DK2780039T3 - Cytotoksiske peptider og antistof-lægemiddel-konjugater deraf - Google Patents

Cytotoksiske peptider og antistof-lægemiddel-konjugater deraf Download PDF

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DK2780039T3
DK2780039T3 DK12787111.9T DK12787111T DK2780039T3 DK 2780039 T3 DK2780039 T3 DK 2780039T3 DK 12787111 T DK12787111 T DK 12787111T DK 2780039 T3 DK2780039 T3 DK 2780039T3
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alkyl
antibody
methyl
hydrogen
haloalkyl
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DK12787111.9T
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Matthew David Doroski
Andreas Maderna
Christopher John O'donnell
Chakrapani Subramanyam
Beth Cooper Vetelino
Russell George Dushin
Pavel Strop
Edmund Idris Graziani
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Pfizer
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
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    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
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    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
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Claims (42)

1. Forbindelse med formel I:
i eller et farmaceutisk acceptabelt salt eller solvat deraf, hvor uafhængigt ved hver forekomst Wer
R1 er hydrogen, CrC8 alkyl eller CrC8 halogenalkyl; R2 er hydrogen, CrC8 alkyl eller CrC8 halogenalkyl; R3A og R3B er et af følgende: (i) R3A er Ci-C8 alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen; og R3B er Ci-C8 alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen; eller (ii) R3A og R3B sammen er enten C2-C8 alkylen, hvilken C2-C8 alkylen, når den er sammen med carbonet, som den er bundet til, danner en mættet carbo-cyklisk ring; eller CrC8 heteroalkylen, hvilken CrC8 heteroalkylen sammen med carbonet, som den er bundet til, danner en mættet heterocyklisk ring; R5 er
C-i-C-ιο heterocyclyl, C3-C8 carbocycly og C6-Ci4 aryl eventuelt substitueret med 1,2,3,4 eller 5 grupper uafhængigt udvalgt fra gruppen bestående af -Ci-C8 alkyl, -CrC8 alkyl-N(R')2, -CrC8 alkyl-C(0)R', -CrC8 alkyl-C(0)0R', -0-(CrC8alkyl),-C(0)R', -0C(0)R', -C(0)0R', -C(0)N(R')2, -NHC(0)R', S(0)2R', -S(0)R', -OH, halogen, -N3, -N(R')2, -CN, -NHC(=NH)NH2, -NHCONH2, -S(=0)2R’ og -SR’, hvor hvert R’ uafhængigt er udvalgt fra gruppen bestående af hydrogen, CrC8 alkyl og usubstitueret aryl eller to R’ kan sammenmed nitrogenet, som de er bundet til, danne en C-i-C-m heterocyclyl; eller R5er
eventuelt substitueret med 1, 2, 3, 4 eller 5 grupper uafhængigt udvalgt fra gruppen bestående af CrC8 alkyl, -CrC8 alkyl-N(R’)2, -CrC8 alkyl-C(0)R’, -CrC8 alkyl-C(0)0R', -0-(CrC8 alkyl), -C(0)R', -0C(0)R',-C(0)0R', -C(0)N(R')2, -NHC(0)R', -S(0)2R', -S(0)R', -OH, halogen, -N3, -N(R')2, -CN, -NHC(=NH)NH2, -NHCONH2, -S(=0)2R', -SR' og arylen-R’, hvor hvert R’ er uafhængigt udvalgt fra gruppen bestående af hydrogen, CrC8 alkyl, CrC8heterocyclyl, CrCi0alkylen-C3-C8heterocyclyl og aryl, eller to R’ kan sammen med nitrogenet, som de er bundet til, danne en C-i-C-m heterocyclyl; R6 er hydrogen, -CrC8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl eller -CrC8 halo-genalkyl; R12 er hydrogen, CrC4 alkyl, C-i-C-m heterocyclyl eller C6-Ci4 aryl; R13 er C1-C10 heterocyclyl; og XerO.
