ｃ（Ｏ）ＮＲ^２０Ｒ^２０’により置換されていてよく；
Ｒ^１７およびＲ^１７’は、それぞれ独立してＨ、Ｄ、ハロゲン、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^２２、−ＯＣ（Ｏ）Ｒ^２２、−ＯＣ（Ｏ）ＮＲ^２２Ｒ^２２’、−ＯＳ（Ｏ）Ｒ^２２、−ＯＳ（Ｏ）_２Ｒ^２２、−ＳＲ^２２、−Ｓ（Ｏ）Ｒ^２２、−Ｓ（Ｏ）_２Ｒ^２２、−Ｓ（Ｏ）ＮＲ^２２Ｒ^２２’、−Ｓ（Ｏ）_２ＮＲ^２２Ｒ^２２’、−ＯＳ（Ｏ）ＮＲ^２２Ｒ^２２’、−ＯＳ（Ｏ）_２ＮＲ^２２Ｒ^２２’、−ＮＲ^２２Ｒ^２２’、−ＮＲ^２２Ｃ（Ｏ）Ｒ^２３、−ＮＲ^２２Ｃ（Ｏ）ＯＲ^２３、−ＮＲ^２２Ｃ（Ｏ）ＮＲ^２３Ｒ^２３’、−ＮＲ^２２Ｓ（Ｏ）Ｒ^２３、−ＮＲ^２２Ｓ（Ｏ）_２Ｒ^２３、−ＮＲ^２２Ｓ（Ｏ）ＮＲ^２３Ｒ^２３’、−ＮＲ^２２Ｓ（Ｏ）_２ＮＲ^２３Ｒ^２３’、−Ｃ（Ｏ）Ｒ^２２、−Ｃ（Ｏ）ＯＲ^２２および−Ｃ（Ｏ）ＮＲ^２２Ｒ^２２’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、置換されていてよくハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、−ＯＲ^２４、−ＯＣ（Ｏ）Ｒ^２４、−ＯＣ（Ｏ）ＮＲ^２４Ｒ^２４’、−ＯＳ（Ｏ）Ｒ^２４、−ＯＳ（Ｏ）_２Ｒ^２４、−ＳＲ^２４、−Ｓ（Ｏ）Ｒ^２４、−Ｓ（Ｏ）_２Ｒ^２４、−Ｓ（Ｏ）ＮＲ^２４Ｒ^２４’、−Ｓ（Ｏ）_２ＮＲ^２４Ｒ^２４’、−ＯＳ（Ｏ）ＮＲ^２４Ｒ^２４’、−ＯＳ（Ｏ）_２ＮＲ^２４Ｒ^２４’、−ＮＲ^２４Ｒ^２４’、−ＮＲ^２４Ｃ（Ｏ）Ｒ^２５、−ＮＲ^２４Ｃ（Ｏ）ＯＲ^２５、−ＮＲ^２４Ｃ（Ｏ）ＮＲ^２５Ｒ^２５’、−ＮＲ^２４Ｓ（Ｏ）Ｒ^２５、−ＮＲ^２４Ｓ（Ｏ）_２Ｒ^２５、−ＮＲ^２４Ｓ（Ｏ）ＮＲ^２５Ｒ^２５’、−ＮＲ^２４Ｓ（Ｏ）_２ＮＲ^２５Ｒ^２５’、−Ｃ（Ｏ）Ｒ^２４、−Ｃ（Ｏ）ＯＲ^２４または−Ｃ（Ｏ）ＮＲ^２４Ｒ^２４’により置換されていてよく；または
Ｒ^１７およびＲ^１７’は、結合してＣ_４〜Ｃ_６シクロアルキルまたは４〜６員環ヘテロ環を形成し、ここでＣ_４〜Ｃ_６シクロアルキルまたは４〜６員環ヘテロ環における各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^２４、−ＯＣ（Ｏ）Ｒ^２４、−ＯＣ（Ｏ）ＮＲ^２４Ｒ^２４’、−ＯＳ（Ｏ）Ｒ^２４、−ＯＳ（Ｏ）_２Ｒ^２４、−ＳＲ^２４、−Ｓ（Ｏ）Ｒ^２４、−Ｓ（Ｏ）_２Ｒ^２４、−Ｓ（Ｏ）ＮＲ^２４Ｒ^２４’、−Ｓ（Ｏ）_２ＮＲ^２４Ｒ^２４’、−ＯＳ（Ｏ）ＮＲ^２４Ｒ^２４’、−ＯＳ（Ｏ）_２ＮＲ^２４Ｒ^２４’、−ＮＲ^２４Ｒ^２４’、−ＮＲ^２４Ｃ（Ｏ）Ｒ^２５、−ＮＲ^２４Ｃ（Ｏ）ＯＲ^２５、−ＮＲ^２４Ｃ（Ｏ）ＮＲ^２５Ｒ^２５’、−ＮＲ^２４Ｓ（Ｏ）Ｒ^２５、−ＮＲ^２４Ｓ（Ｏ）_２Ｒ^２５、−ＮＲ^２４Ｓ（Ｏ）ＮＲ^２５Ｒ^２５’、−ＮＲ^２４Ｓ（Ｏ）_２ＮＲ^２５Ｒ^２５’、−Ｃ（Ｏ）Ｒ^２４、−Ｃ（Ｏ）ＯＲ^２４または−Ｃ（Ｏ）ＮＲ^２４Ｒ^２４’により置換されていてよく； In the conjugates described herein, L ¹ may or may not be present. When L ¹ is present, L ¹ can be any group that covalently attaches the linker moiety to the binding ligand, the linker moiety to each other or to D ¹ or D ² . It is understood that the structure of L ¹ is not particularly limited in any method. Furthermore, L ¹ is understood to include a number of functional groups well known to those skilled in the art which covalently attach the linker moiety to the binding ligand, the linker moiety to each other or to D ¹ or D ² , including but not limited to alkyl groups, It includes an ether group, an amide group, a carboxy group, a sulfonic acid group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heterocycloalkyl, a heteroaryl group and the like. In some embodiments, L ¹ is of formula II

[In the formula,
R ¹⁶ is H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, —C(O)R ¹⁹ , —C(O)OR ¹⁹ and —C(O)NR. Each hydrogen atom in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl selected from the group consisting of ¹⁹ R ^{19 ′} , independently, optionally halogen, C ₁ -C _{6 alkyl,} C 2 -C ₆ alkenyl, and _C 2 -C ₆ ^{alkynyl, -OR 20, -OC (O)} R 20, -OC (O) NR 20 R 20 ', -OS (O) R 20 _{^{, -OS (O) 2 R 20}} , -SR 20, -S (O) R 20, -S (O) 2 R 20, -S (O) NR 20 R 20 ', -S (O) 2 NR 20 ^{R 20 ', -OS (O)} NR 20 R 20', -OS (O) 2 NR 20 R 20 ', -NR 20 R 20', -NR 20 C (O) R 21, -NR 20 C (O ^{) OR 21, -NR 20 C (} O) NR 21 R 21 ', -NR 20 S (O) R 21, -NR 20 S (O) 2 R 21, -NR 20 S (O) NR 21 R 21' _{^{, -NR 20 S (O) 2}} NR 21 R 21 may be substituted by ^{', -C (O) R 20} , -C (O) oR 20 or ^{-C (O) NR 20 R 20} ';
R ¹⁷ and ^{R 17 'is,} H independently, D, _halogen, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 22, -OC (O)} R 22, -OC (O) NR 22 R 22 ', -OS (O) R _{^{22, -OS (O) 2 R}} 22, -SR 22, -S (O) R 22, -S (O) 2 R 22, -S (O) NR 22 R 22 ', -S (O) 2 NR ^{22 R 22 ', -OS (O} ) NR 22 R 22', -OS (O) 2 NR 22 R 22 ', -NR 22 R 22', -NR 22 C (O) R 23, -NR 22 C ( ^{O) OR 23, -NR 22 C} (O) NR 23 R 23 ', -NR 22 S (O) R 23, -NR 22 S (O) 2 R 23, -NR 22 S (O) NR 23 R 23 _{^{', -NR 22 S (O)}} 2 NR 23 R 23', are selected from the group consisting of ^{-C (O) R 22, -C} (O) oR 22 and ^{-C (O) NR 22 R 22} ', wherein in _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5- to 7-membered Each hydrogen atom in a ring heteroaryl is independently optionally substituted halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, —OR ²⁴ , —OC. ^{(O) R 24, -OC (} O) NR 24 R 24 ', -OS (O) R 24, -OS (O) 2 R 24, -SR 24, -S (O) R 24, -S (O _{^{) 2 R 24, -S (O}} ) NR 24 R 24 ', -S (O) 2 NR 24 R 24', -OS (O) NR 24 R 24 ', -OS (O) 2 NR 24 R 24' ^{, -NR 24 R 24 ', -NR} 24 C (O) R 25, -NR 24 C (O) OR 25, -NR 24 C (O) NR 25 R 25', -NR 24 S (O) R 25 , -NR ²⁴ S(O) ₂ R ²⁵ , -NR ^24. S(O)NR ²⁵ R ^25' , -NR ²⁴ S(O) ₂ NR ²⁵ R ^25' , -C(O)R ²⁴ , -C(O)OR ²⁴ or -C(O)NR ²⁴ R ^24'. Or R ¹⁷ and R ^17′ are joined to form a C ₄ -C ₆ cycloalkyl or a 4-6 membered heterocycle, wherein C ₄ -C ₆ cycloalkyl or 4 each hydrogen atom in the six-membered ring heterocycle is independently optionally _halogen, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3 To 7-membered ring heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7-membered ring heteroaryl, -OR ²⁴ , -OC(O)R ²⁴ , -OC(O)NR ²⁴ R ^24' , -OS(O. _{^{) R 24, -OS (O)}} 2 R 24, -SR 24, -S (O) R 24, -S (O) 2 R 24, -S (O) NR 24 R 24 ', -S (O) _{^{2 NR 24 R 24 ', -OS}} (O) NR 24 R 24', -OS (O) 2 NR 24 R 24 ', -NR 24 R 24', -NR 24 C (O) R 25, -NR 24 C(O)OR ²⁵ , -NR ²⁴ C(O)NR ²⁵ R ^25' , -NR ²⁴ S(O)R ²⁵ , -NR ²⁴ S(O) ₂ R ²⁵ , -NR ²⁴ S(O)NR ^{25. _{R 25 ', -NR 24 S (}} O) 2 NR 25 R 25', -C (O) R 24, may be replaced by -C (O) ^{oR 24} or ^{-C (O) NR 24 R 24} ';

R ¹⁸ is _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 26, -OC (O)} R 26, -OC (O) NR 26 R 26 ', -OS (O) R 26, -OS (O) 2 R 26, _{^{-SR 26, -S (O) R}} 26, -S (O) 2 R 26, -S (O) NR 26 R 26 ', -S (O) 2 NR 26 R 26', -OS (O) NR _{^{26 R 26 ', -OS (O}} ) 2 NR 26 R 26', -NR 26 R 26 ', -NR 26 C (O) R 27, -NR 26 C (O) OR 27, -NR 26 C (O ^{) NR 27 R 27 ', -NR} 26 C (= NR 26'') NR 27 R 27', -NR 26 S (O) R 27, -NR 26 S (O) 2 R 27, -NR 26 S ( ^{O) NR 27 R} 27 consists of _{^{', -NR 26 S (O)}} 2 NR 27 R 27', -C (O) R 26, -C (O) oR 26 and ^{-C (O) NR 26 R 26} ' is selected from the group, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} Each hydrogen atom in aryl and 5-7 membered heteroaryl is optionally halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -(CH ₂ ) _p OR ²⁸ , -(CH. _{2) p (OCH 2) q} OR 28, - (CH 2) p (OCH 2 CH 2) q OR 28, -OR 29, -OC (O) R 29, -OC (O) NR 29 R 29 ', _{^{-OS (O) R 29, -OS}} (O) 2 R 29, - (CH 2) p OS (O) 2 OR 29, -OS (O) 2 OR 29, -SR 29, -S (O) R _{^{29, -S (O) 2 R}} 29, -S (O) NR 29 R 29 ', -S (O) 2 NR 29 R 29', -OS (O) NR 29 R 29 ', -OS (O) ₂ NR ²⁹ R ^29' , -NR ^{29 R 29 ', -NR 29 C (} O) R 30, -NR 29 C (O) OR 30, -NR 29 C (O) NR 30 R 30', -NR 29 S (O) R 30, -NR 29 _{^{S (O) 2 R 30,}} -NR 29 S (O) NR 30 R 30 ', -NR 29 S (O) 2 NR 30 R 30', -C (O) R 29, -C (O) OR 29 Or optionally substituted by -C(O)NR ²⁹ R ^29' ;
R ¹⁹ , R ^19′ , R ²⁰ , R ^20′ , R ²¹ , R ^21′ , R ²² , R ^22′ , R ²³ , R ^23′ , R ²⁴ , R ^24′ , R ²⁵ , R ^25′ , R ²⁶ , R ^26′ , R ^26″ , R ²⁹ , R ^29′ , R ³⁰ and R ^30′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C. ₂ -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, is selected from the group consisting of 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl, wherein _C 1 -C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} each of the C 6 _{-C 10} aryl, or 5-7 membered heteroaryl hydrogen atoms are independently optionally halogen, -OH, -SH, it may be substituted by -NH ₂ or -CO ₂ H;
R ²⁷ and R ^27′ are each independently H, C ₁ -C ₉ alkyl, C ₂ -C ₉ alkenyl, C ₂ -C ₉ alkynyl, C ₃ -C ₆ cycloalkyl, —(CH ₂ ) _p ( _{sugar), - (CH 2) p} (OCH 2 CH 2) q - ( sugar) and _{- (CH 2) p (OCH} 2 CH 2 CH 2) is selected from the group consisting of _q (sugars);
R ²⁸ is H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C _10. Aryl, 5-7 membered heteroaryl or sugar;
n is 1, 2, 3, 4 or 5;
p is 1, 2, 3, 4 or 5;
q is 1, 2, 3, 4 or 5; and * is a covalent bond]
Is a linker of.

またはIIb

〔式中、
Ｒ^１６、Ｒ^１７、Ｒ^１７’、Ｒ^１８、ｎおよび＊のそれぞれは、式IIで定義されている通りである〕
である。 When L ¹ is represented according to formula II, it is understood that both R-configuration and S-configuration are contemplated. In some embodiments, L ¹ is of formula IIa

Or IIb

[In the formula,
Each of R ¹⁶ , R ¹⁷ , R ^17′ , R ¹⁸ , n and * is as defined in Formula II]
Is.

〔式中、
Ｒ^１６はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、−Ｃ（Ｏ）Ｒ^１９、−Ｃ（Ｏ）ＯＲ^１９および−Ｃ（Ｏ）ＮＲ^１９Ｒ^１９’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニルおよびＣ_２〜Ｃ_６アルキニルにおける各水素原子は、独立して、場合により、置換ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニルおよびＣ_２〜Ｃ_６アルキニル、−ＯＲ^２０、−ＯＣ（Ｏ）Ｒ^２０、−ＯＣ（Ｏ）ＮＲ^２０Ｒ^２０’、−ＯＳ（Ｏ）Ｒ^２０、−ＯＳ（Ｏ）_２Ｒ^２０、−ＳＲ^２０、−Ｓ（Ｏ）Ｒ^２０、−Ｓ（Ｏ）_２Ｒ^２０、−Ｓ（Ｏ）ＮＲ^２０Ｒ^２０’、−Ｓ（Ｏ）_２ＮＲ^２０Ｒ^２０’、−ＯＳ（Ｏ）ＮＲ^２０Ｒ^２０’、−ＯＳ（Ｏ）_２ＮＲ^２０Ｒ^２０’、−ＮＲ^２０Ｒ^２０’、−ＮＲ^２０Ｃ（Ｏ）Ｒ^２１、−ＮＲ^２０Ｃ（Ｏ）ＯＲ^２１、−ＮＲ^２０Ｃ（Ｏ）ＮＲ^２１Ｒ^２１’、−ＮＲ^２０Ｓ（Ｏ）Ｒ^２１、−ＮＲ^２０Ｓ（Ｏ）_２Ｒ^２１、−ＮＲ^２０Ｓ（Ｏ）ＮＲ^２１Ｒ^２１’、−ＮＲ^２０Ｓ（Ｏ）_２ＮＲ^２１Ｒ^２１’、−Ｃ（Ｏ）Ｒ^２０、−Ｃ（Ｏ）ＯＲ^２０または−Ｃ（Ｏ）ＮＲ^２０Ｒ^２０’により置換されていてよく； In some embodiments, each L ¹ is

[In the formula,
R ¹⁶ is H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, —C(O)R ¹⁹ , —C(O)OR ¹⁹ and —C(O)NR. Each hydrogen atom in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl is independently selected from the group consisting of ¹⁹ R ^{19 ′,} each optionally substituted halogen, C ₁ -C _{6 alkyl,} C 2 -C ₆ alkenyl and _C 2 -C ₆ ^{alkynyl, -OR 20, -OC (O)} R 20, -OC (O) NR 20 R 20 ', -OS (O) R 20 _{^{, -OS (O) 2 R 20}} , -SR 20, -S (O) R 20, -S (O) 2 R 20, -S (O) NR 20 R 20 ', -S (O) 2 NR 20 ^{R 20 ', -OS (O)} NR 20 R 20', -OS (O) 2 NR 20 R 20 ', -NR 20 R 20', -NR 20 C (O) R 21, -NR 20 C (O ^{) OR 21, -NR 20 C (} O) NR 21 R 21 ', -NR 20 S (O) R 21, -NR 20 S (O) 2 R 21, -NR 20 S (O) NR 21 R 21' _{^{, -NR 20 S (O) 2}} NR 21 R 21 may be substituted by ^{', -C (O) R 20} , -C (O) oR 20 or ^{-C (O) NR 20 R 20} ';

R ¹⁸ is _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 26, -OC (O)} R 26, -OC (O) NR 26 R 26 ', -OS (O) R 26, -OS (O) 2 R 26, _{^{-SR 26, -S (O) R}} 26, -S (O) 2 R 26, -S (O) NR 26 R 26 ', -S (O) 2 NR 26 R 26', -OS (O) NR _{^{26 R 26 ', -OS (O}} ) 2 NR 26 R 26', -NR 26 R 26 ', -NR 26 C (O) R 27, -NR 26 C (O) OR 27, -NR 26 C (O ^{) NR 27 R 27 ', -NR} 26 C (= NR 26'') NR 27 R 27', -NR 26 S (O) R 27, -NR 26 S (O) 2 R 27, -NR 26 S ( ^{O) NR 27 R} 27 consists of _{^{', -NR 26 S (O)}} 2 NR 27 R 27', -C (O) R 26, -C (O) oR 26 and ^{-C (O) NR 26 R 26} ' is selected from the group, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} Each hydrogen atom in aryl and 5-7 membered heteroaryl is, independently, optionally halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, —(CH ₂ ) _p OR ²⁸ , —(CH. _{2) p (OCH 2) q} OR 28, - (CH 2) p (OCH 2 CH 2) q OR 28, -OR 29, -OC (O) R 29, -OC (O) NR 29 R 29 ', _{^{-OS (O) R 29, -OS}} (O) 2 R 29, - (CH 2) p OS (O) 2 OR 29, -OS (O) 2 OR 29, -SR 29, -S (O) R _{^{29, -S (O) 2 R}} 29, -S (O) NR 29 R 29 ', -S (O) 2 NR 29 R 29', -OS (O) NR 29 R 29 ', -OS (O) ₂ NR ²⁹ R ^29' , -NR ^{29 R 29 ', -NR 29 C (} O) R 30, -NR 29 C (O) OR 30, -NR 29 C (O) NR 30 R 30', -NR 29 S (O) R 30, -NR 29 _{^{S (O) 2 R 30,}} -NR 29 S (O) NR 30 R 30 ', -NR 29 S (O) 2 NR 30 R 30', -C (O) R 29, -C (O) OR 29 Or optionally substituted by -C(O)NR ²⁹ R ^29' ;
R ¹⁹ , R ^19′ , R ²⁰ , R ^20′ , R ²¹ , R ^21′ , R ²⁶ , R ^26′ , R ^26″ , R ²⁹ , R ^29′ , R ³⁰ and R ^30′ are each independently. And H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl And 5-7 membered heteroaryl, wherein C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 member. Each hydrogen atom in a ring heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-7 membered ring heteroaryl is, independently, optionally by halogen, —OH, —SH, —NH ₂ or —CO ₂ H. May be replaced;
R ²⁷ and ^{R 27 'are} each independently _H, C 1 _{~C 9 alkyl,} C 2 -C _{9 alkenyl,} C 2 -C _{9 alkynyl,} C 3 -C ₆ cycloalkyl, - _{(CH 2) p} (sugar _{), - (CH 2) p} (OCH 2 CH 2) q - ( sugar) and _{- (CH 2) p (OCH} 2 CH 2 CH 2) is selected from the group consisting of _q (sugars);
R ²⁸ is H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C _10. Aryl, 5-7 membered heteroaryl or sugar;
n is 1, 2, 3, 4 or 5;
p is 1, 2, 3, 4 or 5;
q is 1, 2, 3, 4 or 5; and * is a covalent bond]
And a combination thereof.

〔式中、
Ｒ^１６は本明細書に記載のように定義され、そして＊は共有結合である〕
から成る群から選択される。 In some embodiments, each L ¹ is

[In the formula,
R ¹⁶ is defined as described herein and * is a covalent bond]
Is selected from the group consisting of:

In some embodiments, R ¹⁶ is H. In some embodiments, R ¹⁸ is H, a 5-7 membered heteroaryl, —OR ²⁶ , —NR ²⁶ C(O)R ²⁷ , —NR ²⁶ C(O)NR ²⁷ R ^27′ , —NR ²⁶ C. (=NR ^26″ )NR ²⁷ R ^27′ and —C(O)NR ²⁶ R ^26′ , wherein each hydrogen atom in the 5-7 membered heteroaryl is independently, Accordingly, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -(CH ₂ ) _p OR ²⁸ , -(CH ₂ ) _p (OCH ₂ ) _q OR ²⁸ , -(CH ₂ ) _p (OCH _{2 ^{CH 2) q OR 28, -OR}} 29, -OC (O) R 29, -OC (O) NR 29 R 29 ', -OS (O) R 29, -OS (O) 2 R 29, - (CH ^{_{2) p OS (O) 2}} OR 29, -OS (O) 2 OR 29, -SR 29, -S (O) R 29, -S (O) 2 R 29, -S (O) NR 29 R 29 _{^{', -S (O) 2 NR}} 29 R 29', -OS (O) NR 29 R 29 ', -OS (O) 2 NR 29 R 29', -NR 29 R 29 ', -NR 29 C (O ^{) R 30, -NR 29 C (} O) OR 30, -NR 29 C (O) NR 30 R 30 ', -NR 29 S (O) R 30, -NR 29 S (O) 2 R 30, -NR ²⁹ S(O)NR ³⁰ R ^30' , -NR ²⁹ S(O) ₂ NR ³⁰ R ^30' , -C(O)R ²⁹ , -C(O)OR ²⁹ or -C(O)NR ²⁹ R ^{29. May be} replaced by ^' ;
R ²⁶ , R ^26′ , R ^26″ , R ²⁹ , R ^29′ , R ³⁰ and R ^30′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C. ₂ -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, is selected from the group consisting of 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl, wherein _C 1 -C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} the C 6 _{-C 10} aryl, or 5-7 membered heteroaryl, each hydrogen atom is independently optionally halogen, -OH, -SH, it may be substituted by -NH ₂ or -CO ₂ H;
R ²⁷ and R ^27′ are each independently H, C ₁ -C ₉ alkyl, C ₂ -C ₉ alkenyl, C ₂ -C ₉ alkynyl, C ₃ -C ₆ cycloalkyl, -(CH ₂ ) _p (sugar). _{), - (CH 2) p} (OCH 2 CH 2) q - ( sugar) and _{- (CH 2) p (OCH} 2 CH 2 CH 2) is selected from the group consisting of _q (sugars);
R ²⁸ is H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C _10. Aryl, 5-7 membered heteroaryl or sugar;
n is 1, 2, 3, 4 or 5;
p is 1, 2, 3, 4 or 5;
q is 1, 2, 3, 4 or 5; and * is a covalent bond.

In some embodiments, R ¹⁸ is H, a 5-7 membered heteroaryl, —OR ²⁶ , —NR ²⁶ C(O)R ²⁷ , —NR ²⁶ C(O)NR ²⁷ R ^27′ , —NR ²⁶ C. (= ^{NR 26 '')} is selected from the group consisting of ^NR 27 ^{R 27 'and -C (O) NR 26 R 26} ', wherein each hydrogen atom in the 5-7 membered heteroaryl is independently an optionally the _{^{- (CH 2) p oR 28}} , -OR 29, - (CH 2) p OS (O) may be substituted by 2 ^{oR 29} and -OS _(O) 2 ^{oR 29,}
R ²⁶ , R ^26′ , R ^26″ and R ²⁹ are each independently H or C ₁ -C ₇ alkyl, wherein each hydrogen atom in C ₁ -C ₇ alkyl is independently, if by halogen, -OH, -SH, it may be substituted by -NH ₂ or -CO ₂ H;
R ²⁷ and ^{R 27 'are} each independently _{H, - (CH 2) p} ( _{sugar), - (CH 2) p} (OCH 2 CH 2) q ( sugar) and _{- (CH 2) p (OCH} 2 CH ₂ CH ₂ ) _q (sugar);
R ²⁸ is H or sugar;
n is 1, 2, 3, 4 or 5;
p is 1, 2, 3, 4 or 5;
q is 1, 2, 3, 4 or 5; and * is a covalent bond.

〔式中、
Ｒ^１８はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^２６、−ＯＣ（Ｏ）Ｒ^２６、−ＯＣ（Ｏ）ＮＲ^２６Ｒ^２６’、−ＯＳ（Ｏ）Ｒ^２６、−ＯＳ（Ｏ）_２Ｒ^２６、−ＳＲ^２６、−Ｓ（Ｏ）Ｒ^２６、−Ｓ（Ｏ）_２Ｒ^２６、−Ｓ（Ｏ）ＮＲ^２６Ｒ^２６’、−Ｓ（Ｏ）_２ＮＲ^２６Ｒ^２６’、−ＯＳ（Ｏ）ＮＲ^２６Ｒ^２６’、−ＯＳ（Ｏ）_２ＮＲ^２６Ｒ^２６’、−ＮＲ^２６Ｒ^２６’、−ＮＲ^２６Ｃ（Ｏ）Ｒ^２７、−ＮＲ^２６Ｃ（Ｏ）ＯＲ^２７、−ＮＲ^２６Ｃ（Ｏ）ＮＲ^２７Ｒ^２７’、−ＮＲ^２６Ｃ（＝ＮＲ^２６’’）ＮＲ^２７Ｒ^２７’、−ＮＲ^２６Ｓ（Ｏ）Ｒ^２７、−ＮＲ^２６Ｓ（Ｏ）_２Ｒ^２７、−ＮＲ^２６Ｓ（Ｏ）ＮＲ^２７Ｒ^２７’、−ＮＲ^２６Ｓ（Ｏ）_２ＮＲ^２７Ｒ^２７’、−Ｃ（Ｏ）Ｒ^２６、−Ｃ（Ｏ）ＯＲ^２６および−Ｃ（Ｏ）ＮＲ^２６Ｒ^２６’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、−（ＣＨ_２）_ｐＯＲ^２８、−（ＣＨ_２）_ｐ（ＯＣＨ_２）_ｑＯＲ^２８、−（ＣＨ_２）_ｐ（ＯＣＨ_２ＣＨ_２）_ｑＯＲ^２８、−ＯＲ^２９、−ＯＣ（Ｏ）Ｒ^２９、−ＯＣ（Ｏ）ＮＲ^２９Ｒ^２９’、−ＯＳ（Ｏ）Ｒ^２９、−ＯＳ（Ｏ）_２Ｒ^２９、−（ＣＨ_２）_ｐＯＳ（Ｏ）_２ＯＲ^２９、−ＯＳ（Ｏ）_２ＯＲ^２９、−ＳＲ^２９、−Ｓ（Ｏ）Ｒ^２９、−Ｓ（Ｏ）_２Ｒ^２９、−Ｓ（Ｏ）ＮＲ^２９Ｒ^２９’、−Ｓ（Ｏ）_２ＮＲ^２９Ｒ^２９’、−ＯＳ（Ｏ）ＮＲ^２９Ｒ^２９’、−ＯＳ（Ｏ）_２ＮＲ^２９Ｒ^２９’、−ＮＲ^２９Ｒ^２９’、−ＮＲ^２９Ｃ（Ｏ）Ｒ^３０、−ＮＲ^２９Ｃ（Ｏ）ＯＲ^３０、−ＮＲ^２９Ｃ（Ｏ）ＮＲ^３０Ｒ^３０’、−ＮＲ^２９Ｓ（Ｏ）Ｒ^３０、−ＮＲ^２９Ｓ（Ｏ）_２Ｒ^３０、−ＮＲ^２９Ｓ（Ｏ）ＮＲ^３０Ｒ^３０’、−ＮＲ^２９Ｓ（Ｏ）_２ＮＲ^３０Ｒ^３０’、−Ｃ（Ｏ）Ｒ^２９、−Ｃ（Ｏ）ＯＲ^２９または−Ｃ（Ｏ）ＮＲ^２９Ｒ^２９’により置換されていてよく；
Ｒ^２６、Ｒ^２６’、Ｒ^２６’’、Ｒ^２９、Ｒ^２９’、Ｒ^３０およびＲ^３０’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され、ここでＣ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、または５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、ハロゲン、−ＯＨ、−ＳＨ、−ＮＨ_２または−ＣＯ_２Ｈにより置換されていてよく；
Ｒ^２７およびＲ^２７’は、それぞれ独立してＨ、Ｃ_１〜Ｃ_９アルキル、Ｃ_２〜Ｃ_９アルケニル、Ｃ_２〜Ｃ_９アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、−（ＣＨ_２）_ｐ（糖）、−（ＣＨ_２）_ｐ（ＯＣＨ_２ＣＨ_２）_ｑ−（糖）および−（ＣＨ_２）_ｐ（ＯＣＨ_２ＣＨ_２ＣＨ_２）_ｑ（糖）から成る群から選択され；
Ｒ^２８はＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリールまたは糖であり；
ｎは１、２、３、４または５であり；
ｐは１、２、３、４または５であり；
ｑは１、２、３、４または５であり；そして
＊は共有結合である〕
およびそれらの組合せから成る群から選択される。 In some embodiments, each L ¹ is

[In the formula,
R ¹⁸ is _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 26, -OC (O)} R 26, -OC (O) NR 26 R 26 ', -OS (O) R 26, -OS (O) 2 R 26, _{^{-SR 26, -S (O) R}} 26, -S (O) 2 R 26, -S (O) NR 26 R 26 ', -S (O) 2 NR 26 R 26', -OS (O) NR _{^{26 R 26 ', -OS (O}} ) 2 NR 26 R 26', -NR 26 R 26 ', -NR 26 C (O) R 27, -NR 26 C (O) OR 27, -NR 26 C (O ^{) NR 27 R 27 ', -NR} 26 C (= NR 26'') NR 27 R 27', -NR 26 S (O) R 27, -NR 26 S (O) 2 R 27, -NR 26 S ( ^{O) NR 27 R} 27 consists of _{^{', -NR 26 S (O)}} 2 NR 27 R 27', -C (O) R 26, -C (O) oR 26 and ^{-C (O) NR 26 R 26} ' is selected from the group, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} Each hydrogen atom in aryl and 5-7 membered heteroaryl is optionally halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -(CH ₂ ) _p OR ²⁸ , -(CH. _{2) p (OCH 2) q} OR 28, - (CH 2) p (OCH 2 CH 2) q OR 28, -OR 29, -OC (O) R 29, -OC (O) NR 29 R 29 ', _{^{-OS (O) R 29, -OS}} (O) 2 R 29, - (CH 2) p OS (O) 2 OR 29, -OS (O) 2 OR 29, -SR 29, -S (O) R _{^{29, -S (O) 2 R}} 29, -S (O) NR 29 R 29 ', -S (O) 2 NR 29 R 29', -OS (O) NR 29 R 29 ', -OS (O) ₂ NR ²⁹ R ^29' , -NR ^{29 R 29 ', -NR 29 C (} O) R 30, -NR 29 C (O) OR 30, -NR 29 C (O) NR 30 R 30', -NR 29 S (O) R 30, -NR 29 _{^{S (O) 2 R 30,}} -NR 29 S (O) NR 30 R 30 ', -NR 29 S (O) 2 NR 30 R 30', -C (O) R 29, -C (O) OR 29 Or optionally substituted by -C(O)NR ²⁹ R ^29' ;
R ²⁶ , R ^26′ , R ^26″ , R ²⁹ , R ^29′ , R ³⁰ and R ^30′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C. ₂ -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, is selected from the group consisting of 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl, wherein _C 1 -C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} the C 6 _{-C 10} aryl, or 5-7 membered heteroaryl, each hydrogen atom is independently optionally halogen, -OH, -SH, it may be substituted by -NH ₂ or -CO ₂ H;
R ²⁷ and R ^27′ are each independently H, C ₁ -C ₉ alkyl, C ₂ -C ₉ alkenyl, C ₂ -C ₉ alkynyl, C ₃ -C ₆ cycloalkyl, —(CH ₂ ) _p ( _{sugar), - (CH 2) p} (OCH 2 CH 2) q - ( sugar) and _{- (CH 2) p (OCH} 2 CH 2 CH 2) is selected from the group consisting of _q (sugars);
R ²⁸ is H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C _10. Aryl, 5-7 membered heteroaryl or sugar;
n is 1, 2, 3, 4 or 5;
p is 1, 2, 3, 4 or 5;
q is 1, 2, 3, 4 or 5; and * is a covalent bond]
And a combination thereof.

In some embodiments, R ¹⁸ is H, a 5-7 membered heteroaryl, —OR ²⁶ , —NR ²⁶ C(O)R ²⁷ , —NR ²⁶ C(O)NR ²⁷ R ^27′ , —NR ²⁶ C. (=NR ^26″ )NR ²⁷ R ^27′ and —C(O)NR ²⁶ R ^26′ , wherein each hydrogen atom in the 5-7 membered heteroaryl is independently, Accordingly, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -(CH ₂ ) _p OR ²⁸ , -(CH ₂ ) _p (OCH ₂ ) _q OR ²⁸ , -(CH ₂ ) _p (OCH _{2 ^{CH 2) q OR 28, -OR}} 29, -OC (O) R 29, -OC (O) NR 29 R 29 ', -OS (O) R 29, -OS (O) 2 R 29, - (CH ^{_{2) p OS (O) 2}} OR 29, -OS (O) 2 OR 29, -SR 29, -S (O) R 29, -S (O) 2 R 29, -S (O) NR 29 R 29 _{^{', -S (O) 2 NR}} 29 R 29', -OS (O) NR 29 R 29 ', -OS (O) 2 NR 29 R 29', -NR 29 R 29 ', -NR 29 C (O ^{) R 30, -NR 29 C (} O) OR 30, -NR 29 C (O) NR 30 R 30 ', -NR 29 S (O) R 30, -NR 29 S (O) 2 R 30, -NR ²⁹ S(O)NR ³⁰ R ^30' , -NR ²⁹ S(O) ₂ NR ³⁰ R ^30' , -C(O)R ²⁹ , -C(O)OR ²⁹ or -C(O)NR ²⁹ R ^{29. May be} replaced by ^' ;
R ²⁶ , R ^26′ , R ^26″ , R ²⁹ , R ^29′ , R ³⁰ and R ^30′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C. ₂ -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, is selected from the group consisting of 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl, wherein _C 1 -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5-7 membered heteroaryl. hydrogen atoms are independently optionally halogen, -OH, -SH, it may be substituted by -NH ₂ or -CO ₂ H;
R ²⁷ and R ^27′ are each independently H, C ₁ -C ₉ alkyl, C ₂ -C ₉ alkenyl, C ₂ -C ₉ alkynyl, C ₃ -C ₆ cycloalkyl, —(CH ₂ ) _p ( _{sugar), - (CH 2) p} (OCH 2 CH 2) q - ( sugar) and _{- (CH 2) p (OCH} 2 CH 2 CH 2) is selected from the group consisting of _q (sugars);
R ²⁸ is H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C _10. Aryl, 5-7 membered heteroaryl or sugar;
n is 1, 2, 3, 4 or 5;
p is 1, 2, 3, 4 or 5;
q is 1, 2, 3, 4 or 5; and * is a covalent bond.

In some embodiments, R ¹⁸ is H, a 5-7 membered heteroaryl, —OR ²⁶ , —NR ²⁶ C(O)R ²⁷ , —NR ²⁶ C(O)NR ²⁷ R ^27′ , —NR ²⁶ C. ^{(= NR 26 '') NR} 27 R 27 ', and is selected from the group consisting of ^{-C (O) NR 26 R 26} ', wherein each hydrogen atom in the 5-7 membered heteroaryl is independently _{^{optionally, - (CH 2) p oR}} 28, -OR 29, - (CH 2) p OS (O) may be substituted by 2 ^{oR 29} and -OS _(O) 2 ^{oR 29,}
R ²⁶ , R ^26′ , R ^26″ and R ²⁹ are each independently H or C ₁ -C ₇ alkyl, wherein each hydrogen atom in C ₁ -C ₇ alkyl is independently, if by halogen, -OH, -SH, it may be substituted by -NH ₂ or -CO ₂ H;
R ²⁷ and ^{R 27 'are} each independently _{H, - (CH 2) p} ( _{sugar), - (CH 2) p} (OCH 2 CH 2) q ( sugar) and _{- (CH 2) p (OCH} 2 CH ₂ CH ₂ ) _q (sugar);
R ²⁸ is H or sugar;
n is 1, 2, 3, 4 or 5;
p is 1, 2, 3, 4 or 5;
q is 1, 2, 3, 4 or 5; and * is a covalent bond.

In some aspects of the conjugates described herein, L ¹ is present. In some aspects of the conjugates described herein, L ¹ is absent. In some embodiments, z4 is 0. In some embodiments, z4 is 1. In some embodiments, z4 is 2.

L ² is a releasable linker. The term "releasable linker" as used herein refers to pH-labile, acid-labile, base-labile, oxidatively-labile, metabolically-labile, biochemistry. Refers to a linker containing at least one bond that is cleavable under physiological conditions, such as a chemically labile or an enzyme labile bond. Physiological conditions that result in the breaking of such bonds do not necessarily involve biological or metabolic processes, and instead, for example, cells such as endosomes at physiological pH or having a pH below cytoplasmic pH. It is understood that standard chemistry may be involved, such as hydrolysis reactions as a result of compartmentalization into organs.

The cleavable bond can join two adjacent atoms within an atom releasable linker, and/or as described herein, at either end of the releasable linker, with another linker or B , D ¹ and/or D ² can be combined. If a cleavable bond joins two adjacent atoms within a releasable linker, following cleavage of the bond, the releasable linker is cleaved into two or more fragments. Alternatively, if the cleavable bond is a bond between a releasable linker and another moiety, such as another linker, drug or binding ligand, the releasable linker is separated from the other moiety and subsequently bonded. Is disconnected.

The instability of the cleavable bond may be due to, for example, substituents at or near the cleavable bond, such as involving an α-branch adjacent to the cleavable disulfide bond, in moieties with hydrolyzable silicon-oxygen bonds. It can be prepared by increasing the hydrophobicity of the substituents on the silicon, by homologating the alkoxy groups which form part of the hydrolysable ketals or acetals.

Specific releasable linkers described herein include linkers including hemiacetals and their sulfur variants, acetals and their sulfur variants, hemiaminal, aminal, etc., substituted with at least one heteroatom. It may be formed from a methylene fragment, 1-alkoxyalkylene, 1-alkoxycycloalkylene, 1-alkoxyalkylenecarbonyl, 1-alkoxycycloalkylenecarbonyl and the like. Specific releasable linkers described herein include linkers including carbonylarylcarbonyl, carbonyl(carboxyaryl)carbonyl, carbonyl(biscarboxyaryl)carbonyl, haloalkylenecarbonyl, and the like. Specific releasable linkers described herein include alkylene(dialkylsilyl), alkylene(alkylarylsilyl), alkylene(diarylsilyl), (dialkylsilyl)aryl, (alkylarylsilyl)aryl, (diarylsilyl). ) Including a linker including aryl and the like. Specific releasable linkers described herein include oxycarbonyloxy, oxycarbonyloxyalkyl, sulfonyloxy, oxysulfonylalkyl, and the like. Specific releasable linkers described herein include linkers including iminoalkylidenyl, carbonylalkylideneiminyl, iminocycloalkylidenyl, carbonylcycloalkylideneiminyl, and the like. Specific releasable linkers described herein include linkers including alkylenethio, alkylenearylthio, carbonylalkylthio, and the like.

〔式中、
Ｒ^３１はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３２、−ＯＣ（Ｏ）Ｒ^３２、−ＯＣ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）Ｒ^３２、−ＯＳ（Ｏ）_２Ｒ^３２、−ＳＲ^３２、−Ｓ（Ｏ）Ｒ^３２、−Ｓ（Ｏ）_２Ｒ^３２、−Ｓ（Ｏ）ＮＲ^３２Ｒ^３２’、−Ｓ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｃ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｃ（Ｏ）ＯＲ^３３、−ＮＲ^３２Ｃ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）_２Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）_２ＮＲ^３３Ｒ^３３’、−Ｃ（Ｏ）Ｒ^３２、−Ｃ（Ｏ）ＯＲ^３２または−Ｃ（Ｏ）ＮＲ^３２Ｒ^３２’により置換されていてよく；
Ｘ^６はＣ_１〜Ｃ_６アルキルまたはＣ_６〜Ｃ_１０アリール（Ｃ_１〜Ｃ_６アルキル）であり、ここでＣ_１〜Ｃ_６アルキルおよびＣ_６〜Ｃ_１０アリール（Ｃ_１〜Ｃ_６アルキル）における各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３４、−ＯＣ（Ｏ）Ｒ^３４、−ＯＣ（Ｏ）ＮＲ^３４Ｒ^３４’、−ＯＳ（Ｏ）Ｒ^３４、−ＯＳ（Ｏ）_２Ｒ^３４、−ＳＲ^３４、−Ｓ（Ｏ）Ｒ^３４、−Ｓ（Ｏ）_２Ｒ^３４、−Ｓ（Ｏ）ＮＲ^３４Ｒ^３４’、−Ｓ（Ｏ）_２ＮＲ^３４Ｒ^３４’、−ＯＳ（Ｏ）ＮＲ^３４Ｒ^３４’、−ＯＳ（Ｏ）_２ＮＲ^３４Ｒ^３４’、−ＮＲ^３４Ｒ^３４’、−ＮＲ^３４Ｃ（Ｏ）Ｒ^３５、−ＮＲ^３４Ｃ（Ｏ）ＯＲ^３５、−ＮＲ^３４Ｃ（Ｏ）ＮＲ^３５Ｒ^３５’、−ＮＲ^３４Ｓ（Ｏ）Ｒ^３５、−ＮＲ^３４Ｓ（Ｏ）_２Ｒ^３５、−ＮＲ^３４Ｓ（Ｏ）ＮＲ^３５Ｒ^３５’、−ＮＲ^３４Ｓ（Ｏ）_２ＮＲ^３５Ｒ^３５’、−Ｃ（Ｏ）Ｒ^３４、−Ｃ（Ｏ）ＯＲ^３４または−Ｃ（Ｏ）ＮＲ^３４Ｒ^３４’により置換されていてよく；
Ｒ^３２、Ｒ^３２’、Ｒ^３３、Ｒ^３３’、Ｒ^３４、Ｒ^３４’、Ｒ^３５およびＲ^３５’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、および５〜７員環ヘテロアリールから成る群から選択され；
Ｒ^３６は独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３７、−ＯＣ（Ｏ）Ｒ^３７、−ＯＣ（Ｏ）ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）Ｒ^３７、−ＯＳ（Ｏ）_２Ｒ^３７、−ＳＲ^３７、−Ｓ（Ｏ）Ｒ^３７、−Ｓ（Ｏ）_２Ｒ^３７、−Ｓ（Ｏ）ＮＲ^３７Ｒ^３７’、−Ｓ（Ｏ）_２ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）_２ＮＲ^３７Ｒ^３７’、−ＮＲ^３７Ｒ^３７’、−ＮＲ^３７Ｃ（Ｏ）Ｒ^３８、−ＮＲ^３７Ｃ（Ｏ）ＯＲ^３８、−ＮＲ^３７Ｃ（Ｏ）ＮＲ^３８Ｒ^３８’、−ＮＲ^３７Ｓ（Ｏ）Ｒ^３８、−ＮＲ^３７Ｓ（Ｏ）_２Ｒ^３８、−ＮＲ^３７Ｓ（Ｏ）ＮＲ^３８Ｒ^３８’、−ＮＲ^３７Ｓ（Ｏ）_２ＮＲ^３８Ｒ^３８’、−Ｃ（Ｏ）Ｒ^３７、−Ｃ（Ｏ）ＯＲ^３７または−Ｃ（Ｏ）ＮＲ^３７Ｒ^３７’により置換されていてよく；
Ｒ^３７、Ｒ^３７’、Ｒ^３８およびＲ^３８’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
から成る群から選択する。 In some embodiments, L ² is

[In the formula,
R ³¹ is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₁ -C ₆ alkyl. each hydrogen atom in _C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl , _C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 32, -OC (O)} R ³² , -OC(O)NR ³² R ^32' , -OS(O)R ³² , -OS(O) ₂ R ³² , -SR ³² , -S(O)R ³² , -S(O) ₂ R ^32. , -S(O)NR ³² R ^32' , -S(O) ₂ NR ³² R ^32' , -OS(O)NR ³² R ^32' , -OS(O) ₂ NR ³² R ^32' , -NR ^{32. R 32 ', -NR 32 C (} O) R 33, -NR 32 C (O) OR 33, -NR 32 C (O) NR 33 R 33', -NR 32 S (O) R 33, -NR 32 _{^{S (O) 2 R 33,}} -NR 32 S (O) NR 33 R 33 ', -NR 32 S (O) 2 NR 33 R 33', -C (O) R 32, -C (O) OR 32 Or optionally substituted by -C(O)NR ³² R ^32' ;
X ⁶ is C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl), wherein C ₁ -C ₆ alkyl and C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl). Each hydrogen atom in is optionally halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. _cycloalkyl, C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 34, -OC (O)} R 34, -OC (O) NR 34 R 34 ', -OS (O) R 34, - _{^{OS (O) 2 R 34,}} -SR 34, -S (O) R 34, -S (O) 2 R 34, -S (O) NR 34 R 34 ', -S (O) 2 NR 34 R 34 ^{', -OS (O) NR 34} R 34', -OS (O) 2 NR 34 R 34 ', -NR 34 R 34', -NR 34 C (O) R 35, -NR 34 C (O) OR ^{35, -NR 34 C (O)} NR 35 R 35 ', -NR 34 S (O) R 35, -NR 34 S (O) 2 R 35, -NR 34 S (O) NR 35 R 35', - _{^{NR 34 S (O) 2 NR}} 35 R 35 may be substituted by ^{', -C (O) R 34} , -C (O) oR 34 or ^{-C (O) NR 34 R 34} ';
^{R 32, R 32 ', R} 33, R 33', R 34, R 34 ', R 35 and ^{R 35'} is, H _{independently, D,} C 1 ~C _{7 alkyl,} C 2 -C ₇ alkenyl , _C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, is selected from the group consisting of 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, and 5-7 membered heteroaryl;
R ³⁶ is independently selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₁ -. C _{6 alkyl,} C 2 -C _{6 alkenyl,} each hydrogen atom in the C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl, C} 2 ~ C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, -OR 37, -OC ( ^{O) R 37, -OC (O} ) NR 37 R 37 ', -OS (O) R 37, -OS (O) 2 R 37, -SR 37, -S (O) R 37, -S (O) _{^{2 R 37, -S (O)}} NR 37 R 37 ', -S (O) 2 NR 37 R 37', -OS (O) NR 37 R 37 ', -OS (O) 2 NR 37 R 37', ^{-NR 37 R 37 ', -NR 37} C (O) R 38, -NR 37 C (O) OR 38, -NR 37 C (O) NR 38 R 38', -NR 37 S (O) R 38, -NR ³⁷ S(O) ₂ R ³⁸ , -NR ³⁷ S(O)NR ³⁸ R ^38' , -NR ³⁷ S(O) ₂ NR ³⁸ R ^38' , -C(O)R ³⁷ , -C(O ) OR ³⁷ or -C(O)NR ³⁷ R ^{37' which} may be substituted;
R ³⁷ , R ^37′ , R ³⁸ and R ^38′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a covalent bond]
Selected from the group consisting of.

In some embodiments, R ³¹ is H. In some embodiments, R ³⁶ is H. In some embodiments, ^{X 6} is _C 1 -C ₆ alkyl. In some embodiments, ^{X 6} is _C 1 -C ₆ alkyl. C ₆ -C ₁₀ aryl _(C 1 -C ₆ alkyl).

〔式中、
Ｒ^３１はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３２、−ＯＣ（Ｏ）Ｒ^３２、−ＯＣ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）Ｒ^３２、−ＯＳ（Ｏ）_２Ｒ^３２、−ＳＲ^３２、−Ｓ（Ｏ）Ｒ^３２、−Ｓ（Ｏ）_２Ｒ^３２、−Ｓ（Ｏ）ＮＲ^３２Ｒ^３２’、−Ｓ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｃ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｃ（Ｏ）ＯＲ^３３、−ＮＲ^３２Ｃ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）_２Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）_２ＮＲ^３３Ｒ^３３’、−Ｃ（Ｏ）Ｒ^３２、−Ｃ（Ｏ）ＯＲ^３２または−Ｃ（Ｏ）ＮＲ^３２Ｒ^３２’により置換されていてよく；
Ｘ^６はＣ_１〜Ｃ_６アルキルまたはＣ_６〜Ｃ_１０アリール（Ｃ_１〜Ｃ_６アルキル）であり、ここでＣ_１〜Ｃ_６アルキルおよびＣ_６〜Ｃ_１０アリール（Ｃ_１〜Ｃ_６アルキル）における各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３４、−ＯＣ（Ｏ）Ｒ^３４、−ＯＣ（Ｏ）ＮＲ^３４Ｒ^３４’、−ＯＳ（Ｏ）Ｒ^３４、−ＯＳ（Ｏ）_２Ｒ^３４、−ＳＲ^３４、−Ｓ（Ｏ）Ｒ^３４、−Ｓ（Ｏ）_２Ｒ^３４、−Ｓ（Ｏ）ＮＲ^３４Ｒ^３４’、−Ｓ（Ｏ）_２ＮＲ^３４Ｒ^３４’、−ＯＳ（Ｏ）ＮＲ^３４Ｒ^３４’、−ＯＳ（Ｏ）_２ＮＲ^３４Ｒ^３４’、−ＮＲ^３４Ｒ^３４’、−ＮＲ^３４Ｃ（Ｏ）Ｒ^３５、−ＮＲ^３４Ｃ（Ｏ）ＯＲ^３５、−ＮＲ^３４Ｃ（Ｏ）ＮＲ^３５Ｒ^３５’、−ＮＲ^３４Ｓ（Ｏ）Ｒ^３５、−ＮＲ^３４Ｓ（Ｏ）_２Ｒ^３５、−ＮＲ^３４Ｓ（Ｏ）ＮＲ^３５Ｒ^３５’、−ＮＲ^３４Ｓ（Ｏ）_２ＮＲ^３５Ｒ^３５’、−Ｃ（Ｏ）Ｒ^３４、−Ｃ（Ｏ）ＯＲ^３４または−Ｃ（Ｏ）ＮＲ^３４Ｒ^３４’により置換されていてよく；
Ｒ^３２、Ｒ^３２’、Ｒ^３３、Ｒ^３３’、Ｒ^３４、Ｒ^３４’、Ｒ^３５およびＲ^３５’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
である。 In some embodiments, L ² is

[In the formula,
R ³¹ is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₁ -C ₆ alkyl. each hydrogen atom in _C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl , _C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 32, -OC (O)} R ³² , -OC(O)NR ³² R ^32' , -OS(O)R ³² , -OS(O) ₂ R ³² , -SR ³² , -S(O)R ³² , -S(O) ₂ R ^32. , -S(O)NR ³² R ^32' , -S(O) ₂ NR ³² R ^32' , -OS(O)NR ³² R ^32' , -OS(O) ₂ NR ³² R ^32' , -NR ^{32. R 32 ', -NR 32 C (} O) R 33, -NR 32 C (O) OR 33, -NR 32 C (O) NR 33 R 33', -NR 32 S (O) R 33, -NR 32 _{^{S (O) 2 R 33,}} -NR 32 S (O) NR 33 R 33 ', -NR 32 S (O) 2 NR 33 R 33', -C (O) R 32, -C (O) OR 32 Or optionally substituted by -C(O)NR ³² R ^32' ;
X ⁶ is C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl), wherein C ₁ -C ₆ alkyl and C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl). Each hydrogen atom in is optionally halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. _cycloalkyl, C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 34, -OC (O)} R 34, -OC (O) NR 34 R 34 ', -OS (O) R 34, - _{^{OS (O) 2 R 34,}} -SR 34, -S (O) R 34, -S (O) 2 R 34, -S (O) NR 34 R 34 ', -S (O) 2 NR 34 R 34 ^{', -OS (O) NR 34} R 34', -OS (O) 2 NR 34 R 34 ', -NR 34 R 34', -NR 34 C (O) R 35, -NR 34 C (O) OR ^{35, -NR 34 C (O)} NR 35 R 35 ', -NR 34 S (O) R 35, -NR 34 S (O) 2 R 35, -NR 34 S (O) NR 35 R 35', - _{^{NR 34 S (O) 2 NR}} 35 R 35 may be substituted by ^{', -C (O) R 34} , -C (O) oR 34 or ^{-C (O) NR 34 R 34} ';
^{R 32, R 32 ', R} 33, R 33', R 34, R 34 ', R 35 and ^{R 35'} is, H _{independently, D,} C 1 ~C _{7 alkyl,} C 2 -C ₇ alkenyl It is selected from the group consisting of _C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * share Is a bond]
Is.

In some embodiments, R ³¹ is H and X ⁶ is C ₁ -C ₆ alkyl. In some embodiments, R ³¹ is H and X ⁶ is C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl).

〔式中、
Ｒ^３１はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、は独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３２、−ＯＣ（Ｏ）Ｒ^３２、−ＯＣ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）Ｒ^３２、−ＯＳ（Ｏ）_２Ｒ^３２、−ＳＲ^３２、−Ｓ（Ｏ）Ｒ^３２、−Ｓ（Ｏ）_２Ｒ^３２、−Ｓ（Ｏ）ＮＲ^３２Ｒ^３２’、−Ｓ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｃ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｃ（Ｏ）ＯＲ^３３、−ＮＲ^３２Ｃ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）_２Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）_２ＮＲ^３３Ｒ^３３’、−Ｃ（Ｏ）Ｒ^３２、−Ｃ（Ｏ）ＯＲ^３２または−Ｃ（Ｏ）ＮＲ^３２Ｒ^３２’により置換されていてよく；
Ｘ^６はＣ_１〜Ｃ_６アルキルまたはＣ_６〜Ｃ_１０アリール（Ｃ_１〜Ｃ_６アルキル）であり、ここでＣ_１〜Ｃ_６アルキルおよびＣ_６〜Ｃ_１０アリール（Ｃ_１〜Ｃ_６アルキル）における各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３４、−ＯＣ（Ｏ）Ｒ^３４、−ＯＣ（Ｏ）ＮＲ^３４Ｒ^３４’、−ＯＳ（Ｏ）Ｒ^３４、−ＯＳ（Ｏ）_２Ｒ^３４、−ＳＲ^３４、−Ｓ（Ｏ）Ｒ^３４、−Ｓ（Ｏ）_２Ｒ^３４、−Ｓ（Ｏ）ＮＲ^３４Ｒ^３４’、−Ｓ（Ｏ）_２ＮＲ^３４Ｒ^３４’、−ＯＳ（Ｏ）ＮＲ^３４Ｒ^３４’、−ＯＳ（Ｏ）_２ＮＲ^３４Ｒ^３４’、−ＮＲ^３４Ｒ^３４’、−ＮＲ^３４Ｃ（Ｏ）Ｒ^３５、−ＮＲ^３４Ｃ（Ｏ）ＯＲ^３５、−ＮＲ^３４Ｃ（Ｏ）ＮＲ^３５Ｒ^３５’、−ＮＲ^３４Ｓ（Ｏ）Ｒ^３５、−ＮＲ^３４Ｓ（Ｏ）_２Ｒ^３５、−ＮＲ^３４Ｓ（Ｏ）ＮＲ^３５Ｒ^３５’、−ＮＲ^３４Ｓ（Ｏ）_２ＮＲ^３５Ｒ^３５’、−Ｃ（Ｏ）Ｒ^３４、−Ｃ（Ｏ）ＯＲ^３４または−Ｃ（Ｏ）ＮＲ^３４Ｒ^３４’により置換されていてよく；
Ｒ^３２、Ｒ^３２’、Ｒ^３３、Ｒ^３３’、Ｒ^３４、Ｒ^３４’、Ｒ^３５およびＲ^３５’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
である。 In some embodiments, L ² is

[In the formula,
R ³¹ is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₁ -C ₆ alkyl. , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl are each independently, optionally, halogen, C ₁ -C ₆ alkyl, C ₂ -C _{6. alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, -OR ^32, -OC (O) ^{R 32, -OC (O) NR} 32 R 32 ', -OS (O) R 32, -OS (O) 2 R 32, -SR 32, -S (O) R 32, -S (O) 2 R ³² , -S(O)NR ³² R ^32' , -S(O) ₂ NR ³² R ^32' , -OS(O)NR ³² R ^32' , -OS(O) ₂ NR ³² R ^32' , -NR. ³² R ^32' , -NR ³² C(O)R ³³ , -NR ³² C(O)OR ³³ , -NR ³² C(O)NR ³³ R ^33' , -NR ³² S(O)R ³³ , -NR. ³² S(O) ₂ R ³³ , -NR ³² S(O)NR ³³ R ^33' , -NR ³² S(O) ₂ NR ³³ R ^33' , -C(O)R ³² , -C(O)OR. ³² or -C(O)NR ³² R ^32' may be substituted;
X ⁶ is C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl), wherein C ₁ -C ₆ alkyl and C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl). Each hydrogen atom in is optionally halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. _cycloalkyl, C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 34, -OC (O)} R 34, -OC (O) NR 34 R 34 ', -OS (O) R 34, - _{^{OS (O) 2 R 34,}} -SR 34, -S (O) R 34, -S (O) 2 R 34, -S (O) NR 34 R 34 ', -S (O) 2 NR 34 R 34 ^{', -OS (O) NR 34} R 34', -OS (O) 2 NR 34 R 34 ', -NR 34 R 34', -NR 34 C (O) R 35, -NR 34 C (O) OR ^{35, -NR 34 C (O)} NR 35 R 35 ', -NR 34 S (O) R 35, -NR 34 S (O) 2 R 35, -NR 34 S (O) NR 35 R 35', - _{^{NR 34 S (O) 2 NR}} 35 R 35 may be substituted by ^{', -C (O) R 34} , -C (O) oR 34 or ^{-C (O) NR 34 R 34} ';
^{R 32, R 32 ', R} 33, R 33', R 34, R 34 ', R 35 and ^{R 35'} is, H _{independently, D,} C 1 ~C _{7 alkyl,} C 2 -C ₇ alkenyl It is selected from the group consisting of _C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * share Is a bond]
Is.

In some embodiments, R ³¹ is H and X ⁶ is C ₁ -C ₆ alkyl. In some embodiments, R ³¹ is H and X ⁶ is C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl).

〔式中、
Ｒ^３１はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３２、−ＯＣ（Ｏ）Ｒ^３２、−ＯＣ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）Ｒ^３２、−ＯＳ（Ｏ）_２Ｒ^３２、−ＳＲ^３２、−Ｓ（Ｏ）Ｒ^３２、−Ｓ（Ｏ）_２Ｒ^３２、−Ｓ（Ｏ）ＮＲ^３２Ｒ^３２’、−Ｓ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｃ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｃ（Ｏ）ＯＲ^３３、−ＮＲ^３２Ｃ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）_２Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）_２ＮＲ^３３Ｒ^３３’、−Ｃ（Ｏ）Ｒ^３２、−Ｃ（Ｏ）ＯＲ^３２または−Ｃ（Ｏ）ＮＲ^３２Ｒ^３２’により置換されていてよく；
Ｘ^６はＣ_１〜Ｃ_６アルキルまたはＣ_６〜Ｃ_１０アリール（Ｃ_１〜Ｃ_６アルキル）であり、ここでＣ_１〜Ｃ_６アルキルおよびＣ_６〜Ｃ_１０アリール（Ｃ_１〜Ｃ_６アルキル）における各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３４、−ＯＣ（Ｏ）Ｒ^３４、−ＯＣ（Ｏ）ＮＲ^３４Ｒ^３４’、−ＯＳ（Ｏ）Ｒ^３４、−ＯＳ（Ｏ）_２Ｒ^３４、−ＳＲ^３４、−Ｓ（Ｏ）Ｒ^３４、−Ｓ（Ｏ）_２Ｒ^３４、−Ｓ（Ｏ）ＮＲ^３４Ｒ^３４’、−Ｓ（Ｏ）_２ＮＲ^３４Ｒ^３４’、−ＯＳ（Ｏ）ＮＲ^３４Ｒ^３４’、−ＯＳ（Ｏ）_２ＮＲ^３４Ｒ^３４’、−ＮＲ^３４Ｒ^３４’、−ＮＲ^３４Ｃ（Ｏ）Ｒ^３５、−ＮＲ^３４Ｃ（Ｏ）ＯＲ^３５、−ＮＲ^３４Ｃ（Ｏ）ＮＲ^３５Ｒ^３５’、−ＮＲ^３４Ｓ（Ｏ）Ｒ^３５、−ＮＲ^３４Ｓ（Ｏ）_２Ｒ^３５、−ＮＲ^３４Ｓ（Ｏ）ＮＲ^３５Ｒ^３５’、−ＮＲ^３４Ｓ（Ｏ）_２ＮＲ^３５Ｒ^３５’、−Ｃ（Ｏ）Ｒ^３４、−Ｃ（Ｏ）ＯＲ^３４または−Ｃ（Ｏ）ＮＲ^３４Ｒ^３４’により置換されていてよく；
Ｒ^３２、Ｒ^３２’、Ｒ^３３、Ｒ^３３’、Ｒ^３４、Ｒ^３４’、Ｒ^３５およびＲ^３５’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
である。 In some embodiments, L ² is

[In the formula,
R ³¹ is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₁ -C ₆ alkyl. each hydrogen atom in _C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl , _C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 32, -OC (O)} R ³² , -OC(O)NR ³² R ^32' , -OS(O)R ³² , -OS(O) ₂ R ³² , -SR ³² , -S(O)R ³² , -S(O) ₂ R ^32. , -S(O)NR ³² R ^32' , -S(O) ₂ NR ³² R ^32' , -OS(O)NR ³² R ^32' , -OS(O) ₂ NR ³² R ^32' , -NR ^{32. R 32 ', -NR 32 C (} O) R 33, -NR 32 C (O) OR 33, -NR 32 C (O) NR 33 R 33', -NR 32 S (O) R 33, -NR 32 _{^{S (O) 2 R 33,}} -NR 32 S (O) NR 33 R 33 ', -NR 32 S (O) 2 NR 33 R 33', -C (O) R 32, -C (O) OR 32 Or optionally substituted by -C(O)NR ³² R ^32' ;
X ⁶ is C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl), wherein C ₁ -C ₆ alkyl and C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl). Each hydrogen atom in is optionally halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. _cycloalkyl, C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 34, -OC (O)} R 34, -OC (O) NR 34 R 34 ', -OS (O) R 34, - _{^{OS (O) 2 R 34,}} -SR 34, -S (O) R 34, -S (O) 2 R 34, -S (O) NR 34 R 34 ', -S (O) 2 NR 34 R 34 ^{', -OS (O) NR 34} R 34', -OS (O) 2 NR 34 R 34 ', -NR 34 R 34', -NR 34 C (O) R 35, -NR 34 C (O) OR ^{35, -NR 34 C (O)} NR 35 R 35 ', -NR 34 S (O) R 35, -NR 34 S (O) 2 R 35, -NR 34 S (O) NR 35 R 35', - _{^{NR 34 S (O) 2 NR}} 35 R 35 may be substituted by ^{', -C (O) R 34} , -C (O) oR 34 or ^{-C (O) NR 34 R 34} ';
^{R 32, R 32 ', R} 33, R 33', R 34, R 34 ', R 35 and ^{R 35'} is, H _{independently, D,} C 1 ~C _{7 alkyl,} C 2 -C ₇ alkenyl It is selected from the group consisting of _C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * share Is a bond]
Is.

