WO2017054080A1 - Composés cytotoxiques et antimitotiques et leurs procédés d'utilisation - Google Patents

Composés cytotoxiques et antimitotiques et leurs procédés d'utilisation Download PDF

Info

Publication number
WO2017054080A1
WO2017054080A1 PCT/CA2016/051135 CA2016051135W WO2017054080A1 WO 2017054080 A1 WO2017054080 A1 WO 2017054080A1 CA 2016051135 W CA2016051135 W CA 2016051135W WO 2017054080 A1 WO2017054080 A1 WO 2017054080A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
alkyl
aryl
cycloalkyl
compound
Prior art date
Application number
PCT/CA2016/051135
Other languages
English (en)
Inventor
Geoffrey C. Winters
James R. RICH
Alexander L. Mandel
Tom Han Hsiao HSIEH
Graham Albert Edwin GARNETT
Original Assignee
Zymeworks Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zymeworks Inc. filed Critical Zymeworks Inc.
Publication of WO2017054080A1 publication Critical patent/WO2017054080A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0207—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)4-C(=0), e.g. 'isosters', replacing two amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present disclosure relates to biologically active compounds, compositions comprising the same, and methods of using such biologically active compounds and compositions for the treatment of cancer and other diseases.
  • Tubulysins are a class of cytostatic compounds originally isolated from strains of Mycobacteria (Sasse, F., et al , (2000) J. Antibiot. (Tokyo) 53:879-885).
  • Tubulysins have a tetrapeptidyl scaffold constructed from one proteinogenic and three non-proteinogenic amino acid subunits as shown in Formula A: N-methylpipecolic acid (Mep), isoleucine (He), tubuvaline (Tuv), and either tubuphenylalanine (Tup, R" is H) or tubutyrosine (Tut, R" is OH).
  • Various tubulysins have been identified. Some examples of naturally occurring tubulysins are shown in Table 1 :
  • tubulysin A induced apoptosis in cancer cells but not normal cells and showed significant potential anti-angiogenic properties in in vitro assays.
  • tubulysins have also been evaluated and generally have been found to compare favorably against those of non- tubulysin antimitotic agents (see, e.g., Balasubramanian et al , (2009) J. Med. Chem. 52(2):238- 240; Steinmetz et al, (2004) Angew. Chem. Int. Ed. 43:4888-4892; Wipf et al, (2004) Org. Lett. 6(22):4057-4060). For these reasons, there is considerable interest in the tubulysins as anti-cancer agents (see, e.g. , Domling et al, (2005) Mol. Diversity 9: 141-147; and Hamel et al, (2002) Curr. Med. Chem.-Anti-Cancer Agents 2: 19-53).
  • Tubulysins conjugated to various targeting moieties have also been described, including those described in International Patent Publication Nos. WO 2015/113760, WO 2014/009774, WO
  • tubulysin V was reported to be less potent by about 200 ⁇ to 600 ⁇ , depending on the assay (Balasubramanian et al , (2009) J. Med. Chem. 52(2):238-240).
  • the present disclosure relates to biologically active compounds, compositions comprising the same, and methods of using such compounds and compositions.
  • the present disclosure relates to a compound of general Formula I:
  • R is selected from: amino-Ci-C6 alkyl, amino-aryl, amino-C3-C? cycloalkyl, amino- heterocyclyl, and heterocyclyl, each optionally substituted with one or more substituents selected from aryl, aryl-G-C6 alkyl, G-C6 alkyl, G-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl -G-G; alkyl, guanidino, halo, G-C6 haloalkyl, heterocyclyl, heterocyclyl -G-C6 alkyl, hydroxyl, and thio; or
  • R is R ⁇ NCH R 3 )-; is selected from: H and G-C6 alkyl; R 2 is C1-C6 alkyl; and
  • R 3 is selected from: H, R 15 and R 7 -CH(CH 3 ) 2 -; or
  • R 2 and R 3 taken together with the atoms to which they are each bonded form a heterocyclyldiyl
  • R 4 is selected from: C1-C4 alkyl and C3-C6 cycloalkyl
  • R 5 is selected from: H and C1-C4 alkyl optionally substituted with one substituent selected from: C1-C4 alkyloxy and C1-C4 acyloxy;
  • R 6 is selected from: G-C6 alkyl, aryl, aryl-Ci-C6 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more substituents selected from: G- G alkyloxy, G-C6 alkoxycarbonyl, G-C6 alkyl, G-C6 alkylamino, amino, amino-G-G alkyl, amino-aryl, amino-G-G cycloalkyl, amino-heteroaryl, amino-heterocyclyl, aryl, carboxamide, carboxyl, G-G cycloalkyl, cyano, G-G haloacyl, G-C6 haloalkyl, G-C6 haloalkoxy, halo, hydroxyl, nitro, thio, and thio-G-G alkyl;
  • R 7 is selected from: H, aryl, G-G cycloalkyl, and heteroaryl, each of which is optionally substituted with one or more substituents selected from: G-G acylthio, G-G alkenyl, G- G alkyl, G-G alkylamino, G-G alkyloxy, amino, amino-G-G alkyl, halo, G-G haloalkyl, hydroxyl, hydroxy-G-G alkyl, and thio, wherein G-G alkenyl, G-G alkylamino and G-G alkyloxy are further optionally substituted with one substituent selected from G-G alkylaryl, hydroxyl, and thio;
  • R 8 is selected from: aryl, heteroaryl, and G-G cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl;
  • R 9 and R 10 are each independently selected from: H, G-G alkyl, aryl, aryl-G-G alkyl, G- G cycloalkyl-G-G alkyl, and hydroxy-G-G alkyl;
  • R 15 is G-G alkyl
  • X is selected from C2-C3 alkenyldiyl and C2 alkyldiyl, wherein C2 alkyldiyl is substituted with one substituent selected from: G-C6 acyloxy, G-C6 alkyloxy, hydroxyl, oxo, -OC(0)NR 9 R 10 , -OC(S)NR 9 R 10 , -OC(0)OR 9 , and -OC(S)OR 9 ;
  • Y is heteroaryldiyl, or Y is absent
  • the present disclosure relates to a compound of Formula le:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 15 and Z are as defined above for general Formula I;
  • R 9 and R 10 are each independently H or G-G alkyl, and R 11 is selected from: H, G-G acyl, G-G alkyl, and -C(0)NR 9 R 10 , with the proviso that when R 1 is H; R 2 and R 3 taken together with the atoms to which they are each bonded form piperidin-2-yl; R 4 is fert-butyl or sec-butyl; R 5 is methyl; R 11 is acetyl; Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )- and R 8 is phenyl, then R 6 is other than cyclopropyl.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described above and a pharmaceutically acceptable carrier.
  • the present disclosure relates to a method of inhibiting proliferation of cancer cells comprising contacting the cancer cells with an effective amount of a compound as described above.
  • the present disclosure relates to a method of inhibiting tumor growth in a subject comprising administering to the subject an effective amount of a compound as described above.
  • the present disclosure relates to a method of treating cancer in a subject comprising administering to the subject an effective amount of a compound as described above.
  • the present disclosure relates to a conjugate of general Formula VI: T-(L-(D) m ) n
  • T is a targeting moiety
  • L is an optional linker
  • D is a monovalent radical of a compound of any one of claims 1 to 32
  • m is an integer between 1 and about 10
  • n is an integer between 1 and about 20.
  • the present disclosure relates to a pharmaceutical composition comprising a conjugate as described above and a pharmaceutically acceptable carrier.
  • the present disclosure relates to a method of inhibiting proliferation of cancer cells comprising contacting the cancer cells with an effective amount of a conjugate as described above.
  • the present disclosure relates to a method of inhibiting tumor growth in a subject comprising administering to the subject an effective amount of a conjugate as described above.
