Granted Patent B2

US 12,643,879 · App. 17/783,940 · Granted Jun 2, 2026

Inventors: Magdalena Izabela Zawadzka (Gdansk, PL); Luigi Piero Stasi (Monza, IT); Maciej Krzysztof Rogacki (Cracow, PL); Grzegorz Wojciech Cwiertnia (Kamesznica, PL); Lukasz Piotr Dudek (Wieliczka, PL); Agnieszka Justyna Gibas (Cracow, PL); Anna Rajda (Wroclaw, PL); Charles-Henry Fabritius (Poznan, PL); Adam Radzimierski (Cracow, PL); Tushar Ravindra Mahajan (Cracow, PL); Marcin Wojciech Les (Mielec, PL); Karol Zuchowicz (Gnojnik, PL); Marek Wronowski (Debowa Góra, PL); David Jörg Synak (Cracow, PL); Sundara Raghuram Tangirala (Cracow, PL)

Assignee: Ryvu Therapeutics S.A.

C07D401/14A61K47/545A61P37/02C07D405/14C07D413/14C07D471/04C07B2200/07

Abstract

Claims (208)

1 . A compound-linker construct comprising

(i) a compound of formula (I); and

(ii) a linker L 1

wherein the compound of formula (I) is a compound of the following formula

or a salt, stereoisomer, tautomer, or N-oxide thereof,

wherein

X 1 is CH or N;

X 2 is CR 3 or N;

R 1 , R 2 and R 3 are independently H, OH, NR C R D , CN, halogen, C 1 -C 4 -alkyl, NR C R D —C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, aryloxy, benzyloxy, C(═O)R E , NR F C(═O)R E , NR F —(C 1 -C 4 -alkylene)-C(═O)R E , NR F —(C 1 -C 4 -alkylene)-NR C R D , O—(C 1 -C 4 -alkylene)-NR C R D , or 4- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, heterocyclyl, heterocyclyloxy, or heterocyclyl-C 1 -C 2 -alkyl, or 8- to 10-membered saturated, partially or fully unsaturated, or aromatic carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic rings comprise one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R X ;

R 4 is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, or a 9- or 10-membered aromatic carbobicyclic or heterobicyclic ring, wherein the heterocyclic or heterobicyclic ring comprises at least one nitrogen atom and optionally one or more, same or different additional heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic rings is independently unsubstituted or substituted with one or more same or different substituents R X ;

R 5 is selected from the group consisting of

and wherein

R N is H, C 1 -C 4 -alkyl, HO(C═O)—C 1 -C 4 -alkyl, NR C R D —C 1 -C 4 -alkyl, C 1 -C 2 -alkoxy-C 1 -C 4 -alkyl, or a 3- or 4-membered saturated carbocyclyl or heterocyclyl, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R X ;

R C and R D are independently H, or C 1 -C 2 -alkyl; or

R C and R D together with the nitrogen atom to which they are bonded form a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the heterocyclic ring is independently unsubstituted or substituted with one or more, same or different substituents R X ;

R E is H, C 1 -C 2 -alkyl, NR C R D —C 1 -C 4 -alkyl, phenyl, benzyl, OR G , or NR H R I ; or a 5- or 6-membered saturated, partially or fully unsaturated heterocyclyl, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R F ;

R F is H, C 1 -C 2 -alkyl, C 3 -C 6 -cycloalkyl, phenyl, benzyl, or C(═O) NR H R I ;

R G is H, C 1 -C 2 -alkyl, or 5- or 6-membered aromatic carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, heterocyclyl, or heterocyclyl-C 1 -C 2 -alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N or S, wherein said N-atoms are independently oxidized or non-oxidized;

R H and R I are independently H, C 1 -C 2 -alkyl, or 5- or 6-membered aromatic carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, heterocyclyl, or heterocyclyl-C 1 -C 2 -alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N or S, wherein said N-atoms are independently oxidized or non-oxidized; or

R H and R I together with the nitrogen atom to which they are bonded form a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the heterocyclic ring is independently unsubstituted or substituted with one or more, same or different substituents R X ;