In some embodiments, R ³¹ is H and X ⁶ is C ₁ -C ₆ alkyl. In some embodiments, R ³¹ is H and X ⁶ is C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl).

〔式中、
Ｒ^３１はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３２、−ＯＣ（Ｏ）Ｒ^３２、−ＯＣ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）Ｒ^３２、−ＯＳ（Ｏ）_２Ｒ^３２、−ＳＲ^３２、−Ｓ（Ｏ）Ｒ^３２、−Ｓ（Ｏ）_２Ｒ^３２、−Ｓ（Ｏ）ＮＲ^３２Ｒ^３２’、−Ｓ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｃ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｃ（Ｏ）ＯＲ^３３、−ＮＲ^３２Ｃ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）_２Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）_２ＮＲ^３３Ｒ^３３’、−Ｃ（Ｏ）Ｒ^３２、−Ｃ（Ｏ）ＯＲ^３２または−Ｃ（Ｏ）ＮＲ^３２Ｒ^３２’により置換されていてよく；
Ｒ^３２、Ｒ^３２’、Ｒ^３３およびＲ^３３’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
である。いくつかの態様において、Ｒ^３１はＨである。 In some embodiments, L ² is

[In the formula,
R ³¹ is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₁ -C ₆ alkyl. each hydrogen atom in _C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl , _C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 32, -OC (O)} R ³² , -OC(O)NR ³² R ^32' , -OS(O)R ³² , -OS(O) ₂ R ³² , -SR ³² , -S(O)R ³² , -S(O) ₂ R ^32. , -S(O)NR ³² R ^32' , -S(O) ₂ NR ³² R ^32' , -OS(O)NR ³² R ^32' , -OS(O) ₂ NR ³² R ^32' , -NR ^{32. R 32 ', -NR 32 C (} O) R 33, -NR 32 C (O) OR 33, -NR 32 C (O) NR 33 R 33', -NR 32 S (O) R 33, -NR 32 _{^{S (O) 2 R 33,}} -NR 32 S (O) NR 33 R 33 ', -NR 32 S (O) 2 NR 33 R 33', -C (O) R 32, -C (O) OR 32 Or optionally substituted by -C(O)NR ³² R ^32' ;
R ³² , R ^32′ , R ³³ and R ^33′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a covalent bond]
Is. In some embodiments, R ³¹ is H.

〔式中、
Ｒ^３１はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３２、−ＯＣ（Ｏ）Ｒ^３２、−ＯＣ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）Ｒ^３２、−ＯＳ（Ｏ）_２Ｒ^３２、−ＳＲ^３２、−Ｓ（Ｏ）Ｒ^３２、−Ｓ（Ｏ）_２Ｒ^３２、−Ｓ（Ｏ）ＮＲ^３２Ｒ^３２’、−Ｓ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｃ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｃ（Ｏ）ＯＲ^３３、−ＮＲ^３２Ｃ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）_２Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）_２ＮＲ^３３Ｒ^３３’、−Ｃ（Ｏ）Ｒ^３２、−Ｃ（Ｏ）ＯＲ^３２または−Ｃ（Ｏ）ＮＲ^３２Ｒ^３２’により置換されていてよく；
Ｒ^３２、Ｒ^３２’、Ｒ^３３およびＲ^３３は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
である。いくつかの態様において、Ｒ^３１はＨである。 In some embodiments, L ² is

[In the formula,
R ³¹ is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₁ -C ₆ alkyl. each hydrogen atom in _C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl , _C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 32, -OC (O)} R ³² , -OC(O)NR ³² R ^32' , -OS(O)R ³² , -OS(O) ₂ R ³² , -SR ³² , -S(O)R ³² , -S(O) ₂ R ^32. , -S(O)NR ³² R ^32' , -S(O) ₂ NR ³² R ^32' , -OS(O)NR ³² R ^32' , -OS(O) ₂ NR ³² R ^32' , -NR ^{32. R 32 ', -NR 32 C (} O) R 33, -NR 32 C (O) OR 33, -NR 32 C (O) NR 33 R 33', -NR 32 S (O) R 33, -NR 32 _{^{S (O) 2 R 33,}} -NR 32 S (O) NR 33 R 33 ', -NR 32 S (O) 2 NR 33 R 33', -C (O) R 32, -C (O) OR 32 Or optionally substituted by -C(O)NR ³² R ^32' ;
^{R 32, R 32 ', R} 33 and ^{R 33,} H _{independently, D,} C 1 ~C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl it is selected from the group consisting of 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a covalent bond]
Is. In some embodiments, R ³¹ is H.

〔式中、
Ｒ^３１はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３２、−ＯＣ（Ｏ）Ｒ^３２、−ＯＣ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）Ｒ^３２、−ＯＳ（Ｏ）_２Ｒ^３２、−ＳＲ^３２、−Ｓ（Ｏ）Ｒ^３２、−Ｓ（Ｏ）_２Ｒ^３２、−Ｓ（Ｏ）ＮＲ^３２Ｒ^３２’、−Ｓ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｃ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｃ（Ｏ）ＯＲ^３３、−ＮＲ^３２Ｃ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）_２Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）_２ＮＲ^３３Ｒ^３３’、−Ｃ（Ｏ）Ｒ^３２、−Ｃ（Ｏ）ＯＲ^３２または−Ｃ（Ｏ）ＮＲ^３２Ｒ^３２’により置換されていてよく；
Ｒ^３２、Ｒ^３２’、Ｒ^３３およびＲ^３３’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、および５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
である。いくつかの態様において、Ｒ^３１はＨである In some embodiments, L ² is

[In the formula,
R ³¹ is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₁ -C ₆ alkyl. each hydrogen atom in _C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl , _C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 32, -OC (O)} R ³² , -OC(O)NR ³² R ^32' , -OS(O)R ³² , -OS(O) ₂ R ³² , -SR ³² , -S(O)R ³² , -S(O) ₂ R ^32. , -S(O)NR ³² R ^32' , -S(O) ₂ NR ³² R ^32' , -OS(O)NR ³² R ^32' , -OS(O) ₂ NR ³² R ^32' , -NR ^{32. R 32 ', -NR 32 C (} O) R 33, -NR 32 C (O) OR 33, -NR 32 C (O) NR 33 R 33', -NR 32 S (O) R 33, -NR 32 _{^{S (O) 2 R 33,}} -NR 32 S (O) NR 33 R 33 ', -NR 32 S (O) 2 NR 33 R 33', -C (O) R 32, -C (O) OR 32 Or optionally substituted by -C(O)NR ³² R ^32' ;
^{R 32, R 32 ', R} 33 and ^{R 33'} is, H _{independently, D,} C 1 ~C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl, and 5-7 membered heteroaryl; and * is a covalent bond]
Is. In some embodiments, R ³¹ is H

〔式中、
Ｒ^３１はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立してハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３２、−ＯＣ（Ｏ）Ｒ^３２、−ＯＣ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）Ｒ^３２、−ＯＳ（Ｏ）_２Ｒ^３２、−ＳＲ^３２、−Ｓ（Ｏ）Ｒ^３２、−Ｓ（Ｏ）_２Ｒ^３２、−Ｓ（Ｏ）ＮＲ^３２Ｒ^３２’、−Ｓ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｃ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｃ（Ｏ）ＯＲ^３３、−ＮＲ^３２Ｃ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）_２Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）_２ＮＲ^３３Ｒ^３３’、−Ｃ（Ｏ）Ｒ^３２、−Ｃ（Ｏ）ＯＲ^３２または−Ｃ（Ｏ）ＮＲ^３２Ｒ^３２’により置換されていてよく；
Ｒ^３２、Ｒ^３２’、Ｒ^３３およびＲ^３３’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
である。いくつかの態様において、Ｒ^３１はＨである。 In some embodiments, L ² is

[In the formula,
R ³¹ is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₁ -C ₆ alkyl. each hydrogen atom in _C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl, halogen _{independently,} C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl, C} 2 ~ C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 32, -OC (O)} R 32, -OC (O)NR ³² R ^32' , -OS(O)R ³² , -OS(O) ₂ R ³² , -SR ³² , -S(O)R ³² , -S(O) ₂ R ³² , -S( ^{O) NR 32 R 32 ',} -S (O) 2 NR 32 R 32', -OS (O) NR 32 R 32 ', -OS (O) 2 NR 32 R 32', -NR 32 R 32 ', -NR ³² C(O)R ³³ , -NR ³² C(O)OR ³³ , -NR ³² C(O)NR ³³ R ^33' , -NR ³² S(O)R ³³ , -NR ³² S(O). _{^{2 R 33, -NR 32 S (}} O) NR 33 R 33 ', -NR 32 S (O) 2 NR 33 R 33', -C (O) R 32, -C (O) oR 32 or -C ( O) optionally substituted by NR ³² R ^32′ ;
R ³² , R ^32′ , R ³³ and R ^33′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a covalent bond]
Is. In some embodiments, R ³¹ is H.

〔式中、
Ｒ^３１はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３２、−ＯＣ（Ｏ）Ｒ^３２、−ＯＣ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）Ｒ^３２、−ＯＳ（Ｏ）_２Ｒ^３２、−ＳＲ^３２、−Ｓ（Ｏ）Ｒ^３２、−Ｓ（Ｏ）_２Ｒ^３２、−Ｓ（Ｏ）ＮＲ^３２Ｒ^３２’、−Ｓ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｃ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｃ（Ｏ）ＯＲ^３３、−ＮＲ^３２Ｃ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）_２Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）_２ＮＲ^３３Ｒ^３３’、−Ｃ（Ｏ）Ｒ^３２、−Ｃ（Ｏ）ＯＲ^３２または−Ｃ（Ｏ）ＮＲ^３２Ｒ^３２’により置換されていてよく；
それぞれのＲ^３２、Ｒ^３２’、Ｒ^３３およびＲ^３３’は、独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
である。いくつかの態様において、Ｒ^３１はＨである。 In some embodiments, L ² is

[In the formula,
R ³¹ is selected _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 _{~ 6} alkynyl and _C 3 -C ₆ group consisting of cycloalkyl, wherein _C 1 -C ₆ alkyl, C ₂ -C _{6 alkenyl,} each hydrogen atom in the C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl, C ₂ -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 32, -OC (O)} R 32 , -OC(O)NR ³² R ^32' , -OS(O)R ³² , -OS(O) ₂ R ³² , -SR ³² , -S(O)R ³² , -S(O) ₂ R ³² , -S(O)NR ³² R ^32' , -S(O) ₂ NR ³² R ^32' , -OS(O)NR ³² R ^32' , -OS(O) ₂ NR ³² R ^32' , -NR ³² R ^{32 ', -NR 32 C (O} ) R 33, -NR 32 C (O) OR 33, -NR 32 C (O) NR 33 R 33', -NR 32 S (O) R 33, -NR 32 S _{^{(O) 2 R 33, -NR}} 32 S (O) NR 33 R 33 ', -NR 32 S (O) 2 NR 33 R 33', -C (O) R 32, -C (O) oR 32 or -C(O)NR ³² R ^32' may be substituted;
Each ^{R 32, R 32 ', R} 33 and ^{R 33'} is, H _{independently, D,} C 1 ~C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a covalent bond]
Is. In some embodiments, R ³¹ is H.

〔式中、
Ｒ^３１はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３２、−ＯＣ（Ｏ）Ｒ^３２、−ＯＣ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）Ｒ^３２、−ＯＳ（Ｏ）_２Ｒ^３２、−ＳＲ^３２、−Ｓ（Ｏ）Ｒ^３２、−Ｓ（Ｏ）_２Ｒ^３２、−Ｓ（Ｏ）ＮＲ^３２Ｒ^３２’、−Ｓ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｃ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｃ（Ｏ）ＯＲ^３３、−ＮＲ^３２Ｃ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）_２Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）_２ＮＲ^３３Ｒ^３３’、−Ｃ（Ｏ）Ｒ^３２、−Ｃ（Ｏ）ＯＲ^３２または−Ｃ（Ｏ）ＮＲ^３２Ｒ^３２’により置換されていてよく；
Ｒ^３２、Ｒ^３２’、Ｒ^３３およびＲ^３３’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
である。いくつかの態様において、Ｒ^３１はＨである。 In some embodiments, L ² is

[In the formula,
R ³¹ is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₂ -C ₆ alkenyl. , Each hydrogen atom in C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl is independently, optionally, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl. , C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-7 membered heteroaryl, —OR ³² , —OC(O)R ³² , —OC(O). ^{NR 32 R 32 ', -OS (} O) R 32, -OS (O) 2 R 32, -SR 32, -S (O) R 32, -S (O) 2 R 32, -S (O) NR _{^{32 R 32 ', -S (O}} ) 2 NR 32 R 32', -OS (O) NR 32 R 32 ', -OS (O) 2 NR 32 R 32', -NR 32 R 32 ', -NR 32 C(O)R ³³ , -NR ³² C(O)OR ³³ , -NR ³² C(O)NR ³³ R ^33' , -NR ³² S(O)R ³³ , -NR ³² S(O) ₂ R ^33. , -NR ³² S(O)NR ³³ R ^33' , -NR ³² S(O) ₂ NR ³³ R ^33' , -C(O)R ³² , -C(O)OR ³² or -C(O)NR. ³² R ^32′ may be substituted;
R ³² , R ^32′ , R ³³ and R ^33′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a covalent bond]
Is. In some embodiments, R ³¹ is H.

〔式中、
Ｒ^３１はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここで、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３２、−ＯＣ（Ｏ）Ｒ^３２、−ＯＣ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）Ｒ^３２、−ＯＳ（Ｏ）_２Ｒ^３２、−ＳＲ^３２、−Ｓ（Ｏ）Ｒ^３２、−Ｓ（Ｏ）_２Ｒ^３２、−Ｓ（Ｏ）ＮＲ^３２Ｒ^３２’、−Ｓ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｃ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｃ（Ｏ）ＯＲ^３３、−ＮＲ^３２Ｃ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）_２Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）_２ＮＲ^３３Ｒ^３３’、−Ｃ（Ｏ）Ｒ^３２、−Ｃ（Ｏ）ＯＲ^３２または−Ｃ（Ｏ）ＮＲ^３２Ｒ^３２’により置換されていてよく；
Ｒ^３２、Ｒ^３２’、Ｒ^３３およびＲ^３３’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
である。いくつかの態様において、Ｒ^３１はＨである。 In some embodiments, L ² is

[In the formula,
R ³¹ is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₂ -C _{6 alkenyl,} each hydrogen atom in the C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 32, -OC (O)} R 32, -OC (O ^{) NR 32 R 32 ', -OS} (O) R 32, -OS (O) 2 R 32, -SR 32, -S (O) R 32, -S (O) 2 R 32, -S (O) NR ³² R ^32' , -S(O) ₂ NR ³² R ^32' , -OS(O)NR ³² R ^32' , -OS(O) ₂ NR ³² R ^32' , -NR ³² R ^32' , -NR. ³² C(O)R ³³ , -NR ³² C(O)OR ³³ , -NR ³² C(O)NR ³³ R ^33' , -NR ³² S(O)R ³³ , -NR ³² S(O) ₂ R. ³³ , -NR ³² S(O)NR ³³ R ^33' , -NR ³² S(O) ₂ NR ³³ R ^33' , -C(O)R ³² , -C(O)OR ³² or -C(O). Optionally substituted by NR ³² R ^32′ ;
R ³² , R ^32′ , R ³³ and R ^33′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a covalent bond]
Is. In some embodiments, R ³¹ is H.

〔式中、
Ｒ^３１はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３２、−ＯＣ（Ｏ）Ｒ^３２、−ＯＣ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）Ｒ^３２、−ＯＳ（Ｏ）_２Ｒ^３２、−ＳＲ^３２、−Ｓ（Ｏ）Ｒ^３２、−Ｓ（Ｏ）_２Ｒ^３２、−Ｓ（Ｏ）ＮＲ^３２Ｒ^３２’、−Ｓ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｃ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｃ（Ｏ）ＯＲ^３３、−ＮＲ^３２Ｃ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）_２Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）_２ＮＲ^３３Ｒ^３３’、−Ｃ（Ｏ）Ｒ^３２、−Ｃ（Ｏ）ＯＲ^３２または−Ｃ（Ｏ）ＮＲ^３２Ｒ^３２’により置換されていてよく；
Ｒ^３２、Ｒ^３２’、Ｒ^３３およびＲ^３３’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
である。いくつかの態様において、Ｒ^３１はＨである。 In some embodiments, L ² is

[In the formula,
R ³¹ is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₂ -C ₆ alkenyl. , Each hydrogen atom in C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl is independently, optionally, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl. , C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-7 membered heteroaryl, —OR ³² , —OC(O)R ³² , —OC(O). ^{NR 32 R 32 ', -OS (} O) R 32, -OS (O) 2 R 32, -SR 32, -S (O) R 32, -S (O) 2 R 32, -S (O) NR _{^{32 R 32 ', -S (O}} ) 2 NR 32 R 32', -OS (O) NR 32 R 32 ', -OS (O) 2 NR 32 R 32', -NR 32 R 32 ', -NR 32 C(O)R ³³ , -NR ³² C(O)OR ³³ , -NR ³² C(O)NR ³³ R ^33' , -NR ³² S(O)R ³³ , -NR ³² S(O) ₂ R ^33. , -NR ³² S(O)NR ³³ R ^33' , -NR ³² S(O) ₂ NR ³³ R ^33' , -C(O)R ³² , -C(O)OR ³² or -C(O)NR. ³² R ^32′ may be substituted;
R ³² , R ^32′ , R ³³ and R ^33′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a covalent bond]
Is. In some embodiments, R ³¹ is H.

〔式中、
Ｒ^３１はＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３２、−ＯＣ（Ｏ）Ｒ^３２、−ＯＣ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）Ｒ^３２、−ＯＳ（Ｏ）_２Ｒ^３２、−ＳＲ^３２、−Ｓ（Ｏ）Ｒ^３２、−Ｓ（Ｏ）_２Ｒ^３２、−Ｓ（Ｏ）ＮＲ^３２Ｒ^３２’、−Ｓ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）ＮＲ^３２Ｒ^３２’、−ＯＳ（Ｏ）_２ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｒ^３２’、−ＮＲ^３２Ｃ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｃ（Ｏ）ＯＲ^３３、−ＮＲ^３２Ｃ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）_２Ｒ^３３、−ＮＲ^３２Ｓ（Ｏ）ＮＲ^３３Ｒ^３３’、−ＮＲ^３２Ｓ（Ｏ）_２ＮＲ^３３Ｒ^３３’、−Ｃ（Ｏ）Ｒ^３２、−Ｃ（Ｏ）ＯＲ^３２または−Ｃ（Ｏ）ＮＲ^３２Ｒ^３２’により置換されていてよく；
Ｒ^３２、Ｒ^３２’、Ｒ^３３およびＲ^３３’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
である。いくつかの態様において、Ｒ^３１はＨである。 In some embodiments, L ² is

[In the formula,
R ³¹ is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₂ -C ₆ alkenyl. , Each hydrogen atom in C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl is independently, optionally, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl. , C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-7 membered heteroaryl, —OR ³² , —OC(O)R ³² , —OC(O). ^{NR 32 R 32 ', -OS (} O) R 32, -OS (O) 2 R 32, -SR 32, -S (O) R 32, -S (O) 2 R 32, -S (O) NR _{^{32 R 32 ', -S (O}} ) 2 NR 32 R 32', -OS (O) NR 32 R 32 ', -OS (O) 2 NR 32 R 32', -NR 32 R 32 ', -NR 32 C(O)R ³³ , -NR ³² C(O)OR ³³ , -NR ³² C(O)NR ³³ R ^33' , -NR ³² S(O)R ³³ , -NR ³² S(O) ₂ R ^33. , -NR ³² S(O)NR ³³ R ^33' , -NR ³² S(O) ₂ NR ³³ R ^33' , -C(O)R ³² , -C(O)OR ³² or -C(O)NR. ³² R ^32′ may be substituted;
R ³² , R ^32′ , R ³³ and R ^33′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a covalent bond]
Is. In some embodiments, R ³¹ is H.

〔式中、
Ｒ^３６は独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３７、−ＯＣ（Ｏ）Ｒ^３７、−ＯＣ（Ｏ）ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）Ｒ^３７、−ＯＳ（Ｏ）_２Ｒ^３７、−ＳＲ^３７、−Ｓ（Ｏ）Ｒ^３７、−Ｓ（Ｏ）_２Ｒ^３７、−Ｓ（Ｏ）ＮＲ^３７Ｒ^３７’、−Ｓ（Ｏ）_２ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）_２ＮＲ^３７Ｒ^３７’、−ＮＲ^３７Ｒ^３７’、−ＮＲ^３７Ｃ（Ｏ）Ｒ^３８、−ＮＲ^３７Ｃ（Ｏ）ＯＲ^３８、−ＮＲ^３７Ｃ（Ｏ）ＮＲ^３８Ｒ^３８’、−ＮＲ^３７Ｓ（Ｏ）Ｒ^３８、−ＮＲ^３７Ｓ（Ｏ）_２Ｒ^３８、−ＮＲ^３７Ｓ（Ｏ）ＮＲ^３８Ｒ^３８’、−ＮＲ^３７Ｓ（Ｏ）_２ＮＲ^３８Ｒ^３８’、−Ｃ（Ｏ）Ｒ^３７、−Ｃ（Ｏ）ＯＲ^３７または−Ｃ（Ｏ）ＮＲ^３７Ｒ^３７’により置換されていてよく；
Ｒ^３７、Ｒ^３７’、Ｒ^３８およびＲ^３８’は、それぞれ独立してＨ、Ｄ、Ｃ_１−Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
である。いくつかの態様において、Ｒ^３６はＨである。 In some embodiments, L ² is

[In the formula,
R ³⁶ is independently selected _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C _{6 alkenyl,} a C 2 -C ₆ alkynyl and _C 3 -C ₆ group consisting of cycloalkyl, wherein _C 2 ~ each hydrogen atom in C _{6 alkenyl,} C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl, C} 2 ~ C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 37, -OC (O)} R 37, -OC ^{(O) NR 37 R 37 '} , -OS (O) R 37, -OS (O) 2 R 37, -SR 37, -S (O) R 37, -S (O) 2 R 37, -S ( ^{O) NR 37 R 37 ',} -S (O) 2 NR 37 R 37', -OS (O) NR 37 R 37 ', -OS (O) 2 NR 37 R 37', -NR 37 R 37 ', ^{-NR 37 C (O) R 38} , -NR 37 C (O) OR 38, -NR 37 C (O) NR 38 R 38 ', -NR 37 S (O) R 38, -NR 37 S (O) _{^{2 R 38, -NR 37 S (}} O) NR 38 R 38 ', -NR 37 S (O) 2 NR 38 R 38', -C (O) R 37, -C (O) oR 37 or -C ( O) optionally substituted by NR ³⁷ R ^37′ ;
R ³⁷ , R ^37′ , R ³⁸ and R ^38′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a covalent bond]
Is. In some embodiments, R ³⁶ is H.

〔式中、
Ｒ^３６は、独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３７、−ＯＣ（Ｏ）Ｒ^３７、−ＯＣ（Ｏ）ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）Ｒ^３７、−ＯＳ（Ｏ）_２Ｒ^３７、−ＳＲ^３７、−Ｓ（Ｏ）Ｒ^３７、−Ｓ（Ｏ）_２Ｒ^３７、−Ｓ（Ｏ）ＮＲ^３７Ｒ^３７’、−Ｓ（Ｏ）_２ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）_２ＮＲ^３７Ｒ^３７’、−ＮＲ^３７Ｒ^３７’、−ＮＲ^３７Ｃ（Ｏ）Ｒ^３８、−ＮＲ^３７Ｃ（Ｏ）ＯＲ^３８、−ＮＲ^３７Ｃ（Ｏ）ＮＲ^３８Ｒ^３８’、−ＮＲ^３７Ｓ（Ｏ）Ｒ^３８、−ＮＲ^３７Ｓ（Ｏ）_２Ｒ^３８、−ＮＲ^３７Ｓ（Ｏ）ＮＲ^３８Ｒ^３８’、−ＮＲ^３７Ｓ（Ｏ）_２ＮＲ^３８Ｒ^３８’、−Ｃ（Ｏ）Ｒ^３７、−Ｃ（Ｏ）ＯＲ^３７または−Ｃ（Ｏ）ＮＲ^３７Ｒ^３７’により置換されていてよく；
Ｒ^３７、Ｒ^３７’、Ｒ^３８およびＲ^３８’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
である。いくつかの態様において、Ｒ^３６はＨである。 In some embodiments, L ² is

[In the formula,
R ³⁶ is independently selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₂ -C _{6 alkenyl,} each hydrogen atom in the C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl, _{C 2} -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 37, -OC (O)} R 37, - ^{OC (O) NR 37 R 37} ', -OS (O) R 37, -OS (O) 2 R 37, -SR 37, -S (O) R 37, -S (O) 2 R 37, -S ^{(O) NR 37 R 37 '} , -S (O) 2 NR 37 R 37', -OS (O) NR 37 R 37 ', -OS (O) 2 NR 37 R 37', -NR 37 R 37 ' ^{, -NR 37 C (O) R} 38, -NR 37 C (O) OR 38, -NR 37 C (O) NR 38 R 38 ', -NR 37 S (O) R 38, -NR 37 S (O _{^{) 2 R 38, -NR 37 S}} (O) NR 38 R 38 ', -NR 37 S (O) 2 NR 38 R 38', -C (O) R 37, -C (O) oR 37 or -C (O) NR ³⁷ R ^37′ may be substituted;
R ³⁷ , R ^37′ , R ³⁸ and R ^38′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a covalent bond]
Is. In some embodiments, R ³⁶ is H.

〔式中、
Ｒ^３６は、独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルから成る群から選択され、ここでＣ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニルおよびＣ_３〜Ｃ_６シクロアルキルにおける各水素原子は、独立して、場合により、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^３７、−ＯＣ（Ｏ）Ｒ^３７、−ＯＣ（Ｏ）ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）Ｒ^３７、−ＯＳ（Ｏ）_２Ｒ^３７、−ＳＲ^３７、−Ｓ（Ｏ）Ｒ^３７、−Ｓ（Ｏ）_２Ｒ^３７、−Ｓ（Ｏ）ＮＲ^３７Ｒ^３７’、−Ｓ（Ｏ）_２ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）ＮＲ^３７Ｒ^３７’、−ＯＳ（Ｏ）_２ＮＲ^３７Ｒ^３７’、−ＮＲ^３７Ｒ^３７’、−ＮＲ^３７Ｃ（Ｏ）Ｒ^３８、
−ＮＲ^３７Ｃ（Ｏ）ＯＲ^３８、−ＮＲ^３７Ｃ（Ｏ）ＮＲ^３８Ｒ^３８’、−ＮＲ^３７Ｓ（Ｏ）Ｒ^３８、−ＮＲ^３７Ｓ（Ｏ）_２Ｒ^３８、−ＮＲ^３７Ｓ（Ｏ）ＮＲ^３８Ｒ^３８’、−ＮＲ^３７Ｓ（Ｏ）_２ＮＲ^３８Ｒ^３８’、−Ｃ（Ｏ）Ｒ^３７、−Ｃ（Ｏ）ＯＲ^３７または−Ｃ（Ｏ）ＮＲ^３７Ｒ^３７’により置換されていてよく；
Ｒ^３７、Ｒ^３７’、Ｒ^３８およびＲ^３８’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は共有結合である〕
である。いくつかの態様において、Ｒ^３６はＨである。 In some embodiments, L ² is

[In the formula,
R ³⁶ is independently selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₂ -C _{6 alkenyl,} each hydrogen atom in the C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl, _{C 2} -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 37, -OC (O)} R 37, - ^{OC (O) NR 37 R 37} ', -OS (O) R 37, -OS (O) 2 R 37, -SR 37, -S (O) R 37, -S (O) 2 R 37, -S ^{(O) NR 37 R 37 '} , -S (O) 2 NR 37 R 37', -OS (O) NR 37 R 37 ', -OS (O) 2 NR 37 R 37', -NR 37 R 37 ' , -NR ³⁷ C(O)R ³⁸ ,
^{-NR 37 C (O) OR 38} , -NR 37 C (O) NR 38 R 38 ', -NR 37 S (O) R 38, -NR 37 S (O) 2 R 38, -NR 37 S (O ) ^NR 38 ^{R 38} is substituted by _{^{', -NR 37 S (O)}} 2 NR 38 R 38', -C (O) R 37, -C (O) oR 37 or ^{-C (O) NR 37 R 37} ' You may;
R ³⁷ , R ^37′ , R ³⁸ and R ^38′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a covalent bond]
Is. In some embodiments, R ³⁶ is H.

In conjugates described herein, L ³ may not be present. When L ³ is present, L ³ can be any group that covalently attaches the linker moieties to each other or to D ¹ or D ² . It is understood that the structure of L ³ is not particularly limited in any method. In addition, L ³ includes, but is not limited to, alkyl groups, ether groups, amide groups, carboxy groups, sulfonic acid groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocycloalkyl, heteroaryl groups, It is understood to include a number of functional groups well known to those skilled in the art that covalently link the linker moieties to each other or to D ¹ or D ² . In some embodiments, ^{L 3} is _C 1 -C ₆ ^{alkyl, - (CR 39 R 39 '} ) r C (O) -, - (CR 39 R 39') r OC (O) -, - NR 39 R ^{39 'C (O) (CR} 39 R 39') r -, - (CH 2) r NR 39 -, - (OCR 39 R 39 'CR 39 R 39') r C (O) - and - ^{(OCR 39 R 39 'CR 39 R 39'} CR 39 R 39 ') - r C (O) - is selected from the group consisting of,
here,
R ³⁹ and R ^39′ are each independently H, D, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7. membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 40, -OC (O)} R 40, -OC (O) NR 40 R 40 ', -OS (O) R _{^{40, -OS (O) 2 R}} 40, -SR 40, -S (O) R 40, -S (O) 2 R 40, -S (O) NR 40 R 40 ', -S (O) 2 NR ^{40 R 40 ', -OS (O} ) NR 40 R 40', -OS (O) 2 NR 40 R 40 ', -NR 40 R 40', -NR 40 C (O) R 41, -NR 40 C ( ^{O) OR 41, -NR 40 C} (O) NR 41 R 41 ', -NR 40 S (O) R 41, -NR 40 S (O) 2 R 41, -NR 40 S (O) NR 41 R 41 _{^{', -NR 40 S (O)}} 2 NR 41 R 41', are selected from the group consisting of ^{-C (O) R 40, -C} (O) oR 40 and ^{-C (O) NR 40 R 40} ';
R ⁴⁰ , R ^40′ , R ⁴¹ and R ^41′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and r in each case is 1, 2, 3, 4 or 5. In some embodiments of the conjugates described herein, L ³ is present. In some embodiments of the conjugates described herein, L ³ is absent. In some embodiments, z2 is 0. In some embodiments, z2 is 1. In some embodiments, z2 is 2. In some embodiments, z6 is 0. In some embodiments, z6 is 1. In some embodiments, z6 is 2. In some embodiments, r is 5. In some embodiments, r is 4. In some embodiments, r is 3. In some embodiments, r is 5, each R ³⁹ is H, and each R ^39′ is H. In some embodiments, r is 4, each R ³⁹ is H, and each R ^39′ is H. In some embodiments, r is 3, each R ³⁹ is H, and each R ^39′ is H.

In some embodiments, ^{L 3} is ^{- (CR 39 R 39 ')} r C (O) - is. In some embodiments, ^{L 3} is ^{- (CR 39 R 39 ')} r C (O) - and is, r is 5, each ^{R 39} is H, and each ^{R 39'} is H. In some embodiments, ^{L 3} is ^{- (CR 39 R 39 ')} r C (O) - and is, r is 4, each ^{R 39} is H, and each ^{R 39'} is H. In some embodiments, ^{L 3} is ^{- (CR 39 R 39 ')} r C (O) - and is, r is 3, each ^{R 39} is H, and each ^{R 39'} is H.

In some embodiments, ^{L 3} is ^{- (CR 39 R 39 ')} r OC (O) - and is, r is 5, each ^{R 39} is H, and each ^{R 39'} is H. In some embodiments, ^{L 3} is ^{- (CR 39 R 39 ')} r OC (O) - and is, r is 4, each ^{R 39} is H, and each ^{R 39'} is H. In some embodiments, ^{L 3} is ^{- (CR 39 R 39 ')} r OC (O) - and is, r is 3, each ^{R 39} is H, and each ^{R 39'} is H.

In some embodiments, ^{L 3} is ^{-NR 39 R 39 'C (O} ) (CR 39 R 39') r - a and, r is 5, each ^{R 39} is H, and each ^{R 39 '} Is H. In some embodiments, L ³ is —NR ³⁹ R ^39′ C(O)(CR ³⁹ R ^39′ ) _r −, r is 4, each R ³⁹ is H, and each R ^39′. Is H. In some embodiments, ^{L 3} is ^{-NR 39 R 39 'C (O} ) (CR 39 R 39') r - a and, r is 3, each ^{R 39} is H, and each ^{R 39 '} Is H.

In some embodiments, ^{L 3} is ^{_{- (CH 2) r NR 39}} - a and, r is 5 and ^{R 39} is H. In some embodiments, ^{L 3} is ^{_{- (CH 2) r NR 39}} - a and, r is 4, and ^{R 39} is H. In some embodiments, ^{L 3} is ^{_{- (CH 2) r NR 39}} - a and, r is 3 and ^{R 39} is H. In some embodiments, ^{L 3} is ^{_{- (CH 2) r NR 39}} - a and, r is 2 and ^{R 39} is H.

In some embodiments, ^{L 3} is ^{- (OCR 39 R 39 'CR} 39 R 39') r C (O) - and is, r is 5, each ^{R 39} is H, and each ^{R 39 '} Is H. In some embodiments, ^{L 3} is ^{- (OCR 39 R 39 'CR} 39 R 39') r C (O) - and is, r is 4, each ^{R 39} is H, and each ^{R 39 'is} H Is. In some embodiments, ^{L 3} is ^{- (OCR 39 R 39 'CR} 39 R 39') r C (O) - and is, r is 3, each ^{R 39} is H, and each ^{R 39 '} Is H.

In conjugates described herein, L ⁴ may or may not be present. When L ⁴ is present, L ⁴ can be any group that covalently attaches the linker moieties to each other or to D ¹ or D ² . It is understood that the structure of L ⁴ is not particularly limited in any method. Further, L ⁴ includes, but is not limited to, alkyl groups, ether groups, amide groups, carboxy groups, sulfonic acid groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocycloalkyl, heteroaryl groups, and the like. It is understood that it comprises a number of functional groups well known to those skilled in the art which covalently link the linker moieties to each other or to D ¹ or D ² . In some embodiments, ^{L 4} is ^{-C (O) (CR 44 R} 44 ') t -, - NR 42 CR 43 R 43' CR 43 R 43 '(OCR 44 R 44' CR 44 R 44 ') t -, -NR ⁴² CR ⁴³ R ^43' CR ⁴³ R ^43' (OCR ⁴⁴ R ^44' CR ⁴⁴ R ^44' ) _t -, -NR ⁴² CR ⁴³ R ^43' CR ⁴³ R ^43' (OCR ⁴⁴ R ^44' CR _{^{44 R 44 ') t C (}} O) -, - NR 42 CR 43 R 43' CR 43 R 43 '(CR 44 = CR 44') t - and ^-NR 42 _C 6 _{~C 10} aryl _(C 1 -C ₆ alkyl)OC(O)-;
here,
R ⁴² is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, wherein C ₁ -C ₆ alkyl. each hydrogen atom in _C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl , _C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 45, -OC (O)} R ⁴⁵ , -OC(O)NR ⁴⁵ R ^45' , -OS(O)R ⁴⁵ , -OS(O) ₂ R ⁴⁵ , -SR ⁴⁵ , -S(O)R ⁴⁵ , -S(O) ₂ R ^45. , -S(O)NR ⁴⁵ R ^45' , -S(O) ₂ NR ⁴⁵ R ^45' , -OS(O)NR ⁴⁵ R ^45' , -OS(O) ₂ NR ⁴⁵ R ^45' , -NR ^{45. R 45 ', -NR 45 C (} O) R 46, -NR 45 C (O) OR 46, -NR 45 C (O) NR 46 R 46', -NR 45 S (O) R 46, -NR 45 _{^{S (O) 2 R 46,}} -NR 45 S (O) NR 46 R 46 ', -NR 45 S (O) 2 NR 46 R 46', -C (O) R 45, -C (O) OR 45 Or optionally substituted by -C(O)NR ⁴⁵ R ^45' ,
R ^{43, R 43 ', R 44} and ^{R 44} are each independently _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl Each hydrogen atom in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl is independently, optionally, selected from the group consisting of: _halogen, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 47, -OC (O)} R 47, -OC (O) NR 47 R 47 ', -OS (O) R 47, -OS (O) 2 R 47, -SR 47, - S(O)R ⁴⁷ , -S(O) ₂ R ⁴⁷ , -S(O)NR ⁴⁷ R ^47' , -S(O) ₂ NR ⁴⁷ R ^47' , -OS(O)NR ⁴⁷ R ^47' , _{^{-OS (O) 2 NR 47 R}} 47 ', -NR 47 R 47', -NR 47 C (O) R 48, -NR 47 C (O) OR 48, -NR 47 C (O) NR 48 R 48 ^{', -NR 47 S (O)} R 48, -NR 47 S (O) 2 R 48, -NR 47 S (O) NR 48 R 48', -NR 47 S (O) 2 NR 48 R 48 ', Optionally substituted by -C(O)R ⁴⁷ , -C(O)OR ⁴⁷ or -C(O)NR ⁴⁷ R ^47' ;
R ⁴⁵ , R ^45′ , R ⁴⁶ , R ^46′ , R ⁴⁷ , R ^47′ , R ⁴⁸ and R ^48′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl. is selected from the group consisting of _C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl;
T in each case is 1, 2, 3, 4 or 5; and * is a covalent bond.

In some embodiments of the conjugates described herein, L ⁴ is present. In some embodiments of the conjugates described herein, L ⁴ is absent. In some embodiments, z5 is 0. In some embodiments, z5 is 1. In some embodiments, z5 is 2. In some embodiments, z7 is 0. In some embodiments, z7 is 1. In some embodiments, z7 is 2. In some embodiments, z9 is 0. In some embodiments, z9 is 1. In some embodiments, z9 is 2. In some embodiments, z7 is 0 and z9 is 0. In some embodiments, z7 is 0 and z9 is 1. In some embodiments, z7 is 1 and z9 is 1. In some embodiments, z7 is 1 and z9 is 0.

In some embodiments, L ⁴ is —NR ⁴² C ₆ -C ₁₀ aryl(C ₁ -C ₆ alkyl)OC(O)—, where R ⁴² is H. In some embodiments, z5 is 1 and L ⁴ is —NR ⁴² C ₆ -C ₁₀ aryl(C ₁ -C ₆ alkyl)OC(O)—, where R ⁴² is H. In some embodiments, z7 is 1 and L ⁴ is —NR ⁴² C ₆ -C ₁₀ aryl(C ₁ -C ₆ alkyl)OC(O)—, where R ⁴² is H. In some embodiments, z9 is 1 and L ⁴ is —NR ⁴² C ₆ -C ₁₀ aryl(C ₁ -C ₆ alkyl)OC(O)— and R ⁴² is H. In some embodiments, ^{L 4} is ^{-NR 42 CR 43 R 43 'CR} 43 R 43' (OCR 44 R 44 'CR 44 R 44') t C (O) - and is, wherein ^{R 42, R 43} , R ^43′ , R ⁴⁴ and R ^44′ are H and t is 4. In some embodiments, ^{L 4} is ^{-NR 42 CR 43 R 43 'CR} 43 R 43' (OCR 44 R 44 'CR 44 R 44') t C (O) - or ^-NR 42 _C 6 ^~C ₁₀ aryl _(C 1 -C ₆ alkyl) OC (O) - and is, wherein ^{R 42, R 43, R 43} ', R 44 and ^{R 44'} are each H, z7 is 1, z9 is 1 Yes, and t is 4.

In some embodiments, ^-L 3 -L ⁴ - is ^{_{- (CH 2) r NR 39}} C (O) (CR 44 R 44 ') t - a, where r is the 2, t is 2 , R ³⁹ is H, each R ⁴⁴ is H, and each R ^44′ is H. In some ^{embodiments, -L 3 -L 4 - (AA} ) 2 is ^{- (CR 39 R 39 ')} r C (O) -NR 42 CR 43 R 43' CR 43 R 43 '(OCR 44 R 44' _{^{CR 44 R 44 ') t C}} (O) is ^{-Val-Ala-, -L 3 -L 4} - (AA) 2 -L 4 is ^{- (CR 39 R 39')} r C (O) -NR 42 ^{CR 43 R 43 'CR 43 R} 43' (OCR 44 R 44 'CR 44 R 44') t C (O) -Val-Ala-NR 42 C 6 ~C 10 aryl _(C 1 -C ₆ alkyl) OC ( O)-, where R ³⁹ , R ^39′ , R ⁴² , R ⁴³ , R ^43′ , R ⁴⁴ and R ^44′ are each H, r is 2 and t is 4.

In the conjugates described herein, L ⁵ may or may not be present. When L ⁵ is present, L ⁵ can be any group that covalently bonds D ¹ to D ² . It is understood that the structure of L ⁵ is not particularly limited in any method. Further, L ⁵ includes, but is not limited to, alkyl groups, ether groups, amide groups, carboxy groups, sulfonic acid groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocycloalkyl, heteroaryl groups, and the like. It is understood to include a number of functional groups well known to those skilled in the art that covalently attach D ¹ to D ² . In some embodiments, ^{L 5} is _C 1 _{-C 10} ^{alkyl, - (CR 49 = CR 49} ') u -, - (CR 49 R 49') u C (O) -, - CH 2 CH 2 (OCR ⁴⁹ R ^{49 ′} CR ⁴⁹ R ^{49 ′} ) _u −, —CH ₂ CH ₂ CH ₂ (OCR ⁴⁹ R ^{49 ′} CR ⁴⁹ R ^{49 ′} CR ⁴⁹ R ^{49 ′} ) _u −, —CH ₂ CH ₂ (OCR ⁴⁹ R ^{49 _{'CR 49 R 49') u}} C (O) - and _{^{-CH 2 CH 2 (OCR 49 R}} 49 'CR 49 R 49' CR 49 R 49 ') u C (O) - is selected from the group consisting of,
here,
R ⁴⁹ and R ^49′ are each independently selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl. , Wherein each hydrogen atom in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl is, independently, optionally halogen, C ₁ -C. ₆ alkyl, C _{2 to} C ₆ alkenyl, C _{2 to} C ₆ alkynyl, C _{3 to} C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, − ^{OR 50, -OC (O) R} 50, -OC (O) NR 50 R 50 ', -OS (O) R 50, -OS (O) 2 R 50, -SR 50, -S (O) R 50 ^{_{, -S (O) 2 R 50}} , -S (O) NR 50 R 50 ', -S (O) 2 NR 50 R 50', -OS (O) NR 50 R 50 ', -OS (O) 2 ^{NR 50 R 50 ', -NR 50} R 50', -NR 50 C (O) R 51, -NR 50 C (O) OR 51, -NR 50 C (O) NR 51 R 51 ', -NR 50 S _{^{(O) R 51, -NR 50}} S (O) 2 R 51, -NR 50 S (O) NR 51 R 51 ', -NR 50 S (O) 2 NR 51 R 51', -C (O) R ^50, may be replaced by -C (O) ^{oR 50} or ^{-C (O) NR 50 R 50} ';
^{R 50, R 50 ', R} 51 and ^{R 51'} is, H _{independently, D,} C 1 ~C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl alkyl is selected from the group consisting of 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl;
U in each case is 0, 1, 2, 3, 4 or 5; and * is a covalent bond.

In some embodiments of the conjugates described herein, L ⁵ is present. In some embodiments of the conjugates described herein, L ⁵ is absent. In some embodiments, ^{L 5} is _C 1 -C ₆ alkyl. In some embodiments, ^{L 5} is ^{- (CR 49 R 49 ')} u C (O) - and is, wherein ^{R 49} and ^{R 49'} are each H, and u is 3. In some embodiments, ^{L 5} is ^{- (CR 49 R 49 ')} u C (O) - and is, wherein ^{R 49} and ^{R 49'} are each H, and u is 4. In some embodiments, ^{L 5} is ^{- (CR 49 R 49 ')} u C (O) - and is, wherein ^{R 49} and ^{R 49'} are each H, and u is 5.

In some embodiments, the linker has the formula ^{_{- (AA) z1 -L 2 -}} (L 3) z2 - (AA) z3 - (L 1) z4 - (L 4) z5 - are of where AA, L ¹ , L ² , L ³ , L ⁴ , z1, z2, z3, z4 and z5 are defined as described herein. In some embodiments, the linker has the formula ^{-L 1 -AA-L 1 -AA-} L 1 -L 2 - (L 3) z6 - (L 4) z7 - (AA) z8 - (L 4) z9 - the Where AA, L ¹ , L ² , L ³ , L ⁴ , z6, z7, z8 and z9 are defined as described herein. In some embodiments, the linker has the formula _{- (AA)} z10 -L ² _- is of, where AA, ^{L 2} and z10 are defined as described herein. In some embodiments, the linker has the formula _{- (AA)} z11 -L ² _- is of, where AA, ^{L 2} and z11 are defined as described herein. In some embodiments, the linker has the formula ^-L 2 - _{(AA) z12} - are of where AA, ^{L 2} and z12 are defined as described herein. In some embodiments, the linker has the formula ^- (AA) 4 _-L 2 - is of, where AA and L ² are defined as described herein. In some embodiments, the linker has the formula - _(AA) 4 -L ² - are of, wherein - _{(AA) 4} - sequences -Asp-Arg-Asp-Asp- and ^{L 2} herein Is defined as described in. In some embodiments, the linker has the formula _- is of, where ^{- - (AA) 4 -L 2} -L 3 -AA-L 1 -L 4 (AA) 4 - the sequence of -Asp-Arg- Asp-Asp-, and AA, L ¹ , L ² , L ³ and L ⁴ are defined as described herein. In some embodiments, the linker has the formula ^{_{- (AA) 4 -L 2 -L}} 3 - (AA) 2 - is of, where ^AA, L 1, ^{L 2} and ^{L 3,} as described herein Is defined as In some embodiments, the linker has the formula _- is of, where ^{- - (AA) 4 -L 2} -L 3 - (AA) 2 (AA) 4 - the sequence of -Asp-Arg-Asp-Asp - and, - _{(AA) 2} - sequences are Val-Ala, and ^L 1, ^{L 2} and ^{L 3} are defined as described herein. In some embodiments, the linker has the formula _- is of, where ^{- - (AA) 4 -L 2} -L 3 - (AA) 2 (AA) 4 - the sequence of -Asp-Arg-Asp-Asp - and, - _{(AA) 2} - sequences are Val-CIT, and ^L 1, ^{L 2} and ^{L 3} are defined as described herein. In some embodiments, the linker is of formula -L ¹ -AA-L ¹ -AA-L ¹ -L ² -, where AA, L ¹ and L ² are defined as described herein. To be done. In some embodiments, the linker is of formula -L1-AA-L1-AA- L1-L2-L3- (AA) 2 -L4-, where ^AA, L ^1, L 2, ^{L 3} and L ⁴ is defined as described herein. In some embodiments, the linker is of the formula -L ¹ -AA-L ¹ -AA-L ¹ -L ² -L ³ -L ⁴ -(AA) ₂ -L ⁴ -, where AA, L ¹ , L ² , L ³ and L ⁴ are defined as described herein. In some embodiments, the linker has the formula ^{-L 1 -AA-L 1 -AA-} L 1 -L 2 -L 3 -L 4 - are ^{of, AA, L 1, L 2} , L 3 and ^{L 4} Is defined as described herein. In some embodiments, the linker has the formula ^{-L 1 -AA-L 1 -AA-} L 1 -L 2 -L 3 - (AA) 2 - is of, where ^AA, L 1, ^{L 2} and L ³ is defined as described herein. ^{-L 1 -AA-L 1 -AA-} L 1 -L 2 -L 3 - in and, where ^AA, L 1, ^{L 2} and ^{L 3} are defined as described herein.

〔式中、
＊は結合である〕
のものである。 In some embodiments, the linker is of the formula

[In the formula,
* Is a bond]
belongs to.

〔式中、
＊は結合である〕
のものである。 In some embodiments, the linker is of the formula

[In the formula,
* Is a bond]
belongs to.

〔式中、
＊は結合である〕
のものである。 In some embodiments, the linker is of the formula

[In the formula,
* Is a bond]
belongs to.

〔式中、
＊は結合である〕
のものである。 In some embodiments, the linker is of the formula

[In the formula,
* Is a bond]
belongs to.

〔式中、
＊は結合である〕
のものである。 In some embodiments, the linker is of the formula

[In the formula,
* Is a bond]
belongs to.

〔式中、
＊は結合である〕
のものである。 In some embodiments, the linker is of the formula

[In the formula,
* Is a bond]
belongs to.

〔式中、
＊は結合である〕
のものである。 In some embodiments, the linker is of the formula

[In the formula,
* Is a bond]
belongs to.

〔式中、
＊は結合である〕
のものである。 In some embodiments, the linker is of the formula

[In the formula,
* Is a bond]
belongs to.

〔式中、
＊は結合である〕
のものである。 In some embodiments, the linker is of the formula

[In the formula,
* Is a bond]
belongs to.

In the conjugates described herein, drug (Drug) represents one or more agents covalently attached to the linker moiety of one or more conjugates. In some embodiments, both D ¹ and D ² are present. In some embodiments, the drug (D) comprises ^structure, a -D 1 ^-L 5 -D ^2. In some embodiments, the drug (Drug) the structure ^{-D 1 -L} 5 ^-D 1 - including.

Certain drugs D ¹ and D ² described herein include pyrrolobenzodiazepine (PBD) prodrugs. It is understood that such PBD prodrugs undergo processing in the body after delivery of the conjugates described herein to undergo conversion to therapeutically active PBD compounds. In some embodiments, at least one of the agents included in at least the conjugates described herein is a PBD prodrug described herein.

〔式中、
Ｒ^１ａ、Ｒ^２ａ、Ｒ^３ａおよびＲ^４ａは、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｃ（Ｏ）Ｒ^１１ａ、−Ｃ（Ｏ）ＯＲ^１１ａおよび−Ｃ（Ｏ）ＮＲ^１１ａＲ^１１ａ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合によりＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１１ａ、−ＯＣ（Ｏ）Ｒ^１１ａ、−ＯＣ（Ｏ）ＮＲ^１１ａＲ^１１ａ’、−ＯＳ（Ｏ）Ｒ^１１ａ、−ＯＳ（Ｏ）_２Ｒ^１１ａ、−ＳＲ^１１ａ、−Ｓ（Ｏ）Ｒ^１１ａ、−Ｓ（Ｏ）_２Ｒ^１１ａ、−Ｓ（Ｏ）ＮＲ^１１ａＲ^１１ａ’、−Ｓ（Ｏ）_２ＮＲ^１１ａＲ^１１ａ’、−ＯＳ（Ｏ）ＮＲ^１１ａＲ^１１ａ’、−ＯＳ（Ｏ）_２ＮＲ^１１ａＲ^１１ａ’、−ＮＲ^１１ａＲ^１１ａ’、−ＮＲ^１１ａＣ（Ｏ）Ｒ^１２ａ、−ＮＲ^１１ａＣ（Ｏ）ＯＲ^１２ａ、−ＮＲ^１１ａＣ（Ｏ）ＮＲ^１２ａＲ^１２ａ’、−ＮＲ^１１ａＳ（Ｏ）Ｒ^１２ａ、−ＮＲ^１１ａＳ（Ｏ）_２Ｒ^１２ａ、−ＮＲ^１１ａＳ（Ｏ）ＮＲ^１２ａＲ^１２ａ’、−ＮＲ^１１ａＳ（Ｏ）_２ＮＲ^１２ａＲ^１２ａ’、−Ｃ（Ｏ）Ｒ^１１ａ、−Ｃ（Ｏ）ＯＲ^１１ａまたは−Ｃ（Ｏ）ＮＲ^１１ａＲ^１１ａ’により置換されていてよく；またはＲ^１ａは結合であり；またはＲ^４ａは結合であり；
Ｒ^５ａ、Ｒ^６ａおよびＲ^７ａは、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｃ（Ｏ）Ｒ^１３ａ、−Ｃ（Ｏ）ＯＲ^１３ａおよび−Ｃ（Ｏ）ＮＲ^１３ａＲ^１３ａ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１４ａ、−ＯＣ（Ｏ）Ｒ^１４ａ、−ＯＣ（Ｏ）ＮＲ^１４ａＲ^１４ａ’、−ＯＳ（Ｏ）Ｒ^１４ａ、−ＯＳ（Ｏ）_２Ｒ^１４ａ、−ＳＲ^１４ａ、−Ｓ（Ｏ）Ｒ^１４ａ、−Ｓ（Ｏ）_２Ｒ^１４ａ、−Ｓ（Ｏ）ＮＲ^１４ａＲ^１４ａ’、−Ｓ（Ｏ）_２ＮＲ^１４ａＲ^１４ａ’、−ＯＳ（Ｏ）ＮＲ^１４ａＲ^１４ａ’、−ＯＳ（Ｏ）_２ＮＲ^１４ａＲ^１４ａ’、−ＮＲ^１４ａＲ^１４ａ’、−ＮＲ^１４ａＣ（Ｏ）Ｒ^１５ａ、−ＮＲ^１４ａＣ（Ｏ）ＯＲ^１５ａ、−ＮＲ^１４ａＣ（Ｏ）ＮＲ^１５ａＲ^１５ａ’、−ＮＲ^１４ａＳ（Ｏ）Ｒ^１５ａ、−ＮＲ^１４ａＳ（Ｏ）_２Ｒ^１５ａ、−ＮＲ^１４ａＳ（Ｏ）ＮＲ^１５ａＲ^１５ａ’、−ＮＲ^１４ａＳ（Ｏ）_２ＮＲ^１５ａＲ^１５ａ’、−Ｃ（Ｏ）Ｒ^１４ａ、−Ｃ（Ｏ）ＯＲ^１４ａまたは−Ｃ（Ｏ）ＮＲ^１４ａＲ^１４ａ’により置換されていてよく；ここでＲ^６ａおよびＲ^７ａは、それらが結合する原子と一緒になって、場合により結合して３〜７員環ヘテロシクロアルキルを形成し、またはＲ^５ａおよびＲ^６ａは、それらが結合する原子と一緒になって、場合により結合して３〜７員環ヘテロシクロアルキルまたは５〜７員環ヘテロアリールを形成し、ここで３〜７員環ヘテロシクロアルキルまたは５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１６ａ、−ＯＣ（Ｏ）Ｒ^１６ａ、−ＯＣ（Ｏ）ＮＲ^１６ａＲ^１６ａ’、−ＯＳ（Ｏ）Ｒ^１６ａ、−ＯＳ（Ｏ）_２Ｒ^１６ａ、−ＳＲ^１６ａ、−Ｓ（Ｏ）Ｒ^１６ａ、−Ｓ（Ｏ）_２Ｒ^１６ａ、−Ｓ（Ｏ）ＮＲ^１６ａＲ^１６ａ’、−Ｓ（Ｏ）_２ＮＲ^１６ａＲ^１６ａ’、−ＯＳ（Ｏ）ＮＲ^１６ａＲ^１６ａ’、−ＯＳ（Ｏ）_２ＮＲ^１６ａＲ^１６ａ’、−ＮＲ^１６ａＲ^１６ａ’、−ＮＲ^１６ａＣ（Ｏ）Ｒ^１７ａ、−ＮＲ^１６ａＣ（Ｏ）ＣＨ_２ＣＨ_２−、−ＮＲ^１６ａＣ（Ｏ）ＯＲ^１７ａ、−ＮＲ^１６ａＣ（Ｏ）ＮＲ^１７ａＲ^１７ａ’、−ＮＲ^１６ａＳ（Ｏ）Ｒ^１７ａ、−ＮＲ^１６ａＳ（Ｏ）_２Ｒ^１７ａ、−ＮＲ^１６ａＳ（Ｏ）ＮＲ^１７ａＲ^１７ａ’、−ＮＲ^１６ａＳ（Ｏ）_２ＮＲ^１７ａＲ^１７ａ’、−Ｃ（Ｏ）Ｒ^１６ａ、−Ｃ（Ｏ）ＯＲ^１６ａまたは−Ｃ（Ｏ）ＮＲ^１６ａＲ^１６ａ’により置換されていてよく、そしてここで５〜７員環ヘテロアリールにおける１個の水素原子は場合により結合であり、またはＲ^５ａは結合であり； D ¹ is the formula III

[In the formula,
R ^1a , R ^2a , R ^3a and R ^4a are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -C(O)R ^11a , -C(O)OR ^11a and -C(O)NR ^11a R ^11a'. Selected from the group consisting of: C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -. Each hydrogen atom in C ₁₀ aryl and 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cyclo. Alkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -OR ^11a , -OC(O)R ^11a , -OC(O)NR ^11a R ^11a' , -. OS(O)R ^11a , -OS(O) ₂ R ^11a , -SR ^11a , -S(O)R ^11a , -S(O) ₂ R ^11a , -S(O)NR ^11a R ^11a' , -S. (O) ₂ NR ^11a R ^11a′ , —OS(O)NR ^11a R ^11a′ , —OS(O) ₂ NR ^11a R ^11a′ , —NR ^11a R ^11a′ , —NR ^11a C(O)R ^12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a R ^12a' , -NR ^11a S(O)R ^12a , -NR ^11a S(O) ₂ R ^12a , -NR ^11a S(O). ) ^NR 12a ^{R 12a} is substituted by _{^{', -NR 11a S (O)}} 2 NR 12a R 12a', -C (O) R 11a, -C (O) oR 11a or ^{-C (O) NR 11a R 11a} ' Or R ^1a is a bond; or R ^4a is a bond;
R ^{5a, R 6a} and ^{R 7a} are, H independently, _D, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, the group consisting of -C (O) R 13a, -C (O) oR 13a , and ^{-C (O) NR 13a R 13a} ' Selected from where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl. and each hydrogen atom in the 5- to 7-membered heteroaryl, _optionally, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 14a, -OC (O)} R 14a, -OC (O) NR 14a R 14a ', -OS (O) R 14a _{^{, -OS (O) 2 R 14a}} , -SR 14a, -S (O) R 14a, -S (O) 2 R 14a, -S (O) NR 14a R 14a ', -S (O) 2 NR 14a ^{R 14a ', -OS (O)} NR 14a R 14a', -OS (O) 2 NR 14a R 14a ', -NR 14a R 14a', -NR 14a C (O) R 15a, -NR 14a C (O ) OR ^15a , -NR ^14a C(O)NR ^15a R ^15a' , -NR ^14a S(O)R ^15a , -NR ^14a S(O) ₂ R ^15a , -NR ^14a S(O)NR ^15a R ^15a'. , -NR ^14a S(O) ₂ NR ^15a R ^15a' , -C(O)R ^14a , -C(O)OR ^14a or -C(O)NR ^14a R ^14a' ; R ^6a and R ^7a , together with the atom to which they are attached, are optionally joined to form a 3-7 membered ring heterocycloalkyl, or R ^5a and R ^6a are together with the atom to which they are attached. To optionally combine to form a 3-7 membered heterocycloalkyl or a 5-7 membered heteroaryl, wherein the 3-7 membered heterocycloalkyl is Or each hydrogen atom in a 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -OR ^16a , -OC(O)R ^16a , -OC(O)NR ^16a R ^16a' , -OS( _{^{O) R 16a, -OS (O}} ) 2 R 16a, -SR 16a, -S (O) R 16a, -S (O) 2 R 16a, -S (O) NR 16a R 16a ', -S (O _{^{) 2 NR 16a R 16a ',}} -OS (O) NR 16a R 16a', -OS (O) 2 NR 16a R 16a ', -NR 16a R 16a', -NR 16a C (O) R 17a, -NR ^16a C(O)CH ₂ CH ₂ -, -NR ^16a C(O)OR ^17a , -NR ^16a C(O)NR ^17a R ^17a' , -NR ^16a S(O)R ^17a , -NR ^16a S(O). _{^{) 2 R 17a, -NR 16a S}} (O) NR 17a R 17a ', -NR 16a S (O) 2 NR 17a R 17a', -C (O) R 16a, -C (O) oR 16a or -C (O)NR ^16a R ^16a′ may be substituted and wherein one hydrogen atom in the 5-7 membered heteroaryl is optionally a bond or R ^5a is a bond;

R ^8a and R ^9a are each independently H, D, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 member. _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered _{^{heteroaryl, -CN, -NO 2, -NCO,}} -OR 18a, -OC (O) R 18a, -OC (O) NR 18a R _{^{18a ', -OS (O) R}} 18a, -OS (O) 2 R 18a, -SR 18a, -S (O) R 18a, -S (O) 2 R 18a,
-S(O)NR ^18a R ^18a' , -S(O) ₂ NR ^18a R ^18a' , -OS(O)NR ^18a R ^18a' , -OS(O) ₂ NR ^18a R ^18a' , -NR ^18a R. ^18a' , -NR ^18a C(O)R ^19a , -NR ^18a C(O)OR ^19a , -NR ^18a C(O)NR ^19a R ^19a' , -NR ^18a S(O)R ^19a , -NR ^18a S. _{^{(O) 2 R 19a, -NR}} 18a S (O) NR 19a R 19a ', -NR 18a S (O) 2 NR 19a R 19a', -C (O) R 18a, -C (O) oR 18a , and —C(O)NR ^18a R ^18a′ selected from the group consisting of C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 Each hydrogen atom in the 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 20a, -OC (O)} R 20a, - OC(O)NR ^20a R ^20a' , -OS(O)R ^20a , -OS(O) ₂ R ^20a , -SR ^20a , -S(O)R ^20a , -S(O) ₂ R ^20a , -S. (O)NR ^20a R ^20a' , -S(O) ₂ NR ^20a R ^20a' , -OS(O)NR ^20a R ^20a' , -OS(O) ₂ NR ^20a R ^20a' , -NR ^20a R ^20a'. , -NR ^20a C(O)R ^21a , -NR ^20a C(O)OR ^21a , -NR ^20a C(O)NR ^21a R ^21a' , -NR ^20a S(O)R ^21a , -NR ^20a S(O). _{^{) 2 R 21a, -NR 20a S}} (O) NR 21a R 21a ', -NR 20a S (O) 2 NR 21a R 21a', -C (O) R 20a, -C (O) oR 20a or -C (O)NR ^20a R ^20a′ may be substituted;
R ^10a is _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} Aryl, 5- to 7-membered heteroaryl, -OR ^22a , -OC(O)R ^22a , -OC(O)NR ^22a R ^22a' , -OS(O)R ^22a , -OS(O) ₂ R ^22a , -SR ^22a , -S(O)R ^22a , -S(O) ₂ R ^22a , -S(O)NR ^22a R ^22a' , -S(O) ₂ NR ^22a R ^22a' , -OS(O)NR. _{^{22a R 22a ', -OS (O}} ) 2 NR 22a R 22a', -NR 22a R 22a ', -NR 22a C (O) R 23a, -NR 22a C (O) OR 23a, -NR 22a C (O ) NR ^23a R ^23a' ,
_{^{-NR 22a S (O) R 23a}} , -NR 22a S (O) 2 R 23a, -NR 22a S (O) NR 23a R 23a ', -NR 22a S (O) 2 NR 23a R 23a, -C ( ^O) R 22a, is selected from the group consisting of -C ^{(O) oR 23a,} and ^{-C (O) NR 22a R 22a} ', C 1 ~C 6 _alkyl, C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl , C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-7 membered heteroaryl each hydrogen atom independently, optionally C ₁ -C _{6. alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered heteroaryl, -OR ^24a , -OC(O)R ^24a , -OC(O)NR ^24a R ^24a' , -OS(O)R ^24a , -OS(O) ₂ R ^24a , -SR ^24a , -S(O)R ^{24a,. _{-S (O) 2 R 24a,}} -S (O) NR 24a R 24a ', -S (O) 2 NR 24a R 24a', -OS (O) NR 24a R 24a ', -OS (O) 2 NR ^24a R ^24a' , -NR ^24a R ^24a' , -NR ^24a C(O)R ^25a , -NR ^24a C(O)OR ^25a , -NR ^24a C(O)NR ^25a R ^25a' , -NR ^24a S( O)R ^25a , -NR ^24a S(O) ₂ R ^25a , -NR ^24a S(O)NR ^25a R ^25a' , -NR ^24a S(O) ₂ NR ^25a R ^25a' , -C(O)R ^24a. , -C(O)OR ^24a or -C(O)NR ^24a R ^24a' ; and R ^11a , R ^11a' , R ^12a , R ^12a' , R ^13a , R ^13a' , R ^14a. , R ^14a′ , R ^15a , R ^15a′ , R ^16a , R ^16a′ , R ^17a , R ^17a′ , R ^18a , R ^18a′ , R ^19a , R ^19a′ , R ^20a , R ^20a′ , R ^21a , R ^21a′ , R ^22a , R ^22a′ , R ^23a , R ^23a′ , R ^24a , R ^24a′ , R ^25a and R ^25a′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ —. C ₁₃ cycloalkyl, selected from the group consisting of 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-7 membered heteroaryl;
Provided that at least two of R ^1a , R ^4a and R ^5a are a bond, or R ^5a and R ^6a together with the atom to which they are bonded, optionally bonded to a 3-7 membered ring hetero When forming a cycloalkyl or a 5-7 membered heteroaryl, one of the 5-7 membered heteroaryl is a bond, and one of R ^1a or R ^4a is a bond]
Can be described as a PBD prodrug.

