US 12,410,148 B2
Antibody drug conjugates
Carmen Cuevas Marchante, Madrid (ES); Juan Manuel Dominguez Correa, Madrid (ES); Andres Francesch Solloso, Madrid (ES); Maria Garranzo Garcia-Ibarrola, Madrid (ES); Maria Jose Munoz Alonso, Madrid (ES); Francisco Sanchez Madrid, Madrid (ES); Juan Manuel Zapata Hernandez, Madrid (ES); Alicia Garcia Arroyo, Madrid (ES); and Maria Angeles Ursa Pecharroman, Madrid (ES)
Assigned to PARMA MAR, S.A., Madrid (ES)
Filed by Pharma Mar, S.A., Madrid (ES)
Filed on Dec. 16, 2021, as Appl. No. 17/553,745.
Application 17/553,745 is a division of application No. 14/894,685, granted, now 11,224,663, previously published as PCT/EP2014/061392, filed on Jun. 2, 2014.
Claims priority of application No. 1309807 (GB), filed on May 31, 2013.
Prior Publication US 2022/0168436 A1, Jun. 2, 2022
Int. Cl. A61K 47/68 (2017.01); C07D 309/30 (2006.01); C07D 309/32 (2006.01); C07D 405/12 (2006.01)
CPC C07D 309/32 (2013.01) [A61K 47/6803 (2017.08); A61K 47/6849 (2017.08); A61K 47/6855 (2017.08); C07D 309/30 (2013.01); C07D 405/12 (2013.01)] 8 Claims
OG exemplary drawing
 
1. A compound of formula D-X-(AA)w-L1 or of formula D-X-(AA)w—H, wherein:
L1 is a linker selected from the group of formulas consisting of: of formula

OG Complex Work Unit Chemistry
wherein the wavy line indicates the point of covalent attachment to (AA)w if any, or to X;
R19 is selected from —C1-C12 alkylene-, —C3-C8 carbocyclo, —O—(C1-C12 alkylene), —C6-C18 arylene in one or more rings which may optionally be substituted with one or more substituents Rx, —C1-C12 alkylene-C6-C18 arylene- wherein the arylene group is in one or more rings which may optionally be substituted with one or more substituents Rx, —C6-C18 arylene-C1-C12 alkylene- wherein the arylene group is in one or more rings which may optionally be substituted with one or more substituents Rx, —C1-C12 alkylene-(C3-C8 carbocyclo)-, —(C3-C8 carbocyclo)-C1-C12 alkylene-, —C5-C14 heterocyclo- wherein said heterocyclo group may be a saturated or unsaturated group having one or more rings and comprising at least one oxygen, nitrogen or sulphur atom in said ring(s), said group optionally being substituted with one or more substituents Rx, —C1-C12 alkylene-(C5-C14 heterocyclo)- wherein said heterocyclo group may be a saturated or unsaturated group having one or more rings and comprising at least one oxygen, nitrogen or sulphur atom in said ring(s), said group optionally being substituted with one or more substituents Rx, —(C5-C14 heterocyclo)-C1-C12 alkylene-, wherein said heterocyclo group may be a saturated or unsaturated group having one or more rings and comprising at least one oxygen, nitrogen or sulphur atom in said ring(s), said group optionally being substituted with one or more substituents Rx, —(OCH2CH2)r- and —CH2—(OCH2CH2)r-, wherein each of the above alkylene substituents whether alone or attached to another moiety the carbon chain may optionally be substituted by one or more substituents Rx;
r is an integer ranging from 1-10;
D is a drug moiety selected from formulas (Ia) and (Ib), or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof,

OG Complex Work Unit Chemistry
wherein the wavy lines of (Ia) and (Ib) indicate the point of covalent attachment to X;
A is

OG Complex Work Unit Chemistry
wherein the wavy line of the moiety A indicates the point of covalent attachment to the rest of the drug moiety;
each of R1, R2 and R3 is independently selected from hydrogen and ORa;
each of R4, R5, R6, R7, R8, R9, R10 and R12 is independently selected from the group consisting of hydrogen and substituted or unsubstituted C1-C12 alkyl, wherein the optional substituents are one or more substituents Rx;
R11 is hydrogen;
R13 is hydrogen;
each of R15, R16, R17, R17, R18′, R24, R24′, R25 and R26 is independently selected from the group consisting of hydrogen and substituted or unsubstituted C1-C12 alkyl, wherein the optional substituents are one or more substituents Rx;
R18 is hydrogen;
R27 is selected from hydrogen, substituted or unsubstituted C1-C12 alkyl and halogen, wherein the optional substituents are one or more substituents Rx;
Ra is selected from the group consisting of hydrogen and substituted or unsubstituted C1-C12 alkyl, wherein the optional substituents are one or more substituents Rx;
and each dotted line represents an optional additional bond, but when a triple bond exists between the C atom to which R25 is attached and the C atom to which R26 and R27 are attached, then R25 and either R26 or R27 are absent;
(AA)w is of formula (II):