R X is OH, NR C R D , halogen, CN, NO 2 , C 1 -C 2 -alkyl, C 1 -C 2 -haloalkyl, NR C R D —C 1 -C 4 -alkyl, R C O—C 1 -C 4 -alkyl, C 1 -C 2 -alkoxy, C(═O)R E , or two R X form ═O, or two R X together with the carbon atom to which they are bonded form a 3- to 5-membered saturated, partially or fully unsaturated, or aromatic carbocyclic ring;

with the proviso that at least one of the following conditions is met:

any one of

R 1 , R 2 , or R 3 is independently NR C R D , NR C R D —C 1 -C 4 -alkyl, NR F —(C 1 -C 4 -alkylene)-NR C R D , O—(C 1 -C 4 -alkylene)-NR C R D , and R C is H;

or

any one of

R 1 , R 2 , or R 3 is NR F C(═O)R E , wherein R E is NR C R D —C 1 -C 4 -alkyl, and R C is H; or

R N is NR C R D —C 1 -C 4 -alkyl and R C is H;

or

any one of the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R N carries a substituent R X , wherein

R X is OH, NR C R D , NR C R D —C 1 -C 4 -alkyl, or R C O—C 1 -C 4 -alkyl, and R C is H;

wherein a covalent bond between the compound of formula (I) and the linker L 1 is established by the reaction of a functional group of the compound of formula (I) with a functional group handle of the linker L 1 ; and wherein the functional group of the compound of formula (I) is attached to or part of the substituents R 2 , R 4 , R 5 , or R N so that the linker L 1 is covalently bonded to the compound of formula (I) according to any one of the following structures;

wherein the linker L 1 has the structure H 1A -L C -H 1B ;

L C is a chain of 2 to 100 atoms selected from carbon, nitrogen, oxygen, and sulfur atoms, which may be interrupted by 5- to 10-membered aryl and heteroaryl groups and/or 3- to 8-membered saturated carbocyclyl or heterocyclyl groups, wherein the aforementioned heteroaryl and heterocyclic groups comprise one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the chain is independently unsubstituted or substituted with one or more same or different substituents selected from halogen, OH, ═O, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, and C 1 -C 6 -haloalkoxy;

H 1A is a first functional group handle which is covalently bonded to the compound of formula (I); and

H 1B is a second functional group handle suitable for forming a covalent bond to a targeting moiety T.

2 . The compound-linker construct according to claim 1 , wherein the linker L 1 is covalently bonded to the compound of formula (I) according to

3 . The compound-linker construct according to claim 1 , wherein the linker L 1 is selected from the group consisting of:

wherein

L C is a chain L C of units selected from the group consisting of a linear or branched polyethylene glycol chain, a sequence of amino acids, and a linear or branched C 1 -C 10 -alkyl chain, and any combinations thereof, wherein each substitutable carbon or heteroatom of the afore mentioned units may be unsubstituted or substituted with one or more, same or different substituents selected from halogen, OH, ═O, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, and C 1 -C 6 -haloalkoxy; and

§ marks the connection to the compound of formula (I); and

X represents a leaving group selected from

4 . The compound-linker construct according claim 1 , wherein the linker L 1 is selected from the group consisting of:

wherein

§ marks the connection to the compound of formula (I).

5 . A conjugate comprising

(i) a compound of formula (I);

(ii) a linker L 2 ; and

(iii) a targeting moiety T;

wherein the compound of formula (I) is a compound of the following formula

or a salt, stereoisomer, tautomer, or N-oxide thereof,

wherein

X 1 is CH or N;

X 2 is CR 3 or N;

R 1 , R 2 and R 3 are independently H, OH, NR C R D , CN, halogen, C 1 -C 4 -alkyl, NR C R D —C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, aryloxy, benzyloxy, C(═O)R E , NR F C(═O)R E , NR F —(C 1 -C 4 -alkylene)-C(═O)R E , NR F —(C 1 -C 4 -alkylene)-NR C R D , O—(C 1 -C 4 -alkylene)-NR C R D , or 4- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, heterocyclyl, heterocyclyloxy, or heterocyclyl-C 1 -C 2 -alkyl, or 8- to 10-membered saturated, partially or fully unsaturated, or aromatic carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic rings comprise one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R X ;