  • the present disclosure relates to a method of treating cancer in a subj comprising administering to the subject an effective amount of a conjugate as described above.
  • FIG. 1 presents an example of a synthetic scheme that may be used to prepare certain compounds of general Formula I as described in Example 1 herein.
  • FIG. 2 presents another example of a synthetic scheme that may be used to prepare certain compounds of general Formula I as described in Examples 2.1 to 2.5.
  • FIG. 3 presents another example of a synthetic scheme that may be used to prepare certain compounds of general Formula I as described in Examples 2.6 to 2.9.
  • FIG. 4 presents another example of a synthetic scheme that may be used to prepare certain compounds of general Formula I as described in Examples 2.10 and 2.11.
  • FIG. 5 presents another example of a synthetic scheme that may be used to prepare certain compounds of general Formula I as described in Example 2.12.
  • the present disclosure relates to compounds of general Formula I as described below and conjugates comprising such compounds in which the compound is attached, directly or via a linker, to a targeting moiety, such as an antibody.
  • the compounds exhibit cytotoxic activity.
  • the compounds exhibit cytotoxic activity against cancer cells.
  • the cytotoxic activity of the compounds may be exhibited when the free compound is administered, or it may be exhibited when the compound is administered as a conjugate and delivered to a cell by means of the targeting moiety.
  • some embodiments relate to compounds of general Formula I that exhibit cytotoxic activity as free compounds.
  • Some embodiments relate to compounds of general Formula I that exhibit cytotoxic activity in the context of a conjugate targeted to a specific cell type or types, such as an antibody conjugate.
  • Certain embodiments of the present disclosure relate to the use of the compounds and conjugates in the treatment of a disease or disorder in a subject, for example, an immunological disease or a cancer.
  • the term "about” refers to an approximately +/-10% variation from a given value. It is to be understood that such a variation is always included in any given value provided herein, whether or not it is specifically referred to.
  • compositions, use or method are inclusive or open-ended and do not exclude additional, unrecited elements and/or method steps.
  • the term “consisting of when used herein in connection with a composition, use or method excludes the presence of additional elements and/or method steps.
  • a composition, use or method described herein as comprising certain elements and/or steps may also, in certain embodiments consist essentially of those elements and/or steps, and in other embodiments consist of those elements and/or steps, whether or not these embodiments are specifically referred to.
  • acyl refers to the group -C(0)R, where R is hydrogen or alkyl, wherein alkyl is as defined herein.
  • acyloxy refers to -OC(0)-alkyl, wherein alkyl is as defined herein.
  • alkyl is as defined herein.
  • acyloxy include, but are not limited to: formyloxy, acetoxy, propionyloxy, isobutyryloxy, pivaloyloxy, and the like.
  • acylthio refers to -SC(0)-alkyl, wherein alkyl is as defined herein.
  • alkyl is as defined herein.
  • acylthio include, but are not limited to: formylthio, acetylthio, propionylthio, isobutyrylthio, pivaloylthio, and the like.
  • alkoxycarbonyl refers to -C(0)0-alkyl, wherein alkyl is as defined herein.
  • alkoxycarbonyl include, but are not limited to: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl, Z-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, t- pentyloxycarbonyl, neo-pentyloxycarbonyl, 1-methylbutoxycarbonyl, 2-methylbutoxycarbonyl, n- hexyloxycarbonyl, and the like.
  • alkenyldiyl refers to a straight or branched unsaturated hydrocarbon di-radical containing the specified number of carbon atoms, and one or more carbon- carbon double bonds, e.g. , d- e alkenyldiyl, C2-C4 alkenyldiyl, or C2 alkenyldiyl.
  • alkenyldiyl examples include, but are not limited to: ethenyldiyl, n-propenyldiyl, isopropenyldiyl, n- butenyldiyl, sec-butenyldiyl, isobutenyldiyl, i-butenyldiyl, pentenyldiyl, isopentenyldiyl, t- pentenyldiyl, neo-pentenyldiyl, 1-methylbutenyldiyl, 2-methylbutenyldiyl, n-hexenyldiyl, and the like.
  • alkyl refers to a straight or branched saturated hydrocarbon radical containing the specified number of carbon atoms, e.g. , alkyl, C 1 -C4 alkyl, or C 2 alkyl.
  • alkyl include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, /-butyl, pentyl, isopentyl, 7-pentyl, neo-pentyl, 1-methylbutyl, 2-methylbutyl, n- hexyl, and the like.
  • alkyldiyl refers to a straight or branched saturated hydrocarbon di-radical containing the specified number of carbon atoms, e.g. , Ci-Ce alkyldiyl, C1-C4 alkyldiyl, or C2 alkyldiyl.
  • alkyldiyl examples include, but are not limited to: methyldiyl, ethyldiyl, n- propyldiyl, isopropyldiyl, n-butyldiyl, sec-butyldiyl, isobutyldiyl, 7-butyldiyl, pentyldiyl, isopentyldiyl, 7-pentyldiyl, neo-pentyldiyl, 1-methylbutyldiyl, 2-methylbutyldiyl, n-hexyldiyl, and the like.
  • alkylamino refers to -NH-alkyl, wherein alkyl is as defined herein.
  • alkylamino include, but are not limited to: methylamino, ethylamino, n- propylamino, isopropylamino, n-butylamino, sec-butylamino, isobutylamino, 7-butylamino, pentylamino, isopentylamino, 7-pentylamino, neo-pentylylamino, 1 -methylbutylamino, 2- methylbutylamino, n-hexylylamino, and the like.
  • alkyloxy refers to -O-alkyl, wherein alkyl is as defined herein.
  • alkyl include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, sec-butoxy, isobutoxy, 7-butoxy, pentyloxy, isopentyloxy, 7-pentyloxy, neo-pentyloxy, 1- methylbutoxy, 2-methylbutoxy, n-hexyloxy, and the like.
  • alkylthio and "thio-alkyl” are used interchangeably herein to refer to -S-alkyl, wherein alkyl is as defined herein.
  • alkylthio include, but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, isobutylthio, t- butylthio, pentylthio, isopentylthio, 7-pentylthio, neo-pentylthio, 1-methylbutylthio, 2- methylbutylthio, n-hexylthio, and the like.
  • amino refers to -NH2.
  • amino-cycloalkyl refers to a cycloalkyl group substituted with one amino substituent, as those terms are defined herein.
  • amino-cycloalkyl include, but are not limited to: aminocyclopropyl, aminocyclobutyl, aminocyclopentyl, aminocyclohexyl, and the like.
  • amino-alkyl refers to an alkyl group substituted with one amino substituent, as those terms are defined herein.
  • amino-alkyl examples include, but are not limited to: aminomethyl, aminoethyl, amino-n -propyl, amino-isopropyl, amino-n-butyl, amino-sec- butyl, amino-isobutyl, amino-7-butyl, amino-pentyl, amino-isopentyl, amino-7-pentyl, amino-neo- pentyl, amino-l-methylbutyl, amino-2-methylbutyl, amino-n-hexyl, and the like.
  • amino-aryl refers to an aryl group substituted with one amino substituent, as those terms are defined herein.
  • amino-aryl include, but are not limited to: amino-phenyl, amino-naphthalenyl, and the like.
  • amino-heteroaryl refers to a heteroaryl group substituted with one amino substituent, as those terms are defined herein.
  • amino-heteroaryl include, but are not limited to, amino-pyridyl, amino-benzofuranyl, amino-pyrazinyl, and the like.
  • amino-heterocyclyl refers to an heterocyclyl group substituted with one amino substituent, as those terms are defined herein.
  • amino-heterocyclyl include, but are not limited to: amino-pyrrolidinyl, amino-piperidinyl, and the like.
  • aryl refers to a radical derived from a 6- to 12-membered mono- or bicyclic hydrocarbon ring system wherein at least one ring aromatic.
