US 12,215,100 B2
Anticancer compounds
María Jesús Martín López, Madrid (ES); Raquel Rodríguez Acebes, Madrid (ES); Patricia Gema Cruz López, Madrid (ES); Andrés M. Francesch Solloso, Madrid (ES); and Maria del Carmen Cuevas Marchante, Madrid (ES)
Assigned to PHARMA MAR, S.A., Madrid (ES)
Appl. No. 17/414,946
Filed by Pharma Mar, S.A., Madrid (ES)
PCT Filed Dec. 17, 2019, PCT No. PCT/EP2019/085544
§ 371(c)(1), (2) Date Jun. 16, 2021,
PCT Pub. No. WO2020/127194, PCT Pub. Date Jun. 25, 2020.
Claims priority of application No. 18382934 (EP), filed on Dec. 17, 2018.
Prior Publication US 2022/0056021 A1, Feb. 24, 2022
Int. Cl. C07D 417/12 (2006.01); C07D 417/14 (2006.01); C07D 493/14 (2006.01); C07H 15/26 (2006.01)
CPC C07D 417/12 (2013.01) [C07D 417/14 (2013.01); C07D 493/14 (2013.01); C07H 15/26 (2013.01)] 28 Claims
 
1. A compound of formula I or a pharmaceutically acceptable salt or ester thereof

OG Complex Work Unit Chemistry
wherein:
R1 is selected from hydrogen, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, and substituted or unsubstituted C2-C12 alkynyl, wherein the optional substituents are one or more substituents Rx;
R2 is selected from hydrogen, halogen, substituted or unsubstituted C1-C24 alkyl, substituted or unsubstituted C2-C24 alkenyl, substituted or unsubstituted C2-C24 alkynyl, —ORa, —OSO2Rb, —NRcRd, —NRc(C═O)Rf, and —NRcSO2Rb, wherein the optional substituents are one or more substituents Rx;
R3 is selected from halogen-substituted or unsubstituted C1-C12 alkyl, halogen-substituted or unsubstituted C2-C12 alkenyl, halogen-substituted or unsubstituted C2-C12 alkynyl and substituted or unsubstituted C3-C6 cycloalkyl-C1-C12 alkyl, wherein the optional substituents are one or more substituents Rx and the halogen substituents are one or more substituents independently selected from F, Cl, Br and I;
R4 is selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl and substituted or unsubstituted C2-C12 alkynyl, wherein the optional substituents are one or more substituents Rx;
R5 is selected from —C(ORe)2Rg, —C(SRe)2Rg, —CH(ORa)Rg, —CH(O—(C═O)Rf)Rg, —CH(NRcRd)Rg, —CH(NRc—(C═O)Rf)Rg, —CH(NRc—ORh)Rg, —(C═O)Rg, —(C═NRc)Rg, —(C═N—ORh)Rg, —(C═N—O—(C═O)Rf)Rg, —(C═N—O—(C═O)ORa)Rg, —(C═N—O—[(P═O)(ORa)2])Rg, —(C═N—NRcRd)Rg, —(C═O)ORa, —(C═O)NRc—ORh, —(C═O)NRcRd, —(C═CH2)Rg, and —(C═CH2)ORa; or R5 is a

OG Complex Work Unit Chemistry
group where m is 0, 1 or 2 and each E group is independently selected from O and S;
Y is —O—;
Z is —S—;
each group Ra is independently selected from hydrogen, a protecting group for OH, substituted or unsubstituted C1-C24 alkyl, substituted or unsubstituted C2-C24 alkenyl, substituted or unsubstituted C2-C24 alkynyl, substituted or unsubstituted C3-C6cycloalkyl-C1-C12alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, —(CH2CH2O)pCH2CH3, and —(CH2CH2O)pCH3 wherein p is from 1 to about 25 and the optional substituents are one or more substituents Rx;
each group Rb is independently selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, wherein the optional substituents are one or more substituents Rx;
each group Rc and Rd is independently selected from hydrogen, a protecting group for amino, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, and substituted or unsubstituted C2-C12 alkynyl, wherein the optional substituents are one or more substituents Rx; or Rc and Rd together with the nitrogen atom to which they are attached form a heterocyclic group;
each group Re is substituted or unsubstituted C1-C12 alkyl group, wherein the optional substituents are one or more substituents Rx;
each group Rf is independently selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, —CH2O(CH2CH2O)pCH2CH3, —CH2O(CH2CH2O)pCH3 wherein p is from 1 to about 25 and the optional substituents are one or more substituents Rx, and a group of formula:

OG Complex Work Unit Chemistry
where each R group is, at each occurrence, independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted —(C═O)—(C1-C6)alkyl, and substituted or unsubstituted —(C═O)NH(C1-C6)alkyl, wherein the optional substituents are one or more substituents Rx; or two adjacent OR groups form an isopropylidene ketal or an acetal group selected from methylene-, methoxymethylene-, ethoxymethylene-, ethylidene-, benzylidene-, and p-methoxybenzylidene- acetals;
each group Rg is independently selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl and substituted or unsubstituted C2-C12 alkynyl, wherein the optional substituents are one or more substituents Rx;
each group Rh is independently selected from hydrogen, a protecting group for OH, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted C3-C6cycloalkyl-C1-C12alkyl, substituted or unsubstituted heterocyclo-C1-C12alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, —(CH2CH2O)pCH2CH3, —(CH2CH2O)pCH3 wherein p is from 1 to about 25, and substituted or unsubstituted monosaccharide residue, wherein the optional substituents are one or more substituents Rx; and
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, SRy, S(═O)Ry, SO2Ry, OSO2ORy, SSRy, P(═O)(Ry)ORz, OP(═O)(ORy)2, NRyRz, NRyC(═O)Rz, NRyC(═O)ORz, 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 groups 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 substituents on any given group the optional substituents Ry may be the same or different; and
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 group comprising a C1-C12 alkyl group that is substituted with 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);
wherein the compound of formula I is not a natural product.