R 4 is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, or a 9- or 10-membered aromatic carbobicyclic or heterobicyclic ring, wherein the heterocyclic or heterobicyclic ring comprises at least one nitrogen atom and optionally one or more, same or different additional heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned cyclic rings is independently unsubstituted or substituted with one or more same or different substituents R X ;

R 5 is selected from consisting of

and wherein

R N is H, C 1 -C 4 -alkyl, HO(C═O)—C 1 -C 4 -alkyl, NR C R D —C 1 -C 4 -alkyl, C 1 -C 2 -alkoxy-C 1 -C 4 -alkyl, or a 3- or 4-membered saturated carbocyclyl or heterocyclyl, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R X ;

R C and R D are independently H, or C 1 -C 2 -alkyl; or

R C and R D together with the nitrogen atom to which they are bonded form a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the heterocyclic ring is independently unsubstituted or substituted with one or more, same or different substituents R X ;

R E is H, C 1 -C 2 -alkyl, NR C R D —C 1 -C 4 -alkyl, phenyl, benzyl, OR G , or NR H R I ; or a 5- or 6-membered saturated, partially or fully unsaturated heterocyclyl, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R F ;

R F is H, C 1 -C 2 -alkyl, C 3 -C 6 -cycloalkyl, phenyl, benzyl, or C(═O) NR H R I ;

R G is H, C 1 -C 2 -alkyl, or 5- or 6-membered aromatic carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, heterocyclyl, or heterocyclyl-C 1 -C 2 -alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N or S, wherein said N-atoms are independently oxidized or non-oxidized;

R H and R I are independently H, C 1 -C 2 -alkyl, or 5- or 6-membered aromatic carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, heterocyclyl, or heterocyclyl-C 1 -C 2 -alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N or S, wherein said N-atoms are independently oxidized or non-oxidized; or

R H and R I together with the nitrogen atom to which they are bonded form a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the heterocyclic ring is independently unsubstituted or substituted with one or more, same or different substituents R X ;

R X is OH, NR C R D , halogen, CN, NO 2 , C 1 -C 2 -alkyl, C 1 -C 2 -haloalkyl, NR C R D —C 1 -C 4 -alkyl, R C O—C 1 -C 4 -alkyl, C 1 -C 2 -alkoxy, C(═O)R E , or two R X form ═O, or two R X together with the carbon atom to which they are bonded form a 3- to 5-membered saturated, partially or fully unsaturated, or aromatic carbocyclic ring;

with the proviso that at least one of the following conditions is met;

any one of

R 1 , R 2 , or R 3 is independently NR C R D , NR C R D —C 1 -C 4 -alkyl, NR F —(C 1 -C 4 -alkylene)-NR C R D , O—(C 1 -C 4 -alkylene)-NR C R D , and R C is H;

or

any one of

R 1 , R 2 , or R 3 is NR F C(═O)R E , wherein R E is NR C R D —C 1 -C 4 -alkyl and R C is H;

or

R N is NR C R D —C 1 -C 4 -alkyl and R C is H;

or

any one of the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R N carries a substituent R X , wherein

R X is OH, NR C R D , NR C R D —C 1 -C 4 -alkyl, or R C O—C 1 -C 4 -alkyl, and R C is H;

wherein a covalent bond between the compound of formula (I) and the linker L 2 is established by the reaction of a functional group of the compound of formula (I) with a first functional group handle H 1A of the linker L 2 and wherein a covalent bond between the targeting moiety T and the linker L 2 is established by the reaction of a functional group of the targeting moiety T with a second functional group handle H 2B of the linker L 2 ;

wherein the functional group of the compound of formula (I) is attached to or part of the substituents R 2 , R 4 , R 5 , or R N so that the linker L 1 , is covalently bonded to the compound of formula (I) at one end according to any one of the following structures:

wherein the linker L 2 comprises

(i) a chain L C of 2 to 100 atoms selected from carbon, nitrogen, oxygen, and sulfur atoms, which may be interrupted by 5- to 10-membered aryl and heteroaryl groups and/or 3- to 8-membered saturated carbocyclyl or heterocyclyl groups, wherein the aforementioned heteroaryl and heterocyclic groups comprise one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the chain is independently unsubstituted or substituted with one or more same or different substituents selected from halogen, OH, ═O, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, and C 1 -C 6 -haloalkoxy;

(i) the functional group handle H 1A , which is covalently bonded to the compound of formula (I); and

(iii) the functional group handle H 2B , which is covalently bonded to the targeting moiety T.