2. Forbindelse med formel Ila:
Ila eller et farmaceutisk acceptabelt salt eller solvat deraf, hvor uafhængigt ved hver forekomst Wer
R1 Pr
Y er -C2-C20 alkylen-, -C2-C20 heteroalkylen-; -C3-C8 carbocyclo-, -arylen-, -C3-C8heterocyclo-, -CrCi0alkylen-arylen-, -arylen-CrCi0alkylen-, -Ci-Cioalkylen-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-Ci-Ci0alkylen-, -CrCioalkylen-(C3-C8heterocyclo)- eller-(C3-C8 heterocyclo)-Ci-Ci0alkylen-; Z er
eller-NH2; G er halogen, -OH, -SH eller -S-CrC6alkyl; R2 er hydrogen, C-|-C8 alkyl eller C-|-C8 halogenalkyl; R3A og R3B er et af følgende: (i) R3A er CrC8 alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen; og R3B er CrC8 alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen; eller (ii) R3A og R3B sammen er enten C2-C8 alkylen, hvilken C2-C8 alkylen, når den er sammen med carbonet, som den er bundet til, danner en mættet carbo-cyklisk ring; eller CrC8 heteroalkylen, hvilken CrC8 heteroalkylen sammen med carbonet, som den er bundet til, danner en mættet heterocyklisk ring; R5 er
C-i-C-io heterocyclyl, C3-C8 carbocycly og C6-Ci4 aryl eventuelt substitueret med 1,2,3,4 eller 5 grupper uafhængigt udvalgt fra gruppen bestående af -CrC8 alkyl, -CrC8 alkyl-N(R')2, -CrC8 alkyl-C(0)R', -CrC8 alkyl-C(0)0R' -0-(CrC8alkyl),-C(0)R', -0C(0)R', -C(0)0R', -C(0)N(R')2, -NHC(0)R', -S(0)2R', -S(0)R', -OH, halogen, -N3, -N(R')2, -CN, -NHC(=NH)NH2, -NHCONH2, -S(=0)2R' og -SR', hvor hvert R’ er uafhængigt udvalgt fra gruppen bestående af hydrogen, Cr C8 alkyl og usubstitueret aryl, eller to R’ kan sammen med nitrogenet, som de er bundet til, danne en C-i-C-io heterocyclyl; eller R5 er
eventuelt substitueret med 1, 2, 3, 4 eller 5 grupper uafhængigt udvalgt fra gruppen bestående af CrC8 alkyl, -CrC8 alkyl-N(R’)2, -CrC8 alkyl-C(0)R’, -CrC8 alkyl-C(0)0R’, -0-(CrC8alkyl), -C(0)R', -0C(0)R',-C(0)0R', -C(0)N(R')2, -NHC(0)R', -S(0)2R', -S(0)R', -OH, halogen, -N3, -N(R')2, -CN, -NHC(=NH)NH2, -NHCONH2, -S(=0)2R', -SR' og arylen-R’, hvor hvert R’ er uafhængigt udvalgt fra gruppen bestående af hydrogen, CrC8 alkyl, CrC8heterocyclyl, CrCi0alkylen-C3-C8heterocyclyl og aryl, eller to R’ kan sammen med nitrogenet, som de er bundet til, danne en C-i-C-io heterocyclyl; R6 er hydrogen, -CrC8alkyl, -C2-C8alkenyl, -C2-C8alkynyl eller -Cr C8halogenalkyl; R12 er hydrogen, CrC4alkyl, CrCioheterocyclyl eller C6-Ci4aryl; R13 er CrCioheterocyclyl; og R7 er ved hver forekomst uafhængigt udvalgt fra gruppen bestående af F, Cl, I, Br, N02, CN og CF3; R10 er hydrogen, -CrCi0alkyl, -C3-C8carbocyclyl, -aryl, -CrCioheteroalkyl, -C3-C8heterocyclo, -CrCi0alkylen-aryl, -arylen-CrCi0alkyl, -CrCi0alkylen-(C3-C8carbocyclo),-(C3-C8 carbocyclo)-Ci-Ci0alkyl, -CrCi0alkylen-(C3-Csheterocyclo) og -(C3-C8 heterocyclo)-Ci-Ci0alkyl, hvor aryl i Ri0, der omfatter aryl, eventuelt er substitueret med [R7]h! h er 1,2, 3, 4 eller 5; og XerO.
