US 11,052,155 B2
Conjugates of CC-1065 analogs and bifunctional linkers
Patrick Henry Beusker, Nijmegen (NL); Rudy Gerardus Elisabeth Coumans, Nijmegen (NL); Ronald Christiaan Elgersma, Nijmegen (NL); Wiro Michael Petrus Bernardus Menge, Nijmegen (NL); Johannes Albertus Frederikus Joosten, Nijmegen (NL); Henri Johannes Spijker, Nijmegen (NL); and Franciscus Marinus Hendrikus De Groot, Nijmegen (NL)
Assigned to SYNTARGA BV, Nijmegen (NL)
Filed by SYNTARGA BV, Nijmegen (NL)
Filed on Mar. 17, 2017, as Appl. No. 15/461,560.
Application 15/461,560 is a division of application No. 13/642,847, granted, now 96,299,240, previously published as PCT/NL2011/050278, filed on Apr. 21, 2011.
Claims priority of provisional application 61/421,824, filed on Dec. 10, 2010.
Claims priority of provisional application 61/326,437, filed on Apr. 21, 2010.
Prior Publication US 2017/0274090 A1, Sep. 28, 2017
Prior Publication US 2018/0133316 A9, May 17, 2018
Int. Cl. A61K 39/44 (2006.01); A61K 47/64 (2017.01); A61K 31/437 (2006.01); C07D 471/04 (2006.01); A61K 47/65 (2017.01); A61K 47/60 (2017.01); A61K 47/54 (2017.01); A61K 38/38 (2006.01); A61K 47/68 (2017.01)
CPC A61K 47/64 (2017.08) [A61K 31/437 (2013.01); A61K 38/385 (2013.01); A61K 39/44 (2013.01); A61K 47/545 (2017.08); A61K 47/60 (2017.08); A61K 47/643 (2017.08); A61K 47/646 (2017.08); A61K 47/65 (2017.08); A61K 47/6803 (2017.08); A61K 47/6851 (2017.08); C07D 471/04 (2013.01)] 8 Claims
OG exemplary drawing
 
1. A compound of formula (IV):

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or a pharmaceutically acceptable salt thereof, wherein
RM is a reactive moiety,
L is independently absent or a linking group linking RM to one or more V1 and/or Y;
each V1 is independently absent or a conditionally-cleavable or conditionally-transformable moiety, which can be cleaved or transformed by a chemical, photochemical, physical, biological, or enzymatic process;
each Y is a self-eliminating spacer system which is comprised of 1 or more self-elimination ω-amino aminocarbonyl cyclization spacers selected from

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and each Y is linked to V1, optionally L, and one or more Z;
p is a number representing a degree of branching and is a positive integer;
z is a positive integer equal to or smaller than the total number of attachment sites for Z;
each Z is independently a compound of formula (I), (II), (I′), or (II′):

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or a pharmaceutically acceptable salt thereof, wherein
DB is a DNA-binding moiety which is selected from

