ANTIFOLATE CONJUGATES FOR TREATING INFLAMMATION

TECHNICAL FIELD

The present invention relates to compositions and methods for use in targeted drug delivery. More particularly, the invention is directed to cell-surface receptor binding conjugates containing hydrophilic spacer linkers for use in treating disease states caused by pathogenic cell populations and to methods and pharmaceutical compositions that use and include such conjugates.

BACKGROUND

The mammalian immune system provides a means for the recognition and elimination of foreign pathogens. While the immune system normally provides a line of defense against foreign pathogens, there are many instances where the immune response itself is involved in the progression of disease. Exemplary of diseases caused or worsened by an immune response are autoimmune diseases and other diseases in which the immune response contributes to pathogenesis. For example, macrophages are generally the first cells to encounter foreign pathogens, and accordingly, they play an important role in the immune response, but activated macrophages can also contribute to the pathophysiology of disease in some instances.

The folate receptor is a 38 KD GPI-anchored protein that binds the vitamin folic acid with high affinity (<1 nM). Following receptor binding, rapid endocytosis delivers the vitamin into the cell, where it is unloaded in an endosomal compartment at low pH. Importantly, covalent conjugation of small molecules, proteins, and even liposomes to folic acid does not block the vitamin's ability to bind the folate receptor, and therefore, folate-drug conjugates can readily be delivered to and can enter cells by receptor-mediated endocytosis.

Because most cells use an unrelated reduced folate carrier to acquire the necessary folic acid, expression of the folate receptor is restricted to a few cell types. With the exception of kidney, choroid plexus, and placenta, normal tissues express low or nondetectable levels of the folate receptor. It has been reported that the folate receptor β, the nonepithelial isoform of the folate receptor, is expressed on activated (but not resting) synovial macrophages. Thus, folate receptors are expressed on a subset of macrophages (i.e., activated macrophages). Folate receptors of the β isoform are also found on activated monocytes.

Accordingly, the present invention relates to the development of vitamin-targeted therapeutics, such as folate-targeted therapeutics, to treat inflammation. The folate conjugates described herein can be used to treat inflammatory diseases by targeting inflammatory cells that overexpress the folate receptor.

SUMMARY

In one aspect, the disclosure provides conjugates of the formula B-L-D¹, wherein B is a binding ligand, L is a linker comprising a releaseable linker (L¹), at least one AA, and at least one L¹, and D¹is a drug; wherein B, D¹, L¹, L²and AA are defined as described herein in various embodiments and examples; or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides conjugates of the formula B-L-D¹, wherein B is a binding ligand as described herein, L is a linker comprising at least one AA as described herein, at least one L¹as described herein and an L²as described herein, or a pharmaceutically acceptable salt thereof.

In some embodiments, the disclosure provides a conjugate of the formula B-L¹-AA-L¹-AA-L¹-L²-D¹, B-AA-L¹-AA-AA-L²-D¹, or B-AA-AA-AA-AA-L²-D¹, wherein B, AA, L¹, L²and D¹are as described herein; or a pharmaceutically acceptable salt thereof.

In some embodiments, the disclosure provides a conjugate of the formula B-L-D¹, wherein B is a binding ligand of the formula

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wherein

R¹and R²in each instance are independently selected from the group consisting of H, D, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR⁷, —SR⁷and —NR⁷R^7′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl is independently optionally substituted by halogen, —OR⁸, —SR⁸, —NR⁸R^8′, —C(O)R⁸, —C(O)OR⁸or —C(O)NR⁸R^8′;

R³, R⁴, R⁵and R⁶are each independently selected from the group consisting of H, D, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —CN, —NO₂, —NCO, —OR⁹, —SR⁹, —NR⁹R^9′, —C(O)R⁹, —C(O)OR⁹and —C(O)NR⁹R^9′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl is independently optionally substituted by halogen, —OR¹⁰, —SR¹⁰, —NR¹⁰R^10′, —C(O)R¹⁰, —C(O)OR¹⁰or —C(O)NR¹⁰R^10′;

each R⁷, R^7′, R⁸, R^8′, R⁹, R^9′, R¹⁰and R^10′ is independently H, D, C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl;

X¹is —NR¹¹—, ═N—, —N═, —C(R¹¹)═ or ═C(R¹¹)—;

X²is —NR^11′- or ═N—;

X³is —NR^11″—, —N═ or —C(R^11′)═;

X⁴is —N═ or —C═;

X⁵is NR¹²or CR¹²R^12′;

Y¹is H, D, —OR¹³or —SR¹³when X¹is —N═ or —C(R¹¹)═, or Y¹is ═O when X is —NR¹¹—, ═N— or ═C(R¹¹)—;

Y²is H, D, C₁-C₆alkyl, C₂-C₆alkenyl, —C(O)R¹⁴, —C(O)OR¹⁴or —C(O)NR¹⁴R¹⁴when X⁴is —C═, or Y²is absent when X⁴is —N═;

R^1′, R^2′, R^3′, R^4′, R¹¹, R^11′, R¹², R^12′, R¹³, R¹⁴and R^14′are each independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —C(O)R¹⁵, —C(O)OR¹⁵and —C(O)NR¹⁵R^15′;

R¹⁵and R^15′are each independently H or C₁-C₆alkyl; and

m is 1, 2, 3 or 4;

L is a linker comprising at least one AA, at least one L¹and an L², wherein each AA is an amino acid, each L¹is of the formula

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wherein

R¹⁶is selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —C(O)R¹⁹, —C(O)OR¹⁹and —C(O)NR¹⁹R^19′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR²⁰, —OC(O)R²⁰, —OC(O)NR²OR^20′, —OS(O)R²⁰, —OS(O)₂R²⁰, —SR²⁰, —S(O)R²⁰, —S(O)₂R²⁰, —S(O)NR²⁰R^20′, —S(O)₂NR²⁰R^20′, —OS(O)NR²⁰R^20′, —OS(O)₂NR²⁰R^20′, —NR²⁰R^20′, —NR²⁰C(O)R²¹, —NR²⁰C(O)OR²¹, —NR²⁰C(O)NR²¹R^21′, —NR²⁰S(O)R²¹, —NR²⁰S(O)₂R²¹, —NR²⁰S(O)NR²¹R^21′, —NR²⁰S(O)₂NR²¹R^21′, —C(O)R²⁰, —C(O)OR²⁰or —C(O)NR²⁰R^20′;

each R¹⁷and R^17′ is independently selected from the group consisting of H, D, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²², —OC(O)R²², —OC(O)NR²²R^22′, —OS(O)R²², —OS(O)₂R²², —SR²², —S(O)R²², —S(O)₂R²², —S(O)NR²²R^22′, —S(O)₂NR²²R^21′, —OS(O)NR²²R^22′, —OS(O)₂NR²²R^22′, —NR²²R^22′, —NR²²C(O)R²³, —NR²²C(O)OR²³, —NR²²C(O)NR²³R^23′, —NR²²S(O)R²³, —NR²²S(O)₂R²³, —NR²²S(O)NR²³R^23′, —NR²²S(O)₂NR²³R^23′, —C(O)R²², —C(O)OR²², and —C(O)NR²²R^22′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR²⁴, —OC(O)R²⁴, —OC(O)NR²⁴R^24′, —OS(O)R²⁴, —OS(O)₂R²⁴, —SR²⁴, —S(O)R²⁴, —S(O)₂R²⁴, —S(O)NR²⁴R²⁴, —S(O)₂NR²⁴R^24′, —OS(O)NR²⁴R^24′, —OS(O)₂NR²⁴R^24′, —NR²⁴R^24′, —NR²⁴C(O)R²⁵, —NR²⁴C(O)OR²⁵, —NR²⁴C(O)NR²⁵R^25′, —NR²⁴S(O)R²⁵, —NR²⁴S(O)₂R²⁵, —NR²⁴S(O)NR²⁵R^25′, —NR²⁴S(O)₂NR²⁵R^25′, —C(O)R²⁴, —C(O)OR²⁴or —C(O)NR²⁴R^24′; or R¹⁷and R^17′ may combine to form a C₄-C₆cycloalkyl or a 4- to 6-membered heterocycle, wherein each hydrogen atom in C₄-C₆cycloalkyl or 4- to 6-membered heterocycle is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²⁴, —OC(O)R²⁴, —OC(O)NR²⁴R^24′, —OS(O)R²⁴, —OS(O)₂R²⁴, —SR²⁴, —S(O)R²⁴, —S(O)₂R²⁴, —S(O)NR²⁴R^24′, —S(O)₂NR²⁴R^24′, —OS(O)NR²⁴R^24′, —OS(O)₂NR²⁴R^24′, —NR²⁴R^24′, —NR²⁴C(O)R²⁵, —NR²⁴C(O)OR²⁵, —NR²⁴C(O)NR²⁵R^25′, —NR²⁴S(O)R²⁵, —NR²⁴S(O)₂R²⁵, —NR²⁴S(O)NR²⁵R^25′, —NR²⁴S(O)₂NR²⁵R^25′, —C(O)R²⁴, —C(O)OR²⁴or —C(O)NR²⁴R^24′;

R¹⁸is selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²⁶, —OC(O)R²⁶, —OC(O)NR²⁶R^26′, —OS(O)R²⁶, —OS(O)₂R²⁶, —SR²⁶, —S(O)R²⁶, —S(O)₂R²⁶, —S(O)NR²⁶R^26′, —S(O)₂NR²⁶R²⁶, —OS(O)NR²⁶R^26′, —OS(O)₂NR²⁶R^26′, —NR²⁶R²⁶, —NR²⁶C(O)R²⁷, —NR²⁶C(O)OR²⁷, —NR²⁶C(O)NR²⁷R^27′, —NR²⁶C(═NR^26″)NR²⁷R^27′, —NR²⁶S(O)R²⁷, —NR²⁶S(O)₂R²⁷, —NR²⁶S(O)NR²⁷R^27′, —NR²⁶S(O)₂NR²⁷R^27′, —C(O)R²⁶, —C(O)OR²⁶and —C(O)NR²⁶R^26′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, —(CH₂)_pOR²⁸, —(CH₂)_p(OCH₂)_qOR²⁸, —(CH₂)_p(OCH₂CH₂)_qOR²⁸, —OR²⁹, —OC(O)R²⁹, —OC(O)NR²⁹R^29′, —OS(O)R²⁹, —OS(O)₂R²⁹, —(CH₂)_pOS(O)₂OR²⁹, —OS(O)₂OR²⁹, —SR²⁹, —S(O)R²⁹, —S(O)₂R²⁹, —S(O)NR²⁹R^29′, —S(O)₂NR²⁹R^29′, —OS(O)NR²⁹R²⁹, —OS(O)₂NR²⁹R^29′, —NR²⁹R^29′, —NR²⁹C(O)R³⁰, —NR²⁹C(O)OR³⁰, —NR²⁹C(O)NR³⁰R³⁰, —NR²⁹S(O)R³⁰, —NR²⁹S(O)₂R³⁰, —NR²⁹S(O)NR³⁰R^30′, —NR²⁹S(O)₂NR³⁰R^30′, —C(O)R²⁹, —C(O)OR²⁹, or —C(O)NR²⁹R^29′;

each R¹⁹, R^19′, R²⁰R^20′, R²¹R^21′, R²²R^22′, R²³R²³, R²⁴R^24′, R²⁵R^25′, R²⁶R^26′, R^26″, R²⁹, R^29′, R³⁰and R^30′ is independently selected from the group consisting of H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by halogen, —OH, —SH, —NH₂or —CO₂H;

R²⁷and R^27′ are each independently selected from the group consisting of H, C₁-C₉alkyl, C₂-C₉alkenyl, C₂-C₉alkynyl, C₃-C₆cycloalkyl, —(CH₂)_p(sugar), —(CH₂)_p(OCH₂CH₂)— (sugar) and —(CH₂)_p(OCH₂CH₂CH₂)_q(sugar);

R²⁸is H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl or sugar;

n is 1, 2, 3, 4 or 5;

p is 1, 2, 3, 4 or 5; and

q is 1, 2, 3, 4 or 5;

and L²is of the formula

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wherein

X⁸is —NR⁵⁰— or —O—;

each R³⁹, R^39′, R⁴⁰and R^40′is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, —OR⁴⁸, —OC(O)R⁴⁸, —OC(O)NR⁴⁸R^48′, —OS(O)R⁴⁸, —OS(O)₂R⁴⁸, —SR⁴⁸, —S(O)R⁴⁸, —S(O)₂R⁴⁸, —S(O)NR⁴⁸R^48′, —S(O)₂NR⁴⁸R^48′, —OS(O)NR⁴⁸R^48′, —OS(O)₂NR⁴⁸R^48′, —NR⁴⁸R^48′, —NR⁴⁸C(O)R⁴⁹, —NR⁴⁸C(O)OR⁴⁹, —NR⁴⁸C(O)NR⁴⁹R^49′, —NR⁴⁸S(O)R⁴⁹, —NR⁴⁸S(O)₂R⁴⁹, —NR⁴⁸S(O)NR⁴⁹R^49′, —NR⁴⁸S(O)₂NR⁴⁹R^49′, —C(O)R⁴⁸, —C(O)OR⁴⁸or —C(O)NR⁴⁸R^48′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR⁴⁴, —OC(O)R⁴⁴, —OC(O)NR⁴⁴R^44′, —OS(O)R⁴⁴, —OS(O)₂R⁴⁴, —SR⁴⁴, —S(O)R⁴⁴, —S(O)₂R⁴⁴, —S(O)NR⁴⁴R^44′, —S(O)₂NR⁴⁴R^44′, —OS(O)NR⁴⁴R^44′, —OS(O)₂NR⁴⁴R^44′, —NR⁴⁴R^44′, —NR⁴⁴C(O)R⁴⁵, —NR⁴⁴C(O)OR⁴⁵, —NR⁴⁴C(O)NR⁴⁵R^45′, —NR⁴⁴S(O)R⁴⁵, —NR⁴⁴S(O)₂R⁴⁵, —NR⁴⁴S(O)NR⁴⁵R^45′, —NR⁴⁴S(O)₂NR⁴⁵R^45′, —C(O)R⁴⁴, —C(O)OR⁴⁴or —C(O)NR⁴⁴R^44′;

each R⁴¹is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR⁴⁶, —OC(O)R⁴⁶, —OC(O)NR⁴⁶R^46′, —OS(O)R⁴⁶, —OS(O)₂R⁴⁶, —SR⁴⁶, —S(O)R⁴⁶, —S(O)₂R⁴⁶, —S(O)NR⁴⁶R^46′, —S(O)₂NR⁴⁶R^46′, —OS(O)NR⁴⁶R^46′, —OS(O)₂NR⁴⁶R^46′, —NR⁴⁶R^46′, —NR⁴⁶C(O)R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, —NR⁴⁶C(O)NR⁴⁷R^47′, —NR⁴⁶S(O)R⁴⁷, —NR⁴⁶S(O)₂R⁴⁷, —NR⁴⁶S(O)NR⁴⁷R^47′, —NR⁴⁶S(O)₂NR⁴⁷R^47′, —C(O)R⁴⁶, —C(O)OR⁴⁶or —C(O)NR⁴⁶R^46′;

each R⁴²is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR⁴³, —OC(O)R⁴³, —OC(O)NR⁴³R^43′, —OS(O)R⁴³, —OS(O)₂R⁴³, —SR⁴³, —S(O)R⁴³, —S(O)₂R⁴³, —S(O)NR⁴³R^43′, —S(O)₂NR⁴³R^43′, —OS(O)NR⁴³R^43′, —OS(O)₂NR⁴³R^43′, —NR⁴³R^43′, —C(O)R⁴³, —C(O)R⁴³or —C(O)NR⁴³R^43′; and

each R⁴³, R^43′, R⁴⁴, R^44′, R⁴⁵, R^45′, R⁴⁶, R^46′, R⁴⁷, R^47′, R⁴⁸, R^48′, R⁴⁹R^49′, and R⁵⁰is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl; and

u is 1, 2, 3 or 4; and

D¹is a drug of the formula

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wherein

R^1aand R^2ain each instance are independently selected from the group consisting of H, D, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR^7a, —SR^7aand —NR^7a, R^7a′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl is independently optionally substituted by halogen, —OR^8a, —SR^8a, —NR^8a, R^8a′, —C(O)R^8a, —C(O)OR^8aor —C(O)NR^8aR^8a′;