3. Forbindelse med formel Illa:
Illa eller et farmaceutisk acceptabelt salt eller solvat deraf, hvor uafhængigt ved hver forekomst Wer
R1 er hydrogen, CrC8 alkyl eller CrC8 halogenalkyl; R2 er hydrogen, CrC8 alkyl eller CrC8 halogenalkyl; R3A og R3B er et af følgende: (i) R3A er C-i-Cs alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen; og R3B er Ci-C8 alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen; eller (ii) R3A og R3B sammen er enten C2-C8 alkylen, hvilken C2-C8 alkylen, når den er sammen med carbonet, som den er bundet til, danner en mættet carbo-cyklisk ring; eller CrC8 heteroalkylen, hvilken CrC8 heteroalkylen sammen med carbonet, som den er bundet til, danner en mættet heterocyklisk ring; R5 er
eventuelt substitueret med 1, 2, 3, 4 eller 5 grupper uafhængigt udvalgt fra gruppen bestående af C-i-C8 alkyl, -0-(CrC8alkyl), -C(0)R', -0C(0)R', -C(0)0R', -C(0)NH2, -C(0)NHR', -C(0)N(R')2, -NHC(0)R', -S(0)2R', -S(0)R', -OH, halogen, -N3, -NH2, -NH(R'), -N(R')2, -CN, -NHC(=NH)NH2, -NHCONH2, -S(=0)2R’ og -SR’, hvor hvert R’ er uafhængigt udvalgt fra gruppen bestående af hydrogen, CrC8 alkyl og usubstitueret aryl; R11 er
Y er -C2-C20 alkylen-, -C2-C20 heteroalkylen-, C3-C8 carbocyclo-, -arylen-, -C3-Csheterocyclo-, -CrCi0alkylen-arylen-, -arylen-CrCi0alkylen-, -Cr Ci0alkylen-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-Ci-Ci0alkylen-, -Cr Ci0alkylen-(C3-C8heterocyclo)- eller -(C3-C8 heterocyclo)-Ci-Ci0alkylen-; Z er
eller-NH2; G er halogen, -OH, -SH, eller -S-CrC6alkyl; R7 er ved hver forekomst uafhængigt udvalgt fra gruppen bestående af F, Cl, I, Br, N02, CN og CF3; h er 1,2, 3, 4 eller 5; og XerO.
4. Forbindelse med formel I Ib:
Ilb eller et farmaceutisk acceptabelt salt eller solvat deraf, hvor uafhængigt ved hver forekomst Wer
Y er -C2-C20 alkylen-, -C2-C20 heteroalkylen-, -C3-C8 carbocyclo-, -arylen-, -C3-C8heterocyclo-, -CrCi0alkylen-arylen-, -arylen-CrCi0alkylen-, -Ci-Cioalkylen-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-Ci-Ci0alkylen-, -CrCioalkylen-(C3-C8heterocyclo)-, eller-(C3-C8 heterocyclo)-CrCi0alkylen-; Z er
eller-NHL; L er et antistof; R2 er hydrogen, C-|-C8 alkyl eller C-|-C8 halogenalkyl; R3A og R3B er et af følgende: (i) R3A er CrC8 alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen; og R3B er CrC8 alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen; eller (ii) R3A og R3B sammen er enten C2-C8 alkylen, hvilken C2-C8 alkylen, når den er sammen med carbonet, som den er bundet til, danner en mættet carbo-cyklisk ring; eller CrC8 heteroalkylen, hvilken CrC8 heteroalkylen sammen med carbonet, som den er bundet til, danner en mættet heterocyklisk ring; R5 er