In some embodiments, R ^1a is a bond and R ^5a is a bond. In some embodiments, R ^1a is a bond and R ^4a is a bond. In some embodiments, R ^1a is a bond and R ^2a is C ₁ -C ₆ alkyl. In some embodiments, R ^1a is a bond, R ^3a is H, and R ^4a is H. In some embodiments, R ^1a is a bond and R ^2a is C ₁ -C ₆ alkyl. In some embodiments, R ^1a is a bond, R ^2a is C ₁ -C ₆ alkyl, R ^3a is H, and R ^4a is H. In some embodiments, R ^1a is a bond, R ^5a is a bond, and R ^6a and R ^7a are taken together with the atom to which they are attached, optionally together with a 3-7 membered ring heterocycle. Form a cycloalkyl. In some embodiments, R ^1a is a bond, and R ^5a and R ^6a are taken together with the atom to which they are attached, optionally attached to a 3-7 membered heterocycloalkyl or 5-7 membered ring. It forms a ring heteroaryl, wherein one hydrogen atom in the 5-7 membered heteroaryl is a bond.

In some embodiments, R ^5a , R ^6a and R ^7a are each independently selected from the group consisting of H, C ₁ -C ₆ alkyl, —C(O)R ^13a , —C(O)OR ^13a , Here each hydrogen atom in C ₁ -C ₆ alkyl may be optionally substituted by —OC(O)R ^14a ; wherein R ^6a and R ^7a are taken together with the atom to which they are attached. , Optionally joined to form a 3-7 membered heterocycloalkyl, or where R ^5a and R ^6a are taken together with the atom to which they are attached, optionally joined to a 3-7 membered heterocycle. Forming a cycloalkyl or a 5-7 membered heteroaryl, if at least two of R ^1a , R ^4a and R ^5a are a bond, or if R ^5a and R ^6a together with the atom to which they are attached, When bonded to form a 3-7 membered heterocycloalkyl or a 5-7 membered heteroaryl, one hydrogen atom in the 5-7 membered heteroaryl is a bond, and R ^1a or R ^4a One is a bond; and R ^13a and R ^14a are each independently H or C ₁ -C ₇ alkyl.

〔式中、
Ｒ^２ａ、Ｒ^３ａおよびＲ^４ａはそれぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｃ（Ｏ）Ｒ^１１ａ、−Ｃ（Ｏ）ＯＲ^１１ａおよび−Ｃ（Ｏ）ＮＲ^１１ａＲ^１１ａ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合によりＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１１ａ、−ＯＣ（Ｏ）Ｒ^１１ａ、−ＯＣ（Ｏ）ＮＲ^１１ａＲ^１１ａ’、−ＯＳ（Ｏ）Ｒ^１１ａ、−ＯＳ（Ｏ）_２Ｒ^１１ａ、−ＳＲ^１１ａ、−Ｓ（Ｏ）Ｒ^１１ａ、−Ｓ（Ｏ）_２Ｒ^１１ａ、−Ｓ（Ｏ）ＮＲ^１１ａＲ^１１ａ’、−Ｓ（Ｏ）_２ＮＲ^１１ａＲ^１１ａ’、−ＯＳ（Ｏ）ＮＲ^１１ａＲ^１１ａ’、−ＯＳ（Ｏ）_２ＮＲ^１１ａＲ^１１ａ’、−ＮＲ^１１ａＲ^１１ａ’、−ＮＲ^１１ａＣ（Ｏ）Ｒ^１２ａ、−ＮＲ^１１ａＣ（Ｏ）ＯＲ^１２ａ、−ＮＲ^１１ａＣ（Ｏ）ＮＲ^１２ａＲ^１２ａ’、−ＮＲ^１１ａＳ（Ｏ）Ｒ^１２ａ、−ＮＲ^１１ａＳ（Ｏ）_２Ｒ^１２ａ、−ＮＲ^１１ａＳ（Ｏ）ＮＲ^１２ａＲ^１２ａ’、−ＮＲ^１１ａＳ（Ｏ）_２ＮＲ^１２ａＲ^１２ａ’、−Ｃ（Ｏ）Ｒ^１１ａ、−Ｃ（Ｏ）ＯＲ^１１ａまたは−Ｃ（Ｏ）ＮＲ^１１ａＲ^１１ａ’により置換されていてよく；
Ｒ^８ａおよびＲ^９ａは、それぞれ独立してＨ、Ｄ、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＣＮ、−ＮＯ_２、−ＮＣＯ、−ＯＲ^１８ａ、−ＯＣ（Ｏ）Ｒ^１８ａ、−ＯＣ（Ｏ）ＮＲ^１８ａＲ^１８ａ’、−ＯＳ（Ｏ）Ｒ^１８ａ、−ＯＳ（Ｏ）_２Ｒ^１８ａ、−ＳＲ^１８ａ、−Ｓ（Ｏ）Ｒ^１８ａ、−Ｓ（Ｏ）_２Ｒ^１８ａ、−Ｓ（Ｏ）ＮＲ^１８ａＲ^１８ａ’、−Ｓ（Ｏ）_２ＮＲ^１８ａＲ^１８ａ’、−ＯＳ（Ｏ）ＮＲ^１８ａＲ^１８ａ’、−ＯＳ（Ｏ）_２ＮＲ^１８ａＲ^１８ａ’、−ＮＲ^１８ａＲ^１８ａ’、−ＮＲ^１８ａＣ（Ｏ）Ｒ^１９ａ、−ＮＲ^１８ａＣ（Ｏ）ＯＲ^１９ａ、−ＮＲ^１８ａＣ（Ｏ）ＮＲ^１９ａＲ^１９ａ’、−ＮＲ^１８ａＳ（Ｏ）Ｒ^１９ａ、−ＮＲ^１８ａＳ（Ｏ）_２Ｒ^１９ａ、−ＮＲ^１８ａＳ（Ｏ）ＮＲ^１９ａＲ^１９ａ’、−ＮＲ^１８ａＳ（Ｏ）_２ＮＲ^１９ａＲ^１９ａ’、−Ｃ（Ｏ）Ｒ^１８ａ、−Ｃ（Ｏ）ＯＲ^１８ａおよび−Ｃ（Ｏ）ＮＲ^１８ａＲ^１８ａ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^２０ａ、−ＯＣ（Ｏ）Ｒ^２０ａ、−ＯＣ（Ｏ）ＮＲ^２０ａＲ^２０ａ’、−ＯＳ（Ｏ）Ｒ^２０ａ、−ＯＳ（Ｏ）_２Ｒ^２０ａ、−ＳＲ^２０ａ、−Ｓ（Ｏ）Ｒ^２０ａ、−Ｓ（Ｏ）_２Ｒ^２０ａ、−Ｓ（Ｏ）ＮＲ^２０ａＲ^２０ａ’、−Ｓ（Ｏ）_２ＮＲ^２０ａＲ^２０ａ’、−ＯＳ（Ｏ）ＮＲ^２０ａＲ^２０ａ’、−ＯＳ（Ｏ）_２ＮＲ^２０ａＲ^２０ａ’、−ＮＲ^２０ａＲ^２０ａ’、−ＮＲ^２０ａＣ（Ｏ）Ｒ^２１ａ、−ＮＲ^２０ａＣ（Ｏ）ＯＲ^２１ａ、−ＮＲ^２０ａＣ（Ｏ）ＮＲ^２１ａＲ^２１ａ’、−ＮＲ^２０ａＳ（Ｏ）Ｒ^２１ａ、−ＮＲ^２０ａＳ（Ｏ）_２Ｒ^２１ａ、−ＮＲ^２０ａＳ（Ｏ）ＮＲ^２１ａＲ^２１ａ’、−ＮＲ^２０ａＳ（Ｏ）_２ＮＲ^２１ａＲ^２１ａ’、−Ｃ（Ｏ）Ｒ^２０ａ、−Ｃ（Ｏ）ＯＲ^２０ａまたは−Ｃ（Ｏ）ＮＲ^２０ａＲ^２０ａ’により置換されていてよく；
Ｒ^１１ａ、Ｒ^１１ａ’、Ｒ^１２ａ、Ｒ^１２ａ’、Ｒ^１８ａ、Ｒ^１８ａ’、Ｒ^１９ａ、Ｒ^１９ａ’、Ｒ^２０ａ、Ｒ^２０ａ’、Ｒ^２１ａおよびＲ^２１ａ’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_１３シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は結合である〕
のＰＢＤプロドラッグである。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａおよびＲ^４ａは、それぞれ独立してＨまたはＣ_１〜Ｃ_６アルキルから成る群から選択され；Ｒ^８ａおよびＲ^９ａはそれぞれＨであり、そして＊は結合である。 In some embodiments, D ¹ has the formula IIIa

[In the formula,
R ^2a , R ^3a and R ^4a are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 member. From a group consisting of ring heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-7 membered heteroaryl, —C(O)R ^11a , —C(O)OR ^11a and —C(O)NR ^11a R ^11a′. Selected from where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and Each hydrogen atom in the 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 -. 7-membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 11a, -OC (O)} R 11a, -OC (O) NR 11a R 11a ', -OS (O) _{^{R 11a, -OS (O) 2}} R 11a, -SR 11a, -S (O) R 11a, -S (O) 2 R 11a, -S (O) NR 11a R 11a ', -S (O) 2 NR ^11a R ^11a' , -OS(O)NR ^11a R ^11a' , -OS(O) ₂ NR ^11a R ^11a' , -NR ^11a R ^11a' , -NR ^11a C(O)R ^12a , -NR ^11a C. (O)OR ^12a , -NR ^11a C(O)NR ^12a R ^12a' , -NR ^11a S(O)R ^12a , -NR ^11a S(O) ₂ R ^12a , -NR ^11a S(O)NR ^12a R. ^12a′ , —NR ^11a S(O) ₂ NR ^12a R ^12a′ , —C(O)R ^11a , —C(O)OR ^11a or —C(O)NR ^11a R ^11a′ may be substituted;
R ^8a and R ^9a are each independently H, D, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 member. _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered _{^{heteroaryl, -CN, -NO 2, -NCO,}} -OR 18a, -OC (O) R 18a, -OC (O) NR 18a R _{^{18a ', -OS (O) R}} 18a, -OS (O) 2 R 18a, -SR 18a, -S (O) R 18a, -S (O) 2 R 18a, -S (O) NR 18a R 18a _{^{', -S (O) 2 NR}} 18a R 18a', -OS (O) NR 18a R 18a ', -OS (O) 2 NR 18a R 18a', -NR 18a R 18a ', -NR 18a C (O ) R ^19a , -NR ^18a C(O)OR ^19a , -NR ^18a C(O)NR ^19a R ^19a' , -NR ^18a S(O)R ^19a , -NR ^18a S(O) ₂ R ^19a , -NR. ^18a S(O)NR ^19a R ^19a' , -NR ^18a S(O) ₂ NR ^19a R ^19a' , -C(O)R ^18a , -C(O)OR ^18a and -C(O)NR ^18a R ^{18a. '} Wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ Each hydrogen atom in -C ₁₀ aryl and 5-7 membered heteroaryl is independently, optionally, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C. ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 20a, -OC (O)} R 20a, -OC (O) NR 20a R 20a ' , -OS(O)R ^20a , -OS(O) ₂ R ^20a , -SR ^20a , -S(O)R ^20a , -S(O) ₂ R ^20a , -S(O)NR ^20a R ^20a' , _{^{-S (O) 2 NR 20a R}} 20a ', -OS (O) NR 20a R 20a', -OS (O) 2 NR 20a R 20a ', -NR ^20a R ^20a' , -NR ^20a C(O)R ^21a , -NR ^20a C(O)OR ^21a , -NR ^20a C(O)NR ^21a R ^21a' , -NR ^20a S(O)R ^21a , -NR ^20a S(O) ₂ R ^21a , -NR ^20a S(O)NR ^21a R ^21a' , -NR ^20a S(O) ₂ NR ^21a R ^21a' , -C(O)R ^20a , -C(O). ) OR ^20a or -C(O)NR ^20a R ^20a' may be substituted;
R ^11a , R ^11a′ , R ^12a , R ^12a′ , R ^18a , R ^18a′ , R ^19a , R ^19a′ , R ^20a , R ^20a′ , R ^21a and R ^21a′ are each independently H and D. , C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₁₃ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-7 membered. Selected from the group consisting of ring heteroaryl; and * is a bond]
Is a PBD prodrug of. In some embodiments, R ^2a , R ^3a and R ^4a are each independently selected from the group consisting of H or C ₁ -C ₆ alkyl; R ^8a and R ^9a are each H, and * is a bond. Is.

〔式中、
Ｒ^２ａおよびＲ^３ａは、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｃ（Ｏ）Ｒ^１１ａ、−Ｃ（Ｏ）ＯＲ^１１ａおよび−Ｃ（Ｏ）ＮＲ^１１ａＲ^１１ａ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１１ａ、−ＯＣ（Ｏ）Ｒ^１１ａ、−ＯＣ（Ｏ）ＮＲ^１１ａＲ^１１ａ’、−ＯＳ（Ｏ）Ｒ^１１ａ、−ＯＳ（Ｏ）_２Ｒ^１１ａ、−ＳＲ^１１ａ、−Ｓ（Ｏ）Ｒ^１１ａ、−Ｓ（Ｏ）_２Ｒ^１１ａ、−Ｓ（Ｏ）ＮＲ^１１ａＲ^１１ａ’、−Ｓ（Ｏ）_２ＮＲ^１１ａＲ^１１ａ’、−ＯＳ（Ｏ）ＮＲ^１１ａＲ^１１ａ’、−ＯＳ（Ｏ）_２ＮＲ^１１ａＲ^１１ａ’、−ＮＲ^１１ａＲ^１１ａ’、−ＮＲ^１１ａＣ（Ｏ）Ｒ^１２ａ、−ＮＲ^１１ａＣ（Ｏ）ＯＲ^１２ａ、−ＮＲ^１１ａＣ（Ｏ）ＮＲ^１２ａＲ^１２ａ’、−ＮＲ^１１ａＳ（Ｏ）Ｒ^１２ａ、−ＮＲ^１１ａＳ（Ｏ）_２Ｒ^１２ａ、−ＮＲ^１１ａＳ（Ｏ）ＮＲ^１２ａＲ^１２ａ’、−ＮＲ^１１ａＳ（Ｏ）_２ＮＲ^１２ａＲ^１２ａ’、−Ｃ（Ｏ）Ｒ^１１ａ、−Ｃ（Ｏ）ＯＲ^１１ａまたは−Ｃ（Ｏ）ＮＲ^１１ａＲ^１１ａ’により置換されていてよく；
Ｒ^５ａはＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｃ（Ｏ）Ｒ^１３ａ、−Ｃ（Ｏ）ＯＲ^１３ａおよび−Ｃ（Ｏ）ＮＲ^１３ａＲ^１３ａ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１４ａ、−ＯＣ（Ｏ）Ｒ^１４ａ、−ＯＣ（Ｏ）ＮＲ^１４ａＲ^１４ａ’、−ＯＳ（Ｏ）Ｒ^１４ａ、−ＯＳ（Ｏ）_２Ｒ^１４ａ、−ＳＲ^１４ａ、−Ｓ（Ｏ）Ｒ^１４ａ、−Ｓ（Ｏ）_２Ｒ^１４ａ、−Ｓ（Ｏ）ＮＲ^１４ａＲ^１４ａ’、−Ｓ（Ｏ）_２ＮＲ^１４ａＲ^１４ａ’、−ＯＳ（Ｏ）ＮＲ^１４ａＲ^１４ａ’、−ＯＳ（Ｏ）_２ＮＲ^１４ａＲ^１４ａ’、−ＮＲ^１４ａＲ^１４ａ’、−ＮＲ^１４ａＣ（Ｏ）Ｒ^１５ａ、−ＮＲ^１４ａＣ（Ｏ）ＯＲ^１５ａ、−ＮＲ^１４ａＣ（Ｏ）ＮＲ^１５ａＲ^１５ａ’、−ＮＲ^１４ａＳ（Ｏ）Ｒ^１５ａ、−ＮＲ^１４ａＳ（Ｏ）_２Ｒ^１５ａ、−ＮＲ^１４ａＳ（Ｏ）ＮＲ^１５ａＲ^１５ａ’、−ＮＲ^１４ａＳ（Ｏ）_２ＮＲ^１５ａＲ^１５ａ’、−Ｃ（Ｏ）Ｒ^１４ａ、−Ｃ（Ｏ）ＯＲ^１４ａまたは−Ｃ（Ｏ）ＮＲ^１４ａＲ^１４ａ’により置換されていてよく；
Ｒ^８ａおよびＲ^９ａは、それぞれ独立してＨ、Ｄ、ハロゲン、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＣＮ、−ＮＯ_２、−ＮＣＯ、−ＯＲ^１８ａ、−ＯＣ（Ｏ）Ｒ^１８ａ、−ＯＣ（Ｏ）ＮＲ^１８ａＲ^１８ａ’、−ＯＳ（Ｏ）Ｒ^１８ａ、−ＯＳ（Ｏ）_２Ｒ^１８ａ、−ＳＲ^１８ａ、−Ｓ（Ｏ）Ｒ^１８ａ、−Ｓ（Ｏ）_２Ｒ^１８ａ、
−Ｓ（Ｏ）ＮＲ^１８ａＲ^１８ａ’、−Ｓ（Ｏ）_２ＮＲ^１８ａＲ^１８ａ’、−ＯＳ（Ｏ）ＮＲ^１８ａＲ^１８ａ’、−ＯＳ（Ｏ）_２ＮＲ^１８ａＲ^１８ａ’、−ＮＲ^１８ａＲ^１８ａ’、−ＮＲ^１８ａＣ（Ｏ）Ｒ^１９ａ、−ＮＲ^１８ａＣ（Ｏ）ＯＲ^１９ａ、−ＮＲ^１８ａＣ（Ｏ）ＮＲ^１９ａＲ^１９ａ’、−ＮＲ^１８ａＳ（Ｏ）Ｒ^１９ａ、−ＮＲ^１８ａＳ（Ｏ）_２Ｒ^１９ａ、−ＮＲ^１８ａＳ（Ｏ）ＮＲ^１９ａＲ^１９ａ’、−ＮＲ^１８ａＳ（Ｏ）_２ＮＲ^１９ａＲ^１９ａ’、−Ｃ（Ｏ）Ｒ^１８ａ、−Ｃ（Ｏ）ＯＲ^１８ａおよび−Ｃ（Ｏ）ＮＲ^１８ａＲ^１８ａ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^２０ａ、−ＯＣ（Ｏ）Ｒ^２０ａ、−ＯＣ（Ｏ）ＮＲ^２０ａＲ^２０ａ’、−ＯＳ（Ｏ）Ｒ^２０ａ、−ＯＳ（Ｏ）_２Ｒ^２０ａ、−ＳＲ^２０ａ、−Ｓ（Ｏ）Ｒ^２０ａ、−Ｓ（Ｏ）_２Ｒ^２０ａ、−Ｓ（Ｏ）ＮＲ^２０ａＲ^２０ａ’、−Ｓ（Ｏ）_２ＮＲ^２０ａＲ^２０ａ’、−ＯＳ（Ｏ）ＮＲ^２０ａＲ^２０ａ’、−ＯＳ（Ｏ）_２ＮＲ^２０ａＲ^２０ａ’、−ＮＲ^２０ａＲ^２０ａ’、−ＮＲ^２０ａＣ（Ｏ）Ｒ^２１ａ、−ＮＲ^２０ａＣ（Ｏ）ＯＲ^２１ａ、−ＮＲ^２０ａＣ（Ｏ）ＮＲ^２１ａＲ^２１ａ’、−ＮＲ^２０ａＳ（Ｏ）Ｒ^２１ａ、−ＮＲ^２０ａＳ（Ｏ）_２Ｒ^２１ａ、−ＮＲ^２０ａＳ（Ｏ）ＮＲ^２１ａＲ^２１ａ’、−ＮＲ^２０ａＳ（Ｏ）_２ＮＲ^２１ａＲ^２１ａ’、−Ｃ（Ｏ）Ｒ^２０ａ、−Ｃ（Ｏ）ＯＲ^２０ａまたは−Ｃ（Ｏ）ＮＲ^２０ａＲ^２０ａ’により置換されていてよく；
Ｒ^１１ａ、Ｒ^１１ａ’、Ｒ^１２ａ、Ｒ^１２ａ’、Ｒ^１３ａ、Ｒ^１３ａ’、Ｒ^１４ａ、Ｒ^１４ａ’、Ｒ^１５ａ、Ｒ^１５ａ’、Ｒ^１８ａ、Ｒ^１８ａ’、Ｒ^１９ａ、Ｒ^１９ａ’、Ｒ^２０ａ、Ｒ^２０ａ’、Ｒ^２１ａおよびＲ^２１ａ’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_１３シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして＊は結合である〕
のＰＢＤプロドラッグである。いくつかの態様において、Ｒ^２ａおよびＲ^３ａは、それぞれ独立してＨまたはＣ_１〜Ｃ_６アルキルであり；Ｒ^５ａはＨ、Ｃ_１〜Ｃ_６アルキル、−Ｃ（Ｏ）Ｒ^１３ａおよび−Ｃ（Ｏ）ＯＲ^１３ａから成る群から選択され、ここでＣ_１〜Ｃ_６アルキルにおける各水素原子は、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１４ａ、−ＯＣ（Ｏ）Ｒ^１４ａにより置換されていてよく、Ｒ^１３ａおよびＲ^１４ａは、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_１３シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；Ｒ^８ａおよびＲ^９ａはそれぞれＨであり、そして＊は結合である〕
のＰＢＤプロドラッグである。 In some embodiments, D ¹ has the formula IIIb

[In the formula,
R ^2a and R ^3a are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. Selected from the group consisting of cycloalkyl, C ₆ -C ₁₀ aryl, 5-7 membered heteroaryl, —C(O)R ^11a , —C(O)OR ^11a and —C(O)NR ^11a R ^11a′. , Where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5- Each hydrogen atom in the 7-membered ring heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7. membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 11a, -OC (O)} R 11a, -OC (O) NR 11a R 11a ', -OS (O) R _{^{11a, -OS (O) 2 R}} 11a, -SR 11a, -S (O) R 11a, -S (O) 2 R 11a, -S (O) NR 11a R 11a ', -S (O) 2 NR ^11a R ^11a' , -OS(O)NR ^11a R ^11a' , -OS(O) ₂ NR ^11a R ^11a' , -NR ^11a R ^11a' , -NR ^11a C(O)R ^12a , -NR ^11a C( O)OR ^12a , -NR ^11a C(O)NR ^12a R ^12a' , -NR ^11a S(O)R ^12a , -NR ^11a S(O) ₂ R ^12a , -NR ^11a S(O)NR ^12a R ^{12a. '} , -NR ^11a S(O) ₂ NR ^12a R ^12a' , -C(O)R ^11a , -C(O)OR ^11a or -C(O)NR ^11a R ^11a' may be substituted;
R ^5a is _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} Aryl, 5-7 membered heteroaryl, -C(O)R ^13a , -C(O)OR ^13a and -C(O)NR ^13a R ^13a' , wherein C ₁ -C _{6 is selected. alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} each hydrogen in aryl and 5-7 membered heteroaryl atoms, _optionally, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl , 5- to 7-membered heteroaryl, -OR ^14a , -OC(O)R ^14a , -OC(O)NR ^14a R ^14a' , -OS(O)R ^14a , -OS(O) ₂ R ^14a , -. SR ^14a , -S(O)R ^14a , -S(O) ₂ R ^14a , -S(O)NR ^14a R ^14a' , -S(O) ₂ NR ^14a R ^14a' , -OS(O)NR ^{14a. _{R 14a ', -OS (O)}} 2 NR 14a R 14a', -NR 14a R 14a ', -NR 14a C (O) R 15a, -NR 14a C (O) OR 15a, -NR 14a C (O) ^{NR 15a R 15a ', -NR 14a} S (O) R 15a, -NR 14a S (O) 2 R 15a, -NR 14a S (O) NR 15a R 15a', -NR 14a S (O) 2 NR 15a R ^15a′ , —C(O)R ^14a , —C(O)OR ^14a or —C(O)NR ^14a R ^14a′ may be substituted;
R ^8a and R ^9a are each independently H, D, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 member. _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered _{^{heteroaryl, -CN, -NO 2, -NCO,}} -OR 18a, -OC (O) R 18a, -OC (O) NR 18a R _{^{18a ', -OS (O) R}} 18a, -OS (O) 2 R 18a, -SR 18a, -S (O) R 18a, -S (O) 2 R 18a,
-S(O)NR ^18a R ^18a' , -S(O) ₂ NR ^18a R ^18a' , -OS(O)NR ^18a R ^18a' , -OS(O) ₂ NR ^18a R ^18a' , -NR ^18a R. ^18a' , -NR ^18a C(O)R ^19a , -NR ^18a C(O)OR ^19a , -NR ^18a C(O)NR ^19a R ^19a' , -NR ^18a S(O)R ^19a , -NR ^18a S. _{^{(O) 2 R 19a, -NR}} 18a S (O) NR 19a R 19a ', -NR 18a S (O) 2 NR 19a R 19a', -C (O) R 18a, -C (O) oR 18a , and —C(O)NR ^18a R ^18a′ selected from the group consisting of C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 Each hydrogen atom in the 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 20a, -OC (O)} R 20a, - OC(O)NR ^20a R ^20a' , -OS(O)R ^20a , -OS(O) ₂ R ^20a , -SR ^20a , -S(O)R ^20a , -S(O) ₂ R ^20a , -S. (O)NR ^20a R ^20a' , -S(O) ₂ NR ^20a R ^20a' , -OS(O)NR ^20a R ^20a' , -OS(O) ₂ NR ^20a R ^20a' , -NR ^20a R ^20a'. , -NR ^20a C(O)R ^21a , -NR ^20a C(O)OR ^21a , -NR ^20a C(O)NR ^21a R ^21a' , -NR ^20a S(O)R ^21a , -NR ^20a S(O). _{^{) 2 R 21a, -NR 20a S}} (O) NR 21a R 21a ', -NR 20a S (O) 2 NR 21a R 21a', -C (O) R 20a, -C (O) oR 20a or -C (O)NR ^20a R ^20a′ may be substituted;
R ^11a , R ^11a′ , R ^12a , R ^12a′ , R ^13a , R ^13a′ , R ^14a , R ^14a′ , R ^15a , R ^15a′ , R ^18a , R ^18a′ , R ^19a , R ^19a′ , R ^{20a, R 20a ', R 21a} and ^{R 21a'} are, H _{independently, D,} C 1 ~C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 _{-C 13} cycloalkyl it is selected from the group consisting of 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a bond]
Is a PBD prodrug of. In some embodiments, R ^2a and R ^3a are each independently H or C ₁ -C ₆ alkyl; R ^5a is H, C ₁ -C ₆ alkyl, —C(O)R ^13a and —C. (O)OR ^13a , wherein each hydrogen atom in C ₁ -C ₆ alkyl is optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, -OR 14a, may be substituted by -OC ^{(O) R 14a,} R ^13a and R ^14a are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₁₃ cycloalkyl, 3-7 membered ring hetero. Selected from the group consisting of cycloalkyl, C ₆ -C ₁₀ aryl and 5-7 membered heteroaryl; R ^8a and R ^9a are each H, and * is a bond]
Is a PBD prodrug of.

〔式中、
Ｒ^２ａ、Ｒ^３ａおよびＲ^４ａは、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｃ（Ｏ）Ｒ^１１ａ、−Ｃ（Ｏ）ＯＲ^１１ａおよび−Ｃ（Ｏ）ＮＲ^１１ａＲ^１１ａ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１１ａ、−ＯＣ（Ｏ）Ｒ^１１ａ、−ＯＣ（Ｏ）ＮＲ^１１ａＲ^１１ａ’、−ＯＳ（Ｏ）Ｒ^１１ａ、−ＯＳ（Ｏ）_２Ｒ^１１ａ、−ＳＲ^１１ａ、−Ｓ（Ｏ）Ｒ^１１ａ、−Ｓ（Ｏ）_２Ｒ^１１ａ、−Ｓ（Ｏ）ＮＲ^１１ａＲ^１１ａ’、−Ｓ（Ｏ）_２ＮＲ^１１ａＲ^１１ａ’、−ＯＳ（Ｏ）ＮＲ^１１ａＲ^１１ａ’、−ＯＳ（Ｏ）_２ＮＲ^１１ａＲ^１１ａ’、−ＮＲ^１１ａＲ^１１ａ’、−ＮＲ^１１ａＣ（Ｏ）Ｒ^１２ａ、−ＮＲ^１１ａＣ（Ｏ）ＯＲ^１２ａ、−ＮＲ^１１ａＣ（Ｏ）ＮＲ^１２ａＲ^１２ａ’、−ＮＲ^１１ａＳ（Ｏ）Ｒ^１２ａ、−ＮＲ^１１ａＳ（Ｏ）_２Ｒ^１２ａ、−ＮＲ^１１ａＳ（Ｏ）ＮＲ^１２ａＲ^１２ａ’、−ＮＲ^１１ａＳ（Ｏ）_２ＮＲ^１２ａＲ^１２ａ’、−Ｃ（Ｏ）Ｒ^１１ａ、−Ｃ（Ｏ）ＯＲ^１１ａまたは−Ｃ（Ｏ）ＮＲ^１１ａＲ^１１ａ’により置換されていてよく；
Ｒ^７ａはＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｃ（Ｏ）Ｒ^１３ａ、−Ｃ（Ｏ）ＯＲ^１３ａおよび−Ｃ（Ｏ）ＮＲ^１３ａＲ^１３ａ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１４ａ、−ＯＣ（Ｏ）Ｒ^１４ａ、−ＯＣ（Ｏ）ＮＲ^１４ａＲ^１４ａ’、−ＯＳ（Ｏ）Ｒ^１４ａ、−ＯＳ（Ｏ）_２Ｒ^１４ａ、−ＳＲ^１４ａ、−Ｓ（Ｏ）Ｒ^１４ａ、−Ｓ（Ｏ）_２Ｒ^１４ａ、−Ｓ（Ｏ）ＮＲ^１４ａＲ^１４ａ’、−Ｓ（Ｏ）_２ＮＲ^１４ａＲ^１４ａ’、−ＯＳ（Ｏ）ＮＲ^１４ａＲ^１４ａ’、
−ＯＳ（Ｏ）_２ＮＲ^１４ａＲ^１４ａ’、−ＮＲ^１４ａＲ^１４ａ’、−ＮＲ^１４ａＣ（Ｏ）Ｒ^１５ａ、−ＮＲ^１４ａＣ（Ｏ）ＯＲ^１５ａ、−ＮＲ^１４ａＣ（Ｏ）ＮＲ^１５ａＲ^１５ａ’、−ＮＲ^１４ａＳ（Ｏ）Ｒ^１５ａ、−ＮＲ^１４ａＳ（Ｏ）_２Ｒ^１５ａ、−ＮＲ^１４ａＳ（Ｏ）ＮＲ^１５ａＲ^１５ａ’、−ＮＲ^１４ａＳ（Ｏ）_２ＮＲ^１５ａＲ^１５ａ’、−Ｃ（Ｏ）Ｒ^１４ａ、−Ｃ（Ｏ）ＯＲ^１４ａまたは−Ｃ（Ｏ）ＮＲ^１４ａＲ^１４ａ’により置換されていてよく；
Ｒ^１１ａ、Ｒ^１１ａ’、Ｒ^１２ａ、Ｒ^１２ａ’、Ｒ^１３ａ、Ｒ^１３ａ’、Ｒ^１４ａ、Ｒ^１４ａ’、Ｒ^１５ａ、Ｒ^１５ａ’、Ｒ^１８ａ、Ｒ^１８ａ’、Ｒ^１９ａ、Ｒ^１９ａ’、Ｒ^２０ａ、Ｒ^２０ａ’、Ｒ^２１ａおよびＲ^２１ａ’は、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_７アルキル、Ｃ_２〜Ｃ_７アルケニル、Ｃ_２〜Ｃ_７アルキニル、Ｃ_３〜Ｃ_１３シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールから成る群から選択され；そして
＊は結合である〕
のＰＢＤプロドラッグである。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａおよびＲ^４ａは、それぞれ独立してＨまたはＣ_１〜Ｃ_６アルキルであり；Ｒ^７ａはＨまたはＣ_１〜Ｃ_６アルキルであり；Ｒ^８ａおよびＲ^９ａはそれぞれＨであり、そして＊は結合である〕
のＰＢＤプロドラッグである。 In some embodiments, D ¹ has the formula IIIc

[In the formula,
R ^2a , R ^3a and R ^4a are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7. membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, the group consisting of -C (O) R 11a, -C (O) oR 11a , and ^{-C (O) NR 11a R 11a} ' Selected from where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl. And each hydrogen atom in the 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -OR ^11a , -OC(O)R ^11a , -OC(O)NR ^11a R ^11a' , -OS( O)R ^11a , -OS(O) ₂ R ^11a , -SR ^11a , -S(O)R ^11a , -S(O) ₂ R ^11a , -S(O)NR ^11a R ^11a' , -S(O). ) ₂ NR ^11a R ^11a' , -OS(O)NR ^11a R ^11a' , -OS(O) ₂ NR ^11a R ^11a' , -NR ^11a R ^11a' , -NR ^11a C(O)R ^12a , -NR. ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a R ^12a' , -NR ^11a S(O)R ^12a , -NR ^11a S(O) ₂ R ^12a , -NR ^11a S(O)NR. ^12a R ^12a′ , —NR ^11a S(O) ₂ NR ^12a R ^12a′ , —C(O)R ^11a , —C(O)OR ^11a or —C(O)NR ^11a R ^11a′ , Often;
R ^7a is _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} Aryl, 5-7 membered heteroaryl, -C(O)R ^13a , -C(O)OR ^13a and -C(O)NR ^13a R ^13a' , wherein C ₁ -C _{6 is selected. alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} each hydrogen in aryl and 5-7 membered heteroaryl atoms, _optionally, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl , 5- to 7-membered heteroaryl, -OR ^14a , -OC(O)R ^14a , -OC(O)NR ^14a R ^14a' , -OS(O)R ^14a , -OS(O) ₂ R ^14a , -. SR ^14a , -S(O)R ^14a , -S(O) ₂ R ^14a , -S(O)NR ^14a R ^14a' , -S(O) ₂ NR ^14a R ^14a' , -OS(O)NR ^14a. R ^14a′ ,
_{^{-OS (O) 2 NR 14a R}} 14a ', -NR 14a R 14a', -NR 14a C (O) R 15a, -NR 14a C (O) OR 15a, -NR 14a C (O) NR 15a R 15a ^{', -NR 14a S (O)} R 15a, -NR 14a S (O) 2 R 15a, -NR 14a S (O) NR 15a R 15a', -NR 14a S (O) 2 NR 15a R 15a ', Optionally substituted by -C(O)R ^14a , -C(O)OR ^14a or -C(O)NR ^14a R ^14a' ;
R ^11a , R ^11a′ , R ^12a , R ^12a′ , R ^13a , R ^13a′ , R ^14a , R ^14a′ , R ^15a , R ^15a′ , R ^18a , R ^18a′ , R ^19a , R ^19a′ , R ^{20a, R 20a ', R 21a} and ^{R 21a'} are, H _{independently, D,} C 1 ~C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 _{-C 13} cycloalkyl it is selected from the group consisting of 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a bond]
Is a PBD prodrug of. In some embodiments, R ^2a , R ^3a and R ^4a are each independently H or C ₁ -C ₆ alkyl; R ^7a is H or C ₁ -C ₆ alkyl; R ^8a and R ^9a Are each H, and * is a bond]
Is a PBD prodrug of.

For example, when D ¹ is a PBD prodrug as described herein, D ² can be any other drug useful in producing the desired biological effect. It is understood that the nature of D ² is not limited, and that various drugs known in the art can be used as D ² for conjugation with the conjugates described herein. In some embodiments, D ² can be a DNA binding agent. In some embodiments, D ² can be a DNA alkylator. It is understood that DNA binding agents and DNA alkylating agents are well known in the art, and the nature of such DNA binding agents and DNA alkylating agents is not limited. In some embodiments, D ² is a DNA minor groove binding drug.

〔式中、
Ｒ^１ｂ、Ｒ^２ｂ、Ｒ^３ｂおよびＲ^４ｂは、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｃ（Ｏ）Ｒ^１３ｂ、−Ｃ（Ｏ）ＯＲ^１３ｂおよび−Ｃ（Ｏ）ＮＲ^１３ｂＲ^１３ｂ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１３ｂ、−ＯＣ（Ｏ）Ｒ^１３ｂ、−ＯＣ（Ｏ）ＮＲ^１３ｂＲ^１３ｂ’、−ＯＳ（Ｏ）Ｒ^１３ｂ、−ＯＳ（Ｏ）_２Ｒ^１３ｂ、−ＳＲ^１３ｂ、−Ｓ（Ｏ）Ｒ^１３ｂ、−Ｓ（Ｏ）_２Ｒ^１３ｂ、−Ｓ（Ｏ）ＮＲ^１３ｂＲ^１３ｂ’、−Ｓ（Ｏ）_２ＮＲ^１３ｂＲ^１３ｂ’、−ＯＳ（Ｏ）ＮＲ^１３ｂＲ^１３ｂ’、−ＯＳ（Ｏ）_２ＮＲ^１３ｂＲ^１３ｂ’、−ＮＲ^１３ｂＲ^１３ｂ’、−ＮＲ^１３ｂＣ（Ｏ）Ｒ^１４ｂ、−ＮＲ^１３ｂＣ（Ｏ）ＯＲ^１４ｂ、−ＮＲ^１３ｂＣ（Ｏ）ＮＲ^１４ｂＲ^１４ｂ’、−ＮＲ^１３ｂＳ（Ｏ）Ｒ^１４ｂ、−ＮＲ^１３ｂＳ（Ｏ）_２Ｒ^１４ｂ、−ＮＲ^１３ｂＳ（Ｏ）ＮＲ^１４ｂＲ^１４ｂ’、−ＮＲ^１３ｂＳ（Ｏ）_２ＮＲ^１４ｂＲ^１４ｂ’、−Ｃ（Ｏ）Ｒ^１３ｂ、−Ｃ（Ｏ）ＯＲ^１３ｂまたは−Ｃ（Ｏ）ＮＲ^１３ｂＲ^１３ｂ’により置換されていてよく；またはＲ^１ｂ、Ｒ^２ｂ、Ｒ^３ｂおよびＲ^４ｂのいずれか１つは結合であり；
Ｒ^５ｂ、Ｒ^６ｂおよびＲ^７ｂはそれぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｃ（Ｏ）Ｒ^１５ｂ、−Ｃ（Ｏ）ＯＲ^１５ｂおよび−Ｃ（Ｏ）ＮＲ^１５ｂＲ^１５ｂ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｌ^４Ｈ、−Ｌ^３Ｈ、−ＯＲ^１５ｂ、−ＯＣ（Ｏ）Ｒ^１５ｂ、−ＯＣ（Ｏ）ＮＲ^１５ｂＲ^１５ｂ’、−ＯＳ（Ｏ）Ｒ^１５ｂ、−ＯＳ（Ｏ）_２Ｒ^１５ｂ、−ＳＲ^１５ｂ、−Ｓ（Ｏ）Ｒ^１５ｂ、−Ｓ（Ｏ）_２Ｒ^１５ｂ、−Ｓ（Ｏ）ＮＲ^１５ｂＲ^１５ｂ’、−Ｓ（Ｏ）_２ＮＲ^１５ｂＲ^１５ｂ’、−ＯＳ（Ｏ）ＮＲ^１５ｂＲ^１５ｂ’、−ＯＳ（Ｏ）_２ＮＲ^１５ｂＲ^１５ｂ’、−ＮＲ^１５ｂＲ^１５ｂ’、−ＮＲ^１５ｂＣ（Ｏ）Ｒ^１６ｂ、−ＮＲ^１５ｂＣ（Ｏ）ＯＲ^１６ｂ、−ＮＲ^１５ｂＣ（Ｏ）ＮＲ^１６ｂＲ^１６ｂ’、−ＮＲ^１５ｂＳ（Ｏ）Ｒ^１６ｂ、−ＮＲ^１５ｂＳ（Ｏ）_２Ｒ^１６ｂ、−ＮＲ^１５ｂＳ（Ｏ）ＮＲ^１６ｂＲ^１６ｂ’、−ＮＲ^１５ｂＳ（Ｏ）_２ＮＲ^１６ｂＲ^１６ｂ’、−Ｃ（Ｏ）Ｒ^１５ｂ、−Ｃ（Ｏ）ＯＲ^１５ｂまたは−Ｃ（Ｏ）ＮＲ^１５ｂＲ^１５ｂ’により置換されていてよく；ここで
Ｒ^６ｂおよびＲ^７ｂは、それらが結合する原子と一緒になって、場合により結合して３〜７員環ヘテロシクロアルキルを形成し、またはＲ^５ｂおよびＲ^６ｂは、それらが結合する原子と一緒になって、場合により結合して３〜７員環ヘテロシクロアルキルまたは５〜７員環ヘテロアリールを形成し、ここで３〜７員環ヘテロシクロアルキルおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１７ｂ、−ＯＣ（Ｏ）Ｒ^１７ｂ、−ＯＣ（Ｏ）ＮＲ^１７ｂＲ^１７ｂ’、−ＯＳ（Ｏ）Ｒ^１７ｂ、−ＯＳ（Ｏ）_２Ｒ^１７ｂ、−ＳＲ^１７ｂ、−Ｓ（Ｏ）Ｒ^１７ｂ、−Ｓ（Ｏ）_２Ｒ^１７ｂ、−Ｓ（Ｏ）ＮＲ^１７ｂＲ^１７ｂ’、−Ｓ（Ｏ）_２ＮＲ^１７ｂＲ^１７ｂ’、−ＯＳ（Ｏ）ＮＲ^１７ｂＲ^１７ｂ’、−ＯＳ（Ｏ）_２ＮＲ^１７ｂＲ^１７ｂ’、−ＮＲ^１７ｂＲ^１７ｂ’、−ＮＲ^１７ｂＣ（Ｏ）Ｒ^１８ｂ、−ＮＲ^１７ｂＣ（Ｏ）ＯＲ^１８ｂ、−ＮＲ^１７ｂＣ（Ｏ）ＮＲ^１８ｂＲ^１８ｂ’、−ＮＲ^１７ｂＳ（Ｏ）Ｒ^１８ｂ、−ＮＲ^１７ｂＳ（Ｏ）_２Ｒ^１８ｂ、−ＮＲ^１７ｂＳ（Ｏ）ＮＲ^１８ｂＲ^１８ｂ’、−ＮＲ^１７ｂＳ（Ｏ）_２ＮＲ^１８ｂＲ^１８ｂ’、−Ｃ（Ｏ）Ｒ^１７ｂ、−Ｃ（Ｏ）ＯＲ^１７ｂまたは−Ｃ（Ｏ）ＮＲ^１７ｂＲ^１７ｂにより置換されていてよく；またはＲ^５ｂ、Ｒ^６ｂまたはＲ^７ｂのいずれか１つは結合であり； In some embodiments, D ² is

[In the formula,
R ^1b , R ^2b , R ^3b and R ^4b are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -C(O)R ^13b , -C(O)OR ^13b and -C(O)NR ^13b R ^13b'. Selected from the group consisting of: C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -. Each hydrogen atom in C ₁₀ aryl and 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C _6. Cycloalkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -OR ^13b , -OC(O)R ^13b , -OC(O)NR ^13b R ^13b' , -OS(O)R ^13b , -OS(O) ₂ R ^13b , -SR ^13b , -S(O)R ^13b , -S(O) ₂ R ^13b , -S(O)NR ^13b R ^13b' , -. _{^{S (O) 2 NR 13b R}} 13b ', -OS (O) NR 13b R 13b', -OS (O) 2 NR 13b R 13b ', -NR 13b R 13b', -NR 13b C (O) R 14b , -NR ^13b C(O)OR ^14b , -NR ^13b C(O)NR ^14b R ^14b' , -NR ^13b S(O)R ^14b , -NR ^13b S(O) ₂ R ^14b , -NR ^13b S(. ^{O) NR 14b R} 14b substituted _{^{', -NR 13b S (O)}} 2 NR 14b R 14b', -C (O) R 13b, -C (O) oR 13b or ^{-C (O) NR 13b R 13b} ' Or any one of R ^1b , R ^2b , R ^3b and R ^4b is a bond;
R ^{5b, R 6b} and ^{R 7b} each independently _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, -C (O) R ^15b, from the group consisting of -C ^{(O) oR 15b} and ^{-C (O) NR 15b R 15b} ' Selected from where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and Each hydrogen atom in the 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7-membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -L 4 H, -L 3 H} , -OR 15b, -OC (O) R 15b, -OC (O) ^{NR 15b R 15b ', -OS (} O) R 15b, -OS (O) 2 R 15b, -SR 15b, -S (O) R 15b, -S (O) 2 R 15b, -S (O) NR _{^{15b R 15b ', -S (O}} ) 2 NR 15b R 15b', -OS (O) NR 15b R 15b ', -OS (O) 2 NR 15b R 15b', -NR 15b R 15b ', -NR 15b C(O)R ^16b , -NR ^15b C(O)OR ^16b , -NR ^15b C(O)NR ^16b R ^16b' , -NR ^15b S(O)R ^16b , -NR ^15b S(O) ₂ R ^16b. , -NR ^15b S(O)NR ^16b R ^16b' , -NR ^15b S(O) ₂ NR ^16b R ^16b' , -C(O)R ^15b , -C(O)OR ^15b or -C(O)NR. ^15b R ^15b′ may be substituted; wherein R ^6b and R ^7b are taken together with the atom to which they are attached, optionally combined to form a 3-7 membered heterocycloalkyl, or R ^5b and R ^6b , together with the atoms to which they are attached, are optionally joined to form a 3-7 membered heterocycloalkyl or a 5-7 membered heteroaryl. Here, each hydrogen atom in the 3-7 membered heterocycloalkyl and the 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 17b, -OC (O)} R 17b, -OC (O ^{) NR 17b R 17b ', -OS} (O) R 17b, -OS (O) 2 R 17b, -SR 17b, -S (O) R 17b, -S (O) 2 R 17b, -S (O) NR ^17b R ^17b' , -S(O) ₂ NR ^17b R ^17b' , -OS(O)NR ^17b R ^17b' , -OS(O) ₂ NR ^17b R ^17b' , -NR ^17b R ^17b' , -NR. ^17b C(O)R ^18b , -NR ^17b C(O)OR ^18b , -NR ^17b C(O)NR ^18b R ^18b' , -NR ^17b S(O)R ^18b , -NR ^17b S(O) ₂ R. ^18b , -NR ^17b S(O)NR ^18b R ^18b' , -NR ^17b S(O) ₂ NR ^18b R ^18b' , -C(O)R ^17b , -C(O)OR ^17b or -C(O). NR ^17b may be substituted by R ^17b ; or any one of R ^5b , R ^6b or R ^7b is a bond;

R ^8b and R ^9b are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. _cycloalkyl, C 6 _{-C 10} aryl, 5-7 membered _{^{heteroaryl, -CN, -NO 2, -NCO,}} -OR 19b, -OC (O) R 19b, -OC (O) NR 19b R 19b ' , -OS(O)R ^19b , -OS(O) ₂ R ^19b , -SR ^19b , -S(O)R ^19b , -S(O) ₂ R ^19b , -S(O)NR ^19b R ^19b' , _{^{-S (O) 2 NR 19b R}} 19b ', -OS (O) NR 19b R 19b', -OS (O) 2 NR 19b R 19b ', -NR 19b R 19b', -NR 19b C (O) R ^20b , -NR ^19b C(O)OR ^20b , -NR ^19b C(O)NR ^20b R ^20b' , -NR ^19b S(O)R ^20b , -NR ^19b S(O) ₂ R ^20b , -NR ^19b S. From (O)NR ^20b R ^20b' , -NR ^19b S(O) ₂ NR ^20b R ^20b' , -C(O)R ^19b , -C(O)OR ^19b and -C(O)NR ^19b R ^19b'. is selected from the group consisting of, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 -C Each hydrogen atom in the ₁₀ aryl and the 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cyclo. Alkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -OR ^21b , -OC(O)R ^21b , -OC(O)NR ^21b R ^21b' , -. OS(O)R ^21b , -OS(O) ₂ R ^21b , -SR ^21b , -S(O)R ^21b , -S(O) ₂ R ^21b , -S(O)NR ^21b R ^21b' , -S. (O) ₂ NR ^21b R ^21b' , -OS(O)NR ^21b R ^21b' , -OS(O) ₂ NR ^21b R ^21b' , -NR ^{2 1b} R ^21b' , -NR ^21b C(O)R ^22b , -NR ^21b C(O)OR ^22b , -NR ^21b C(O)NR ^22b R ^22b' , -NR ^21b S(O)R ^22b , -NR. ^21b S(O) ₂ R ^22b , -NR ^21b S(O)NR ^22b R ^22b' , -NR ^21b S(O) ₂ NR ^22b R ^22b' , -C(O)R ^21b , -C(O)OR. ^21b or -C(O)NR ^21b R ^21b may be substituted;
R ^{10b, R 11b} and ^{R 12b} are, H independently, _D, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 23b, -OC (O)} R 23b, -OC (O) NR 23b R 23b ', -OS (O) R _{^{23b, -OS (O) 2 R}} 23b, -SR 23b, -S (O) R 23b, -S (O) 2 R 23b, -S (O) NR 23b R 23b ', -S (O) 2 NR ^{23b R 23b ', -OS (O} ) NR 23b R 23b', -OS (O) 2 NR 23b R 23b ', -NR 23b R 23b', -NR 23b C (O) R 24b, -NR 23b C ( O)OR ^24b , -NR ^23b C(O)NR ^24b R ^24b' , -NR ^23b S(O)R ^24b , -NR ^23b S(O) ₂ R ^24b , -NR ^23b S(O)NR ^24b R ^{24b. _{', -NR 23b S (O)}} 2 NR 24b R 24b', is selected from the group consisting of ^{-C (O) R 23b, -C} (O) oR 23b and ^{-C (O) NR 23b R 23b} ', wherein in _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5- to 7-membered Each hydrogen atom in a ring heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. _cycloalkyl, C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 25b, -OC (O)} R 25b, -OC (O) NR 25b R 25b ', -OS (O) R 25b, - _{^{OS (O) 2 R 25b,}} -SR 25b, -S (O) R 25b, -S (O) 2 R 25b, -S (O) NR 25b R 25b ', -S (O) 2 NR 25b R 25b ^' , -OS(O)NR ^25b R ^25b' , -OS(O) ₂ NR ^25b R ^25b' , -NR ^25b R ^{25b. '} , -NR ^25b C(O)R ^26b , -NR ^25b C(O)OR ^26b , -NR ^25b C(O)NR ^26b R ^26b' , -NR ^25b S(O)R ^26b , -NR ^25b S( _{^{O) 2 R 26b, -NR 25b}} S (O) NR 26b R 26b ', -NR 25b S (O) 2 NR 26b R 26b', -C (O) R 25b, -C (O) oR 25b or - C(O)NR ^25b R ^25b may be substituted, or R ^10b and R ^11b together with the atom to which they are attached, optionally combined to form a C ₆ -C ₁₀ aryl, or R ^11b and R ^12b , together with the atom to which they are attached, optionally combine to form exo-methylene; or R ^12b is absent;
R ^13b , R ^13b' , R ^14b , R ^14b' , R ^15b , R ^15b' , R ^16b , R ^16b' , R ^17b , R ^17b' , R ^18b , R ^18b' , R ^19b , R ^19b' , R. ^20b , R ^20b' , R ^21b , R ^21b' , R ^22b , R ^22b' , R ^23b , R ^23b' , R ^24b , R ^24b' , R ^25b , R ^25b' , R ^26b and R ^26b' are respectively. independently _{H, D,} C 1 ~C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 _{-C 13} cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} Selected from the group consisting of aryl, C ₁ -C ₆ alkyl (C ₆ -C ₁₀ aryl) and 5-7 membered heteroaryl, wherein C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkyl (C ₆ -aryl). C ₁₀ aryl) and 5-7 membered heteroaryl are, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered _{heteroaryl, -CN, -NO 2, -NCO,} -OH, -SH, -NH 2, -SO 3 H, - C (O) OH and -C (O) may be substituted by NH _2;
Provided that one of R ^1b , R ^2b , R ^3b , R ^4b , R ^5b , R ^6b and R ^7b is a bond;
R ^1c , R ^2c and R ^5c are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7. membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, the group consisting of -C (O) R 6c, -C (O) oR 6c and ^{-C (O) NR 6c R 6c} ' Selected from where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl. And each hydrogen atom in the 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered ring heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered ring heteroaryl, -OR ^7c , -OC(O)R ^7c , -OC(O)NR ^7c R ^7c' , -OS( _{^{O) R 7c, -OS (O}} ) 2 R 7c, -SR 7c, -S (O) R 7c, -S (O) 2 R 7c, -S (O) 2 OR 7c, -S (O) NR _{^{7c R 7c ', -S (O}} ) 2 NR 7c R 7c', -OS (O) NR 7c R 7c ', -OS (O) 2 NR 7c R 7c', -NR 7c R 7c ', -NR 7c C(O)R ^8c , -NR ^7c C(O)OR ^8c , -NR ^7c C(O)NR ^8c R ^8c' , -NR ^7c S(O)R ^8c , -NR ^7c S(O) ₂ R ^8c. , -NR ^7c S(O)NR ^8c R ^8c' , -NR ^7c S(O) ₂ NR ^8c R ^8c' , -C(O)R ^7c , -C(O)OR ^7c or -C(O)NR. ^7c R ^7c′ may be substituted; or when J is —CR ^13c =, R ^5c is absent; provided that one of R ^1c or R ^2c is a bond;
R ^3c and R ^4c are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. _cycloalkyl, C 6 _{-C 10} aryl, 5-7 membered _{^{heteroaryl, -CN, -NO 2, -NCO,}} -OR 9c, -OC (O) R 9c, -OC (O) NR 9c R 9c ' , -OS(O)R ^9c , -OS(O) ₂ R ^9c , -SR ^9c , -S(O)R ^9c , -S(O) ₂ R ^9c , -S(O)NR ^9c R ^9c' , _{^{-S (O) 2 NR 9c R}} 9c ', -OS (O) NR 9c R 9c', -OS (O) 2 NR 9c R 9c ', -NR 9c R 9c', -NR 9c C (O) R ^{10c, -NR 9c C (O)} OR 10c, -NR 9c C (O) NR 10c R 10c ', -NR 9c S (O) R 10c, -NR 9c S (O) 2 R 10c, -NR 9c S ^{(O) NR 10c R 10c '} , -NR 9c S (O) 2 NR 10c R 10c', -C (O) R 9c, the -C (O) ^{oR 9c} and ^{-C (O) NR 9c R 9c} ' is selected from the group consisting of, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 -C Each hydrogen atom in the ₁₀ aryl and the 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cyclo. Alkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -OR ^11c , -OC(O)R ^11c , -OC(O)NR ^11c R ^11c' , -. OS(O)R ^11c , -OS(O) ₂ R ^11c , -SR ^11c , -S(O)R ^11c , -S(O) ₂ R ^11c , -S(O)NR ^11c R ^11c' , -S. (O) ₂ NR ^11c R ^11c' , -OS(O)NR ^11c R ^11c' , -OS(O) ₂ NR ^11c R ^11c' , -NR ^11c R ^11c' , -NR ^11c C(O)R ^12c , -NR ^11c C(O)OR ^12c , -NR ^11c C(O)NR ^12c R ^12c' , -NR ^11c S(O)R ^12c , -NR ^11c S(O) ₂ R ^12c , -NR ^11c S(O). ^{) NR 12c R 12c ', -NR} 11c S (O) 2 NR 12c R 12c', -C (O) R 11c, substituted by -C ^{(O) oR 11c} or ^{-C (O)} NR ^{11c R 11c} Well;

J is ^{-C (O) -, - CR} 13c = , or ^{- (CR 13c R 13c ')} - a and,
^R6c , ^R6c' , ^R7c , ^R7c' , ^R8c , ^R8c' , ^R9c , ^R9c' , ^R10c , ^R10c' , ^R11c , ^R11c' , ^R12c , ^R12c' , R. ^13c and R ^13c′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. Selected from the group consisting of cycloalkyl, C ₆ -C ₁₀ aryl and 5-7 membered heteroaryl;
R ^1d is H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ Aryl, 5-7 membered heteroaryl, —OR ^2d , —SR ^2d and —NR ^2d R ^2d′ selected from the group consisting of:
R ^2d and R ^2d′ are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. is selected from the group consisting of _cycloalkyl, C 6 _{-C 10} aryl and 5-7 membered heteroaryl, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl, C} 3 ~ Each hydrogen atom in C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-7 membered heteroaryl is optionally -OR ^3d , -SR ^3d and -NR ^{3d. Optionally} substituted by R ^3d′ ;
R ^3d and R ^3d′ are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring. is selected from the group consisting of _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl;
R ^1e is H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ It is selected from the group consisting of aryl and 5-7 membered heteroaryl, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 each hydrogen atom in membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5- to 7-membered ring heteroaryl is independently _optionally, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl, C} 2 ~ C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 2e, -OC (O)} R 2e, -OC ^{(O) NR 2e R 2e '} , -OS (O) R 2e, -OS (O) 2 R 2e, -SR 2e, -S (O) R 2e, -S (O) 2 R 2e, -S ( ^{O) NR 2e R 2e ',} -S (O) 2 NR 2e R 2e', -OS (O) NR 2e R 2e ', -OS (O) 2 NR 2e R 2e', -NR 2e R 2e ', ^{-NR 2e C (O) R 3e} , -NR 2e C (O) OR 3e, -NR 2e C (O) NR 3e R 3e ', -NR 2e S (O) R 3e, -NR 2e S (O) _{^{2 R 3e, -NR 2e S (}} O) NR 2e R 2e ', -NR 2e S (O) 2 NR 3e R 3e', -C (O) R 2e, -C (O) oR 2e or -C ( O) optionally substituted by NR ^2e R ^2e ;
R ^2e , R ^2e′ , R ^3e and R ^3e′ are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl, wherein _C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl, _{C 2} -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} each hydrogen atom in the C 6 _{-C 10} aryl and 5- to 7-membered ring heteroaryl, optionally, ^{-OR 4e,} - ^Optionally substituted by SR ^4e or —NR ^4e R ^4e′ ;
R ^4e and R ^4e′ are independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. Selected from the group consisting of cycloalkyl, C ₆ -C ₁₀ aryl and 5-7 membered heteroaryl;
v is 1, 2 or 3; and * is a covalent bond]
Is selected from the group consisting of:

〔式中、
Ｌ^５、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^６ａ、Ｒ^７ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｂ、Ｒ^３ｂ、Ｒ^４ｂ、Ｒ^５ｂ、Ｒ^６ｂ、Ｒ^７ｂ、Ｒ^８ｂ、Ｒ^９ｂ、Ｒ^１０ｂ、Ｒ^１１ｂおよびＲ^１２ｂは、本明細書に記載で定義されるものである〕
により表記できる。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｂ、Ｒ^３ｂ、Ｒ^４ｂ、Ｒ^８ｂおよびＲ^９ｂはＨであり、Ｌ^５はＣ_１〜Ｃ_１０アルキル、−（ＣＲ^４９＝ＣＲ^４９’）_ｕ−、−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−，−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−または−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はＨであり、そしてｕは１、２、３、４または５である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｂ、Ｒ^３ｂ、Ｒ^４ｂ、Ｒ^８ｂおよびＲ^９ｂはＨであり、そしてＬ^５はＣ_１〜Ｃ_１０アルキルである。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｂ、Ｒ^３ｂ、Ｒ^４ｂ、Ｒ^８ｂおよびＲ^９ｂはＨであり、Ｌ^５は−（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−であり、ここでＲ^４９およびＲ^４９’はＨであり、そしてｕは４である。いくつかの態様において、Ｒ^４ａは結合であり、Ｒ^２ａ、Ｒ^３ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｂ、Ｒ^３ｂ、Ｒ^４ｂ、Ｒ^８ｂおよびＲ^９ｂはＨであり、Ｌ^５はＣ_１〜Ｃ_１０アルキル、−（ＣＲ^４９＝ＣＲ^４９’）_ｕ−、−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−，−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−または−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、ｕは１、２、３、４または５である。いくつかの態様において、Ｒ^４ａは結合であり、Ｒ^２ａ、Ｒ^３ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｂ、Ｒ^３ｂ、Ｒ^４ｂ、Ｒ^８ｂおよびＲ^９ｂはＨであり、そしてＬ^５はＣ_１〜Ｃ_１０アルキルである。 In some embodiments, the drug (Drug) can be represented by the general formula —D ¹ -L ⁵ —D ² , and in some embodiments, the drug (Drug) has the formula

[In the formula,
^{L 5, R 2a, R 3a} , R 4a, R 5a, R 6a, R 7a, R 8a, R 9a, R 10a, R 2b, R 3b, R 4b, R 5b, R 6b, R 7b, R 8b , R ^9b , R ^10b , R ^11b and R ^12b are as defined herein.]
Can be written as In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a , R ^2b , R ^3b , R ^4b , R ^8b and R ^9b are H and L ⁵ is C ₁ -C. ₁₀ ^{alkyl, - (CR 49 = CR 49} ') u -, - (CR 49 R 49') u C (O) -, - CH 2 CH 2 (OCR 49 R 49 'CR 49 R 49') u -, ^{_{-CH 2 CH 2 CH 2 (OCR}} 49 R 49 'CR 49 R 49' CR 49 R 49 ') u -, - CH 2 CH 2 (OCR 49 R 49' CR 49 R 49 ') u C (O) - or _{^{-CH 2 CH 2 (OCR 49 R}} 49 'CR 49 R 49' CR 49 R 49 ') u C (O) - and is, wherein ^{R 49} and ^{R 49'} is H, and u is 1, 2, 3, 4 or 5. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a , R ^2b , R ^3b , R ^4b , R ^8b and R ^9b are H, and L ⁵ is C ₁ -. It is C ₁₀ alkyl. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a , R ^2b , R ^3b , R ^4b , R ^8b and R ^9b are H and L ⁵ is -(OCR ⁴⁹ R ^49′ CR ⁴⁹ R ^49′ ) _u −, where R ⁴⁹ and R ^49′ are H and u is 4. In some embodiments, R ^4a is a bond, R ^2a , R ^3a , R ^8a , R ^9a , R ^10a , R ^2b , R ^3b , R ^4b , R ^8b and R ^9b are H, and L ⁵ is C ₁ -C ₁₀ ^{alkyl, - (CR 49 = CR 49} ') u -, - (CR 49 R 49') u C (O) -, - CH 2 CH 2 (OCR 49 R 49 'CR 49 R 49' _{) u -, - CH 2 CH} 2 CH 2 (OCR 49 R 49 'CR 49 R 49' CR 49 R 49 ') u -, - CH 2 CH 2 (OCR 49 R 49' CR 49 R 49 ') u C (O) - or _{^{-CH 2 CH 2 (OCR 49 R}} 49 'CR 49 R 49' CR 49 R 49 ') u C (O) - and is, wherein ^{R 49} and ^{R 49'} are each H, u is 1, 2, 3, 4 or 5. In some embodiments, R ^4a is a bond, R ^2a , R ^3a , R ^8a , R ^9a , R ^10a , R ^2b , R ^3b , R ^4b , R ^8b and R ^9b are H, and L ⁵ Is C ₁ -C ₁₀ alkyl.

In some embodiments, R ^5a is a bond, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a , R ^2b , R ^3b , R ^4b , R ^8b and R ^9b are H, L ⁵ represents _C 1 _{-C 10} ^{alkyl, - (CR 49 = CR 49} ') u -, - (CR 49 R 49') u C (O) -, - CH 2 CH 2 (OCR 49 R 49 'CR 49 _{^{R 49 ') u -, -}} CH 2 CH 2 CH 2 (OCR 49 R 49' CR 49 R 49 'CR 49 R 49') u -, - CH 2 CH 2 (OCR 49 R 49 'CR 49 R 49' ) _u C (O) - or _{^{-CH 2 CH 2 (OCR 49 R}} 49 'CR 49 R 49' CR 49 R 49 ') u C (O) - and is, wherein ^{R 49} and ^{R 49'} each H And u is 1, 2, 3, 4 or 5. In some embodiments, R ^5a is a bond, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a , R ^2b , R ^3b , R ^4b , R ^8b and R ^9b are H, And L ⁵ is C ₁ -C ₁₀ alkyl.