  • aryl examples include, but are not limited to: phenyl, naphthalenyl, 1,2,3,4-tetrahydro-naphthalenyl, 5,6,7,8- tetrahydro-naphthalenyl, indanyl, and the like.
  • aryl-alkyl refers to an alkyl group substituted with one aryl substituent, as those terms are defined herein.
  • aryl-alkyl include, but are not limited to: benzyl, phenethyl, phenylpropyl, naphthalenylmethyl, and the like.
  • aryldiyl refers to a divalent radical derived from a 6- to 12- membered mono- or bicyclic hydrocarbon ring system wherein at least one ring aromatic.
  • aryldiyl include, phenyldiyl, naphthalenyldiyl, 1,2,3,4-tetrahydro-naphthalenyldiyl, 5,6,7,8-tetrahydro-naphthalenyldiyl, indanyldiyl, and the like.
  • cycloalkyl refers to a cyclic saturated hydrocarbon radical containing the specified number of carbon atoms, e.g., C3-C7 alkyl.
  • examples of cycloalkyl include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • cycloalkyl-alkyl refers to an alkyl group substituted with one cycloalkyl substituent, as those terms are defined herein.
  • cycloalkyl-alkyl examples include, but are not limited to: cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, and the like.
  • cycloalkyldiyl refers to a divalent cyclic saturated hydrocarbon radical containing the specified number of carbon atoms, e.g., C3-C7 cycloalkyldiyl, or C4-C7 alkyldiyl.
  • cycloalkyldiyl include, but are not limited to: cyclopropyldiyl, cyclobutyldiyl, cyclopentyldiyl, cyclohexyldiyl, and the like.
  • halo refers to -F, -CI, -Br, and -I.
  • haloacyl refers to -C(0)-haloalkyl, wherein haloalkyl is as defined herein. Examples of haloacyl include, but are not limited to: difluoroacetyl, trifluoroacetyl, 3,3,3-trifluoropropanoyl, pentafluoroproponyl, and the like.
  • haloalkoxy refers to -O-haloalkyl, wherein haloalkyl is as defined herein.
  • haloalkoxy include, but are not limited to: difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, and the like.
  • haloalkyl refers to an alkyl group as defined herein substituted with from one or more halogens. When more than one halogen is present then they may be the same or different and selected from the group consisting of F, CI, Br, and I. Examples of haloalkyl groups include, but are not limited to: fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.
  • heteroaryl refers to a radical derived from a 6- to 12-membered mono- or bicyclic ring system wherein at least one ring atom is a heteroatom and at least one ring is aromatic. Examples of a heteroatom include, but are not limited to: O, S, N, and the like.
  • heteroaryl examples include, but are not limited to: pyridyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinolinyl, benzoxazolyl, benzothiazolyl, lH-benzimidazolyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrrolyl, indolyl, lH-benzoimidazol-2-yl, benzo[l,3]dioxol-5-yl, 3,4- dihydro-2H-benzo[l,4]oxazin-7-yl, 2,3-dihydro-benzofurn-7-yl, 2,3-dihydro-indol-l-yl, and the like.
  • heteroaryldiyl refers to a divalent radical derived from a 6- to 12-membered mono- or bicyclic ring system wherein at least one ring atom is a heteroatom and at least one ring is aromatic. Examples of a heteroatom include, but are not limited to: O, S, N, and the like.
  • heteroaryldiyl examples include, but are not limited to: thiazolyldiyl, 2,4-thiazolyldiyl, triazolyldiyl, l,2,3-triazolyl-l,4-diyl, pyridyldiyl, benzofuranyldiyl, pyrazinyldiyl, pyridazinyldiyl, pyrimidinyldiyl, triazinyldiyl, quinolinyldiyl, benzoxazolyldiyl, benzothiazolyldiyl, 1H- benzimidazolyldiyl, isoquinolinyldiyl, quinazolinyldiyl, quinoxalinyldiyl, pyrrolyldiyl, indolyldiyl, lH-benzoimidazol-2-yldiyl,
  • heterocyclyl refers to a radical derived from a 3- to 12- membered mono- or bicyclic non-aromatic ring system wherein at least one ring atom is a heteroatom.
  • a heteroatom include, but are not limited to: O, S, N, and the like.
  • a heterocyclyl substituent can be attached via any of its available ring atoms, for example, a ring carbon, or a ring nitrogen.
  • the heterocyclyl group is a 3-, 4-, 5-, 6- or 7- membered containing ring.
  • heterocyclyl group examples include, but are not limited to: aziridin-l-yl, aziridin-2-yl, azetidin-l-yl, azetidin-2-yl, azetidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, piperazin-l-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, [l,3]-dioxolan-2-yl, thiomorpholin-4-yl, [l,4]oxazepan-4-yl, l,l-dioxo- 6 -thiomorpholin-4-yl,
  • heterocyclyl-alkyl refers to an alkyl group substituted with one heterocyclyl substituent, as those terms are defined herein.
  • heterocyclyl-alkyl include, but are not limited to: azetidin-3 -ylmethyl, piperidin-1 -ylmethyl, piperidin-2 -ylmethyl, piperidin-3- ylmethyl, piperidin-4-ylmethyl, morpholin-2-ylmethyl, morpholin-3 -ylmethyl, morpholin-4- ylmethyl, piperazin-l-ylmethyl, piperazin-2 -ylmethyl, piperazin-3 -ylmethyl, piperazin-4-ylmethyl, pyrrolidin-1 -ylmethyl, pyrrolidin-2 -ylmethyl, pyrrolidin-3 -ylmethyl, [1, 3] -dioxolan-2 -ylmethyl, thiomo ⁇ holin-4-yl
  • heterocyclyldiyl refers to a divalent radical derived from a 3- to 12-membered mono- or bicyclic non-aromatic ring system wherein at least one ring atom is a heteroatom.
  • a heteroatom include, but are not limited to: O, S, N, and the like.
  • a heterocyclyldiyl substituent can be attached via any two of its available ring atoms, for example, ring carbons, or ring nitrogens.
  • the heterocyclyldiyl is a 3-, 4-, 5-, 6- or 7- membered containing ring.
  • heterocyclyldiyl group examples include, but are not limited to: aziridin-l-yldiyl, aziridin-2-yldiyl, azetidin-l-yldiyl, azetidin-2-yldiyl, azetidin-3 -yldiyl, piperidin- 1-yldiyl, piperidin-2-yldiyl, piperidin-3 -yldiyl, piperidin-4-yldiyl, morpholin-2-yldiyl, morpholin- 3-yldiyl, morpholin-4-yldiyl, piperazin-1 -yldiyl, piperazin-2 -yldiyl, piperazin-3 -yldiyl, piperazin-4- yldiyl, pyrrolidin-1 -yldiyl, pyrrolidin-2 -yl,
  • hydroxyl refers to -OH.
  • hydroxy-alkyl refers to an alkyl group substituted with one hydroxy substituent, as those terms are defined herein.
  • hydroxy-alkyl include, but are not limited to: hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxy-isopropyl, hydroxy-n- butyl, hydroxy-sec-butyl, hydroxy-isobutyl, hydroxy-7-butyl, hydroxy-pentyl, hydroxy-isopentyl, hydroxy-7-pentyl, hydroxy-neo-pentyl, hydroxy- 1 -methylbutyl, hydroxy-2-methylbutyl, hydroxy-n- hexyl, and the like.
  • nitro refers to -NO2.
  • thio refers to -SH.
  • substituted indicates that at least one hydrogen atom of the chemical group is replaced by a non-hydrogen substituent or group, the non-hydrogen substituent or group can be monovalent or divalent. When the substituent or group is divalent, then it is understood that this group is further substituted with another substituent or group.