R^3a, R^4a, R^5aand R^6aare each independently selected from the group consisting of H, D, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —CN, —NO₂, —NCO, —OR^9a, —SR^9a,—NR^9aR^9a′, —C(O)R^9a, —C(O)OR^9aand —C(O)NR^9aR^9a, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl is independently optionally substituted by halogen, —OR^10a, —SR^10a, —NR^10aR^10a′, —C(O)R^10a, —C(O)OR^10aor —C(O)NR^10aR^10a′;

each R^7a, R^7a′, R^8a, R^8a′, R^9a, R^9a′, R^10aand R^10a′ is independently H, D, C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl;

X^1ais —NR^11a—, ═N—, —N═, —C(R^11a)═ or ═C(R^11a)—;

X^2ais —NR^11a′— or ═N—;

X^3ais —NR^11a″—, —N═ or —C(R^11a′)═;

X^4ais —N═ or —C═;

X^5ais —NR^12a— or —CR^12aR^12a′—;

Y^1ais —NR^13aR^13awhen X^1ais —N═ or —C(R^11a)═, or Y^1ais ═NR^13awhen X^1ais —NR^11a—, ═N— or ═C(R^11a)—;

Y^2ais H, D, C₁-C₆alkyl, C₂-C₆alkenyl, —C(O)R^14a, —C(O)OR^14aor —C(O)NR^14aR^14a′ when X^4ais —C═, or Y^2ais absent when X^4ais —N═;

R^1a′, R^2a′, R^3a′, R^11a, R^11a′, R^11a″, R^12a, R^12a′, R^13a, R^3a′, R^14aand R^14a′are each independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —C(O)R^15a, —C(O)OR^15aand —C(O)NR^15aR^15a′;

R^4aand R^5a′ are each independently selected from the group consisting of C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR^16a, —SR^16a, —NR^16aR^16a′, provided that one of R^4a′ and R^5a′ is a covalent bond to an AA, a L¹or a L²;

R^15a, R^15a′, R^16aand R^16a′ are each independently H or C₁-C₆alkyl;

m¹is 1, 2, 3 or 4; and

each * is a covalent bond;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the disclosure provides a conjugate of the formula B-L-D¹, wherein B is a binding ligand of the formula

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wherein

R¹and R²in each instance are independently selected from the group consisting of H, D, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR⁷, —SR⁷and —NR⁷R^7′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl is independently optionally substituted by halogen, —OR⁸, —SR^8′, —NR⁸R^8′, —C(O)R⁸, —C(O)OR⁸or —C(O)NR⁸R^8′;

each R⁷, R^7′, R⁸, R^8′, R⁹, R^9′, R¹⁰and R^10′ is independently H, D, C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl;

X¹is —NR¹¹—, ═N—, —N═, —C(R¹¹)═ or ═C(R¹¹)—;

X²is —NR^11′— or ═N—;

X³is —NR^11″—, —N═ or —C(R^11′)═;

X⁴is —N═ or —C═;

X⁵is NR¹²or CR¹²R¹²;

Y¹is H, D, —OR¹³or —SR¹³when X¹is —N═ or —C(R¹¹)═, or Y¹is ═O when X¹is —NR¹¹—, ═N— or ═C(R¹¹)—;

Y²is H, D, C₁-C₆alkyl, C₂-C₆alkenyl, —C(O)R¹⁴, —C(O)OR¹⁴or —C(O)NR¹⁴R^14′when X⁴is —C═, or Y²is absent when X⁴is —N═;

R^1′, R^2′, R^3′, R^4′, R¹¹, R^11′, R^11″, R^12′, R¹³, R¹⁴and R^14′are each independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —C(O)R¹⁵, —C(O)OR¹⁵and —C(O)NR¹⁵R^15′;

R¹⁵and R^15′ are each independently H or C₁-C₆alkyl; and

m is 1, 2, 3 or 4;

L is a linker comprising at least one AA, at least one L¹and an L², wherein each AA is an amino acid, each L¹is of the formula

embedded image

wherein

R¹⁶is selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —C(O)R¹⁹, —C(O)OR¹⁹and —C(O)NR¹⁹R^19′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR²⁰, —OC(O)R²⁰, —OC(O)NR²⁰R^20′, —OS(O)R²⁰, —OS(O)₂R²⁰, —SR²⁰, —S(O)R²⁰, —S(O)₂R²⁰, —S(O)NR²⁰R^20′, —S(O)₂NR²⁰R^20′, —OS(O)NR²⁰R^20′, —OS(O)₂NR²⁰R^20′, —NR²⁰R^20′, —NR²⁰C(O)R²¹, —NR²⁰C(O)OR²¹, —NR²⁰C(O)NR²¹R^21′, —NR²⁰S(O)R²¹, —NR²⁰S(O)₂R²¹, —NR²⁰S(O)NR²¹R^21′, —NR²⁰S(O)NR²¹R^21′, —C(O)R²⁰, —C(O)OR²⁰or —C(O)NR²⁰R^20′;

each R¹⁷and R^17′ is independently selected from the group consisting of H, D, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²², —OC(O)R²², —OC(O)NR²²R^22′, —OS(O)R²², —OS(O)₂R²², —SR²², —S(O)R²², —S(O)₂R²², —S(O)NR²²R^22′, —S(O)₂NR²²R^22′, —OS(O)NR²²R^22′, —OS(O)₂NR²²R^22′, —NR²²R^22′, —NR²²C(O)R²³, —NR²²C(O)OR²³, —NR²²C(O)NR²³R^23′, —NR²²S(O)R²³, —NR²²S(O)₂R²³, —NR²²S(O)NR²³R^23′, —NR²²S(O)₂NR²³R^23′, —C(O)R²², —C(O)OR²², and —C(O)NR²²R^22′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR²⁴, —OC(O)R²⁴, —OC(O)NR²⁴R^24′, —OS(O)R²⁴, —OS(O)₂R²⁴, —SR²⁴, —S(O)R²⁴, —S(O)₂R²⁴, —S(O)NR²⁴R^24′, —S(O)₂NR²⁴R^24′, —OS(O)NR²⁴R^24′, —OS(O)₂NR²⁴R^24′, —NR²⁴R^24′, —NR²⁴C(O)R²⁵, —NR²⁴C(O)OR²⁵, —NR²⁴C(O)NR²⁵R^25′, —NR²⁴S(O)R²⁵, —NR²⁴S(O)₂R²⁵, —NR²⁴S(O)NR²⁵R^25′, —NR²⁴S(O)₂NR²⁵R²⁵, —C(O)R²⁴, —C(O)OR²⁴or —C(O)NR²⁴R^24′; or R¹⁷and R^17′ may combine to form a C₄-C₆cycloalkyl or a 4- to 6-membered heterocycle, wherein each hydrogen atom in C₄-C₆cycloalkyl or 4- to 6-membered heterocycle is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²⁴, —OC(O)R²⁴, —OC(O)NR²⁴R^24′, —OS(O)R²⁴, —OS(O)₂R⁴², —SR²⁴, —S(O)R²⁴, —S(O)₂R²⁴, —S(O)NR²⁴R^24′, —S(O)₂NR²⁴R^24′, —OS(O)NR²⁴R^24′, —OS(O)₂NR²⁴R^24′, —NR²⁴R²⁵, —NR²⁴C(O)R²⁵, —NR²⁴C(O)OR²⁵, —NR²⁴C(O)NR²⁵R^25′, —NR²⁴S(O)R²⁵, —NR²⁴S(O)₂R²⁵, —NR²⁴S(O)NR²⁵R^25′, —NR²⁴S(O)₂NR²⁵R^25′, —C(O)R²⁴, —C(O)OR²⁴or —C(O)NR²⁴R^24′;

R¹⁸is selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²⁶, —OC(O)R²⁶, —OC(O)NR²⁶R^26′, —OS(O)R²⁶, —OS(O)₂R²⁶, —SR²⁶, —S(O)R²⁶, —S(O)₂R²⁶, —S(O)NR²⁶R^26′, —S(O)₂NR²⁶R^26′, —OS(O)NR²⁶R^26′, —OS(O)₂NR²⁶R^26′, —NR²⁶R^26′, —NR²⁶C(O)R²⁷, —NR²⁶C(O)OR²⁷, —NR²⁶C(O)NR²⁷R^27′, —NR²⁶C(═NR^26″)NR²⁷R^27′, —NR²⁶S(O)R²⁷, —NR²⁶S(O)₂R²⁷, —NR²⁶S(O)NR²⁷R^27′, —NR²⁶S(O)₂NR²⁷R^27′, —C(O)R²⁶, —C(O)OR²⁶and —C(O)NR²⁶R^26′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, —(CH₂)_pOR²⁸, —(CH₂)_p(OCH₂)_qOR²⁸, —(CH₂)_p(OCH₂CH₂)_qOR²⁸, —OR²⁹, —OC(O)R²⁹, —OC(O)NR²⁹R^29′, —OS(O)R²⁹, —OS(O)₂R²⁹, —(CH₂)_pOS(O)₂OR²⁹, —OS(O)₂OR²⁹, —SR²⁹, —S(O)R²⁹, —S(O)₂R²⁹, —S(O)NR²⁹R^29′, —S(O)₂NR²⁹R^29′, —OS(O)NR²⁹R^29′, —OS(O)₂NR²⁹R^29′, —NR²⁹R^29′, —NR²⁹C(O)R³⁰, —NR²⁹C(O)OR³⁰, —NR²⁹C(O)NR³⁰R^30′, —NR²⁹S(O)R³⁰, —NR²⁹S(O)₂R³⁰, —NR²⁹S(O)NR³⁰R^30′, —NR²⁹S(O)₂NR³⁰R^30′, —C(O)R²⁹, —C(O)R²⁹or —C(O)NR²⁹R^29′;

each R¹⁹, R^19′, R²⁰, R^20′, R²¹, R^21′, R²², R^22′, R²³, R^23′, R²⁴, R^24′, R²⁵, R^25′, R²⁶, R^26′, R^26″, R²⁹, R^29′, R³⁰and R^30′is independently selected from the group consisting of H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by halogen, —OH, —SH, —NH₂or —CO₂H;

R²⁷and R^27′ are each independently selected from the group consisting of H, C₁-C₉alkyl, C₂-C₉alkenyl, C₂-C₉alkynyl, C₃-C₆cycloalkyl, —(CH₂)_p(sugar), —(CH₂)_p(OCH₂CH₂)_q-(sugar) and —(CH₂)_p(OCH₂CH₂CH₂)_q(sugar);

R²⁸is H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl or sugar;

n is 1, 2, 3, 4 or 5;

p is 1, 2, 3, 4 or 5; and

q is 1, 2, 3, 4 or 5; and

L²is of the formula

embedded image

wherein

each X⁶is independently C₁-C₆alkyl or C₆-C₁₀aryl(C₁-C₆alkyl), wherein each hydrogen atom in C₁-C₆alkyl and C₆-C₁₀aryl(C₁-C₆alkyl) is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR³⁴, —OC(O)R³⁴, —OC(O)NR³⁴R^34′, —OS(O)R³⁴, —OS(O)₂R³⁴, —SR³⁴, —S(O)R³⁴, —S(O)₂R³⁴, —S(O)NR³⁴R^34′, —S(O)₂NR³⁴R^34′, —OS(O)NR³⁴R^34′, —OS(O)₂NR³⁴R^34′, —NR³⁴R^34′, —NR³⁴C(O)R³⁵, —NR³⁴C(O)OR³⁵, —NR³⁴C(O)NR³⁵R^35′, —NR³⁴S(O)R³⁵, —NR³⁴S(O)₂R³⁵, —NR³⁴S(O)NR³⁵R^35′, —NR³⁴S(O)₂NR³⁵R^35′, —C(O)R³⁴or —C(O)NR³⁴R^34′;

each X⁷is —NR^31a— or —O—, and when X⁶is C₁-C₆alkyl and X⁷is —O—, then at least one hydrogen atom in C₁-C₆alkyl is substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR³⁴, —OC(O)R³⁴, —OC(O)NR³⁴R^34′, —OS(O)R³⁴, —OS(O)₂R³⁴, —SR³⁴, —S(O)R³⁴, —S(O)₂R³⁴, —S(O)NR³⁴R^34′, —S(O)₂NR³⁴R^34′, —OS(O)NR³⁴R^34′, —OS(O)₂NR³⁴R^34′, —NR³⁴R^34′, —NR³⁴C(O)R³⁵, —NR³⁴C(O)OR³⁵, —NR³⁴C(O)NR³⁵R^35′, —NR³⁴S(O)R³⁵, —NR³⁴S(O)₂R³⁵, —NR³⁴S(O)NR³⁵R^35′, —NR³⁴S(O)₂NR³⁵R^35′, —C(O)R³⁴or —C(O)NR³⁴R^34′;

each R³¹and R^31ais independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR³², —OC(O)R³², —OC(O)NR³²R^32′, —OS(O)R³², —OS(O)₂R³², —SR³², —S(O)R³², —S(O)₂R³², —S(O)NR³²R^32′, —S(O)₂NR³²R^32′, —OS(O)NR³²R^32′, —OS(O)₂NR³²R^32′, —NR³²R^32′, —NR³²C(O)R³³, —NR³²C(O)OR³³, —NR³²C(O)NR³³R^33′, —NR³²S(O)R³³, —NR³²S(O)₂R³³, —NR³²S(O)NR³³R^33′, —NR³²S(O)₂NR³³R^33′, —C(O)R³², —C(O)OR³²or —C(O)NR³²R^32′;

each R^31′is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR^32a, —OC(O)R^32a, —OC(O)NR^32aR^32a, —OS(O)R^32a, —OS(O)₂R^32a, —SR^32a, —S(O)R^32a, —S(O)₂R^32a, —S(O)NR^32aR^32a′, —S(O)₂NR^32aR^32a′, —OS(O)NR^32aR^32a′, —OS(O)₂NR^32aR^32a′, —NR^32aR^32a′, —C(O)R^32a, —C(O)OR^32aor —C(O)NR^32aR^32a′;

each R^32a, R^32a′, R³², R^32′, R³³, R^33′, R³⁴, R^34′, R³⁵and R^35′is independently selected from the group consisting of H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, and 5- to 7-membered heteroaryl;

each R⁵¹and R⁵³is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR⁵⁴, —OC(O)R⁵⁴, —OC(O)NR⁵⁴R^54′, —OS(O)R⁵⁴, —OS(O)₂R⁵⁴, —SR⁵⁴, —S(O)R⁵⁴, —S(O)₂R⁵⁴, —S(O)NR⁵⁴R⁵⁴, —S(O)₂NR⁵⁴R^54′, —OS(O)NR⁵⁴R^54′, —OS(O)₂NR⁵⁴R^54′, —NR⁵⁴R^54′, —NR⁵⁴C(O)R⁵⁵, —NR⁵⁴C(O)OR⁵⁵, —NR⁵⁴C(O)NR⁵⁵R^55′, —NR⁵⁴S(O)R⁵⁵, —NR⁵⁴S(O)₂R⁵⁵, —NR⁵⁴S(O)NR⁵⁵R^55′, —NR⁵⁴S(O)₂NR⁵⁵R^55′, —C(O)R⁵⁴, —C(O)R⁵⁴or —C(O)NR⁵⁴R⁵⁴;

each R⁵²is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR⁵⁶, —OC(O)R⁵⁶, —OC(O)NR⁵⁶R^56′, —OS(O)R⁵⁶, —OS(O)₂R⁵⁶, —SR⁵⁶, —S(O)R⁵⁶, —S(O)₂R⁵⁶, —S(O)NR⁵⁶R^56′, —S(O)₂NR⁵⁶R^56′, —OS(O)NR⁵⁶R^56′, —OS(O)₂NR⁵⁶R^56′′, —NR⁵⁶R^56′, —C(O)R⁵⁶, —C(O)OR⁵⁶or —C(O)NR⁵⁶R^56′;

each R⁵⁴, R^54′, R⁵⁵, R^55′, R⁵⁶and R^56′is independently selected from the group consisting of H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl; and

v is 1, 2, 3, 4, 5 or 6; and

D¹is a drug of the formula I

embedded image

wherein

R^1aand R^2ain each instance are independently selected from the group consisting of H, D, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR^7a, —SR^7aand —NR^7aR^7a′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl is independently optionally substituted by halogen, —OR^8a, —SR^8a, —NR^8aR^8a′, —C(O)R^8a, —C(O)OR^8aor —C(O)NR^8aR^8a′;