C-i-C-ιο heterocyclyl, C3-C8 carbocycly og C6-Ci4 aryl eventuelt substitueret med 1,2,3,4 eller 5 grupper uafhængigt udvalgt fra gruppen bestående af -CrC8 alkyl, -CrC8 alkyl-N(R')2, -CrC8 alkyl-C(0)R', -CrC8 alkyl-C(0)0R' -0-(CrC8alkyl),-C(0)R', -0C(0)R', -C(0)0R', -C(0)N(R')2, -NHC(0)R', -S(0)2R', -S(0)R', -OH, halogen, -N3, -N(R')2, -CN, -NHC(=NH)NH2, -NHCONH2, -S(=0)2R’ og -SR’, hvor hvert R’ er uafhængigt udvalgt fra gruppen bestående af hydrogen, CrC8 alkyl og usubstitueret aryl, eller to R’ kan sammen med nitrogenet, som de er bundet til, danne en C-i-C-ιο heterocyclyl; eller R5 er
eventuelt substitueret med 1, 2, 3, 4 eller 5 grupper uafhængigt udvalgt fra gruppen bestående af CrC8 alkyl, -CrC8 alkyl-N(R’)2, -CrC8 alkyl-C(O) R’, -CrC8 alkyl-C(0)0R', -0-(CrC8alkyl), -C(0)R', -0C(0)R',-C(0)0R', -C(0)N(R')2, -NHC(0)R', -S(0)2R', -S(0)R', -OH, halogen, -N3, -N(R')2, -CN, -NHC(=NH)NH2, -NHCONH2, -S(=0)2R', -SR' og arylen-R’, hvor hvert R’ er uafhængigt udvalgt fra gruppen bestående af hydrogen, CrC8 alkyl, CrC8heterocyclyl, CrCi0alkylen-C3-C8heterocyclyl og aryl, eller to R’ kan sammen med nitrogenet, som de er bundet til, danne en C-i-C-ιο heterocyclyl; R6 er hydrogen, -CrC8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl eller -CrC8 halo-genalkyl; R12 er hydrogen, C1-C4 alkyl, C1-C10 heterocyclyl eller C6-Ci4 aryl; R13 er C1-C10 heterocyclyl; og XerO.
5. Forbindelse med formel 11 Ib:
Illb eller et farmaceutisk acceptabelt salt eller solvat deraf, hvor uafhængigt ved hver forekomst Wer
R1 er hydrogen, CrC8 alkyl eller CrC8 halogenalkyl; R2 er hydrogen, CrC8 alkyl eller CrC8 halogenalkyl; R3A og R3B er et af følgende: (i) R3A er C-i-Cs alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen; og R3B er C-i-Cs alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen; eller (ii) R3A og R3B sammen er enten C2-C8 alkylen, hvilken C2-C8 alkylen, når den er sammen med carbonet, som den er bundet til, danner en mættet carbo-cyklisk ring; eller CrC8 heteroalkylen, hvilken CrC8 heteroalkylen sammen med carbonet, som den er bundet til, danner en mættet heterocyklisk ring; R5 er
eventuelt substitueret med 1, 2, 3, 4 eller 5 grupper uafhængigt udvalgt fra gruppen bestående af CrC8 alkyl, -0-(CrC8alkyl), -C(0)R', -0C(0)R', -C(0)0R', -C(0)NH2, -C(0)NHR', -C(0)N(R')2, -NHC(0)R', -S(0)2R', -S(0)R', -OH, halogen, -N3, -NH2, -NH(R'), -N(R')2, -CN, -NHC(=NH)NH2, -NHCONH2, -S(=0)2R' og -SR', hvor hvert R' er uafhængigt udvalgt fra gruppen bestående af hydrogen, C-|-C8 alkyl og usubstitueret aryl; R11 er
Y er -C2-C20 alkylen-, -C2-C20 heteroalkylen-, -C3-C8 carbocyclo-, -arylen-, -C3-C8heterocyclo-, -CrCi0alkylen-arylen-, -arylen-CrCi0alkylen-, -Ci-Cioalkylen-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-Ci-Ci0alkylen-, -Ci-Cioalkylen-(C3-C8heterocyclo)- eller-(C3-C8 heterocyclo)-CrCi0alkylen-; Z er
eller-NHL; L er et antistof; XerO.