  • a chemical group herein when a chemical group herein is "substituted” it may have up to the full valance of substitution; for example, a methyl group can be substituted by 1, 2, or 3 substituents, a methylene (methyldiyl) group can be substituted by 1 or 2 substituents, a phenyl group can be substituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1, 2, 3, 4, 5, 6, or 7 substituents, and the like, unless otherwise specified.
  • substituted with one or more substituents refers to the substitution of a group with one substituent up to the total number of substituents physically allowed by the group.
  • protecting group refers to a labile chemical moiety which is known in the art to protect reactive groups including without limitation, hydroxyl and amino groups, against undesired reactions during synthetic procedures. Protecting groups are typically used selectively and/or orthogonally to protect sites during reactions at other reactive sites and can then be removed to leave the unprotected group as is or available for further reactions. Protecting groups as known in the art are described generally in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Groups can be selectively incorporated into compounds of the present disclosure as precursors.
  • an amino group can be placed into a compound described herein as an azido group that can be chemically converted to the amino group at a desired point in the synthesis.
  • groups are protected or present as a precursor that will be inert to reactions that modify other areas of the parent molecule for conversion into their final groups at an appropriate time. Further representative protecting or precursor groups are discussed in Agrawal, et al, Protocols for Oligonucleotide Conjugates, Eds, Humana Press; New Jersey, 1994; Vol. 26 pp. 1 72.
  • hydroxyl protecting groups include, but are not limited to, /-butyl, 7-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1- ethoxyethyl, l-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, 7-butyldimethylsilyl, 7-butyldiphenylsilyl (TBDPS), triphenylsilyl, benzoylformate, acetate, chloroacetate, trichloroacetate, trifluoroacetate, pivaloate, benzoate, p-phenylbenzoate, 9- fluorenylmethyl carbonate, mesylate and to
  • amino protecting groups include, but are not limited to, carbamate -protecting groups, such as 2-trimethylsilylethoxycarbonyl (Teoc), 1 -methyl -1 -(4 -biphenylyl)ethoxycarbonyl (Bpoc), 7-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); amide protecting groups, such as formyl, acetyl, trihaloacetyl, benzoyl, and nitrophenylacetyl; sulfonamide- protecting groups, such as 2-nitrobenzenesulfonyl; and imine and cyclic imide protecting groups, such as phthalimido and dithiasuccinoyl.
  • carbamate -protecting groups such as 2-trimethylsilylethoxycarbonyl (Teoc), 1 -methyl -1 -
  • “Stable compound” and “stable structure”, as used herein, refer to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10 -sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethane sulfonic acid, 2-
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Ammonium, sodium, potassium, calcium, and magnesium salts are particularly useful in this context.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2 dimethylaminoethanol, 2 diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.
  • basic ion exchange resins such as
  • solvate refers to an aggregate that comprises one or more molecules of a compound with one or more molecules of solvent.
  • the solvent may be water, in which case the solvate may be a hydrate.
  • the solvent may be an organic solvent.
  • compounds may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms.
  • Compounds may be true solvates, or may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
  • the term "antibody” refers to a full-length immunoglobulin molecule or a functionally active portion of a full-length immunoglobulin molecule, i.e. , a molecule that contains an antigen binding site that immunospecifically binds an antigen of a target of interest or part thereof.
  • the immunoglobulin may be of any type (e.g., IgG, IgE, IgM, IgD, and IgA), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass of immunoglobulin molecule.
  • the antibodies may be derived from any species.
  • antibodies of human, murine, camelid or rabbit origin may be polyclonal, monoclonal, multi-specific (e.g., bispecific), human, humanized, chimeric, linear or single chain antibodies.
  • antibody also includes diabodies, maxibodies, minibodies, scFv fragments, Fab fragments, F(ab') fragments, F(ab')2 fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, and epitope -binding fragments of any of the above which immunospecifically bind to a target antigen.
  • An antibody "which binds" an antigen of interest is one capable of binding that antigen with sufficient affinity that the antibody is useful in targeting a cell expressing the antigen.
  • intracellular metabolite refers to a compound resulting from a metabolic process or reaction inside a cell on a composition described herein (e.g. , an antibody drug conjugate (ADC)).
  • the metabolic process or reaction may be an enzymatic process such as proteolytic cleavage of a peptide linker of the subject composition, or hydrolysis of a functional group such as a hydrazone, ester, or amide within the subject composition.
  • intracellular metabolites include, but are not limited to, antibodies and free drug which have been separated intracellularly, i.e. , after entry, diffusion, uptake or transport into a cell (e.g. , by enzymatic cleavage of an ADC by an intracellular enzyme).
  • the terms “intracellularly cleaved” and “intracellular cleavage” refer to metabolic processes or reactions inside a cell on a composition described herein whereby the covalent attachment, e.g., the linker (L), between the drug moiety (D) and the targeting moiety (T) (e.g. , an antibody) is broken, resulting in the free drug dissociated from (T) inside the cell.
  • the cleaved moieties of the subject compositions are thus intracellular metabolites (e.g., T, T-L fragment, D-L fragment, and D).
  • some embodiments of the present disclosure relate to compositions that are cleavage products of a composition of Formula II as described herein, which cleavage products include compositions comprising compounds of Formula I as described herein.
  • extracellular cleavage refers a metabolic process or reaction outside a cell on a composition described herein whereby the covalent attachment, e.g. , the linker (L), between the drug moiety (D) and the targeting moiety (T) (e.g. , an antibody) is broken, resulting in the free drug dissociated from (T) outside the cell.
  • the cleaved moieties of the subject compositions are thus initially extracellular metabolites (e.g., T, T-L fragment, D-L fragment, and D), which may move intracellularly by diffusion and cell permeability or transport.
  • subject and “patient” as used herein refer to an animal, typically a mammal, in need of treatment.
  • mammal includes humans and both domestic animals, such as laboratory animals, farm animals and household pets (e.g. , cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife, and the like.
  • Optional or “optionally” means that the subsequently described event of circumstances may or may not occur, and that some embodiments of the present disclosure relate to instances where said event or circumstance occurs and some embodiments relate to instances in which it does not.
  • optionally substituted aryl means that the aryl substituent may or may not be substituted and that the description includes both substituted aryl substituents and aryl substituents having no substitution.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration (or other similar regulatory agency of another jurisdiction) as being acceptable for use in humans or domestic animals.
  • the term "therapeutically effective amount” refers to that amount of a compound or composition which, when administered to a subject is sufficient to effect treatment of the particular indication to be treated (e.g., cancer or tumor cells in the subject).
  • the amount of a compound or composition described herein which constitutes a "therapeutically effective amount” will vary depending on the compound, the condition and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • Treating covers the treatment of the disease or condition of interest in a subject having the disease or condition of interest, and may include one or more of preventing the disease or condition from occurring for example in a subject predisposed to the condition who has not yet been diagnosed as having it; inhibiting the disease or condition, for example, arresting its development; relieving the disease or condition, for example, causing regression of the disease or condition, and/or relieving one or more symptoms resulting from the disease or condition.
  • an "effective amount” in respect of a particular result to be achieved is an amount sufficient to achieve the desired result.
  • an "effective amount” of compound when referred to in the context of the killing of cancer cells refers to an amount of drug sufficient to produce a killing effect.