R^3a, R^4a, R^5aand R^6aare each independently selected from the group consisting of H, D, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —CN, —NO₂, —NCO, —OR^9a, —SR^9a, —NR^9aR^9a′, —C(O)R^9a, —C(O)OR^9aand —C(O)NR^9aR^9a, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl is independently optionally substituted by halogen, —OR^10a, —SR^10a, —NR^10aR^10a, —C(O)R^10a, —C(O)OR^10aor —C(O)NR^10aR^10a′;

each R^7a, R^7a′, R^8a, R^8a′, R^9a, R^9a′, R^10aand R^10a′is independently H, D, C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl;

X^1ais —NR^11a—, ═N—, —N═, —C(R^11a)═ or ═C(R^11a)—;

X^2ais —NR^11a′— or ═N—;

X^3ais —NR^11a″—, —N═ or —C(R^11a′)═;

X^4ais —N═ or —C═;

X^5ais —NR^12a— or —CR^12aR^12a′—;

Y^1ais H, D, —OR^13a, —SR^13aor NR^13aR^13a′ when X^1ais —N═ or —C(R^11a)═, or Y^1ais ═NR^13awhen X^1ais —NR^11a—, ═N— or ═C(R^11a)—;

Y^2ais H, D, C₁-C₆alkyl, C₂-C₆alkenyl, —C(O)R^14a, —C(O)OR^14aor —C(O)NR^14aR^14a′when X^4ais —C═, or Y^2ais absent when X^4ais —N═;

R^1a′, R^2a′, R^3a′, R^11a, R^11a′, R^11a″, R^12a, R^12a′, R^13a, R^13a′, R^14aand R^14a′are each independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —C(O)R^15a, —C(O)OR^15aand —C(O)NR^15aR^15a′;

R^4a′ and R^5a′ are each independently selected from the group consisting of C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR^16a, —SR^16a, —NR^16aR^16a′, provided that one of R^4a′ and R^5a′ is a covalent bond to an AA, a L¹or a L²;

R^15a, R^15a′, R^16aand R^16a′ are each independently H or C₁-C₆alkyl;

m¹is 1, 2, 3 or 4; and

each * is a covalent bond;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the disclosure provides a conjugate selected from the group consisting of

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or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides a pharmaceutical composition comprising a conjugate as described herein, or a pharmaceutically acceptable salt thereof, and at least one excipient. In one embodiment, a conjugate as described herein, or a pharmaceutically acceptable salt thereof, is included in an amount effective to treat disease states caused by pathogenic populations of cells, such as inflammatory cells.

In another aspect, the disclosure provides methods for treating diseases and disease states caused by pathogenic populations of cells, such as inflammatory cells comprising administering a therapeutically effective amount of a conjugate as described herein to a patient in need of such treatment.

In another aspect, the disclosure provides for the use of a conjugate as described herein in the preparation of a medicament for the treatment of inflammation.

In another aspect, the disclosure provides for the use of a conjugate as described herein for the treatment of inflammation.

The conjugates of the present disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another.

1. A conjugate of the formula B-L-D¹, wherein B is a binding ligand of the formula

embedded image

wherein

each R⁷, R^7′, R⁸, R^8′, R⁹, R^9′, R¹⁰and R^10′ is independently H, D, C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl;

X¹is —NR¹¹—, ═N—, —N═, —C(R¹¹)═ or ═C(R¹¹)—;

X²is —NR^11′— or ═N—;

X³is —NR^11″—, —N═ or —C(R^11′)—;

X⁴is —N═ or —C═;

X⁵is NR¹²or CR¹²R^12′;

Y¹is H, D, —OR¹³or —SR¹³when X¹is —N═ or —C(R¹¹)═, or Y¹is ═O when X¹is —NR¹¹—, ═N— or ═C(R¹¹)—;

Y²is H, D, C₁-C₆alkyl, C₂-C₆alkenyl, —C(O)R¹⁴, —C(O)OR¹⁴or —C(O)NR¹⁴R^14′when X⁴is —C═, or Y²is absent when X⁴is —N═;

R¹⁵and R^15′ are each independently H or C₁-C₆alkyl; and

m is 1, 2, 3 or 4;

L is a linker comprising at least one AA, at least one L¹and an L², wherein each AA is an amino acid, each L¹is of the formula

embedded image

wherein

R¹⁶is selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —C(O)R¹⁹, —C(O)OR¹⁹and —C(O)NR¹⁹R^19′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR²⁰, —OC(O)R²⁰, —OC(O)NR²⁰R^20′, —OS(O)R²⁰, —OS(O)₂R²⁰, —SR²⁰, —S(O)R²⁰, —S(O)₂R²⁰, —S(O)NR²⁰R^20′, —S(O)₂NR²⁰R^20′, —OS(O)NR²⁰R^20′, —OS(O)₂NR²⁰R^20′, —NR²⁰R^20′, —NR²⁰C(O)R²¹, —NR²⁰C(O)OR²¹, —NR²⁰C(O)NR²¹R^21′, —NR²⁰S(O)R²¹, —NR²⁰S(O)₂R²¹, —NR²⁰S(O)NR²¹R^21′, —NR²⁰S(O)₂NR²¹R^21′, —C(O)R²⁰, —C(O)OR²⁰or —C(O)NR²⁰R^20′;

each R¹⁷and R^17′ is independently selected from the group consisting of H, D, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²², —OC(O)R²², —OC(O)NR²²R^22′, —OS(O)R²², —OS(O)₂R²², —SR²², —S(O)R²², —S(O)₂R²², —S(O)NR²²R^22′, —S(O)₂NR²²R^22′, —OS(O)NR²²R^22′, —OS(O)₂NR²²R^22′, —NR²²R^22′, —NR²²C(O)R²³, —NR²²C(O)OR²³, —NR²²C(O)NR²³R^23′, —NR²²S(O)R²³, —NR²²S(O)₂R²³, —NR²²S(O)NR²³R^23′, —NR²²S(O)₂NR²³R^23′, —C(O)R²², —C(O)OR²², and —C(O)NR²²R^22′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR²⁴, —OC(O)R²⁴, —OC(O)NR²⁴R^24′, —OS(O)R²⁴, —OS(O)₂R²⁴, —SR²⁴, —S(O)R²⁴, —S(O)₂R²⁴, —S(O)NR²⁴R^24′—S(O)₂NR²⁴R^24′, —OS(O)NR²⁴R^24′, —OS(O)₂NR²⁴R^24′, —NR²⁴R^24′, —NR²⁴C(O)R²⁵, —NR²⁴C(O)OR²⁵, —NR²⁴C(O)NR²⁵R^25′, —NR²⁴S(O)R²⁵, —NR²⁴S(O)₂R²⁵, —NR²⁴S(O)NR²⁵R^25′, —NR²⁴S(O)₂NR²⁵R^25′, —C(O)R²⁴, —C(O)OR²⁴or —C(O)NR²⁴R^24′; or R¹⁷and R^17′ may combine to form a C₄-C₆cycloalkyl or a 4- to 6-membered heterocycle, wherein each hydrogen atom in C₄-C₆cycloalkyl or 4- to 6-membered heterocycle is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²⁴, —OC(O)R²⁴, —OC(O)NR²⁴R^24′, —OS(O)R²⁴, —OS(O)₂R²⁴, —SR²⁴, —S(O)R²⁴, —S(O)₂R²⁴, —S(O)NR²⁴R^24′, —S(O)₂NR²⁴R^24′, —OS(O)NR²⁴R^24′, —OS(O)₂NR²⁴R^24′, —NR²⁴R^24′, —NR²⁴C(O)R²⁵, —NR²⁴C(O)OR²⁵, —NR²⁴C(O)NR²⁵R^25′, —NR²⁴S(O)R²⁵, —NR²⁴S(O)₂R²⁵, —NR²⁴S(O)NR²⁵R^25′, —NR²⁴S(O)₂NR²⁵R^25′, —C(O)R²⁴, —C(O)OR²⁴or —C(O)NR²⁴R^24′;

R¹⁸is selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²⁶, —OC(O)R²⁶, —OC(O)NR²⁶R^26′, —OS(O)R²⁶, —OS(O)₂R²⁶, —SR²⁶, —S(O)R²⁶, —S(O)₂R²⁶, —S(O)NR²⁶R^26′, —S(O)₂NR²⁶R^26′, —OS(O)NR²⁶R^26′, —OS(O)₂NR²⁶R^26′, —NR²⁶R^26′, —NR²⁶C(O)R²⁷, —NR²⁶C(O)OR²⁷, —NR²⁶C(O)NR²⁷R^27′, —NR²⁶C(═NR^26″)NR²⁷R^27′, —NR²⁶S(O)R²⁷, —NR²⁶S(O)₂R²⁷, —NR²⁶S(O)NR²⁷R^27′, —NR²⁶S(O)₂NR²⁷R²⁷, —C(O)R²⁶, —C(O)OR²⁶and —C(O)NR²⁶R^26′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, —(CH₂)_pOR²⁸, —(CH₂)_p(OCH₂)_qOR²⁸, —(CH₂)_p(OCH₂CH₂)_qOR²⁸, —OR²⁹, —OC(O)R²⁹, —OC(O)NR²⁹R^29′, —OS(O)R²⁹, —OS(O)₂R²⁹, —(CH₂)_pOS(O)₂OR²⁹, —OS(O)₂OR²⁹, —SR²⁹, —S(O)R²⁹, —S(O)₂R²⁹, —S(O)NR²⁹R^29′, —S(O)₂NR²⁹R^29′, —OS(O)NR²⁹R^29′, —OS(O)₂NR²⁹R^29′, —NR²⁹R^29′, —NR²⁹C(O)R³⁰, —NR²⁹C(O)OR³⁰, —NR²⁹C(O)NR³⁰R^30′, —NR²⁹S(O)R³⁰, —NR²⁹S(O)₂R³⁰, —NR²⁹S(O)NR³⁰R^30′, —NR²⁹S(O)₂NR³⁰R^30′, —C(O)R²⁹, —C(O)OR²⁹or —C(O)NR²⁹R^29′;

each R¹⁹, R^19′, R²⁰, R^20′, R²¹, R^21′, R²², R^22′, R²³, R^23′, R²⁴R^24′, R²⁵, R^25′, R²⁶, R^26′, R^26″, R²⁹, R^29′, R³⁰and R^30′ is independently selected from the group consisting of H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by halogen, —OH, —SH, —NH₂or —CO₂H;

R²⁷and R^27′ are each independently selected from the group consisting of H, C₁-C₉alkyl, C₂-C₉alkenyl, C₂-C₉alkynyl, C₃-C₆cycloalkyl, —(CH₂)_p(sugar), —(CH₂)_p(OCH₂CH₂)_q-(sugar) and —(CH₂)_p(OCH₂CH₂CH₂)_q(sugar);

R²⁸is H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl or sugar;

n is 1, 2, 3, 4 or 5;

p is 1, 2, 3, 4 or 5; and

q is 1, 2, 3, 4 or 5;

and L²is of the formula

embedded image

wherein

X⁸is —NR⁵⁰— or —O—;

each R³⁹, R^39′, R⁴⁰and R^40′ is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl C₃-C₆cycloalkyl, —OR⁴⁸, —OC(O)R⁴⁸, —OC(O)NR⁴⁸R^48′, —OS(O)R⁴⁸, —OS(O)₂R⁴⁸, —SR⁴⁸, —S(O)R⁴⁸, —S(O)₂R⁴⁸, —S(O)NR⁴⁸R^48′, —S(O)₂NR⁴⁸R^48′, —OS(O)NR⁴⁸R^48′, —OS(O)₂NR⁴⁸R^48′, —NR⁴⁸R^48′, —NR⁴⁸C(O)R⁴⁹, —NR⁴⁸C(O)OR⁴⁹, —NR⁴⁸C(O)NR⁴⁹R^49′, —NR⁴⁸S(O)R⁴⁹, —NR⁴⁸S(O)₂R⁴⁹, —NR⁴⁸S(O)NR⁴⁹R^49′—NR⁴⁸S(O)₂NR⁴⁹R^49′, —C(O)R⁴⁸, —C(O)OR⁴⁸or —C(O)NR⁴⁸R^48′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR⁴⁴, —OC(O)R⁴⁴, —OC(O)NR⁴⁴R^44′, —OS(O)R⁴⁴, —OS(O)₂R⁴⁴, —SR⁴⁴, —S(O)R⁴⁴, —S(O)₂R⁴⁴, —S(O)NR⁴⁴R^44′, —S(O)₂NR⁴⁴R^44′, —OS(O)NR⁴⁴R^44′, —OS(O)₂NR⁴⁴R^44′, —NR⁴⁴R^44′, —NR⁴⁴C(O)R⁴⁵, —NR⁴⁴C(O)OR⁴⁵, —NR⁴⁴C(O)NR⁴⁵R^45′, —NR⁴⁴S(O)R⁴⁵, —NR⁴⁴S(O)₂R⁴⁵, —NR⁴⁴S(O)NR⁴⁵R^45′, —NR⁴⁴S(O)₂NR⁴⁵R⁴⁵, —C(O)R⁴⁴, —C(O)OR⁴⁴or —C(O)NR⁴⁴R^44′;

each R⁴³, R^43′, R⁴⁴, R^44′, R⁴⁵, R^45′, R⁴⁶, R^46′, R⁴⁷, R^47′, R⁴⁸, R^48′, R⁴⁹, R^49′ and R⁵⁰is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl; and

u is 1, 2, 3 or 4; and

D is a drug of the formula

embedded image

wherein

R^3a, R^4a, R^5aand R^6aare each independently selected from the group consisting of H, D, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —CN, —NO₂, —NCO, —OR^9a, —SR^9a, —NR^9aR^9a′, —C(O)R^9a, —C(O)OR^9aand —C(O)NR^9aR^9a′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl is independently optionally substituted by halogen, —OR^10a, —SR^10a, —NR^10aR^10a′, —C(O)R^10a, —C(O)OR^10aor —C(O)NR^10aR^10a;

each R^7a, R^7a′, R^8a, R^8a′, R^9a, R^9a′, R^10aand R^10a′ is independently H, D, C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl;

X^1ais —NR^11a—, ═N—, —N═, —C(R^11a)═ or ═C(R^11a)—;

X^2ais —NR′— or ═N—;

X^3ais —NR^11a″—, —N═ or —C(R^11a′)═;

X^4ais —N═ or —C═;

X^5ais —NR^12aor —CR^12aR^12a′—;

Y^1ais —NR^13aR^13a′when X^1ais —N═ or —C(R^11a)═, or Y^1ais ═NR^13awhen X^1ais —NR^11a—, ═N— or ═C(R^11a)—;

Y^2ais H, D, C₁-C₆alkyl, C₂-C₆alkenyl, —C(O)R^14a, —C(O)OR^14aor —C(O)NR^14aR^14a′ when X^4ais —C═, or Y^2ais absent when X^4ais —N═;

R^1a′, R^2a′, R^3a′, R^11a, R^11a′, R^11a″, R^12a, R^12a′, R^13a, R^13a′, R^14aand R^14a′ are each independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —C(O)R^15a, —C(O)OR^15aand —C(O)NR^15aR^15a′;

R^4a′and R^5a′ are each independently selected from the group consisting of C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR^16a, —SR^16a, —NR^16aR^16a′, provided that one of R^4a′ and R^5a′ is a covalent bond to an AA, a L¹or a L²;

R^15a, R^15a′, R^16aand R^16a′ are each independently H or C₁-C₆alkyl;

m¹is 1, 2, 3 or 4; and

each * is a covalent bond;

or a pharmaceutically acceptable salt thereof.