〔式中、
Ｌ^５、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^６ａ、Ｒ^７ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｃ、Ｒ^３ｃ、Ｒ^４ｃ、Ｒ^５ｃおよびＪは、本明細書で定義されるものである〕
により表記できる。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｃ、Ｒ^３ｃ、Ｒ^４ｃおよびＲ^５ｃはＨであり、Ｌ^５はＣ_１〜Ｃ_１０アルキルであり、−（ＣＲ^４９＝ＣＲ^４９’）_ｕ−、−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−，−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−または−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは１、２、３、４または５である。いくつかの態様において、Ｊは−Ｃ（Ｏ）−、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｃ、Ｒ^３ｃ、Ｒ^４ｃおよびＲ^５ｃはＨであり、そしてＬ^５はＣ_１〜Ｃ_１０アルキルである。いくつかの態様において、Ｊは−ＣＲ^１３ｃ＝、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｃ、Ｒ^３ｃ、Ｒ^４ｃ、Ｒ^５ｃおよびＲ^１３ｃはＨであり、そしてＬ^５はＣ_１〜Ｃ_１０アルキルである。いくつかの態様において、Ｊは−（ＣＲ^１３ｃＲ^１３ｃ’）−、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｃ、Ｒ^３ｃ、Ｒ^４ｃ、Ｒ^５ｃ、Ｒ^１３ｃおよびＲ^１３ｃ’はＨであり、そしてＬ^５はＣ_１〜Ｃ_１０アルキルである。 In some embodiments, the drug (Drug) can be represented by the general formula —D ¹ -L ⁵ —D ² , and in some embodiments, the drug (Drug) has the formula

[In the formula,
L ⁵ , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^2c , R ^3c , R ^4c , R ^5c and J are defined herein. Will be done]
Can be written as In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a , R ^2c , R ^3c , R ^4c and R ^5c are H and L ⁵ is C ₁ -C ₁₀ alkyl. ^{Yes, - (CR 49 = CR 49} ') u -, - (CR 49 R 49') u C (O) -, - CH 2 CH 2 (OCR 49 R 49 'CR 49 R 49') u -, - ^{_{CH 2 CH 2 CH 2 (OCR}} 49 R 49 'CR 49 R 49' CR 49 R 49 ') u -, - CH 2 CH 2 (OCR 49 R 49' CR 49 R 49 ') u C (O) - or _{^{-CH 2 CH 2 (OCR 49 R}} 49 'CR 49 R 49' CR 49 R 49 ') u C (O) - and is, wherein ^{R 49} and ^{R 49'} are each H, and u is 1, 2, 3, 4 or 5. In some embodiments, J is -C(O)-, ^R2a , ^R3a , ^R4a , ^R8a , ^R9a , ^R10a , ^R2c , ^R3c , ^R4c and ^R5c are H, and L ⁵ is C ₁ -C ₁₀ alkyl. In some embodiments, J is -CR ^13c =, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a , R ^2c , R ^3c , R ^4c , R ^5c and R ^13c are H, And L ⁵ is C ₁ -C ₁₀ alkyl. In some embodiments, J is ^{- (CR 13c R 13c ')} -, R 2a, R 3a, R 4a, R 8a, R 9a, R 10a, R 2c, R 3c, R 4c, R 5c, R 13c And R ^13c′ is H, and L ⁵ is C ₁ -C ₁₀ alkyl.

〔式中、
Ｌ^５、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^６ａ、Ｒ^７ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａは本明細書で定義されるものである〕
により表記できる。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａはＨであり、Ｌ^５はＣ_１−Ｃ_１０アルキル、−（ＣＲ^４９＝ＣＲ^４９’）_ｕ−、−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−，−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−または−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは１、２、３、４または５である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａはＨであり、そしてＬ^５はＣ_１〜Ｃ_１０アルキルである。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａはＨであり、Ｌ^５は−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは３である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａはＨであり、Ｌ^５は−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは４である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａはＨであり、Ｌ^５は−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは５である。 In some embodiments, the drug (Drug) can be expressed in general ^formula, the -D 1 ^-L 5 -D ^2. In some embodiments, the Drug (Drug) is of the formula

[In the formula,
L ⁵ , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a and R ^10a are as defined herein]
Can be written as In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a and R ^10a are H, L ⁵ is C ₁ -C ₁₀ alkyl, —(CR ⁴⁹ =CR ^49′ ) _u −, ^{- (CR 49 R 49 ')} u C (O) -, - CH 2 CH 2 (OCR 49 R 49' CR 49 R 49 ') u -, - CH 2 CH 2 CH 2 (OCR 49 R 49' CR 49 ^{R 49 'CR 49 R 49'} ) u -, - CH 2 CH 2 (OCR 49 R 49 'CR 49 R 49') u C (O) - or _{^{-CH 2 CH 2 (OCR 49 R}} 49 'CR 49 R ^49′ CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H and u is 1, 2, 3, 4 or 5. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a and R ^10a are H and L ⁵ is C ₁ -C ₁₀ alkyl. In some ^{embodiments, R 2a, R 3a, R} 4a, R 8a, R 9a and ^{R 10a} are H, ^{L 5} is ^{- (CR 49 R 49 ')} u C (O) - and it is, here R ⁴⁹ and R ^49′ are each H and u is 3. In some ^{embodiments, R 2a, R 3a, R} 4a, R 8a, R 9a and ^{R 10a} are H, ^{L 5} is ^{- (CR 49 R 49 ')} u C (O) - and it is, here R ⁴⁹ and R ^49′ are each H and u is 4. In some ^{embodiments, R 2a, R 3a, R} 4a, R 8a, R 9a and ^{R 10a} are H, ^{L 5} is ^{- (CR 49 R 49 ')} u C (O) - and it is, here R ⁴⁹ and R ^49′ are each H and u is 5.

〔式中、
Ｌ^５、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^６ａ、Ｒ^７ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅは、本明細書で定義されるものである〕
により表記できる。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅはＨであり、Ｌ^５はＣ_１〜Ｃ_１０アルキル、−（ＣＲ^４９＝ＣＲ^４９’）_ｕ−、−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−，−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−または−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、Ｒ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは１、２、３、４または５である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅはＨであり、そしてＬ^５はＣ_１〜Ｃ_１０アルキル．いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅはＨであり、Ｌ^５は−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは３である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅはＨであり、Ｌ^５は−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは４である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅはＨであり、Ｌ^５は−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは５である。 In some embodiments, the drug (Drug) general ^formula, can be expressed in -D 1 ^-L 5 -D ^2. In some embodiments, the Drug (Drug) is of the formula

[In the formula,
L ⁵ , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a and R ^1e are as defined herein]
Can be written as In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a and R ^1e are H and L ⁵ is C ₁ -C ₁₀ alkyl, -(CR ⁴⁹ =CR ^49' ). _{^{u -, - (CR 49 R}} 49 ') u C (O) -, - CH 2 CH 2 (OCR 49 R 49' CR 49 R 49 ') u -, - CH 2 CH 2 CH 2 (OCR 49 R 49 ^{'CR 49 R 49' CR 49} R 49 ') u -, - CH 2 CH 2 (OCR 49 R 49' CR 49 R 49 ') u C (O) - or _{^{-CH 2 CH 2 (OCR 49 R}} 49' CR ⁴⁹ R ^49′ CR ⁴⁹ R ^49′ ) _u C(O)—, R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3, 4 or 5. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a and R ^1e are H, and L ⁵ is C ₁ -C ₁₀ alkyl. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a and R ^1e are H and L ⁵ is —(CR ⁴⁹ R ^49′ ) _u C(O)—. , Where R ⁴⁹ and R ^49′ are each H and u is 3. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a and R ^1e are H and L ⁵ is —(CR ⁴⁹ R ^49′ ) _u C(O)—. , Where R ⁴⁹ and R ^49′ are each H and u is 4. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a and R ^1e are H and L ⁵ is —(CR ⁴⁹ R ^49′ ) _u C(O)—. , Where R ⁴⁹ and R ^49′ are each H and u is 5.

〔式中、
Ｌ^５、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^６ａ、Ｒ^７ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^１ｄおよびｖは、本明細書で定義されるものである〕
により表記できる。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅはＨであり、Ｌ^５はＣ_１〜Ｃ_１０アルキル、−（ＣＲ^４９＝ＣＲ^４９’）_ｕ−、−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−，−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−または−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは１、２、３、４または５である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅはＨであり、そしてＬ^５はＣ_１〜Ｃ_１０アルキル．いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅはＨであり、Ｌ^５は−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは４である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅはＨであり、Ｌ^５は−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは５である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅはＨであり、Ｌ^５はＣ_１〜Ｃ_１０アルキルであり、そしてｖは２である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅはＨであり、Ｌ^５はＣ_１〜Ｃ_１０アルキルであり、そしてｖは３である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅはＨであり、Ｌ^５は−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、ｕは４であり、そしてｖは２である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅはＨであり、Ｌ^５は−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、ｕは４であり、そしてｖは３である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅはＨであり、Ｌ^５は−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、ｕは５であり、そしてｖは２である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａおよびＲ^１ｅはＨであり、Ｌ^５は−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、ｕは５であり、そしてｖは３である。 In some embodiments, the drug (Drug) can be expressed in general ^formula, the -D 1 ^-L 5 -D ^2. In some embodiments, the Drug (Drug) is of the formula

[In the formula,
L ⁵ , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^1d and v are as defined herein]
Can be written as In some ^{embodiments, R 2a, R 3a, R} 4a, R 8a, R 9a, R 10a and ^{R 1e} are H, ^{L 5} is _C 1 _{-C 10} ^{alkyl, - (CR 49 = CR 49} ') _{^{u -, - (CR 49 R}} 49 ') u C (O) -, - CH 2 CH 2 (OCR 49 R 49' CR 49 R 49 ') u -, - CH 2 CH 2 CH 2 (OCR 49 R 49 ^{'CR 49 R 49' CR 49} R 49 ') u -, - CH 2 CH 2 (OCR 49 R 49' CR 49 R 49 ') u C (O) - or _{^{-CH 2 CH 2 (OCR 49 R}} 49' ^{CR 49 R 49 'CR 49 R} 49') u C (O) - and is, wherein ^{R 49} and ^{R 49 'are} each H, and u is 1, 2, 3, 4 or 5. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a and R ^1e are H, and L ⁵ is C ₁ -C ₁₀ alkyl. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a and R ^1e are H and L ⁵ is —(CR ⁴⁹ R ^49′ ) _u C(O)—. , Where R ⁴⁹ and R ^49′ are each H and u is 4. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a and R ^1e are H and L ⁵ is —(CR ⁴⁹ R ^49′ ) _u C(O)—. , Where R ⁴⁹ and R ^49′ are each H and u is 5. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a and R ^1e are H, L ⁵ is C ₁ -C ₁₀ alkyl, and v is 2. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a and R ^1e are H, L ⁵ is C ₁ -C ₁₀ alkyl, and v is 3. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a and R ^1e are H and L ⁵ is —(CR ⁴⁹ R ^49′ ) _u C(O)—. , Where R ⁴⁹ and R ^49′ are each H, u is 4 and v is 2. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a and R ^1e are H and L ⁵ is —(CR ⁴⁹ R ^49′ ) _u C(O)—. , Where R ⁴⁹ and R ^49′ are each H, u is 4 and v is 3. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a and R ^1e are H and L ⁵ is —(CR ⁴⁹ R ^49′ ) _u C(O)—. , Where R ⁴⁹ and R ^49′ are each H, u is 5 and v is 2. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a and R ^1e are H and L ⁵ is —(CR ⁴⁹ R ^49′ ) _u C(O)—. , Where R ⁴⁹ and R ^49′ are each H, u is 5 and v is 3.

〔式中、
Ｌ^５、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^６ａ、Ｒ^７ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａは、本明細書で定義されるものである〕
により表記できる。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａはＨであり、Ｌ^５はＣ_１〜Ｃ_１０アルキル、−（ＣＲ^４９＝ＣＲ^４９’）_ｕ−、−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−，−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−または−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは１、２、３、４または５である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａはＨであり、そしてＬ^５はＣ_１〜Ｃ_１０アルキルである。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａはＨであり、Ｌ^５は−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは４である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａはＨであり、Ｌ^５は−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは５である。 In some embodiments, the drug (Drug) can be expressed in general ^formula, the -D 1 ^-L 5 -D ^2. In some embodiments, the Drug (Drug) is of the formula

[In the formula,
L ⁵ , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a and R ^10a are as defined herein]
Can be written as In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a and R ^10a are H, L ⁵ is C ₁ -C ₁₀ alkyl, —(CR ⁴⁹ =CR ^49′ ) _u −, ^{- (CR 49 R 49 ')} u C (O) -, - CH 2 CH 2 (OCR 49 R 49' CR 49 R 49 ') u -, - CH 2 CH 2 CH 2 (OCR 49 R 49' CR 49 ^{R 49 'CR 49 R 49'} ) u -, - CH 2 CH 2 (OCR 49 R 49 'CR 49 R 49') u C (O) - or _{^{-CH 2 CH 2 (OCR 49 R}} 49 'CR 49 R ^49′ CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H and u is 1, 2, 3, 4 or 5. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a and R ^10a are H and L ⁵ is C ₁ -C ₁₀ alkyl. In some ^{embodiments, R 2a, R 3a, R} 4a, R 8a, R 9a and ^{R 10a} are H, ^{L 5} is ^{- (CR 49 R 49 ')} u C (O) - and it is, here R ⁴⁹ and R ^49′ are each H and u is 4. In some ^{embodiments, R 2a, R 3a, R} 4a, R 8a, R 9a and ^{R 10a} are H, ^{L 5} is ^{- (CR 49 R 49 ')} u C (O) - and it is, here R ⁴⁹ and R ^49′ are each H and u is 5.

〔式中、
Ｌ^５、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^６ａ、Ｒ^７ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａは、本明細書で定義されるものである〕
により表記できる。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａはＨであり、Ｌ^５はＣ_１〜Ｃ_１０アルキル、−（ＣＲ^４９＝ＣＲ^４９’）_ｕ−、−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−，−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−または−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは１、２、３、４または５である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａはＨであり、そしてＬ^５はＣ_１〜Ｃ_１０アルキルである。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａはＨであり、Ｌ^５は−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは４である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａおよびＲ^１０ａはＨであり、Ｌ^５は−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは５である。 In some embodiments, the drug (Drug) can be expressed in general ^formula, the -D 1 ^-L 5 -D ^2. In some embodiments, the Drug (Drug) is of the formula

[In the formula,
L ⁵ , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a and R ^10a are as defined herein]
Can be written as In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a and R ^10a are H, L ⁵ is C ₁ -C ₁₀ alkyl, —(CR ⁴⁹ =CR ^49′ ) _u −, ^{- (CR 49 R 49 ')} u C (O) -, - CH 2 CH 2 (OCR 49 R 49' CR 49 R 49 ') u -, - CH 2 CH 2 CH 2 (OCR 49 R 49' CR 49 ^{R 49 'CR 49 R 49'} ) u -, - CH 2 CH 2 (OCR 49 R 49 'CR 49 R 49') u C (O) - or _{^{-CH 2 CH 2 (OCR 49 R}} 49 'CR 49 R ^49′ CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H and u is 1, 2, 3, 4 or 5. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a and R ^10a are H and L ⁵ is C ₁ -C ₁₀ alkyl. In some ^{embodiments, R 2a, R 3a, R} 4a, R 8a, R 9a and ^{R 10a} are H, ^{L 5} is ^{- (CR 49 R 49 ')} u C (O) - and it is, here R ⁴⁹ and R ^49′ are each H and u is 4. In some ^{embodiments, R 2a, R 3a, R} 4a, R 8a, R 9a and ^{R 10a} are H, ^{L 5} is ^{- (CR 49 R 49 ')} u C (O) - and it is, here R ⁴⁹ and R ^49′ are each H and u is 5.

〔式中、
Ｌ^５、Ｒ^２ａ、Ｒ^３ａ、Ｒ^５ａ、Ｒ^６ａ、Ｒ^７ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｂ、Ｒ^３ｂ、Ｒ^４ｂ、Ｒ^５ｂ、Ｒ^６ｂ、Ｒ^７ｂ、Ｒ^８ｂ、Ｒ^９ｂ、Ｒ^１０ｂ、Ｒ^１１ｂおよびＲ^１２ｂは本明細書に記載のように定義される〕
のように表記できる。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｂ、Ｒ^３ｂ、Ｒ^４ｂ、Ｒ^８ｂおよびＲ^９ｂはＨであり、Ｌ^５はＣ_１〜Ｃ_１０アルキル、−（ＣＲ^４９＝ＣＲ^４９’）_ｕ−、−（ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−，−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕ−、−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−または−ＣＨ_２ＣＨ_２（ＯＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’ＣＲ^４９Ｒ^４９’）_ｕＣ（Ｏ）−であり、ここでＲ^４９およびＲ^４９’はそれぞれＨであり、そしてｕは１、２、３、４または５である。いくつかの態様において、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^８ａ、Ｒ^９ａ、Ｒ^１０ａ、Ｒ^２ｂ、Ｒ^３ｂ、Ｒ^４ｂ、Ｒ^８ｂおよびＲ^９ｂはＨであり、そしてＬ^５はＣ_１〜Ｃ_１０アルキルである。 In some embodiments, the drug (Drug) general ^formula, may be able by -D 1 ^-L 5 -D ^2. In some embodiments, the Drug (Drug) is of the formula

[In the formula,
^{L 5, R 2a, R 3a} , R 5a, R 6a, R 7a, R 8a, R 9a, R 10a, R 2b, R 3b, R 4b, R 5b, R 6b, R 7b, R 8b, R 9b , R ^10b , R ^11b and R ^12b are defined as described herein]
Can be written as. In some embodiments, R ^2a , R ^3a , R ^8a , R ^9a , R ^10a , R ^2b , R ^3b , R ^4b , R ^8b and R ^9b are H, L ⁵ is C ₁ -C ₁₀ alkyl, ^{- (CR 49 = CR 49 '} ) u -, - (CR 49 R 49') u C (O) -, - CH 2 CH 2 (OCR 49 R 49 'CR 49 R 49') u -, - CH 2 _{^{CH 2 CH 2 (OCR 49 R}} 49 'CR 49 R 49' CR 49 R 49 ') u -, - CH 2 CH 2 (OCR 49 R 49' CR 49 R 49 ') u C (O) - or -CH _{^{2 CH 2 (OCR 49 R 49}} 'CR 49 R 49' CR 49 R 49 ') u C (O) - and is, wherein ^{R 49} and ^{R 49'} are each H, and u is 1, 3, 4 or 5. In some embodiments, R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a , R ^2b , R ^3b , R ^4b , R ^8b and R ^9b are H, and L ⁵ is C ₁ -. It is C ₁₀ alkyl.

〔式中、
Ｒ^１ｂ、Ｒ^２ｂ、Ｒ^３ｂおよびＲ^４ｂは、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｃ（Ｏ）Ｒ^１３ｂ、−Ｃ（Ｏ）ＯＲ^１３ｂであり、そして−Ｃ（Ｏ）ＮＲ^１３ｂＲ^１３ｂ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１３ｂ、−ＯＣ（Ｏ）Ｒ^１３ｂ、−ＯＣ（Ｏ）ＮＲ^１３ｂＲ^１３ｂ’、−ＯＳ（Ｏ）Ｒ^１３ｂ、−ＯＳ（Ｏ）_２Ｒ^１３ｂ、−ＳＲ^１３ｂ、−Ｓ（Ｏ）Ｒ^１３ｂ、−Ｓ（Ｏ）_２Ｒ^１３ｂ、−Ｓ（Ｏ）ＮＲ^１３ｂＲ^１３ｂ’、−Ｓ（Ｏ）_２ＮＲ^１３ｂＲ^１３ｂ’、−ＯＳ（Ｏ）ＮＲ^１３ｂＲ^１３ｂ’、−ＯＳ（Ｏ）_２ＮＲ^１３ｂＲ^１３ｂ’、−ＮＲ^１３ｂＲ^１３ｂ’、−ＮＲ^１３ｂＣ（Ｏ）Ｒ^１４ｂ、−ＮＲ^１３ｂＣ（Ｏ）ＯＲ^１４ｂ、−ＮＲ^１３ｂＣ（Ｏ）ＮＲ^１４ｂＲ^１４ｂ’、−ＮＲ^１３ｂＳ（Ｏ）Ｒ^１４ｂ、−ＮＲ^１３ｂＳ（Ｏ）_２Ｒ^１４ｂ、−ＮＲ^１３ｂＳ（Ｏ）ＮＲ^１４ｂＲ^１４ｂ’、−ＮＲ^１３ｂＳ（Ｏ）_２ＮＲ^１４ｂＲ^１４ｂ’、−Ｃ（Ｏ）Ｒ^１３ｂ、−Ｃ（Ｏ）ＯＲ^１３ｂまたは−Ｃ（Ｏ）ＮＲ^１３ｂＲ^１３ｂ’により置換されていてよく；またはＲ^１ｂ、Ｒ^２ｂ、Ｒ^３ｂおよびＲ^４ｂのいずれか１つは結合であり；
Ｒ^５ｂ、Ｒ^６ｂおよびＲ^７ｂは、それぞれ独立してＨ、Ｄ、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｃ（Ｏ）Ｒ^１５ｂ、−Ｃ（Ｏ）ＯＲ^１５ｂであり、そして−Ｃ（Ｏ）ＮＲ^１５ｂＲ^１５ｂ’から成る群から選択され、ここでＣ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリールおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−Ｌ^４Ｈ、−Ｌ^３Ｈ、−ＯＲ^１５ｂ、−ＯＣ（Ｏ）Ｒ^１５ｂ、−ＯＣ（Ｏ）ＮＲ^１５ｂＲ^１５ｂ’、−ＯＳ（Ｏ）Ｒ^１５ｂ、−ＯＳ（Ｏ）_２Ｒ^１５ｂ、−ＳＲ^１５ｂ、−Ｓ（Ｏ）Ｒ^１５ｂ、−Ｓ（Ｏ）_２Ｒ^１５ｂ、−Ｓ（Ｏ）ＮＲ^１５ｂＲ^１５ｂ’、−Ｓ（Ｏ）_２ＮＲ^１５ｂＲ^１５ｂ’、−ＯＳ（Ｏ）ＮＲ^１５ｂＲ^１５ｂ’、−ＯＳ（Ｏ）_２ＮＲ^１５ｂＲ^１５ｂ’、−ＮＲ^１５ｂＲ^１５ｂ’、−ＮＲ^１５ｂＣ（Ｏ）Ｒ^１６ｂ、−ＮＲ^１５ｂＣ（Ｏ）ＯＲ^１６ｂ、−ＮＲ^１５ｂＣ（Ｏ）ＮＲ^１６ｂＲ^１６ｂ’、−ＮＲ^１５ｂＳ（Ｏ）Ｒ^１６ｂ、−ＮＲ^１５ｂＳ（Ｏ）_２Ｒ^１６ｂ、−ＮＲ^１５ｂＳ（Ｏ）ＮＲ^１６ｂＲ^１６ｂ’、−ＮＲ^１５ｂＳ（Ｏ）_２ＮＲ^１６ｂＲ^１６ｂ’、−Ｃ（Ｏ）Ｒ^１５ｂ、−Ｃ（Ｏ）ＯＲ^１５ｂまたは−Ｃ（Ｏ）ＮＲ^１５ｂＲ^１５ｂ’により置換されていてよく；ここで、Ｒ^６ｂおよびＲ^７ｂは、それらが結合する原子と一緒になって、場合により結合して３〜７員環ヘテロシクロアルキルを形成し、またはＲ^５ｂおよびＲ^６ｂは、それらが結合する原子と一緒になって、場合により結合して３〜７員環ヘテロシクロアルキルまたは５〜７員環ヘテロアリールを形成し、ここで３〜７員環ヘテロシクロアルキルおよび５〜７員環ヘテロアリールにおける各水素原子は、独立して、場合により、Ｃ_１〜Ｃ_６アルキル、Ｃ_２〜Ｃ_６アルケニル、Ｃ_２〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_６シクロアルキル、３〜７員環ヘテロシクロアルキル、Ｃ_６〜Ｃ_１０アリール、５〜７員環ヘテロアリール、−ＯＲ^１７ｂ、−ＯＣ（Ｏ）Ｒ^１７ｂ、−ＯＣ（Ｏ）ＮＲ^１７ｂＲ^１７ｂ’、−ＯＳ（Ｏ）Ｒ^１７ｂ、−ＯＳ（Ｏ）_２Ｒ^１７ｂ、−ＳＲ^１７ｂ、−Ｓ（Ｏ）Ｒ^１７ｂ、−Ｓ（Ｏ）_２Ｒ^１７ｂ、−Ｓ（Ｏ）ＮＲ^１７ｂＲ^１７ｂ’、−Ｓ（Ｏ）_２ＮＲ^１７ｂＲ^１７ｂ’、−ＯＳ（Ｏ）ＮＲ^１７ｂＲ^１７ｂ’、−ＯＳ（Ｏ）_２ＮＲ^１７ｂＲ^１７ｂ’、−ＮＲ^１７ｂＲ^１７ｂ’、−ＮＲ^１７ｂＣ（Ｏ）Ｒ^１８ｂ、−ＮＲ^１７ｂＣ（Ｏ）ＯＲ^１８ｂ、−ＮＲ^１７ｂＣ（Ｏ）ＮＲ^１８ｂＲ^１８ｂ’、−ＮＲ^１７ｂＳ（Ｏ）Ｒ^１８ｂ、−ＮＲ^１７ｂＳ（Ｏ）_２Ｒ^１８ｂ、−ＮＲ^１７ｂＳ（Ｏ）ＮＲ^１８ｂＲ^１８ｂ’、−ＮＲ^１７ｂＳ（Ｏ）_２ＮＲ^１８ｂＲ^１８ｂ’、−Ｃ（Ｏ）Ｒ^１７ｂ、−Ｃ（Ｏ）ＯＲ^１７ｂまたは−Ｃ（Ｏ）ＮＲ^１７ｂＲ^１７ｂにより置換されていてよく；またはＲ^５ｂ、Ｒ^６ｂまたはＲ^７ｂのいずれか１つは結合であり； In some embodiments, D ¹ may be absent. When D ¹ does not exist, D ² is an expression

[In the formula,
R ^1b , R ^2b , R ^3b and R ^4b are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, -C (O) R ^13b, a -C ^{(O) OR 13b,} and -C ^{(O) NR 13b} R ^{13b′ is} selected from the group consisting of C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, each hydrogen atom in C ₆ -C ₁₀ aryl and 5- to 7-membered ring heteroaryl is independently _optionally, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl, _{C 3} -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 13b, -OC (O)} R 13b, -OC (O) NR 13b R _{^{13b ', -OS (O) R}} 13b, -OS (O) 2 R 13b, -SR 13b, -S (O) R 13b, -S (O) 2 R 13b, -S (O) NR 13b R 13b _{^{', -S (O) 2 NR}} 13b R 13b', -OS (O) NR 13b R 13b ', -OS (O) 2 NR 13b R 13b', -NR 13b R 13b ', -NR 13b C (O ) R ^14b , -NR ^13b C(O)OR ^14b , -NR ^13b C(O)NR ^14b R ^14b' , -NR ^13b S(O)R ^14b , -NR ^13b S(O) ₂ R ^14b , -NR. ^13b S(O)NR ^14b R ^14b' , -NR ^13b S(O) ₂ NR ^14b R ^14b' , -C(O)R ^13b , -C(O)OR ^13b or -C(O)NR ^13b R ^{13b. '} May be substituted by; or any one of R ^1b , R ^2b , R ^3b and R ^4b is a bond;
R ^{5b, R 6b} and ^{R 7b} is, H independently, _D, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, -C (O) R ^15b, a -C ^{(O) OR 15b,} and ^{-C (O) NR 15b R 15b} ' Selected from the group consisting of: C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -. Each hydrogen atom in C ₁₀ aryl and 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C _6. cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -L 4 H, -L 3 H} , -OR 15b, -OC (O) R 15b, - ^{OC (O) NR 15b R 15b} ', -OS (O) R 15b, -OS (O) 2 R 15b, -SR 15b, -S (O) R 15b, -S (O) 2 R 15b, -S (O)NR ^15b R ^15b' , -S(O) ₂ NR ^15b R ^15b' , -OS(O)NR ^15b R ^15b' , -OS(O) ₂ NR ^15b R ^15b' , -NR ^15b R ^15b'. , -NR ^15b C(O)R ^16b , -NR ^15b C(O)OR ^16b , -NR ^15b C(O)NR ^16b R ^16b' , -NR ^15b S(O)R ^16b , -NR ^15b S(O). _{^{) 2 R 16b, -NR 15b S}} (O) NR 16b R 16b ', -NR 15b S (O) 2 NR 16b R 16b', -C (O) R 15b, -C (O) oR 15b or -C (O)NR ^15b R ^15b′ may be substituted; wherein R ^6b and R ^7b are taken together with the atom to which they are attached, optionally together with a 3-7 membered heterocycloalkyl. formed or R ^5b and R ^6b, together with the atom to which they are attached combine to 3-7 membered heterocycloalkyl or 5- to 7-membered ring heteroarylene Each hydrogen atom in a 3-7 membered heterocycloalkyl and a 5-7 membered heteroaryl independently forms an optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 17b, -OC (O)} R 17b ^{, -OC (O) NR 17b R} 17b ', -OS (O) R 17b, -OS (O) 2 R 17b, -SR 17b, -S (O) R 17b, -S (O) 2 R 17b, -S(O)NR ^17b R ^17b' , -S(O) ₂ NR ^17b R ^17b' , -OS(O)NR ^17b R ^17b' , -OS(O) ₂ NR ^17b R ^17b' , -NR ^17b R. ^17b' , -NR ^17b C(O)R ^18b , -NR ^17b C(O)OR ^18b , -NR ^17b C(O)NR ^18b R ^18b' , -NR ^17b S(O)R ^18b , -NR ^17b S. _{^{(O) 2 R 18b, -NR}} 17b S (O) NR 18b R 18b ', -NR 17b S (O) 2 NR 18b R 18b', -C (O) R 17b, -C (O) oR 17b or -C(O)NR ^17b may be substituted by R ^17b ; or any one of R ^5b , R ^6b or R ^7b is a bond;

R ^8b and R ^9b are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. _cycloalkyl, C 6 _{-C 10} aryl, 5-7 membered _{^{heteroaryl, -CN, -NO 2, -NCO,}} -OR 19b, -OC (O) R 19b, -OC (O) NR 19b R 19b ' , -OS(O)R ^19b , -OS(O) ₂ R ^19b , -SR ^19b , -S(O)R ^19b , -S(O) ₂ R ^19b , -S(O)NR ^19b R ^19b' , _{^{-S (O) 2 NR 19b R}} 19b ', -OS (O) NR 19b R 19b', -OS (O) 2 NR 19b R 19b ', -NR 19b R 19b', -NR 19b C (O) R ^20b , -NR ^19b C(O)OR ^20b , -NR ^19b C(O)NR ^20b R ^20b' , -NR ^19b S(O)R ^20b , -NR ^19b S(O) ₂ R ^20b , -NR ^19b S. From (O)NR ^20b R ^20b' , -NR ^19b S(O) ₂ NR ^20b R ^20b' , -C(O)R ^19b , -C(O)OR ^19b and -C(O)NR ^19b R ^19b'. is selected from the group consisting of, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 -C Each hydrogen atom in the ₁₀ aryl and the 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cyclo. Alkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -OR ^21b , -OC(O)R ^21b , -OC(O)NR ^21b R ^21b' , -. OS(O)R ^21b , -OS(O) ₂ R ^21b , -SR ^21b , -S(O)R ^21b , -S(O) ₂ R ^21b , -S(O)NR ^21b R ^21b' , -S. (O) ₂ NR ^21b R ^21b' , -OS(O)NR ^21b R ^21b' , -OS(O) ₂ NR ^21b R ^21b' , -NR ^{2 1b} R ^21b' , -NR ^21b C(O)R ^22b , -NR ^21b C(O)OR ^22b , -NR ^21b C(O)NR ^22b R ^22b' , -NR ^21b S(O)R ^22b , -NR. ^21b S(O) ₂ R ^22b , -NR ^21b S(O)NR ^22b R ^22b' , -NR ^21b S(O) ₂ NR ^22b R ^22b' , -C(O)R ^21b , -C(O)OR. ^21b or -C(O)NR ^21b R ^21b may be substituted;
R ^{10b, R 11b} and ^{R 12b} are, H independently, _D, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 23b, -OC (O)} R 23b, -OC (O) NR 23b R 23b ', -OS (O) R _{^{23b, -OS (O) 2 R}} 23b, -SR 23b, -S (O) R 23b, -S (O) 2 R 23b, -S (O) NR 23b R 23b ', -S (O) 2 NR ^{23b R 23b ', -OS (O} ) NR 23b R 23b', -OS (O) 2 NR 23b R 23b ', -NR 23b R 23b', -NR 23b C (O) R 24b, -NR 23b C ( O)OR ^24b , -NR ^23b C(O)NR ^24b R ^24b' , -NR ^23b S(O)R ^24b , -NR ^23b S(O) ₂ R ^24b , -NR ^23b S(O)NR ^24b R ^{24b. '} , -NR ^23b S(O) ₂ NR ^24b R ^24b' , -C(O)R ^23b , -C(O)OR ^23b and -C(O)NR ^23b R ^23b' , and C ₁ -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl Each hydrogen atom in aryl is, optionally, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocyclo. _alkyl, C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 25b, -OC (O)} R 25b, -OC (O) NR 25b R 25b ', -OS (O) R 25b, -OS (O) ₂ R ^25b , -SR ^25b , -S(O)R ^25b , -S(O) ₂ R ^25b , -S(O)NR ^25b R ^25b' , -S(O) ₂ NR ^25b R ^25b'. , -OS(O)NR ^25b R ^25b' , -OS(O) ₂ NR ^25b R ^25b' , -NR ^25b R ^25b'. , -NR ^25b C(O)R ^26b , -NR ^25b C(O)OR ^26b , -NR ^25b C(O)NR ^26b R ^26b' , -NR ^25b S(O)R ^26b , -NR ^25b S(O). _{^{) 2 R 26b, -NR 25b S}} (O) NR 26b R 26b ', -NR 25b S (O) 2 NR 26b R 26b', -C (O) R 25b, -C (O) oR 25b or -C (O)NR ^25b R ^25b may be substituted, or R ^10b and R ^11b may be taken together with the atom to which they are attached, optionally combined to form a C ₆ -C ₁₀ aryl, or R ^11b and R ^12b together with the atom to which they are attached optionally combine to form exo-methylene; or R ^12b is absent;
R ^13b , R ^13b' , R ^14b , R ^14b' , R ^15b , R ^15b' , R ^16b , R ^16b' , R ^17b , R ^17b' , R ^18b , R ^18b' , R ^19b , R ^19b' , R. ^20b , R ^20b' , R ^21b , R ^21b' , R ^22b , R ^22b' , R ^23b , R ^23b' , R ^24b , R ^24b' , R ^25b , R ^25b' , R ^26b and R ^26b' are respectively. independently _{H, D,} C 1 ~C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 _{-C 13} cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} Selected from the group consisting of aryl, C ₁ -C ₆ alkyl (C ₆ -C ₁₀ aryl) and 5-7 membered heteroaryl, wherein C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkyl (C ₆ -aryl). Each hydrogen atom in C ₁₀ aryl) and a 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C. ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered _{heteroaryl, -CN, -NO 2, -NCO,} -OH, -SH, -NH 2, -SO ₃ H, -C(O)OH and -C(O)NH ₂ may be substituted; and * is a bond]
belongs to.

The conjugates described herein can be used for both human clinical medicine and veterinary applications. As a result, the host animal having a population of pathogenic cells and treated with the conjugates described herein can be a human, or for veterinary use, an experimental animal, agricultural animal, domestic animal or It can be a wild animal. The conjugates described herein include, but are not limited to, humans, laboratory animals such as rodents (eg, mice, rats, hamsters, etc.), domestic animals such as rabbits, monkeys, chimpanzees, dogs, cats, and rabbits. Including agricultural animals such as animals, cows, horses, pigs, sheep, goats and captured wild animals such as bears, pandas, lions, tigers, leopards, elephants, zebras, giraffes, gorillas, dolphins and whales, It can be applied to host animals.

The conjugates, compositions, methods and uses described herein are useful for treating diseases caused at least in part by a population of pathogenic cells that can cause various etiologies in host cells. As used herein, the term "pathogenic cell" or "population of pathogenic cells" generally refers to cancerous cells, infectious agents such as bacteria and viruses, bacterial or viral infected cells, inflammatory cells. , Uniquely expresses, preferentially expresses or overexpresses activated macrophages capable of causing disease states and cell surface receptors or antigens that can be bound or targeted by the conjugates herein. Refers to any other type of pathogenic cell that expresses. Pathogenic cells can also include any cell that causes a disease state in which treatment with the conjugates described herein results in symptom relief of the disease. For example, a pathogenic cell can be a host cell that is pathogenic in some circumstances but not in others, such as immune system cells responsible for graft-versus-host disease.

As a result, the population of pathogenic cells can be a tumorigenic cancer cell population, including benign and malignant tumors, or can be a non-tumorigenic cancer cell population. Cancer cell populations can arise spontaneously or by processes such as mutations that are present in the germline of the host animal, or somatic mutations, or can be chemically, virally or radiation-induced. The conjugates described herein can be used to treat cancers such as carcinoma, sarcoma, lymphoma, Hodgkin's disease, melanoma, mesothelioma, Burkitt lymphoma, nasopharyngeal cancer, leukemia and myeloma. .. The cancer cell population includes, but is not limited to, oral cancer, thyroid cancer, endocrine cancer, skin, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, ovarian cancer, cervical cancer, uterine cancer, breast cancer. , Testicular cancer, prostate cancer, rectal cancer, kidney cancer, liver cancer and lung cancer.

The invention provides all pharmaceutically acceptable, isotope-labeled conjugates included herein and their Drugs (Drugs) (where one or more atoms have the same atomic number, but atomic mass or atomic Replaced by an atom whose mass number is naturally occurring or which differs from the atomic mass number).

Examples of suitable isotopes for inclusion in the conjugates included herein and their agents (Drug) include hydrogen isotopes such as ² H and ³ H, ¹¹ C, ¹³ C and ¹⁴ C. Carbon isotopes, chlorine isotopes such as ³⁶ Cl, fluorine isotopes such as ¹⁸ F, iodine isotopes such as ¹²³ I and ¹²⁵ I, nitrogen isotopes such as ¹³ N and ¹⁵ N, ¹⁵ O, ^It includes oxygen isotopes such as ¹⁷ O and ¹⁸ O, phosphorus isotopes such as ³² P and sulfur isotopes such as ³⁵ S.

Certain isotopically-labeled conjugates and their agents (Drugs), eg, radioactive conjugates and their agents (Drugs), included herein are useful for drug and/or substrate tissue distribution studies. .. The radioactive isotopes tritium, ie ³ H, and carbon-14, ie ¹⁴ C, are particularly useful for this purpose in view of their ease of inclusion and ready means of detection.

Substitution with heavier isotopes, such as deuterium, ie, ² H, may confer some therapeutic benefit resulting from higher metabolic stability, eg, increased in vivo half-life or reduced dosage requirements. Therefore, it may be preferable in some situations.

Substitution with positron-emitting isotopes such as ¹¹ C, ¹⁸ F, and ¹³ N can be useful in Positron Tomography (PET) to analyze substrate receptor occupancy. Isotopically-labeled conjugates and their agents (Drugs) included herein are generally those in which a suitable isotopically-labeled reagent is used in place of the previously used unlabeled reagent. It can be prepared by conventional techniques known to those skilled in the art or those described in the accompanying examples.

The conjugates and compositions described herein may be administered orally. Oral administration may involve swallowing the conjugate or composition to enter the gastrointestinal tract, or buccal or sublingual administration may be used in which the conjugate or composition enters the bloodstream directly from the oral cavity.

Formulations suitable for oral administration include tablets, particles, capsules containing liquids or powders, troches (including those filled with liquid), chewable tablets, multi- and nanoparticle agents, gels, solid solutions, liposomes. , Solid formulations such as films, ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations are used as fillers in soft or hard capsules and generally contain a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil and one or more emulsifying and/or suspending agents. Including. Liquid formulations may also be prepared by reconstitution from a solid such as a sachet.

The conjugates and compositions described herein also have fast-dissolving, fast-disintegrating properties, as described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001). It can be a dosage form. For tablet dosage forms, depending on dose, the conjugate may make up from 1% to 80% by weight of the dosage form, more usually from 5% to 60% by weight. In addition to the conjugates and compositions described herein, tablets generally include a disintegrant. Examples of disintegrants are sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropylcellulose, starch, pregelatinized starch and Contains sodium alginate. Generally, the disintegrant comprises 1% to 25% by weight of the dosage form, preferably 5% to 20%.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycols, natural gums and synthetic gums, polyvinylpyrrolidone, alpha starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets are also like lactose (monohydrate, spray-dried monohydrate, anhydrous etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Diluent may be included.

Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 wt% to 5 wt% of the tablet, and glidants may comprise from 0.2 wt% to 1 wt% of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium fumarate stearate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally make up 0.25% to 10% by weight of the tablet, preferably 0.5% to 3%.

Other possible ingredients include anti-oxidants, colourants, flavoring agents, preservatives and taste-masking agents. A typical tablet will contain up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegration. Agent and about 0.25% to about 10% by weight lubricant.

Tablet blends are compressed directly or by roller to form tablets. Alternatively, tablet blends or portions of blends may be wet granulated, dry granulated or melt granulated, melt congealed or extruded prior to tableting. The final formulation may include one or more layers and may be coated or uncoated; the tablet blend may be encapsulated. Tablet formulations are discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Digestible oral films, for human or veterinary use, may generally be fast-dissolving or mucoadhesive, and are generally conjugates, film-forming polymers, as described herein. Flexible, water-soluble or water-swellable thin film dosage forms containing binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity modifiers and solvents.

Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release and programmed release. Suitable modified release formulations for the purposes of the present invention are described in US Patent No. 6/106,864. Details of other suitable release technologies, such as high energy dispersion and permeability and coated particles, details of other suitable release technologies such as high energy dispersion and permeability and coated particles, Pharmaceutical Technology On-line , 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

The conjugates described herein can be administered directly into the bloodstream, intramuscularly or viscera. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.

Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. Parenteral formulations generally include aqueous solutions that may contain excipients such as salts, carbohydrates and buffers (preferably of pH 3-9), although for some applications sterile non-aqueous It may be more suitably formulated as a solution or in dry form for simultaneous use with a stable solvent such as sterile water, pyrogen-free water.

The manufacture of parenteral formulations under sterile conditions, eg, by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of the conjugates described herein used to prepare parenteral solutions can be increased by the use of appropriate formulation techniques, such as the inclusion of solubility enhancers.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release and programmed release. As a result, the conjugates described herein can be formulated as solid, semi-solid, or thixotropic liquids for administration as implantable depots that provide modified release of the active compounds. Examples of such formulations include drug-coated stents and poly(lactic-glycolic acid) (PGLA) microspheres. The conjugates described herein can also be administered topically to the skin or mucous membranes, ie transdermally. Common formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusts, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. .. Liposomes can also be used. Common carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers can also be included-see, for example, J. Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other methods of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (eg Powderject ^™ , Bioject ^™, etc.) injection.

Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release and programmed release. The conjugates described herein may also be intranasally or generally dry powder (alone or in a mixture, for example a dry mixture with lactose, a mixed particle component, for example a mixture with a phospholipid such as phosphatidylcholine. As a form by inhalation from a dry powder inhaler or a suitable propellant such as 1,1,1,2,4-tetrafluoroethane or 1,1,1,2,3,3,3-pentafluoropropane Can be administered as a aerosol spray from a pressurized container, a pump, a spray, an atomizer (preferably an atomizer that uses atomizer electrohydrodynamics to form a fine mist) or a nebulizer. For intranasal use, the powder may include a bioadhesive such as chitosan or cyclodecyne. Pressurized vessels, pumps, sprays, atomizers or nebulizers are suitable, for example, for ethanol, aqueous ethanol or suitable alternative agents for dispersion release, dissolution release, prolongation of active substances, propellants as solvents and sorbitan trioleate, oleic acid. Alternatively, it includes a solution or suspension of the conjugate of the present invention containing any surfactant such as oligolactic acid. Prior to use in a dry powder or suspension formulation, the conjugate is micronized to a size suitable for delivery by inhalation (generally less than 5 microns). This can be accomplished by any suitable milling method, such as a spiral jet mill, fluid bed jet mill, supercritical fluid in the process of forming nanoparticles, high pressure homogenization or spray drying. Capsules (eg, made from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be a stable powder base such as a conjugate, lactose or starch as described herein. , And a mixed powder of performance modifiers such as isoleucine, mannitol, or magnesium stearate.

Lactose can be anhydrous or monohydrate, preferably the latter form. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A typical formulation may include a conjugate of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that may be used instead of propylene glycol include glycerol and polyethylene glycol.

The conjugates described herein are cyclodextrins and their stable forms in order to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability in any of the aforementioned methods of administration. It can be combined with soluble polymeric elements such as derivatives or polyethylene glycol containing polymers.

Drug (Drug)-cyclodextrin complexes, for example, are generally known to be useful in many dosage forms and administration methods. Both inclusion and non-inclusion complexes can be used. Instead of direct complexation with the drug, cyclodextrin can be used as a co-additive, ie carrier, diluent or solubilizer. Most often used for these purposes are α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, which are international patent application numbers, WO 91/11172, WO 94/02518. And WO 98/55148.

Two or more pharmaceutical compositions comprising at least one of the conjugates described herein are provided as compositions, so long as the administration of a combination of active compounds is desired, eg for the treatment of a particular disease or condition. It is within the scope of the present invention that they may be conveniently combined in the form of a kit suitable for co-administration of As a result, the kit of the invention comprises two or more separate pharmaceutical compositions comprising at least one of the conjugates described herein and said composition, such as a container, a divided bottle or a divided foil packet. And means for holding separately. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering various dosage forms, for example parenterally, for administering separate compositions at different dosing intervals, or for titrating separate compositions with one another. There is. To aid in compliance, kits generally include instructions for administration and can be provided with so-called memory aids.

Example
Chemical Examples It should be understood that the conjugates described herein are made according to the processes described herein and/or conventional processes. Specifically, the stereocenters of the conjugates described herein are substantially pure (S), substantially pure (R), or any of (S) and (R) at any asymmetric carbon atom. It may be a mixture, each of which may be used in the processes described herein. Similarly, the steps described in these specific examples are routinely selected from alternative starting materials and reagents to carry out the various steps described herein by It is applicable to the manufacture of the described conjugates. Also, the groups in these examples should be understood to include PBD prodrugs, polyPBD prodrugs, mixed PBDs, conjugates and conjugates described herein.

Example: Process for producing intermediate proline derivative

Example: Process for producing the intermediate mono Fmoc-proPBD

Example: Process for manufacturing proPBD-SN-38

Example. Process for manufacturing EC1879

Example. Process for manufacturing EC1884

Example. Process for producing MC-VA-PAB bound to PBD-FmocPBD

Example. Steps for Modifying Enantiomers of Proline Derivatives Further, for the conjugates of particular examples, the steps described herein are specific examples of general steps, each of which produces other exemplary conjugates described herein. It should be understood that it may be applied for. Corresponding preparations using various optical mixtures of proline, including for example D-proline, L-proline, or racemic proline, should also be understood to be described herein. For example, the olefination and reduction of D-proline, L-proline or proline as described herein is as follows:

ＭＯＭエーテルＥＣ２１７３は、Boger, D. L.; Hughes, T. V.; Hedrick, H. P. J. Org. Chem. 2001, 66, 2207-2216に記載の方法に従って、収率５８％で合成された。^１Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ_３）：δ ８．２０−８．０９（ｍ、１Ｈ）、７．７４−７．６６（ｍ、１Ｈ）、７．４３（ｄｄｄ、Ｊ＝８．３、６．８、１．３Ｈｚ、１Ｈ）、７．３５（ｄｄｄ、Ｊ＝８．２、６．８、１．２Ｈｚ、１Ｈ）、７．０５（ｄ、Ｊ＝２．０Ｈｚ、１Ｈ）、６．９０−６．８２（ｍ、１Ｈ）、６．７２（ｓ、１Ｈ）、５．３６（ｓ、２Ｈ）、３．５３（ｓ、３Ｈ）、１．５４（ｓ、９Ｈ）。［Ｍ＋Ｈ］^＋＝計算値３０４．１６、実測値３０４．１ Example. Synthesis of EC2177.

MOM ether EC2173 was synthesized in 58% yield according to the method described in Boger, DL; Hughes, TV; Hedrick, HPJ Org. Chem. 2001, 66, 2207-2216. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.20-8.09 (m, 1H), 7.74-7.66 (m, 1H), 7.43 (ddd, J=8.3, 6) .8, 1.3 Hz, 1H), 7.35 (ddd, J=8.2, 6.8, 1.2 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6. 90-6.82 (m, 1H), 6.72 (s, 1H), 5.36 (s, 2H), 3.53 (s, 3H), 1.54 (s, 9H). [M+H] ⁺ =calculated value 304.16, measured value 304.1

EC2174 was synthesized in 54% yield according to the method described by Boger, DL; Hughes, TV; Hedrick, HPJ Org. Chem. 2001, 66, 2207-2216. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.21 (dd, J=8.4, 1.3 Hz, 1H), 8.10-7.98 (m, 2H), 7.54 (ddd, J) =8.5, 6.8, 1.4 Hz, 1H), 7.42 (ddd, J=8.2, 6.8, 1.1 Hz, 1H), 7.32-7.16 (m, 1H) ), 5.46 (s, 2H), 3.58 (s, 3H), 1.59 (s, 9H). [M+H] ⁺ =calculated value 430.05, measured value 430.08

Allyl chloride EC2175 was synthesized in 48% yield according to the method described by Boger, DL; Hughes, TV; Hedrick, HPJ Org. Chem. 2001, 66, 2207-2216. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.30-8.14 (m, 2H), 7.64-7.45 (m, 2H), 6.99 (s, 1H), 6.18-. 6.03 (m, 2H), 5.37 (s, 2H), 4.68-4.55 (m, 1H), 4.31 (dd, J=15.8, 6.8Hz, 1H), 3.53 (s, 3H), 1.35 (s, 9H). [M+H] ⁺ =calculated value 504.05, measured value 504.06

EC2176 was synthesized in 78% yield according to the method described by Boger, DL; Hughes, TV; Hedrick, HPJ Org. Chem. 2001, 66, 2207-2216. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.29-8.20 (m, 1H), 7.92 (s, 1H), 7.67 (dd, J=24.1, 8.3 Hz, 1H) ), 7.49 (dddd, J=16.4, 8.3, 6.8, 1.3 Hz, 1H), 7.35 (tdd, J=8.2, 7.5, 1.2 Hz, 1H) ), 5.42 (s, 2H), 4.15 (ddd, J=22.0, 15.5, 10.1 Hz, 1H), 4.00-3.88 (m, 1H), 3.75. -3.66 (m, 1H), 3.56 (d, J=1.5Hz, 3H), 1.63 (s, 9H). [M+H] ⁺ =calculated value 378.15, measured value 378.15

EC2177 was synthesized in a yield of 64% according to the method described in Boger, DL; Hughes, TV; Hedrick, HPJ Org. Chem. 2001, 66, 2207-2216. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.20 (t, J=8.2 Hz, 1H), 7.81 (s, 1H), 7.65 (dd, J=24.5, 8.4 Hz). 1H), 7.53-7.41 (m, 1H), 7.37-7.28 (m, 1H), 4.22-4.05 (m, 1H), 4.00-3.87. (M, 1H), 3.83-3.64 (m, 1H), 1.61 (d, J=6.3Hz, 9H).

ＥＣ２１７８は、Wang, Y.; Li, L.; Tian, Z.; Jiang, W.; Larrick, J. W. Bioorg. Med. Chem. 2006, 14, 7854-7861に記載の方法に従って合成された。^１Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ_３）：δ ８．２４−８．１７（ｍ、２Ｈ）、８．１５（ｄｄ、Ｊ＝９．２、２．５Ｈｚ、２Ｈ）、７．４９−７．４２（ｍ、２Ｈ）、７．４２−７．３４（ｍ、１Ｈ）、７．２８−７．２０（ｍ、１Ｈ）、４．３４−４．１８（ｍ、１Ｈ）、４．１５−４．０３（ｍ、１Ｈ）、３．９７（ｔｄ、Ｊ＝９．２、３．８Ｈｚ、１Ｈ）、３．９１−３．８２（ｍ、１Ｈ）、３．５３−３．４１（ｍ、１Ｈ）、３．３６−３．２３（ｍ、１Ｈ）、１．５６（ｓ、９Ｈ）。［Ｍ＋Ｈ］^＋＝計算値４９９．１２、実測値４９９．０２

EC2178 was synthesized according to the method described in Wang, Y.; Li, L.; Tian, Z.; Jiang, W.; Larrick, JW Bioorg. Med. Chem. 2006, 14, 7854-7861. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.24-8.17 (m, 2H), 8.15 (dd, J=9.2, 2.5 Hz, 2H), 7.49-7.42. (M, 2H), 7.42-7.34 (m, 1H), 7.28-7.20 (m, 1H), 4.34-4.18 (m, 1H), 4.15-4 0.03 (m, 1H), 3.97 (td, J=9.2, 3.8 Hz, 1H), 3.91-3.82 (m, 1H), 3.53-3.41 (m, 1H), 3.36-3.23 (m, 1H), 1.56 (s, 9H). [M+H] ⁺ =calculated value 499.12, measured value 499.02

EC2179 was synthesized according to the method described in Wang, Y.; Li, L.; Tian, Z.; Jiang, W.; Larrick, JW Bioorg. Med. Chem. 2006, 14, 7854-7861. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.88 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.37 (ddd, J=8.2, 6.7, 1.2 Hz, 1H), 7.30-7.22 (m, 1H), 4.23-4.08 (m, 1H), 4 .01 (dd, J=11.8, 8.7 Hz, 1H), 3.95-3.84 (m, 1H), 3.81 (dd, J=11.1, 3.3 Hz, 1H), 3.74 (s, 2H), 3.54 (s, 2H), 3.37 (t, J = 10.7Hz, 1H), 2.47-2.33 (m, 4H), 2.27 ( s, 3H), 1.50 (s, 9H). [M+H] ⁺ =calculated value 460.98, measured value 460.20

ＥＣ２１８９は、本明細書に記載のようにして製造された。^１Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ_３）：δ ８．３７（ｓ、１Ｈ）、７．８７（ｄ、Ｊ＝８．４Ｈｚ、１Ｈ）、７．７１（ｄ、Ｊ＝８．４Ｈｚ、１Ｈ）、７．５２（ｄｄｄ、Ｊ＝８．１、６．７、１．２Ｈｚ、１Ｈ）、７．４１（ｄｄｄ、Ｊ＝８．０、６．８、１．１Ｈｚ、１Ｈ）、７．０６（ｄ、Ｊ＝１．９Ｈｚ、１Ｈ）、７．０１（ｄ、Ｊ＝１．９Ｈｚ、１Ｈ）、４．３７−４．１８（ｍ、２Ｈ）、４．０６（ｔ、Ｊ＝６．５Ｈｚ、３Ｈ）、３．９５（ｄｄ、Ｊ＝１１．２、３．３Ｈｚ、１Ｈ）、３．８６（ｓ、３Ｈ）、３．８５（ｓ、３Ｈ）、３．６９−３．６２（ｍ、２Ｈ）、３．４５（ｔ、Ｊ＝１０．９Ｈｚ、１Ｈ）、２．５６（ｄｔ、Ｊ＝２４．１、１７．９Ｈｚ、６Ｈ）、２．４０（ｓ、３Ｈ）、１．８４（ｐ、Ｊ＝６．９Ｈｚ、５Ｈ）、１．６７−１．５６（ｍ、２Ｈ）。［Ｍ＋Ｈ］^＋＝計算値６５３．２８、実測値６５３．２９

EC2189 was produced as described herein. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.37 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.52 (ddd, J=8.1, 6.7, 1.2 Hz, 1H), 7.41 (ddd, J=8.0, 6.8, 1.1 Hz, 1H), 7.06 ( d, J=1.9 Hz, 1H), 7.01 (d, J=1.9 Hz, 1H), 4.37-4.18 (m, 2H), 4.06 (t, J=6.5 Hz). 3H), 3.95 (dd, J=11.2, 3.3 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.69-3.62 (m. , 2H), 3.45 (t, J=10.9 Hz, 1H), 2.56 (dt, J=24.1, 17.9 Hz, 6H), 2.40 (s, 3H), 1.84. (P, J=6.9 Hz, 5H), 1.67-1.56 (m, 2H). [M+H] ⁺ =calculated value 653.28, measured value 653.29

エステルＥＣ２１８９（７２ｍｇ、０．１１ｍｍｏｌ）のＴＨＦ／ＭｅＯＨ／Ｈ_２Ｏ（３：１：１、１ｍｌ）溶液に、ＬｉＯＨ（１．１ｍｌ、１．１ｍｍｏｌ）を添加した。反応液を室温で撹拌し、ＬＣＭＳにより観察した。反応の完了後、反応混合物を１Ｍ ＨＣｌでｐＨ２まで酸性化し、揮発性溶液を減圧下で除去した。生成物を、Ｃ１８固定相を用いた低圧クロマトグラフィーにより精製し、Ｈ_２Ｏおよびアセトニトリルで溶出し、続いて凍結乾燥して所望の酸ＥＣ２１９０（４２ｍｇ、６０％）を無色油状物として得た。^１Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ_３）主要シグナル：δ ８．３１−８．２０（ｍ、１Ｈ）、７．８１−７．７２（ｍ、１Ｈ）、７．６６（ｄ、Ｊ＝８．４Ｈｚ、１Ｈ）、７．５２−７．４１（ｍ、１Ｈ）、７．４０−７．３０（ｍ、１Ｈ）、７．１１−７．０１（ｍ、１Ｈ）、７．０１−６．９２（ｍ、１Ｈ）、４．２２（ｄｄ、Ｊ＝２３．９、１０．０Ｈｚ、３Ｈ）、４．０７−３．９１（ｍ、４Ｈ）、３．９０−３．８１（ｍ、２Ｈ）、３．７８（ｓ、３Ｈ）。［Ｍ＋Ｈ］^＋＝計算値６３９．２６、測値６３９．３０

LiOH (1.1 ml, 1.1 mmol) was added to a solution of the ester EC2189 (72 mg, 0.11 mmol) in THF/MeOH/H ₂ O (3:1:1, 1 ml). The reaction was stirred at room temperature and observed by LCMS. After completion of the reaction, the reaction mixture was acidified to pH 2 with 1M HCl and the volatile solution was removed under reduced pressure. The product was purified by low pressure chromatography with C18 stationary phase, eluting with H ₂ O and acetonitrile, followed by lyophilization to give the desired acid EC2190 (42 mg, 60%) as a colorless oil. ¹ H NMR (500 MHz, CDCl ₃ ) main signal: δ 8.31-8.20 (m, 1H), 7.81-7.72 (m, 1H), 7.66 (d, J=8.4 Hz). 1H), 7.52-7.41 (m, 1H), 7.40-7.30 (m, 1H), 7.11-7.01 (m, 1H), 7.01-6.92. (M, 1H), 4.22 (dd, J=23.9, 10.0 Hz, 3H), 4.07-3.91 (m, 4H), 3.90-3.81 (m, 2H) 3.78 (s, 3H). [M+H] ⁺ =calculated value 633.26, measured value 639.30

Boc amine EC1693 (21 mg, 44.1 μmol) was dissolved in a 50:50 TFA:CH ₂ Cl ₂ solution and stirred for 30 minutes. The solution was removed in vacuo, the residue was taken up in saturated NaHCO ₃ and extracted 3 times with ethyl acetate. The organic extracts were combined, dried over Na ₂ SO ₄ , filtered and the solution removed to give the amine. The crude amine was dissolved in DMF (2 ml) under argon atmosphere and added to acid EC2190 (18.8 mg, 29.4 μmol). PyBOP (33.6 mg, 64.7 μmol) and DIPEA (31.5 μl, 0.177 mmol) were added to the solution, and the mixture was stirred for 5 hours. After completion of the reaction, the reaction solution was diluted with water (10 ml), saturated NH ₄ Cl (10 ml), and extracted with ethyl acetate three times. The organic extracts were combined, dried over Na ₂ SO ₄ , filtered, and the solution removed under reduced pressure. The product was purified by silica gel chromatography using dichloromethane and methanol as eluents to give the desired amide EC2191 (23 mg, 79%). ¹ H NMR (500 MHz, CDCl ₃ ) main signals: δ 8.36 (s, 1H), 8.26 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.67−. 7.50 (m, 3H), 7.43 (t, J=7.6Hz, 1H), 7.33 (t, J=7.6Hz, 1H), 7.29-7.20 (m, 2H) ), 7.07-6.94 (m, 1H), 6.42 (t, J=15.6Hz, 1H), 5.14-4.77 (m, 3H), 4.34-4.14. (M, 3H), 3.73 (s, 3H), 2.42 (s, 3H), 2.30-2.10 (m, 1H). [M+H] ⁺ =calculated value 988.35, measured value 988.45

ラセミ体のＥＣ２１７６のキラル分離には、キラル固定相の順相ＨＰＬＣが用いられ、ＥＣ２１７６は（Ｒ）−ＥＣ２１７６および（Ｓ）−ＥＣ２１７に分離された。条件は以下の通りである：カラム名：（Ｓ，Ｓ）−Ｗｈｅｌｋ−Ｏ１、カラムサイズ：２５０ｍｍｘ４．６ｍｍ、移動相：ヘキサン／ＩＰＡ（７０／３０）。

Normal-phase HPLC of a chiral stationary phase was used for chiral separation of racemic EC2176, and EC2176 was separated into (R)-EC2176 and (S)-EC217. The conditions are as follows: column name: (S,S)-Whelk-O1, column size: 250 mm x 4.6 mm, mobile phase: hexane/IPA (70/30).