6 . The conjugate according to claim 5 , wherein the linker L 2 has the structure H 1A -L C -H 2B and is selected from the group consisting of:

wherein

L C is a chain L C of units selected from a linear or branched polyethylene glycol chain, a sequence of amino acids, and a linear or branched C 1 -C 10 -alkyl chain, wherein each substitutable carbon or heteroatom of the afore mentioned units may be unsubstituted or substituted with one or more, same or different substituents selected from halogen, OH, ═O, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, and C 1 -C 6 -haloalkoxy;

§ marks the connection to the compound of formula (I); and

$ marks the connection to the targeting moiety T.

7 . The conjugate of claim 5 , wherein the targeting moiety T comprises an antibody, an antibody fragment, a nucleic acid based molecule, a carbohydrate, a peptide, or a modified peptide.

8 . The compound-linker construct of claim 1 , wherein the functional group of the compound of formula (I), which forms the covalent bond to the first functional group handle H 1A of the linker L 1 , is selected from one of the following options:

R 2 is NHR D , NHR D —C 1 -C 4 -alkyl, NH—(C 1 -C 4 -alkylene)-NR C R D , NR F —(C 1 -C 4 -alkylene)-NHR D , O—(C 1 -C 4 -alkylene)-NHR D ;

or

R 2 is NR F C(═O)R E , wherein R E is NHR D —C 1 -C 4 -alkyl;

or

R N is NHR D —C 1 -C 4 -alkyl;

or

any one of the substituents R 2 , R 4 , R 5 , R N carries a substituent R X , wherein

R X is OH, NHR D , NHR D —C 1 -C 4 -alkyl, or HO—C 1 -C 4 -alkyl.

9 . The compound-linker construct of claim 1 , wherein in the compound of formula (I)

X 1 is CH;

X 2 is CR 3 with R 3 being H;

R 1 is H or F;

R 2 is H, OH, NR C R D , CN, halogen, NR C R D —C 1 -C 4 -alkyl, NR F C(═O)R E , NR F —(C 1 -C 4 -alkylene)-C(═O)R E , NR F —(C 1 -C 4 -alkylene)-NR C R D , O—(C 1 -C 4 -alkylene)-NR C R D , or 4- to 6-membered saturated heterocyclyl, or 8- to 10-membered saturated heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic rings comprise a nitrogen atom and optionally one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R X ;

R 4 is pyridinyl, wherein each substitutable carbon atom in the cyclic ring is independently unsubstituted or substituted by one or more, same or different substituents R X ;

R N is H, C 1 -C 4 -alkyl, HO(C═O)—C 1 -C 3 -alkyl, NHR D —C 1 -C 3 -alkyl, C 1 -C 2 -alkoxy-C 1 -C 3 -alkyl, or cyclopropyl;

wherein

R C is H or C 1 -C 2 -alkyl;

R D is H or C 1 -C 2 -alkyl;

R E is NH 2 —C 1 -C 4 -alkyl;

R F is H;

R X is halogen, OH, NH 2 , NHCH 3 , C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy, NH 2 —C 1 -C 2 -alkyl, HO—C 1 -C 2 -alkyl, or two R X together with the carbon atom to which they are bonded form a 3-membered saturated carbocyclic ring;

with the proviso that at least one of the following conditions is met:

R 2 is NH 2 , NH 2 —C 1 -C 2 -alkyl, NH—(C 1 -C 3 -alkylene)-NH 2 , NH—(C 1 -C 3 -alkylene)-NHCH 3 , NH—(C 1 -C 3 -alkylene)-N(CH 3 ) 2 , O—(C 1 -C 3 -alkylene)-NH 2 , or O—(C 1 -C 3 -alkylene)-NHCH 3 ;

or

R 2 is NHC(═O)R E , wherein R E is NH 2 —C 1 -C 4 -alkyl;

or

R N is NH 2 —C 1 -C 3 -alkyl;

or

any one of the substituents R 2 , R 4 , or R 5 carries a substituent R X , wherein

R X is OH, NH 2 , NHCH 3 , NH 2 —C 1 -C 2 -alkyl, or HO—C 1 -C 2 -alkyl.