6. Forbindelse med formel Ile:
lie eller et farmaceutisk acceptabelt salt eller solvat deraf, hvor uafhængigt ved hver forekomst R1' er
Y er -C2-C20 alkylen-, -C2-C20 heteroalkylen-, -C3-C8 carbocyclo-, -arylen-, -C3-C8heterocyclo-, -CrCi0alkylen-arylen-, -arylen-CrCi0alkylen-, -Ci-Cioalkylen-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-Ci-Ci0alkylen-, -Cr Ci0alkylen-(C3-C8heterocyclo)- eller-(C3-C8 heterocyclo)-Ci-Ci0alkylen-; Z' er
eller-NH-; L er et antistof; D er fraværende; R2' er hydrogen, C-|-C8 alkyl, C-|-C8 halogenalkyl eller er fraværende, hvis ** 's er til stede; R3Ai og R3B' er et af følgende: (i) R3A' er CrC8 alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen; og R3B' er CrC8 alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen eller R3B er C2-C4 alkylen og danner en mættet 5- til 6-leddet ring som angivet af '\ > eller (ii) R3Ai og R3Bi sammen er enten C2-C8 alkylen, hvilken C2-C8 alkylen, når den er sammen med carbonet, som den er bundet til, danner en mættet car-bocyklisk ring; eller C-|-C8 heteroalkylen, hvilken C-|-C8 heteroalkylen sammen med carbonet, som den er bundet til, danner en mættet heterocyklisk ring; R5 er
C-i-C-io heterocyclyl, C3-C8 carbocycly og C6-Ci4 aryl eventuelt substitueret med 1,2,3,4 eller 5 grupper uafhængigt udvalgt fra gruppen bestående af -CrC8 alkyl, -CrC8 alkyl-N(R’)2, -CrC8 alkyl-C(0)R', -CrC8 alkyl-C(0)0R' -0-(C1-C8alkyl),-C(0)R', -0C(0)R', -C(0)0R', -C(0)N(R')2, -NHC(0)R', -S(0)2R\ -S(0)R', -OH, halogen, -N3, -N(R')2, -CN, -NHC(=NH)NH2, -NHCONH2, -S(=0)2R' og -SR', hvor hvert R’ er uafhængigt udvalgt fra gruppen bestående af hydrogen, Cr C8 alkyl og usubstitueret aryl, eller to R’ kan sammen med nitrogenet, som de er bundet til, danne en C-i-C-io heterocyclyl; eller R5er
eventuelt substitueret med 1, 2, 3, 4 eller 5 grupper uafhængigt udvalgt fra gruppen bestående af CrC8alkyl, -CrC8alkyl-N(R’)2, -CrC8alkyl-C(0)R’, -Cr C8alkyl-C(0)0R’, -0-(CrC8alkyl), -C(0)R', -0C(0)R',-C(0)0R', -C(0)N(R')2, -NHC(0)R', -S(0)2R', -S(0)R', -OH, halogen, -N3, -N(R')2, -CN, -NHC(=NH)NH2, -NHCONH2, -S(=0)2R', -SR' og arylen-R’, hvor hvert R’ er uafhængigt udvalgt fra gruppen bestående af hydrogen, CrC8 alkyl, CrC8heterocyclyl, CrCioalkylen-C3-C8heterocyclyl og aryl, eller to R’ kan sammen med nitrogenet, som de er bundet til, danne en C-i-C-io heterocyclyl; R6 er hydrogen, -CrC8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl eller -CrC8 halo-genalkyl; R12 er hydrogen, C1-C4 alkyl, C1-C10 heterocyclyl eller C6-Ci4 aryl; R13 er C1-C10 heterocyclyl; og XerO.