  • the present disclosure relates to compounds of general Formula I:
  • R is selected from: amino-Ci-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino- heterocyclyl, and heterocyclyl, each optionally substituted with one or more substituents selected from aryl, aryl-G-C6 alkyl, C1-C6 alkyl, G-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl -G-G alkyl, guanidino, halo, G-G haloalkyl, heterocyclyl, heterocyclyl-G-G alkyl, hydroxyl, and thio; or R is R ⁇ NCHCR 3 )-;
  • R 1 is selected from: H and G-G alkyl
  • R 2 is G-G alkyl
  • R 3 is selected from: H, R 15 and R 7 -CH(CH 3 ) 2 -; or R 2 and R 3 taken together with the atoms to which they are each bonded form a heterocyclyldiyl;
  • R 4 is selected from: C1-C4 alkyl and C3-C6 cycloalkyl
  • R 5 is selected from: H and C1-C4 alkyl optionally substituted with one substituent selected from: C1-C4 alkyloxy and C1-C4 acyloxy;
  • R 6 is selected from: G-C6 alkyl, aryl, aryl-Ci-C6 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more substituents selected from: G- G alkyloxy, G-G alkoxycarbonyl, G-G alkyl, G-G alkylamino, amino, amino-G-C6 alkyl, amino-aryl, amino-G-G cycloalkyl, amino-heteroaryl, amino-heterocyclyl, aryl, carboxamide, carboxyl, G-G cycloalkyl, cyano, G-G haloacyl, G-G haloalkyl, G-G haloalkoxy, halo, hydroxyl, nitro, thio, and thio-G-G alkyl;
  • R 7 is selected from: H, aryl, G-G cycloalkyl, and heteroaryl, each of which is optionally substituted with one or more substituents selected from: G-G acylthio, G-G alkenyl, G-G alkyl, G-G alkylamino, G-G alkyloxy, amino, amino-G-G alkyl, halo, G-G haloalkyl, hydroxyl, hydroxy-G-G alkyl, and thio, wherein G-G alkenyl, G-G alkylamino and G-G alkyloxy are further optionally substituted with one substituent selected from G-G alkylaryl, hydroxyl, and thio;
  • R 8 is selected from: aryl, heteroaryl, and G-G cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl;
  • R 9 and R 10 are each independently selected from: H, G-G alkyl, aryl, aryl-G-G alkyl, C3-C7 cycloalkyl-G-G alkyl, and hydroxy-G-G alkyl;
  • R 15 is G-G alkyl
  • X is selected from G-G alkenyldiyl and G alkyldiyl, wherein G alkyldiyl is substituted with one substituent selected from: G-G acyloxy, G-G alkyloxy, hydroxyl, oxo, -OC(0)NR 9 R 10 , -OC(S)NR 9 R 10 , -OC(0)OR 9 , and -OC(S)OR 9 ;
  • Certain embodiments relate to compounds having general Formula I as defined above, with the proviso that when R is piperidin-2-yl; R 4 is fert-butyl or sec-butyl; R 5 is methyl; X is C 2 alkyldiyl substituted with acetoxy; Y is 2,4,-thiazolyl; Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )- and R 8 is phenyl, then R 6 is other than cyclopropyl.
  • Certain embodiments relate to compounds having general Formula I as defined above, with the proviso that when R is l-methylpiperidin-2-yl; R 4 is fert-butyl or sec-butyl and R 5 is methyl, then X is C 2 alkyldiyl as defined above.
  • X is C 2 alkyldiyl substituted with one substituent selected from: G-C6 acyloxy, G-C6 alkyloxy, hydroxyl, oxo, -OC(0)NR 9 R 10 , -OC(S)NR 9 R 10 , -OC(0)OR 9 , and -OC(S)OR 9 , and
  • Y is heteroaryldiyl.
  • R is selected from: amino-G-C6 alkyl, amino-aryl, amino-C 3 -C7 cycloalkyl, amino-heterocyclyl, and heterocyclyl, each optionally substituted with one or more substituents selected from G-C6 alkyl and halo.
  • R is selected from: l-(dimethylamino)-2-methylpropyl, 2-methyl- l-(methylamino)propyl, 1-aminocyclopentyl, 1-aminocyclopropyl, 4-aminophenyl, 2- aminopropan-2-yl, 1-aminocyclohexyl, 3-aminooxetan-3-yl, 2-(methylamino)propan-2-yl, 1- amino-2-methylpropan-2-yl, 2-methylpyrrolidin-2-yl, 2-amino-3-methylbutan-2-yl, 2-aminobutan- 2-yl, 2-methyl-l-(methylamino)propan-2-yl, 2-methylpiperidin-2-yl, 3-fluoropyrrolidin-3-yl, 1,2- dimethylpyrrolidin-2-yl, 2-(dimethylamino)propan-2-yl. [00101] In some embodiments, R is R ⁇
  • R 1 is selected from: H and C1-C4 alkyl.
  • R 1 is selected from: H, methyl, and propyl.
  • R 1 is selected from: H, methyl, and isopropyl.
  • R 2 is C1-C4 alkyl. In some embodiments, R 2 is methyl.
  • R 3 is R 7 -CH(CI3 ⁇ 4)2-. In some embodiments, R 3 is H. In some embodiments, R 3 is R 15 .
  • R 4 is C1-C4 alkyl or cyclopropyl.
  • R 4 is selected from: propyl, butyl, and cyclopropyl
  • R 4 is selected from: sec-propyl, sec-butyl, fert-butyl, cyclohexyl, cyclopentyl and cyclopropyl.
  • R 5 is selected from: H and C1-C4 alkyl optionally substituted with C1-C4 acyloxy.
  • R 5 is C1-C4 alkyl optionally substituted with C1-C4 acyloxy.
  • R 5 is methyl optionally substituted with C1-C4 acyloxy.
  • R 6 is selected from: G-C6 alkyl, aryl, aryl-Ci-C6 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more substituents selected from: 1-aminocyclopropyl, 4-aminophenyl, amino, aminomethyl, bromo, fert-butyl, carboxamide, carboxyl, chloro, cyano, cyclopentyl, ethyl, fluoro, hydroxy, isopropyl, methoxy, methyl, nitro, phenyl, pyridin-3-yl, thio, thiomethyl, trifluoromethoxy, and trifluoromethyl.
  • substituents selected from: 1-aminocyclopropyl, 4-aminophenyl, amino, aminomethyl, bromo, fert-butyl, carboxamide, carboxyl, chloro, cyano, cyclopenty
  • R 6 is selected from: C1-C4 alkyl, aryl, aryl-G-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, wherein the C1-C4 alkyl is substituted with a substituent selected from: amino-aryl, amino-C3-C7 cycloalkyl, amino -heteroaryl or amino-heterocyclyl, and the aryl, aryl-G-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from: amino, amino-G-C4 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, C1-C4 haloacyl, C1-C4 haloal
  • R 6 is selected from: 5,6,7,8-tetrahydronaphthalen-l-yl, benzyl, cyclohexyl, ethyl, hexan-2-yl, methyl, naphthalen-2-yl, piperidin-l-yl, phenyl, propyl, pyridin-3-yl, and thien-2-yl, each optionally substituted with one or more substituents selected from: 1- aminocyclopropyl, 4-aminophenyl, amino, aminomethyl, bromo, fert-butyl, carboxamide, carboxyl, chloro, cyano, cyclopentyl, ethyl, fluoro, hydroxy, isopropyl, methoxy, methyl, nitro, phenyl, pyridin-3-yl, thio, thiomethyl, trifluoromethoxy, and trifluoromethyl.
  • R 6 is selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4- (aminomethyl)phenyl, 4-aminophenyl, 3-aminobenzyl, 3-(aminomethyl)benzyl, 3- (aminomethyl)phenyl, 3-aminophenyl, benzyl, phenyl, 3-mercaptopropyl, 2-mercaptoethyl, 4- (mercaptomethyl)phenyl, 7-tolyl, methyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-fert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4- methoxy-2-nitrophenyl, 4-aminocarbonyl-2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperid
  • R 6 is aryl or aryl-G-C4 alkyl, each optionally substituted with one or more substituents selected from: amino, amino-G-C4 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, C1-C4 haloacyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, hydroxyl, nitro, thio, and thio-G-C6 alkyl.
  • R 6 is benzyl or phenyl, each optionally substituted with one or more substituent selected from amino and aminomethyl.