10 . A pharmaceutical composition comprising a pharmaceutically effective amount of the compound-linker construct of claim 1 and optionally a pharmaceutically acceptable carrier, diluent or excipient.

11 . The compound-linker construct according to claim 1 , wherein L C of the linker L 1 comprises units selected from the group consisting of a linear or branched polyethylene glycol chain, a sequence of amino acids, and a linear or branched C 1 -C 10 -alkyl chain, and wherein each substitutable carbon or heteroatom of the aforementioned units is unsubstituted or substituted with one or more, same or different substituents selected from halogen, OH, ═O, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, and C 1 -C 6 -haloalkoxy.

12 . The compound-linker construct according to claim 3 , wherein L C is selected from the group consisting of

wherein n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

13 . The conjugate according to claim 5 , wherein the linker L 2 comprises a chain L C of units selected from the group consisting of a linear or branched polyethylene glycol chain, a sequence of amino acids, and a linear or branched C 1 -C 10 -alkyl chain, wherein each substitutable carbon or heteroatom of the afore mentioned units is unsubstituted or substituted with one or more, same or different substituents selected from halogen, OH, ═O, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, and C 1 -C 6 -haloalkoxy.

14 . The conjugate of claim 6 , wherein L C is selected from the group consisting of

wherein n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

15 . The conjugate according to claim 7 , wherein the targeting moiety T is an antibody or an antigen-binding fragment, which is designed to target any one or more of the following: the Human Epidermal Growth Factor Receptor (EGFR), a plasminogen activator, a cytotoxic T-lymphocyte associated antigen (CTLA), vascular endothelial growth factor (VEGF), fibroblast growth factor receptor (FGFR), platelet-derived growth factor (PDGF), transforming growth factor (TGF), neurotrophic factors, a nerve growth factor, platelet-derived growth factor (PDGF), interleukin receptors, transforming growth factor (TGF), estrogen receptor, progesterone receptor, c-Kit, cMET, ErbB2/Her2, ErbB3/Her3, ErbB4/Her4, CD3, CD20, CD22, CD30, CD33, CD40, CD47, CD79, CD123, CD133, CD166, CD137, the mesothelin protein, EpCAM, FLT3, PSMA, PSCA, STEAP, CEA, folate receptor, the CD39/CD73 receptors, adenosine receptors, SLC34A2 gene product, the EphA2 tyrosine kinase, the Muc1/Muc16 cell-surface antigens, ALK, AFP, bcr-Abl, or PAP.

16 . The conjugate of claim 5 , wherein the functional group of the compound of formula (I), which forms the covalent bond to the functional group handle H 1A of the linker L 2 , is selected from one of the following options:

R 2 is NHR D , NHR D —C 1 -C 4 -alkyl, NH—(C 1 -C 4 -alkylene)-NR C R D , NR F —(C 1 -C 4 -alkylene)-NHR D , O—(C 1 -C 4 -alkylene)-NHR D ;

or

R 2 is NR F C(═O)R E , wherein R E is NHR D —C 1 -C 4 -alkyl;

or

R N is NHR D —C 1 -C 4 -alkyl;

or

any one of the substituents R 2 , R 4 , R 5 , R N carries a substituent R X , wherein

R X is OH, NHR D , NHR D —C 1 -C 4 -alkyl, or HO—C 1 -C 4 -alkyl.

17 . The conjugate of claim 5 , wherein in the compound of formula (I)

X 1 is CH;

X 2 is CR 3 with R 3 being H;

R 1 is H or F;

R 2 is H, OH, NR C R D , CN, halogen, NR C R D —C 1 -C 4 -alkyl, NR F C(═O)R E , NR F —(C 1 -C 4 -alkylene)-C(═O)R E , NR F —(C 1 -C 4 -alkylene)-NR C R D , O—(C 1 -C 4 -alkylene)-NR C R D , or 4- to 6-membered saturated heterocyclyl, or 8- to 10-membered saturated heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic rings comprise a nitrogen atom and optionally one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R X ;

R 4 is pyridinyl, wherein each substitutable carbon atom in the cyclic ring is independently unsubstituted or substituted by one or more, same or different substituents R X ;