2. A conjugate of the formula B-L-D¹, wherein B is a binding ligand of the formula

embedded image

wherein

each R⁷, R^7′, R⁸, R^8′, R⁹, R^9′, R¹⁰and R^10′ is independently H, D, C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl;

X¹is —NR¹¹—, ═N—, —N═, —C(R¹¹)═ or ═C(R¹¹)—;

X²is —NR^11′— or ═N—;

X³is —NR^11″—, —N═ or —C(R^11′)═;

X⁴is —N═ or —C═;

X⁵is NR¹²or CR¹²R^12′;

Y¹is H, D, —OR¹³or —SR¹³when X¹is —N═ or —C(R¹¹)═, or Y¹is ═O when X is —NR¹¹—, ═N— or ═C(R¹¹)—;

Y²is H, D, C₁-C₆alkyl, C₂-C₆alkenyl, —C(O)R¹⁴, —C(O)OR¹⁴or —C(O)NR¹⁴R^14′ when X⁴is —C═, or Y²is absent when X⁴is —N═;

R^1′, R^2′, R^3′, R^4′, R¹¹, R^11′, R^11″, R¹², R^12′, R¹³, R¹⁴and R^14′ are each independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —C(O)R¹⁵, —C(O)OR¹⁵and —C(O)NR¹⁵R^15′;

R¹⁵and R^15′ are each independently H or C₁-C₆alkyl; and

m is 1, 2, 3 or 4;

L is a linker comprising at least one AA, at least one L¹and an L², wherein each AA is an amino acid, each L¹is of the formula

embedded image

wherein

R¹⁶is selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —C(O)R¹⁹, —C(O)OR¹⁹and —C(O)NR¹⁹R^19′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR²⁰, —OC(O)R²⁰, —OC(O)NR²⁰R^20′, —OS(O)R²⁰, —OS(O)₂R²⁰, —SR²⁰, —S(O)R²⁰, —S(O)₂R²⁰, —S(O)NR²⁰R²⁰, —S(O)₂NR²⁰R²⁰, —OS(O)NR²⁰R²⁰, —OS(O)₂NR²⁰R^20′, —NR²⁰R^20′, —NR²⁰C(O)R²¹, —NR²⁰C(O)OR²¹, —NR²⁰C(O)NR²¹R^21′, —NR²⁰S(O)R²¹, —NR²⁰S(O)₂R²¹, —NR²⁰S(O)NR²¹R^21′, —NR²⁰S(O)₂NR²¹R^21′, —C(O)R²⁰, —C(O)OR²⁰or —C(O)NR²⁰R^20′;

each R¹⁷and R^17′ is independently selected from the group consisting of H, D, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²², —OC(O)R²², —OC(O)NR²²R^22′, —OS(O)R²², —OS(O)₂R²², —SR²², —S(O)R²², —S(O)₂R²², —S(O)NR²²R^22′, —S(O)₂NR²²R^22′, —OS(O)NR²²R^22′, —OS(O)₂NR²²R^22′, —NR²²R^22′, —NR²²C(O)R²³, —NR²²C(O)OR²³, —NR²²C(O)NR²³R^23′, —NR²²S(O)R²³, —NR²²S(O)₂R²³, —NR²²S(O)NR²³R^23′, —NR²²S(O)₂NR²³R^23′, —C(O)R²², —C(O)OR²², and —C(O)NR²²R^22′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR², —OC(O)R²⁴, —OC(O)NR²⁴R^24′, —OS(O)R²⁴, —OS(O)₂R²⁴, —SR²⁴, —S(O)R²⁴, —S(O)₂R²⁴, —S(O)NR²⁴R^24′, —S(O)₂NR²⁴R^24′, —OS(O)NR²⁴R^24′, —OS(O)₂NR²⁴R^24′, —NR²⁴R^24′, —NR²⁴C(O)R²⁵, —NR²⁴C(O)OR²⁵, —NR²⁴C(O)NR²⁴R^25′, —NR²⁴S(O)R²⁵, —NR²⁴S(O)₂R²⁵, —NR²⁴S(O)NR²⁵R^25′, —NR²⁴S(O)₂NR²⁵R^25′, —C(O)R²⁴, —C(O)OR²⁴or —C(O)NR²⁴R^24′; or R¹⁷and R^17′ may combine to form a C₄-C₆cycloalkyl or a 4- to 6-membered heterocycle, wherein each hydrogen atom in C₄-C₆cycloalkyl or 4- to 6-membered heterocycle is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²⁴, —OC(O)R²⁴, —OC(O)NR²⁴R^24′, —OS(O)R²⁴, —OS(O)₂R²⁴, —SR²⁴, —S(O)R²⁴, —S(O)₂R²⁴, —S(O)NR²⁴R^24′, —S(O)₂NR²⁴R^24′, —OS(O)NR²⁴R^24′, —OS(O)₂NR²⁴R^24′, —NR²⁴R²⁴, —NR²⁴C(O)R²⁵, —NR²⁴C(O)OR²⁵, —NR²⁴C(O)NR²⁵R^25′, —NR²⁴S(O)R²⁵, —NR²⁴S(O)₂R²⁵, —NR²⁴S(O)NR²⁵R^25′, —NR²⁴S(O)₂NR²⁵R^25′, —C(O)R²⁴, —C(O)OR²⁴or —C(O)NR²⁴R^24′;

R¹⁸is selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²⁶, —OC(O)R²⁶, —OC(O)NR²⁶R^26′, —OS(O)R²⁶, —OS(O)₂R²⁶, —SR²⁶, —S(O)R²⁶, —S(O)₂R²⁶, —S(O)NR²⁶R^26′, —S(O)₂NR²⁶R^26′, —OS(O)NR²⁶R^26′, —OS(O)₂NR²⁶R^26′, —NR²⁶R^26′, —NR²⁶C(O)R²⁷, —NR²⁶C(O)OR²⁷, —NR²⁶C(O)NR²⁷R^27′, —NR²⁶C(═NR²⁶″)NR²⁷R^27′, —NR²⁶S(O)R²⁷, —NR²⁶S(O)₂R²⁷, —NR²⁶S(O)NR²⁷R^27′, —NR²⁶S(O)₂NR²⁷R^27′, —C(O)R²⁶, —C(O)OR²⁶and —C(O)NR²⁶R^26′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, —(CH₂)_pOR²⁸, —(CH₂)_p(OCH₂)_qOR²⁸, —(CH₂)_p(OCH₂CH₂)_qOR²⁸, —OR²⁹, —OC(O)R²⁹, —OC(O)NR²⁹R^29′, —OS(O)R²⁹, —OS(O)₂R²⁹, —(CH₂)_pOS(O)₂OR²⁹, —OS(O)₂OR²⁹, —SR²⁹, —S(O)R²⁹, —S(O)₂R²⁹, —S(O)NR²⁹R^29′, —S(O)₂NR²⁹R^29′, —OS(O)NR²⁹R^29′, —OS(O)₂NR²⁹R^29′, —NR²⁹R^29′, —NR²⁹C(O)R³⁰, —NR²⁹C(O)OR³⁰, —NR²⁹C(O)NR³⁰R^30′, —NR²⁹S(O)R³⁰, —NR²⁹S(O)₂R³⁰, —NR²⁹S(O)NR³⁰R^30′, —NR²⁹S(O)₂NR³⁰R^30′, —C(O)R²⁹, —C(O)OR²⁹or —C(O)NR²⁹R^29′;

R²⁷and R^27′are each independently selected from the group consisting of H, C₁-C₉alkyl, C₂-C₉alkenyl, C₂-C₉alkynyl, C₃-C₆cycloalkyl, —(CH₂)_p(sugar), —(CH₂)_p(OCH₂CH₂)_q-(sugar) and —(CH₂)_p(OCH₂CH₂CH₂)_q(sugar);

R²⁸is H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl or sugar;

n is 1, 2, 3, 4 or 5;

p is 1, 2, 3, 4 or 5; and

q is 1, 2, 3, 4 or 5;

and L²is of the formula

embedded image

wherein

each X⁶is independently C₁-C₆alkyl or C₆-C₁₀aryl(C₁-C₆alkyl), wherein each hydrogen atom in C₁-C₆alkyl and C₆-C₁₀aryl(C₁-C₆alkyl) is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR³⁴, —OC(O)R³⁴, —OC(O)NR³⁴R^34′, —OS(O)R³⁴, —OS(O)₂R³⁴, —SR′, —S(O)R³⁴, —S(O)₂R³⁴, —S(O)NR³⁴R^34′, —S(O)₂NR³⁴R^34′, —OS(O)NR³⁴R^34′, —OS(O)₂NR³⁴R^34′, —NR³⁴R^34′, —NR³⁴C(O)R³⁵, —NR³⁴C(O)OR³⁵, —NR³⁴C(O)NR³⁵R^35′, —NR³⁴S(O)R³⁵, —NR³⁴S(O)₂R³⁵, —NR³⁴S(O)NR³⁵R^35′, —NR³⁴S(O)₂NR³⁵R^35′, —C(O)R³⁴or —C(O)NR³⁴R^34′;

each X⁷is —NR^31a— or —O—, and when X⁶is C₁-C₆alkyl and X⁷is —O—, then at least one hydrogen atom in C₁-C₆alkyl is substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR³⁴, —OC(O)R³⁴, —OC(O)NR³⁴R^34′, —OS(O)R³⁴, —OS(O)₂R³⁴, —SR³⁴, —S(O)R³⁴, —S(O)₂R³⁴, —S(O)NR³⁴R^34′, —S(O)₂NR³⁴R^34′, —OS(O)NR³⁴R^34′, —OS(O)₂NR³⁴R^34′, —NR³⁴R^34′, —NR³⁴C(O)R³⁵, —NR³⁴C(O)OR³⁵, —NR³⁴C(O)NR³⁵R³⁵, —NR³⁴S(O)R³⁵, —NR³⁴S(O)₂R³⁵, —NR³⁴S(O)NR³⁵R^35′, —NR³⁴S(O)₂NR³⁵R^35′, —C(O)R³⁴or —C(O)NR³⁴R^34′;

each R³¹and R^31ais independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR³², —OC(O)R³², —OC(O)NR³²R³², —OS(O)R³², —OS(O)₂R³², —SR³², —S(O)R³², —S(O)₂R³², —S(O)NR³²R^32′, —S(O)₂NR³²R^32′, —OS(O)NR³²R³², —OS(O)₂NR³²R³², —NR³²R³², —NR³²C(O)R³³, —NR³²C(O)OR³³, —NR³²C(O)NR³³R³³, —NR³²S(O)R³³, —NR³²S(O)₂R³³, —NR³²S(O)NR³³R^33′, —NR³²S(O)₂NR³³R^33′, —C(O)R³², —C(O)OR³²or —C(O)NR³²R^32′;

each R^31′is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR^32a, —OC(O)R^32a, —OC(O)NR^32aR^32a′, —OS(O)R^32a, —OS(O)₂R^32a, —SR^32a, —S(O)R^32a, —S(O)₂R^32a, —S(O)NR^32aR^32a′, —S(O)₂NR^32aR^32a′, —OS(O)NR^32aR^32a′, —OS(O)₂NR^32aR^32a′, —NR^32aR^32a′, —C(O)R^32a, —C(O)OR^32aor —C(O)NR^32aR^32a′;

each R^32aR^32a′, R³², R^32′, R³³, R^33′, R³⁴, R^34′, R³⁵and R^35′is independently selected from the group consisting of H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, and 5- to 7-membered heteroaryl;

each R⁵¹and R⁵³is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR⁵⁴, —OC(O)R⁵⁴, —OC(O)NR⁵⁴R^54′, —OS(O)R⁵⁴, —OS(O)₂R⁵⁴, —SR⁵⁴, —S(O)R⁵⁴, —S(O)₂R⁵⁴, —S(O)NR⁵⁴R^54′, —S(O)₂NR⁵⁴R^54′, —OS(O)NR⁵⁴R^54′, —OS(O)₂NR⁵⁴R^54′, —NR⁵⁴R^54′, —NR⁵⁴C(O)R⁵⁵, —NR⁵⁴C(O)OR⁵⁵, —NR⁵⁴C(O)NR⁵⁵R^55′, —NR⁵⁴S(O)R⁵⁵, —NR⁵⁴S(O)₂R⁵⁵, —NR⁵⁴S(O)NR⁵⁵R^55′, —NR⁵⁴S(O)₂NR⁵⁵R^55′, —C(O)R⁵⁴, —C(O)OR⁵⁴or —C(O)NR⁵⁴R^54′;

each R⁵²is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR⁵⁶, —OC(O)R⁵⁶, —OC(O)NR⁵⁶R^56′, —OS(O)R⁵⁶, —OS(O)₂R⁵⁶, —SR⁵⁶, —S(O)R⁵⁶, —S(O)₂R⁵⁶, —S(O)NR⁵⁶R^56′, —S(O)₂NR⁵⁶R^56′, —OS(O)NR⁵⁶R^56′, —OS(O)₂NR⁵⁶R^56′, —NR⁵⁶R^56′, —C(O)R⁵⁶, —C(O)OR⁵⁶or —C(O)NR⁵⁶R^56′;

v is 1, 2, 3, 4, 5 or 6; and

D¹is a drug of the formula I

embedded image

wherein

R^3a, R^4a, R^5aand R^6aare each independently selected from the group consisting of H, D, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —CN, —NO₂, —NCO, —OR^9a, —SR^9a, —NR^9aR^9a′, —C(O)R^9a, —C(O)OR^9aand —C(O)NR^9aR^9a′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl is independently optionally substituted by halogen, —OR^10a, —SR^10a, —NR^10aR^10a′, —C(O)R^10a, —C(O)OR^10aor —C(O)NR^10aR^10a′;

each R^7a, R^7a′, R^8a, R^8a′, R^9a, R^9a′, R^10aand R^10a′ is independently H, D, C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl;

X^1ais —NR^11a—, ═N—, —N═, —C(R^11a)═ or ═C(R^11a)—;

X^2ais —NR^11a′— or ═N—;

X^3ais —NR^11a″—, —N═ or —C(R^11a′)═;

X^4ais —N═ or —C═;

X^5ais —NR^12aor —CR^12aR^12a′;

Y^1ais H, D, —OR^13a, —SR^13aor —NR^13aR′ when X^1ais —N═ or —C(R^11a)═, or Y^1ais ═NR^13awhen X^1ais —NR^11a—, ═N— or ═C(R^11a)—;

Y^2ais H, D, C₁-C₆alkyl, C₂-C₆alkenyl, —C(O)R^14a, —C(O)OR^14aor —C(O)NR^14aR^14a′ when X^4ais —C═, or Y^2ais absent when X^4ais —N═;

R^4a′and R^5a′ are each independently selected from the group consisting of C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR^16a, —SR^16a, —NR^16aR^16a′, provided that one of R^4a′and R^5a′ is a covalent bond to an AA, a L¹or a L²;

R^15a, R^15a′, R^16aand R^16a′are each independently H or C₁-C₆alkyl;

m¹is 1, 2, 3 or 4; and

each * is a covalent bond;

or a pharmaceutically acceptable salt thereof.