  • R 6 is selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4- (aminomethyl)phenyl, 4-aminophenyl, and benzyl.
  • the Variable R 7 is selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4- (aminomethyl)phenyl, 4-aminophenyl, and benzyl.
  • R 7 is selected from: H, aryl, C3-C7 cycloalkyl, and heteroaryl, each of which is optionally substituted with one or more substituents selected from: G-G acylthio, G- G alkenyl, G-G alkyl, G-G alkylamino, G-G alkyloxy, amino, amino-G-G alkyl, halo, G-G haloalkyl, hydroxyl, hydroxy-G-G alkyl, and thio, wherein G-G alkenyl, G-G alkylamino and G-G alkyloxy are further optionally substituted with one substituent selected from /j>-tolyl, hydroxyl, and thio.
  • R 7 is selected from: H, aryl, G-G cycloalkyl, and heteroaryl, each of which is optionally substituted with one or more substituents selected from: (2- hydroxyethyl)amino, (2-mercaptoethyl)amino, 2-(acetylthio)ethoxy, 2-aminoethoxy, 2- hydroxyethoxy, 2-mercaptoethoxy, 3-methoxy, 4-methylstyryl, amino, aminomethyl, chloro, fluoro, hydroxyl, hydroxymethyl, methyl, thio, trifluoromethyl.
  • R 7 is selected from: H, lH-indol-3-yl, 1 -methyl- lH-indol-3-yl, 2- methoxyphenyl, 3-((2-hydroxyethyl)amino)phenyl, 3-((2-mercaptoethyl)amino)phenyl, 3-(2- hydroxyethoxy)phenyl, 3-(2-mercaptoethoxy)phenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3- chlorophenyl, 3-mercaptophenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 4-((2- hydroxyethyl)amino)phenyl, 4-((2-mercaptoethyl)amino)phenyl, 4- 4-(2-hydroxyethoxy)phenyl, 4- (2-mercaptoethoxy)phenyl, 4-mercaptophenyl, 4-methoxyphenyl
  • R 8 is selected from aryl, heteroaryl and C5-C7 cycloalkyl, optionally substituted with one substituent selected from amino and hydroxyl.
  • R 8 is aryl optionally substituted with one substituent selected from amino and hydroxyl.
  • R 8 is selected from: lH-indol-3-yl, 4-aminophenyl, 4- hydroxyphenyl, 5-hydroxypyridin-2-yl, cyclohexyl, and phenyl.
  • R 9 is ⁇ . In some embodiments, R 9 is C1-C4 alkyl. In some embodiments, R 9 is aryl. In some embodiments, R 9 is aryl-G-C4 alkyl. In some embodiments, R 9 is C3-C7 cycloalkyl-Ci-C4 alkyl. In some embodiments, R 9 is hydroxy-G-C4 alkyl.
  • R 10 is ⁇ . In some embodiments, R 10 is C1-C4 alkyl. In some embodiments, R 10 is aryl. In some embodiments, R 10 is aryl-G-C4 alkyl. In some embodiments, R 10 is C3-C7 cycloalkyl-Ci-C4 alkyl. In some embodiments, R 10 is hydroxy-Ci-C4 alkyl.
  • R 11 is selected from: ⁇ , C1-C4 acyl, and C1-C4 alkyl. [00129] In some embodiments, R 11 is C1-C6 acyl or G-C6 alkyl.
  • R 11 is selected from: ⁇ , acetyl, propyl, ethyl, and methyl.
  • R 12 is C1-C4 acyl. In some embodiments, R 12 is C1-C4 alkyl.
  • X is selected from C2-C3 alkenyldiyl and C2 alkyldiyl, wherein C2 alkyldiyl is substituted with one substituent selected from: G-C6 acyloxy, C1-C6 alkyloxy, hydroxyl, and oxo.
  • X is selected from C2-C3 alkenyldiyl and C2 alkyldiyl, wherein C2 alkyldiyl is substituted with one substituent selected from: G-C6 acyloxy, G-C6 alkyloxy, hydroxyl, and -OC(0)NR 9 R 10 .
  • X is selected from C2-C3 alkenyldiyl and C2 alkyldiyl, wherein C2 alkyldiyl is substituted with one substituent selected from: C1-C4 acyloxy, C1-C4 alkyloxy, hydroxyl, and -OC(0)NR 9 R 10 .
  • Y is 2,4-thiazolyldiyl. In some embodiments, Y is 1,2,3-triazolyl- 1,4-diyl. In some embodiments, Y is absent.
  • Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-. In some embodiments, Z is absent.
  • R 2 is G-C 6 alkyl; and R 3 is R 7 -CH(CH 3 ) 2 - [00139] In some embodiments, R 2 and R 3 taken together with the atoms to which they are each bonded form a heterocyclyldiyl.
  • R 2 and R 3 taken together with the atoms to which they are each bonded form a heterocyclyldiyl selected from: pyrrolidinyldiyl, piperidinyldiyl, and azepanyldiyl.
  • R 1 is selected from: H and G-C6 alkyl
  • R 4 is selected from: C1-C4 alkyl and C3-C6 cycloalkyl
  • R 5 is selected from: H and C1-C4 alkyl optionally substituted with one substituent selected from: C1-C4 alkyloxy and C1-C4 acyloxy;
  • R 6 is selected from: G-C6 alkyl, aryl, aryl-Ci-C6 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more substituents selected from: G- G alkyloxy, G-G alkoxycarbonyl, G-G alkyl, G-G alkylamino, amino, amino-G-G alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl, amino-heterocyclyl, aryl, carboxamide, carboxyl, G-G cycloalkyl, cyano, G-C6 haloalkyl, G-C6 haloalkoxy, halo, hydroxyl, nitro, thio, and thio-G-G alkyl;
  • R 8 is selected from: aryl, heteroaryl, and G-G cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl;
  • R 9 and R 10 are each independently selected from: H, G-G alkyl, aryl, aryl-G-G alkyl, C3-C7 cycloalkyl-G-G alkyl, and hydroxy-G-G alkyl;
  • X is selected from C2-C3 alkenyldiyl and C2 alkyldiyl, wherein C2 alkyldiyl is substituted with one substituent selected from: G-C6 acyloxy, G-C6 alkyloxy, hydroxyl, oxo, -OC(0)NR 9 R 10 , -OC(S)NR 9 R 10 , -OC(0)OR 9 , and -OC(S)OR 9 ;
  • Y is heteroaryldiyl, or Y is absent;
  • Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-, or Z is absent; and n is 0, 1, or 2.
  • Certain embodiments relate to compounds having Formula la as defined above, with the proviso that when R is piperidin-2-yl; R 4 is fert-butyl or sec-butyl; R 5 is methyl; X is C2 alkyldiyl substituted with acetoxy; Y is 2,4,-thiazolyl; Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )- and R 8 is phenyl, then R 6 is other than cyclopropyl.
  • Certain embodiments relate to compounds having Formula la as defined above, with the proviso that when R is l-methylpiperidin-2-yl; R 4 is fert-butyl or sec-butyl and R 5 is methyl, then X is C2 alkyldiyl as defined above.
  • X is C2 alkyldiyl substituted with one substituent selected from: G-C6 acyloxy, G-C6 alkyloxy, hydroxyl, oxo, -OC(0)NR 9 R 10 , -OC(S)NR 9 R 10 , -OC(0)OR 9 , and -OC(S)OR 9 , and
  • Y is heteroaryldiyl.
  • R 1 is selected from: H and C1-C4 alkyl.
  • R 4 is C1-C4 alkyl or cyclopropyl.
  • R 5 is C1-C4 alkyl optionally substituted with one substituent selected from: C1-C4 alkyloxy and C1-C4 acyloxy.
  • R 6 is selected from: C1-C4 alkyl, aryl, aryl- C1-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, wherein the C1-C4 alkyl is substituted with a substituent selected from: amino-aryl, amino-C3-C?