Ｂｏｃアミン（Ｓ）−ＥＣ２１７６（４９ｍｇ、０．１３ｍｍｏｌ）を、０℃で、ＴＦＡのＣＨ_２Ｃｌ_２溶液（３０％、５ｍｌ）に溶解し、３時間撹拌させた。脱保護が完了するまで、ＬＣＭＳを用いて反応を観察した。反応混合物を飽和ＮａＨＣＯ_３でクエンチし、酢酸エチルで３回抽出した。有機抽出物を合わせ、Ｎａ_２ＳＯ_４で乾燥させ、ろ過し、そして溶媒を真空下で除去し、粗製のアミンを得た。アルゴン雰囲気下、該アミンおよびＥＣ２１８０（４０ｍｇ、０．１３ｍｍｏｌ）をＤＭＦ（１ｍｌ）に溶解した。反応混合物に、ＰｙＢＯＰ（１３４ｍｇ、０．２６ｍｍｏｌ）、その後ＤＩＰＥＡ（０．１１４ｍｌ、０．６５ｍｍｏｌ）を添加し、反応混合物を５時間撹拌した。反応混合物を飽和ＮＨ_４Ｃｌでクエンチし、酢酸エチルで３回抽出した。有機抽出物を合わせＮａ_２ＳＯ_４で乾燥させ、ろ過し、そして溶媒を真空下で除去し、シリカゲルクロマトグラフィーを用いてＥＣ２２５６を精製し、所望のアミド（２０ｍｇ、２８％）を得た。［Ｍ＋Ｈ］^＋＝計算値５７１．２１、実測値５７１．３０

Boc amine (S)-EC2176 (49 mg, 0.13 mmol) was dissolved in a CH ₂ Cl ₂ solution of TFA (30%, 5 ml) at 0° C. and allowed to stir for 3 hours. The reaction was monitored using LCMS until deprotection was complete. The reaction mixture was quenched with saturated NaHCO ₃ and extracted 3 times with ethyl acetate. The organic extracts were combined, dried over Na ₂ SO ₄ , filtered and the solvent removed under vacuum to give the crude amine. The amine and EC2180 (40 mg, 0.13 mmol) were dissolved in DMF (1 ml) under argon atmosphere. To the reaction mixture was added PyBOP (134 mg, 0.26 mmol) followed by DIPEA (0.114 ml, 0.65 mmol) and the reaction mixture was stirred for 5 hours. The reaction mixture was quenched with saturated NH 4 _Cl, and extracted three times with ethyl acetate. The organic extracts were combined, dried over Na ₂ SO ₄ , filtered and the solvent removed under vacuum and EC2256 was purified using silica gel chromatography to give the desired amide (20 mg, 28%). [M+H] ⁺ =calculated value 571.21, measured value 571.30

The ester EC2256 (19 mg, 0.033 mmol) was dissolved in a 3:1:1 mixture of THF:H ₂ O:MeOH (1 ml) and LiOH (0.33 ml, 0.33 mmol) was added. The reaction was monitored until all conversions were complete. The organic solvent was removed under vacuum and the crude product was purified by low pressure chromatography using a C18 stationary phase and eluted with H 2 _O and ACN. The desired product fractions were combined. , CAN was removed and the aqueous layer was extracted with ethyl acetate, dried over Na ₂ SO ₄ and concentrated to give acid EC2257 (17.5 mg, 94%). [M+H] ⁺ =calculated value 558.03, measured value 557.31

Boc amine EC1693 (19 mg, 0.04 mmol) was dissolved in CH ₂ Cl ₂ solution of TFA (50%, 5 ml) at 0° C. and stirred for 3 hours. The reaction was monitored using LCMS until deprotection was complete. The reaction mixture was quenched with saturated NaHCO ₃ and extracted 3 times with ethyl acetate. The organic extracts were combined, dried over Na ₂ SO ₄ , filtered and the solvent removed under vacuum to give the crude amine. The amine and EC2257 (17.5 mg, 0.03 mmol) were dissolved in DMF (1 ml) under argon atmosphere. To the reaction mixture was added PyBOP (36 mg, 0.07 mmol) followed by DIPEA (0.033 ml, 0.19 mmol) and the reaction mixture was stirred for 5 hours. The reaction mixture was quenched with saturated NH 4 _Cl, and extracted three times with ethyl acetate. The organic extracts were combined, dried over Na ₂ SO ₄ , filtered and the solvent removed under vacuum and the crude product was purified using silica gel chromatography to give the desired amide EC2258 (22 mg, 77%). It was [M+H] ⁺ =calculated value 906.29, measured value 906.47

ＥＣ２２５９：
アルゴン下、ジスルフィドＥＣ２２５８（１５ｍｇ、０．０１７ｍｍｏｌ）および葉酸スペーサーＥＣ１５７９（３６．６ｍｇ、０．０２２ｍｍｏｌ）を無水ＤＭＳＯに溶解した。ＤＩＰＥＡ（１８μｌ、０．１ｍｍｏｌ）を反応混合物に添加し、２時間撹拌した。粗生成物を、Ｃ１８固定相を使用した低圧クロマトグラフィーにより精製し、そしてＰｈ７緩衝液およびアセトニトリルで溶出し、続いて凍結乾燥し、コンジュゲートＥＣ２２５９（１２．４ｍｇ、３０％）を得た。［Ｍ＋Ｈ］^＋＝計算値２４７３．８９、１２３７．９４、実測値１２３８．１９

EC2259:
The disulfide EC2258 (15 mg, 0.017 mmol) and the folic acid spacer EC1579 (36.6 mg, 0.022 mmol) were dissolved in anhydrous DMSO under argon. DIPEA (18 μl, 0.1 mmol) was added to the reaction mixture and stirred for 2 hours. The crude product was purified by low pressure chromatography using a C18 stationary phase and eluted with Ph7 buffer and acetonitrile followed by lyophilization to give conjugate EC2259 (12.4 mg, 30%). [M+H] ⁺ = calculated values 2473.89, 1237.94, measured value 1238.19.

ＥＣ２２５９（７ｍｇ、２．８３μｍｏｌ）を、濃ＨＣｌ（６滴）を添加したＤＩ Ｈ_２Ｏ（３ｍｌ）に溶解した。脱保護が完了するまで反応を観察し、生成物を、Ｃ１８固定相を使用した低圧クロマトグラフィーで精製し、Ｈ_２Ｏおよびアセトニトリルで溶出し、続いて凍結乾燥して所望のコンジュゲートＥＣ２２８８（５．５ｍｇ、８０％）を得た。［Ｍ＋Ｈ］^＋＝計算値２４２９．８６、１２１５．９３、実測値１２１５．８８

EC2259 (7 mg, 2.83 μmol) was dissolved in DI H ₂ O (3 ml) with the addition of concentrated HCl (6 drops). The reaction was observed until deprotection was complete and the product was purified by low pressure chromatography using C18 stationary phase, eluting with H ₂ O and acetonitrile, followed by lyophilization to give the desired conjugate EC2288 (5). 0.5 mg, 80%) was obtained. [M+H] ⁺ =calculated values 2429.86, 1215.93, measured value 1215.88

バニリン酸メチル（２．１８ｇ、１１．９８ｍｍｏｌ）およびＰｈ_３Ｐ（４．７１ｇ、１７．９７ｍｍｏｌ）のＴＨＦ（２０ｍＬ）溶液を０℃まで冷却し、これにＤＩＡＤ（２．５９ｍＬ、１３．１８ｍｍｏｌ）を滴下添加した。反応液を０℃で１時間撹拌した。１，５−ペンタンジオール（０．６ｍＬ、５．７５ｍｍｏｌ）のＴＨＦ（２０ｍＬ）溶液を３０分かけて滴下した。反応液を一晩撹拌し、そして形成した沈殿をろ過で回収した。ろ液を濃縮し、さらに固体を形成させた。固体を合わせ、ＭｅＯＨ（５ｍＬ）で粉砕して完全に清浄な生成物ＥＣ１６２４を１．７４ｇ、７０％の収率で得た。^１Ｈ ＮＭＲ（ＣＤＣｌ_３、ｐｐｍにおけるδ）：７．６６（ｍ、２Ｈ）、７．６２（ｍ、２Ｈ）、６．８７（ｍ、２Ｈ）、４．１０（ｍ、４Ｈ）、３．８９（ｍ、１２Ｈ）、１．９５（ｍ、４Ｈ）、１．６９（ｍ、２Ｈ）。^１３ＣＮＭＲ：６６．８８、１５２．５０、１４８．８６、１３２．１２、１３２．０４、１３１．８８、１２８．５２、１２８．４２、１２３．５０、１２２．５５、１１２．３５、１１１．４６、６８．６７、５６．０３、５１．９３、２８．７３、２２．５２、２１．９２。

A solution of methyl vanillate (2.18 g, 11.98 mmol) and Ph ₃ P (4.71 g, 17.97 mmol) in THF (20 mL) was cooled to 0° C. and DIAD (2.59 mL, 13.18 mmol) was added thereto. Was added dropwise. The reaction solution was stirred at 0° C. for 1 hour. A solution of 1,5-pentanediol (0.6 mL, 5.75 mmol) in THF (20 mL) was added dropwise over 30 minutes. The reaction was stirred overnight and the precipitate that formed was collected by filtration. The filtrate was concentrated and more solid formed. The solids were combined and triturated with MeOH (5 mL) to give the completely clean product EC1624 in 1.74 g, 70% yield. ¹ H NMR (CDCl ₃ , δ in ppm): 7.66 (m, 2H), 7.62 (m, 2H), 6.87 (m, 2H), 4.10 (m, 4H), 3. 89 (m, 12H), 1.95 (m, 4H), 1.69 (m, 2H). ¹³ CNMR: 66.88, 152.50, 148.86, 132.12, 132.04, 131.88, 128.52, 128.42, 123.50, 122.55, 112.35, 111.46. , 68.67, 56.03, 51.93, 28.73, 22.52, 21.92.

A solution of EC1624 (201.2 mg, 0.465 mmol) in Ac ₂ O (1.2 mL) was cooled to 0° C. and then Cu(NO ₃ ) ₂ .3H ₂ O (280.3 mg, 1.16 mmol) was slowly added. The mixture was added dropwise, and after 1 hour, the ice bath was removed. The reaction solution was stirred at room temperature for 4 hours. The reaction solution was poured into ice water, stirred until a yellow precipitate was formed, and collected by filtration. The solid was washed with additional cold water (2 mL, 3x) and air dried. 198.4 mg of EC1686 was obtained with 82%. ^{_{LCMS: [M + NH 4]}} + m / z = 540.

EC1686 (198.4 mg) was dissolved in THF (2 mL), treated with aqueous NaOH (2 mL, 1 M) and heated at 40° C. for 3 hours. The solvent was removed in vacuum. The aqueous layer was acidified to pH 1 with concentrated HCl to form a precipitate, collected by filtration and washed with H ₂ O (1 mL, 3x). The solid was air dried to give 187.7 mg of acid EC1687 in quantitative yield. ^{_{LCMS: [M + NH 4]}} + m / z = 512.

Acid EC1687 was dissolved in 0.5 M aqueous NaOH (6 mL) and hydrogenation was carried out with Pd/C (10%, 4.82 mg) under H ₂ (45 PSI) in hydrogenated pearls. The reaction was shaken for 5 hours, filtered through a pad of Celite and adjusted to pH 2-3 with concentrated HCl with stirring. The formed precipitate was isolated by filtration and washed with water (1 mL, 3x). The solid was dried in a dessicator or under high vacuum in the presence of P ₂ O ₅ overnight. EC1709 was obtained as dark brown crystals in 34.2 mg, 81% yield. ^{LCMS: [M-H] -} m / z = 433.

（Ｓ）−１−ｔｅｒｔ−ブチル ２−メチル ４−オキソピロリジン−１，２−ジカルボキシレートはＷｉｔｔｉｇ反応によりＥＣ１６９２に変換された：Ｐｈ_３ＰＣＨ_３Ｂｒ（９１７．８ｍｇ、２．５７ｍｍｏｌ）のＴＨＦ（３０ｍＬ）溶液を０℃で、滴下添加によりＫＯ^ｔＢｕ（ＴＨＦ中に１Ｍ、２．５７μＬ、２．５７ｍｍｏｌ）で処理した。反応液を室温で２時間保持した。撹拌している溶液に０〜１０℃でケトン（２５０ｍｇ、１．０２８ｍｍｏｌ）のＴＨＦ（２０ｍＬ）溶液を添加した。反応液をその後室温で一晩撹拌した。真空中で大部分のＴＨＦを除去した後、反応液をＨ_２Ｏ／ＥｔＯＡｃ（１：１、４０ｍＬ）でクエンチした。水層をＥｔＯＡｃ（２０ｍＬ、３ｘ）で抽出し、有機層をＨ_２Ｏ、続いて塩水で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。Ｔ残渣を０〜５０％ＥｔＯＡｃ／ｐ−エーテル中、ＣｏｍｂｉＦｌａｓｈで精製し、ＥＣ１６９２を７７．２ｍｇ、３１％の収率で得た。ＬＣＭＳ：［Ｍ−Ｂｏｃ＋Ｈ］^＋ ｍ／ｚ＝１４２。

(S)-1-tert-Butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate was converted to EC1692 by Wittig reaction: Ph ₃ PCH ₃ Br (917.8 mg, 2.57 mmol) in THF. The (30 mL) solution was treated with KO ^t Bu (1M in THF, 2.57 μL, 2.57 mmol) by dropwise addition at 0°C. The reaction solution was kept at room temperature for 2 hours. To the stirring solution at 0-10°C was added a solution of ketone (250 mg, 1.028 mmol) in THF (20 mL). The reaction was then stirred overnight at room temperature. After removing most of the THF in vacuo, the reaction was quenched with H ₂ O/EtOAc (1:1, 40 mL). The aqueous layer was extracted with EtOAc (20 mL, 3x), the organic layer was washed with _H 2 O, followed by brine, dried over anhydrous _Na 2 SO _4, and concentrated. The T residue was purified by CombiFlash in 0-50% EtOAc/p-ether to give EC1692 in 77.2 mg, 31% yield. LCMS: [M-Boc+H] ⁺ m/z=142.

Under argon at −78° C. (S)-1-tert-butyl 2-methyl 4-methylenepyrrolidine-1,2-dicarboxylate (353.2 mg, 1.46 mmol) DCM/toluene (1:3, The solution was treated dropwise with Dibal (1 M in toluene, 2 eq, 2.92 mmol). The reaction was stirred at -78°C for about 4 hours. The reaction was then quenched at −78 ^° C. by the addition of 60 μL MeOH followed by 5% HCl (5 mL) and EtOAc (18 mL). The cooling bath was removed and the reaction was stirred for 30 minutes. The EtOAc layer was separated, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give crude aldehyde intermediate.

The crude aldehyde was redissolved in dry DCM (10 mL) under argon and treated with ethanolamine (106 μL, 1.75 mmol) in the presence of anhydrous MgSO ₄ (5 mmol, mg) at room temperature. The reaction solution was stirred for 1 hour. Then FmocCl (755.4 mg, 2.92 mmol) and TEA (611 μL, 4.38 mmol) were added to the reaction mixture and the reaction was stirred overnight at room temperature under argon. The reaction was purified by CombiFlash in 0-50% EtOAc/petroleum ether to give EC1768 334.2 mg, 3 steps 46%. LCMS: [M+H] ⁺ m/z=477. ¹ H NMR (CD ₃ OD, δ in ppm): 7.81 (d, J=7.5 Hz, 2H), 7.60 (d, J=7 Hz, 2H), 7.40 (m, 2H), 7.32 (m, 2H), 4.96 (br, 2H), 4.60 (br, 1H), 4.23 (t, J=5.5Hz, 1H), 3.97 (br, 2H) 3.73 (br, m, 3H), 2.50 (br, 2H), 1.47 (s, 1H), 1.39 (s, 9H).

ＥＣ１７６８を、ＴＦＡ／ＤＣＭ（１：１）中、室温で３０分間脱保護した、溶媒を真空中で除去した。生成物（ＥＣ１７６９）はさらに精製することなく、ＥＣ１７０９とのカップリング反応に用いた。ＬＣＭＳ：［Ｍ＋Ｈ］^＋ ｍ／ｚ＝３７７。

EC1768 was deprotected in TFA/DCM (1:1) at room temperature for 30 minutes, the solvent was removed in vacuo. The product (EC1769) was used in the coupling reaction with EC1709 without further purification. LCMS: [M+H] ⁺ m/z=377.

ＥＣ１７０９（４２．０ｍｇ、０．０９７ｍｍｏｌ）、ＥＣ１７６９（０．０５３ｍｍｏｌ）およびＰｙＢＯＰ（２９．０ｍｇ、０．０５６ｍｍｏｌ）をＤＭＦ／ＤＣＭ（０．５ｍＬ／０．５ｍＬ）に溶解し、アルゴン下、室温で、ＤＩＰＥＡ（７４μＬ、０．４３ｍｍｏｌ）で処理した。反応は１時間以内に完結し、その後０〜２０％ＭｅＯＨ／ＤＣＭ中、ＣｏｍｂｉＦｌａｓｈカラムに充填し、ＥＣ１７７０（２５．５ｍｇ、６０％）を得た。ＬＣＭＳ：［Ｍ＋Ｈ］^＋ ｍ／ｚ＝７９３。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ、ｐｐｍにおけるδ）。

EC1709 (42.0 mg, 0.097 mmol), EC1769 (0.053 mmol) and PyBOP (29.0 mg, 0.056 mmol) were dissolved in DMF/DCM (0.5 mL/0.5 mL) at room temperature under argon. , DIPEA (74 μL, 0.43 mmol). The reaction was complete within 1 h and then loaded onto a CombiFlash column in 0-20% MeOH/DCM to give EC1770 (25.5 mg, 60%). LCMS: [M+H] ⁺ m/z=793. ¹ H NMR (CD ₃ OD, δ in ppm).

EC1770 (25.5 mg, 0.032 mmol) was dissolved in DCM (1 mL) and treated with diethylamine (DEA, 83.5 μL, 0.80 mmol) at room temperature under argon. The reaction was stirred for 2 hours then the solvent removed in vacuo. The imine was dissolved in DCM (0.3 mL) and absolute ethanol (0.6 mL) and cooled to 0 °C. NaBH ₄ (1.33 mg, 0.0352 mmol) was added to the cooled solution and the reaction was stirred at 0° C. for 5 minutes then the ice bath was removed. The reaction solution was stirred at room temperature for 2 hours. After removing EtOH, the reaction mixture was purified by CombiFlash in 0-15% MeOH/DCM to give 9.9 mg of EC2170 (2 steps, 60% yield). ^{LCMS: [M-H] -} m / z = 510. ¹ H NMR (CD ₃ OD, δ in ppm): 7.41 (s, 1H), 7.31 (s, 1H), 6.32 (s, 1H), 6.26 (s, 1H), 5 0.07 (m, 2H), 4.27 (m, 2H), 4.00 (q, J=7Hz, 4H), 3.75 (s, 3H), 3.73 (s, 3H), 3. 57 (dd, J=1.5, 13 Hz, 1H), 2.98 (m, 1H), 2.49 (m, 1H), 1.88 (m, 4H), 1.68 (m, 2H) ..

ＥＣ１６９３は、ＥＣ１７６８と同一の方法により合成された。ＬＣＭＳ：［Ｍ＋Ｈ］^＋ ｍ／ｚ＝４６８。^１Ｈ ＮＭＲ（ＣＤＣｌ_３、ｐｐｍにおけるδ）：８．４７（ｄ、Ｊ＝５Ｈｚ、１Ｈ）、７．６６（ｍ、２Ｈ）、７．０９（ｍ、１Ｈ）、５．１６（ｂｒ、１Ｈ）、４．９７（ｂｒ、２Ｈ）、４．３８（ｂｒ、３Ｈ）、４．０５（ｂｒ、２Ｈ）、３．８５（ｂｒ、３Ｈ）、３．２０（ｍ、１Ｈ）、３．０６（ｂｒ、２Ｈ）、２．８５（ｂｒ、１Ｈ）、２．５２（ｍ、１Ｈ）、１．５５（ｓ、３Ｈ）、１．４３（ｓ、９Ｈ）。

EC1693 was synthesized by the same method as EC1768. LCMS: [M+H] ⁺ m/z=468. ¹ H NMR (CDCl ₃ , δ at ppm): 8.47 (d, J=5 Hz, 1H), 7.66 (m, 2H), 7.09 (m, 1H), 5.16 (br, 1H). ), 4.97 (br, 2H), 4.38 (br, 3H), 4.05 (br, 2H), 3.85 (br, 3H), 3.20 (m, 1H), 3.06. (Br, 2H), 2.85 (br, 1H), 2.52 (m, 1H), 1.55 (s, 3H), 1.43 (s, 9H).

EC2186 was synthesized by the same method as EC1769. LCMS: [M+H] ⁺ m/z=368.

ＥＣ２１８１：酸ＥＣ２１７０（４．９５ｍｇ、０．００９７ｍｍｏｌ）を乾燥ＤＭＦ（０．５ｍＬ）に溶解し、ＰｙＢＯＰ（１０．１ｍｇ、０．０１９４ｍｍｏｌ）で処理した。反応混合物に、ＥＣ２１８６（０．０１ｍｍｏｌ、４．７６ｍｇのＥＣ１６９３から）およびＤＩＰＥＡ（３０μＬ、０．１７ｍｍｏｌ）のＤＣＭ（０．５ｍＬ）溶液を添加した。反応液を５時間撹拌し、１０〜１００％ ＭｅＣＮ／ｐＨ７緩衝液中、分取ＨＰＬＣで精製し、純粋なＥＣ２１８１を２．３ｍｇ（収率３０％）得た。ＬＣＭＳ：［Ｍ＋Ｈ］^＋ ｍ／ｚ＝８６１。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ、ｐｐｍにおけるδ）：８．３７（ｓ、１Ｈ）、７．７７（ｍ、２Ｈ）、７．４０（ｓ、１Ｈ）、７．１９（ｓ、１Ｈ）、６．４２（ｓ、１Ｈ）、６．２６（ｓ、１Ｈ）、５．０７（ｍ、４Ｈ）、５．０１（ｓ、１Ｈ）、４．５６（ｄ、Ｊ＝１Ｈｚ、１Ｈ）、４．２０（ｍ、６Ｈ）、４．０１（ｍ、７Ｈ）、３．７５（ｓ、３Ｈ）、３．７３（ｓ、３Ｈ）、３．６７（ｄ、Ｊ＝１１Ｈｚ、２Ｈ）、３．４４（ｍ、４Ｈ）、３．１３（ｂｒ、２Ｈ）、３．０５（ｍ、１Ｈ）、２．５０（，３Ｈ）、２．４８（ｍ、２Ｈ）、１．８５（ｍ、３Ｈ）１．２６（ｍ、４Ｈ）。

EC2181: Acid EC2170 (4.95 mg, 0.0097 mmol) was dissolved in dry DMF (0.5 mL) and treated with PyBOP (10.1 mg, 0.0194 mmol). To the reaction mixture was added EC2186 (0.01 mmol, from 4.76 mg EC1693) and DIPEA (30 μL, 0.17 mmol) in DCM (0.5 mL). The reaction was stirred for 5 hours and purified by preparative HPLC in 10-100% MeCN/pH7 buffer to give 2.3 mg of pure EC2181 (30% yield). LCMS: [M+H] ⁺ m/z=861. ¹ H NMR (CD ₃ OD, δ in ppm): 8.37 (s, 1H), 7.77 (m, 2H), 7.40 (s, 1H), 7.19 (s, 1H), 6 .42 (s, 1H), 6.26 (s, 1H), 5.07 (m, 4H), 5.01 (s, 1H), 4.56 (d, J=1 Hz, 1H), 4. 20 (m, 6H), 4.01 (m, 7H), 3.75 (s, 3H), 3.73 (s, 3H), 3.67 (d, J=11Hz, 2H), 3.44 (M, 4H), 3.13 (br, 2H), 3.05 (m, 1H), 2.50 (, 3H), 2.48 (m, 2H), 1.85 (m, 3H) 1. .26 (m, 4H).

アルゴン下、ＥＣ１５７９（８．７ｍｇ、０．００５２ｍｍｏｌ）のＤＭＳＯ（０．５ｍＬ）溶液を透明な溶液になるまで撹拌し、ＥＣ２１８１（３．７ｍｇ、０．００４３ｍｍｏｌ）のＤＭＳＯ（０．５ｍＬ）溶液を添加し、続いてＴＥＡ（３．６μＬ、０．０２６ｍｍｏｌ）を添加した。アルゴン下、反応溶液を室温で１時間撹拌した。生成物を、１０〜１００％ ＭｅＣＮ／ｐＨ ７緩衝液中、分取ＨＰＬＣで単離し、凍結乾燥後にＥＣ２１８２を固体として６．５ｍｇ（収率６２％）得た。ＬＣＭＳ：［Ｍ＋３Ｈ］^３＋ ｍ／ｚ＝８１０。^１Ｈ ＮＭＲ（９：１ ＤＭＳＯ−ｄ６：Ｄ_２Ｏ、ｐｐｍにおけるδ）：８．５３（ｓ、１Ｈ）、７．５５（ｄ、Ｊ＝８Ｈｚ、２Ｈ）、７．２１（ｓ、１Ｈ）、６．６０（ｄ、Ｊ＝７．５Ｈｚ、３Ｈ）、６．２９（ｓ、１Ｈ）、６．２２（ｓ、１Ｈ）、４．９７（ｓ、２Ｈ）、４．９１（ｓ、１Ｈ）、４．４５（ｓ、３Ｈ）。

Under argon, a solution of EC1579 (8.7 mg, 0.0052 mmol) in DMSO (0.5 mL) was stirred until it became a clear solution, and a solution of EC2181 (3.7 mg, 0.0043 mmol) in DMSO (0.5 mL) was added. TEA (3.6 μL, 0.026 mmol) was added, followed by TEA (3.6 μL, 0.026 mmol). The reaction solution was stirred at room temperature under argon for 1 hour. The product was isolated by preparative HPLC in 10-100% MeCN/pH 7 buffer to give 6.5 mg (62% yield) of EC2182 as a solid after lyophilization. LCMS: [M+3H] ³⁺ m/z=810. ¹ H NMR (9:1 DMSO-d6:D ₂ O, δ at ppm): 8.53 (s, 1H), 7.55 (d, J=8 Hz, 2H), 7.21 (s, 1H). , 6.60 (d, J=7.5 Hz, 3H), 6.29 (s, 1H), 6.22 (s, 1H), 4.97 (s, 2H), 4.91 (s, 1H) ) 4.45 (s, 3H).

メチル−４−ベンジルオキシ−３−メトキシ ベンゾエート（５．００ｇ、１８．４ｍｍｏｌ）をＡｃ_２Ｏ（２３．５ｍＬ）に溶解し、０℃まで冷却した。Ｃｕ（ＮＯ_３）_２（５．０５ｇ、２７．０ｍｍｏｌ）を少しずつ１０分間かけて添加した。９０分後、ＬＣＭＳは生成物の形成を示した。混合物を水に注ぎ、４５分間撹拌した。粗生成物を遠心分離により回収し水で洗浄し、乾燥させた。粗生成物を、石油エーテル／酢酸エチルグラディエントを用いて、Ｃｏｍｂｉｆｌａｓｈ系のリカゲルクロマトグラフィーで精製した。５．８０ｇ（９９％）、灰白色固体として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ、ｐｐｍにおけるδ）：７．６２（ｓ、１Ｈ）、７．４５（ｄ、２Ｈ）、７．４０（ｔ、２Ｈ）、７．３５（ｍ、１Ｈ）、７．２５（ｓ、１Ｈ）、５．２０（ｓ、２Ｈ）、３．９５（ｓ、３Ｈ）、３．９０（ｓ、３Ｈ）。ＭＳ（ＥＳＩ−ＱＭＳ）：ｍ／ｚ＝３１８．０３（Ｍ＋Ｈ）。

Methyl-4-benzyloxy-3-methoxy benzoate (5.00 g, 18.4 mmol) was dissolved in Ac ₂ O (23.5 mL) and cooled to 0°C. Cu(NO ₃ ) ₂ (5.05 g, 27.0 mmol) was added portionwise over 10 minutes. After 90 minutes, LCMS showed product formation. The mixture was poured into water and stirred for 45 minutes. The crude product was recovered by centrifugation, washed with water and dried. The crude product was purified by combiflash-based Ricagel chromatography using a petroleum ether/ethyl acetate gradient. Obtained 5.80 g (99%) as an off-white solid. ¹ H NMR (CD ₃ OD, δ in ppm): 7.62 (s, 1H), 7.45 (d, 2H), 7.40 (t, 2H), 7.35 (m, 1H), 7 0.25 (s, 1H), 5.20 (s, 2H), 3.95 (s, 3H), 3.90 (s, 3H). MS (ESI-QMS): m/z = 318.03 (M+H).

EC2093 (5.80g, 18.2mmol) was dissolved in _CH 2 _Cl 2 (10mL). A mixture of CH ₂ Cl ₂ (2.5 mL) and 2.5 mL CH ₃ SO ₂ OH (2.5 mL) was added and the reaction mixture was stirred. After 3 hours, LCMS showed product formation. The solvent was removed and the product was purified by Combiflash based Ricagel chromatography using a CH ₂ Cl ₂ /CH ₃ OH gradient to afford EC4682 as 3.46 g (84%), an off-white solid. ¹ H NMR (CD ₃ OD, δ in ppm): 7.35 (s, 1H), 7.2 (s, 1H), 3.95 (s, 3H), 3.90 (s, 3H). MS (ESI-QMS): m/z = 225.78 (MH).

EC1882 (1.0331 g, 4.55 mmol) was dissolved in ethanol (200 proof, 70 mL). Pd/C (10%, 200 mg) was added. The reaction flask was degassed and filled with H ₂ three times. H ₂ was used with a balloon for 3 hours, at which time the flask was degassed and filled with air three times. Celite was added and the product was filtered with ethanol and concentrated. General yield 781.0 mg, 90% recovery, dark brown solid. ¹ H NMR (CD ₃ OD, δ in ppm): 7.25 (s, 1H), 6.20 (s, 1H), 3.85 (s, 3H), 3.80 (s, 3H). MS (ESI): m/z = 196.23 (MH).

フェノール化合物（２．２０４４ｇ、１２．１ｍｍｏｌ）をアセトン（Ｎａ_２ＳＯ_４パッドで乾燥、４８．４ｍＬ）に溶解し、この溶液に１，５−ジブロモペンタン（４９．４ｍＬ、３６．３ｍｍｏｌ）およびＫ_２ＣＯ_３（６．６９ｇ、４８．４ｍｍｏｌ）を添加した。アルゴン下、反応液を６時間加熱還流した。反応液を室温まで冷却し、固体をろ過した。ろ液を濃縮し、０〜３０％ ＥｔＯＡｃ／ｐ−エーテル中、ＣｏｍｂｉＦｌａｓｈで精製し、ＥＣ１８５１（３．３８９３ｇ、収率８４．５％）を固体として得た。ＬＣＭＳ：［Ｍ＋Ｈ］^＋ ｍ／ｚ＝３３１．^１Ｈ ＮＭＲ（ＣＤＣｌ_３、ｐｐｍにおけるδ）：７．６５（ｄｄ、Ｊ＝８．５、２．０Ｈｚ、１Ｈ）、７．５４（ｄ、Ｊ＝２．０Ｈｚ、１Ｈ）、６．８６（ｄ、Ｊ＝８．５０Ｈｚ、１Ｈ）、４．０８（ｔ、Ｊ＝６．５０Ｈｚ、２Ｈ）、３．９１（ｓ、３Ｈ）、３．８９（ｓ、３Ｈ）、３．４４（ｔ、Ｊ＝６．５Ｈｚ、２Ｈ）、１．９５（ｍ、４Ｈ）、１．６５（ｍ、２Ｈ）。

The phenolic compound (2.2044 g, 12.1 mmol) was dissolved in acetone (Na ₂ SO ₄ pad, 48.4 mL) and to this solution 1,5-dibromopentane (49.4 mL, 36.3 mmol) and K. ₂ CO ₃ (6.69 g, 48.4 mmol) was added. The reaction was heated to reflux under argon for 6 hours. The reaction solution was cooled to room temperature and the solid was filtered. The filtrate was concentrated and purified by CombiFlash in 0-30% EtOAc/p-ether to give EC1851 (3.33893 g, 84.5% yield) as a solid. LCMS: [M+H] ⁺ m/z=331. ¹ H NMR (CDCl ₃ , δ in ppm): 7.65 (dd, J=8.5, 2.0 Hz, 1 H), 7.54 (d, J=2.0 Hz, 1 H), 6.86 ( d, J=8.50 Hz, 1H), 4.08(t, J=6.50 Hz, 2H), 3.91(s, 3H), 3.89(s, 3H), 3.44(t, J=6.5 Hz, 2H), 1.95 (m, 4H), 1.65 (m, 2H).

EC1851 (3.3893g, 10.23mmol) was cooled to 0 ℃ to _Ac 2 O (52mL) solution _{of, Cu (NO 3) · 3H} 2 O (2.967g, 12.28mmol) by the slow addition of Processed. The reaction was stirred at 0° C. for 1 hour and then at room temperature for 2 hours. After the reaction was completed, the reaction mixture was poured into ice water and stirred for 1 hour. The resulting precipitate was collected by filtration. The product was washed with water (3x) and air dried to give EC1852 (3.7097g, 96% yield). LCMS: [M+H] ⁺ m/z=376. ¹ H NMR (CDCl ₃ , δ at ppm): 7.41 (s, 1H), 7.05 (s, 1H), 4.08 (t, J=6.50 Hz, 2H), 3.94 (s). 3H), 3.89 (s, 3H), 3.42 (t, J=7.0Hz, 2H), 1.93 (m, 4H), 1.63 (m, 2H).

Under argon, EC1852 (37.6mg, 0.1mmol) and Hochest dye (53.3mg, 0.1mmol) and DMF (1.5 mL) solution at room temperature _was treated with K 2 CO _3. The reaction was heated to 60° C. and maintained overnight. Then, the reaction liquid was cooled to room temperature and solid was filtered. The residue was purified by preparative HPLC (mobile phase A: 50mM _NH 4 HCO ₃ buffer, pH7.0; B = ACN methods:. 10~100B% (30 min)) to give, EC1859 (13.1mg, yield: 18 %) was obtained. LCMS: [M+H] ⁺ m/z=720.71.

EC1859 (13.1 mg, 0.0182 mmol) was dissolved in THF/MeOH/H ₂ O (3/1/1, 0.2 mL) and treated with aqueous LiOH solution (1 M, 36 μL) under argon for 4 hours. Most of the solution was removed in vacuo, the aqueous phase was acidified to pH 2-3 with concentrated HCl and the precipitate was collected by filtration as a solid (EC1863, 12.8 mg, no purification). The filtrate was washed with water (3x) and air dried for the next step. LCMS: [M+H] ⁺ m/z=706.

A solution of EC1863 (15.7 mg, 0.022 mmol) in MeOH (10 mL) was subjected to hydrogenation (10% wet Pd/C, 5% wt, 7.85 mg, H ₂ 41 PSI) in a Parr shaker for 2 hours. The product was isolated by filtration through a Celite pad. The solvent was removed in vacuo to give crude EC1870. LCMS: [M+H] ⁺ m/z=676.79. A solution of the crude product in DMF (0.5 mL) was mixed with a solution of EC2186 (8.81 mg, 0.024 mmol) in DCM (2.0 mL). The reaction mixture was treated with PyBOP (20.8 mg, 0.04 mmol) and DIPEA (13.9 uL, 0.08 mmol) at room temperature under argon. The reaction was stirred overnight, collected thereafter min HPLC (mobile phase A: 50mM _NH 4 HCO ₃ buffer, pH 7.0; B = ACN methods:. 10~100B% (30 min)) to give 17. 4 mg of EC1869 was obtained in two steps with a yield of 85%. LCMS: [M+H] ⁺ m/z=1025.9. ¹ H NMR (CD ₃ OD, δ in ppm, selection data): 8.36 (s, 1H), 8.25 (d, J=1.0 Hz, 1H), 8.03 (m, 2H), 7 .96 (m, 1H), 7.77 (m, 3H), 7.69 (d, J=8.5Hz, 1H), 7.52 (d, J=9.0Hz, 1H), 7.16 (M, 2H), 7.06 (m, 4H), 6.43 (m, 1H).

ＥＣ１５７９（１０．２４ｍｇ、０．００６ｍｍｏｌ）をＤＭＳＯ（０．３ｍＬ）および水（０．２ｍＬ）に溶解し、琥珀色バイアル中室温で、アルゴンでバブリングした。この溶液にＥＣ１８６９（５．０ｍｇ、０．００４９ｍｍｏｌ）のＤＭＳＯ（０．２ｍＬ）溶液を添加し、続いてＤＩＰＥＡ（５．１μＬ、０．０２９ｍｍｏｌ）を添加した。アルゴン下、反応液を室温で３０分間撹拌した。反応液を分取ＨＰＬＣ（５０ｍＭ ＮＨ_４ＨＣＯ_３中１０〜１００％ ＡＣＮ、ｐＨ７．４）で精製し、コンジュゲートＥＣ１８７９（３．９ｍｇ、収率３０％）を得た。ＬＣＭＳ：［Ｍ＋２Ｈ］^２＋ ｍ／ｚ＝１２９７、［Ｍ＋３Ｈ］^３＋ ｍ／ｚ＝８６５。

EC1579 (10.24 mg, 0.006 mmol) was dissolved in DMSO (0.3 mL) and water (0.2 mL) and bubbled with argon in an amber vial at room temperature. To this solution was added a solution of EC1869 (5.0 mg, 0.0049 mmol) in DMSO (0.2 mL), followed by DIPEA (5.1 μL, 0.029 mmol). The reaction was stirred at room temperature under argon for 30 minutes. Preparative reaction min HPLC (50mM _NH 4 HCO ₃ in 10 to 100% ACN, pH 7.4) to give the conjugate EC1879 (3.9mg, 30% yield). LCMS: [M+2H] ²⁺ m/z=1297, [M+3H] ³⁺ m/z=865.

Ｖａｌ−Ａｌａ−ＯＨ（１ｇ、５．３１ｍＭ）の水（４０ｍｌ）溶液に、Ｎａ_２ＣＯ_３（１．４２ｇ、１３．２８ｍＭ）を添加し、０℃に冷却し、その後ジオキサン（４０ｍＬ）を添加した。Ｆｍｏｃ−Ｃｌ（１．４４ｇ、５．５８ｍＭ）のジオキサン（４０ｍＬ）溶液を、０℃で１０分間かけて滴下添加した。反応混合物を０℃で２時間撹拌した。その後、反応混合物を室温で１６時間撹拌した。ジオキサンを真空下で除去し、反応混合物水（４５０ｍＬ）で希釈し、１Ｎ ＨＣｌを用いてｐＨを２に調整し、ＥｔＯＡｃで抽出（３ｘ２５０ｍＬ）した。合わせた有機層を塩水で洗浄し、ＭｇＳＯ_４で乾燥させ、ろ過し、減圧下で濃縮し、乾燥させてＦｍｏｃ−Ｖａｌ−Ａｌａ−ＯＨを得た。この生成物を乾燥ＤＣＭ（２５ｍｌ）に懸濁し、ＰＡＢＡ（０．７８５ｇ、６．３８ｍＭ）およびＥＥＤＱ（１．９７１ｇ、７．９７ｍＭ）を添加した。アルゴン下、得られた混合物を、透明な溶液が得られるまでメタノールで処理した。反応液を一晩撹拌し、ろ過した。ろ液をジエチルエーテルで洗浄（４ｘ）し、高真空下で乾燥させ、ＥＣ１９３０（１．８５ｇ、６８％）を得た。^１Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤ_３ＯＤ）：δ７．７９（ｄ、Ｊ_１＝８．０Ｈｚ、２Ｈ）、７．６５（ｔ、Ｊ_１＝７．０Ｈｚ、Ｊ_２＝７．５Ｈｚ、２Ｈ）、７．５４（ｄ、Ｊ_１＝８．０Ｈｚ、２Ｈ）、７．３８（ｔ、Ｊ_１＝７．５Ｈｚ、Ｊ_２＝７．５Ｈｚ、２Ｈ）、７．３３−７．２４（ｍ、４Ｈ）、４．５４（ｓ、２Ｈ）、４．４８（ｑ、Ｊ_１＝１４．０Ｈｚ、Ｊ_２＝７．０Ｈｚ、１Ｈ）、４．４２−４．３２（ｍ、２Ｈ）、４．２２（ｔ、Ｊ_１＝７．０Ｈｚ、Ｊ_２＝６．５Ｈｚ、１Ｈ）、３．９４（ｄ、Ｊ_１＝７．０Ｈｚ、１Ｈ）、２．０７（ｍ、１Ｈ）、１．４３（ｄ、Ｊ_１＝７．５Ｈｚ、３Ｈ）、０．９７（ｄ、Ｊ_１＝７．０Ｈｚ、３Ｈ）、０．９５（ｄ、Ｊ_１＝７．０Ｈｚ、３Ｈ）；ＬＣＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）^＋＝Ｃ_３０Ｈ_３３Ｎ_３Ｏ_５の計算値、５１６．２４；実測値５１６．２４

To a solution of Val-Ala-OH (1 g, 5.31 mM) in water (40 ml) was added Na ₂ CO ₃ (1.42 g, 13.28 mM), cooled to 0° C., then dioxane (40 mL) was added. did. A solution of Fmoc-Cl (1.44 g, 5.58 mM) in dioxane (40 mL) was added dropwise at 0°C over 10 minutes. The reaction mixture was stirred at 0° C. for 2 hours. Then the reaction mixture was stirred at room temperature for 16 hours. Dioxane was removed under vacuum, the reaction mixture was diluted with water (450 mL), pH was adjusted to 2 with 1N HCl and extracted with EtOAc (3×250 mL). The combined organic layers were washed with brine, dried over MgSO _4, filtered, and concentrated in vacuo to give the Fmoc-Val-Ala-OH and dried. The product was suspended in dry DCM (25 ml) and PABA (0.785 g, 6.38 mM) and EEDQ (1.971 g, 7.97 mM) were added. The resulting mixture was treated with methanol under argon until a clear solution was obtained. The reaction was stirred overnight and filtered. The filtrate was washed with diethyl ether (4x) and dried under high vacuum to give EC1930 (1.85g, 68%). ¹ H NMR (500 MHz, CD ₃ OD): δ 7.79 (d, J ₁ =8.0 Hz, 2H), 7.65 (t, J ₁ =7.0 Hz, J ₂ =7.5 Hz, 2H), 7.54 (d, J ₁ =8.0 Hz, 2H), 7.38 (t, J ₁ =7.5 Hz, J ₂ =7.5 Hz, 2H), 7.33-7.24 (m, 4H) ), 4.54 (s, 2H), 4.48 (q, J ₁ =14.0 Hz, J ₂ =7.0 Hz, 1H), 4.42-4.32 (m, 2H), 4.22. (T, J ₁ =7.0 Hz, J ₂ =6.5 Hz, 1H), 3.94 (d, J ₁ =7.0 Hz, 1H), 2.07 (m, 1H), 1.43 (d , J ₁ =7.5 Hz, 3H), 0.97 (d, J ₁ =7.0 Hz, 3H), 0.95 (d, J ₁ =7.0 Hz, 3H); LCMS (ESI): (M+H ) ⁺ = calculated _{C 30 H 33 N 3 O 5} , 516.24; Found 516.24

アルゴン下、１−（ｔｅｒｔ−ブチル）２−メチル（Ｓ）−４−メチレンピロリジン−１，２−ジカルボキシレート（０．５ｇ、２．０７ｍｍｏｌ）のＴＨＦ（１０ｍＬ）溶液に、０℃でＬｉＢＨ_４（６７．７ｍｇ、３．１１ｍｍｏｌ）を少しずつ添加した。混合物を２．５時間かけて室温まで昇温させた。混合物を０℃に冷却し、Ｈ_２Ｏでクエンチした。混合物をＥｔＯＡｃで抽出（３ｘ３０ｍＬ）し、有機相をＨ_２Ｏ、塩水で順次洗浄し、無水ＭｇＳＯ_４で乾燥させた。それをろ過し、真空中で濃縮した。粗生成物であるＥＣ２４０４は、さらに精製することなく、次工程に使用した。

Under argon, into a solution of 1-(tert-butyl)2-methyl(S)-4-methylenepyrrolidine-1,2-dicarboxylate (0.5 g, 2.07 mmol) in THF (10 mL) at 0° C., LiBH. ₄ (67.7 mg, 3.11 mmol) was added in small portions. The mixture was warmed to room temperature over 2.5 hours. The mixture was cooled to 0° C. and quenched with H ₂ O. The mixture was extracted with EtOAc (3 × 30 mL), the organic phase _H 2 O, successively washed with brine, dried over anhydrous MgSO _4. It was filtered and concentrated in vacuo. The crude product EC2404 was used in the next step without further purification.

At 0° C., Dess-Martin periodinane (1.2 g, 2.90 mmol) was added to a solution of a mixture of EC2404 and pyridine (0.84 ml, 10.35 mmol) in dichloromethane (8 ml). The reaction solution was stirred at room temperature for 2 hours. The crude product was purified by CombiFlash in 0-40% EtOAc/p-ether to give 0.26 g of EC2405 in 59.3% yield. ¹ H NMR (500 MHz, CDCl ₃ ) (rotomer): δ9.56 and 9.49 (s, 1H), 5.03 (m, 2H), 4.35-4.20 (m, 1H), 4.13-4.02 (m, 2H), 2.86-2.71 (m, 1H), 2.67-2.64 (m, 1H), 1.49 and 1.44 (s, 9H) ).

A solution of a mixture of EC2405 (42.7 mg, 0.20 mmol), 2-aminoethan-1-ol (12.8 μl, 0.21 mmol) and molecular sieves in toluene (1 ml) was stirred at room temperature for 1.5 hours and tert. -Butyl (2S)-4-methylene-2-(oxazolidin-2-yl)pyrrolidine-1-carboxylate was generated in situ.

プロリン由来アルデヒド（５５０ｍｇ、２．６ｍｍｏｌ）をＤＣＭ（１０ｍＬ）に溶解し、ＭｇＳＯ_４（３ｇ）を添加し、続いてエタノールアミン（０．１６ｍＬ、２．６ｍｍｏｌ）のＤＣＭ（１０ｍＬ）溶液を滴下添加し、これをＥＣ２４０５混合物に添加した。反応液を室温で１時間撹拌した。ろ過および真空下で濃縮することにより、オキサゾリン中間体を得た。別のフラスコで、ＥＣ１９３０（５１６ｍｇ、１．０ｍｍｏｌ）をＴＨＦ（４０ｍＬ）に溶解し、ピリジン（０．８ｍＬ、１０ｍｍｏｌ）を添加した。溶液を−７８℃に冷却し、ジホスゲン（０．１６ｍＬ、１．５ｍｍｏｌ）を添加した。反応液を−７８℃で１時間撹拌し、ＤＣＭ（２０ｍＬ）およびオキサゾリジン中間体の溶液を滴下添加した。反応混合物を数時間かけて−２０℃まで昇温した。ＬＣ−ＭＳおよびＴＬＣは生成物の形成を示した。反応混合物をシリカゲルで濃縮し、フラッシュクロマトグラフィー（１２０ ｇｏｌｄ Ｒｅｄｉｓｅｐカラム、石油エーテル中０〜１００％ ＥｔＯＡｃ）により精製し、ＥＣ２０７６（０．５９ｇ、７４％）を得た。ＬＣＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）^＋＝Ｃ_４４Ｈ_５３Ｎ_５Ｏ_９の計算値、７９６．３８；実測値７９６．７４。

Proline-derived aldehyde (550 mg, 2.6 mmol) was dissolved in DCM (10 mL), MgSO ₄ (3 g) was added, followed by dropwise addition of ethanolamine (0.16 mL, 2.6 mmol) in DCM (10 mL). Which was then added to the EC2405 mixture. The reaction solution was stirred at room temperature for 1 hour. The oxazoline intermediate was obtained by filtration and concentration under vacuum. In a separate flask, EC1930 (516 mg, 1.0 mmol) was dissolved in THF (40 mL) and pyridine (0.8 mL, 10 mmol) was added. The solution was cooled to −78° C. and diphosgene (0.16 mL, 1.5 mmol) was added. The reaction was stirred at −78° C. for 1 hour and DCM (20 mL) and a solution of the oxazolidine intermediate was added dropwise. The reaction mixture was heated to -20°C over several hours. LC-MS and TLC showed product formation. The reaction mixture was concentrated on silica gel and purified by flash chromatography (120 gold Redisep column, 0-100% EtOAc in petroleum ether) to give EC2076 (0.59 g, 74%). _{^{LCMS (ESI) :( M + H}} ) + = Calculated _{C 44 H 53 N 5 O 9} , 796.38; Found 796.74.

ＥＣ２０７６（１０１．０ｍｇ、０．１２７ｍｍｏｌ）をＴＦＡ／ＤＣＭ（各０．５ｍＬ）中、室温で３０分撹拌した。ＬＣ−ＭＳはＢｏｃ基の完全な除去を示した。反応混合物を高真空下で濃縮し、ＴＦＡおよびＤＣＭを除去し、ＤＭＦ（１．０ｍＬ）に再溶解し、Ｈｕｎｉｇ’ｓ塩基（０．３ｍＬ）を添加することにより、ｐＨを８〜９に調整した。ＥＣ１８７０（８６．０ｍｇ、０．１２７ｍｍｏｌ）、続いてＰｙＢｏＰ（８４ｍｇ、０．１６ｍｍｏｌ）を添加し、反応液を室温で２時間撹拌した。９０分でＬＣ−ＭＳは、主要ピークが所望の化合物を含んだことを示した。反応混合物をシリカゲルカートリッジに充填し、フラッシュクロマトグラフィー（１２ｇ ｇｏｌｄ、０〜３０％ ＭｅＯＨ／ＤＣＭ）により精製し、所望の生成物であるＥＣ２０７８（１４０ｍｇ、８１％）を得た。ＬＣＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）^＋＝Ｃ_７７Ｈ_８４Ｎ_１２Ｏ_１１の計算値、１３５３．６４；実測値１３５４．１８。

EC2076 (101.0 mg, 0.127 mmol) was stirred in TFA/DCM (0.5 mL each) for 30 minutes at room temperature. LC-MS showed complete removal of Boc group. The reaction mixture was concentrated under high vacuum to remove TFA and DCM, redissolved in DMF (1.0 mL) and adjusted to pH 8-9 by adding Hunig's base (0.3 mL). did. EC1870 (86.0 mg, 0.127 mmol) was added followed by PyBoP (84 mg, 0.16 mmol) and the reaction was stirred at room temperature for 2 hours. At 90 minutes LC-MS showed the major peak contained the desired compound. The reaction mixture was loaded onto a silica gel cartridge and purified by flash chromatography (12 g gold, 0-30% MeOH/DCM) to give the desired product EC2078 (140 mg, 81%). _{^{LCMS (ESI) :( M + H}} ) + = Calculated _{C 77 H 84 N 12 O 11} , 1353.64; Found 1354.18.

ＥＣ２０７８（１４０ｍｇ、０．１０ｍｍｏｌ）をＤＥＡ／ＤＣＭ（１２／１８ｍＬ）に溶解し、室温で３０分間撹拌した。ＬＣ−ＭＳは完全なＦｍｏｃ基の脱保護を示した。反応混合物を高真空下で濃縮して過剰のジエチルアミンを除去し、ＤＣＭ（５ｍＬ）に再溶解した。ＭＰ−テトラ−ＥＧ−Ｏｓｕ（６２ｍｇ、０．１２ｍｍｏｌ）を添加し、反応液を室温で１時間撹拌した。反応混合物を濃縮し、ＤＭＳＯに再溶解し、ＨＰＬＣカラムに直接充填し、そして分取ＨＰＬＣ（Ｃ１８カラム、５〜８０％ ＡＣＮ／ｐＨ７緩衝液）により精製して所望の生成物ＥＣ２０７９（５５．８ｍｇ、３６％）を得た。ＬＣＭＳ：［Ｍ＋２Ｈ］^２＋ ｍ／ｚ＝Ｃ_８０Ｈ_１００Ｎ_１４Ｏ_１７の計算値、７６５．３７；実測値７６５．７４。

EC2078 (140 mg, 0.10 mmol) was dissolved in DEA/DCM (12/18 mL) and stirred at room temperature for 30 minutes. LC-MS showed complete Fmoc group deprotection. The reaction mixture was concentrated under high vacuum to remove excess diethylamine and redissolved in DCM (5 mL). MP-Tetra-EG-Osu (62 mg, 0.12 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in DMSO, loaded directly onto an HPLC column and purified by preparative HPLC (C18 column, 5-80% ACN/pH7 buffer) to give the desired product EC2079 (55.8 mg). , 36%). ^LCMS: Calculated _{[M + 2H] 2+ m /} z = C 80 H 100 N 14 O 17, 765.37; Found 765.74.

ＥＣ１５７９（９．８５ｍｇ、０．００６ｍｍｏｌ）をＤＭＳＯ（２ｍＬ）中で、溶解するまで撹拌した。ＤＩＰＥＡ（５０ｕＬ）、続いてＥＣ２０７９（６．２４ｍｇ、０．００４ｍｍｏｌ）のＤＭＳＯ（２ｍＬ）溶液を添加した。反応液を室温で５０分間撹拌した。１０分で、ＬＣ−ＭＳ分析は完全な変換を示した。反応混合物を分取ＨＰＬＣカラムに充填し、精製（１０〜１００％ ＭｅＣＮ／炭酸水素アンモニウム、ｐＨ７緩衝液）して、所望の生成物ＥＣ２０８０（５．５ｍｇ、４２％）．^１Ｈ ＮＭＲ（５００ＭＨｚ、ＤＭＳＯ−Ｄ_６＋Ｄ_２Ｏ）（選択データ）：δ ８．６０（ｓ、１Ｈ）、８．４４−８．０８（ｍ＊、１Ｈ）、８．０７（ｄ、Ｊ＝８．５Ｈｚ、２Ｈ）、８．０６−７．８４（ｍ＊、２Ｈ）、７．８０−７．５７（ｍ＊、２Ｈ）、７．５７（ｄ、Ｊ＝８Ｈｚ、２Ｈ）、７．５１（ｄ、Ｊ＝６．５Ｈｚ、２Ｈ）、７．４４（ｍ＊、１Ｈ）、７．２２（ｍ＊、２Ｈ）、７．０８（ｄ、Ｊ＝８Ｈｚ、２Ｈ）、６．９３（ｄ、Ｊ＝８．５Ｈｚ、１Ｈ）、６．６０（ｄ、Ｊ＝８．５Ｈｚ、２Ｈ）、６．３３（ｓ、１Ｈ）、４．９５（ｍ＊、４Ｈ）、４．４５（ｍ＊、３Ｈ）；ＬＣＭＳ：［Ｍ＋４Ｈ］^４＋ｍ／ｚ＝Ｃ_１４５Ｈ_１９８Ｎ_３０Ｏ_５１Ｓの計算値、８０３．３４；実測値８０３．８０。
＊化合物のジアステレオ異性体および／または回転異性体の性質による

EC1579 (9.85 mg, 0.006 mmol) was stirred in DMSO (2 mL) until dissolved. DIPEA (50 uL) was added followed by a solution of EC2079 (6.24 mg, 0.004 mmol) in DMSO (2 mL). The reaction was stirred at room temperature for 50 minutes. At 10 minutes, LC-MS analysis showed complete conversion. The reaction mixture was loaded onto a preparative HPLC column and purified (10-100% MeCN/ammonium hydrogen carbonate, pH 7 buffer) to give the desired product EC2080 (5.5 mg, 42%). ¹ H NMR (500 MHz, DMSO-D ₆ +D ₂ O) (selection data): δ 8.60 (s, 1H), 8.44-8.08 (m*, 1H), 8.07 (d, J =8.5 Hz, 2H), 8.06-7.84 (m*, 2H), 7.80-7.57 (m*, 2H), 7.57 (d, J=8Hz, 2H), 7 .51 (d, J=6.5 Hz, 2H), 7.44 (m*, 1H), 7.22 (m*, 2H), 7.08 (d, J=8 Hz, 2H), 6.93 (D, J=8.5 Hz, 1H), 6.60 (d, J=8.5 Hz, 2H), 6.33 (s, 1H), 4.95 (m*, 4H), 4.45( ^{m *, 3H); LCMS:} [M + 4H] calculated _{4+ m / z = C 145 H} 198 N 30 O 51 S, 803.34; Found 803.80.
*Depending on the diastereomeric and/or rotamer properties of the compound

ＥＣ２２３４は、Murray et al. 国際公開2008/098368号に記載の方法に従って、９１％の収率で合成された。^１Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ_３）（回転異性体）：δ ６−５．８（ｍ、１Ｈ）、５．４−５．１（ｍ、２Ｈ）、４．６−４．４（ｍ、４Ｈ）、３．８−３．５（ｍ、２Ｈ）、２．４−２（ｍ、２Ｈ）。

EC2234 was synthesized in 91% yield according to the method described in Murray et al. WO 2008/098368. ¹ H NMR (500 MHz, CDCl ₃ ) (rotomer): δ 6-5.8 (m, 1H), 5.4-5.1 (m, 2H), 4.6-4.4 (m, 4H), 3.8-3.5 (m, 2H), 2.4-2 (m, 2H).

To a solution of a mixture of EC2234 (1 g, 4.36 mmol) and imidazole (0.59 g, 8.72 mmol) in DMF was added tert-butyldiphenylchlorosilane (1.36 ml, 5.23 mmol) dropwise. The mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with EtOAc (3×30 ml), the organic phase was washed successively with H ₂ O, brine, dried over anhydrous MgSO ₄ and concentrated. The residue was purified by CombiFlash in 0-80% EtOAc/p-ether to give EC2235 1.84 g, 90% yield. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.68-7.60 (m, 4H), 7.48-7.36 (m, 6H), 5.91 (m, 1H), 5.25 ( m, 2H), 4.59 (m, 2H), 4.43 (m, 1H), 4.24-3.60 (m, 4H), 3.53 (m, 2H), 1.05 (m , 9H). LCMS: [M+H] ⁺ m/z=468.41.

LiBH ₄ (65.7 mg, 3.02 mmol) was added portionwise to a solution of a mixture of EC2235 (0.94 g, 2.01 mmol) in THF (15 ml) at 0° C. under argon. The mixture was warmed to room temperature over 2.5 hours. It was cooled to 0° C. and quenched with H ₂ O. The mixture was extracted with EtOAc (3×30 ml), the organic phase was washed successively with H ₂ O, brine and dried over anhydrous MgSO ₄ . It was filtered and concentrated in vacuo. The crude product was used in the next step without further purification. 0.88 g of EC2236 was obtained with a yield of 99%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.68-7.60 (m, 4H), 7.48-7.36 (m, 6H), 5.91 (m, 1H), 5.25 ( m, 2H), 4.59 (m, 2H), 4.43 (m, 1H), 4.24-3.60 (m, 4H), 3.53 (m, 2H), 1.05 (m , 9H). LCMS: [M+H] ⁺ m/z=440.41.

To a solution of EC2236 (0.88 g, 2.0 mmol) in DCM (6 ml) at room temperature was added Dess-Martin reagent (1.02 g, 2.4 mmol). The mixture was stirred at room temperature for 4 hours. The crude product was purified by CombiFlash in 0-40% EtOAc/p-ether to give 0.69 g of EC2237 in 80% yield. ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.46 (d, J=48 Hz, 1H), 7.64-7.59 (m, 4H), 7.46-7.26 (m, 6H), 5.90 (m, 1H), 5.30 (d, J=11 Hz, 1H), 5.22 (m, 1H), 4.62 (m, 2H), 4.38 (m, 2H), 3 .62 (dd, J ₁ =11 Hz, J ₂ =62.5 Hz, 1H), 3.44 (m, 2H), 2.10 (M, 1H), 1.82 (M, 2H), 1.05 (S, 9H). LCMS: [M+H] ⁺ m/z=438.35.

At room temperature, p-TsOH (catalytic amount) was added to a solution of a mixture of EC2237 (0.395 g, 0.9 mmol) and trimethyl orthoformate (0.6 ml, 3.6 mmol) in ethanol (5 ml). The mixture was stirred at room temperature for 3 hours. The crude product was purified by CombiFlash in 0-40% EtOAc/p-ether to give 0.45 g EC2238 in 97% yield. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.63 (m, 4H), 7.37 (m, 6H), 5.93 (m, 1H), 5.30-5.19 (m, 2H). 4.77-4.49 (m, 4H), 4.11 (m, 1H), 3.67 (m, 2H), 3.54-3.42 (m, 2H), 3.37-3 .23 (m, 2H), 2.22 (m, 1H), 1.98 (m, 1H), 1.19 (m, 3H), 1.04 (s, 9H), 0.98 (m, 3H). LCMS: [M+H] ⁺ m/z=512.58.

A TBAF solution (1.05 mlg, 1.05 mmol) was added to a solution of EC2238 (0.446 g, 0.87 mmol) in THF (6 ml) at room temperature under argon. The mixture was stirred at room temperature overnight. The crude product was purified by CombiFlash in 0-40% EtOAc/p-ether to give 0.23 g of EC2239 in 95% yield. ¹ H NMR (500 MHz, CDCl ₃ ): δ 5.95 (m, 1H), 5.31 (d, J=17.5 Hz, 1H), 5.21 (d, J=10.5 Hz, 1H), 4.87 (s, 1H), 4.60 (m, 3H), 4.13 (m, 1H), 3.74 (m, 2H), 3.53 (m, 5H), 2.41 (m , 1H), 1.89 (m, 1H), 1.21 (t, J ₁ =J ₂ =7.5Hz, 3H) 1.16 (t, J ₁ =J ₂ =7.5Hz, 3H).

Oxalyl chloride (1.13 ml, 2M methylene chloride solution, 2.25 mmol) in a solution of DMSO (0.32 g, 4.51 mmol) in DCM (10 ml) at −78° C. under argon. After stirring for 30 minutes, EC2239 (0.56 g, 2.05 mmol) was added at −78° C. The mixture was stirred at −78° C. for 2 hours then treated with Et ₃ N (1.42 ml, 10.25 mmol). This was heated to room temperature. The reaction mixture was diluted with DCM and quenched with brine. It was washed with brine and dried over anhydrous MgSO ₄ . The crude product was purified by CombiFlash in 0-40% EtOAc/p-ether to give 0.43 g of EC2242 in 77% yield. ¹ H NMR (500 MHz, CDCl ₃ ): δ 5.95 (m, 1H), 5.35-5.22 (m, 2H), 4.70-4.58 (m, 3H), 4.40 ( dd, J ₁ =9.5 Hz, J ₂ =31.5 Hz, 1H), 3.89 (m, 1H), 3.77 (m, 3H), 3.54 (m, 1H), 3.46 ( m, 1H), 2.72 (d, J=18.5 Hz, 1H), 2.48 (m, 1H), 1.23 (t, J ₁ =J ₂ =7.5 Hz, 3H), 1. 13 (t, J ₁ =J ₂ =7.5 Hz, 3H).

Potassium tert-butoxide (2.54 ml, 1M THF solution, 2.54 mmol) was added to a suspension of methyltriphenylphosphonium bromide (0.91 g, 2.54 mmol) in THF (10 ml) at 0° C. under argon. It was added dropwise. After stirring at 0° C. for 2 hours, a solution of EC2242 (0.345 g, 1.27 mmol) in THF (8 ml) was added dropwise, and the reaction solution was warmed to room temperature. After stirring overnight, the reaction mixture was diluted with EtOAc, washed successively with H ₂ O, brine and dried over anhydrous MgSO ₄ . It was filtered and concentrated in vacuo. The crude product was purified by CombiFlash in 0-20% EtOAc/p-ether to give 0.306 g EC2246 in 89.5% yield. ¹ H NMR (500 MHz, CDCl ₃ ): δ 5.94 (5.94, m, 1H), 5.31 (d, J=17.5 Hz, 1H), 5.20 (d, J=11 Hz, 1H ), 4.91 (m, 2H), 4.71 (m, 3H), 4.14 (m, 2H), 3.94 (d, J=15Hz, 1H), 3.72 (M, 2H). 3.48 (m, 2H), 2.79 (d, J=16.5 Hz, 1H), 2.60 (m, 1H), 1.20 (t, J ₁ =J ₂ =7.5 Hz, _{3H), 1.14 (t, J} 1 = J 2 = 7.5Hz, 3H).

A mixture of EC2246 (43.3 mg, 0.16 mmol), thionyl chloride (2.34 ml, 0.032 mmol) and acetyl chloride (18.4 ml, 0.26 mmol) was stirred at 70° C. for 2 hours. It was cooled to room temperature and concentrated under reduced pressure. The crude chlorohemiacetal was used in the next step without further purification.

DMSO solution of a mixture of methyl 3-(1H-imidazol-4-yl)propanoate (29.6 mg, 0.19 mmol) and sodium hydride (7.04 mg, 60% dispersion in mineral oil, 0.18 mmol) at room temperature. Stirred for 30 minutes. This was transferred to a flask containing chlorohemiacetal and the mixture was stirred at room temperature overnight. The crude product was purified by CombiFlash in 0-100% EtOAc/p-ether to give 23.1 mg EC2247 in 38.3% yield. ¹ H NMR (500 MHz, CDCl ₃ ) (diastereomer): δ 7.55 (m, 1H), 7.36 (s, 1H), 6.77 (s, 1H), 6.64 (s, 1H) ), 5.92, (m, 2H), 5.34-5.19 (m, 2H), 5.03 (m, 2H), 4.90-4.75 (m, 2H), 4.63. -4.52 (m, 4H), 4.40 (m, 2H), 4.22 (m, 2H), 3.932 (m, 2H), 3.67 (s, 6H), 3.56- 3.41 (m, 6H), 3.39-2.85 (m, 4H), 2.76 (m, 2H), 2.72-2.63 (m, 6H), 1.21-1. 14 (m, 6H). LCMS: [M+H] ⁺ m/z=378.68.

A mixture of EC2247 (42 mg, 0.11 mmol), pyrrolidine (10.2 μL, 0.12 mmol) and Pd(PPh ₃ ) ₄ (6.4 mg, 0.0055 mmol) in DCM (0.6 ml) was stirred at room temperature for 3 hours. did. It was diluted with DCM, washed sequentially with H ₂ O, brine and dried over anhydrous MgSO ₄ . It was filtered and concentrated in vacuo. The crude product was used in the next step without further purification. LCMS: [M+H] ⁺ m/z=294.60.

DMSO (1 ml) of a mixture of EC2248 (10.72 mg, 0.037 mmol), EC1870 (24.7 mg, 0.037 mmol), PyBop (28.9 mg, 0.056 mmol) and DIEA (19.4 μl, 0.11 mmol). The solution was stirred at room temperature overnight. The crude product was purified by preparative HPLC (20mM _NH 4 HCO ₃ in 10-100% acetonitrile, pH 7.4) to give the pure EC2224 (14.4mg, 41%). LCMS: [M+H] ⁺ m/z=952.15.

At room temperature, EC2224 (16 mg, 0.017 mmol) in THF (1.5 ml), MeOH (0.5 ml) and H ₂ O (0.5 ml) was added with LiOH (85 μl, 1.0 M solution, 0.085 mmol). Was added. The mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the crude product was used in the next step without further purification. LCMS: [M+H] ⁺ m/z=938.58.