3. The conjugate of clause 1 or 2, having the formula B-L¹-AA-L¹-AA-L¹-L²-D¹, B-AA-L¹-AA-AA-L²-D¹, or B-AA-AA-AA-AA-L²-D¹, or a pharmaceutically acceptable salt thereof.

4. The conjugate of clauses 1 to 3, or a pharmaceutically acceptable salt thereof, wherein m is 1.

5. The conjugate of clauses 1 or 4, or a pharmaceutically acceptable salt thereof, wherein X is —NR¹¹—.

6. The conjugate of any one of clauses 1 to 5, or a pharmaceutically acceptable salt thereof, wherein X²is ═N—.

7. The conjugate of any one of clauses 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y¹is ═O.

8. The conjugate of any one of clauses 1 to 7, or a pharmaceutically acceptable salt thereof, wherein X¹is —NR¹¹—, and R¹¹is H.

9. The conjugate of any one of clauses 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X³is —C(R^11′)═.

10. The conjugate of clause 9, or a pharmaceutically acceptable salt thereof, wherein R^11′ is H.

11. The conjugate of any one of clauses 1 to 10, or a pharmaceutically acceptable salt thereof, wherein X⁴is —C═.

12. The conjugate of any one of clauses 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Y²is H.

13. The conjugate of any one of clauses 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X³is —N═.

14. The conjugate of any one of clauses 1 to 8 or 13, or a pharmaceutically acceptable salt thereof, wherein X⁴is —N═.

15. The conjugate of any one of clauses 1 to 14, or a pharmaceutically acceptable salt thereof, wherein X⁵is —NR¹²—.

16. The conjugate of any one of clauses 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R¹²is H.

17. The conjugate of any one of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R^1′and R^2′are H.

18. The conjugate of any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R^3′ is H.

19. The conjugate of any one of clauses 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R^4′is H.

20. The conjugate of any one of clauses 1 to 19, or a pharmaceutically acceptable salt thereof, wherein each R¹and R²is H.

21. The conjugate of any one of clauses 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R³, R⁴, R⁵and R⁶are H.

22. The conjugate of any one of clauses 1 to 21, or a pharmaceutically acceptable salt thereof, wherein m¹is 1.

23. The conjugate of any one of clauses 1 to 22, or a pharmaceutically acceptable salt thereof, wherein X^1ais NR^11a—.

24. The conjugate of any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof, wherein X^2ais ═N—.

25. The conjugate of any one of clauses 1 to 24, or a pharmaceutically acceptable salt thereof, wherein Y^1ais ═NR^13a.

26. The conjugate of any one of clauses 1 to 25, or a pharmaceutically acceptable salt thereof, wherein X^1ais —NR^11a—, and R^11ais H.

27. The conjugate of any one of clauses 1 to 26, or a pharmaceutically acceptable salt thereof, wherein X^3ais —C(R^11a′)═.

28. The conjugate of clause 27, or a pharmaceutically acceptable salt thereof, wherein R^11a′is H.

29. The conjugate of any one of clauses 1 to 28, or a pharmaceutically acceptable salt thereof, wherein X^4ais —C═.

30. The conjugate of any one of clauses 1 to 29, or a pharmaceutically acceptable salt thereof, wherein Y^2ais H.

31. The conjugate of any one of clauses 1 to 26, or a pharmaceutically acceptable salt thereof, wherein X^3ais —N═.

32. The conjugate of any one of clauses 1 to 26 or 31, or a pharmaceutically acceptable salt thereof, wherein X^4ais —N═.

33. The conjugate of any one of clauses 1 to 32, or a pharmaceutically acceptable salt thereof, wherein X^5ais —NR^12a.

34. The conjugate of any one of clauses 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R^12aa is H.

35. The conjugate of any one of clauses 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^1a′ and R^2a′are H.

36. The conjugate of any one of clauses 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R^3a′is H.

37. The conjugate of any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R^4a′is H.

38. The conjugate of any one of clauses 1 to 37, or a pharmaceutically acceptable salt thereof, wherein each R^1aand R^2ais H.

39. The conjugate of any one of clauses 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R^3a, R^4a, R^5aand R^6aare H.

40. The conjugate of any one of clauses 1 to 39, or a pharmaceutically acceptable salt thereof, wherein X⁸is —NR⁵⁰—.

41. The conjugate of clause 40, or a pharmaceutically acceptable salt thereof, wherein R⁵⁰is H.

42. The conjugate of any one of clauses 1 to 39, or a pharmaceutically acceptable salt thereof, wherein X⁸is —O—.

43. The conjugate of any one of clauses 1 to 42, or a pharmaceutically acceptable salt thereof, wherein u is 2.

44. The conjugate of any one of clauses 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R⁴²is C₁-C₆alkyl.

45. The conjugate of any one of clauses 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R⁴²is H.

46. The conjugate of any one of clauses 1 to 45, or a pharmaceutically acceptable salt thereof, wherein R⁴¹is H.

47. The conjugate of any one of clauses 1 to 46, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰and R^40′are selected from H, C₁-C₆alkyl and —C(O)OR⁴⁸.

48. The conjugate of any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰and R^40′are C₁-C₆alkyl.

49. The conjugate of clause 48, wherein R⁴⁰and R^40′ are methyl.

50. The conjugate of any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰and R^40′ are H.

51. The conjugate of clause 50, or a pharmaceutically acceptable salt thereof, wherein R⁴⁸is H.

52. The conjugate of any one of clauses 1 or 2 to 39, or a pharmaceutically acceptable salt thereof, wherein L²is of a formula selected from

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53. The conjugate of clause 52, or a pharmaceutically acceptable salt thereof, wherein L²is of the formula

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54. The conjugate of any one of clauses 2 to 39, or a pharmaceutically acceptable salt thereof, wherein X⁶is C₁-C₆alkyl, and each hydrogen atom in C₁-C₆alkyl is optionally substituted by a C₁-C₆alkyl.

55. The conjugate of any one of clauses 2 to 39 or 54, or a pharmaceutically acceptable salt thereof, wherein X⁷is —NR^31a—.

56. The conjugate of clause 55, or a pharmaceutically acceptable salt thereof, wherein R^31ais H.

57. The conjugate of any one of clauses 2 to 39 or 54 to 56, or a pharmaceutically acceptable salt thereof, wherein X⁷is —O—.

58. The conjugate of any one of clauses 2 to 39 or 54 to 57, or a pharmaceutically acceptable salt thereof, wherein R³¹is H.

59. The conjugate of any one of clauses 2 to 39 or 54 to 58, or a pharmaceutically acceptable salt thereof, R^31′ is H.

60. The conjugate of any one of clauses 2 to 39, or a pharmaceutically acceptable salt thereof, wherein v is 4.

61. The conjugate of any one of clauses 2 to 39 or 60, or a pharmaceutically acceptable salt thereof, wherein R⁵¹is H.

62. The conjugate of any one of clauses 2 to 39, 60 or 61, or a pharmaceutically acceptable salt thereof, wherein R⁵²is C₁-C₆alkyl.

63. The conjugate of clause 62, or a pharmaceutically acceptable salt thereof, wherein R⁵²is methyl.

64. The conjugate of any one of clauses 2 to 39 or 60 to 63, or a pharmaceutically acceptable salt thereof, wherein R⁵³is H.

65. The conjugate of any one of clauses 1 to 64, or a pharmaceutically acceptable salt thereof, wherein at least one AA is in the D-configuration.

66. The conjugate of any one of clauses 1 to 64, or a pharmaceutically acceptable salt thereof, wherein at least two AA are in the D-configuration.

67. The conjugate of any one of clauses 1 to 66, or a pharmaceutically acceptable salt thereof, wherein AA is selected from the group consisting of 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-leucine, D-isoleucine and D-citrulline.

68. The conjugate of any one of clauses 1 to 67, or a pharmaceutically acceptable salt thereof, wherein AA is selected from the group consisting of L-arginine, D-arginine, L-aspartic acid, D-aspartic acid, L-glutamic acid and D-glutamic acid.

69. The conjugate of clause 1, selected from the group consisting of

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or a pharmaceutically acceptable salt thereof.

70. The conjugate of clause 2, selected from the group consisting of

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or a pharmaceutically acceptable salt thereof.

71. A pharmaceutical composition comprising a conjugate of any one of clauses 1 to 70, or a pharmaceutically acceptable salt thereof, and optionally at least one excipient.

72. The pharmaceutical composition of clause 71, wherein the conjugate, or a pharmaceutically acceptable salt thereof, is included in an amount effective to treat disease states caused by inflammatory cells.

73. A method for treating diseases and disease states caused by inflammation comprising administering a therapeutically effective amount of a conjugate of any one of clauses 1 to 70, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment.

74. The method of clause 73, wherein the disease caused by inflammation is selected from the group consisting of arthritis, rheumatoid arthritis, osteoarthritis, glomerulonephritis, proliferative retinopathy, restenosis, ulcerative colitis, Crohn's disease, fibromyalgia, psoriasis and other inflammations of the skin, inflammations of the eye, including uveitis and autoimmune uveitis, osteomyelitis, Sjögren's syndrome, multiple sclerosis, diabetes, atherosclerosis, pulmonary fibrosis, lupus erythematosus, sarcoidosis, systemic sclerosis, organ transplant rejection (GVHD) and chronic inflammations.

75. Use of a conjugate according to any one of clauses 1 to 70, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of inflammation.

76. Use of a conjugate according to any one of clauses 1 to 70, or a pharmaceutically acceptable salt thereof, for the treatment of inflammation.

77. Use of a conjugate according to any one of clauses 1 to 70, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a disease or disease state caused by inflammatory cells.

78. The use of clause 77, wherein the disease or disease state caused by inflammatory cells is selected from the group consisting of arthritis, rheumatoid arthritis, osteoarthritis, glomerulonephritis, proliferative retinopathy, restenosis, ulcerative colitis, Crohn's disease, fibromyalgia, psoriasis and other inflammations of the skin, inflammations of the eye, including uveitis and autoimmune uveitis, osteomyelitis, Sjögren's syndrome, multiple sclerosis, diabetes, atherosclerosis, pulmonary fibrosis, lupus erythematosus, sarcoidosis, systemic sclerosis, organ transplant rejection (GVHD) and chronic inflammation.

79. Use of a conjugate according to any one of clauses 1 to 70, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or disease state caused by inflammatory cells.

80. The use of clause 79, wherein disease or disease state caused by inflammatory cells is selected from the group consisting of arthritis, rheumatoid arthritis, osteoarthritis, glomerulonephritis, proliferative retinopathy, restenosis, ulcerative colitis, Crohn's disease, fibromyalgia, psoriasis and other inflammations of the skin, inflammations of the eye, including uveitis and autoimmune uveitis, osteomyelitis, Sjögren's syndrome, multiple sclerosis, diabetes, atherosclerosis, pulmonary fibrosis, lupus erythematosus, sarcoidosis, systemic sclerosis, organ transplant rejection (GVHD) and chronic inflammation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the relative affinity of EC2319 was measured using KB cells. EC2319 displayed a high relative affinity value of 0.493 normalized against 1 for FA.

FIG. 2A shows that EC2319 was evaluated for its anti-proliferative activity against mouse RAW264.7 macrophage cells. As determined by the XTT assay, EC2319 showed a dose-dependent inhibition of cell proliferation with relative IC₅₀values of ˜2.9 nM.

FIG. 2B shows that EC2319 was evaluated for its anti-proliferative activity against human THP-1-FRβ cells. As determined by the XTT assay, EC2319 showed a dose-dependent inhibition of cell proliferation with relative IC₅₀values of ˜8.7 nM on THP-1-FRβ cells.

FIG. 3A shows a comparison of arthritic scores in rats treated according to the methods described herein; (●) control, (⋄) EC1669, (▴) EC2285, (▾) EC2318 and (♦) EC2319.

FIG. 3B shows a comparison of increased paw weight in rats treated according to the methods described herein between control, EC1669, EC2285, EC2318 and EC2319.

FIG. 3C shows a comparison of increased spleen weight in rats treated according to the methods described herein between control, EC1669, EC2285, EC2318 and EC2319.

FIG. 3D shows a comparison of body weight change in rats treated according to the methods described herein; (●) control, (⋄) EC1669, (▴) EC2285, (▾) EC2318 and (▾) EC2319.

FIG. 4A shows a comparison of arthritic scores in rats treated according to the methods described herein; (●) control, (∘) EC1669 (500 nmol/kg, BIW), (▴) EC2285 (500 nmol/kg, BIW), (Δ) EC2285 (500 nmol/kg, BIW)+500-fold excess EC0923, (♦) EC2319 (500 nmol/kg, BIW) and (⋄) EC2319 (500 nmol/kg, BIW)+500-fold excess EC0923.

FIG. 4B shows a comparison of increased paw weight in rats treated according to the methods described herein between control, EC1669, EC2285, EC2285+EC0923, EC2319 and EC2319+EC0923.

FIG. 4C shows a comparison of increased spleen weight in rats treated according to the methods described herein between control, EC1669, EC2285, EC2285+EC0923, EC2319 and EC2319+EC0923.

FIG. 4D shows a comparison of body weight change in rats treated according to the methods described herein; (●) control, (∘) EC1669 (500 nmol/kg, BIW), (▴) EC2285 (500 nmol/kg, BIW), (Δ) EC2285 (500 nmol/kg, BIW)+500-fold excess EC0923, (♦) EC2319 (500 nmol/kg, BIW) and (0) EC2319 (500 nmol/kg, BIW)+500-fold excess EC0923.

FIG. 5A shows a comparison of arthritic scores in rats treated according to the methods described herein; (●) control, (∘) EC2413 (1000 nmol/kg, SIW), (▴) EC2413 (500 nmol/kg, BIW), (Δ) EC2413 (500 nmol/kg, BIW)+500-fold excess EC0923, (▪) EC1669 (500 nmol/kg, BIW) and (♦) EC2319 (500 nmol/kg, BIW).

FIG. 5B shows a comparison of increased paw weight in rats treated according to the methods described herein between control, EC2413 (1000 nmol/kg, SIW), EC2413 (500 nmol/kg, BIW), EC2413+EC0923, EC1669 and EC2319.

FIG. 5C shows a comparison of spleen weight in rats treated according to the methods described herein between control, EC2413 (1000 nmol/kg, SIW), EC2413 (500 nmol/kg, BIW), EC2413+EC0923, EC1669 and EC2319.

FIG. 5D shows a comparison of body weight change in rats treated according to the methods described herein; (●) control, (∘) EC2413 (1000 nmol/kg, SIW), (▴) EC2413 (500 nmol/kg, BIW), (Δ) EC2413 (500 nmol/kg, BIW)+500-fold excess EC0923, (▪) EC1669 (500 nmol/kg, BIW) and (♦) EC2319 (500 nmol/kg, BIW).

FIG. 6A shows plasma concentration-time profiles for EC1669 and its metabolites (aminopterin gamma-hydrazide and aminopterin) when dosed subcutaneously in rats; (●) EC1669, (▪) aminopterin gamma-hydrazide and (▴) aminopterin.