  • cycloalkyl amino -heteroaryl or amino- heterocyclyl
  • aryl, aryl-G-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from: amino, amino-G-C4 alkyl, amino-aryl, amino-C3-C?
  • cycloalkyl amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, C1-C4 haloacyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, hydroxyl, nitro, thio, and thio- C1-C6 alkyl.
  • X is C 2 alkyldiyl substituted with one substituent selected from: C1-C4 acyloxy, C1-C4 alkyloxy, hydroxyl and -OC(0)NR 9 R 10 .
  • Y is heteroaryldiyl.
  • Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-.
  • Z is absent.
  • compounds of Formula la is selected from: H and C1-C4 alkyl; is C1-C4 alkyl or cyclopropyl;
  • R 5 is C1-C4 alkyl optionally substituted with one substituent selected from: C1-C4 alkyloxy and C1-C4 acyloxy;
  • R 6 is selected from: C1-C4 alkyl, aryl, aryl-G-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, wherein the C1 -C4 alkyl is substituted with a substituent selected from: amino-aryl, amino-C3-C? cycloalkyl, amino-heteroaryl or amino-heterocyclyl, and the aryl, aryl-G-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from: amino, amino-G-C4 alkyl, amino-aryl, amino-C3-C?
  • cycloalkyl amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, C1-C4 haloacyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, hydroxyl, nitro, thio, and thio-Ci-C6 alkyl;
  • R 8 is selected from: aryl, heteroaryl, and C5-C7 cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl;
  • R 9 and R 10 are each independently H or C1-C4 alkyl
  • X is C2 alkyldiyl substituted with one substituent selected from: C1-C4 acyloxy, C1-C4 alkyloxy, hydroxyl and -OC(0)NR 9 R 10 ;
  • Y is heteroaryldiyl
  • R 1 is selected from: H, methyl, and isopropyl
  • R 4 is selected from: sec-propyl, sec-butyl, fert-butyl, cyclohexyl, cyclopentyl and cyclopropyl;
  • R 5 is selected from: H and methyl
  • R 6 is selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4- aminophenyl, 3-aminobenzyl, 3-(aminomethyl)benzyl, 3-(aminomethyl)phenyl, 3- aminophenyl, benzyl, phenyl, 3-mercaptopropyl, 2-mercaptoethyl, 4- (mercaptomethyl)phenyl, 7-tolyl, methyl, 2,4,6-trimethylphenyl, 4- (trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-fert-butylphenyl, 4-chlorophenyl,
  • R 8 is selected from: lH-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin- 2-yl, cyclohexyl, and phenyl;
  • Y is 2,4-thiazolyldiyl, or Y is absent;
  • Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-, or Z is absent; and n is 0, 1, or 2.
  • lb harmaceutically acceptable salts thereof wherein: is selected from: H and G-C6 alkyl; is G-C6 alkyl; is selected from: C1-C4 alkyl and C3-C6 cycloalkyl; R 5 is selected from: H and C1-C4 alkyl optionally substituted with one substituent selected from: C1-C4 alkyloxy and C1-C4 acyloxy;
  • R 6 is selected from: G-C6 alkyl, aryl, aryl-Ci-C6 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more substituents selected from: G- G alkyloxy, G-G alkoxycarbonyl, G-G alkyl, G-G alkylamino, amino, amino-G-G alkyl, amino-aryl, amino-G-G cycloalkyl, amino-heteroaryl, amino-heterocyclyl, aryl, carboxamide, carboxyl, G-G cycloalkyl, cyano, G-G haloalkyl, G-C6 haloalkoxy, halo, hydroxyl, nitro, thio, and thio-G-G alkyl;
  • R 7 is selected from: H, aryl, G-G cycloalkyl, and heteroaryl, each of which is optionally substituted with one or more substituents selected from: G-G acylthio, G-G alkenyl, G-G alkyl, G-G alkylamino, G-G alkyloxy, amino, amino-G-G alkyl, halo, G-G haloalkyl, hydroxyl, hydroxy-G-G alkyl, and thio, wherein G-G alkenyl, G-G alkylamino and G-G alkyloxy are further optionally substituted with one substituent selected from G-G alkylaryl, hydroxyl, and thio;
  • R 8 is selected from: aryl, heteroaryl, and G-G cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl;
  • R 9 and R 10 are each independently selected from: H, G-G alkyl, aryl, aryl-G-G alkyl, C3-C7 cycloalkyl-G-G alkyl, and hydroxy-G-G alkyl;
  • X is selected from G-G alkenyldiyl and G alkyldiyl, wherein G alkyldiyl is substituted with one substituent selected from: G-G acyloxy, G-G alkyloxy, hydroxyl, oxo, -OC(0)NR 9 R 10 , -OC(S)NR 9 R 10 , -OC(0)OR 9 , and -OC(S)OR 9 ;
  • Y is heteroaryldiyl, or Y is absent
  • Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-, or Z is absent.
  • X is C2 alkyldiyl substituted with one substituent selected from: C1-C4 acyloxy, C1-C4 alkyloxy, hydroxyl and -OC(0)NR 9 R 10 ; and
  • Y is heteroaryldiyl.
  • R 1 is H or methyl
  • R 2 is methyl
  • R 4 is selected from: sec-propyl, sec-butyl, fert-butyl, cyclohexyl, cyclopentyl, and cyclopropyl;
  • R 5 is selected from: H and methyl
  • R 6 is selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4- aminophenyl, 3-aminobenzyl, 3-(aminomethyl)benzyl, 3-(aminomethyl)phenyl, 3- aminophenyl, benzyl, phenyl, 3-mercaptopropyl, 2-mercaptoethyl, 4- (mercaptomethyl)phenyl, /j>-tolyl, methyl, 2,4,6-trimethylphenyl, 4- (trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-fert-butylphenyl, 4-chlorophenyl,
  • R 7 is selected from: H, lH-indol-3-yl, l-methyl-lH-indol-3-yl, 2-methoxyphenyl, 3-((2- hydroxyethyl)amino)phenyl, 3 -((2-mercaptoethyl)amino)phenyl, 3 -(2-
  • R 8 is selected from: lH-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin- 2-yl, cyclohexyl, and phenyl;
  • Y is 2,4-thiazolyldiyl, or Y is absent;
  • Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-, or Z is absent.
  • R 1 is selected from: H and G-C6 alkyl
  • R 2 is C1-C6 alkyl
  • R 3 is selected from H, R 15 , and R 7 -CH(CH 3 ) 2 -; or
  • R 2 and R 3 taken together with the atoms to which they are each bonded form a heterocyclyldiyl
  • R 4 is selected from: C1-C4 alkyl and C3-C6 cycloalkyl
  • R 5 is selected from: H and C1-C4 alkyl optionally substituted with one substituent selected from: C1-C4 alkyloxy and C1-C4 acyloxy;
  • R 6 is selected from: G-C6 alkyl, aryl, aryl-Ci-C6 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more substituents selected from: G- G alkyloxy, G-G alkoxycarbonyl, G-G alkyl, G-G alkylamino, amino, amino-G-G alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl, amino-heterocyclyl, aryl, carboxamide, carboxyl, G-G cycloalkyl, cyano, G-C6 haloalkyl, G-C6 haloalkoxy, halo, hydroxyl, nitro, thio, and thio-G-G alkyl;
  • R 7 is selected from: H, aryl, G-G cycloalkyl, and heteroaryl, each of which is optionally substituted with one or more substituents selected from: G-G acylthio, G-G alkenyl, G-G alkyl, G-G alkylamino, G-G alkyloxy, amino, amino-G-G alkyl, halo, G-G haloalkyl, hydroxyl, hydroxy-G-G alkyl, and thio, wherein G-G alkenyl, G-G alkylamino and G-G alkyloxy are further optionally substituted with one substituent selected from G-G alkylaryl, hydroxyl, and thio;
  • R 8 is selected from: aryl, heteroaryl, and G-G cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl;
  • R 9 and R 10 are each independently H or G-G alkyl
  • R 11 is selected from: H, G-G acyl, G-G alkyl, and -C(0)NR 9 R 10 ;
  • R 15 is C1-C6 alkyl;
  • Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-, or Z is absent.