ＥＣ２２５０（１２．５ｍｇ、０．０１３ｍｍｏｌ）、１−（２−アミノエチル）−１Ｈ−ピロール−２，５−ジオンＴＦＡ塩（３．４ｍｇ、０．０１３ｍｍｏｌ）、ＰｙＢｏｐ（１０．４ｍｇ、０．０２ｍｍｏｌ）およびＤＩＥＡ（６．８μｌ、０．０４ｍｍｏｌ）の混合物のＤＭＳＯ（１ｍｌ）溶液を室温で１時間撹拌した。その後、室温でＥＣ１５７９水溶液を添加した。混合物ＥＣ１５７９（３２．８ｍｇ、０．０２ｍｍｏｌ）のＨ_２Ｏ溶液（０．５ｍｌ）に混合物を添加した。混合物を室温で３０分間撹拌し、粗生成物を分取ＨＰＬＣ（２０ｍＭ ＮＨ_４ＨＣＯ_３中１０〜１００％ アセトニトリル、ｐＨ７．４）で精製し、純粋なＥＣ２２９０（２ｍｇ、５．６％）を得た。ＬＣＭＳ：［Ｍ＋２Ｈ］^２＋ ｍ／ｚ＝１３７０．７６．

EC2250 (12.5 mg, 0.013 mmol), 1-(2-aminoethyl)-1H-pyrrole-2,5-dione TFA salt (3.4 mg, 0.013 mmol), PyBop (10.4 mg, 0.02 mmol). ) And DIEA (6.8 μl, 0.04 mmol) in DMSO (1 ml) was stirred at room temperature for 1 hour. Then, EC1579 aqueous solution was added at room temperature. Mixture EC1579 (32.8mg, 0.02mmol) and the mixture was added in _{H 2} O solution (0.5 ml) of. The mixture was stirred for 30 minutes at room temperature, the crude product was purified by preparative HPLC (20mM _NH 4 HCO ₃ in 10-100% acetonitrile, pH 7.4) was purified to give the pure EC2290 (2mg, 5.6%) It was LCMS: [M+2H] ²⁺ m/z=1370.76.

アルゴン下、０℃で、１−（ｔｅｒｔ−ブチル）２−メチル（Ｓ）−４−メチレンピロリジン−１，２−ジカルボキシレート（０．５ｇ、２．０７ｍｍｏｌ）のＴＨＦ（１０ｍＬ）溶液に、ＬｉＢＨ_４（６７．７ｍｇ、３．１１ｍｍｏｌ）を少しずつ添加した。混合物を２．５時間かけて室温まで昇温させた。これを０℃に冷却し、Ｈ_２Ｏでクエンチした。混合物をＥｔＯＡｃ（３ｘ３０ｍＬ）で抽出し、有機相をＨ_２Ｏ、塩水で順次洗浄し、無水ＭｇＳＯ_４で乾燥させた。これをろ過し、真空中で濃縮した。粗生成物のＥＣ２４０４は、さらに精製することなく、次工程に使用した。

To a solution of 1-(tert-butyl)2-methyl(S)-4-methylenepyrrolidine-1,2-dicarboxylate (0.5 g, 2.07 mmol) in THF (10 mL) at 0° C. under argon, LiBH ₄ (67.7 mg, 3.11 mmol) was added in small portions. The mixture was warmed to room temperature over 2.5 hours. It was cooled to 0° C. and quenched with H ₂ O. The mixture was extracted with EtOAc (3 × 30 mL), the organic phase was washed sequentially with _H 2 O, brine, dried over anhydrous MgSO _4. It was filtered and concentrated in vacuo. The crude product EC2404 was used in the next step without further purification.

At 0° C., Dess-Martin periodinane (1.2 g, 2.90 mmol) was added to a solution of a mixture of EC2404 and pyridine (0.84 ml, 10.35 mmol) in dichloromethane (8 ml). This was stirred at room temperature for 2 hours. The crude product was purified by CombiFlash in 0-40% EtOAc/p-ether to give 0.26 g of EC2405 with a yield of 59.3. ¹ H NMR (500 MHz, CDCl ₃ ) (rotamers): δ 9.56 and 9.49 (s, 1H), 5.03 (m, 2H), 4.35-4.20 (m, 1H), 4 .13-4.02 (m, 2H), 2.86-2.71 (m, 1H), 2.67-2.64 (m, 1H), 1.49 and 1.44 (s, 9H). ..

A solution of a mixture of EC2405 (42.7 mg, 0.20 mmol), 2-aminoethan-1-ol (12.8 μl, 0.21 mmol) and molecular sieves in toluene (1 ml) was stirred at room temperature for 1.5 hours and tert- Butyl (2S)-4-methylene-2-(oxazolidin-2-yl)pyrrolidine-1-carboxylate was generated in situ. A solution of a mixture of Fmoc-Val-Cit-OH (0.11 g, 0.22 mmol) and HATU (0.12 g, 0.30 mmol) in DMF (2 ml) was stirred at room temperature for 1 h, then DIEA (0.11 ml, 0.61 mmol) was added. The tert-butyl (2S)-4-methylene-2-(oxazolidin-2-yl)pyrrolidine-1-carboxylate reaction mixture was transferred to this reaction mixture and stirred at room temperature overnight. The crude product was purified by CombiFlash in 0-20% MeOH/DCM to give 40 mg of EC2369 in 24.8% yield. LCMS: [M+H] ⁺ m/z=733.73.

A solution of EC2369 (40 mg, 0.055 mmol) in 50% TFA/DCM (1 ml) was stirred at room temperature for 3 hours. It was concentrated in vacuo to give EC2370 as a pale yellow solid. This was used in the next step without further purification. LCMS: [M+H] ⁺ m/z=633.62.

A DMSO (1 ml) solution of a mixture of EC2370 (20 mg, 0.032 mmol), EC1870 (21.4 mg, 0.032 mmol), PyBop (24.7 mg, 0.047 mmol) and DIEA (16.6 μl, 0.095 mmol). The mixture was stirred at room temperature for 5 hours. The crude product was purified by CombiFlash in 0-20% MeOH/DCM to give 10 mg EC2371 in 24.5% yield. LCMS: [M+H] ⁺ m/z=1291.92.

At room temperature, Et ₂ NH (12 μl, 0.116 mmol) was added to a solution of EC2371 (10 mg, 0.008 mmol) in acetonitrile (1 ml). The mixture was stirred at room temperature for 4 hours. It was concentrated under reduced pressure. The crude product EC2372 was used in the next step without further purification. [M+H] ⁺ m/z=1069.29.

A solution of a mixture of EC2372 (0.008 mmol), Mal-PEG4-NHS (4.1 mg, 0.008 mmol) and DIEA (4.2 μl, 0.024 mmol) in acetonitrile (1 ml) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (20mM _NH 4 HCO ₃ in 10-100% acetonitrile, pH 7.4) to give the pure EC2373. LCMS: [M+H] ⁺ m/z=1467.99.

A solution of a mixture of EC2373 (46.4 mg, 0.032 mmol) and EC2045 (34.5 mg, 0.032 mmol) in MeOH (0.5 ml) and DMSO (0.5 ml) was stirred at room temperature overnight. The crude product was purified by preparative HPLC (20mM _NH 4 HCO ₃ in 10-100% acetonitrile, pH 7.4) to give the pure EC2374. LCMS: [M+2H] ²⁺ m/z=1280.63.

A solution of a mixture of EC2374 (41 mg, 0.016 mmol) and EMCH (5.4 mg, 0.016 mmol) in MeOH (0.5 ml) and DMSO (0.5 ml) was stirred overnight at room temperature. The crude product was purified by preparative HPLC (20mM _NH 4 HCO ₃ in 10-100% acetonitrile, pH 7.4) to give the pure EC2375. LCMS: [M+2H] ²⁺ m/z=1384.71. ¹ H NMR (500 MHz, DMSO): δ 8.59 (m, 1H), 8.12 (m, 2H), 7.96 (M, 1H), 7.67-7.50 (m, 5H), 7.45 (m, 1H), 7.41-7.18 (m, 3H), 7.17-7.06 (m, 3H), 6.98-6.84 (m, 4H), 6. 76-6.58 (m, 3H), 6.40-6.30 (m, 1H), 5.0-4.8 (m, 2H), 4.20-3.98 (m, 4H), 3.96-3.72 (m, 4H), 3.70-3.60 (m, 6H), 3.2-3.0 (m, 7H), 2.91 (m, 1H), 2. 85 (m, 1H), 2.61-2.65 (m, 4H), 2.43 (m, 3H), 2.34-2.18 (m, 12H), 2.18-2.0 ( m, 3H), 1.98-1.84 (m, 5H), 1.79 (m, 6H), 1.72 (m, 10H), 1.64-1.36 (m, 15H), 1 .3-1.02 (m, 18H), 0.88-0.62 (m, 12H).

Ｂｏｃ−Ｐｙ−Ｐｙ−ＯＭｅ（ＥＣ２１５５）：５００ｍｇのＨＣｌ・Ｈ−Ｐｙ−ＯＭｅ（２．６３ｍｍｏｌ．、１．１当量）、５７３ｍｇのＢｏｃ−Ｐｙ−ＯＨ（２．３８ｍｍｏｌ．、１．０当量）および８５０μＬのＤＩＰＥＡ（４．７７ｍｍｏｌ、２．０当量）の５．４ｍＬ ＤＭＦ溶液（０．４４Ｍ）に、１．２４ｇのＰｙＢＯＰ（２．３８ｍｍｏｌ、１．０当量）を添加した。反応混合物を室温で４時間撹拌し、その後脱イオン水で希釈（１５ｘ）した。沈殿を遠心分離（４０００ｒｐｍ、１０分間）により単離し、上清をデカンテーションして沈殿物を得た。沈殿を脱イオン水に再懸濁し、５分間超音波分解し、その後沈殿を遠心分離（２回繰り返し）により再回収した。残渣の水を凍結乾燥により試料から除去して乾固した。８５３ｍｇ（８６．４％）の生成物を淡褐色固体として得た。^１Ｈ ＮＭＲ（ＣＤＣｌ_３）：δ ７．４５（ｓ、１Ｈ）、７．３９（ｓ、１Ｈ）、６．８３（ｓ、１Ｈ）、６．７２（ｓ、１Ｈ）、６．５６（ｓ、１Ｈ）、６．２２（ｓ、１Ｈ）、３．９０（ｓ、６Ｈ）、３．８１（ｓ、３Ｈ）、１．５０（ｓ、９Ｈ）。ＬＣ／ＭＳ（ＥＳＩ）：ｍ／ｚ＝３７７．１３（Ｍ＋Ｈ）。

Boc-Py-Py-OMe (EC2155): 500 mg HCl.H-Py-OMe (2.63 mmol., 1.1 eq), 573 mg Boc-Py-OH (2.38 mmol., 1.0 eq). And 850 μL of DIPEA (4.77 mmol, 2.0 eq) in 5.4 mL DMF solution (0.44 M), 1.24 g of PyBOP (2.38 mmol, 1.0 eq) was added. The reaction mixture was stirred at room temperature for 4 hours and then diluted with deionized water (15x). The precipitate was isolated by centrifugation (4000 rpm, 10 minutes), and the supernatant was decanted to obtain a precipitate. The precipitate was resuspended in deionized water and sonicated for 5 minutes, after which the precipitate was recollected by centrifugation (repeated twice). The residual water was removed from the sample by freeze drying and dried. Obtained 853 mg (86.4%) of the product as a light brown solid. ¹ H NMR (CDCl ₃ ): δ 7.45 (s, 1H), 7.39 (s, 1H), 6.83 (s, 1H), 6.72 (s, 1H), 6.56 (s). , 1H), 6.22 (s, 1H), 3.90 (s, 6H), 3.81 (s, 3H), 1.50 (s, 9H). LC/MS (ESI): m/z = 377.13 (M+H).

HCl*H-Py-Py-OMe (EC2156): 38 μl (0.03 M) of 2N anhydrous hydrochloric acid (HCl) diethyl ether solution was added to 424 mg of EC2155 (1.13 mmol) and stirred at room temperature for 5 hours. The reaction mixture was then diluted with 1 volume of diethyl ether and filtered through a fritted glass funnel. The filter cake was washed with excess diethyl ether (5x reaction volume) and dried in vacuo to give 343 mg (97.5%) of product as tan crystals. ¹ H NMR (d6-DMSO): δ 10.07 (s, 1H), 9.97 (brs, 3H), 7.46 (d, J=2.0 Hz, 1H), 7.10 (d, J). =2.0 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 3.87 (s, 3H), 3.83 (S, 3H), 3.72 (s, 3H). LC/MS (ESI): m/z = 277.07 (M+H).

Boc-Py-Py-Py-OMe (EC2157): EC2157 was synthesized by the same method as EC2155. From 832 mg of EC2156, 1.19 g of EC2157 was obtained as light brown crystals in a yield of 89.7%. ¹ H NMR (d ₆ -DMSO): δ 9.89 (s, 1H), 9.84 (s, 1H), 9.07 (s, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.20 (d, J=1.7 Hz, 1H), 7.04 (d, J=1.5 Hz, 1H), 6.89 (m, 2H), 6.82 (s, 1H) 3.82 (s, 6H), 3.79 (s, 3H), 3.72 (s, 3H), 1.44 (s, 9H). LC/MS (ESI): m/z=499.46 (M+H).

HCl*H-Py-Py-Py-OMe (EC2158): EC2158 was synthesized by the same method as EC2156. From 541 mg of EC2157, 343 mg of EC2158 was obtained as pale yellow crystals in a yield of 92.1%. ¹ H NMR (d ₆ -DMSO): δ 10.08 (s, 1H), 10.03 (brs, 3H), 9.93 (s, 1H), 7.44 (d, J=1.9 Hz, 1H), 7.23 (d, J=1.9 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 7.05 (d, J=1.5 Hz, 1H), 6. 99 (d, J=1.9 Hz, 1H), 6.89 (d, J=1.9 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.82 ( s, 3H), 3.72 (s, 3H). LC/MS (ESI): m/z=402.44 (M+H).

Boc-Py-Py-Py-Py-OMe (EC2159): EC2159 was synthesized by the same method as EC2155. Obtained from 200 mg of EC2158 as 267 mg of EC2159 as a light brown solid in a yield of 93.6%. ¹ H-NMR (d ₆ -DMSO): δ 9.92 (s, 2H), 9.85 (s, 1H), 9.07 (s, 1H), 7.46 (d, J=2.0 Hz). , 1H), 7.22 (d, J=2.0 Hz, 1H), 7.21 (d, J=1.4 Hz, 1H), 7.06 (d, J=1.9 Hz, 1H), 7 .04 (d, J=1.5 Hz, 1H), 6.90 (d, J=1.9 Hz, 1H), 6.88 (s, 1H), 6.83 (s, 1H), 3.85. (S, 6H), 3.84 (s, 3H), 3.83 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 3.73 (s, 3H) , 1.45 (s, 9H). LC/MS (ESI): m/z=621.78 (M+H).

Boc-Py-Py-Py-OH (EC2161): 316 mg (0.643 mmol) of EC2157 was added to 12.5 mL of 1,4-dioxane and 12.5 mL of 1N aqueous sodium hydroxide solution (0.025M). .. The reaction mixture was stirred at room temperature for 4 hours and then concentrated to dryness. The solid was dissolved in water, acidified to pH 3 with water, HCl and extracted with ethyl acetate (3X). The combined organic layers were dried over sodium sulfate to give 290 mg (93.1%) of a brown/orange solid. ¹ H NMR (CDCl ₃ ) δ 7.41 (s, 1H), 7.21 (2, 2H), 6.82 (d, J=2.0 Hz, 2H), 6.74 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 1.48 (s, 9H). LC/MS (ESI): m/z = 485.49 (M+H).

_{Boc-Py-Py-Py-} NH (CH 2) 3 N (CH 3) 2 (EC2162): EC2161 (0.351mmol, 1.0 eq) of 170mg, 53.0μl of 3- (dimethylamino) -1 To a solution of propylamine (0.421 mmol, 1.2 eq) and 125 μl DIPEA (0.702 mmol, 2.0 eq) in 3.5 ml DMF (0.1 M), 201 mg PyBOP (0.386 mmol, 1). .1 eq.) was added. The reaction mixture was stirred at room temperature for 4 hours and concentrated in vacuo to give a dark brown oil. The crude product was further purified by silica chromatography (0-10% methanol in DCM) to give 147 mg (73.6%) of product as a white solid. ¹ H NMR (d ₆ -DMSO): δ 9.87 (s, 1H), 9.83 (s, 1H), 9.06 (s, 1H), 8.13 (t, J=1.2 Hz, 1H ), 7.18 (d, J=0.3 Hz, 1H), 7.15 (d, J=1.9 Hz, 1H), 7.04 (d, J=1.5 Hz, 1H), 6.92. (D, J=1.5 Hz, 1H), 6.87 (s, 1H), 6.82 (s, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3. 79(s, 3H), 3.22(t, J=6.1Hz, 2H), 3.15(d, J=2.4Hz, 2H), 2.77(s, 6H), 1.82( m, 2H), 1.44 (s, 9H). LC/MS (ESI): m/z = 569.67 (M+H).

_{2HCl * H-Py-Py-} Py-NH (CH 2) 3 N (CH 3) 2 (EC2163): EC2163 was synthesized by the same method as EC2156. From 110 mg of EC2162, 99 mg of EC2163 was obtained as a light brown solid in a yield of 98%. ¹ H NMR (d ₆ -DMSO): δ 10.05 (s, 1H), 9.91 (m, 4H), 9.89 (brs, 1H), 8.16 (t, J=1.2 Hz, 1H), 7.22 (d, J=1.4 Hz, 1H), 7.15 (d, J=1.9 Hz, 1H), 7.10 (d, J=1.9 Hz, 1H), 7. 05 (d, J=1.5 Hz, 1H), 6.97 (d, J=1.9 Hz, 1H), 6.92 (d, J=1.5 Hz, 1H), 3.88 (s, 3H ), 3.83 (s, 3H), 3.79 (s, 3H), 3.23 (m, 2H), 3.04 (m, 2H), 2.75 (s, 3H), 2.74. (S, 3H), 1.82 (m, 2H). LC/MS (ESI): m/z = 469.43 (M+H).

Boc-Py-Py-Py-Py-OH (EC2164): EC2164 was synthesized by the same method as EC2161. From 359 mg EC2159, 340 mg EC2164 was obtained as a brown/orange solid in 97.0% yield. ¹ H NMR (d ⁶ -DMSO): δ 9.98 (s, 1H), 9.84 (s, 1H), 9.74 (s, 1H), 9.07 (s, 1H), 7.21. (S, 2H), 7.17 (s, 1H), 7.03 (d, J=1.5Hz, 1H), 7.00 (s, 1H), 6.87 (s, 1H), 6. 82 (s, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 1.44 (s, 9H) ). LC/MS (ESI): m/z = 607.72 (M+H).

_{Boc-Py-Py-Py-} Py-NH (CH 2) 3 N (CH 3) 2 (EC2165): EC2165 was synthesized according to the same method as EC2162. From 335 mg of EC2164, 240 mg of EC2165 was obtained as a white solid in a yield of 62.9%. ¹ H NMR (d ₆ -DMSO): δ 9.90 (s, 1H), 9.86 (s, 1H), 9.84 (s, 1H), 9.07 (s, 1H), 8.05. (T, J=5.7 Hz, 1H), 7.22 (d, J=2.5 Hz, 1H), 7.20 (d, J=1.4 Hz), 7.17 (d, J=2. 0 Hz, 1H), 7.04 (d, J=1.5 Hz, 1H), 7.03 (d, J=1.9 Hz), 6.87 (s, 1H), 6.82 (s, 1H) , 6.81 (s, 1H), 3.83 (s, 6H), 3.79 (s, 3H), 3.78 (s, 3H), 3.22 (m, 2H), 2.22 ( t, J=7.2 Hz, 2H), 2.12 (s, 6H), 1.60 (m, 2H), 1.44 (s, 9H). LC/MS (ESI): m/z=691.56 (M+H).

_{2HCl * H-Py-Py-} Py-Py-NH (CH 2) 3 N (CH 3) 2 (EC2166): EC2166 was synthesized according to the same method as EC2156. From 115 mg EC2165, 92 mg EC2166 was obtained as a brown solid in 92% yield. ¹ H NMR (d ₆ -DMSO): δ 9.89 (s, 1H), 9.85 (m, 4H), 9.58 (s, 1H), 8.03 (t, J=1.2 Hz, 1H), 7.21 (d, J=2.0 Hz, 1H), 7.18 (d, J=1.9 Hz), 7.15 (d, J=2.0 Hz, 1H), 7.01 ( d, J=1.9 Hz, 1H), 7.00 (d, J=1.9 Hz, 1H), 6.80 (d, J=1.5 Hz, 1H), 6.35 (d, J=1) .4 Hz, 1 H), 6.24 (d, J=2.0 Hz, 1 H), 3.82 (s, 6 H), 3.77 (s, 3 H), 3.71 (s, 3 H), 3. 23 (q, J=6.8, 23.3 Hz, 2H), 2.21 (t, J=7.1 Hz, 2H), 2.11 (s, 6H), 1.58 (m, 2H). LC/MS (ESI): m/z = 597.67 (M+H).

ＥＣ２１９２。
ＥＣ２１６９（２８．３ｍｇ、０．１ｍｍｏｌ）およびＥＣ２１６６（５６．１ｍｇ、０．１ｍｍｏｌ）をＤＭＦ（１．２ｍＬ）に溶解した。溶液を、アルゴン下、環境温度でＰｙＢＯＰ（１０４．１ｍｇ、０．２ｍｍｏｌ）およびＤＩＰＥＡ（６９．７μＬ、０．４ｍｍｏｌ）で処理した。反応液を２時間撹拌し、０〜２０％ ＭｅＯＨ／ＤＣＭ＋０．１％ ＴＥＡ中、ＣｏｍｂｉＦｌａｓｈで精製し、３０．３ｍｇ（３５％）のＥＣ２１９２を得た。ＬＣＭＳ：［Ｍ＋Ｈ］^＋ ｍ／ｚ＝８５６。

EC 2192.
EC2169 (28.3 mg, 0.1 mmol) and EC2166 (56.1 mg, 0.1 mmol) were dissolved in DMF (1.2 mL). The solution was treated with PyBOP (104.1 mg, 0.2 mmol) and DIPEA (69.7 μL, 0.4 mmol) at ambient temperature under argon. The reaction was stirred for 2 hours and purified by CombiFlash in 0-20% MeOH/DCM+0.1% TEA to give 30.3 mg (35%) of EC2192. LCMS: [M+H] ⁺ m/z=856.

EC 2193.
EC2192 (30.3 mg, 0.035 mmol) was added to EC2194 with LiOH (1 M solution, 0.3 mL) in THF/MeOH/H ₂ O (0.9/0.3/0.3 mL) at ambient temperature. Converted to. EC2194 was isolated under reduced pressure. LCMS: [M+H] ⁺ m/z=842. EC2186 (0.044 mmol, 25.4 mg) and EC2194 (0.035 mmol) were mixed with THF/DMF (1 mL/0.5 mL), PyBOP (36.4 mg, 0.07 mmol) and DIPEA (12.2 μL/0). 0.07 mmol). The reaction was stirred for 2-3 hours, then separated by CombiFlash in 0-20% MeOH/DCM+0.1% TEA to give EC2193 (14.7 mg, 35%). LCMS: [M+H] ⁺ m/z=1192.

バニリン酸メチル（４０２．２ｍｇ、２．２１ｍｍｏｌ）、ＥＣ２１５３（５０２．９ｍｇ、２．４３ｍｍｏｌ）およびＫ_２ＣＯ_３（０．６ｇ、４．４２ｍｍｏｌ）の混合物の無水アセトン（８．８４ｍＬ）溶液を１．５時間撹拌しながら６０℃に加熱した。反応液を環境温度まで冷却し、固体をろ過し、減圧下で濃縮して残渣を得て、これを０〜２５％ＥｔＯＡｃ／ｐ−エーテル中、ＣｏｍｂｉＦｌａｓｈにより精製し、６７８．８ｍｇ（収率９９％）のＥＣ２３１４を得た。ＬＣＭＳ：［Ｍ＋Ｈ］^＋ ｍ／ｚ＝３０９。^１Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ_３）δ ７．６４（ｄｄ，Ｊ＝８．８０、１．９６Ｈｚ、１Ｈ）、７．５３（ｄ、Ｊ＝１．９６Ｈｚ、１Ｈ）、５．９０（ｍ、１Ｈ）、５．３２（ｄｄ、Ｊ＝１７．６０、１．９５Ｈｚ、１Ｈ）、５．２３（ｄｄ、Ｊ＝１０．２７、０．９８Ｈｚ、１Ｈ）、４．５９（ｄｄ、Ｊ＝５．８７、１．４７Ｈｚ、２Ｈ）、４．１３（ｔ、Ｊ＝６．３５Ｈｚ、２Ｈ）、３．９０（ｓ、３Ｈ）、３．８９（ｓ、３Ｈ）、２．５８（ｔ、Ｊ＝７．０９Ｈｚ、２Ｈ）、２．１９（ｍ、２Ｈ）。

A solution of methyl vanillate (402.2 mg, 2.21 mmol), EC2153 (502.9 mg, 2.43 mmol) and K ₂ CO ₃ (0.6 g, 4.42 mmol) in anhydrous acetone (8.84 mL) was added to the mixture. Heat to 60° C. with stirring for 5 hours. The reaction was cooled to ambient temperature and the solid was filtered and concentrated under reduced pressure to give a residue which was purified by CombiFlash in 0-25% EtOAc/p-ether to yield 678.8 mg (99% yield). %) EC2314 was obtained. LCMS: [M+H] ⁺ m/z=309. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.64 (dd, J=8.80, 1.96 Hz, 1 H), 7.53 (d, J=1.96 Hz, 1 H), 5.90 (m, 1H), 5.32 (dd, J=17.60, 1.95 Hz, 1H), 5.23 (dd, J=10.27, 0.98 Hz, 1H), 4.59 (dd, J=5) .87, 1.47 Hz, 2H), 4.13 (t, J=6.35 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 2.58 (t, J = 7.09 Hz, 2H), 2.19 (m, 2H).

ＥＣ２３１４（５９８．９ｍｇ、１．９４ｍｍｏｌ）の無水酢酸（９．７ｍＬ）溶液を０℃に冷却し、Ｃｕ（ＮＯ_３）_２・３Ｈ_２Ｏをゆっくりと添加することにより処理した。反応液を１時間０℃に保持した。反応液を室温で２時間撹拌した。反応液を撹拌している氷水に注ぎ、１時間撹拌した。水中の反応混合物をＥｔＯＡｃで抽出（３ｘ）した。合わせた有機相を水で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、減圧下で濃縮した。残渣を精製のためにＣｏｍｂｉＦｌａｓｈ系（シリカゲル、グラディエント溶出：ｐ−エーテル中０〜２５％ ＥｔＯＡｃ）に充填し、５５９．７ｍｇのＥＣ２３１５を収率８２％で得た。ＬＣＭＳ：［Ｍ＋Ｈ］^＋ ｍ／ｚ＝３５４．^１Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ_３）δ：７．４３（ｓ、１Ｈ）、７．０５（ｓ、１Ｈ）、５．８９（ｍ、１Ｈ）、５．３０（ｄ、Ｊ＝１７．１Ｈｚ、１Ｈ、５．２２（ｄ、Ｊ＝１０．２７Ｈｚ、１Ｈ）、４．５８（ｄ、Ｊ＝６．８４Ｈｚ、２Ｈ）、４．５７（ｔ、Ｊ＝６．３６Ｈｚ、２Ｈ）、４．１１（ｓ、３Ｈ）、３．９２（ｓ、３Ｈ）、２．５７（ｔ、Ｊ＝７．３４Ｈｚ、２Ｈ）、２．１９（ｍ、２Ｈ）。^１３ＣＮＭＲ（５００ＭＨｚ、ＣＤＣｌ_３）δ：１７２．３９、１６６．２７、１５２．７８、１４９．６４、１４１．１２、１３２．０４、１２１．６２、１１８．４２、１１０．９６、１０８．１３、６８．４１、６５．２７、５６．５２、５３．１９、３０．３８、２４．１４．

A solution of EC2314 (598.9 mg, 1.94 mmol) in acetic anhydride (9.7 mL) was cooled to 0° C. and treated by the slow addition of Cu(NO ₃ ) ₂ .3H ₂ O. The reaction solution was kept at 0° C. for 1 hour. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was poured into stirring ice water and stirred for 1 hour. The reaction mixture in water was extracted with EtOAc (3x). The combined organic phases were washed with water, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was loaded into a CombiFlash system (silica gel, gradient elution: 0-25% EtOAc in p-ether) for purification to give 559.7 mg of EC2315 in 82% yield. LCMS: [M+H] ⁺ m/z=354. ¹ H NMR (500 MHz, CDCl ₃ ) δ: 7.43 (s, 1H), 7.05 (s, 1H), 5.89 (m, 1H), 5.30 (d, J=17.1 Hz, 1H, 5.22 (d, J=10.27 Hz, 1H), 4.58 (d, J=6.84 Hz, 2H), 4.57 (t, J=6.36 Hz, 2H), 4.11 (S, 3H), 3.92 (s, 3H), 2.57 (t, J=7.34 Hz, 2H), 2.19 (m, 2H) ¹³ CNMR (500 MHz, CDCl ₃ ) δ: 172 .39, 166.27, 152.78, 149.64, 141.12, 132.04, 121.62, 118.42, 110.96, 108.13, 68.41, 65.27, 56.52. , 53.19, 30.38, 24.14.

A mixture of EC2315 (559.7 mg, 1.58 mmol) and Pd(PPh ₃ ) ₄ was premixed with piperidine (1.1 mL, 11.06 mmol) and formic acid (417.3 μL, 11.06 mmol) in DCM (40 mL). ) Dissolved in solution. Water (1.0 mL) was added to the solution and the reaction was stirred at room temperature for 30 minutes. When the reaction was complete, the solvent was removed in vacuo. The residue was loaded onto CombiFlash in 0-20% MeOH/DCM to give the corresponding acid EC2316 (264.6 mg, 53%) as a solid. LCMS: [M+H] ⁺ m/z=314.52. ¹ H NMR (500 MHz, MeOH-d ₄ ) δ: 7.55 (s, 1 H), 7.23 (s, 1 H), 4.15 (t, J=5.86 Hz, 2 H), 3.95 ( s, 3H), 3.87 (s, 3H), 2.51 (t, J=7.34Hz, 2H), 2.11 (m, 2H).

アルゴン下、室温で、ＥＣ２１６６（１０７．１ｍｇ、０．１８ｍｍｏｌ）およびＥＣ２３１６（５６．８ｍｇ、０．１８ｍｍｏｌ）の無水ＤＭＦ（１ｍＬ）溶液を、ＰｙＢＯＰ（１８７．３ｍｇ、０．３６ｍｍｏｌ）およびＤＩＰＥＡ（１２５．４μＬ、０．７２ｍｍｏｌ）で処理した。反応物をＣｏｍｂｉＦａｌｓｈ（シリカ、０〜２０％ ＭｅＯＨ／ＤＣＭ）で精製し、ＥＣ２３６５（７９．３ｍｇ、収率５０％）を得た。ＬＣＭＳ：［Ｍ＋Ｈ］^＋ ｍ／ｚ＝８８６．９７。^１３ＣＮＭＲ（５００ＭＨｚ、ＭｅＯＨ−ｄ_４）δ：１６２．８２、１５２．８８、１２３．２６、１２１．８９、１２１．１０、１１９．４０、１１８．９９、１１０．８１、１０７．９７、１０５．１４、１０４．５１、６８．５９、５６．９１、５５．６３、５２．１２、４３．９４、３７．１３、３５．３６、３５．３０、３２．２１、２６．８２、２４．８７．^１Ｈ ＮＭＲ（５００ＭＨｚ、ＭｅＯＨ−ｄ４）：７．５４（ｓ、１Ｈ）、７．２０（ｓ、１Ｈ）、７．１６（ｍ、３Ｈ）、７．１１（ｄ、Ｊ＝１．９５Ｈｚ、１Ｈ）、６．９２（ｍ、２Ｈ）、６．８２（ｄ、Ｊ＝１．９６Ｈｚ、１Ｈ）、６．７８（ｄ、Ｊ＝１．９６Ｈｚ、１Ｈ）、４．１７（ｔ、Ｊ＝５．８７Ｈｚ、２Ｈ）、３．８８（ｍ、１２Ｈ）、３．８６（ｓ、６Ｈ）、３．３３（ｍ、２Ｈ）、２．５３（ｔ、Ｊ＝７．３４Ｈｚ、２Ｈ）、２．４３（ｍ、２Ｈ）、２．２８（ｓ、６Ｈ）、２．２１（ｍ、２Ｈ）、１．７８（ｍ、２Ｈ）．

A solution of EC2166 (107.1 mg, 0.18 mmol) and EC2316 (56.8 mg, 0.18 mmol) in anhydrous DMF (1 mL) was added to PyBOP (187.3 mg, 0.36 mmol) and DIPEA (125) at room temperature under argon. 0.4 μL, 0.72 mmol). The reaction was purified by CombiFalsh (silica, 0-20% MeOH/DCM) to give EC2365 (79.3 mg, 50% yield). LCMS: [M+H] ⁺ m/z=886.97. ¹³ CNMR (500 MHz, MeOH-d ₄ ) δ: 162.82, 152.88, 123.26, 121.89, 121.10, 119.40, 118.99, 110.81, 107.97, 105. 14, 104.51, 68.59, 56.91, 55.63, 52.12, 43.94, 37.13, 35.36, 35.30, 32.21, 26.82, 24.87. ¹ H NMR (500 MHz, MeOH-d4): 7.54 (s, 1H), 7.20 (s, 1H), 7.16 (m, 3H), 7.11 (d, J=1.95 Hz, 1H), 6.92 (m, 2H), 6.82 (d, J = 1.96Hz, 1H), 6.78 (d, J = 1.96Hz, 1H), 4.17 (t, J = 5.87Hz, 2H), 3.88(m, 12H), 3.86(s, 6H), 3.33(m, 2H), 2.53(t, J=7.34Hz, 2H), 2 .43 (m, 2H), 2.28 (s, 6H), 2.21 (m, 2H), 1.78 (m, 2H).

ＥＣ２３６３（６８．９ｍｇ、０．０７８ｍｍｏｌ）をＴＨＦ／ＭｅＯＨ／水（３：１：１、１．６ｍＬ）に溶解し、ＬｉＯＨ（０．３３ｍｍｏｌ）室温で３時間処理した。その後、反応液をＭｅＯＨ（２．０ｍＬ）で希釈し、Ｈ_２風船下、室温で、Ｐｄ／Ｃ（１０％ｗｔ、１０ｍｇ）で一晩処理した。反応液を、セライトパッドを通してろ過し、真空中で濃縮した。得られたアミノ酸（ＥＣ２１９４）は、さらに精製することなく、次工程に使用された。ＬＣＭＳ：［Ｍ＋Ｈ］^＋ ｍ／ｚ＝８４２．８５．

EC2363 (68.9 mg, 0.078 mmol) was dissolved in THF/MeOH/water (3:1:1, 1.6 mL) and treated with LiOH (0.33 mmol) at room temperature for 3 hours. Then the reaction was diluted with MeOH (2.0 mL) and treated with Pd/C (10% wt, 10 mg) under H ₂ balloon at room temperature overnight. The reaction was filtered through Celite pad and concentrated in vacuo. The resulting amino acid (EC2194) was used in the next step without further purification. LCMS: [M+H] ⁺ m/z=842.85.

ＥＣ２１９４（３３．０ｍｇ、０．０３９ｍｍｏｌ）およびＥＣ２１８６（１７．３ｍｇ、０．０４７ｍｍｏｌ）のＤＭＦ（０．５ｍＬ）溶液をＰｙＢＯＰ（４０．６ｍｇ、０．０７８ｍｍｏｌ）およびＤＩＰＥＡ（２７．２μＬ、０．１５６ｍｍｏｌ）室温で一晩処理した。反応物を分取ＨＰＬＣ（５０ｍＭ ＮＨ_４ＨＣＯ_３中１０〜１００％ ＡＣＮ、ｐＨ７．４）で精製し、生成物（８．４ｍｇ、ＥＣ２１９３、精製中の機器の問題による低収率）を得た。ＬＣＭＳ：［Ｍ＋Ｈ］^＋ ｍ／ｚ＝１１９２。

A solution of EC2194 (33.0 mg, 0.039 mmol) and EC2186 (17.3 mg, 0.047 mmol) in DMF (0.5 mL) was added to PyBOP (40.6 mg, 0.078 mmol) and DIPEA (27.2 μL, 0.156 mmol). ) Treated overnight at room temperature. The reaction was purified by preparative HPLC (50mM _NH 4 HCO ₃ in 10~100% ACN, pH7.4), the product was obtained (8.4mg, EC2193, low yields due to equipment problems during purification) .. LCMS: [M+H] ⁺ m/z=1192.

ＥＣ１５７９（１４．４ｍｇ、０．００８６ｍｍｏｌ）をＤＭＳＯ（０．５ｍＬ）に溶解し、ＥＣ２１９３（８．４ｍｇ、０．００７１ｍｍｏｌ）のＤＭＳＯ（０．５ｍＬ）溶液を添加した。アルゴン下、室温で、反応混合物をＴＥＡ（５．９μＬ、０．０４３ｍｍｏＬ）で処理し、３０分間撹拌した。反応物を分取ＨＰＬＣ（５０ｍＭ ＮＨ_４ＨＣＯ_３中１０〜１００％ ＡＣＮ、ｐＨ７．４）で精製し、コンジュゲートＥＣ２２０１（８．０ｍｇ、収率４１％）を得た。ＬＣＭＳ：［Ｍ＋２Ｈ］^２＋ ｍ／ｚ＝１３８０．５６；［Ｍ＋３Ｈ］^３＋ ｍ／ｚ＝９２１．８９。^１Ｈ ＮＭＲ（５００ＭＨｚ、ＤＭＳＯ−ｄ_６、Ｄ_２Ｏ滴下、選択データ）δ：８．５７（ｓ、１Ｈ）、７．５４（ｄ、Ｊ＝８．８０Ｈｚ、２Ｈ）、７．２０（ｍ、４Ｈ）、６．８７（ｍ、２Ｈ）、６．７７（ｍ、２Ｈ）、６．５８（ｄ、Ｊ＝８．８０Ｈｚ、３Ｈ）、６．３１（ｄ、Ｊ＝１３．６９Ｈｚ、１Ｈ）、４．９５（ｄ、ｂｒ、２Ｈ）。

EC1579 (14.4 mg, 0.0086 mmol) was dissolved in DMSO (0.5 mL) and a solution of EC2193 (8.4 mg, 0.0071 mmol) in DMSO (0.5 mL) was added. The reaction mixture was treated with TEA (5.9 μL, 0.043 mmoL) at room temperature under argon and stirred for 30 minutes. Preparative reaction min HPLC (50mM _NH 4 HCO ₃ in 10 to 100% ACN, pH 7.4) to give the conjugate EC2201 (8.0mg, 41% yield). LCMS: [M+2H] ²⁺ m/z=1380.56; [M+3H] ³⁺ m/z=921.89. ¹ H NMR (500 MHz, DMSO-d ₆ , D ₂ O drop, selection data) δ: 8.57 (s, 1 H), 7.54 (d, J=8.80 Hz, 2 H), 7.20 (m 4H), 6.87 (m, 2H), 6.77 (m, 2H), 6.58 (d, J = 8.80Hz, 3H), 6.31 (d, J = 13.69Hz, 1H ), 4.95 (d, br, 2H).

アルゴン下、室温で、イミダゾールカルボン酸（３５．０３ｍｇ、０．１４５ｍｍｏｌ）およびＥＣ２１６３（５６．７ｍｇ、０．１２１ｍｍｏｌ）をＤＭＦ（２ｍＬ）に溶解し、ＰｙＢＯＰ（１２６．０ｍｇ、０．２４２ｍｍｏｌ）およびＤＩＰＥＡ（８４．３μＬ、０．４８４ｍｍｏｌ）で処理した。反応物を１時間撹拌し、その後、ＣｏｍｂｉＦｌａｓｈ（（シリカゲル、グラディエント溶出：ＤＣＭおよび０．１％ ＴＥＡ中０〜２０％ ＭｅＯＨ）に充填し、９０．１ｍｇのＥＣ２３１３を収率９３％で得た。ＬＣＭＳ：［Ｍ＋Ｈ］^＋ ｍ／ｚ＝６９２．９。次工程の前に、室温で０．５時間、ＥＣ２３１３のＢｏｃ基を、ＴＦＡ（５０％ＤＣＭ溶液）を用いてアミンＴＦＡ塩生成物へ脱保護し、溶媒およびＴＦＡを真空中で除去した後、これを直接使用した。

Imidazole carboxylic acid (35.03 mg, 0.145 mmol) and EC2163 (56.7 mg, 0.121 mmol) were dissolved in DMF (2 mL) at room temperature under argon to give PyBOP (126.0 mg, 0.242 mmol) and DIPEA. (84.3 μL, 0.484 mmol). The reaction was stirred for 1 h and then loaded onto CombiFlash ((silica gel, gradient elution: 0-20% MeOH in DCM and 0.1% TEA) to give 90.1 mg of EC2313 in 93% yield. LCMS: [M+H] ⁺ m/z = 692.9. The Boc group of EC2313 was removed to the amine TFA salt product with TFA (50% DCM solution) for 0.5 h at room temperature before the next step. It was used directly after protection and removal of solvent and TFA in vacuo.

室温で、ＥＣ２３１３（９０．１ｍｇ、０．１３ｍｍｏｌ）を、５０％ ＴＦＡ／ＤＣＭで０．５時間処理した。その後溶媒を真空中で除去し、ＤＭＦ（０．５ｍＬ）に再溶解した。この溶液にＥＣ２３１６（４０．８ｍｇ、０．１３ｍｍｏｌ）、ＰｙＢＯＰ（１３４．３ｍｇ、０．２６ｍｍｏｌ）およびＤＩＰＥＡ（９０．６μＬ、０．５２ｍｍｏｌ）を添加した。反応液を室温で一晩撹拌した。反応物を分取ＨＰＬＣ（５０ｍＭ ＮＨ_４ＨＣＯ_３中１０〜１００％ ＡＣＮ、ｐＨ７．４）で精製した。７８．１ｍｇ（収率６８％）の所望の生成物ＥＣ２３６４を得た。ＬＣＭＳ：［Ｍ＋Ｈ］^＋ ｍ／ｚ＝８８７．８。^１Ｈ ＮＭＲ（５００ＭＨｚ、ＭｅＯＨ−ｄ_４、選択データ）δ：７．５６（ｓ、１Ｈ）、７．３８（ｓ、１Ｈ）、７．２６（ｄ、Ｊ＝１．９６Ｈｚ、１Ｈ）、７．２１（ｓ、１Ｈ）、７．１９（ｄ、Ｊ＝１．４６Ｈｚ、１Ｈ）、７．１７（ｄ、Ｊ＝１．９５Ｈｚ、１Ｈ）、６．９５（ｍ、２Ｈ）、６．８５（ｄ、Ｊ＝１．９６Ｈｚ、１Ｈ）、４．２０（ｔ、Ｊ＝５．８７Ｈｚ、２Ｈ）、４．０３（ｓ、３Ｈ）、３．９３（ｓ、３Ｈ）、３．９１（ｓ、３Ｈ）、３．８９（ｓ、３Ｈ）、３．８８（ｓ、３Ｈ）、３．８７（ｓ、３Ｈ）、３．８５（ｓ、３Ｈ）。

At room temperature EC2313 (90.1 mg, 0.13 mmol) was treated with 50% TFA/DCM for 0.5 h. Then the solvent was removed in vacuo and redissolved in DMF (0.5 mL). EC2316 (40.8 mg, 0.13 mmol), PyBOP (134.3 mg, 0.26 mmol) and DIPEA (90.6 μL, 0.52 mmol) were added to this solution. The reaction was stirred overnight at room temperature. Preparative reaction min HPLC (50mM _NH 4 HCO ₃ in 10~100% ACN, pH7.4) and purified by. 78.1 mg (68% yield) of the desired product EC2364 was obtained. LCMS: [M+H] ⁺ m/z=887.8. ¹ H NMR (500 MHz, MeOH-d ₄ , selection data) δ: 7.56 (s, 1 H), 7.38 (s, 1 H), 7.26 (d, J=1.96 Hz, 1 H), 7 .21 (s, 1H), 7.19 (d, J=1.46 Hz, 1H), 7.17 (d, J=1.95 Hz, 1H), 6.95 (m, 2H), 6.85 (D, J=1.96Hz, 1H), 4.20(t, J=5.87Hz, 2H), 4.03(s, 3H), 3.93(s, 3H), 3.91(s). 3H), 3.89 (s, 3H), 3.88 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H).

At room temperature, EC2364 (78.1 mg, 0.088 mmol) was converted to the acid with LiOH (1M solution, 0.3 mL) in THF/MeOH (0.9/0.3 mL). LCMS: [M+H] ⁺ m/z=873.8. After bubbling H ₂ , Pd/C (10%, wet) was added to the reaction mixture. The reaction was stirred under a balloon of hydrogen at room temperature overnight. The mixture was filtered through a Celite pad and concentrated to give the amino acid EC2367, which was used in the next step without further purification. 59.7 mg (81% yield). LCMS: [M+H] ⁺ m/z=843.8.

A solution of the amino acid EC2367 (59.7 mg, 0.071 mmol) in DMF (0.5 mL) was added to EC2186 (29. 4 mg, 0.08 mmol) at room temperature overnight. The product was purified by preparative min HPLC (50mM _NH 4 HCO ₃ in 10 to 100% ACN, pH 7.4) to give the EC2366 (8.1mg, 10% over 3 steps). LCMS: [M+2H] ²⁺ m/z=597.2.

アルゴン下、室温で、ＥＣ２３６６（８．１ｍｇ、０．００６８ｍｍｏｌ）のＭｅＯＨ（０．５ｍＬ）溶液を、ＥＣ１５７９（１５．０ｍｇ、０．００８９ｍｍｏｌ）のＤＭＳＯ（１ｍＬ）溶液に添加した。反応液を０．５〜１時間撹拌した。反応物を分取ＨＰＬＣ（５０ｍＭ ＮＨ_４ＨＣＯ_３中１０〜１００％ ＡＣＮ、ｐＨ７．４）で精製し、３．０ｍｇの生成物ＥＣ２３６８（収率１６％）を得た。ＬＣＭＳ：［Ｍ＋３Ｈ］^３＋ ｍ／ｚ＝９２１、［Ｍ＋２Ｈ］^２＋ ｍ／ｚ＝１３８２。^１Ｈ ＮＭＲ（５００ＭＨｚ、ＤＭＳＯ−ｄ_６、Ｄ_２Ｏ滴下、選択データ）δ：８．５７（ｓ、ｂｒ．、１Ｈ）、７．５７（ｓ、ｂｒ．、２Ｈ）、７．３８（ｓ、１Ｈ）、７．２４（ｓ、１Ｈ）、７．１９（ｓ、１Ｈ）、７．１４（ｓ、１Ｈ）、７．０５（ｓ、１Ｈ）、６．９８（ｓ、１Ｈ）、６．７７（ｓ、１Ｈ）、６．６１（ｓ、ｂｒ、３Ｈ）、６．３３（ｓ、１Ｈ）。

A solution of EC2366 (8.1 mg, 0.0068 mmol) in MeOH (0.5 mL) was added to a solution of EC1579 (15.0 mg, 0.0089 mmol) in DMSO (1 mL) at room temperature under argon. The reaction solution was stirred for 0.5 to 1 hour. The reaction was purified by preparative HPLC (50mM _NH 4 HCO ₃ in 10 to 100% ACN, pH 7.4) to afford the product 3.0 mg EC2368 (16% yield). LCMS: [M+3H] ³⁺ m/z=921, [M+2H] ²⁺ m/z=1382. ¹ H NMR (500 MHz, DMSO-d ₆ , D ₂ O drop, selection data) δ: 8.57 (s, br., 1H), 7.57 (s, br., 2H), 7.38 (s). , 1H), 7.24 (s, 1H), 7.19 (s, 1H), 7.14 (s, 1H), 7.05 (s, 1H), 6.98 (s, 1H), 6 .77 (s, 1H), 6.61 (s, br, 3H), 6.33 (s, 1H).

ＥＣ２１６９。
ＥＣ２１６８（９８２ｍｇ、３．０４ｍｍｏｌ）およびＰｄ（ＰＰｈ_３）_４（４２２ｍｇ、０．３６５ｍｍｏｌ）の混合物を、予め混合したピペリジン（２．１０ｍＬ）／ギ酸（０．８０２ｍＬ）／ＤＣＭ（９８．０ｍＬ）溶液に溶解し、続いて水（２．０ｍＬ）を添加した。反応混合物を環境温度で３０分間撹拌した。減圧下、体積を元の約半分まで減少させ、精製のためにＣｏｍｂｉＦｌａｓｈ系（カラム：シリカゲル。グラディエント溶出：ＤＣＭ中０〜２％ ＭｅＯＨ）に充填し、７２５ｍｇのＥＣ２１６９を灰白色固体として得た。ＭＳ（ＥＳＩ ｍ／ｚ）の計算値Ｃ_１３Ｈ_１８ＮＯ_６（Ｍ＋Ｈ）^＋：２８４．１１；実測値２８４．１４。

EC2169.
EC2168 (982mg, 3.04mmol) and _{Pd (PPh 3) 4 (422mg} , 0.365mmol) the mixture, premixed piperidine (2.10 mL) / formic acid (0.802mL) / DCM (98.0mL) solution Dissolved in water, followed by the addition of water (2.0 mL). The reaction mixture was stirred at ambient temperature for 30 minutes. The volume was reduced to about half of the original under reduced pressure and loaded onto a CombiFlash system (column: silica gel. Gradient elution: 0-2% MeOH in DCM) for purification to give 725 mg of EC2169 as an off-white solid. MS (ESI m/z) calcd C ₁₃ H ₁₈ NO ₆ (M+H) ⁺ : 284.11; found 284.14.

ＥＣ２１８４。
ＥＣ２１６９（２０ｍｇ、０．０７０ｍＭ）およびＥＣ２１６３（３４．４ｍｇ、０．０６０ｍＭ）のＤＭＦ（１ｍＬ）溶液に、ＰｙＢｏｐ（５４．６ｍｇ、０．１０５ｍＭ）およびＤＩＰＥＡ（０．１２２ｍＬ、０．７０ｍＭ）を添加した。反応液を３０分間撹拌した。ＬＣＭＳ分析（２０ｍＭ ＮＨ_４ＨＣＯ_３、ｐＨ７．４）は、反応が完結したことを示した。反応混合物をＣｏｍｂｉＦｌａｓｈ（ＳｉＯ_２）カラムに充填し、ＣＨ_２Ｃｌ_２中０〜３０％ ＭｅＯＨで溶出し、純粋なＥＣ２１８４（２２ｍｇ、５０％）を得た。ＬＣＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）^＋＝Ｃ_３６Ｈ_４８Ｎ_９Ｏ_８の計算値、７３４．３５；実測値７３４．３９

EC2184.
To a solution of EC2169 (20 mg, 0.070 mM) and EC2163 (34.4 mg, 0.060 mM) in DMF (1 mL), PyBop (54.6 mg, 0.105 mM) and DIPEA (0.122 mL, 0.70 mM) were added. did. The reaction was stirred for 30 minutes. LCMS analysis _{(20mM NH 4 HCO 3, pH7.4} ) indicated that the reaction was complete. The reaction mixture was loaded onto a CombiFlash (SiO ₂ ) column and eluted with 0-30% MeOH in CH ₂ Cl ₂ to give pure EC2184 (22 mg, 50%). _{^{LCMS (ESI) :( M + H}} ) + = Calculated _{C 36 H 48 N 9 O 8} , 734.35; Found 734.39

ＥＣ２１８５。
ＥＣ２１８４（１９ｍｇ、０．０２６ｍＭ）のＴＨＦ／ＭｅＯＨ（１ｍＬ／０．３３ｍＬ）溶液に、ＬｉＯＨ・Ｈ_２Ｏ（６．５ｍｇ、０．１５５ｍＭ）の０．３３ｍＬ水溶液を添加した。反応液を１８時間撹拌した。ＬＣＭＳ分析（２０ｍＭ ＮＨ_４ＨＣＯ_３、ｐＨ７．４）は、反応が完結したことを示した。有機溶媒を除去するために反応混合物を濃縮し、２Ｍ ＨＣｌでｐＨ２まで酸性化し、２日間凍結乾燥した。単離された生成物は、さらに精製せずに使用した。ＬＣＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）^＋＝Ｃ_３５Ｈ_４６Ｎ_９Ｏ_８の計算値、７２０．３４；実測値７２０．４６

EC2185.
To a THF/MeOH (1 mL/0.33 mL) solution of EC2184 (19 mg, 0.026 mM), a 0.33 mL aqueous solution of LiOH.H ₂ O (6.5 mg, 0.155 mM) was added. The reaction was stirred for 18 hours. LCMS analysis _{(20mM NH 4 HCO 3, pH7.4} ) indicated that the reaction was complete. The reaction mixture was concentrated to remove organic solvent, acidified to pH 2 with 2M HCl and lyophilized for 2 days. The isolated product was used without further purification. _{^{LCMS (ESI) :( M + H}} ) + = Calculated _{C 35 H 46 N 9 O 8} , 720.34; Found 720.46

ＥＣ２３１６（３３．４ｍｇ、０．１０７ｍＭ）およびＥＣ２１６３（５０ｍｇ、０．１０７ｍＭ）のＤＭＦ（１ｍｌ）溶液にＰｙＢｏｐ（８３．５ｍｇ、０．１６１ｍＭ）およびＤＩＰＥＡ（０．０７５ｍｌ、０．７０ｍＭ）をそれぞれ添加した。反応液を３時間撹拌した。ＬＣＭＳ分析（２０ｍＭ ＮＨ_４ＨＣＯ_３、ｐＨ７．４）は、反応が完結したことを示した。反応混合物をｃｏｍｂｉｆｌｓｈ（ＳｉＯ_２）カラムに充填し、ＣＨ_２Ｃｌ_２（０．２％ ＴＥＡ）中０〜３０％ ＭｅＯＨで溶出し、純粋なＥＣ２４１５（３０ｍｇ、３７％）を得た。^１Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤ_３ＯＤ）：δ ７．５１（ｓ、１Ｈ）、７．１７（ｓ、１Ｈ）、７．１４（ｍ、２Ｈ）、７．１０（ｄ、Ｊ＝２Ｈｚ、１Ｈ）、６．８９（ｄ、Ｊ＝２Ｈｚ、１Ｈ）、６．８０（ｄ、Ｊ＝１．５Ｈｚ、１Ｈ）、６．７６（ｄ、Ｊ＝２Ｈｚ、１Ｈ）、４．１４（ｔ、Ｊ_１＝６．０Ｈｚ、Ｊ_２＝６．５Ｈｚ、２Ｈ）、３．８７（ｓ、６Ｈ）、３．８６（ｓ、３Ｈ）、３．８５（ｓ、３Ｈ）、３．８４（ｓ、３Ｈ）、３．３１（ｔ、Ｊ_１＝７．０Ｈｚ、Ｊ_２＝７．５Ｈｚ、２Ｈ）、２．５２（ｔ、Ｊ_１＝７．５Ｈｚ、Ｊ_２＝７．５Ｈｚ、２Ｈ）、２．３９（ｔ、Ｊ_１＝８．５Ｈｚ、Ｊ_２＝７．０Ｈｚ、２Ｈ）、２．２５（ｓ、６Ｈ）、２．１７（ｍ、２Ｈ）、１．７５（ｍ、２Ｈ）；ＬＣＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）^＋＝Ｃ_３６Ｈ_４５Ｎ_９Ｏ_１０の計算値、７６４．３３；実測値７６４．３８。

Add PyBop (83.5 mg, 0.161 mM) and DIPEA (0.075 ml, 0.70 mM) to a DMF (1 ml) solution of EC2316 (33.4 mg, 0.107 mM) and EC2163 (50 mg, 0.107 mM), respectively. did. The reaction was stirred for 3 hours. LCMS analysis _{(20mM NH 4 HCO 3, pH7.4} ) indicated that the reaction was complete. The reaction mixture was charged into combiflsh (SiO _{2) column,} eluting with _{CH 2 Cl 2 (0.2% TEA} ) in 0 to 30% MeOH, to give the pure EC2415 (30mg, 37%). ¹ H NMR (500 MHz, CD ₃ OD): δ 7.51 (s, 1 H), 7.17 (s, 1 H), 7.14 (m, 2 H), 7.10 (d, J=2 Hz, 1 H ), 6.89 (d, J=2 Hz, 1H), 6.80 (d, J=1.5 Hz, 1H), 6.76 (d, J=2 Hz, 1H), 4.14 (t, J) _{1 = 6.0Hz, J 2 = 6.5Hz} , 2H), 3.87 (s, 6H), 3.86 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H ), 3.31 (t, J ₁ =7.0 Hz, J ₂ =7.5 Hz, 2H), 2.52 (t, J ₁ =7.5 Hz, J ₂ =7.5 Hz, 2H), 2. 39 (t, J ₁ =8.5 Hz, J ₂ =7.0 Hz, 2H), 2.25 (s, 6H), 2.17 (m, 2H), 1.75 (m, 2H); LCMS( _{^{ESI) :( M + H) +}} = calculated _{C 36 H 45 N 9 O 10} , 764.33; Found 764.38.

ＥＣ２４１５（３０ｍｇ、０．０３９ｍＭ）のＴＨＦ／ＭｅＯＨ（０．６ｍＬ／０．２ｍＬ）溶液に、ＬｉＯＨ・Ｈ_２Ｏ（４．９ｍｇ、０．１１８ｍＭ）の０．２ｍＬ水溶液を添加した。反応液を２４時間撹拌した。ＬＣＭＳ分析（２０ｍＭ ＮＨ_４ＨＣＯ_３、ｐＨ７．４）は反応の完結を示した。反応混合物をメタノール（１．０ｍＬ）で希釈し、１０％Ｐｄ／Ｃ（６ｍｇ）を添加した。反応混合物を、Ｈ_２雰囲気（風船）下、２４時間撹拌した。ＬＣＭＳ分析（２０ｍＭ ＮＨ_４ＨＣＯ_３、ｐＨ７．４）は、反応が完結したことを示した（出発物質と同一の保持時間であるが、質量は異なる）。反応混合物をセライトパッドでろ過し、濃縮した。粗生成物（ＥＣ２１８５）を乾燥させ、次反応に直接使用した。ＬＣＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）^＋＝Ｃ_３５Ｈ_４５Ｎ_９Ｏ_８の計算値、７２０．３４；実測値７２０．４０。

To a THF/MeOH (0.6 mL/0.2 mL) solution of EC2415 (30 mg, 0.039 mM), a 0.2 mL aqueous solution of LiOH.H ₂ O (4.9 mg, 0.118 mM) was added. The reaction was stirred for 24 hours. LCMS analysis _{(20mM NH 4 HCO 3, pH7.4} ) indicated that the reaction was complete. The reaction mixture was diluted with methanol (1.0 mL) and 10% Pd/C (6 mg) was added. The reaction mixture was stirred under H ₂ atmosphere (balloon) for 24 hours. LCMS analysis _{(20mM NH 4 HCO 3, pH7.4} ) , the reaction showed that complete (but which is a starting material the same retention time, mass different). The reaction mixture was filtered through Celite pad and concentrated. The crude product (EC2185) was dried and used directly in the next reaction. _{^{LCMS (ESI) :( M + H}} ) + = Calculated _{C 35 H 45 N 9 O 8} , 720.34; Found 720.40.