7. Forbindelse med formel lllc:
II le eller et farmaceutisk acceptabelt salt eller solvat deraf, hvor uafhængigt ved hver forekomst W er
R1 er hydrogen, CrC8 alkyl eller CrC8 halogenalkyl; R2 er hydrogen, CrC8 alkyl eller CrC8 halogenalkyl; R3A og R3B er et af følgende: (i) R3A er Ci-C8 alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen; og R3B er Ci-C8 alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen; eller (ii) R3A og R3B sammen er enten C2-C8 alkylen, hvilken C2-C8 alkylen, når den er sammen med carbonet, som den er bundet til, danner en mættet carbo-cyklisk ring; eller CrC8 heteroalkylen, hvilken CrC8 heteroalkylen sammen med carbonet, som den er bundet til, danner en mættet heterocyklisk ring; R5 er
eventuelt substitueret med 1, 2, 3, 4 eller 5 grupper uafhængigt udvalgt fra gruppen bestående af CrC8 alkyl, -0-(CrC8aikyl), -C(0)R', -0C(0)R',-C(0)0R', -C(0)NH2, -C(0)NHR', -C(0)N(R')2, -NHC(0)R', -S(0)2R', -S(0)R', -OH, halogen, -N3, -NH2, -NH(R'), -N(R')2, -CN, -NHC(=NH)NH2, -NHCONH2, -S(=0)2R' og -SR', hvor hvert R' er uafhængigt udvalgt fra gruppen beståen- de af hydroqen, Ci-C8 alkyl oq usubstitueret aryl; R11' er
Y er -C2-C20 alkylen-, -C2-C20 heteroalkylen-, -C3-C8 carbocyclo-, -arylen-, -C3-C8heterocyclo-, -CrCi0alkylen-arylen-, -arylen-CrCi0alkylen-, -Ci-Cioalkylen-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-Ci-Ci0alkylen-, -CrCi0alkylen-(C3-C8heterocyclo)-, eller-(C3-C8 heterocyclo)-CrCi0alkylen-; Z' er
eller-NH-; L er et antistof; XerO.
8. Forbindelse med formel Ild:
Ild eller et farmaceutisk acceptabelt salt eller solvat deraf, hvor uafhængigt ved hver forekomst L er et antistof; [linker] er en divalent linker; D er fraværende; R2' er hydrogen, C-|-C8 alkyl, C-|-C8 halogenalkyl eller er fraværende, hvis er til stede; R3Ai og R3B' er et af følgende: (i) R3A' er CrC8 alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen; og R3B' er CrC8 alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl, eller R3B' er C2-C4 alkylen og danner en mættet 5- til 6-leddet ring som angivet af '\ · 5 eller (ii) R3A og R3B sammen er enten C2-C8 alkylen, hvilken C2-C8 alkylen, når den er sammen med carbonet, som den er bundet til, danner en mættet carbo-cyklisk ring; eller CrC8 heteroalkylen, hvilken CrC8 heteroalkylen sammen med carbonet, som den er bundet til, danner en mættet heterocyklisk ring; R5 er
C-i-C-io heterocyclyl, C3-C8 carbocycly og C6-Ci4 aryl eventuelt substitueret med 1,2,3,4 eller 5 grupper uafhængigt udvalgt fra gruppen bestående af -CrC8 alkyl, -CrC8 alkyl-N(R')2, -CrC8 alkyl-C(0)R', -CrC8 alkyl-C(0)0R' -0-(CrC8alkyl),-C(0)R', -0C(0)R', -C(0)0R', -C(0)N(R')2, -NHC(0)R', -S(0)2R', -S(0)R', -OH, halogen, -N3, -N(R')2, -CN, -NHC(=NH)NH2, -NHCONH2, -S(=0)2R’ og -SR’, hvor hvert R’ er uafhængigt udvalgt fra gruppen bestående af hydrogen, CrC8 alkyl og usubstitueret aryl, eller to R’ kan sammen med nitrogenet, som de er bundet til, danne en C-i-C-io heterocyclyl; eller R5 er r P
eventuelt substitueret med1, 2, 3, 4 eller 5 grupper uafhængigt udvalgt fra gruppen bestående af CrC8 alkyl, -CrC8 alkyl-N(R’)2, -CrC8 alkyl-C(0)R’, -CrC8 alkyl-C(0)0R', -0-(CrC8alkyl), -C(0)R', -0C(0)R',-C(0)0R', -C(0)N(R')2, -NHC(0)R', -S(0)2R', -S(0)R', -OH, halogen, -N3, -N(R')2, -CN, -NHC(=NH)NH2, -NHCONH2, -S(=0)2R', -SR' og arylen-R', hvor hvert R' er uafhængigt udvalgt fra gruppen bestående af hydrogen, CrC8 alkyl, Cr Csheterocyclyl, CrCi0alkylen-C3-C8heterocyclyl og aryl, eller to R’ kan sammen med nitrogenet, som de er bundet til, danne en C-i-C-io heterocyclyl; R6 er hydrogen, -CrC8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl eller -CrC8 halo-genalkyl; R12 er hydrogen, C1-C4 alkyl, C1-C10 heterocyclyl eller C6-Ci4 aryl; R13 er C1-C10 heterocyclyl; og XerO.