FIG. 6B shows plasma concentration-time profiles for EC2319 and its metabolite aminopterin when dosed subcutaneously in rats; (●) EC1669 and (▴) aminopterin.

FIG. 7 shows plasma concentration-time profiles for EC1669 and its metabolites (aminopterin gamma-hydrazide and aminopterin) when dosed subcutaneously in dogs; (●) EC1669, (▪) aminopterin gamma-hydrazide and (▴) aminopterin.

FIG. 8A shows plasma concentration-time profiles for EC2319 and its metabolites (aminopterin and EC2496) when dosed intravenously in dogs; and subcutaneously in dogs; (●) EC2319, (▴) aminopterin and (▪) EC2496.

FIG. 8B shows plasma concentration-time profiles for EC2319 and its metabolites (aminopterin and EC2496) when dosed intravenously in dogs; and subcutaneously in dogs; (●) EC2319, (▴) aminopterin and (▪) EC2496.

FIG. 9A shows the release of aminopterin from EC1669 after incubation in rat, dog, and human liver cytosol at different pHs.

FIG. 9B shows the release of aminopterin from EC2319 after incubation in rat, dog, and human liver cytosol at different pHs.

FIG. 10 shows the release of aminopterin from EC1669 and EC2319 by gamma-glutamyl hydrolase.

FIG. 11A shows the release of aminopterin from EC1669 and EC2319 after incubation in rat TG macrophage cell lysates.

FIG. 11B shows the release of aminopterin from EC1669 and EC2319 after incubation in RAW264.7, THP-1 FR$, and AIA rat macrophage cell lysates.

FIG. 12 shows plasma protein binding of EC1669 and EC2319. EC2319 exhibited higher plasma protein binding than did EC1669 in all species tested.

FIG. 13A shows stability of EC1669 and EC2319 in rat and human whole blood at 37° C.; (●) EC1669 Human, (▪) EC2319 Human, (▴) EC1669 Rat and (♦) EC2319 Rat.

FIG. 13B shows aminopterin released after incubating EC1669 and EC2319 in rat and human whole blood at 37° C.; (●) EC1669 Human, (▪) EC2319 Human, (▴) EC1669 Rat and (♦) EC2319 Rat.

DEFINITIONS

As used herein, the term “alkyl” includes a chain of carbon atoms, which is optionally branched and contains from 1 to 20 carbon atoms. It is to be further understood that in certain embodiments, alkyl may be advantageously of limited length, including C₁-C₁₂, C₁-C₁₀, C₁-C₉, C₁-C₈, C₁-C₇, C₁-C₆, and C₁-C₄, Illustratively, such particularly limited length alkyl groups, including C₁-C₈, C₁-C₇, C₁-C₆, and C₁-C₄, and the like may be referred to as “lower alkyl.” Illustrative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl, and the like. Alkyl may be substituted or unsubstituted. Typical substituent groups include 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-amido, N-amido, C-carboxy, O-carboxy, nitro, and amino, or as described in the various embodiments provided herein. It will be understood that “alkyl” may be combined with other groups, such as those provided above, to form a functionalized alkyl. By way of example, the combination of an “alkyl” group, as described herein, with a “carboxy” group 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 a chain of carbon atoms, which is optionally branched, and contains from 2 to 20 carbon atoms, and also includes at least one carbon-carbon double bond (i.e. C═C). It will be understood that in certain embodiments, alkenyl may be advantageously of limited length, including C₂-C₁₂, C₂-C₉, C₂-C₈, C₂-C₇, C₂-C₆, and C₂-C₄. Illustratively, such particularly limited length alkenyl groups, including C₂-C₈, C₂-C₇, C₂-C₆, and C₂-C₄may be referred to as lower alkenyl. Alkenyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.

As used herein, the term “alkynyl” includes a chain of carbon atoms, which is optionally branched, and contains from 2 to 20 carbon atoms, and also includes at least one carbon-carbon triple bond (i.e. C═C). It will be understood that in certain embodiments alkynyl may each be advantageously of limited length, including C₂-C₁₂, C₂-C₉, C₂-C₈, C₂-C₇, C₂-C₆, and C₂-C₄. Illustratively, such particularly limited length alkynyl groups, including C₂-C₈, C₂-C₇, C₂-C₆, and C₂-C₄may be referred to as lower alkynyl. Alkenyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative alkenyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.

As used herein, the term “aryl” refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system. It will be understood that in certain embodiments, aryl may be advantageously of limited size such as C₆-C₁₀aryl. Illustrative aryl groups include, but are not limited to, phenyl, naphthalenyl and anthracenyl. The aryl group may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.

As used herein, the term “cycloalkyl” refers to a 3 to 15 member all-carbon monocyclic ring, an all-carbon 5-member/6-member or 6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a “fused” ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group where one or more of the rings may contain one or more double bonds but the cycloalkyl does not contain a completely conjugated pi-electron system. It will be understood that in certain embodiments, cycloalkyl may be advantageously of limited size such as C₃-C₁₃, C₃-C₆, C₃-C₆and C₄-C₆. Cycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative 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.

As used herein, the term “heterocycloalkyl” refers to a monocyclic or fused ring group having in the ring(s) from 3 to 12 ring atoms, in which at least one ring atom is a heteroatom, such as nitrogen, oxygen or sulfur, the remaining ring atoms being carbon atoms. Heterocycloalkyl may optionally contain 1, 2, 3 or 4 heteroatoms. Heterocycloalkyl may also have one of more double bonds, including double bonds to nitrogen (e.g. C═N or N═N) but does not contain a completely conjugated pi-electron system. It will be understood that in certain embodiments, heterocycloalkyl may be advantageously of limited size such as 3- to 7-membered heterocycloalkyl, 5- to 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. Illustrative 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.

As used herein, the term “heteroaryl” refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon atoms, and also having a completely conjugated pi-electron system. It will be understood that in certain embodiments, heteroaryl may be advantageously of limited size such as 3- to 7-membered heteroaryl, 5- to 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. Illustrative 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, quinoxalinyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl and carbazoloyl, and the like.

As used herein, “hydroxy” or ““hydroxyl” refers to an —OH group.

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

As used herein, “mercapto” refers to an —SH group.

As used herein, “alkylthio” refers to an —S-(alkyl) or an —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 an —S-aryl or an —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 having three halo substituents, such as a trifluoromethyl group.

As used herein, “cyano” refers to a —CN group.

As used herein, “sulfinyl” refers to a —S(O)R″ group, where R″ is any R group as described in the various embodiments provided herein, or R″ may be a hydroxyl group.

As used herein, “sulfonyl” refers to a —S(O)₂R″ group, where R″ is any R group as described in the various embodiments provided herein, or R″ may be a hydroxyl group.

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

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

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

As used herein, “N-carbamyl” refers to an R″OC(O)NR″— group, where R″ is any R group as described in the various embodiments provided herein.

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

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

As used herein, “amino” refers to an —NR″R″ group, where R″ is any R group as described in the various embodiments provided herein.

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

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

As used herein, “nitro” refers to a —NO₂group.

As used herein, “bond” refers to a covalent bond.

As used herein, “optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “heterocycle group optionally substituted with an alkyl group” means that the alkyl may but need not be present, and the description includes situations where the heterocycle group is substituted with an alkyl group and situations where the heterocycle group is not substituted with the alkyl group.

As used herein, “independently” means that the subsequently described event or circumstance is to be read on its own relative to other similar events or circumstances. For example, in a circumstance where several equivalent hydrogen groups are optionally substituted by another group described in the circumstance, the use of “independently optionally” means that each instance of a hydrogen atom on the group may be substituted by another group, where the groups replacing each of the hydrogen atoms may be the same or different. Or for example, where multiple groups exist all of which can be selected from a set of possibilities, the use of “independently” means that each of the groups can be selected from the set of possibilities separate from any other group, and the groups selected in the circumstance may be the same or different.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts with counter ions which may be used in pharmaceuticals. Such salts include:

- (1) acid addition salts, which can be obtained by reaction of the free base of the parent conjugate with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or
- (2) salts formed when an acidic proton present in the parent conjugate either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine, and the like.

Pharmaceutically acceptable salts are well known to those skilled in the art, and any such pharmaceutically acceptable salt may be contemplated in connection with the embodiments described herein.

As used herein, “amino acid” (a.k.a. “AA”) means any molecule that includes an alpha-carbon atom covalently bonded to an amino group and an acid group. The acid group may include a carboxyl group. “Amino acid” may include molecules having one of the formulas:

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wherein R′ is a side group and (D includes at least 3 carbon atoms. “Amino acid” includes stereoisomers such as the D-amino acid and L-amino acid forms. Illustrative amino acid groups include, but are not limited to, the twenty 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), alpha-amino-adipic acid (AAA), beta-alanine (BALA), ethanolamine (ETN), gamma-amino-butyric acid (GABA), beta-amino-isobutyric acid (BAIA), alpha-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 derivatives thereof. It will be appreciated that each of these examples are also contemplated in connection with the present disclosure in the D-configuration as noted above. Specifically, 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), and the like. In connection with the embodiments described herein, amino acids can be covalently attached to other portions of the conjugates described herein through their alpha-amino and carboxy functional groups (i.e. in a peptide bond configuration), or through their side chain functional groups (such as the side chain carboxy group in glutamic acid) and either their alpha-amino or carboxy functional groups. It will be understood that amino acids, when used in connection with the conjugates described herein, may exist as zwitterions in a conjugate in which they are incorporated.

As used herein, “sugar” refers to carbohydrates, such as monosaccharides, disaccharides, or oligosaccharides. In connection with the present disclosure, monosaccharides are preferred. Non-limiting examples of sugars include erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, galactose, ribulose, fructose, sorbose, tagatose, and the like. It will be understood that as used in connection with the present disclosure, sugar includes 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, sugars for use in connection with the present disclosure include

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As used herein, “prodrug” refers to a compound that can be administered to a subject in a pharmacologically inactive form which then can be converted to a pharmacologically active form through a normal metabolic process, such as hydrolysis of an oxazolidine. It will be understood that the metabolic processes through which a prodrug can be converted to an active drug include, but are not limited to, one or more spontaneous chemical reaction(s), enzyme-catalyzed chemical reaction(s), and/or other metabolic chemical reaction(s), or a combination thereof. It will be appreciated that a variety of metabolic processes are known in the art, and the metabolic processes through which the prodrugs described herein are converted to active drugs are non-limiting. A prodrug can be a precursor chemical compound of a drug that has a therapeutic effect on a subject.

As used herein, the term “therapeutically effective amount” refers to an amount of a drug or pharmaceutical agent that elicits the biological or medicinal response in a subject (i.e. a tissue system, animal or human) that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes, but is not limited to, alleviation of the symptoms of the disease or disorder being treated. In one aspect, the therapeutically effective amount is that amount of an active which compound may treat or alleviate the disease or symptoms of the disease at a reasonable benefit/risk ratio applicable to any medical treatment. In another aspect, the therapeutically effective amount is that amount of an inactive prodrug which when converted through normal metabolic processes produces an amount of active drug capable of eliciting the biological or medicinal response in a subject that is being sought.

It is also appreciated that the dose, whether referring to monotherapy or combination therapy, is advantageously selected with reference to any toxicity, or other undesirable side effect, that might occur during administration of one or more of the conjugates described herein. Further, it is appreciated that the co-therapies described herein may allow for the administration of lower doses of conjugates that show such toxicity, or other undesirable side effect, where those lower doses are below thresholds of toxicity or lower in the therapeutic window than would otherwise be administered in the absence of a co-therapy.

As used herein, “administering” includes all means of introducing the conjugates and compositions described herein to the patient, including, but are not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, and the like. The conjugates and compositions described herein may be administered in unit dosage forms and/or formulations containing conventional nontoxic pharmaceutically-acceptable carriers, adjuvants, and/or vehicles.

As used herein “pharmaceutical composition” or “composition” refers to a mixture of one or more of the conjugates described herein, or pharmaceutically acceptable salts, solvates, hydrates thereof, with other chemical components, such as pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of a conjugate to a subject. Pharmaceutical compositions suitable for the delivery of conjugates described and methods for their preparation will be readily apparent to those skilled in the art.

Such compositions and methods for their preparation may be found, for example, in ‘Remington's Pharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995).

A “pharmaceutically acceptable excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a conjugate such as a diluent or a carrier.

DETAILED DESCRIPTION

In each of the foregoing and each of the following embodiments, it is to be understood that the formulae include and represent not only all pharmaceutically acceptable salts of the conjugates, but also include any and all hydrates and/or solvates of the conjugate formulae. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and/or coordination conjugates with water and/or various solvents, in the various physical forms of the conjugates. Accordingly, the above formulae are to be understood to include and represent those various hydrates and/or solvates. It is also to be understood that the non-hydrates and/or non-solvates of the conjugate formulae are described by such formula, as well as the hydrates and/or solvates of the conjugate formulae.

The conjugates described herein can be expressed by the generalized descriptors B, L and D¹, for example B-L-D¹, where B is a cell surface receptor binding ligand (a.k.a. a “binding ligand”), L is a linker that may include one or more releasable portions (i.e. a releasable linker) and L may be described by, for example, one or more of the groups AA, L¹or L²as defined herein, and D¹represents a drug covalently attached to the conjugates described herein.

The conjugates described herein can be described according to various embodiments including but not limited to B-L¹-AA-L-AA-L¹-L²-D¹, B-AA-L¹-AA-AA-L²-D¹, or B-AA-AA-AA-AA-L²-D¹, wherein B, AA, L¹, L²and D¹are defined by the various embodiments described herein, or a pharmaceutically acceptable salt thereof.

As used herein, the term cell surface receptor binding ligand (aka a “binding ligand”), generally refers to compounds that bind to and/or target receptors that are found on cell surfaces, and in particular those that are found on, over-expressed by, and/or preferentially expressed on the surface of pathogenic cells, such as inflammation. Illustrative ligands include, but are not limited to, vitamins and vitamin receptor binding compounds.

Illustrative vitamin moieties include carnitine, inositol, lipoic acid, pyridoxal, ascorbic acid, niacin, pantothenic acid, folic acid, riboflavin, thiamine, biotin, vitamin B₁₂, and the lipid soluble vitamins A, D, E and K. These vitamins, and their receptor-binding analogs and derivatives, constitute the targeting entity covalently attached to the linker. Illustrative biotin analogs that bind to biotin receptors include, but are not limited to, biocytin, biotin sulfoxide, oxybiotin, and the like).

Illustrative folic acid analogs that bind to folate receptors include, but are not limited to folinic acid, pteropolyglutamic acid, and folate receptor-binding pteridines such as tetrahydropterins, dihydrofolates, tetrahydrofolates, and their deaza and dideaza analogs. The terms “deaza” and “dideaza” analogs refer to the art-recognized analogs having a carbon atom substituted for one or two nitrogen atoms in the naturally occurring folic acid structure, or analog or derivative thereof. For example, the deaza analogs include the 1-deaza, 3-deaza, 5-deaza, 8-deaza, and 10-deaza analogs of folate, folinic acid, pteropolyglutamic acid, and folate receptor-binding pteridines such as tetrahydropterins, dihydrofolates, and tetrahydrofolates. The dideaza analogs include, for example, 1,5-dideaza, 5,10-dideaza, 8,10-dideaza, and 5,8-dideaza analogs of folate, folinic acid, pteropolyglutamic acid, and folate receptor-binding pteridines such as tetrahydropterins, dihydrofolates, and tetrahydrofolates. The foregoing folic acid analogs and/or derivatives are conventionally termed “folates,” reflecting their ability to bind to folate-receptors, and such ligands when conjugated with exogenous molecules are effective to enhance transmembrane transport, such as via folate-mediated endocytosis as described herein.