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R1 is a leaving group;
R2, R2′, R3, R3′, R4, R4′, R12, and R19 are independently selected from the group consisting of H, OH, SH, NH2, N3, NO2, NO, CF3, CN, C(O)NH2, C(O)H, C(O)OH, halogen, Ra, SRa, S(O)Ra, S(O)2Ra, S(O)ORa, S(O)2ORa, OS(O)Ra, OS(O)2Ra, OS(O)ORa, OS(O)2ORa, ORa, NHRa, N(Ra)Rb, +N(Ra)(Rb)Rc, P(O)(ORa)(ORb), OP(O)(ORa)(ORb), SiRaRbRc, C(O)Ra, C(O)ORa, C(O)N(Ra)Rb, OC(O)Ra, OC(O)ORa, OC(O)N(Ra)Rb, N(Ra)C(O)Rb, N(Ra)C(O)OR, and N(Ra)C(O)N(Rb)Rc, wherein
Ra, Rb, and Rc are independently selected from H and optionally substituted C1-3 alkyl or C1-3 heteroalkyl,
or R3+R3′ and/or R4+R4′ are independently selected from ═O, ═S, ═NOR18, ═C(R18)R18′, and ═NR18, R18 and R18′ being independently selected from H and optionally substituted C1-3 alkyl, two or more of R2, R2′, R3, R3′, R4, R4′, and R12 optionally being joined by one or more bonds to form one or more optionally substituted carbocycles and/or heterocycles;
X2 is selected from the group consisting of O, C(R14)(R14′), and NR14′, wherein R14 and R14′ have the same meaning as defined for R7 and are independently selected, or R14′ and R7 are absent resulting in a double bond between the atoms designated to bear R7 and R14′;
R5, R5′, R6, R6′, R7, and R7′ are independently selected from the group consisting of H, OH, SH, NH2, N3, NO2, NO, CF3, CN, C(O)NH2, C(O)H, C(O)OH, halogen, Re, SRe, S(O)Re, S(O)2Re, S(O)ORe, S(O)2ORe, OS(O)Re, OS(O)2Re, OS(O)ORe, OS(O)2ORe, ORe, NHRe, N(Re)Re, +N(Re)(Rf)Rg, P(O)(ORe)(ORf), OP(O)(ORe)(ORf), SiReRfRg, C(O)Re, C(O)ORe, C(O)N(Re)Rf, OC(O)Re, OC(O)ORe, OC(O)N(Re)Rf, N(Re)C(O)Rf, N(Re)C(O)ORf, N(Re)C(O)N(Rf)Rg, and a water-soluble group, wherein
Re, Rf, and Rg are independently selected from H and optionally substituted (CH2CH2O)eeCH2CH2X13Re1, C1-15 alkyl, C1-15 heteroalkyl, C3-15 cycloalkyl, C1-15 heterocycloalkyl, C5-15 aryl, or C1-15 heteroaryl, wherein ee is selected from 1 to 1000, X13 is selected from O, S, and NRf1, and Rf1 and Re1 are independently selected from H and C1-3 alkyl, one or more of the optional substituents in Re, Rf, and/or Rg optionally being a water-soluble group, two or more of Re, Rf, and Rg optionally being joined by one or more bonds to form one or more optionally substituted carbocycles and/or heterocycles,
or R5+R5′ and/or R6+R6′ and/or R7+R7′ are independently selected from ═O, ═S, ═NORe3, ═C(Re3)Re4, and ═NRe3, Re3 and Re4 being independently selected from H and optionally substituted C1-3 alkyl, or R5′+R6′ and/or R6′+R7′ and/or R7′+R14′ are absent, resulting in a double bond between the atoms designated to bear R5′ and R6′, and/or R6′ and R7′, and/or R7′ and R14′, respectively, two or more of R5, R5′, R6, R6′, R7, R7′, R14, and R14′ optionally being joined by one or more bonds to form one or more optionally substituted carbocycles and/or heterocycles;
X1 is selected from the group consisting of O, S, and NR13, wherein R13 is selected from H and optionally substituted C1-8 alkyl or C1-8 heteroalkyl and not joined with any other substituent;
one of R4 and R4′ may optionally be joined by one or more bonds to form one or more optionally substituted carbocycles and/or heterocycles;
one of R2, R2′, R3, and R3′ and one of R5 and R5′ may optionally be joined by one or more bonds to form one or more optionally substituted carbocycles and/or heterocycles;
a and b are independently selected from 0 and 1;
and
one or more of X1, R5, R5′, R6, R6′, R7, R7′, R14, and R14′ may optionally in addition be substituted by or be a substituent of formula (V):

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wherein each V2′ is absent or a functional moiety,
each L2′ is independently absent or a linking group linking V2′ to L′,
q′ is a number representing a degree of branching and is a positive integer,
L′, V1′, Y′, Z′, p′, and z′ has the same meaning as defined for L, V1, Y, Z, p, and z, respectively, and is independently selected, the one or more substituents of formula (V) being independently connected via Y′ to one or more of X1, R5, R5′, R6, R6′, R7, R7′, R14, R14′, and/or to one or more atoms bearing these R substituents;
each Z is independently connected to Y through either Xi, an atom in R5, R5′, R6, R6′, R7, R7′, R14, R14′, or an atom bearing any of these R substituents,
V1, Y, and Z may contain protecting groups, and the one or more V2′-L2′ moieties optionally present in Z as defined hereinabove may optionally and independently be RM′ instead, which is a reactive moiety, and wherein, if there is more than 1 reactive moiety in (IV), some or all reactive moieties are the same or different.