ＥＣ１６９３（２１ｍｇ、０．０４５ｍＭ）をＴＦＡ／ジクロロメタン／ＴＩＰＳ（１ｍＬ／１ｍＬ／０．０５ｍＬ）の混合物で処理し、３０分間撹拌した。ＬＣＭＳ分析（２０ｍＭ ＮＨ_４ＨＣＯ_３、ｐＨ７．４）は、反応が完結したことを示した。反応混合物を濃縮乾固し、ＤＣＭで共沸（３回）させ、高真空下で１時間乾燥し、ＥＣ２１８６を得た。別のフラスコで、ＥＣ２１８５（２８ｍｇ、０．０３９ｍＭ、先の反応物から）を乾燥ＤＭＦ（１ｍＬ）に溶解した。ＰｙＢｏｐ（４０．６ｍｇ、０．０７８ｍＭ）およびＤＩＰＥＡ（０．１３６ｍＬ、０．７８ｍＭ）をそれぞれ添加した。反応混合物を５分間撹拌後、（先に調製した）ＥＣ２１８６のＤＣＭ（１ｍＬ）溶液を添加し、１時間撹拌した。ＬＣＭＳ分析（２０ｍＭ ＮＨ_４ＨＣＯ_３、ｐＨ７．４）は、反応が完結したことを示した。反応混合物を分取ＨＰＬＣ（２０ｍＭ ＮＨ_４ＨＣＯ_３中１０〜１００％ アセトニトリル、ｐＨ ７．４）で精製し、ＥＣ２１８７（２２ｍｇ、５３％、３工程）を得た。^１Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤ_３ＯＤ）：δ ８．４０（ｍ＊、１Ｈ）、８．３７（ｍ＊、１Ｈ）、８．１６（ｍ＊、１Ｈ）、７．８４−７．７０（ｍ＊、２Ｈ）、７．２６−７．２０（ｍ＊、１Ｈ）、７．１７（ｍ＊、１Ｈ）、７．１３（ｄ、Ｊ＝１．５Ｈｚ、１Ｈ）、６．９２（ｄ、Ｊ＝１．５Ｈｚ、１Ｈ）、６．８２（ｄｄ、Ｊ_１＝６Ｈｚ、Ｊ_２＝１．５Ｈｚ、２Ｈ）、６．４２（ｓ、１Ｈ）、５．１４（ｄ、Ｊ＝５Ｈｚ、１Ｈ）、５．１０−４．９４（ｍ＊、３Ｈ）、４．５０−４．０６（ｍ＊、５Ｈ）、４．０４（ｔ、Ｊ_１＝６Ｈｚ、Ｊ_２＝６．５Ｈｚ、２Ｈ）、３．９０（ｓ、３Ｈ）、３．８８（ｓ、３Ｈ）、３．８７（ｓ、３Ｈ）、３．８５（ｍ＊、１Ｈ）、３．７３（ｓ、３Ｈ）、３．３６（ｔ、Ｊ_１＝６Ｈｚ、Ｊ_２＝７Ｈｚ、２Ｈ）、３．３３（ｍ＊、１Ｈ）、３．２０−３．００（ｍ＊、５Ｈ）、２．７２（ｍ＊、２Ｈ）、２．５５（ｍ＊、２Ｈ）、２．５３（ｓ、６Ｈ）、２．２０−２．１２（ｍ＊、２Ｈ）、１．８５（ｍ、２Ｈ）；ＬＣＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）^＋＝Ｃ_５１Ｈ_６５Ｎ_１２Ｏ_１０Ｓ_２の計算値、１０６９．４３；実測値１０６９．６０
＊化合物のジアステレオマーおよび／または回転異性体の性質による

EC1693 (21 mg, 0.045 mM) was treated with a mixture of TFA/dichloromethane/TIPS (1 mL/1 mL/0.05 mL) and stirred for 30 minutes. LCMS analysis _{(20mM NH 4 HCO 3, pH7.4} ) indicated that the reaction was complete. The reaction mixture was concentrated to dryness, azeotroped with DCM (3 times) and dried under high vacuum for 1 hour to give EC2186. In a separate flask EC2185 (28 mg, 0.039 mM, from the previous reaction) was dissolved in dry DMF (1 mL). PyBop (40.6 mg, 0.078 mM) and DIPEA (0.136 mL, 0.78 mM) were added respectively. After stirring the reaction mixture for 5 minutes, a solution of EC2186 (prepared above) in DCM (1 mL) was added and stirred for 1 hour. LCMS analysis _{(20mM NH 4 HCO 3, pH7.4} ) indicated that the reaction was complete. The reaction mixture was purified by preparative HPLC (20mM _NH 4 HCO ₃ in 10-100% acetonitrile, pH 7.4) to give the EC2187 (22mg, 53%, 3 steps). ¹ H NMR (500 MHz, CD ₃ OD): δ 8.40 (m*, 1H), 8.37 (m*, 1H), 8.16 (m*, 1H), 7.84-7.70 ( m*, 2H), 7.26-7.20(m*, 1H), 7.17(m*, 1H), 7.13(d, J=1.5Hz, 1H), 6.92(d). , J=1.5 Hz, 1H), 6.82 (dd, J ₁ =6 Hz, J ₂ =1.5 Hz, 2H), 6.42 (s, 1H), 5.14 (d, J=5 Hz, 1H), 5.10-4.94 (m*, 3H), 4.50-4.06 (m*, 5H), 4.04 (t, J ₁ =6Hz, J ₂ =6.5Hz, 2H ), 3.90 (s, 3H), 3.88 (s, 3H), 3.87 (s, 3H), 3.85 (m*, 1H), 3.73 (s, 3H), 3. 36 (t, J ₁ =6 Hz, J ₂ =7 Hz, 2H), 3.33 (m*, 1H), 3.20-3.00 (m*, 5H), 2.72 (m*, 2H) , 2.55 (m*, 2H), 2.53 (s, 6H), 2.20-2.12 (m*, 2H), 1.85 (m, 2H); LCMS (ESI): (M+H). ^{_{) + = C 51 H 65 N}} 12 O 10 S 2 calculated, 1069.43; Found 1069.60
*Depending on the diastereomeric and/or rotamer nature of the compound

アルゴン下、ＥＣ１５７９（１３．３ｍｇ、０．００７９ｍｍｏｌ）のＤＭＳＯ（０．５ｍＬ）溶液を透明な溶液になるまで撹拌し、これにＥＣ２１８７（７ｍｇ、０．００６６ｍｍｏｌ）のＤＭＳＯ（０．５ｍＬ）溶液、続いてＤＩＰＥＡ（０．０２３ｍＬ、０．１３１ｍｍｏｌを添加した。アルゴン下、反応液を室温で１時間撹拌した。生成物を１０〜１００％ ＭｅＣＮ／ｐＨ７緩衝液中分取ＨＰＬＣで単離し、凍結乾燥後、ＥＣ２１８８を１０．４ｍｇ（収率６０％）、固体として得た。^１Ｈ ＮＭＲ（５００ＭＨｚ、ＤＭＳＯ−Ｄ_６＋Ｄ_２Ｏ）（選択データ）：δ ８．５９（ｓ、１Ｈ）、７．５７（ｄ、Ｊ＝８．５Ｈｚ、２Ｈ）、７．２０（ｄ、Ｊ＝２Ｈｚ、１Ｈ）、７．１６（ｄ、Ｊ＝２Ｈｚ、１Ｈ）、７．１３（ｄ、Ｊ＝１．５Ｈｚ、１Ｈ）、６．９４（ｄ、Ｊ＝２Ｈｚ、１Ｈ）、６．８２（ｄ、Ｊ＝１．５Ｈｚ、１Ｈ）、６．７７（ｄ、Ｊ＝２Ｈｚ、１Ｈ）、６．６０（ｄ、Ｊ＝９Ｈｚ、２Ｈ）、６．５８（ｍ、１Ｈ）、６．３３（ｓ、１Ｈ）、４．９７（ｓ、２Ｈ）、４．９３（ｓ、１Ｈ）、４．４５（ｓ、２Ｈ）；ＬＣＭＳ：［Ｍ＋２Ｈ］^２＋ ｍ／ｚ＝Ｃ_１１１Ｈ_１５７Ｎ_２７Ｏ_４４Ｓ_２の計算値、１３１９．０２；実測値１３１９．５１

Under argon, a solution of EC1579 (13.3 mg, 0.0079 mmol) in DMSO (0.5 mL) was stirred until it became a clear solution, to which a solution of EC2187 (7 mg, 0.0066 mmol) in DMSO (0.5 mL), Then DIPEA (0.023 mL, 0.131 mmol was added. The reaction was stirred at room temperature for 1 h under argon. The product was isolated by preparative HPLC in 10-100% MeCN/pH7 buffer and lyophilized. ^. after the EC2188 10.4mg (60% yield), as a solid _{1 H NMR (500MHz, DMSO-} D 6 + D 2 O) ( selected data): δ 8.59 (s, 1H ), 7. 57 (d, J=8.5 Hz, 2H), 7.20 (d, J=2 Hz, 1H), 7.16 (d, J=2 Hz, 1H), 7.13 (d, J=1.5 Hz) , 1H), 6.94(d, J=2Hz, 1H), 6.82(d, J=1.5Hz, 1H), 6.77(d, J=2Hz, 1H), 6.60(d). , J=9 Hz, 2H), 6.58 (m, 1H), 6.33 (s, 1H), 4.97 (s, 2H), 4.93 (s, 1H), 4.45 (s, _{^{2H); LCMS: [M +}} 2H] 2+ m / z = C 111 H 157 N 27 O 44 S 2 calculated, 1319.02; Found 1319.51

アルゴン下、環境温度下で、ＥＣ１７７０（１１１ｍｇ）およびジエチルアミン（２．０ｍＬ）の無水ＤＣＭ（５．０ｍＬ）溶液を９０分間撹拌し、濃縮し、ＤＣＭで共沸（３ｍＬ×３）させ、真空下で６０分間撹拌し、ＤＣＭ（２０ｍＬ）に再溶解し、ＮａＨＳＯ_３（１４．６ｍｇ）の水（２０ｍＬ）溶液と混合した。反応混合物を環境温度で６０分間撹拌し、分離した。有機層を水（１５ｍＬ）で抽出し、合わせた水層を凍結乾燥して８６．５ｍｇ（１０１％）のＥＣ２３２２をベージュ色固体として得た。^１Ｈ ＮＭＲ（５００ＭＨｚ、２９８Ｋ、ＤＭＳＯ−ｄ６）δ ７．３０１（ｓ、１Ｈ）、６．９６８（ｓ、１Ｈ），６．４７８（ｓ、１Ｈ）、６．２２０（ｓ、１Ｈ）、５．０７８（ｓ、１Ｈ）、５．０２６（ｓ、１Ｈ）、４．２１５（ｄ、Ｊ＝１７．０Ｈｚ、１Ｈ）、３．９５３（ｍ、４Ｈ）、３．８８４（ｍ、２Ｈ）、３．７１４（ｄ、Ｊ＝２２．５Ｈｚ、１Ｈ）、３．６６９（ｓ、３Ｈ）、３．５９６（ｓ、３Ｈ）、３．１５１（ｄ、Ｊ＝１４．０Ｈｚ、１Ｈ）、 ２．８３０（ｍ、１Ｈ）、１．７５７（ｍ、４Ｈ）、１．５２５（ｍ、２Ｈ）。ＭＳ⁻（ＥＳＩ ｍ／ｚ）Ｃ_２７Ｈ_３２Ｎ_３Ｏ_１０Ｓの計算値：５９０．１８；実測値５９０．２７。

Stir a solution of EC1770 (111 mg) and diethylamine (2.0 mL) in anhydrous DCM (5.0 mL) under argon under ambient temperature for 90 minutes, concentrate, azeotrope with DCM (3 mL x 3), and under vacuum. Stirred at 60 min, redissolved in DCM (20 mL) and mixed with a solution of NaHSO ₃ (14.6 mg) in water (20 mL). The reaction mixture was stirred at ambient temperature for 60 minutes and separated. The organic layer was extracted with water (15 mL) and the combined aqueous layers were lyophilized to give 86.5 mg (101%) of EC2322 as a beige solid. ¹ H NMR (500 MHz, 298 K, DMSO-d6) δ 7.301 (s, 1 H), 6.968 (s, 1 H), 6.478 (s, 1 H), 6.220 (s, 1 H), 5 0.078 (s, 1H), 5.026 (s, 1H), 4.215 (d, J=17.0 Hz, 1H), 3.953 (m, 4H), 3.884 (m, 2H), 3.714 (d, J = 22.5 Hz, 1H), 3.669 (s, 3H), 3.596 (s, 3H), 3.151 (d, J = 14.0 Hz, 1H), 830 (m, 1H), 1.757 (m, 4H), 1.525 (m, 2H). ^{_{MS - (ESI m / z)}} C 27 H 32 N 3 O 10 Calculated S: 590.18; Found 590.27.

ＥＣ１６９３（１９．８ｍｇ）をＴＦＡ（０．１５ｍＬ）およびＤＣＭ（０．８５ｍＬ）の溶液に溶解し、環境温度で３０分間撹拌し、濃縮し、ＤＣＭで共沸（１ｍＬ×３）させ、真空下で６０分間乾燥させた。残渣を無水ＤＭＦ（２．５ｍＬ）に溶解し、ＥＣ２３２２（１８．３ｍｇ）およびＰｙＢＯＰ（１９．４ｍｇ）を含む小バイアルに移した。得られた溶液にＴＥＡ（３２．０μＬ）を添加した。アルゴン下、反応混合物を環境温度で１５分間撹拌し、ＥＣ１５７９（７６．１ｍｇ）の緩衝液（５０ｍＭ ＮＨ_４ＨＣＯ_３、ｐＨ７．０、７．０ｍＬ）を添加した。得られた均一な溶液を、アルゴン下、環境温度で１５分間撹拌し、精製のために分取ＨＰＬＣ（移動相Ａ：５０ｍＭ ＮＨ_４ＨＣＯ_３緩衝液、ｐＨ７．０；Ｂ＝ＡＣＮ。方法：１０〜８０Ｂ％（２０分））に直接充填し、７．９ｍｇ（１０．６％）のＥＣ２３２３を淡黄色固体として得た。選択的^１Ｈ ＮＭＲ（５００ＭＨｚ、２９８Ｋ、Ｄ_２Ｏ） δ ８．６７１（ｓ、１Ｈ）、７．７１１（ｂ、２Ｈ）、７．１４６（ｓ、１Ｈ）、６．８２４（ｂ、３Ｈ）、６．７２８（ｓ、１Ｈ）、６．４１９（ｂ、２Ｈ）。ＭＳ⁻（ＥＳＩ ｍ／２ｚ）Ｃ_１０３Ｈ_１４４Ｎ_２１Ｏ_４６Ｓ_３の計算値：１２５３．４４；実測値１２５３．８９．

EC1693 (19.8 mg) was dissolved in a solution of TFA (0.15 mL) and DCM (0.85 mL), stirred at ambient temperature for 30 minutes, concentrated, azeotroped with DCM (1 mL x 3) and under vacuum. And dried for 60 minutes. The residue was dissolved in anhydrous DMF (2.5 mL) and transferred to a small vial containing EC2322 (18.3 mg) and PyBOP (19.4 mg). TEA (32.0 μL) was added to the resulting solution. Under argon, the reaction mixture was stirred for 15 minutes at ambient temperature, buffer _{(50mM NH 4 HCO 3, pH7.0,7.0mL} ) of EC1579 (76.1mg) was added. The resulting homogeneous solution was stirred under argon at ambient temperature for 15 minutes and then purified by preparative HPLC (mobile phase A: 50 mM NH ₄ HCO ₃ buffer, pH 7.0; B=ACN. Method: 10). ~80 B% (20 min)) directly to give 7.9 mg (10.6%) of EC2323 as a pale yellow solid. Selective ¹ H NMR (500 MHz, 298 K, D ₂ O) δ 8.671 (s, 1 H), 7.711 (b, 2 H), 7.146 (s, 1 H), 6.824 (b, 3 H) , 6.728 (s, 1H), 6.419 (b, 2H). MS ^- (ESI _m / _2z) Calculated _{C 103 H 144 N 21 O 46} S 3: 1253.44; Found 1253.89.

ＴＥＡ（８０．０μＬ）を、ＥＣ２３５１（２５．３ｍｇ）、ＥＣ２１６０（５７．１ｍｇ）およびＰｙＢＯＰ（４２．９ｍｇ）の無水ＤＭＦ（３．５ｍＬ）溶液に添加した。アルゴン下、反応混合物を環境温度で１５分間撹拌し、フラッシュカラムを通してＤＣＭ中０〜１０％ ＭｅＯＨで溶出させ、６２．４ｍｇ（９９．１％）の粗製のＥＣ２３６１をベージュ色固体として得て、これをさらに精製することなく、次工程に使用した。ＭＳ^＋（ＥＳＩ ｍ／ｚ）Ｃ_４２Ｈ_５０Ｎ_９Ｏ_１０の計算値：８４０．３７；実測値８４０．４７。

TEA (80.0 μL) was added to a solution of EC2351 (25.3 mg), EC2160 (57.1 mg) and PyBOP (42.9 mg) in anhydrous DMF (3.5 mL). The reaction mixture was stirred under argon at ambient temperature for 15 minutes and eluted through a flash column with 0-10% MeOH in DCM to give 62.4 mg (99.1%) of crude EC2361 as a beige solid. Was used in the next step without further purification. MS ⁺ (ESI _m / _z) calcd _{C 42 H 50 N 9 O 10} : 840.37; Found 840.47.

ＥＣ２３６１（６２．４ｍｇ）、Ｐｄ（ＰＰｈ_３）_４（１４．７ｍｇ）、ピペリジン（５１．４μＬ）、ギ酸（１９．６μＬ）および水（３０．０μＬ）の混合物のＤＣＭ（３．０ｍＬ）溶液を、環境温度で２５分間撹拌し、その後精製のためにＣｏｍｂｉＦｌａｓｈ系（シリカゲルカラム。グラディエント：ＤＣＭ中０〜１０％ ＭｅＯＨ）に直接充填し、２０．７ｍｇ（３４．８％）のＥＣ２３６２をベージュ色固体として得た。^１Ｈ ＮＭＲ（５００ＭＨｚ、２９８Ｋ、ＣＤ_３ＯＤ）δ ７．３６０（ｓ、１Ｈ）、７．３１９（ｓ、１Ｈ）、７．２１７（ｓ、１Ｈ）、７．１８９（ｓ、１Ｈ）、７．１３５（ｓ、１Ｈ）、６．９３７（ｓ、１Ｈ）、６．９３１（ｓ、２Ｈ）、６．８３３（ｓ、１Ｈ）、６．３３４（ｓ、１Ｈ）、４．０１３（ｔ、Ｊ＝６．５Ｈｚ、２Ｈ）、３．９１９（ｓ、６Ｈ）、３．９０８（ｓ、３Ｈ）、３．８９５（ｓ、３Ｈ）、３．８０３（ｓ、３Ｈ）、３．７２３（ｓ、３Ｈ）、２．３６８（ｔ、Ｊ＝７．０Ｈｚ、２Ｈ）、１．８７２（ｍ、２Ｈ）、１．７９３（ｍ、２Ｈ）、１．５８５（ｍ、２Ｈ）。ＭＳ^＋（ＥＳＩ ｍ／ｚ）の計算値Ｃ_３９Ｈ_４６Ｎ_９Ｏ_１０：８００．３４；実測値８４０．６３。

A solution of a mixture of EC2361 (62.4 mg), Pd(PPh ₃ ) ₄ (14.7 mg), piperidine (51.4 μL), formic acid (19.6 μL) and water (30.0 μL) in DCM (3.0 mL) was added. , Stirred at ambient temperature for 25 minutes, then directly loaded onto a CombiFlash system (silica gel column; gradient: 0-10% MeOH in DCM) for purification, 20.7 mg (34.8%) EC2362 as a beige solid. Got as. ¹ H NMR (500 MHz, 298 K, CD ₃ OD) δ 7.360 (s, 1 H), 7.319 (s, 1 H), 7.217 (s, 1 H), 7.189 (s, 1 H), 7 .135 (s, 1H), 6.937 (s, 1H), 6.931 (s, 2H), 6.833 (s, 1H), 6.334 (s, 1H), 4.013 (t, J=6.5Hz, 2H), 3.919(s, 6H), 3.908(s, 3H), 3.895(s, 3H), 3.803(s, 3H), 3.723(s). 3H), 2.368 (t, J=7.0Hz, 2H), 1.872 (m, 2H), 1.793 (m, 2H), 1.585 (m, 2H). MS ⁺ (ESI m / z) Calcd _C 39 of _{H 46 N 9 O 10: 800.34} ; Found 840.63.

ＥＣ１６９３（１５．１ｍｇ）をＴＦＡ（０．２０ｍＬ）およびＤＣＭ（１．５ｍＬ）の溶液に溶解し、環境温度で１５分間撹拌し、濃縮し、ＤＣＭで共沸（１．５ｍＬ×３）させ、真空下で６０分間乾燥させた。残渣を無水ＤＭＦ（１．５ｍＬ）に溶解し、ＥＣ２３６２（２０．７ｍｇ）およびＰｙＢＯＰ（１４．８ｍｇ）を含む小バイアルに移した。得られた溶液にＴＥＡ（３０．０μＬ）を添加した。アルゴン下、反応混合物を環境温度で１０分間撹拌し、ＤＭＳＯ（３．０ｍＬ）で希釈し、ＥＣ１５７９（５６．６ｍｇ）の緩衝液（５０ｍＭ ＮＨ_４ＨＣＯ_３、ｐＨ７．０、５．０ｍＬ）を添加した。アルゴン下、反応混合物を環境温度で１０分間撹拌し、４０℃でさらに１０分間撹拌し、精製のために分取ＨＰＬＣ（移動相Ａ：５０ｍＭ ＮＨ_４ＨＣＯ_３緩衝液、ｐＨ７．０；Ｂ＝ＡＣＮ。方法：１０〜８０Ｂ％（２０分））に直接充填し、３５．６ｍｇ（５０．６％）のＥＣ２３６３を淡黄色固体として得た。選択的^１Ｈ ＮＭＲ（５００ＭＨｚ、２９８Ｋ、Ｄ_２Ｏ） δ ８．４３８（ｓ、１Ｈ）、７．４７６（ｄ、Ｊ＝８．０Ｈｚ、２Ｈ）、７．１１３（ｓ、１Ｈ）、７．０３１（ｓ、２Ｈ）、６．９８４（ｓ、１Ｈ）、６．７３４（ｓ、１Ｈ）、６．６８６（ｓ、２Ｈ）、６．６４３（ｓ、１Ｈ）、６．５３１（ｄ、Ｊ＝９．０Ｈｚ、２Ｈ）、６．２６２（ｂ、１Ｈ）。ＭＳ⁻（ＥＳＩ ｍ／２ｚ）Ｃ_１１５Ｈ_１５６Ｎ_２７Ｏ_４６Ｓ_２の計算値：１３５７．５１；実測値１３５７．８９。

EC1693 (15.1 mg) was dissolved in a solution of TFA (0.20 mL) and DCM (1.5 mL), stirred at ambient temperature for 15 minutes, concentrated and azeotroped with DCM (1.5 mL x 3), It was dried under vacuum for 60 minutes. The residue was dissolved in anhydrous DMF (1.5 mL) and transferred to a small vial containing EC2362 (20.7 mg) and PyBOP (14.8 mg). TEA (30.0 μL) was added to the resulting solution. The reaction mixture was stirred at ambient temperature under argon for 10 minutes, diluted with DMSO (3.0 mL) and EC1579 (56.6 mg) in buffer (50 mM NH ₄ HCO ₃ , pH 7.0, 5.0 mL) was added. did. The reaction mixture was stirred at ambient temperature for 10 minutes under argon and at 40° C. for a further 10 minutes, and then purified by preparative HPLC (mobile phase A: 50 mM NH ₄ HCO ₃ buffer, pH 7.0; B=ACN). Method: 10-80 B% (20 min)) directly loaded to give 35.6 mg (50.6%) of EC2363 as a pale yellow solid. Selective ¹ H NMR (500 MHz, 298 K, D ₂ O) δ 8.438 (s, 1 H), 7.476 (d, J=8.0 Hz, 2 H), 7.113 (s, 1 H), 7. 031 (s, 2H), 6.984 (s, 1H), 6.734 (s, 1H), 6.686 (s, 2H), 6.643 (s, 1H), 6.531 (d, J = 9.0 Hz, 2H), 6.262 (b, 1H). ^{_{MS - (ESI m / 2z)}} C 115 H 156 N 27 O 46 S 2 Calculated: 1357.51; Found 1357.89.

ＤＩＰＥＡ（０．２０ｍＬ）を、ＥＣ２１６０（１１５．０ｍｇ）および６−ブロモヘキサノイルクロリド（５５．０μＬ）の無水ＤＭＦ（３．２ｍＬ）溶液に滴下添加した。アルゴン下、反応混合物を環境温度で５分間撹拌し、ＤＭＳＯ（１０ｍＬ）で希釈し、精製のために分取ＨＰＬＣ（移動相Ａ：５０ｍＭ ＮＨ_４ＨＣＯ_３緩衝液、ｐＨ７．０；Ｂ＝ＡＣＮ。方法：１０〜１００Ｂ％（２０分））に直接充填し、６６．５ｍｇのＥＣ２２７０を白色固体として得た。ＭＳ（ＥＳＩ ｍ／ｚ）Ｃ_３１Ｈ_３８ＢｒＮ_８Ｏ_６（Ｍ＋Ｈ）^＋の計算値：６９７．２１；実測値６９７．５３。

DIPEA (0.20 mL) was added dropwise to a solution of EC2160 (115.0 mg) and 6-bromohexanoyl chloride (55.0 μL) in anhydrous DMF (3.2 mL). Under argon, the reaction mixture was stirred for 5 minutes at ambient temperature, diluted with DMSO (10 mL), preparative HPLC for purification (mobile phase A: 50mM _NH 4 HCO ₃ buffer, pH7.0; B = ACN. Method: 10-100 B% (20 min)) directly loaded to give 66.5 mg of EC2270 as a white solid. _{MS (ESI m / z) C} 31 H 38 BrN 8 O 6 (M + H) + Calculated: 697.21; found 697.53.

ＥＣ２２６７（１５．０ｍｇ）、ＥＣ２２７０（１８．７ｍｇ）およびＫ_２ＣＯ_３（２６．１ｍｇ）の混合物の無水ＤＭＦ（２．０ｍＬ）溶液を、密閉容器で８０℃に加熱して８分間撹拌し、氷浴中で冷却し、ＤＭＳＯ（７．５ｍＬ）で希釈し、ろ過し、ろ液を精製のために分取ＨＰＬＣ（移動相Ａ：５０ｍＭ ＮＨ_４ＨＣＯ_３緩衝液、ｐＨ７．０；Ｂ＝ＡＣＮ。方法：１０〜１００Ｂ％（２０分））に充填し、１１．５ｍｇのＥＣ２２９２を白色固体として得た。ＭＳ（ＥＳＩ ｍ／ｚ）Ｃ_４２Ｈ_５０Ｎ_９Ｏ_１０（Ｍ＋Ｈ）^＋の計算値：８４０．３７；実測値８４０．８１。

A solution of EC2267 (15.0 mg), EC2270 (18.7 mg) and K ₂ CO ₃ (26.1 mg) in anhydrous DMF (2.0 mL) was heated to 80° C. in a closed container and stirred for 8 minutes, Cool in an ice bath, dilute with DMSO (7.5 mL), filter and filter the filtrate for purification by preparative HPLC (mobile phase A: 50 mM NH ₄ HCO ₃ buffer, pH 7.0; B=ACN). Method: 10-100 B% (20 min)) to give 11.5 mg of EC2292 as a white solid. _{MS (ESI m / z) C} 42 H 50 N 9 O 10 (M + H) + Calculated: 840.37; found 840.81.

予め混合したピペリジン（２．６０μＬ）およびギ酸（０．９９４μＬ）のＤＣＭ（９８０μＬ）および水（２０μＬ）の溶液に、ＥＣ２２９２（３．２ｍｇ）およびＰｄ（ＰＰｈ_３）_４（０．７０ｍｇ）を並行して添加した。アルゴン下、反応混合物を環境温度で１時間撹拌し、精製のためにＣｏｍｂｉＦｌａｓｈ系（カラム：シリカゲル。移動相Ａ：ＤＣＭ；Ｂ：ＭｅＯＨ。グラディエント：０〜１０％Ｂ）に直接充填し、１．２ｍｇのＥＣ２２９９を白色固体として得た。ＭＳ（ＥＳＩ ｍ／ｚ）Ｃ_３９Ｈ_４６Ｎ_９Ｏ_１０（Ｍ＋Ｈ）^＋の計算値：８００．３４；実測値８００．５９。

To a premixed solution of piperidine (2.60 μL) and formic acid (0.994 μL) in DCM (980 μL) and water (20 μL) was added EC2292 (3.2 mg) and Pd(PPh ₃ ) ₄ (0.70 mg) in parallel. And added. The reaction mixture was stirred at ambient temperature under argon for 1 h and directly loaded onto the CombiFlash system (column: silica gel; mobile phase A: DCM; B: MeOH. gradient: 0-10% B) for purification. 2 mg of EC2299 was obtained as a white solid. _{MS (ESI m / z) C} 39 H 46 N 9 O 10 (M + H) + Calculated: 800.34; found 800.59.

ＥＣ１９６３（１．４ｍｇ）をＴＦＡ（５０μＬ）およびＤＣＭ（１５０μＬ）の溶液に溶解し、環境温度で１０分間撹拌し、濃縮し、ＤＣＭで共沸（０．５ｍＬ×３）させ、真空下で１時間乾燥させた。残渣を無水ＤＭＦ（３５０μＬ）に溶解し、ＥＣ２２９９（０．５０ｍｇ）およびＰｙＢＯＰ（１．２ｍｇ）を含む小バイアルに移した。得られた溶液にＴＥＡ（１．８μＬ）を添加した。アルゴン下反応混合物を環境温度で１５分撹拌し、ＤＭＳＯ（５００μＬ）で希釈し、ＥＣ１５７９（３．２ｍｇ）の緩衝液（５０ｍＭ ＮＨ_４ＨＣＯ_３、ｐＨ７．０、１．３ｍＬ）を添加した。得られた均一な溶液をアルゴン下、環境温度で２０分間撹拌し、分取ＨＰＬＣ（移動相Ａ：５０ｍＭ ＮＨ_４ＨＣＯ_３緩衝液、ｐＨ７．０；Ｂ＝ＡＣＮ。方法：１０〜１００Ｂ％（２０ｍｉｎ））に直接充填し、０．３５ｍｇのＥＣ２２９９を白色固体として得た。ＭＳ（ＥＳＩ ｍ／２ｚ）Ｃ_１１５Ｈ_１５９Ｎ_２７Ｏ_４６Ｓ_２［（Ｍ＋２Ｈ）／２］^＋の計算値：１３５９．０２；実測値１３６０．１５。

EC1963 (1.4 mg) was dissolved in a solution of TFA (50 μL) and DCM (150 μL), stirred at ambient temperature for 10 minutes, concentrated, azeotroped with DCM (0.5 mL×3), and 1 in vacuo. Allowed to dry for hours. The residue was dissolved in anhydrous DMF (350 μL) and transferred to a small vial containing EC2299 (0.50 mg) and PyBOP (1.2 mg). TEA (1.8 μL) was added to the resulting solution. The reaction mixture was stirred under argon at ambient temperature for 15 minutes, diluted with DMSO (500 μL) and a buffer of EC1579 (3.2 mg) (50 mM NH ₄ HCO ₃ , pH 7.0, 1.3 mL) was added. The resulting homogeneous solution was stirred under argon for 20 min at ambient temperature and purified by preparative HPLC (mobile phase A: 50mM _NH 4 HCO ₃ buffer, pH 7.0; B = ACN methods:. 10~100B% (20min )) directly to give 0.35 mg of EC2299 as a white solid. _{MS (ESI m / 2z) C} 115 H 159 N 27 O 46 S 2 [(M + 2H) / 2] + Calculated: 1359.02; Found 1360.15.

アルゴン下、Ｉ（３７６ｍｇ）、２−エタノールアミン（８０．６μＬ）およびＭｇＳＯ_４（９６０ｍｇ）のＤＣＭ（２０ｍＬ）懸濁液を環境温度で２時間撹拌した。固体をろ過し、ろ液をＦｍｏｃ−Ｇｌｕ−Ｏａｌｌ（６５６ｍｇ）およびＨＡＴＵ（６０９ｍｇ）の無水ＤＭＦ（６．０ｍＬ）溶液に移し、続いてＤＩＰＥＡ（０．６２ｍＬ）を添加した。アルゴン下、環境温度で１時間撹拌後、反応混合物を精製のためにＣｏｍｂｉＦｌａｓｈ系（シリカゲルカラム。グラディエント：石油エーテル中０〜５０％ ＥｔＯＡｃ）に直接充填し、３６５ｍｇ（４２．５％）のＥＣ２４０７を白色固体として得た。^１Ｈ ＮＭＲ（５００ＭＨｚ、２９８Ｋ、ＣＤＣｌ_３）δ ７．７６４（ｂ、２Ｈ）、７．６０５（ｂ、２Ｈ）、７．３９２（ｂ、２Ｈ）、７．３１２（ｂ、２Ｈ）、５．９０５（ｍ、１Ｈ）、５．４９５−４．９７９（ｍ、３Ｈ）、５．００４−４．９２８（ｍ、２Ｈ）、４．６５５−３．４０９（ｍ、１３Ｈ）、２．７３０−２．１７２（ｍ、６Ｈ）、１．４３３（ｍ、９Ｈ）。ＭＳ^＋（ＥＳＩ ｍ／ｚ）Ｃ_３９Ｈ_４６Ｎ_９Ｏ_１０の計算値：８００．３４；実測値８４０．６３。ＭＳ^＋（ＥＳＩ ｍ／ｚ）Ｃ_３６Ｈ_４４Ｎ_３Ｏ_８の計算値：６４６．３１；実測値６４６．５０。

A suspension of I (376 mg), 2-ethanolamine (80.6 μL) and MgSO ₄ (960 mg) in DCM (20 mL) was stirred at ambient temperature under argon for 2 hours. The solid was filtered and the filtrate was transferred to a solution of Fmoc-Glu-Oall (656 mg) and HATU (609 mg) in anhydrous DMF (6.0 mL), followed by the addition of DIPEA (0.62 mL). After stirring for 1 h at ambient temperature under argon, the reaction mixture was directly loaded into a CombiFlash system (silica gel column. Gradient: 0-50% EtOAc in petroleum ether) for purification and charged with 365 mg (42.5%) of EC2407. Obtained as a white solid. ¹ H NMR (500 MHz, 298 K, CDCl ₃ )δ 7.764 (b, 2H), 7.605 (b, 2H), 7.392 (b, 2H), 7.312 (b, 2H), 5. 905 (m, 1H), 5.495-4.979 (m, 3H), 5.004-4.928 (m, 2H), 4.655-3.409 (m, 13H), 2.730-. 2.172 (m, 6H), 1.433 (m, 9H). MS ⁺ (ESI _m / _z) calcd _{C 39 H 46 N 9 O 10} : 800.34; Found 840.63. MS ⁺ (ESI _m / _z) calcd _{C 36 H 44 N 3 O 8} : 646.31; Found 646.50.

アルゴン下、ＥＣ２４０７（３６５ｍｇ）およびジエチルアミン（４．０ｍＬ）の無水ＤＣＭ（４．０ｍＬ）溶液を環境温度で３．５時間撹拌し、濃縮し、ＤＣＭで共沸（５ｍＬ×３）させ、真空下で６０分間乾燥させ、ＤＣＭ（４５ｍＬ）およびＤＭＦ（１．０ｍＬ）に再溶解し、Ｆｍｏｃ−Ｇｌｕ−Ｏ^ｔＢｕ（２２９ｍｇ）およびＨＡＴＵ（２０４ｍｇ）の混合物に添加した。反応混合物をアルゴン下、環境温度で３５分間撹拌し、少体積まで濃縮し、精製のためにＣｏｍｂｉＦｌａｓｈ系（シリカゲルカラム。グラディエント：石油エーテル中０〜７０％ ＥｔＯＡｃ）に直接充填し、３００ｍｇ（６７．２％）のＥＣ２４３８を白色固体として得た。^１Ｈ ＮＭＲ（５００ＭＨｚ、２９８Ｋ、ＣＤＣｌ_３）δ ７．７６８（ｄ、Ｊ＝７．５Ｈｚ、２Ｈ）、７．６２０（ｄ、Ｊ＝７．５Ｈｚ、２Ｈ）、７．３９８（ｔ、Ｊ＝７．５Ｈｚ、２Ｈ）、７．３１７（ｔ、Ｊ＝７．５Ｈｚ、２Ｈ）、５．９０１（ｍ、１Ｈ）、５．３３８（ｄ、Ｊ＝１９．５Ｈｚ、２Ｈ）、５．２４４（ｍ、１Ｈ）、４．９５９（ｍ、２Ｈ）、４．６１７（ｍ、３Ｈ）、４．３７５（ｍ、２Ｈ）、４．２２０（ｍ、２Ｈ）、４．１１６−３．８１３（ｍ、４Ｈ）、３．６１１（ｂ、１Ｈ）、３．３８８（ｍ、１Ｈ）、２．７５５−１．９１３（ｍ、１０Ｈ）、１．４３０（ｍ、１８Ｈ）。ＭＳ^＋（ＥＳＩ ｍ／ｚ）Ｃ_４５Ｈ_５９Ｎ_４Ｏ_１１の計算値：８３１．４２；実測値８３１．６５。

A solution of EC2407 (365 mg) and diethylamine (4.0 mL) in anhydrous DCM (4.0 mL) under argon was stirred at ambient temperature for 3.5 hours, concentrated, azeotroped with DCM (5 mL x 3) and under vacuum. in dried 60 minutes, redissolved in DCM (45 mL) and DMF (1.0 mL), was added to a mixture of ^{Fmoc-Glu-O t Bu (} 229mg) and HATU (204 mg). The reaction mixture was stirred under argon at ambient temperature for 35 minutes, concentrated to a small volume and directly loaded onto a CombiFlash system (silica gel column. Gradient: 0-70% EtOAc in petroleum ether) for purification, 300 mg (67. 2%) EC2438 was obtained as a white solid. ¹ H NMR (500 MHz, 298 K, CDCl ₃ ) δ 7.768 (d, J=7.5 Hz, 2 H), 7.620 (d, J=7.5 Hz, 2 H), 7.398 (t, J= 7.5Hz, 2H), 7.317(t, J=7.5Hz, 2H), 5.901(m, 1H), 5.338(d, J=19.5Hz, 2H), 5.244( m, 1H), 4.959 (m, 2H), 4.617 (m, 3H), 4.375 (m, 2H), 4.220 (m, 2H), 4.116-3.813 (m. 4H), 3.611 (b, 1H), 3.388 (m, 1H), 2.755-1.913 (m, 10H), 1.430 (m, 18H). MS ⁺ (ESI _m / _z) calcd _{C 45 H 59 N 4 O 11} : 831.42; Found 831.65.

アルゴン下、ＥＣ２４０８（３００ｍｇ）およびジエチルアミン（１０．０ｍＬ）の無水ＤＣＭ（５．０ｍＬ）を環境温度で１．５時間撹拌し、濃縮し、ＤＣＭで共沸（１０ｍＬ×３）させ、真空下で１時間乾燥させ、ＤＣＭ（１０ｍＬ）に再溶解した。この溶液に３−（マレイミド）プロピオン酸Ｎ−スクシンイミジルエステル（１１５ｍｇ）およびＤＩＰＥＡ（０．１５ｍＬ）を並行して添加した。反応混合物をアルゴン下、環境温度で５０分撹拌し、元の体積の約半分まで濃縮し、フラッシュカラムを通して０〜１００％ＥｔＯＡｃ石油エーテル中０〜１００％ ＥｔＯＡｃで溶出させ、１３８ｍｇ（５０．３％）の粗製のＥＣ２４３９を白色固体として得て、これをさらに精製することなく、次工程に使用した。ＭＳ^＋（ＥＳＩ ｍ／ｚ）Ｃ_３７Ｈ_５４Ｎ_５Ｏ_１２の計算値：７６０．３８；実測値７６０．５６。

Under argon, EC2408 (300 mg) and diethylamine (10.0 mL) in anhydrous DCM (5.0 mL) were stirred at ambient temperature for 1.5 hours, concentrated, azeotroped with DCM (10 mL x 3), and under vacuum. It was dried for 1 hour and redissolved in DCM (10 mL). To this solution was added 3-(maleimido)propionic acid N-succinimidyl ester (115 mg) and DIPEA (0.15 mL) in parallel. The reaction mixture was stirred under argon at ambient temperature for 50 minutes, concentrated to about half its original volume and eluted through a flash column with 0-100% EtOAc in petroleum ether 0-100% EtOAc, 138 mg (50.3%). ) Crude EC2439 was obtained as a white solid and used in the next step without further purification. MS ⁺ (ESI _m / _z) calcd for _{C 37 H 54 N 5 O 12} : 760.38; Found 760.56.

アルゴン下、ＥＣ２４３９（１９２ｍｇ）、Ｐｄ（ＰＰｈ_３）_４（７６．１ｍｇ）、ピペリジン（２５．０μＬ）およびギ酸（９．５３μＬ）の混合物のＤＣＭ（５．０ｍＬ）溶液を環境温度で１時間撹拌した。この混合物にＴＦＡ（２．５ｍＬ）を添加した。アルゴン下、反応混合物を環境温度で１．５時間撹拌し、濃縮し、ＤＭＳＯ（９．５ｍＬ）に再溶解し、精製のために分取ＨＰＬＣ（移動相Ａ：０．１％ ＴＦＡ緩衝液；Ｂ＝ＡＣＮ。方法：０〜３０Ｂ％（２０分））に直接充填し、６５．０ｍｇ（４５．６％）のＥＣ２４４６を白色固体として得た。^１Ｈ ＮＭＲ（５００ＭＨｚ、２９８Ｋ、ＤＭＳＯ−ｄ_６）δ １２．６０５（ｂ、２Ｈ）、８．２７０（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）、８．１１１（ｄ、Ｊ＝８．５Ｈｚ、１Ｈ）、７．００２（ｓ、２Ｈ）、５．４１５（ｓ、１Ｈ）、５．１０４（ｓ、２Ｈ）、４．２８４（ｍ、１Ｈ）、４．１５１（ｍ、２Ｈ）、４．００３（ｍ、２Ｈ）、３．８６７（ｄ、Ｊ＝１５．０Ｈｚ、１Ｈ）、３．７８９（ｍ、２Ｈ）、３．６００（ｍ、２Ｈ）、３．５４６（ｍ、１Ｈ）、２．６０７（ｍ、１Ｈ）、２．５２２（ｍ、１Ｈ）、２．４４８（ｍ、１Ｈ）、２．４２８（ｍ、２Ｈ）、２．３３９（ｍ、１Ｈ）、２．１９５（ｍ、２Ｈ）、２．０４７（ｍ、２Ｈ）、１．７４１（ｍ、２Ｈ）。ＭＳ⁻（ＥＳＩ ｍ／ｚ）Ｃ_２５Ｈ_３２Ｎ_５Ｏ_１０の計算値：５６２．２２；実測値５６２．５３。

A solution of EC2439 (192 mg), Pd(PPh ₃ ) ₄ (76.1 mg), piperidine (25.0 μL) and formic acid (9.53 μL) in DCM (5.0 mL) was stirred at ambient temperature for 1 hour under argon. did. TFA (2.5 mL) was added to the mixture. The reaction mixture was stirred at ambient temperature under argon for 1.5 h, concentrated, redissolved in DMSO (9.5 mL) and purified by preparative HPLC (mobile phase A: 0.1% TFA buffer; B=ACN. Method: 0-30 B% (20 min)) directly loaded to give 65.0 mg (45.6%) of EC2446 as a white solid. ¹ H NMR (500 MHz, 298 K, DMSO-d ₆ ) δ 12.605 (b, 2 H), 8.270 (d, J=8.0 Hz, 1 H), 8.111 (d, J=8.5 Hz, 1H), 7.002 (s, 2H), 5.415 (s, 1H), 5.104 (s, 2H), 4.284 (m, 1H), 4.151 (m, 2H), 4. 003 (m, 2H), 3.867 (d, J=15.0 Hz, 1H), 3.789 (m, 2H), 3.600 (m, 2H), 3.546 (m, 1H), 2 .607 (m, 1H), 2.522 (m, 1H), 2.448 (m, 1H), 2.428 (m, 2H), 2.339 (m, 1H), 2.195 (m, 2H), 2.047 (m, 2H), 1.741 (m, 2H). MS ^- (ESI _m / _z) calcd _{C 25 H 32 N 5 O 10} : 562.22; Found 562.53.

ＴＥＡ（１９．０μＬ）を、ＥＣ２３２２（８．４ｍｇ）、ＥＣ２４４６（８．４ｍｇ）およびＰｙＢＯＰ（７．５ｍｇ）の無水ＤＭＦ（３．０ｍＬ）溶液に添加し、アルゴン下、その溶液を環境温度６０分間撹拌した。この溶液にＥＣ１５７９（２５．３ｍｇ）の緩衝液（５０ｍＭ ＮＨ_４ＨＣＯ_３、ｐＨ７．０、６．０ｍＬ）を添加し、アルゴン下、反応混合物を環境温度で２０分間撹拌した。その後精製のために分取ＨＰＬＣ（移動相Ａ：５０ｍＭ ＮＨ_４ＨＣＯ_３緩衝液、ｐＨ７．０；Ｂ＝ＡＣＮ。方法：１０〜８０Ｂ％（２０分））に直接充填し、２．３ｍｇ（５．８％）のＥＣ２４５１を淡黄色固体として得た。選択的^１Ｈ ＮＭＲ（５００ＭＨｚ、２９８Ｋ、Ｄ_２Ｏ）δ ８．６８８（ｓ、１Ｈ）、７．６９９（ｄ、Ｊ＝８．０Ｈｚ、２Ｈ）、７．１４４（ｓ、１Ｈ）、６．８４１（ｂ、３Ｈ）、６．７４６（ｓ、１Ｈ）、６．４９７（ｓ、１Ｈ）。ＭＳ⁻（ＥＳＩ ｍ／２ｚ）Ｃ_１１７Ｈ_１６１Ｎ_２４Ｏ_５３Ｓ_２の計算値：１４０７．０１；実測値１４０７．６９。

TEA (19.0 μL) was added to a solution of EC2322 (8.4 mg), EC2446 (8.4 mg) and PyBOP (7.5 mg) in anhydrous DMF (3.0 mL) and the solution was placed under argon at ambient temperature 60. Stir for minutes. The buffer solution _{EC1579 (25.3mg) (50mM NH 4} HCO 3, pH7.0,6.0mL) was added under argon, the reaction mixture was stirred at ambient temperature for 20 minutes. It was then directly loaded onto a preparative HPLC (mobile phase A: 50 mM NH ₄ HCO ₃ buffer, pH 7.0; B=ACN. Method: 10-80 B% (20 min)) for purification and 2.3 mg (5 0.8%) of EC2451 was obtained as a pale yellow solid. Selective ¹ H NMR (500 MHz, 298 K, D ₂ O) δ 8.688 (s, 1 H), 7.699 (d, J=8.0 Hz, 2 H), 7.144 (s, 1 H), 6. 841 (b, 3H), 6.746 (s, 1H), 6.497 (s, 1H). ^{_{MS - (ESI m / 2z)}} C 117 H 161 N 24 O 53 S 2 Calculated: 1407.01; Found 1407.69.

ＥＣ２４６１（１０．４ｍｇ）をＴＦＡ（０．３０ｍＬ）およびＤＣＭ（１．１ｍＬ）の溶液に溶解し、環境温度で３０分間撹拌し、濃縮し、ＤＣＭで共沸（２ｍＬ×３）させ、真空下で６０分間乾燥させた。残渣を無水ＤＭＦ（３．０ｍＬ）に溶解し、これにＥＣ２３２２（９．３ｍｇ）およびＰｙＢＯＰ（８．１ｍｇ）、続いてＴＥＡ（２１．０μＬ）を添加した。アルゴン下、反応混合物を環境温度で２５分間撹拌し、ＤＭＦ（１．５ｍＬ）で希釈し、ＥＣ１５７９（３２．１ｍｇ）の緩衝液（５０ｍＭ ＮＨ_４ＨＣＯ_３、ｐＨ７．０、５．０ｍＬ）を添加した。アルゴン下、得られた均一な溶液を環境温度で１０分間撹拌し、精製のために分取ＨＰＬＣ（移動相Ａ：５０ｍＭ ＮＨ_４ＨＣＯ_３緩衝液、ｐＨ７．０；Ｂ＝ＡＣＮ。方法：５〜５０Ｂ％（２０分））に直接充填し、７．３ｍｇ（１８％）のＥＣ２４６４を淡黄色固体として得た。選択的^１Ｈ ＮＭＲ（５００ＭＨｚ、２９８Ｋ、Ｄ_２Ｏ）δ ８．６２３（ｓ、１Ｈ）、７．６６６（ｂ、２Ｈ）、７．０８９（ｓ、１Ｈ）、６．７８０（ｂ、３Ｈ）、６．６８７（ｓ、１Ｈ）、６．４９２（ｂ、２Ｈ）。ＭＳ⁻（ＥＳＩ ｍ／２ｚ）Ｃ_１１５Ｈ_１６１Ｎ_２４Ｏ_４９Ｓ_２の計算値：１３６３．０２；実測値１３６３．７９。

EC2461 (10.4 mg) was dissolved in a solution of TFA (0.30 mL) and DCM (1.1 mL), stirred at ambient temperature for 30 minutes, concentrated, azeotroped with DCM (2 mL x 3) and under vacuum. And dried for 60 minutes. The residue was dissolved in anhydrous DMF (3.0 mL), to which EC2322 (9.3 mg) and PyBOP (8.1 mg) were added, followed by TEA (21.0 μL). The reaction mixture was stirred at ambient temperature for 25 minutes under argon, diluted with DMF (1.5 mL) and EC1579 (32.1 mg) in buffer (50 mM NH ₄ HCO ₃ , pH 7.0, 5.0 mL) was added. did. The resulting homogeneous solution was stirred under argon for 10 min at ambient temperature and preparative HPLC for purification (mobile phase A: 50 mM NH ₄ HCO ₃ buffer, pH 7.0; B=ACN. Method: 5 50 B% (20 min)) directly to give 7.3 mg (18%) of EC2464 as a pale yellow solid. Selective ¹ H NMR (500 MHz, 298 K, D ₂ O) δ 8.623 (s, 1 H), 7.666 (b, 2 H), 7.089 (s, 1 H), 6.780 (b, 3 H) , 6.687 (s, 1H), 6.492 (b, 2H). ^{_{MS - (ESI m / 2z)}} C 115 H 161 N 24 O 49 S 2 Calculated: 1363.02; Found 1363.79.

アルゴン下、マレイミドエタノール（０．６５５ｍｇ、４．６４ｍＭ）の乾燥ＤＣＭ（５ｍＬ）溶液に、ｐ−ニトロフェニルクロロホルメート（１．１２ｇ、５．５６ｍＭ）およびＤＩＰＥＡ（１．１３ｍＬ、６．５０ｍＭ）をそれぞれ添加した。反応液を室温で１８時間撹拌した。ＴＬＣ分析（塩化メチレン中５％メタノール）は、反応が完結したことを示した。反応混合物を濃縮し、ＣｏｍｂｉＦｌａｓｈ（ＳｉＯ_２）カラムを使用して、石油エーテル中０〜１００％ ＥｔＯＡｃで溶出して精製し、純粋なＥＣ２４７４（０．７８ｇ、５５％）を得た。^１Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ_３）：δ ８．２８（ｄ、Ｊ_１＝９．０Ｈｚ、２Ｈ）、７．４１（（ｄ、Ｊ_１＝９．０Ｈｚ、２Ｈ））、６．７７（ｓ、２Ｈ）、４．４１（ｔ、Ｊ_１＝４．５Ｈｚ、Ｊ_２＝５．５Ｈｚ、２Ｈ）、３．９５（ｔ、Ｊ_１＝４．５Ｈｚ、Ｊ_２＝５．５Ｈｚ、２Ｈ）；^１３ＣＮＭＲ（５００ＭＨｚ、ＣＤＣｌ_３）：δ １７０．３７、１５５．４０、１５２．４０、１４５．５９、１３４．３６、１２５．３２、１２１．９９、６６．１５、３６．３５

P-Nitrophenyl chloroformate (1.12 g, 5.56 mM) and DIPEA (1.13 mL, 6.50 mM) in a solution of maleimide ethanol (0.655 mg, 4.64 mM) in dry DCM (5 mL) under argon. Were added respectively. The reaction was stirred at room temperature for 18 hours. TLC analysis (5% methanol in methylene chloride) showed the reaction was complete. The reaction mixture was concentrated and purified using a CombiFlash(SiO ₂ ) column eluting with 0-100% EtOAc in petroleum ether to give pure EC2474 (0.78 g, 55%). ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.28 (d, J ₁ =9.0 Hz, 2H), 7.41 ((d, J ₁ =9.0 Hz, 2H)), 6.77 (s) 2H), 4.41 (t, J ₁ =4.5 Hz, J ₂ =5.5 Hz, 2H), 3.95 (t, J ₁ =4.5 Hz, J ₂ =5.5 Hz, 2H); ¹³ CNMR (500 MHz, CDCl ₃ ): δ 170.37, 155.40, 152.40, 145.59, 134.36, 125.32, 121.99, 66.15, 36.35.

アルデヒド（１５８ｍｇ、０．７５ｍＭ）の乾燥ＤＣＭ（２ｍＬ）溶液に、ＭｇＳＯ_４（７９ｍｇ）およびエタノールアミン（６７．８３μＬ、１．１３ｍＭ）をそれぞれ添加した。反応物を１時間撹拌した。別のフラスコで、ＥＣ２４７４（４５９ｍｇ、１．５ｍＭ）を乾燥ＤＣＭ（２ｍＬ）に溶解し、トリエチルアミン（０．３１４ｍＬ、２．２５ｍＭ）を添加した。上記（工程１）の反応混合物をこの溶液にゆっくりと添加し、２０時間撹拌した。ＬＣＭＳ分析（２０ｍＭ ＮＨ_４ＨＣＯ_３、ｐＨ７．４）は、反応が完結したことを示した（質量のみ、ＵＶなし）。ＴＬＣ分析（石油エーテル中５０％ＥｔＯＡｃ）は、反応が完結したことを示した。反応混合物を濃縮し、ＣｏｍｂｉＦｌａｓｈ（ＳｉＯ_２）カラムを使用して、石油エーテル中０〜５０％ＥｔＯＡｃで溶出し、純粋なＥＣ２４７５（１５８ｍｇ、５０％）を得た。^１Ｈ ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ_３）： δ ６．７２（ｓ、２Ｈ）、４．８５−５．３０（ｍ、３Ｈ）、３．９５−４．２５（ｍ、５Ｈ）、３．７０−３．９５（ｍ、５Ｈ）、３．２５（ｂｒｓ、１Ｈ）、２．４０−２．８５（ｍ、２Ｈ）、１．４１（ｓ、９Ｈ）；ＬＣＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）^＋＝の計算値Ｃ_２０Ｈ_２７Ｎ_３Ｏ_７、４２２．１８；実測値４２２．３９

To a solution of aldehyde (158 mg, 0.75 mM) in dry DCM (2 mL) was added MgSO ₄ (79 mg) and ethanolamine (67.83 μL, 1.13 mM), respectively. The reaction was stirred for 1 hour. In a separate flask, EC2474 (459 mg, 1.5 mM) was dissolved in dry DCM (2 mL) and triethylamine (0.314 mL, 2.25 mM) was added. The reaction mixture from (Step 1) above was added slowly to this solution and stirred for 20 hours. LCMS analysis _{(20mM NH 4 HCO 3, pH7.4} ) indicated that the reaction was complete (by weight only, without UV). TLC analysis (50% EtOAc in petroleum ether) showed the reaction was complete. The reaction mixture was concentrated, using a CombiFlash (SiO ₂₎ column, eluting with petroleum ether 0 to 50% EtOAc, to afford the pure EC2475 (158mg, 50%). ¹ H NMR (500 MHz, CDCl ₃ ): δ 6.72 (s, 2H), 4.85-5.30 (m, 3H), 3.95-4.25 (m, 5H), 3.70- 3.95 (m, 5H), 3.25 (brs, 1H), 2.40-2.85 (m, 2H), 1.41 (s, 9H); LCMS (ESI): (M+H) ⁺ = Calcd for C ₂₀ H ₂₇ N ₃ O ₇ , 422.18; Found 422.39.

ＥＣ２４７５（１０．０ｍｇ、０．０２５ｍＭ）をＴＦＡ／ジクロロメタン／ＴＩＰＳ（１．０ｍＬ／１．０ｍＬ／０．０６ｍＬ）の混合物で処理し、３０分間撹拌した。ＬＣＭＳ分析（２０ｍＭ ＮＨ_４ＨＣＯ_３、ｐＨ７．４）は、反応が完結したことを示した。反応混合物を濃縮乾固し、ＤＣＭで共沸（３回）させ、高真空下で１時間乾燥させ、ＥＣ２４７６を得た。別のフラスコで、ＥＣ２３２２（１３ｍｇ、０．０２ｍＭ）を乾燥ＤＭＦ（１ｍＬ）に溶解した。ＰｙＢｏｐ（１１ｍｇ、０．０２ｍＭ）およびＴＥＡ（２９．５μＬ、０．２１ｍＭ）をそれぞれ添加した。５分間撹拌し、（先に精製した）ＥＣ２４７６のＤＭＦ（１ｍＬ）溶液を添加し、１時間撹拌した。ＬＣＭＳ分析（２０ｍＭ ＮＨ_４ＨＣＯ_３、ｐＨ７．４）は生成物であるＥＣ２４７７が形成されたことを示した。ＥＣ１５７９（５０ｍｇ、０．０３ｍＭ）のリン酸緩衝液（２ｍＬ）を添加し、１時間撹拌した。ＬＣＭＳ分析（２０ｍＭ ＮＨ_４ＨＣＯ_３、ｐＨ７．４）は、生成物の形成を示した。反応混合物を分取ＨＰＬＣ（２０ｍＭ ＮＨ_４ＨＣＯ_３中５〜８０％アセトニトリル、ｐＨ７．４）で精製し、純粋なＥＣ２４７８（７．５ｍｇ、１２％）を得た。^１Ｈ ＮＭＲ（５００ＭＨｚ、ＤＭＳＯ−Ｄ_６＋Ｄ_２Ｏ）（選択データ）：δ ８．６０（ｓ、１Ｈ）、７．５６（ｄ、Ｊ＝８．０Ｈｚ、２Ｈ）、６．９４（ｓ、１Ｈ）、６．６０（ｄ、Ｊ＝８．５Ｈｚ、２Ｈ）、６．６０（ｓ、１Ｈ）、６．４９（ｓ、１Ｈ）、６．２８（ｂｒｓ、１Ｈ）、５．０６（ｓ、１Ｈ）、５．０１（ｓ、１Ｈ）、４．９０（ｍ、２Ｈ）、４．４５（ｓ、４Ｈ）；ＬＣＭＳ（ＥＳＩ）：［Ｍ−２Ｈ］^２−＝Ｃ_１０７Ｈ_１４８Ｎ_２２Ｏ_４８Ｓ_２の計算値、１２８６．２８；実測値１２８６．３１。

EC2475 (10.0 mg, 0.025 mM) was treated with a mixture of TFA/dichloromethane/TIPS (1.0 mL/1.0 mL/0.06 mL) and stirred for 30 minutes. LCMS analysis _{(20mM NH 4 HCO 3, pH7.4} ) indicated that the reaction was complete. The reaction mixture was concentrated to dryness, azeotroped with DCM (3 times) and dried under high vacuum for 1 hour to give EC2476. In a separate flask, EC2322 (13 mg, 0.02 mM) was dissolved in dry DMF (1 mL). PyBop (11 mg, 0.02 mM) and TEA (29.5 μL, 0.21 mM) were added respectively. Stir for 5 minutes, add a solution of EC2476 (previously purified) in DMF (1 mL) and stir for 1 hour. LCMS analysis _{(20mM NH 4 HCO 3, pH7.4} ) showed that the product EC2477 was formed. EC1579 (50 mg, 0.03 mM) in phosphate buffer (2 mL) was added and stirred for 1 hour. LCMS analysis _{(20mM NH 4 HCO 3, pH7.4} ) showed formation of the product. Preparative reaction mixture was purified by HPLC (20mM _NH 4 HCO ₃ in 5% to 80% acetonitrile, pH 7.4) to give the pure EC2478 (7.5mg, 12%). ¹ H NMR (500 MHz, DMSO-D ₆ +D ₂ O) (selection data): δ 8.60 (s, 1H), 7.56 (d, J=8.0 Hz, 2H), 6.94 (s, 1H), 6.60 (d, J=8.5 Hz, 2H), 6.60 (s, 1H), 6.49 (s, 1H), 6.28 (brs, 1H), 5.06 (s , 1H), 5.01 (s, 1H), 4.90 (m, 2H), 4.45 (s, 4H); LCMS (ESI): [M-2H] ² -=C ₁₀₇ H ₁₄₈ N _22. calculated O ₄₈ S _2, 1286.28; Found 1286.31.

The following examples are also described herein. The groups in these examples should be understood to be included in PBD prodrugs, poly-PBD prodrugs, mixed PBDs, conjugates and conjugates described herein.

The following PBD prodrug, poly-PBD prodrug or mixed PBD conjugates are described herein. The conjugate is manufactured according to the processes described herein and conventional processes.

Method examples in general. The following abbreviations are used here: partial response (PR); complete response (CR), biweekly (M/F) (BIW), three times weekly (M/W/F) (TIW). PR is observed when the tumor volume, as defined herein, decreases from the previous height during the observation period, although regrowth can occur. CR is observed when the tumor volume, as defined herein, decreases to 0 during the observation period, although regrowth can occur. Healing is observed when the tumor volume, as defined herein, decreases to 0 during the observation period and does not repopulate during the observation period.

Method. Relative affinity assay. The affinity for folic acid receptor (FR) for folic acid was slightly modified by the method described previously (Westerhof, GR, JH Schornagel, et al. (1995) Mol. Pharm. 48: 459-471). Decided. FR-positive KB cells were heavily seeded in 24-well cell culture plates and allowed to adhere to plastic for 18 hours. Spent incubation medium was replaced with 100 nM ³ H-folate-free folate-free RPMI (FFRPMI) in the absence of test articles or folic acid and increasing concentrations of these in planned wells. The cells were incubated for 60 minutes at 37°C and then washed 3 times with PBS, pH 7.4. 500 microliters of 1% SDS in PBS, pH 7.4 solution was added per well. Cell lysates were then harvested and added to individual vials containing 5 mL scintillation cocktail and then counted for radioactivity. Negative control tubes contained only ³ H-folate in FF RPMI (no competitor). Positive control tubes contained a final concentration of 1 mM folic acid and the CPM (representing non-specific binding of label) measured in these samples was subtracted from all samples. Relative affinity was defined as the inverse molar ratio of compound required to displace 50% of ³ H-folate binding to FRs on KB cells.

An example. The conjugates described herein have a high binding affinity for the folate receptor as determined by an in vitro competitive binding assay that measures the ability of the ligand to compete with ³ H-folate for binding to the cell surface folate receptor (FR). showed that. Without being bound by theory, it is believed that the high binding affinity of the conjugates described herein allows for efficient cellular uptake via FR-mediated endocytosis.

Method. Inhibition of cellular DNA synthesis. The conjugates described herein were used in in vitro cytotoxicity assays that predict the drug's ability to inhibit growth of corresponding target cells, such as, but not limited to:

It is believed that selection of cell type may be based on the sensitivity of the selected cells to the drug forming the conjugate and the relative expression of cell surface receptors or target antigens. The test conjugate was a conjugate of PBD prodrug, poly-PBD prodrug and mixed PBD with a cell surface receptor or target antigen binding compound described herein. The test cells are optionally in the absence of at least a 100-fold excess of unconjugated cell surface receptor or target antigen binding compound for competition studies to assess activity that is specific to the cell surface receptor or target antigen. Or exposed to various concentrations of conjugate in the presence.

An example. The conjugates of PBD prodrug, poly-PBD prodrug and mixed PBD described herein were active on KB cells. Activity was mediated by the folate receptor as shown by competition experiments using folate co-administration. KB cells were exposed to folic acid-drug conjugates at the indicated concentrations for up to 7 hours at 37°C in the absence or presence of at least a 100-fold excess of folic acid. The cells were then rinsed once with fresh culture medium and incubated with fresh culture medium for 72 hours at 37°C. Cell viability was assessed using the ³ H-thymidine incorporation assay. For the conjugates described herein, dose-dependent cytotoxicity is generally measurable and in most cases IC ₅₀ values (reducing ³ H-thymidine incorporation into newly synthesized DNA by 50%. The drug conjugate concentration required) was in the nanomolar range. Without being bound by theory, if the cytotoxicity of the conjugate was reduced in the presence of excess free folic acid, such a result would indicate that the observed cell death was mediated by binding to the folate receptor. Think here.

(A) A method of co-administration with dithiothreitol (DTT). In vitro activity against various cancer cell lines. It created IC ₅₀ values for various cell lines. Cells were heavily seeded in 24-well Falcon plates and allowed to form nearly confluent monolayers overnight. Thirty minutes before the addition of the test compound, the spent medium was aspirated from all wells and replaced with fresh folate-deficient RPMI medium (FFRPMI). Some wells were designated to receive medium containing 100 μM folic acid. Targeting specificity was determined using cells in designated wells. Without being bound by theory, the cytotoxic activity produced by a test compound in the presence of excess folate, ie, in the presence of competition for FR binding, corresponds to a portion of the total activity unrelated to FR-specific delivery and is considered here. .. After rinsing once with 1 mL of fresh FF RPMI containing 10% heat-inactivated fetal bovine serum, 1 mL of medium (4 wells/sample) containing increasing concentrations of test compound was added to each well in the presence of 100 μM free folic acid as indicated. Or added in the absence. Treated cells were pulsed for 2 hours at 37° C., rinsed 4 times with 0.5 mL medium and then chased with 1 mL fresh medium for up to 70 hours. Spent medium was aspirated from all wells and replaced with fresh medium containing 5 μCi/mL ³ H-thymidine. After a further 2 hours of incubation at 37° C., cells were washed 3 times with 0.5 mL PBS and then treated with 0.5 mL ice-cold 5% trichloroacetic acid per well. After 15, trichloroacetic acid was aspirated and the cell material was solubilized by adding 0.5 mL of 0.25N sodium hydroxide for 15 minutes. 450 μL of each solubilized sample was transferred to a scintillation vial containing 3 mL of Ecolume scintillation cocktail and then counted in a liquid scintillation counter. Final results were expressed as percent of ³ H-thymidine incorporation relative to untreated control.

Method. Tumor growth inhibition in mice. 4-7 week old mice (Balb/c or nu/nu strains) were purchased from Harlan Sprague Dawley, Inc. (Indianapolis, IN). Normal rodent chow contains a high concentration of folic acid (6 mg/kg chow), therefore test animals were placed approximately 1 week before tumor implantation to achieve serum folate levels close to the range of normal human serum. And during the method, they were fed a folate-free diet (Harlan diet #TD00434). Regarding tumor cell inoculation, 1×10 ⁶ M109 cells (syngeneic lung carcinoma) were applied to Balb/c strain or 1×10 ⁶ KB cells were applied to nu/nu strain, and 100 μL was applied to subcutaneous tissue in the central back region (right axilla). I made an injection. Tumors were measured every 2-3 days in two vertical directions using a caliper and the volume was 0.5×L×W ² (L=longest axis measurement mm and W=axis measurement perpendicular to L mm). Calculated). Then, logarithmic cell killing (LCK) and treatment versus control (T/C) values were calculated according to published methods (eg, Lee et al., “BMS-247550: a novel epothilone analog with a mode of action similar to. paclitaxel but possessing superior antitumor efficacy” Clin Cancer Res 7:1429-1437 (2001); Rose, “Taxol-based combination chemotherapy and other in vivo preclinical antitumor studies” J Natl Cancer Inst Monogr 47-53 (1993)).

Dosing started typically 8 days post tumor inoculation (PTI) for KB tumors and 11 days PTI for M109 tumors when the subcutaneous tumors had an average volume of 50-100 mm ³ (t ₀ ). Test animals (5/group) were generally dosed three times a week (TIW), three weeks, for 3 weeks at various doses, eg, 1 μmol/kg to 5 μmol/kg drug delivery conjugates or equivalent dose volumes, unless otherwise noted. PBS (control) was injected intravenously. Dosing solutions were prepared fresh in PBS each day and administered via the lateral tail vein of mice.

Method. General 4T-1 tumor assay. 6-7 week old mice (female Balb/c strain) were obtained from Harlan, Inc. (Indianapolis, IN). Prior to and during the start of the method, the mice were bred for a total of 3 weeks on Harlan's folate-free chow. Folate receptor negative 4T-1 tumor cells (1×10 ⁶ cells/animal) were inoculated into the subcutaneous tissue of the right axilla. Approximately 5 days after tumor inoculation, when the 4T-1 tumor average volume reached approximately 100 mm ³ (t ₀ ), mice (5/group) were treated with various doses, eg, 3 μmol/kg of drug delivery conjugate, unless otherwise indicated. Or an equivalent volume of PBS (control) was injected iv three times a week (TIW) for three weeks. Tumor growth was measured with calipers at 2 or 3 day intervals in each treatment group. Tumor volume was calculated using the formula V=a×b ² /2, where “a” is tumor length and “b” is width, expressed in mm.

Method. Drug toxicity. Continuous drug toxicity was collected by cardiac puncture, and serum was added to blood urea nitrogen (BUN), creatinine, total protein, AST-SGOT, ALT-SGPT at Ani-Lytics, Inc. (Gaithersburg, MD). , Were evaluated by subjecting them to an independent analysis of a standard hematological cell panel. In addition, histopathological evaluation of formalin-fixed heart, lung, liver, spleen, kidney, intestine, skeletal muscle and bone (tibia/fibula) at Animal Reference Pathology Laboratories (ARUP; Salt Lake City, Utah). Performed by a recognized pathologist.

Method. Toxicity as measured by weight loss. The percent weight change of the test animals was determined after tumor inoculation (PTI) and on selected days during dosing. The results are graphed.