R N is H, C 1 -C 4 -alkyl, HO(C═O)—C 1 -C 3 -alkyl, NHR D —C 1 -C 3 -alkyl, C 1 -C 2 -alkoxy-C 1 -C 3 -alkyl, or cyclopropyl;

wherein

R C is H or C 1 -C 2 -alkyl;

R D is H or C 1 -C 2 -alkyl;

R E is NH 2 —C 1 -C 4 -alkyl;

R F is H;

R X is halogen, OH, NH 2 , NHCH 3 , C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy, NH 2 —C 1 -C 2 -alkyl, HO—C 1 -C 2 -alkyl, or two R X together with the carbon atom to which they are bonded form a 3-membered saturated carbocyclic ring;

with the proviso that at least one of the conditions is met:

R 2 is NH 2 , NH 2 —C 1 -C 2 -alkyl, NH—(C 1 -C 3 -alkylene)-NH 2 , NH—(C 1 -C 3 -alkylene)-NHCH 3 , NH—(C 1 -C 3 -alkylene)-N(CH 3 ) 2 , O—(C 1 -C 3 -alkylene)-NH 2 , or O—(C 1 -C 3 -alkylene)-NHCH 3 ;

or

R 2 is NHC(═O)R E , wherein R E is NH 2 —C 1 -C 4 -alkyl;

or

R N is NH 2 —C 1 -C 3 -alkyl;

or

any one of the substituents R 2 , R 4 , or R 5 carries a substituent R X , wherein R X is OH, NH 2 , NHCH 3 , NH 2 —C 1 -C 2 -alkyl, or HO—C 1 -C 2 -alkyl.

18 . A pharmaceutical composition comprising a pharmaceutically effective amount of the conjugate of claim 5 and optionally a pharmaceutically acceptable carrier, diluent or excipient.

19 . A compound-linker construct comprising

(i) a compound of formula (I); and

(ii) a linker L 1

wherein the compound of formula (I) is a compound of the following formula

or a salt, stereoisomer, tautomer, or N-oxide thereof,

wherein

X 1 is CH;

X is CH or N;

R 1 is H or F

R 2 is H, OH, NR C R D , CN, halogen, C 1 -C 4 -alkyl, NR C R D —C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, aryloxy, benzyloxy, C(═O)R E , NR F C(═O)R E , NR F —(C 1 -C 4 -alkylene)-C(═O)R E , NR F —(C 1 -C 4 -alkylene)-NR C R D , O—(C 1 -C 4 -alkylene)-NR C R D , or 4- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, heterocyclyl, heterocyclyloxy, or heterocyclyl-C 1 -C 2 -alkyl, or 8- to 10-membered saturated, partially or fully unsaturated, or aromatic carbobicyclyl or heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic rings comprise one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R X ;

R 4 is pyridinyl, wherein each substitutable carbon atom in the cyclic ring is independently unsubstituted or substituted by one or more, same or different substituents R X ;

R 5 is piperidine, wherein each substitutable carbon or heteroatom in the piperidine ring is independently unsubstituted or substituted by one or more, same or different substituents R Y ;

R N is H, C 1 -C 4 -alkyl, HO(C═O)—C 1 -C 3 -alkyl, NHR D —C 1 -C 3 -alkyl, C 1 -C 2 -alkoxy-C 1 -C 3 -alkyl, or cyclopropyl;

R X is halogen, OH, NH 2 , NHCH 3 , C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy, NH 2 —C 1 -C 2 -alkyl, HO—C 1 -C 2 -alkyl, or two R X together with the carbon atom to which they are bonded form a 3-membered saturated carbocyclic ring;

R Y is halogen, OH, NH 2 , or a 5- or 6-membered aromatic heterocyclyl, wherein the aforementioned heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R X ;

R C and R D are independently H, or C 1 -C 2 -alkyl;

R E is H, C 1 -C 2 -alkyl, NR C R D —C 1 -C 4 -alkyl, phenyl, benzyl, OR G , or NR H R I ; or a 5- or 6-membered saturated, partially or fully unsaturated heterocyclyl, wherein said heterocyclic ring comprises one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R F ;

R F is H, C 1 -C 2 -alkyl, C 3 -C 6 -cycloalkyl, phenyl, benzyl, or C(═O) NR H R I ;