OG Complex Work Unit Chemistry
wherein the wavy lines indicate the point of covalent attachments to X (the wavy line to the left) and to L1 or to a hydrogen atom (the wavy line to the right);
R21 is, at each occurrence, selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, —CH2OH, —CH(OH) CH3, —CH2CH2SCH3, —CH2CONH2, —CH2COOH, —CH2CH2CONH2, —CH2CH2COOH, —(CH2) 3NHC(═NH) NH2, —(CH2)3NH2, —(CH2)3NHCOCH3, —(CH2)3NHCHO, —(CH2)4NHC(═NH) NH2, —(CH2)4NH2, —(CH2)4NHCOCH3, —(CH2)4NHCHO, —(CH2)3NHCONH2, —(CH2)4NHCONH2, —CH2CH2CH(OH) CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-phenyl,
cyclohexyl,

OG Complex Work Unit Chemistry
and w is an integer ranging from 0 to 12;
X is selected from the group consisting of: —CONH—(C1-C6 alkylene) NH—; —COO—CH2-(phenylene which may optionally be substituted with one or more substituents Rx)—NH—; —CONH—(C1-C6 alkylene) NH—COO—CH2-(phenylene which may optionally be substituted with one or more substituents Rx)—NH—; —CH2-(phenylene which may optionally be substituted with one or more substituents Rx)—NH—; —COCH2NH—COCH2—NH—; —COCH2NH—; —CONH—(C1-C6 alkylene)S—; —CONH—(C1-C6 alkylene) NHCO(C1-C6 alkylene)S—; —(C1-C6 alkylene) NHCO(C1-C6 alkylene)S—; —(C1-C6 alkylene)S—; —(C1-C6 alkylene) NH—; and —(C1-C6 alkylene) NH—COO—CH2-(phenylene which may optionally be substituted with one or more substituents Rx)—NH—;
substituents Rx are selected from the group consisting of C1-C12 alkyl groups which may be optionally substituted with at least one group Ry, C2-C12 alkenyl groups which may be optionally substituted with at least one group Ry, C2-C12 alkynyl groups which may be optionally substituted with at least one group Ry, halogen atoms, oxo groups, thio groups, cyano groups, nitro groups, ORy, OCORy, OCOORy, CORy, COORy, OCONRyRz, CONRyRz, S(O) Ry, SO2Ry, P(O) (Ry) ORz, NRyRz, NRyCORz, NRyC(═O) NRyRz, NRyC(═NRy) NRyRz, aryl groups having from 6 to 18 carbon atoms in one or more rings which may optionally be substituted with one or more substituents which may be the same or different selected from the group consisting of Ry, ORy, OCORy OCOORy, NRyRz, NRyCORz and NRyC(═NRy) NRyRz, aralkyl groups comprising an alkyl group having from 1 to 12 carbon atoms substituted with an optionally substituted aryl group as defined above, aralkyloxy groups comprising an alkoxy group having from 1 to 12 carbon atoms substituted with an optionally substituted aryl group as defined above, and a 5- to 14-membered saturated or unsaturated heterocyclic group having one or more rings and comprising at least one oxygen, nitrogen or sulphur atom in said ring(s), said heterocyclic group optionally being substituted with one or more substituents Ry, and where there is more than one optional substituent on any given group the optional substituents Ry may be the same or different;
each Ry and Rz is independently selected from the group consisting of hydrogen, C1-C12 alkyl groups, C1-C12 alkyl groups that are substituted with at least one halogen atom, aralkyl groups comprising a C1-C12 alkyl group that is substituted with an aryl group having from 6 to 18 carbon atoms in one or more rings and heterocycloalkyl groups comprising a C1-C12 alkyl group that is substituted with a 5- to 14-membered unsaturated or saturated heterocyclic group having one or more rings and comprising at least one oxygen, nitrogen or sulphur atom in said ring(s).