In some embodiments, B is of the formula I

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wherein

each R⁷, R^7′, R⁸, R^8′, R⁹, R^9′, R¹⁰and R^10′ is independently H, D, C₁-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl;

X¹is —NR¹¹—, ═N—, —N═, —C(R¹¹)═ or ═C(R¹¹)—;

X²is —NR^11′— or ═N—;

X³is —NR^11″—, —N═ or —C(R^11′)═;

X⁴is —N═ or —C═;

X⁵is NR¹²or CR¹²R^12′;

Y¹is H, D, —OR¹³or —SR¹³when X¹is —N═ or —C(R¹¹)═, or Y¹is ═O when X¹is —NR¹¹—═N— or ═C(R¹¹)—;

Y²is H, D, C₁-C₆alkyl, C₂-C₆alkenyl, —C(O)R¹⁴, —C(O)OR¹⁴or —C(O)NR¹⁴R^14′when X⁴is —C═, or Y²is absent when X⁴is —N═;

R¹⁵and R^15′ are each independently H or C₁-C₆alkyl; and

m is 1, 2, 3 or 4;

As used herein, L¹can be any group covalently attaching portions of the linker to the binding ligand, portions of the linker to other portions of the linker, or portions of the linker to D¹. It will be understood that the structure of L¹is not particularly limited in any way. It will be further understood that L¹can comprise numerous functionalities well known in the art to covalently attach portions of the linker to the binding ligand, portions of the linker to other portions of the linker, or portions of the linker to D¹, including but not limited to, alkyl groups, ether groups, amide groups, carboxy groups, sulfonate groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocycloalkyl, heteroaryl groups, and the like. In some embodiments, L¹is a linker of the formula II

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wherein

R¹⁶is selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —C(O)R¹⁹, —C(O)OR¹⁹and —C(O)NR¹⁹R^19′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR²⁰, —OC(O)R²⁰, —OC(O)NR²⁰R^20′, —OS(O)R²⁰, —OS(O)₂R²⁰, —SR²⁰, —S(O)R²⁰, —S(O)₂R²⁰, —S(O)NR²⁰R^20′, —S(O)₂NR²⁰R^20′, —OS(O)NR²⁰R²⁰, —OS(O)₂NR²⁰R^20′, —NR²⁰R^20′, —NR²⁰C(O)R²¹, —NR²⁰C(O)OR²¹, —NR²⁰C(O)NR²¹R^21′, —NR²⁰S(O)R²¹, —NR²⁰S(O)₂R²¹, —NR²⁰S(O)NR²¹R²¹, —NR²⁰S(O)₂NR²¹R²¹, —C(O)R²⁰, —C(O)OR²⁰or —C(O)NR²⁰R^20′;

each R¹⁷and R^17′ is independently selected from the group consisting of H, D, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²², —OC(O)R²², —OC(O)NR²²R^22′, —OS(O)R²², —OS(O)₂R²², —SR²², —S(O)R²², —S(O)₂R²², —S(O)NR²²R^22′, —S(O)₂NR²²R^22′, —OS(O)NR²²R^22′, —OS(O)₂NR²²R^22′, —NR²²R^22′, —NR²²C(O)R²³, —NR²²C(O)OR²³, —NR²²C(O)NR²³R^23′, —NR²²S(O)R²³, —NR²²S(O)₂R²³, —NR²²S(O)NR²³R²³, —NR²²S(O)₂NR²³R^23′, —C(O)R²², —C(O)OR²², and —C(O)NR²²R^22′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR²⁴, —OC(O)R²⁴, —OC(O)NR²⁴R^24′, —OS(O)R²⁴, —OS(O)₂R²⁴, —SR²⁴, —S(O)R²⁴, —S(O)₂R²⁴, —S(O)NR²⁴R^24′, —S(O)₂NR²⁴R^24′, —OS(O)NR²⁴R^24′, —OS(O)₂NR²⁴R^24′, —NR²⁴R^24′, —NR²⁴C(O)R²⁵, —NR²⁴C(O)OR²⁵, —NR²⁴C(O)NR²⁵R²⁵, —NR²⁴S(O)R²⁵, —NR²⁴S(O)₂R²⁵, —NR²⁴S(O)NR²⁵R^25′, —NR²⁴S(O)₂NR²⁵R^25′, —C(O)R²⁴, —C(O)OR²⁴or —C(O)NR²⁴R^24′; or R¹⁷and R^17′ may combine to form a C₄-C₆cycloalkyl or a 4- to 6-membered heterocycle, wherein each hydrogen atom in C₄-C₆cycloalkyl or 4- to 6-membered heterocycle is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²⁴, —OC(O)R²⁴, —OC(O)NR²⁴R^24′, —OS(O)R²⁴, —OS(O)₂R²⁴, —SR²⁴, —S(O)R²⁴, —S(O)₂R²⁴, —S(O)NR²⁴R^24′, —S(O)₂NR²⁴R^24′, —OS(O)NR²⁴R^24′, —OS(O)₂NR²⁴R^24′, —NR²⁴R^24′, —NR²⁴C(O)R²⁵, —NR²⁴C(O)OR²⁵, —NR²⁴C(O)NR²⁵R^25′, —NR²⁴S(O)R²⁵, —NR²⁴S(O)₂R²⁵, —NR²⁴S(O)NR²⁵R^25′ —NR²⁴S(O)₂NR²⁵R^25′, —C(O)R²⁴, —C(O)OR²⁴or —C(O)NR²⁴R^24′;

R¹⁸is selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²⁶, —OC(O)R²⁶, —OC(O)NR²⁶R^26′, —OS(O)R²⁶, —OS(O)₂R²⁶, —SR²⁶, —S(O)R²⁶, —S(O)₂R²⁶, —S(O)NR²⁶R^26′, —S(O)₂NR²⁶R^26′, —OS(O)NR²⁶R²⁶, —OS(O)₂NR²⁶R^26′, —NR²⁶R^26′, —NR²⁶C(O)R²⁷, —NR²⁶C(O)OR²⁷, —NR²⁶C(O)NR²⁷R^27′, —NR²⁶C(═NR^26″)NR²⁷R^27′, —NR²⁶S(O)R²⁷, —NR²⁶S(O)₂R²⁷, —NR²⁶S(O)NR²⁷R^27′, —NR²⁶S(O)₂NR²⁷R^27′, —C(O)R²⁶, —C(O)OR²⁶and —C(O)NR²⁶R^26′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, —(CH₂)_pOR²⁸, —(CH₂)_p(OCH₂)_qOR²⁸, —(CH₂)_p(OCH₂CH₂)_qOR²⁸, —OR²⁹, —OC(O)R²⁹, —OC(O)NR²⁹R^29′, —OS(O)R²⁹, —OS(O)₂R²⁹, —(CH₂)_pOS(O)₂OR²⁹, —OS(O)₂OR²⁹, —SR²⁹, —S(O)R²⁹, —S(O)₂R²⁹, —S(O)NR²⁹R^29′, —S(O)₂NR²⁹R^29′, —OS(O)NR²⁹R^29′, —OS(O)₂NR²⁹R^29′, —NR²⁹R^29′, —NR²⁹C(O)R³⁰, —NR²⁹C(O)OR³⁰, —NR²⁹C(O)NR³⁰R^30′, —NR²⁹S(O)R³⁰, —NR²⁹S(O)₂R³⁰, —NR²⁹S(O)NR³⁰R^30′, —NR²⁹S(O)₂NR³⁰R^30′, —C(O)R²⁹, —C(O)OR²⁹or —C(O)NR²⁹R^29′;

each R¹⁹, R^19′, R²⁰, R^20′, R²¹, R^21′, R²², R^22′, R²³, R^23′, R²⁴, R^24′, R²⁵, R^25′, R²⁶, R^26′, R²⁶″, R²⁹, R^29′, R³⁰and R^30′ is independently selected from the group consisting of H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by halogen, —OH, —SH, —NH₂or —CO₂H;

R²⁷and R^27′ are each independently selected from the group consisting of H, C₁-C₉alkyl, C₂-C₉alkenyl, C₂-C₉alkynyl, C₃-C₆cycloalkyl, —(CH₂)_p(sugar), —(CH₂)_p(OCH₂CH₂)_q-(sugar) and —(CH₂)_p(OCH₂CH₂CH₂)_q(sugar);

R²⁸is H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 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.

It will be appreciated that when L¹is described according to the formula II, that both the R- and S- configurations are contemplated. In some embodiments, L¹is of the formula IIa or IIb

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where each of R¹⁶, R¹⁷, R^17′, R¹⁸, n and * are as defined for the formula II.

In some embodiments, each L¹is selected from the group consisting of

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and combinations thereof,

wherein

R¹⁶is selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —C(O)R¹⁹, —C(O)OR¹⁹and —C(O)NR¹⁹R^19′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, and C₂-C₆alkynyl, —OR²⁰, —OC(O)R²⁰, —OC(O)NR²⁰R^20′, —OS(O)R²⁰, —OS(O)₂R²⁰, —SR²⁰, —S(O)R²⁰, —S(O)₂R²⁰, —S(O)NR²⁰R^20′, —S(O)₂NR²⁰R^20′, —OS(O)NR²⁰R^20′, —OS(O)₂NR²⁰R^20′, —NR²⁰R^20′, —NR²⁰C(O)R²¹, —NR²⁰C(O)OR²¹, —NR²⁰C(O)NR²¹R^21′, —NR²⁰S(O)R²¹, —NR²⁰S(O)₂R²¹, —NR²⁰S(O)NR²¹R²¹, —NR²⁰S(O)₂NR²¹R^21′, —C(O)R²⁰, —C(O)OR²⁰or —C(O)NR²⁰R^20′;

R¹⁸is selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²⁶, —OC(O)R²⁶, —OC(O)NR²⁶R^26′, —OS(O)R²⁶, —OS(O)₂R²⁶, —SR²⁶, —S(O)R²⁶, —S(O)₂R²⁶, —S(O)NR²⁶R^26′, —S(O)₂NR²⁶R^26′, —OS(O)NR²⁶R^26′, —OS(O)₂NR²⁶R^26′′, —NR²⁶R^26′, —NR²⁶C(O)R²⁷, —NR²⁶C(O)OR²⁷, —NR²⁶C(O)NR²⁷R^27′, —NR²⁶C(═NR^26″)NR²⁷R^27′, —NR²⁶S(O)R²⁷, —NR²⁶S(O)₂R²⁷, —NR²⁶S(O)NR²⁷R^27′, —NR²⁶S(O)₂NR²⁷R^27′, —C(O)R²⁶, —C(O)OR²⁶and —C(O)NR²⁶R^26′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, —(CH₂)_pOR²⁸, —(CH₂)_p(OCH₂)_qOR²⁸, —(CH₂)_p(OCH₂CH₂)_qOR²⁸, —OR²⁹, —OC(O)R²⁹, —OC(O)NR²⁹R^29′, —OS(O)R²⁹, —OS(O)₂R²⁹, —(CH₂)_pOS(O)₂OR²⁹, —OS(O)₂OR²⁹, —SR²⁹, —S(O)R²⁹, —S(O)₂R²⁹, —S(O)NR²⁹R^29′, —S(O)₂NR²⁹R^29′, —OS(O)NR²⁹R^29′, —OS(O)₂NR²⁹R^29′, —NR²⁹R^29′, —NR²⁹C(O)R³⁰, —NR²⁹C(O)OR³⁰, —NR²⁹C(O)NR³⁰R^30′, —NR²⁹S(O)R³⁰, —NR²⁹S(O)₂R³⁰, —NR²⁹S(O)NR³⁰R^30′, —NR²⁹S(O)₂NR³⁰R^30′, —C(O)R²⁹, —C(O)OR²⁹or —C(O)NR²⁹R^29′;

each R¹⁹, R^19′, R²⁰, R^20′, R²¹, R^21′, R²⁶, R^26′, R^26″, R²⁹, R^29′, R³⁰and R^30′ is independently selected from the group consisting of H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by halogen, —OH, —SH, —NH₂or —CO₂H;

R²⁷and R^27′are each independently selected from the group consisting of H, C₁-C₉alkyl, C₂-C₉alkenyl, C₂-C₉alkynyl, C₃-C₆cycloalkyl, —(CH₂)_p(sugar), —(CH₂)_p(OCH₂CH₂)_q-(sugar) and —(CH₂)_p(OCH₂CH₂CH₂)_q(sugar);

R²⁸is H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 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, each L¹is selected from the group consisting of

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wherein R¹⁶is defined as described herein, and * is a covalent bond.

In some embodiments, R¹⁶is H. In some embodiments, R¹⁸is selected from the group consisting of H, 5- to 7-membered heteroaryl, —OR²⁶, —NR²⁶C(O)R²⁷, —NR²⁶C(O)NR²⁷R^27′, —NR²⁶C(═NR²⁶″)NR²⁷R^27′, and —C(O)NR²⁶R^26′, wherein each hydrogen atom 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, —(CH₂)_pOR²⁸, —(CH₂)_p(OCH₂)_qOR²⁸, —(CH₂)_p(OCH₂CH₂)_qOR²⁸, —OR²⁹, —OC(O)R²⁹, —OC(O)NR²⁹R^29′, —OS(O)R²⁹, —OS(O)₂R²⁹, —(CH₂)_pOS(O)₂OR²⁹, —OS(O)₂OR²⁹, —SR²⁹, —S(O)R²⁹, —S(O)₂R²⁹, —S(O)NR²⁹R^29′, —S(O)₂NR²⁹R^29′, —OS(O)NR²⁹R^29′, —OS(O)₂NR²⁹R^29′, —NR²⁹R^29′, —NR²⁹C(O)R³⁰, —NR²⁹C(O)OR³⁰, —NR²⁹C(O)NR³⁰R^30′, —NR²⁹S(O)R³⁰, —NR²⁹S(O)₂R³⁰, —NR²⁹S(O)NR³⁰R^30′, —NR²⁹S(O)₂NR³⁰R^30′, —C(O)R²⁹, —C(O)OR²⁹or —C(O)NR²⁹R^29′;

each R²⁶, R^26′, R²⁶″, R²⁹, R^29′, R³⁰and R^30′ is independently selected from the group consisting of H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by halogen, —OH, —SH, —NH₂or —CO₂H;

R²⁷and R^27′ are each independently selected from the group consisting of H, C₁-C₉alkyl, C₂-C₉alkenyl, C₂-C₉alkynyl, C₃-C₆cycloalkyl, —(CH₂)_p(sugar), —(CH₂)_p(OCH₂CH₂)_q-(sugar) and —(CH₂)_p(OCH₂CH₂CH₂)_q(sugar);

R²⁸is a H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 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.

each R²⁶, R^26′, R^26″ and R²⁹is independently H or C₁-C₇alkyl, wherein each hydrogen atom in C₁-C₇alkyl is independently optionally substituted by halogen, —OH, —SH, —NH₂or —CO₂H;

R²⁷and R^27′ are each independently selected from the group consisting of H, —(CH₂)_p(sugar), —(CH₂)_p(OCH₂CH₂)_q(sugar) and —(CH₂)_p(OCH₂CH₂CH₂)_q(sugar);