R G is H, C 1 -C 2 -alkyl, or 5- or 6-membered aromatic carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, heterocyclyl, or heterocyclyl-C 1 -C 2 -alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N or S, wherein said N-atoms are independently oxidized or non-oxidized;

R H and R I are independently H, C 1 -C 2 -alkyl, or 5- or 6-membered aromatic carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, heterocyclyl, or heterocyclyl-C 1 -C 2 -alkyl, wherein the aforementioned heterocyclic rings comprise one or more, same or different heteroatoms selected from O, N or S, wherein said N-atoms are independently oxidized or non-oxidized;

with the proviso that at least one of the following conditions is met:

R 2 is NR C R D , NR C R D —C 1 -C 4 -alkyl, NR F —(C 1 -C 4 -alkylene)-NR C R D , O—(C 1 -C 4 -alkylene)-NR C R D , and R C is H;

or

R 2 is NR F C(═O)R E , wherein R E is NR C R D —C 1 -C 4 -alkyl, and R C is H;

or

R N is NHR D —C 1 -C 4 -alkyl;

or

any one of the substituents R 2 , R 4 , or R 5 carries a substituent R X , wherein

R X is OH, NHR D , NHR D —C 1 -C 4 -alkyl, or HO—C 1 -C 4 -alkyl;

wherein a covalent bond between the compound of formula (I) and the linker L 1 is established by the reaction of a functional group of the compound of formula (I) with a functional group handle of the linker L 1 ; and wherein the functional group of the compound of formula (I) is attached to or part of the substituents R 2 , R 4 , R 5 , or R N so that the linker L 1 is covalently bonded to the compound of formula (I) according to any one of the following structures:

wherein the linker L 1 has the structure H 1A -L C -H 1B ;

L C is a chain of 2 to 100 atoms selected from carbon, nitrogen, oxygen, and sulfur atoms, which may be interrupted by 5- to 10-membered aryl and heteroaryl groups and/or 3- to 8-membered saturated carbocyclyl or heterocyclyl groups, wherein the aforementioned heteroaryl and heterocyclic groups comprise one or more, same or different heteroatoms selected from O, N or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the chain is independently unsubstituted or substituted with one or more same or different substituents selected from halogen, OH, ═O, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, and C 1 -C 6 -haloalkoxy;

H 1A is a first functional group handle which is covalently bonded to the compound of formula (I); and

H 1B is a second functional group handle suitable for forming a covalent bond to a targeting moiety T.

20 . The compound-linker construct of claim 19 , wherein

R 2 is H, Br, F, C 1 , NH 2 ,

21 . The compound-linker construct of claim 20 , wherein R 2 is H, Br, F, C 1 , or NH 2 .

22 . The compound-linker construct of claim 20 , wherein R 4 is methylpyridinyl, aminopyridinyl or methoxypyridinyl.

23 . The compound-linker construct of claim 22 , or the salt, stereoisomer, tautomer, or N-oxide thereof, wherein R 4 is methylpyridinyl.

24 . The compound-linker construct of claim 22 , wherein R N is H, C 1 -C 4 -alkyl, HO(C═O)—C 1 -C 3 -alkyl, NH 2 —C 1 -C 3 -alkyl, C 1 -C 2 -alkoxy-C 1 -C 3 -alkyl, or cyclopropyl.

25 . The compound-linker construct of claim 24 , or the salt, stereoisomer, tautomer, or N-oxide thereof, wherein R N is methyl or cyclopropyl.

26 . The compound-linker construct of claim 24 , wherein R 5 is selected from the group consisting of

27 . The compound-linker construct of claim 26 , wherein R 5 is

28 . The compound-linker construct of claim 26 , wherein the linker L 1 is selected from the group consisting of:

wherein

L C is a chain L C of units selected from a linear or branched polyethylene glycol chain, a sequence of amino acids, and a linear or branched C 1 -C 10 -alkyl chain, wherein each substitutable carbon or heteroatom of the afore mentioned units may be unsubstituted or substituted with one or more, same or different substituents selected from halogen, OH, ═O, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, and C 1 -C 6 -haloalkoxy; and

§ marks the connection to the compound of formula (I); and

X represents a leaving group selected from

Assignments (1)

Priority Claims (1)

Continuity (1)

References Cited (101)