Example. In vivo activity against tumors. The conjugates described herein showed high efficacy and efficacy against KB tumors in nu/nu mice. The conjugates described herein showed specific activity against tumor-expressing folate receptors with low host animal toxicity.

Example. EC1629 in vivo activity against tumor. As shown in FIG. 1, EC1629 (♦) administered at 2 μmol/kg TIW for 2 weeks reduced KB tumors in test animals compared to untreated controls (●). No toxicity was observed as indicated by the total body weight of the test animals.

Example. EC1744 and EC1788 in vivo activity against tumors. As shown in FIG. 2, EC1744 (■) administered at 2 μmol/kg TIW for 2 weeks and EC1788 (▲) administered at 0.2 μmol/kg TIW for 2 weeks were compared to untreated controls (●). KB tumors in. In addition, EC1788 produced a complete response. No toxicity was observed with EC1744 as indicated by the total body weight of the test animals. Slight toxicity was shown by EC1788 as indicated by total body weight of test animals, however, total body weight of test animals increased steadily after the last dosing day.

Example. EC1884, EC1879 and EC1788 in vivo activity against tumors. As shown in FIG. 3, EC1884 (d) administered at 2 μmol/kg TIW for 2 weeks reduced KB tumors in test animals compared to untreated controls (a). No toxicity was observed with EC1884 as indicated by the total body weight of the test animals. FIG. 3 also showed that EC1879 (c) administered at 2 μmol/kg TIW for 1 week reduced KB tumors in test animals compared to untreated controls (a). In addition, EC1879 produced a partial response. A slight toxicity was observed as indicated by the total body weight of the test animals. FIG. 3 also shows that EC1788 (b) administered at 0.4 μmol/kg BIW for 2 weeks reduced KB tumors in test animals compared to untreated controls (a). In addition, EC1788 produced a complete response and cure. A slight toxicity was observed with EC1788, as indicated by total body weight of test animals, however, total body weight of test animals increased after the last dosing day.

Example. EC1879 in vivo activity against tumor. As shown in FIG. 4, EC1879 (A) administered at 2 μmol/kg TIW for 2 weeks reduced KB tumors in test animals compared to untreated controls (A). In addition, EC1879 produced a complete response in 5/5 test animals and a cure in 5/5 test animals. No toxicity was observed for EC1879, as indicated by the total body weight of the test animals.

Example method. TNBC tumor assay.
Triple-negative breast cancer (TNBC) is a subtype characterized by lack of gene expression of estrogen, progesterone and Her2/neu.
TNBC is difficult to treat, and the resulting patient mortality has been reported to be disproportionately higher than any other subtype of breast cancer. A TNBC xenograft model was created by transplanting MDA-MB-231 breast cancer cells into nu/nu mice according to the KB and M109 models described herein. Dosing was typically initiated 17 days after tumor inoculation (PTI) when the subcutaneous tumors had an average volume of 110-150 (generally 130) mm ³ (t ₀ ). Test animals (5/group) were dosed with various doses, for example 1 μmol/kg to 5 μmol/kg drug delivery conjugates or equivalent dose volumes of PBS (control), generally three times weekly unless otherwise noted. (TIW), injected intravenously for 2-3 weeks. Dosing solutions were prepared fresh in PBS each day and administered via the lateral tail vein of mice.

Example. EC1744 in vivo activity against tumor. As shown in FIG. 5, EC1744 (◆) administered at 2 μmol/kg TIW for 2 weeks reduced triple negative breast cancer (TNBC) MDA-MB-231 tumors in test animals compared to untreated controls (■). It was In addition, EC1744 produced a complete response in 5/5 test animals and a cure in 4/5 test animals. No toxicity was observed with EC1744 as indicated by the total body weight of the test animals.

Method. Human cisplatin resistant cell line. A human cisplatin resistant cell line was produced by culturing FR positive KB cells in the presence of cisplatin concentrations (100→2000 nM; >12 months). Cisplatin resistant cells labeled KB-CR2000 cells were found to be tumorigenic and maintain their FR expression status in vivo. KB-CR2000 tumors were confirmed to be resistant to cisplatin treatment. High, toxic doses of cisplatin (mean weight loss 10.3%) did not even result in a single partial response (PR).

Method. Human serum stability. The conjugates described herein can be tested in human serum for stability using conventional protocols and methods. The test compound may be administered to the test animal by, for example, subcutaneous injection. The plasma concentration of the conjugate and optionally one or more metabolites can be monitored over time. Results can be graphed to determine Cmax, Tmax, half-life and AUC of test compounds and metabolites.

Method.
Plasma clearance. In vivo studies include a minimum of 3 test animals per time point, eg rats. Specifically, female Lewis rats (Harlan, normal rodent diet) equipped with a jugular vein catheter may be given a single subcutaneous injection of test compound. Whole blood samples (300 μL) can be taken at the following time points: 1 minute, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours and 12 hours post injection. Blood samples were placed in anticoagulant tubes containing 1.7 mg/mL K ₃ -EDTA and 0.35 mg/mL N-maleoyl-β-alanine (0.35 mg/mL) in 0.15% acetic acid solution. You can Plasma samples can be obtained by centrifugation at about 2,000 g for 3 minutes and stored at -80°C. The amount of test compound and any metabolites in plasma were quantified by LC-MS/MS.

Claims (50)

Formula ^{_{B- (AA) z1 -L 2 -}} (L 3) z2 - (AA) z3 - (L 1) z4 - (L 4) z5 -D 1 -L 5 -D 2,
^{_{B- (AA) z10 -L 2 -D}} 2,
^{_{B- (AA) z11 -L 2 -D}} 1 -L 5 -D 1 -L 2 - (AA) z12 -B or ^{B-L 1 -AA-L 1} -AA-L 1 -L 2 - (L 3 _{^{) z6 - (L 4) z7}} - (AA) z8 - (L 4) z9 -D 1 -L 5 -D 2,
[In the formula,
Each z1, z10, z11 and z12 is independently 2, 3, 4 or 5;
z2 is 0, 1 or 2;
z3 is 0, 1, 2, 3 or 4;
z4 is 0, 1 or 2; and z5 is 0, 1 or 2 and z6 is 0, 1 or 2;
z7 is 0, 1 or 2;
z8 is 0, 1, 2, 3 or 4;
z9 is 0, 1 or 2;
B is the formula I

(In the formula,
In each case, R ¹ and R ² are independently H, D, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, —OR ⁷ , —SR ⁷ and —NR. ⁷ R ^7′ selected from the group consisting of, wherein each hydrogen atom in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl is, independently, optionally halogen, —OR ^{8, -SR 8, -NR 8 R} 8 may be substituted by ^{', -C (O) R 8} , -C (O) oR 8 or ^{-C (O) NR 8 R 8} ';
R ^{3, R} 4, ^{R 5} and ^{R 6,} H independently, D, _halogen, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl, -CN, -NO ₂ , selection ^{-NCO, -OR 9, -SR 9,} -NR 9 R 9 from a group consisting of ^{', -C (O) R 9} , -C (O) oR 9 and ^{-C (O) NR 9 R 9} ' Where each hydrogen atom in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl is independently, optionally, halogen, —OR ¹⁰ , —SR ¹⁰ , —NR ^{10. R 10 ', -C (O)} R 10, -C (O) oR 10 or ^{-C (O) NR 10 R 10} ' may be substituted by;
^{R 7, R 7 ', R} 8, R 8', R 9, R 9 ', R 10 and ^{R 10'} is, H _{independently, D,} C 1 ~C _{6 alkyl,} C 2 -C ₆ alkenyl Or C ₂ -C ₆ alkynyl;
X ¹ is ^{-NR 11 -, = N -,} - N =, - C (R 11) = or = C ^{(R 11)} - a and;
X ² is -NR ^{11 '-} or = a N-;
X ³ is ^{-NR 11 '' -, - N} = or -C ^{(R 11 ')} = a and;
X ⁴ is -N= or -C=;
X ⁵ is NR ¹² or CR ¹² R ^12′ ;
When X ¹ is -N= or -C(R ¹¹ )=, Y ¹ is H, D, -OR ¹³ , -SR ¹³ or -NR ¹³ R ^13' , or X ¹ is -NR ¹¹ -, When =N- or =C(R ¹¹ )-, Y ¹ is =O;
When X ⁴ is -C = a, ^{Y 2} is _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C ₆ ^{alkenyl, -C (O) R 14,} -C (O) OR 14, -C (O ) a ^{NR 14 R} 14 ^', or when ^{X 4} is -N =, ^{Y 2} is absent;
R ¹¹ , R ^11′ , R ^11″ , R ¹² , R ^12′ , R ¹³ , R ^13′ , R ¹⁴ and R ^14′ are each independently H, D, C ₁ -C ₆ alkyl, − Selected from the group consisting of C(O)R ¹⁵ , —C(O)OR ¹⁵ and —C(O)NR ¹⁵ R ^15′ ;
R ¹⁵ and R ^15′ are each independently H or C ₁ -C ₆ alkyl;
m is 1, 2, 3 or 4)
Of that;
AA is an amino acid;
L ¹ is the formula II

(In the formula,
_{^{R 16 H, D, C 1}} ~C 6 _alkyl, C 2 -C _{6 alkenyl,} C 2 -C ₆ ^{alkynyl, -C (O) R 19,} -C (O) OR 19 and -C (O) ^{NR 19} Each hydrogen atom in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl selected from the group consisting of R ^19′ independently, optionally halogen, C ₁ -. C _{6 alkyl,} C 2 -C ₆ alkenyl, and _C 2 -C ₆ ^{alkynyl, -OR 20, -OC (O)} R 20, -OC (O) NR 20 R 20 ', -OS (O) R 20, ^{_{-OS (O) 2 R 20,}} -SR 20, -S (O) R 20, -S (O) 2 R 20, -S (O) NR 20 R 20 ', -S (O) 2 NR 20 R ^{20 ', -OS (O) NR} 20 R 20', -OS (O) 2 NR 20 R 20 ', -NR 20 R 20', -NR 20 C (O) R 21, -NR 20 C (O) ^{OR 21, -NR 20 C (O} ) NR 21 R 21 ', -NR 20 S (O) R 21, -NR 20 S (O) 2 R 21, -NR 20 S (O) NR 21 R 21', ^{_{-NR 20 S (O) 2 NR}} 21 R 21 may be substituted by ^{', -C (O) R 20} , -C (O) oR 20 or ^{-C (O) NR 20 R 20} ';
R ¹⁷ and ^{R 17 'is,} H independently, D, _halogen, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 22, -OC (O)} R 22, -OC (O) NR 22 R 22 ', -OS (O) R ^{_{22, -OS (O) 2 R}} 22, -SR 22, -S (O) R 22, -S (O) 2 R 22, -S (O) NR 22 R 22 ', -S (O) 2 NR ^{22 R 22 ', -OS (O} ) NR 22 R 22', -OS (O) 2 NR 22 R 22 ', -NR 22 R 22', -NR 22 C (O) R 23, -NR 22 C ( ^{O) OR 23, -NR 22 C} (O) NR 23 R 23 ', -NR 22 S (O) R 23, -NR 22 S (O) 2 R 23, -NR 22 S (O) NR 23 R 23 ^{_{', -NR 22 S (O)}} 2 NR 23 R 23', are selected from the group consisting of ^{-C (O) R 22, -C} (O) oR 22 and ^{-C (O) NR 22 R 22} ', wherein in _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5- to 7-membered each hydrogen atom in the ring heteroaryl is independently optionally _halogen, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ ^{alkynyl, -OR 24, -OC (O)} R 24 , -OC(O)NR ²⁴ R ^24' , -OS(O)R ²⁴ , -OS(O) ₂ R ²⁴ , -SR ²⁴ , -S(O)R ²⁴ , -S(O) ₂ R ²⁴ , ^{-S (O) NR 24 R 24} ', -S (O) 2 NR 24 R 24', -OS (O) NR 24 R 24 ', -OS (O) 2 NR 24 R 24', -NR 24 R ^{24 ', -NR 24 C (O} ) R 25, -NR 24 C (O) OR 25, -NR 24 C (O) NR 25 R 25', -NR 24 S (O) R 25, -NR 24 S (O) ₂ R ²⁵ , -NR ²⁴ S(O)NR ^{25 _{R 25 ', -NR 24 S (}} O) 2 NR 25 R 25', -C (O) R 24, may be replaced by -C (O) ^{OR 24} or ^{-C (O) NR 24 R 24} ' Or R ¹⁷ and R ^17′ may be joined to form a C ₄ -C ₆ cycloalkyl or a 4-6 membered heterocycle, wherein each in the C ₄ -C ₆ cycloalkyl or 4-6 membered heterocycle hydrogen atoms are independently optionally _halogen, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl , C ₆ -C ₁₀ aryl, 5 to 7-membered heteroaryl, —OR ²⁴ , —OC(O)R ²⁴ , —OC(O)NR ²⁴ R ^24′ , —OS(O)R ²⁴ , —OS( ^{_{O) 2 R 24, -SR 24}} , -S (O) R 24, -S (O) 2 R 24, -S (O) NR 24 R 24 ', -S (O) 2 NR 24 R 24', ^{-OS (O) NR 24 R 24} ', -OS (O) 2 NR 24 R 24', -NR 24 R 24 ', -NR 24 C (O) R 25, -NR 24 C (O) OR 25, ^{-NR 24 C (O) NR 25} R 25 ', -NR 24 S (O) R 25, -NR 24 S (O) 2 R 25, -NR 24 S (O) NR 25 R 25', -NR 24 ^{_{S (O) 2 NR 25 R}} 25 ', -C (O) R 24, -C (O) oR 24 or ^{-C (O) NR 24 R 24} ' may be substituted by;
R ¹⁸ is _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 26, -OC (O)} R 26, -OC (O) NR 26 R 26 ', -OS (O) R 26, -OS (O) 2 R 26, ^{_{-SR 26, -S (O) R}} 26, -S (O) 2 R 26, -S (O) NR 26 R 26 ', -S (O) 2 NR 26 R 26', -OS (O) NR _{^{26 R 26 ', -OS (O}} ) 2 NR 26 R 26', -NR 26 R 26 ', -NR 26 C (O) R 27, -NR 26 C (O) OR 27, -NR 26 C (O ^{) NR 27 R 27 ', -NR} 26 C (= NR 26'') NR 27 R 27', -NR 26 S (O) R 27, -NR 26 S (O) 2 R 27, -NR 26 S ( ^{O) NR 27 R} 27 consists of ^{_{', -NR 26 S (O)}} 2 NR 27 R 27', -C (O) R 26, -C (O) oR 26 and ^{-C (O) NR 26 R 26} ' is selected from the group, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} Each hydrogen atom in aryl and 5-7 membered heteroaryl is optionally halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -(CH ₂ ) _p OR ²⁸ , -(CH. _{2) p (OCH 2) q} OR 28, - (CH 2) p (OCH 2 CH 2) q OR 28, -OR 29, -OC (O) R 29, -OC (O) NR 29 R 29 ', ^{_{-OS (O) R 29, -OS}} (O) 2 R 29, - (CH 2) p OS (O) 2 OR 29, -OS (O) 2 OR 29, -SR 29, -S (O) R ^{_{29, -S (O) 2 R}} 29, -S (O) NR 29 R 29 ', -S (O) 2 NR 29 R 29', -OS (O) NR 29 R 29 ', -OS (O) ₂ NR ²⁹ R ^29' , -NR ^{29 R 29 ', -NR 29 C (} O) R 30, -NR 29 C (O) OR 30, -NR 29 C (O) NR 30 R 30', -NR 29 S (O) R 30, -NR 29 ^{_{S (O) 2 R 30,}} -NR 29 S (O) NR 30 R 30 ', -NR 29 S (O) 2 NR 30 R 30', -C (O) R 29, -C (O) OR 29 Or optionally substituted by -C(O)NR ²⁹ R ^29' ;
R ¹⁹ , R ^19′ , R ²⁰ , R ^20′ , R ²¹ , R ^21′ , R ²² , R ^22′ , R ²³ , R ^23′ , R ²⁴ , R ^24′ , R ²⁵ , R ^25′ , R ²⁶ , R ^26′ , R ^26″ , R ²⁹ , R ^29′ , R ³⁰ and R ^30′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ To C ₇ alkynyl, C _{3 to} C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl and 5 to 7 membered heteroaryl, where C _{1 to} C _{7 are selected. alkyl,} C 2 -C _{7 alkenyl,} each of C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, or 5-7 membered heteroaryl, hydrogen atoms are independently optionally halogen, -OH, -SH, it may be substituted by -NH ₂ or -CO ₂ H;
R ²⁷ and R ^27′ are each independently H, C ₁ -C ₉ alkyl, C ₂ -C ₉ alkenyl, C ₂ -C ₉ alkynyl, C ₃ -C ₆ cycloalkyl, —(CH ₂ ) _p ( _{sugar), - (CH 2) p} (OCH 2 CH 2) q - ( sugar) and _{- (CH 2) p (OCH} 2 CH 2 CH 2) is selected from the group consisting of _q (sugars);
R ²⁸ is H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C _10. Aryl, 5-7 membered heteroaryl or sugar;
n is 1, 2, 3, 4 or 5;
p is 1, 2, 3, 4 or 5;
q is 1, 2, 3, 4 or 5)
Is a linker of
L ² is a releasable linker;
L ³ is _C 1 -C ₆ ^{alkyl, - (CR 39 R 39 '} ) r C (O) -, - (CR 39 R 39') r OC (O) -, - NR 39 R 39 'C (O) _{^{(CR 39 R 39 ') r}} -, - (CH 2) r NR 39 -, - (OCR 39 R 39' CR 39 R 39 ') r C (O) - and ^{- (OCR 39 R 39' CR} 39 R ^{39 'CR 39 R 39')} - r C (O) - is selected from the group consisting of,
here,
R ³⁹ and R ^39′ are each independently H, D, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7. membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 40, -OC (O)} R 40, -OC (O) NR 40 R 40 ', -OS (O) R ^{_{40, -OS (O) 2 R}} 40, -SR 40, -S (O) R 40, -S (O) 2 R 40, -S (O) NR 40 R 40 ', -S (O) 2 NR ^{40 R 40 ', -OS (O} ) NR 40 R 40', -OS (O) 2 NR 40 R 40 ', -NR 40 R 40', -NR 40 C (O) R 41, -NR 40 C ( ^{O) OR 41, -NR 40 C} (O) NR 41 R 41 ', -NR 40 S (O) R 41, -NR 40 S (O) 2 R 41, -NR 40 S (O) NR 41 R 41 ^{_{', -NR 40 S (O)}} 2 NR 41 R 41', are selected from the group consisting of ^{-C (O) R 40, -C} (O) oR 40 and ^{-C (O) NR 40 R 40} ';
R ⁴⁰ , R ^40′ , R ⁴¹ and R ^41′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. Alkyl, 3-7 membered heterocycloalkyl, selected from the group consisting of C ₆ -C ₁₀ aryl and 5-7 membered heteroaryl; and r in each case is 1, 2, 3, 4 or 5;
L ⁴ represents ^{-C (O) (CR 44 R} 44 ') t -, - NR 42 CR 43 R 43' CR 43 R 43 '(OCR 44 R 44' CR 44 R 44 ') t -, - NR 42 CR ^{43 R 43 'CR 43 R 43} ' (OCR 44 R 44 'CR 44 R 44') t -, - NR 42 CR 43 R 43 'CR 43 R 43' (OCR 44 R 44 'CR 44 R 44') t ^{C (O) -, - NR} 42 CR 43 R 43 'CR 43 R 43' (CR 44 = CR 44 ') t - and ^-NR 42 _C 6 _{~C 10} aryl _(C 1 -C ₆ alkyl) OC (O )-Is selected from the group consisting of;
here,
R ⁴² is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, wherein C ₁ -C ₆ alkyl. each hydrogen atom in _C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl , _C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 45, -OC (O)} R ⁴⁵ , -OC(O)NR ⁴⁵ R ^45' , -OS(O)R ⁴⁵ , -OS(O) ₂ R ⁴⁵ , -SR ⁴⁵ , -S(O)R ⁴⁵ , -S(O) ₂ R ^45. , -S(O)NR ⁴⁵ R ^45' , -S(O) ₂ NR ⁴⁵ R ^45' , -OS(O)NR ⁴⁵ R ^45' , -OS(O) ₂ NR ⁴⁵ R ^45' , -NR ^{45. R 45 ', -NR 45 C (} O) R 46, -NR 45 C (O) OR 46, -NR 45 C (O) NR 46 R 46', -NR 45 S (O) R 46, -NR 45 ^{_{S (O) 2 R 46,}} -NR 45 S (O) NR 46 R 46 ', -NR 45 S (O) 2 NR 46 R 46', -C (O) R 45, -C (O) OR 45 Or optionally substituted by -C(O)NR ⁴⁵ R ^45' ,
R ^{43, R 43 ', R 44} and ^{R 44} are each independently _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl Each hydrogen atom in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl is independently, optionally, selected from the group consisting of: _halogen, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 47, -OC (O)} R 47, -OC (O) NR 47 R 47 ', -OS (O) R 47, -OS (O) 2 R 47, -SR 47, - S(O)R ⁴⁷ , -S(O) ₂ R ⁴⁷ , -S(O)NR ⁴⁷ R ^47' , -S(O) ₂ NR ⁴⁷ R ^47' , -OS(O)NR ⁴⁷ R ^47' , ^{_{-OS (O) 2 NR 47 R}} 47 ', -NR 47 R 47', -NR 47 C (O) R 48, -NR 47 C (O) OR 48, -NR 47 C (O) NR 48 R 48 ^{', -NR 47 S (O)} R 48, -NR 47 S (O) 2 R 48, -NR 47 S (O) NR 48 R 48', -NR 47 S (O) 2 NR 48 R 48 ', Optionally substituted by -C(O)R ⁴⁷ , -C(O)OR ⁴⁷ or -C(O)NR ⁴⁷ R ^47' ;
R ⁴⁵ , R ^45′ , R ⁴⁶ , R ^46′ , R ⁴⁷ , R ^47′ , R ⁴⁸ and R ^48′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl. is selected from the group consisting of _C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl;
T in each case is 1, 2, 3, 4 or 5;
L ⁵ represents _C 1 _{-C 10} ^{alkyl, - (CR 49 = CR 49} ') u -, - (CR 49 R 49') u C (O) -, - CH 2 CH 2 (OCR 49 R 49 'CR 49 ^{_{R 49 ') u -, -}} CH 2 CH 2 CH 2 (OCR 49 R 49' CR 49 R 49 'CR 49 R 49') u -, - CH 2 CH 2 (OCR 49 R 49 'CR 49 R 49' ) _u C (O) - and ^{_{-CH 2 CH 2 (OCR 49 R}} 49 'CR 49 R 49' CR 49 R 49 ') u C (O) - is selected from the group consisting of,
here,
R ⁴⁹ and R ^49′ are each independently selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl. , Wherein each hydrogen atom in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl is, independently, optionally halogen, C ₁ -C. ₆ alkyl, C _{2 to} C ₆ alkenyl, C _{2 to} C ₆ alkynyl, C _{3 to} C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, − ^{OR 50, -OC (O) R} 50, -OC (O) NR 50 R 50 ', -OS (O) R 50, -OS (O) 2 R 50, -SR 50, -S (O) R 50 ^{_{, -S (O) 2 R 50}} , -S (O) NR 50 R 50 ', -S (O) 2 NR 50 R 50', -OS (O) NR 50 R 50 ', -OS (O) 2 ^{NR 50 R 50 ', -NR 50} R 50', -NR 50 C (O) R 51, -NR 50 C (O) OR 51, -NR 50 C (O) NR 51 R 51 ', -NR 50 S ^{_{(O) R 51, -NR 50}} S (O) 2 R 51, -NR 50 S (O) NR 51 R 51 ', -NR 50 S (O) 2 NR 51 R 51', -C (O) R ^50, may be replaced by -C (O) ^{oR 50} or ^{-C (O) NR 50 R 50} ';
^{R 50, R 50 ', R} 51 and ^{R 51'} is, H _{independently, D,} C 1 ~C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl alkyl is selected from the group consisting of 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl;
U in each case is 0, 1, 2, 3, 4 or 5;
D ¹ is a PBD prodrug; and D ² is a DNA binding agent]
A conjugate comprising a binding ligand, a linker, and a drug having: or a pharmaceutically acceptable salt thereof. D ¹ is the formula III

[In the formula,
R ^1a , R ^2a , R ^3a and R ^4a are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -C(O)R ^11a , -C(O)OR ^11a and -C(O)NR ^11a R ^11a'. Selected from the group consisting of: C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -. Each hydrogen atom in C ₁₀ aryl and 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C _6. cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 11a, -OC (O)} R 11a, -OC (O) NR 11a R 11a ', -OS(O)R ^11a , -OS(O) ₂ R ^11a , -SR ^11a , -S(O)R ^11a , -S(O) ₂ R ^11a , -S(O)NR ^11a R ^11a' , -. _{^{S (O) 2 NR 11a R}} 11a ', -OS (O) NR 11a R 11a', -OS (O) 2 NR 11a R 11a ', -NR 11a R 11a', -NR 11a C (O) R 12a , -NR ^11a C(O)OR ^12a , -NR ^11a C(O)NR ^12a R ^12a' , -NR ^11a S(O)R ^12a , -NR ^11a S(O) ₂ R ^12a , -NR ^11a S(. ^{O) NR 12a R} 12a substituted _{^{', -NR 11a S (O)}} 2 NR 12a R 12a', -C (O) R 11a, -C (O) oR 11a or ^{-C (O) NR 11a R 11a} ' R ^1a is a bond; or R ^4a is a bond;
R ^{5a, R 6a} and ^{R 7a} are, H independently, _D, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, the group consisting of -C (O) R 13a, -C (O) oR 13a , and ^{-C (O) NR 13a R 13a} ' Selected from where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl. And each hydrogen atom in the 5- to 7-membered ring heteroaryl is optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring. _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 14a, -OC (O)} R 14a, -OC (O) NR 14a R 14a ', -OS (O) R 14a, _{^{-OS (O) 2 R 14a,}} -SR 14a, -S (O) R 14a, -S (O) 2 R 14a, -S (O) NR 14a R 14a ', -S (O) 2 NR 14a R ^14a' , -OS(O)NR ^14a R ^14a' , -OS(O) ₂ NR ^14a R ^14a' , -NR ^14a R ^14a' , -NR ^14a C(O)R ^15a , -NR ^14a C(O). OR ^15a , -NR ^14a C(O)NR ^15a R ^15a' , -NR ^14a S(O)R ^15a , -NR ^14a S(O) ₂ R ^15a , -NR ^14a S(O)NR ^15a R ^15a' , —NR ^14a S(O) ₂ NR ^15a R ^15a′ , —C(O)R ^14a , —C(O)OR ^14a or —C(O)NR ^14a R ^14a′ may be substituted; where R ^6a and R ^7a together with the atom to which they are attached, optionally combined to form a 3-7 membered ring heterocycloalkyl, or R ^5a and R ^6a are together with the atom to which they are attached. And optionally combined to form a 3-7 membered heterocycloalkyl or a 5-7 membered heteroaryl, a 3-7 membered heterocycloalkyl or Is independently each hydrogen atom in a 5- to 7-membered heteroaryl, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -OR ^16a , -OC(O)R ^16a ,
^{-OC (O) NR 16a R 16a} ', -OS (O) R 16a, -OS (O) 2 R 16a, -SR 16a, -S (O) R 16a, -S (O) 2 R 16a, - S(O)NR ^16a R ^16a' , -S(O) ₂ NR ^16a R ^16a' , -OS(O)NR ^16a R ^16a' , -OS(O) ₂ NR ^16a R ^16a' , -NR ^16a R ^{16a. '} , -NR ^16a C(O)R ^17a , -NR ^16a C(O)CH ₂ CH ₂ -, -NR ^16a C(O)OR ^17a , -NR ^16a C(O)NR ^17a R ^17a' , -NR. ^16a S(O)R ^17a , -NR ^16a S(O) ₂ R ^17a , -NR ^16a S(O)NR ^17a R ^17a' , -NR ^16a S(O) ₂ NR ^17a R ^17a' , -C(O). ) R ^16a , —C(O)OR ^16a or —C(O)NR ^16a R ^16a′ , and one hydrogen atom of the 5-7 membered heteroaryl is optionally bonded. Or R ^5a is a bond;
R ^8a and R ^9a are each independently H, D, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 member. _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered _{^{heteroaryl, -CN, -NO 2, -NCO,}} -OR 18a, -OC (O) R 18a, -OC (O) NR 18a R _{^{18a ', -OS (O) R}} 18a, -OS (O) 2 R 18a, -SR 18a, -S (O) R 18a, -S (O) 2 R 18a, -S (O) NR 18a R 18a _{^{', -S (O) 2 NR}} 18a R 18a', -OS (O) NR 18a R 18a ', -OS (O) 2 NR 18a R 18a', -NR 18a R 18a ', -NR 18a C (O ) R ^19a , -NR ^18a C(O)OR ^19a , -NR ^18a C(O)NR ^19a R ^19a' , -NR ^18a S(O)R ^19a , -NR ^18a S(O) ₂ R ^19a , -NR. ^18a S(O)NR ^19a R ^19a' , -NR ^18a S(O) ₂ NR ^19a R ^19a' , -C(O)R ^18a , -C(O)OR ^18a and -C(O)NR ^18a R ^{18a. '} Wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ Each hydrogen atom in -C ₁₀ aryl and 5-7 membered heteroaryl is independently, optionally, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C. ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 20a, -OC (O)} R 20a, -OC (O) NR 20a R 20a ' , -OS(O)R ^20a , -OS(O) ₂ R ^20a , -SR ^20a , -S(O)R ^20a , -S(O) ₂ R ^20a , -S(O)NR ^20a R ^20a' , _{^{-S (O) 2 NR 20a R}} 20a ', -OS (O) NR 20a R 20a', -OS (O) 2 NR 20a R 20a ', -NR ^20a R ^20a' , -NR ^20a C(O)R ^21a , -NR ^20a C(O)OR ^21a , -NR ^20a C(O)NR ^21a R ^21a' , -NR ^20a S(O)R ^21a , -NR ^20a S(O) ₂ R ^21a , -NR ^20a S(O)NR ^21a R ^21a' , -NR ^20a S(O) ₂ NR ^21a R ^21a' , -C(O)R ^20a , -C(O). ) OR ^20a or -C(O)NR ^20a R ^20a' may be substituted;
R ^10a is _{H, D,} C 1 ~C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} Aryl, 5- to 7-membered heteroaryl, -OR ^22a , -OC(O)R ^22a , -OC(O)NR ^22a R ^22a' , -OS(O)R ^22a , -OS(O) ₂ R ^22a , -SR ^22a , -S(O)R ^22a , -S(O) ₂ R ^22a , -S(O)NR ^22a R ^22a' , -S(O) ₂ NR ^22a R ^22a' , -OS(O)NR. _{^{22a R 22a ', -OS (O}} ) 2 NR 22a R 22a', -NR 22a R 22a ', -NR 22a C (O) R 23a, -NR 22a C (O) OR 23a, -NR 22a C (O ^{) NR 23a R 23a ', -NR} 22a S (O) R 23a, -NR 22a S (O) 2 R 23a, -NR 22a S (O) NR 23a R 23a', -NR 22a S (O) 2 NR ^{23a R 23a, -C (O)} R 22a, is selected from the group consisting of -C ^{(O) oR 23a,} and ^{-C (O) NR 22a R 22a} ', wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} each hydrogen atom in the C 6 _{-C 10} aryl and 5- to 7-membered ring heteroaryl is independently , Optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 To 7-membered ring heteroaryl, -OR ^24a , -OC(O)R ^24a , -OC(O)NR ^24a R ^24a' , -OS(O)R ^24a , -OS(O) ₂ R ^24a , -SR ^24a. , -S(O)R ^24a , -S(O) ₂ R ^24a , -S(O)NR ^24a R ^24a' , -S(O) ₂ NR ^24a R ^24a' , -OS(O)NR ^24a R ^{24a. _{', -OS (O) 2 NR}} 24a R 24a', -NR 24a R 24a ', -NR 24a C (O) R 25a, -N R ^24a C(O)OR ^25a , -NR ^24a C(O)NR ^25a R ^25a' , -NR ^24a S(O)R ^25a , -NR ^24a S(O) ₂ R ^25a , -NR ^24a S(O). NR ^25a R ^25a′ , —NR ^24a S(O) ₂ NR ^25a R ^25a′ , —C(O)R ^24a , —C(O)OR ^24a or —C(O)NR ^24a R ^24a′. And R ^11a , R ^11a′ , R ^12a , R ^12a′ , R ^13a , R ^13a′ , R ^14a , R ^14a′ , R ^15a , R ^15a′ , R ^16a , R ^16a′ , R ^17a , R. ^17a' , ^R18a , ^R18a' , ^R19a , ^R19a' , ^R20a , ^R20a' , ^R21a , ^R21a' , ^R22a , ^R22a' , ^R23a , ^R23a' , ^R24a , ^{R24a. ', R 25a} and ^{R 25a'} are, H independently, _D, C 1 -C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 _{-C 13} cycloalkyl, 3-7 A membered ring heterocycloalkyl, selected from the group consisting of C ₆ -C ₁₀ aryl and 5-7 membered heteroaryl;
Provided that at least two of R ^1a , R ^4a and R ^5a are a bond, or R ^5a and R ^6a together with the atom to which they are bonded, optionally bonded to a 3-7 membered ring hetero When forming a cycloalkyl or a 5-7 membered heteroaryl, one hydrogen atom in the 5-7 membered heteroaryl is a bond, and one of R ^1a or R ^4a is a bond]
The conjugate of claim 1 or a pharmaceutically acceptable salt thereof, which is The conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein D ² is a minor groove-binding drug. D ²

[In the formula,
R ^1b , R ^2b , R ^3b and R ^4b are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -C(O)R ^13b , -C(O)OR ^13b and -C(O)NR ^13b R ^13b'. Selected from the group consisting of: C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -. Each hydrogen atom in C ₁₀ aryl and 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C _6. Cycloalkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -OR ^13b , -OC(O)R ^13b , -OC(O)NR ^13b R ^13b' , -OS(O)R ^13b , -OS(O) ₂ R ^13b , -SR ^13b , -S(O)R ^13b , -S(O) ₂ R ^13b , -S(O)NR ^13b R ^13b' , -. _{^{S (O) 2 NR 13b R}} 13b ', -OS (O) NR 13b R 13b', -OS (O) 2 NR 13b R 13b ', -NR 13b R 13b', -NR 13b C (O) R 14b , -NR ^13b C(O)OR ^14b , -NR ^13b C(O)NR ^14b R ^14b' , -NR ^13b S(O)R ^14b , -NR ^13b S(O) ₂ R ^14b , -NR ^13b S(. ^{O) NR 14b R} 14b substituted _{^{', -NR 13b S (O)}} 2 NR 14b R 14b', -C (O) R 13b, -C (O) oR 13b or ^{-C (O) NR 13b R 13b} ' Or any one of R ^1b , R ^2b , R ^3b and R ^4b is a bond;
R ^{5b, R 6b} and ^{R 7b} is, H independently, _D, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, the group consisting of -C (O) R 15b, -C (O) oR 15b and ^{-C (O) NR 15b R 15b} ' Selected from where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl. And each hydrogen atom in the 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -L 4 H, -L 3 H} , -OR 15b, -OC (O) R 15b, -OC (O ^{) NR 15b R 15b ', -OS} (O) R 15b, -OS (O) 2 R 15b, -SR 15b, -S (O) R 15b, -S (O) 2 R 15b, -S (O) _{^{NR 15b R 15b ', -S (}} O) 2 NR 15b R 15b', -OS (O) NR 15b R 15b ', -OS (O) 2 NR 15b R 15b', -NR 15b R 15b ', -NR ^15b C(O)R ^16b , -NR ^15b C(O)OR ^16b , -NR ^15b C(O)NR ^16b R ^16b' , -NR ^15b S(O)R ^16b , -NR ^15b S(O) ₂ R. ^16b , -NR ^15b S(O)NR ^16b R ^16b' , -NR ^15b S(O) ₂ NR ^16b R ^16b' , -C(O)R ^15b , -C(O)OR ^15b or -C(O). NR ^15b R ^15b′ may be substituted;
here,
R ^6b and R ^7b , together with the atom to which they are attached, optionally combine to form a 3 to 7 membered heterocycloalkyl, or R ^5b and R ^6b are the same as the atom to which they are attached. Together, they are optionally joined to form a 3-7 membered heterocycloalkyl or a 5-7 membered heteroaryl, where each in 3-7 membered heterocycloalkyl and 5-7 membered heteroaryl. The hydrogen atoms are, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-7 membered ^{heteroaryl, -OR 17b, -OC (O)} R 17b, -OC (O) NR 17b R 17b ', -OS (O) R 17b, -OS (O) ₂ R ^17b , -SR ^17b , -S(O)R ^17b , -S(O) ₂ R ^17b , -S(O)NR ^17b R ^17b' , -S(O) ₂ NR ^17b R ^17b' , -OS. (O)NR ^17b R ^17b' , -OS(O) ₂ NR ^17b R ^17b' , -NR ^17b R ^17b' , -NR ^17b C(O)R ^18b , -NR ^17b C(O)OR ^18b , -NR. ^17b C(O)NR ^18b R ^18b' , -NR ^17b S(O)R ^18b , -NR ^17b S(O) ₂ R ^18b , -NR ^17b S(O)NR ^18b R ^18b' , -NR ^17b S( _{^{O) 2 NR 18b R 18b '}} , -C (O) R 17b, -C (O) may be substituted by ^{oR 17b} or ^{-C (O) NR 17b R 17b} ; or ^{R 5b, R 6b} or ^{R 7b} One of which is a bond;
R ^8b and R ^9b are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. _cycloalkyl, C 6 _{-C 10} aryl, 5-7 membered _{^{heteroaryl, -CN, -NO 2, -NCO,}} -OR 19b, -OC (O) R 19b, -OC (O) NR 19b R 19b ' , -OS(O)R ^19b , -OS(O) ₂ R ^19b , -SR ^19b , -S(O)R ^19b , -S(O) ₂ R ^19b , -S(O)NR ^19b R ^19b' , _{^{-S (O) 2 NR 19b R}} 19b ', -OS (O) NR 19b R 19b', -OS (O) 2 NR 19b R 19b ', -NR 19b R 19b', -NR 19b C (O) R ^20b , -NR ^19b C(O)OR ^20b , -NR ^19b C(O)NR ^20b R ^20b' , -NR ^19b S(O)R ^20b , -NR ^19b S(O) ₂ R ^20b , -NR ^19b S. From (O)NR ^20b R ^20b' , -NR ^19b S(O) ₂ NR ^20b R ^20b' , -C(O)R ^19b , -C(O)OR ^19b and -C(O)NR ^19b R ^19b'. is selected from the group consisting of, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 -C Each hydrogen atom in the ₁₀ aryl and the 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cyclo. Alkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -OR ^21b , -OC(O)R ^21b , -OC(O)NR ^21b R ^21b' , -. OS(O)R ^21b , -OS(O) ₂ R ^21b , -SR ^21b , -S(O)R ^21b , -S(O) ₂ R ^21b , -S(O)NR ^21b R ^21b' , -S. (O) ₂ NR ^21b R ^21b' , -OS(O)NR ^21b R ^21b' , -OS(O) ₂ NR ^21b R ^21b' , -NR ^{2 1b} R ^21b' , -NR ^21b C(O)R ^22b , -NR ^21b C(O)OR ^22b , -NR ^21b C(O)NR ^22b R ^22b' , -NR ^21b S(O)R ^22b , -NR. ^21b S(O) ₂ R ^22b , -NR ^21b S(O)NR ^22b R ^22b' , -NR ^21b S(O) ₂ NR ^22b R ^22b' , -C(O)R ^21b , -C(O)OR. ^21b or -C(O)NR ^21b R ^21b may be substituted;
R ^{10b, R 11b} and ^{R 12b} are, H independently, _D, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 23b, -OC (O)} R 23b, -OC (O) NR 23b R 23b ', -OS (O) R _{^{23b, -OS (O) 2 R}} 23b, -SR 23b, -S (O) R 23b, -S (O) 2 R 23b, -S (O) NR 23b R 23b ', -S (O) 2 NR ^{23b R 23b ', -OS (O} ) NR 23b R 23b', -OS (O) 2 NR 23b R 23b ', -NR 23b R 23b', -NR 23b C (O) R 24b, -NR 23b C ( O)OR ^24b , -NR ^23b C(O)NR ^24b R ^24b' , -NR ^23b S(O)R ^24b , -NR ^23b S(O) ₂ R ^24b , -NR ^23b S(O)NR ^24b R ^{24b. _{', -NR 23b S (O)}} 2 NR 24b R 24b', is selected from the group consisting of ^{-C (O) R 23b, -C} (O) oR 23b and ^{-C (O) NR 23b R 23b} ', wherein in _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5- to 7-membered Each hydrogen atom in a ring heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring. _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 25b, -OC (O)} R 25b, -OC (O) NR 25b R 25b ', -OS (O) R 25b, _{^{-OS (O) 2 R 25b,}} -SR 25b, -S (O) R 25b, -S (O) 2 R 25b, -S (O) NR 25b R 25b ', -S (O) 2 NR 25b R ^25b' , -OS(O)NR ^25b R ^25b' , -OS(O) ₂ NR ^25b R ^25b' , -NR ^25b R ^{25. b'} , -NR ^25b C(O)R ^26b , -NR ^25b C(O)OR ^26b , -NR ^25b C(O)NR ^26b R ^26b' , -NR ^25b S(O)R ^26b , -NR ^25b S. _{^{(O) 2 R 26b, -NR}} 25b S (O) NR 26b R 26b ', -NR 25b S (O) 2 NR 26b R 26b', -C (O) R 25b, -C (O) oR 25b or —C(O)NR ^25b R ^25b may be substituted, or R ^10b and R ^11b , together with the carbon atom to which they are attached, are optionally joined to form a C ₆ -C ₁₀ aryl. Or R ^11b and R ^12b , together with the carbon atom to which they are attached, optionally combine to form exo-methylene; or R ^12b is absent;
R ^13b , R ^13b' , R ^14b , R ^14b' , R ^15b , R ^15b' , R ^16b , R ^16b' , R ^17b , R ^17b' , R ^18b , R ^18b' , R ^19b , R ^19b' , R. ^20b , R ^20b' , R ^21b , R ^21b' , R ^22b , R ^22b' , R ^23b , R ^23b' , R ^24b , R ^24b' , R ^25b , R ^25b' , R ^26b and R ^26b' are respectively. independently _{H, D,} C 1 ~C _{7 alkyl,} C 2 -C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 _{-C 13} cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} Selected from the group consisting of aryl, C ₁ -C ₆ alkyl (C ₆ -C ₁₀ aryl) and 5-7 membered heteroaryl, wherein C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkyl (C ₆ -aryl). Each hydrogen atom in C ₁₀ aryl) and a 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C. ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered _{heteroaryl, -CN, -NO 2, -NCO,} -OH, -SH, -NH 2, -SO ₃ H, -C (O) OH and -C (O) may be substituted by NH _2;
Provided that one of R ^1b , R ^2b , R ^3b , R ^4b , R ^5b , R ^6b and R ^7b is a bond;
R ^1c , R ^2c and R ^5c are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7. membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, the group consisting of -C (O) R 6c, -C (O) oR 6c and ^{-C (O) NR 6c R 6c} ' Selected from where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl. And each hydrogen atom in the 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered ring heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered ring heteroaryl, -OR ^7c , -OC(O)R ^7c , -OC(O)NR ^7c R ^7c' , -OS( _{^{O) R 7c, -OS (O}} ) 2 R 7c, -SR 7c, -S (O) R 7c, -S (O) 2 R 7c, -S (O) 2 OR 7c, -S (O) NR _{^{7c R 7c ', -S (O}} ) 2 NR 7c R 7c', -OS (O) NR 7c R 7c ', -OS (O) 2 NR 7c R 7c', -NR 7c R 7c ', -NR 7c C(O)R ^8c , -NR ^7c C(O)OR ^8c , -NR ^7c C(O)NR ^8c R ^8c' , -NR ^7c S(O)R ^8c , -NR ^7c S(O) ₂ R ^8c. , -NR ^7c S(O)NR ^8c R ^8c' , -NR ^7c S(O) ₂ NR ^8c R ^8c' , -C(O)R ^7c , -C(O)OR ^7c or -C(O)NR. ^7c R ^7c′ may be substituted; or when J is —CR ^13c =, R ^5c is absent; provided that one of R ^1c or R ^2c is a bond;
R ^3c and R ^4c are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. _cycloalkyl, C 6 _{-C 10} aryl, 5-7 membered _{^{heteroaryl, -CN, -NO 2, -NCO,}} -OR 9c, -OC (O) R 9c, -OC (O) NR 9c R 9c ' , -OS(O)R ^9c , -OS(O) ₂ R ^9c , -SR ^9c , -S(O)R ^9c , -S(O) ₂ R ^9c , -S(O)NR ^9c R ^9c' , _{^{-S (O) 2 NR 9c R}} 9c ', -OS (O) NR 9c R 9c', -OS (O) 2 NR 9c R 9c ', -NR 9c R 9c', -NR 9c C (O) R ^10c , -NR ^9c C(O)OR ^10c , -NR ^9c C(O)NR ^10c R ^10c' , -NR ^9c S(O)R ^10c , -NR ^9c S(O) ₂ R ^10c , -NR ^9c S. ^{(O) NR 10c R 10c '} , -NR 9c S (O) 2 NR 10c R 10c', -C (O) R 9c, the -C (O) ^{oR 9c} and ^{-C (O) NR 9c R 9c} ' is selected from the group consisting of, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 -C Each hydrogen atom in the ₁₀ aryl and the 5-7 membered heteroaryl is, independently, optionally C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cyclo. Alkyl, 3 to 7 membered heterocycloalkyl, C _{6 to} C ₁₀ aryl, 5 to 7 membered heteroaryl, -OR ^11c , -OC(O)R ^11c , -OC(O)NR ^11c R ^11c' , -. OS(O)R ^11c , -OS(O) ₂ R ^11c , -SR ^11c , -S(O)R ^11c , -S(O) ₂ R ^11c , -S(O)NR ^11c R ^11c' , -S. (O) ₂ NR ^11c R ^11c' , -OS(O)NR ^11c R ^11c' , -OS(O) ₂ NR ^11c R ^11c' , -NR ^11c R ^11c' , -NR ^11c C(O)R ^12c , -NR ^11c C(O)OR ^12c , -NR ^11c C(O)NR ^12c R ^12c' , -NR ^11c S(O)R ^12c , -NR ^11c S(O) ₂ R ^12c , -NR ^11c S(O). ^{) NR 12c R 12c ', -NR} 11c S (O) 2 NR 12c R 12c', -C (O) R 11c, substituted by -C ^{(O) oR 11c} or ^{-C (O)} NR ^{11c R 11c} Well;
J is ^{-C (O) -, - CR} 13c = , or ^{- (CR 13c R 13c ')} - a and ^{R 6c, R 6c', R} 7c, R 7c ', R 8c, R 8c', R 9c, R ^{9c ', R 10c, R 10c} ', R 11c, R 11c ', R 12c, R 12c', R 13c and ^{R 13c 'is,} H _{independently, D,} C 1 ~C _{7 alkyl, C} 2 ~ C _{7 alkenyl,} C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, is selected from the group consisting of 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl;
R ^1d is H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ Aryl, 5-7 membered heteroaryl, —OR ^2d , —SR ^2d and —NR ^2d R ^2d′ selected from the group consisting of:
R ^2d and R ^2d′ are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring. It is selected from the group consisting of _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl, _{C 3} -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} each hydrogen atom in the C 6 _{-C 10} aryl and 5- to 7-membered ring heteroaryl, ^optionally, -OR 3d, ^{-SR 3d} and ^{-NR 3d} R ^Optionally substituted by ^3d′ ;
R ^3d and R ^3d′ are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring. is selected from the group consisting of _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl;
R ^1e is H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered heterocycloalkyl, C ₆ -C ₁₀ It is selected from the group consisting of aryl and 5-7 membered heteroaryl, wherein _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 each hydrogen atom in membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5- to 7-membered ring heteroaryl is independently _optionally, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl, C} 2 ~ C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 2e, -OC (O)} R 2e, -OC ^{(O) NR 2e R 2e '} , -OS (O) R 2e, -OS (O) 2 R 2e, -SR 2e, -S (O) R 2e, -S (O) 2 R 2e, -S ( ^{O) NR 2e R 2e ',} -S (O) 2 NR 2e R 2e', -OS (O) NR 2e R 2e ', -OS (O) 2 NR 2e R 2e', -NR 2e R 2e ', ^{-NR 2e C (O) R 3e} , -NR 2e C (O) OR 3e, -NR 2e C (O) NR 3e R 3e ', -NR 2e S (O) R 3e, -NR 2e S (O) _{^{2 R 3e, -NR 2e S (}} O) NR 2e R 2e ', -NR 2e S (O) 2 NR 3e R 3e', -C (O) R 2e, -C (O) oR 2e or -C ( O) optionally substituted by NR ^2e R ^2e ;
R ^2e , R ^2e′ , R ^3e and R ^3e′ are each independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl, wherein _C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl, _{C 2} -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} each hydrogen atom in the C 6 _{-C 10} aryl and 5- to 7-membered ring heteroaryl, optionally, ^{-OR 4e,} - ^Optionally substituted by SR ^4e or —NR ^4e R ^4e′ ;
R ^4e and R ^4e′ are independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. Selected from the group consisting of cycloalkyl, C ₆ -C ₁₀ aryl and 5-7 membered heteroaryl;
v is 1, 2 or 3; and * is a covalent bond]
4. The conjugate according to any one of claims 1 to 3, which is of the formula selected from the group consisting of: or a pharmaceutically acceptable salt thereof. AA is independently L-lysine, L-asparagine, L-threonine, L-serine, L-isoleucine, L-methionine, L-proline, L-histidine, L-glutamine, L-arginine, L-glycine, L-aspartic acid, L-glutamic acid, L-alanine, L-valine, L-phenylalanine, L-leucine, L-tyrosine, L-cysteine, L-tryptophan, L-phosphoserine, L-sulfo-cysteine, L-arginosuccinate Acid, L-hydroxyproline, L-phosphoethanolamine, L-sarcosine, L-taurine, L-carnosine, L-citrulline, L-anserin, L-1,3-methyl-histidine, L-α-amino-adipine Acid, D-lysine, D-asparagine, D-threonine, D-serine, D-isoleucine, D-methionine, D-proline, D-histidine, D-glutamine, D-arginine, D-glycine, D-aspartic acid , D-glutamic acid, D-alanine, D-valine, D-phenylalanine, D-leucine, D-tyrosine, D-cysteine, D-tryptophan, D-citrulline and D-carnosine. A conjugate or a pharmaceutically acceptable salt thereof according to any one of 1. The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R ¹⁶ is H. A conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein:
R ¹⁷ and R ^17′ are each independently selected from the group consisting of H, C ₁ -C ₆ alkyl and —OR ²² , wherein each hydrogen atom in C ₁ -C ₆ alkyl is independently Or R ¹⁷ and R ^17′ may be joined to form a C ₄ -C ₆ cycloalkyl or a 4-6 membered heterocycle, wherein C ₄ -C _{6 is} substituted by —OR ²⁴ ; Each hydrogen atom in a cycloalkyl or a 4-6 membered heterocycle may be independently substituted, optionally with halogen, C ₁ -C ₆ alkyl or —OR ²⁴ ;
A conjugate or a pharmaceutically acceptable salt thereof. A conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein:
R ¹⁸ is H, C ₁ -C ₆ alkyl, 5- to 7-membered heteroaryl, —OR ²⁶ , —NR ²⁶ C(O)R ²⁷ , —NR ²⁶ C(O)NR ²⁷ R ^27′ , —NR ^26. C(=NR ^26″ )NR ²⁷ R ^27′ and —C(O)NR ²⁶ R ^26′ selected from the group consisting of C ₁ -C ₆ alkyl and each hydrogen in a 5-7 membered heteroaryl. atoms are independently _optionally, C 1 -C _{6 ^{alkyl, -OR 29, - (CH 2}} ) p OS (O) 2 oR 29, -OS (O) 2 oR 29 , or -C, (O) Optionally substituted by NR ²⁹ R ^29′ ;
R ²⁶ , R ^26′ , R ^26″ , R ²⁹ and R ^29′ are each independently selected from the group consisting of H or C ₁ -C ₇ alkyl, wherein each hydrogen in C ₁ -C ₇ alkyl is atoms are independently optionally halogen, -OH, -SH, it may be substituted by -NH ₂ or -CO ₂ H;
R ²⁷ and R ^27′ are each independently H, C ₁ -C ₉ alkyl, C ₂ -C ₉ alkenyl, C ₂ -C ₉ alkynyl, C ₃ -C ₆ cycloalkyl, —(CH ₂ ) _p ( _{sugar), - (CH 2) p} (OCH 2 CH 2) q - ( sugar) and _{- (CH 2) p (OCH} 2 CH 2 CH 2) is selected from the group consisting of _q (sugars);
n is 2, 3, 4 or 5;
p is 1, 2, 3, 4 or 5;
q is 1, 2, 3, 4 or 5;
A conjugate or a pharmaceutically acceptable salt thereof. L ¹ is each

[In the formula,
R ¹⁶ is H and * is a covalent bond]
The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, which is selected from the group consisting of: A conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9,
R ¹ and R ² in each case are H; R ³ , R ⁴ , R ⁵ and R ⁶ are H; X ¹ is —NR ¹¹ —; X ² is ═N—; X ³ and ^{X 4} is a -N =;; is -N = ^{X 5} is an ^{NR 12; Y 1} is an is = O; ^{Y 2} is ^{absent; R 11} and ^{R 12} are H; m is 1, 2, 3 or 4; and * is a covalent bond;
A conjugate or a pharmaceutically acceptable salt thereof. formula

The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, which comprises: formula

The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, which comprises: - _{(AA) 4} - salt sequence is -Asp-Arg-Asp-Asp-, are conjugate or a pharmaceutically acceptable according to any one of claims 1 to 12. The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein the sequence of -(AA) _2- is Val-CIT. L ² is

[In the formula,
R ³¹ is selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₁ -C ₆ alkyl. each hydrogen atom in _C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl , _C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 32, -OC (O)} R ³² , -OC(O)NR ³² R ^32' , -OS(O)R ³² , -OS(O) ₂ R ³² , -SR ³² , -S(O)R ³² , -S(O) ₂ R ^32. , -S(O)NR ³² R ^32' , -S(O) ₂ NR ³² R ^32' , -OS(O)NR ³² R ^32' , -OS(O) ₂ NR ³² R ^32' , -NR ^{32. R 32 ', -NR 32 C (} O) R 33, -NR 32 C (O) OR 33, -NR 32 C (O) NR 33 R 33', -NR 32 S (O) R 33, -NR 32 _{^{S (O) 2 R 33,}} -NR 32 S (O) NR 33 R 33 ', -NR 32 S (O) 2 NR 33 R 33', -C (O) R 32, -C (O) OR 32 Or optionally substituted by -C(O)NR ³² R ^32' ;
X ⁶ is C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl), wherein C ₁ -C ₆ alkyl and C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl). Each hydrogen atom in is optionally halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3-7 membered ring hetero. _cycloalkyl, C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 34, -OC (O)} R 34, -OC (O) NR 34 R 34 ', -OS (O) R 34, - _{^{OS (O) 2 R 34,}} -SR 34, -S (O) R 34, -S (O) 2 R 34, -S (O) NR 34 R 34 ', -S (O) 2 NR 34 R 34 ^{', -OS (O) NR 34} R 34', -OS (O) 2 NR 34 R 34 ', -NR 34 R 34', -NR 34 C (O) R 35, -NR 34 C (O) OR ^{35, -NR 34 C (O)} NR 35 R 35 ', -NR 34 S (O) R 35, -NR 34 S (O) 2 R 35, -NR 34 S (O) NR 35 R 35', - _{^{NR 34 S (O) 2 NR}} 35 R 35 may be substituted by ^{', -C (O) R 34} , -C (O) oR 34 or ^{-C (O) NR 34 R 34} ';
^{R 32, R 32 ', R} 33, R 33', R 34, R 34 ', R 35 and ^{R 35'} is, H _{independently, D,} C 1 ~C _{7 alkyl,} C 2 -C ₇ alkenyl is selected from the group consisting of _C 2 -C _{7 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl and 5-7 membered heteroaryl;
R ³⁶ is independently selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, wherein alkyl, C ₂ -C _{6 alkenyl,} each hydrogen atom in the C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl, C ₂ -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^{heteroaryl, -OR 37, -OC (O)} R 37, ^{-OC (O) NR 37 R 37} ', -OS (O) R 37, -OS (O) 2 R 37, -SR 37, -S (O) R 37, -S (O) 2 R 37, - ^{S (O) NR 37 R 37} ', -S (O) 2 NR 37 R 37', -OS (O) NR 37 R 37 ', -OS (O) 2 NR 37 R 37', -NR 37 R 37 ^{', -NR 37 C (O)} R 38, -NR 37 C (O) OR 38, -NR 37 C (O) NR 38 R 38', -NR 37 S (O) R 38, -NR 37 S ( _{^{O) 2 R 38, -NR 37}} S (O) NR 38 R 38 ', -NR 37 S (O) 2 NR 38 R 38', -C (O) R 37, -C (O) oR 37 or - Optionally substituted by C(O)NR ³⁷ R ^37′ ;
R ³⁷ , R ^37′ , R ³⁸ and R ^38′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered heterocycloalkyl _alkyl, C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a covalent bond]
The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, which is selected from the group consisting of: L ² is an expression

[In the formula,
R ³¹ is H; and X ⁶ is C ₁ -C ₆ alkyl]
The conjugate according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof. L ² is an expression

[In the formula,
R ³¹ is H; and X ⁶ is C ₆ -C ₁₀ aryl (C ₁ -C ₆ alkyl)]
The conjugate according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof. L ² is an expression

[In the formula,
R ³⁶ is independently selected from the group consisting of H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₃ -C ₆ cycloalkyl, where C ₁ -. C _{6 alkyl,} C 2 -C _{6 alkenyl,} each hydrogen atom in the C 2 -C ₆ alkynyl and _C 3 -C ₆ cycloalkyl is, independently, optionally, _halogen, C 1 -C _{6 alkyl, C} 2 ~ C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 3 -C ₆ cycloalkyl, 3-7 membered _{heterocycloalkyl,} C 6 _{-C 10} aryl, 5-7 membered ^heteroaryl, -OR 37, -OC ( ^{O) R 37, -OC (O} ) NR 37 R 37 ', -OS (O) R 37, -OS (O) 2 R 37, -SR 37, -S (O) R 37, -S (O) _{^{2 R 37, -S (O)}} NR 37 R 37 ', -S (O) 2 NR 37 R 37', -OS (O) NR 37 R 37 ', -OS (O) 2 NR 37 R 37', ^{-NR 37 R 37 ', -NR 37} C (O) R 38, -NR 37 C (O) OR 38, -NR 37 C (O) NR 38 R 38', -NR 37 S (O) R 38, -NR ³⁷ S(O) ₂ R ³⁸ , -NR ³⁷ S(O)NR ³⁸ R ^38' , -NR ³⁷ S(O) ₂ NR ³⁸ R ^38' , -C(O)R ³⁷ , -C(O ) OR ³⁷ or -C(O)NR ³⁷ R ^{37' which} may be substituted;
R ³⁷ , R ^37′ , R ³⁸ and R ^38′ are each independently H, D, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₃ -C ₆ cyclo. alkyl, 3-7 membered _{heterocycloalkyl,} selected from the group consisting of C 6 _{-C 10} aryl and 5-7 membered heteroaryl; and * is a covalent bond]
The conjugate according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof. The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein R ³⁶ is H. Linker is an expression

[In the formula,
* Is a bond]
The conjugate according to any one of claims 1 to 15, 18 or 19 or a pharmaceutically acceptable salt thereof. Linker is an expression

[In the formula,
* Is a bond]
The conjugate according to any one of claims 1 to 15, 18 or 19 or a pharmaceutically acceptable salt thereof. Linker is an expression

[In the formula,
* Is a bond]
The conjugate according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof. Linker is an expression

[In the formula,
* Is a bond]
The conjugate according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof. Linker is an expression

[In the formula,
* Is a bond]
The conjugate according to any one of claims 1 to 15 or 16, or a pharmaceutically acceptable salt thereof. Linker is an expression

[In the formula,
* Is a bond]
The conjugate according to any one of claims 1 to 15, 18 or 19 or a pharmaceutically acceptable salt thereof. Linker is an expression

[In the formula,
* Is a bond]
The conjugate according to any one of claims 1 to 15, 18 or 19 or a pharmaceutically acceptable salt thereof. Linker is an expression

[In the formula,
* Is a bond]
The conjugate according to any one of claims 1 to 15, 18 or 19 or a pharmaceutically acceptable salt thereof. Linker is an expression

[In the formula,
* Is a bond]
The conjugate according to any one of claims 1 to 15, 18 or 19 or a pharmaceutically acceptable salt thereof. -D ¹ -L ⁵ -D ² has the formula

[In the formula,
R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a , R ^2b , R ^3b , R ^4b , R ^8b and R ^9b are H]
29. The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, which is R ^2a , R ^3a , R ^4a , R ^8a , R ^9a , R ^10a , R ^2b , R ^3b , R ^4b , R ^8b and R ^9b are H, L ⁵ is C ₁ -C ₁₀ alkyl or -(CR ⁴⁹ R ^49′ ) _u C(O)—, R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3 or 4.
The conjugate according to claim 29 or a pharmaceutically acceptable salt thereof. -D ¹ -L ⁵ -D ² has the formula

[In the formula,
R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^2c , R ^3c , R ^4c and R ^5c are H]
29. The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, which is L ⁵ is C ₁ -C ₁₀ alkyl or —(CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3, 4 or 5;
The conjugate according to claim 31, or a pharmaceutically acceptable salt thereof. -D ¹ -L ⁵ -D ² has the formula

[In the formula,
R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a and R ^10a are H]
29. The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, which is L ⁵ is C ₁ -C ₁₀ alkyl or —(CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3, 4 or 5;
34. The conjugate according to claim 33 or a pharmaceutically acceptable salt thereof. -D ¹ -L ⁵ -D ² has the formula

[In the formula,
R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a and R ^1e are H]
29. The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, which is L ⁵ is C ₁ -C ₁₀ alkyl or —(CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3, 4 or 5;
36. The conjugate of claim 35 or a pharmaceutically acceptable salt thereof. -D ¹ -L ⁵ -D ² has the formula

[In the formula,
R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a and R ^1d are H]
29. The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, which is L ⁵ is C ₁ -C ₁₀ alkyl or —(CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3, 4 or 5;
38. The conjugate of claim 37 or a pharmaceutically acceptable salt thereof. -D ¹ -L ⁵ -D ² has the formula

[In the formula,
R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a and R ^10a are H]
29. The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, which is L ⁵ is C ₁ -C ₁₀ alkyl or —(CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3, 4 or 5;
The conjugate according to claim 39 or a pharmaceutically acceptable salt thereof. -D ¹ -L ⁵ -D ² has the formula

[In the formula,
R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a and R ^10a are H]
29. The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, which is L ⁵ is C ₁ -C ₁₀ alkyl or —(CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3, 4 or 5;
42. The conjugate of claim 41 or a pharmaceutically acceptable salt thereof. -D ¹ -L ⁵ -D ² has the formula

[In the formula,
R ^2a , R ^3a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^2b , R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^8b , R ^9b , R ^10b. , R ^11b and R ^12b are H]
29. The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, which is L ⁵ is C ₁ -C ₁₀ alkyl or —(CR ⁴⁹ R ^49′ ) _u C(O)—, wherein R ⁴⁹ and R ^49′ are each H, and u is 1, 2, 3, 4 or 5;
44. The conjugate of claim 43 or a pharmaceutically acceptable salt thereof. formula

Or a pharmaceutically acceptable salt thereof. 46. A pharmaceutical composition comprising a therapeutically effective amount of the conjugate of any one of claims 1-45 or a pharmaceutically acceptable salt thereof, and at least one excipient. 46. A method of treating abnormal cell proliferation in a mammal, including a human, comprising administering to a mammal the conjugate of any one of claims 1-45. 48. The method of claim 47, wherein the abnormal cell growth is cancer. 49. The method of claim 48, wherein the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, Breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, endometrial cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer and parathyroid cancer, adrenal cancer, soft tissue sarcoma , Urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphoid lymphoma, bladder cancer, kidney cancer or ureter, renal cell carcinoma, renal pelvic cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal axis A method, which is a combination of a tumor, brain stem glioma, pituitary adenoma, or one or more ongoing cancers. In another embodiment of said method, said abnormal cell growth is a benign proliferative disease, including but not limited to psoriasis, benign prostatic hypertrophy or restenosis. 46. Use of a conjugate according to any one of claims 1-45 in the manufacture of a medicament for the treatment of cancer.

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