R²⁸is 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 embodiments, each L is selected from the group consisting of

embedded image

and combinations thereof,

wherein

R¹⁸is selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR²⁶, —OC(O)R²⁶, —OC(O)NR²⁶R^26′, —OS(O)R²⁶, —OS(O)₂R²⁶, —SR²⁶, —S(O)R²⁶, —S(O)₂R²⁶, —S(O)NR²⁶R^26′, —S(O)₂NR²⁶R^26′, —OS(O)NR²⁶R^26′, —OS(O)₂NR²⁶R^26′, —NR²⁶R^26′, —NR²⁶C(O)R²⁷, —NR²⁶C(O)OR²⁷, —NR²⁶C(O)NR²⁷R^27′, —NR²⁶C(═NR²⁶″)NR²⁷R^27′, —NR²⁶S(O)R²⁷, —NR²⁶S(O)₂R²⁷, —NR²⁶S(O)NR²⁷R^27′, —NR²⁶S(O)₂NR²⁷R^27′, —C(O)R²⁶, —C(O)OR²⁶and —C(O)NR²⁶R^26′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, —(CH₂)_pOR²⁸, —(CH₂)_p(OCH₂)_qOR²⁸, —(CH₂)_p(OCH₂CH₂)_qOR²⁸, —OR²⁹, —OC(O)R²⁹, —OC(O)NR²⁹R^29′, —OS(O)R²⁹, —OS(O)₂R²⁹, —(CH₂)_pOS(O)₂OR²⁹, —OS(O)₂OR²⁹, —SR²⁹, —S(O)R²⁹, —S(O)₂R²⁹, —S(O)NR²⁹R^29′, —S(O)₂NR²⁹R^29′, —OS(O)NR²⁹R^29′, —OS(O)₂NR²⁹R^29′, —NR²⁹R^29′, —NR²⁹C(O)R³⁰, —NR²⁹C(O)OR³⁰, —NR²⁹C(O)NR³⁰R^30′, —NR²⁹S(O)R³⁰, —NR²⁹S(O)₂R³⁰, —NR²⁹S(O)NR³⁰R^30′, —NR²⁹S(O)₂NR³⁰R^30′, —C(O)R²⁹, —C(O)R²⁹, —C(O)NR²⁹R^29′;

R²⁷and R^27′ are each independently selected from the group consisting of H, C₁-C₉alkyl, C₂-C₉alkenyl, C₂-C₉alkynyl, C₃-C₆cycloalkyl, —(CH₂)_p(sugar), —(CH₂)_p(OCH₂CH₂)_q-(sugar) and —(CH₂)_p(OCH₂CH₂CH₂)_q(sugar);

R²⁸is a H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 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, R¹⁸is selected from the group consisting of H, 5- to 7-membered heteroaryl, —OR²⁶, —NR²⁶C(O)R²⁷, —NR²⁶C(O)NR²⁷R^27′, —NR²⁶C(═NR^26″)NR²⁷R^27′, and —C(O)NR²⁶R^26′, wherein each hydrogen atom 5- to 7-membered heteroaryl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, —(CH₂)_pOR²⁸, —(CH₂)_p(OCH₂)_qOR², —(CH₂)_p(OCH₂CH₂)_qOR²⁸, —OR²⁹, —OC(O)R²⁹, —OC(O)NR²⁹R^29′, —OS(O)R²⁹, —OS(O)₂R²⁹, —(CH₂)_pOS(O)₂OR, —OS(O)₂OR²⁹, —SR²⁹, —S(O)R²⁹, —S(O)₂R^29′, —S(O)NR²⁹R^29′, —S(O)₂NR²⁹R^29′, —OS(O)NR²⁹R^29′, —OS(O)₂NR²⁹R^29′, —NR²⁹R^29′, —NR²⁹C(O)R³⁰, —NR²⁹C(O)OR³⁰, —NR²⁹C(O)NR³⁰NR^30′, —NR²⁹S(O)R³⁰, —NR²⁹S(O)₂R³⁰, —NR²⁹S(O)NR³⁰R^30′, —NR²⁹S(O)₂NR³⁰R^30′, —C(O)R²⁹, —C(O)OR²⁹or —C(O)NR²⁹R^29′;

each R²⁶, R^26′, R^26″, R²⁹, R^29′, R³⁰and R^30′ is independently selected from the group consisting of H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by halogen, —OH, —SH, —NH₂or —CO₂H;

R²⁷and R^27′are each independently selected from the group consisting of H, C₁-C₉alkyl, C₂-C₉alkenyl, C₂-C₉alkynyl, C₃-C₆cycloalkyl, —(CH₂)_p(sugar), —(CH₂)_p(OCH₂CH₂)_q-(sugar) and —(CH₂)_p(OCH₂CH₂CH₂)_q(sugar);

R²⁸is a H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 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.

R²⁷and R^27′are each independently selected from the group consisting of H, —(CH₂)_p(sugar), —(CH₂)_p(OCH₂CH₂)_q(sugar) and —(CH₂)_p(OCH₂CH₂CH₂)_q(sugar);

R²⁸is 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.

AA is an amino acid as described herein. In certain embodiments, AA is a naturally occurring amino acid. In certain embodiments, AA is in the L-form. In certain embodiments, AA is in the D-form. In other embodiments, AA is an unnatural amino acid. It will be appreciated that in certain embodiments, the conjugates described herein will comprise more than one amino acid as portions of the linker, and the amino acids can be the same or different, and can be selected from a group of amino acids. It will be appreciated that in certain embodiments, the conjugates described herein will comprise more than one amino acid as portions of the linker, and the amino acids can be the same or different, and can be selected from a group of amino acids in D- or L-form. In some embodiments, at least one AA is in the L-configuration. In some embodiments, at least two AA are in the L-configuration. In some embodiments, at least one AA is in the D-configuration. In some embodiments, at least two AA are in the D-configuration. In some embodiments, each AA is independently selected from the group consisting of 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-alpha-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-aspartic acid, D-glutamic acid, D-alanine, D-valine, D-phenylalanine, D-leucine, D-tyrosine, D-cysteine, D-tryptophan, D-citrulline and D-carnosine.

In some embodiments, each AA is independently selected from the group consisting of 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-leucine, D-isoleucine and D-citrulline. In some embodiments, each AA is independently selected from the group consisting of L-arginine, D-arginine, L-aspartic acid, D-aspartic acid, L-glutamic acid and D-glutamic acid.

L²is a releasable linker. As used herein, the term “releasable linker” refers to a linker that includes at least one bond that can be broken under physiological conditions, such as a pH-labile, acid-labile, base-labile, oxidatively labile, metabolically labile, biochemically labile, or enzyme-labile bond. It is appreciated that such physiological conditions resulting in bond breaking do not necessarily include a biological or metabolic process, and instead may include a standard chemical reaction, such as a hydrolysis reaction, for example, at physiological pH, or as a result of compartmentalization into a cellular organelle such as an endosome having a lower pH than cytosolic pH.

It is understood that a cleavable bond can connect two adjacent atoms within the releasable linker and/or connect other linkers, B or D¹, as described herein, at either or both ends of the releasable linker. In the case where a cleavable bond connects two adjacent atoms within the releasable linker, following breakage of the bond, the releasable linker is broken into two or more fragments. Alternatively, in the case where a cleavable bond is between the releasable linker and another moiety, such as another linker, a drug or binding ligand, the releasable linker becomes separated from the other moiety following breaking of the bond.

The lability of the cleavable bond can be adjusted by, for example, substituents at or near the cleavable bond, such as including alpha-branching adjacent to a cleavable disulfide bond, increasing the hydrophobicity of substituents on silicon in a moiety having a silicon-oxygen bond that may be hydrolyzed, homologating alkoxy groups that form part of a ketal or acetal that may be hydrolyzed, and the like.

In some embodiments, releasable linkers described herein include one or more cleavable functional groups, such as a disulfide, a carbonate, a carbamate, an amide, an ester, and the like. Illustrative releasable linkers described herein include linkers that include hemiacetals and sulfur variations thereof, acetals and sulfur variations thereof, hemiaminals, aminals, and the like, and can be formed from methylene fragments substituted with at least one heteroatom, 1-alkoxyalkylene, 1-alkoxycycloalkylene, 1-alkoxyalkylenecarbonyl, 1-alkoxycycloalkylene-carbonyl, and the like. Illustrative releasable linkers described herein include linkers that include carbonylarylcarbonyl, carbonyl(carboxyaryl)carbonyl, carbonyl(biscarboxyaryl)carbonyl, haloalkylenecarbonyl, and the like. Illustrative releasable linkers described herein include linkers that include alkylene(dialkylsilyl), alkylene(alkylarylsilyl), alkylene(diarylsilyl), (dialkylsilyl)aryl, (alkylarylsilyl)aryl, (diarylsilyl)aryl, and the like. Illustrative releasable linkers described herein include oxycarbonyloxy, oxycarbonyloxyalkyl, sulfonyloxy, oxysulfonylalkyl, and the like. Illustrative releasable linkers described herein include linkers that include iminoalkylidenyl, carbonylalkylideniminyl, iminocycloalkylidenyl, carbonylcycloalkyliden-iminyl, and the like. Illustrative releasable linkers described herein include linkers that include alkylenethio, alkylenearylthio, and carbonylalkylthio, and the like.

In some embodiments, the conjugates described herein comprise more than one releasable linker. It will be appreciated that when the conjugates described herein comprise more than one releasable linker, the releasable linkers may be the same. It will be further appreciated that when the conjugates described herein comprise more than one releasable linker, the releasable linkers may be different. In some embodiments, the conjugates described herein comprise more than one releasable linker, wherein the more than one releasable linker comprises in each instance a disulfide bond. In some embodiments, the conjugates described herein comprise two releasable linkers both of which include a disulfide bond.

In some embodiments, L²is of the formula

embedded image

wherein

X⁸is —NR⁵⁰— or —O—;

each R³⁹, R^39′, R⁴⁰and R^40′ is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, —OR⁴⁸, —OC(O)R⁴⁸, —OC(O)NR⁴⁸R^48′, —OS(O)R⁴⁸, —OS(O)₂R⁴⁸, —SR⁴⁸, —S(O)R⁴⁸, —S(O)₂R⁴⁸, —S(O)NR⁴⁸R^48′, —S(O)₂NR⁴⁸R^48′, —OS(O)NR⁴⁸R^48′, —OS(O)₂NR⁴⁸R^48′, —NR⁴⁸R^48′, —NR⁴⁸C(O)R⁴⁹, —NR⁴⁸C(O)OR⁴⁹, —NR⁴⁸C(O)NR⁴⁹R^49′, —NR⁴⁸S(O)R⁴⁹, —NR⁴⁸S(O)₂R⁴⁹, —NR⁴⁸S(O)NR⁴⁹R^49′, —NR⁴⁸S(O)₂NR⁴⁹R^49′, —C(O)R⁴⁸, —C(O)OR⁴⁸or —C(O)NR⁴⁸R^48′, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR⁴⁴, —OC(O)R⁴⁴, —OC(O)NR⁴⁴R^44′, —OS(O)R⁴⁴, —OS(O)₂R⁴⁴, —SR⁴⁴, —S(O)R⁴⁴, —S(O)₂R⁴⁴, —S(O)NR⁴⁴R^44′, —S(O)₂NR⁴⁴R^44′, —OS(O)NR⁴⁴R^44′, —OS(O)₂NR⁴⁴R^44′, —NR⁴⁴R^44′, —NR⁴⁴C(O)R⁴⁵, —NR⁴⁴C(O)OR⁴⁵, —NR⁴⁴C(O)NR⁴⁵R^45′, —NR⁴⁴S(O)R⁴⁵, —NR⁴⁴S(O)₂R⁴⁵, —NR⁴⁴S(O)NR⁴⁵R^45′, —NR⁴⁴S(O)₂NR⁴⁵R^45′, —C(O)R⁴⁴, —C(O)OR⁴⁴or —C(O)NR⁴⁴R^44′;

each R⁴¹is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR⁴⁶, —OC(O)R⁴⁶, —OC(O)NR⁴⁶R^46′, —OS(O)R⁴⁶, —OS(O)₂R⁴⁶, —SR⁴⁶, —S(O)R⁴⁶, —S(O)₂R⁴⁶, —S(O)NR⁴⁶R^46′, —S(O)₂NR⁴⁶R^46′, —OS(O)NR⁴⁶R^46′, —OS(O)₂NR⁴⁶R^46′, —NR⁴⁶R^46′, —NR⁴⁶C(O)R⁴⁷, —NR⁴⁶C(O)OR⁴⁷, —NR⁴⁶C(O)NR⁴⁷R^47′, —NR⁴⁶S(O)R⁴⁷, —NR⁴⁶S(O)₂R⁴⁷, —N⁴⁶S(O)NR⁴⁷R^47′, —NR⁴⁶S(O)₂NR⁴⁷R^47′, —C(O)R⁴⁶, —C(O)OR⁴⁶or —C(O)NR⁴⁶R^46′;

each R⁴³, R^43′, R⁴⁴, R^44′, R⁴⁵, R^45′, R⁴⁶, R^46′, R⁴⁷, R^47′, R⁴⁸, R^48′, R⁴⁹, R^49′, and R⁵⁰is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl; u is 1, 2, 3 or 4; and each * is a covalent bond.

In some embodiments, L²is of the formula

embedded image

wherein

each R³is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR^32a, —OC(O)R^32a, —OC(O)NR^32aR^32a′, —OS(O)R^32a, —OS(O)₂R^32a, —SR^32a, —S(O)R^32a, —S(O)₂R^32a, —S(O)NR^32aR^32a′, —S(O)₂NR^32aR^32a′, —OS(O)NR^32aR^32a′, —OS(O)₂NR^32aR^32a′, —NR^32aR^32a′, —C(O)R^32a, —C(O)OR^32aor —C(O)NR^32aR^32a′;

each R⁵¹and R⁵³is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl and C₃-C₆cycloalkyl is independently optionally substituted by halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR⁵⁴, —OC(O)R⁵⁴, —OC(O)NR⁵⁴R^54′, —OS(O)R⁵⁴, —OS(O)₂R⁵⁴, —SR⁵⁴, —S(O)R⁵⁴, —S(O)₂R⁵⁴, —S(O)NR⁵⁴R^54′, —S(O)₂NR⁵⁴R^54′, —OS(O)NR⁵⁴R^54′, —OS(O)₂NR⁵⁴R⁵⁴, —NR⁵⁴R^54′, —NR⁵⁴C(O)R⁵⁵, —NR⁵⁴C(O)OR⁵⁵, —NR⁵⁴C(O)NR⁵⁵R^55′, —NR⁵⁴S(O)R⁵⁵, —NR⁵⁴S(O)₂R⁵⁵, —NR⁵⁴S(O)NR⁵⁵R^55′, —NR⁵⁴S(O)₂NR⁵⁵R^55′, —C(O)R⁵⁴, —C(O)R⁵⁴or —C(O)NR⁵⁴R^54′;

each R⁵²is independently selected from the group consisting of H, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl is independently optionally substituted by C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 7-membered heteroaryl, —OR⁵⁶, —OC(O)R⁵⁶, —OC(O)NR⁵⁶R^56′, —OS(O)R⁵⁶, —OS(O)₂R⁵⁶, —SR⁵⁶, —S(O)R⁵⁶, —S(O)₂R⁵⁶, —S(O)NR⁵⁶R^56′, —S(O)₂NR⁵⁶R^56′, —OS(O)NR⁵⁶R^56′, —OS(O)₂NR⁵⁶R^56′, —NR⁵⁶R^56′, —C(O)R⁵⁶, —C(O)OR⁵⁶or —C(O)NR⁵⁶R^56′;

each R⁵⁴, R^54′, R⁵⁵, R^55′, R⁵⁶and R^56′ is independently selected from the group consisting of H, D, C₁-C₇alkyl, C₂-C₇alkenyl, C₂-C₇alkynyl, C₃-C₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl and 5- to 7-membered heteroaryl;

v is 1, 2, 3, 4, 5 or 6; and

each * is a covalent bond.

In some embodiments, the linker is of the formula -L¹-AA-L¹-AA-L¹-L²- having the formula

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