9. Forbindelse med formel llld:
Uld eller et farmaceutisk acceptabelt salt eller solvat deraf, hvor uafhængigt ved hver forekomst Wer
R1 er hydrogen, CrC8 alkyl eller CrC8 halogenalkyl; R2 er hydrogen, CrC8 alkyl eller CrC8 halogenalkyl; R3A og R3B er et af følgende: (i) R3A er C-i-Cs alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen; og R3B er Ci-C8 alkyl, CrC8 halogenalkyl, C3-C8 carbocyclyl eller halogen; eller (ii) R3A og R3B sammen er enten C2-C8 alkylen, hvilken C2-C8 alkylen, når den er sammen med carbonet, som den er bundet til, danner en mættet carbo-cyklisk ring; eller CrC8 heteroalkylen, hvilken CrC8 heteroalkylen sammen med carbonet, som den er bundet til, danner en mættet heterocyklisk ring; R5 er
eventuelt substitueret med 1, 2, 3, 4 eller 5 grupper uafhængigt udvalgt fra gruppen bestående af CrC8 alkyl, -0-(CrC8aikyl), -C(0)R', -0C(0)R',-C(0)0R', -C(0)NH2, -C(0)NHR', -C(0)N(R')2, -NHC(0)R', -S(0)2R', -S(0)R', -OH, halogen, -N3, -NH2, -NH(R'), -N(R')2, -CN, -NHC(=NH)NH2, -NHCONH2, -S(=0)2R' og -SR', hvor hvert R' er uafhængigt udvalgt fra gruppen bestående af hydrogen, CrC8 alkyl og usubstitueret aryl; [linker] er en divalent linker; L er et antistof; XerO.
10. Forbindelse, salt eller solvat ifølge et af kravene 1 -5, 7 og 9, hvor W er
11. Forbindelse, salt eller solvat ifølge et af kravene 1 -5, 7 og 9, hvor W er
12. Forbindelse, salt eller solvat ifølge et af kravene 1-5, 7 og 9, hvor R2 er hydrogen eller CrC8 alkyl.
13. Forbindelse, salt eller solvat ifølge et af kravene 1-5, 7 og 9, hvor R3A er C-i-Cs alkyl, fortrinsvis methyl.
14. Forbindelse, salt eller solvat ifølge et af kravene 1-5, 7 og 9, hvor R3A og R3B sammen er enten C2-C8 alkylen, hvilken C2-C8 alkylen, når den er sammen med carbonet, som den er bundet til, danner en mættet carbocyklisk ring; eller CrC8 heteroalkylen, hvilken CrC8 heteroalkylen, sammen med carbonet, som den er bundet til, danner en mættet heterocyklisk ring.
15. Forbindelse, salt eller solvat ifølge krav 14, hvor R3A og R3B sammen er -CH2CH2-, hvilken -CH2CH2- når den er sammen med carbonet, som den er bundet til, danner cyclopropyl.
16. Forbindelse, salt eller solvat ifølge krav 14, hvor R3A og R3B sammen er -CH2CH2CH2CH2-, hvilken -CH2CH2CH2CH2-, når den er sammen med car- bonet, som den er bundet til, danner cyclopentyl.
17. Forbindelse, salt eller solvat ifølge krav 14, hvor R3A og R3B sammen er -CH2OCH2-, hvilken -CH2OCH2- når den er sammen med carbonet, som den er bundet til, danner oxetanyl.
18. Forbindelse, salt eller solvat ifølge et af kravene 1-2, 4, 6 og 8, hvor R5 er
19. Forbindelse, salt eller solvat ifølge et af kravene 4-9, hvor antistoffet er udvalgt blandt trastuzumab, oregovomab, edrecolomab, cetuximab, et humaniseret monoklonalt antistof til vitronectinreceptoren (ανβ3); alemtuzumab; et humaniseret anti-HLA-DR-antistof til behandling af non-Hodgkins lymfom; 1311 Lym-1; et muse-anti-HLA-DrIO-antistof til behandling af non-Hodgkins lymfom; et humaniseret anti-CD2 mAb til behandling af Hodgkins sygdom eller non-Hodgkins lymfom; labetuzumab; bevacizumab; ibritumomabtiuxetan; ofatumumab; panitumumab; rituximab; tositumomab; ipilimumab; gemtuzumab; et anti-IL13-antistof; og et anti-Notch-antistof.
20. Forbindelse eller et farmaceutisk acceptabelt salt eller solvat deraf ifølge krav 1 udvalgt blandt:
I
21. Forbindelse eller et farmaceutisk acceptabelt salt eller solvat deraf ifølge krav 1 udvalgt blandt:
22. Payload-linker eller et antistof-lægemiddel-konjugat eller et farmaceutisk acceptabelt salt eller solvat deraf ifølge et af kravene 2 til 9, omfattende et radikal af en forbindelse ifølge krav 20 eller 21.
23. Antistof-lægemiddel-konjugat eller et farmaceutisk acceptabelt salt eller solvat deraf, omfattende et radikal af en forbindelse ifølge krav 1-3.
24. Forbindelse eller et farmaceutisk acceptabelt salt eller solvat deraf ifølge et af kravene 2 eller 3 udvalgt blandt:
25. Antistof-lægemiddel-konjugat eller et farmaceutisk acceptabelt salt eller solvat deraf ifølge et af kravene 4, 5, 7 eller 9 omfattende et radikal af en forbindelse ifølge krav 24.
26. Forbindelse ifølge krav 1 eller et farmaceutisk acceptabelt salt eller solvat deraf, som er
27. Forbindelse ifølge krav 1 eller et farmaceutisk acceptabelt salt eller solvat deraf, som er
28. Forbindelse ifølge krav 1 eller et farmaceutisk acceptabelt salt eller solvat deraf, som er
29. Forbindelse ifølge krav 1 eller et farmaceutisk acceptabelt salt eller solvat deraf, som er
30. Forbindelse ifølge krav 1 eller et farmaceutisk acceptabelt salt eller solvat deraf, som er
31. Forbindelse ifølge krav 1 eller et farmaceutisk acceptabelt salt eller solvat deraf, som er
32. Forbindelse ifølge krav 1 eller et farmaceutisk acceptabelt salt eller solvat deraf, som er
33. Forbindelse ifølge krav 1 eller et farmaceutisk acceptabelt salt eller solvat deraf, som er
34. Payload-linker eller et antistof-lægemiddel-konjugat eller et farmaceutisk acceptabelt salt eller solvat deraf ifølge et af kravene 2 til 9, omfattende et radikal af en forbindelse ifølge krav 26-33.
35. Forbindelse ifølge krav 24 eller et farmaceutisk acceptabelt salt eller solvat deraf, som er
36. Forbindelse ifølge krav 24 eller et farmaceutisk acceptabelt salt eller solvat deraf, som er
37. Forbindelse ifølge krav 24 eller et farmaceutisk acceptabelt salt eller solvat deraf, som er
38. Forbindelse ifølge krav 24. eller et farmaceutisk acceptabelt salt eller solvat deraf, som er
39. Forbindelse ifølge krav 24. eller et farmaceutisk acceptabelt salt eller solvat deraf, som er
40. Antistof-lægemiddel-konjugat eller et farmaceutisk acceptabelt salt eller solvat deraf ifølge et af kravene 4, 5, 7 eller 9, omfattende et radikal af en forbindelse ifølge krav 35-39.
41. Farmaceutisk sammensætning omfattende en forbindelse ifølge et af kravene 1-40 eller et farmaceutisk acceptabelt salt eller solvat deraf og farmaceutisk acceptabelt hjælpestof.
42. Forbindelse ifølge et af kravene 1-40 eller et farmaceutisk acceptabelt salt eller solvat deraf eller en farmaceutisk sammensætning ifølge krav 41 til anvendelse inden for behandlingen af kræft.
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