  • Certain embodiments relate to compounds having Formula Ie as defined above, with the proviso that when R 1 is H; R 2 and R 3 taken together with the atoms to which they are each bonded form piperidin-2-yl; R 4 is fert-butyl or sec-butyl; R 5 is methyl; R 11 is acetyl; Z is - C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )- and R 8 is phenyl, then R 6 is other than cyclopropyl.
  • R 1 and R 2 are each independently C1-C6 alkyl
  • R 3 is H or R 15 .
  • R 2 and R 3 taken together with the atoms to which they are each bonded form a heterocyclyldiyl.
  • R 2 and R 3 taken together with the atoms to which they are each bonded form a heterocyclyldiyl selected from: pyrrolidinyldiyl, piperidinyldiyl, and azepanyldiyl.
  • R 1 is selected from: H and C1-C4 alkyl.
  • R 4 is C1-C4 alkyl or cyclopropyl.
  • R 5 is C1-C4 alkyl optionally substituted with one substituent selected from: C1-C4 alkyloxy and C1-C4 acyloxy.
  • R 6 is selected from: C1-C4 alkyl, aryl, aryl-Ci-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, wherein the C1-C4 alkyl is substituted with a substituent selected from: amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl or amino-heterocyclyl, and the aryl, aryl-G-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from: amino, amino-G-C4 alkyl, amino-aryl,
  • R 6 is aryl or aryl-G-C4 alkyl, each optionally substituted with one or more substituents selected from: amino, amino-G-C4 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, C1-C4 haloacyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, hydroxyl, nitro, thio, and thio- C1-C6 alkyl.
  • R 6 is benzyl or phenyl, each optionally substituted with one or more substituent selected from amino and aminomethyl.
  • R 11 is selected from: G-C6 acyl, G- G alkyl, and -C(0)NR 9 R 10 .
  • R 11 is selected from: G-C4 acyl, G- G alkyl, and -C(0)NR 9 R 10 .
  • R 11 is G-G acyl or G-G alkyl.
  • R 11 is G-G acyl or G-G alkyl.
  • Z is absent.
  • Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-.
  • Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-;
  • R 8 is aryl optionally substituted with one substituent selected from amino and hydroxyl.
  • R 8 is aryl optionally substituted with one substituent selected from amino and hydroxyl.
  • R 4 is C1-C4 alkyl or cyclopropyl
  • R 5 is C1-C4 alkyl optionally substituted with one substituent selected from: C1-C4 alkyloxy and C1-C4 acyloxy;
  • R 6 is selected from: C1-C4 alkyl, aryl, aryl-Ci-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, wherein the C1 -C4 alkyl is substituted with a substituent selected from: amino -aryl, amino-C3-C?
  • cycloalkyl, amino-heteroaryl or amino-heterocyclyl and the aryl, aryl-Ci-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from: amino, amino-G-C4 alkyl, amino -aryl, amino-C3-C?
  • cycloalkyl amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, C1-C4 haloacyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, hydroxyl, nitro, thio, and thio-Ci-C6 alkyl;
  • R 8 is selected from: aryl, heteroaryl, and C5-C7 cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl;
  • R 9 and R 10 are each independently H or C1-C4 alkyl
  • R 11 is selected from: H, G-C 6 acyl, Ci-C 6 alkyl, and -C(0)NR 9 R 10 ;
  • Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-, or Z is absent.
  • R 1 is selected from: H and C1-C4 alkyl
  • R 2 and R 3 taken together with the atoms to which they are each bonded form a heterocyclyldiyl
  • R 4 is C1-C4 alkyl or cyclopropyl
  • R 5 is C1-C4 alkyl optionally substituted with one substituent selected from: C1-C4 alkyloxy and C1-C4 acyloxy;
  • R 6 is selected from: C1-C4 alkyl, aryl, aryl-Ci-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, wherein the C1-C4 alkyl is substituted with a substituent selected from: amino -aryl, amino-G-G cycloalkyl, amino-heteroaryl or amino-heterocyclyl, and the aryl, aryl-Ci-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from: amino, amino-G-C4 alkyl, amino -aryl, amino-G-G cycloalkyl, amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, C1-C4 haloacyl, C1-C4 haloalkyl, C1-C4
  • R 8 is selected from: aryl, heteroaryl, and C3-C7 cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl;
  • R 9 and R 10 are each independently H or C1-C4 alkyl
  • R 11 is selected from: H, G-C 6 acyl, G-C 6 alkyl, and -C(0)NR 9 R 10 ;
  • R 1 is selected from: H and G-C6 alkyl
  • R 4 is selected from: G-G alkyl and G-G cycloalkyl
  • R 5 is selected from: H and C1-C4 alkyl optionally substituted with one substituent selected from: C1-C4 alkyloxy and C1-C4 acyloxy;
  • R 6 is selected from: G-C6 alkyl, aryl, aryl-Ci-C6 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more substituents selected from: G- G alkyloxy, G-G alkoxycarbonyl, G-G alkyl, G-G alkylamino, amino, amino-G-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl, amino-heterocyclyl, aryl, carboxamide, carboxyl, G-G cycloalkyl, cyano, G-G haloalkyl, G-C6 haloalkoxy, halo, hydroxyl, nitro, thio, and thio-G-G alkyl;
  • R 8 is selected from: aryl, heteroaryl, and G-G cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl;
  • R 9 and R 10 are each independently selected from: H, G-G alkyl, aryl, aryl-G-G alkyl, C3-C7 cycloalkyl-G-G alkyl, and hydroxy-G-G alkyl;
  • R 14 is selected from: G-G acyloxy, G-G alkyloxy, hydroxyl, -OC(0)NR 9 R 10 , -OC(S)NR 9 R 10 , -OC(0)OR 9 , and -OC(S)OR 9 ;
  • Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-, or Z is absent; and n is 0, 1, or 2.
  • Certain embodiments relate to compounds having Formula Ix as defined above, with the proviso that when n is 1; R 1 is H; R 4 is fert-butyl or sec-butyl; R 5 is methyl; R 14 is acetoxy; Z is - C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )- and R 8 is phenyl, then R 6 is other than cyclopropyl.
  • R 1 is selected from: H and G-G alkyl.
  • R 4 is G-G alkyl or cyclopropyl.
  • R 5 is G-G alkyl optionally substituted with G-G acyloxy.
  • R 6 is selected from: C1-C4 alkyl, aryl, aryl-Ci-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, wherein the C1-C4 alkyl is substituted with a substituent selected from: amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl or amino-heterocyclyl, and the aryl, aryl-G-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from: amino, amino-G-C4 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroary
  • R 6 is aryl or aryl-G-C4 alkyl, each optionally substituted with one or more substituents selected from: amino, amino-G-C4 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, C1-C4 haloacyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, hydroxyl, nitro, thio, and thio- C1-C6 alkyl.
  • R 6 is benzyl or phenyl, each optionally substituted with one or more substituent selected from amino and aminomethyl.
  • R 9 and R 10 are each independently H or C1-C4 alkyl.
  • R 14 is selected from: G-C6 acyloxy, Ci-Ce alkyloxy, hydroxyl and -OC(0)NR 9 R 10 .
  • R 14 is selected from: C1-C4 acyloxy, C1-C4 alkyloxy, hydroxyl and -OC(0)NR 9 R 10 .
  • R 14 is G-C acyloxy or G-C6 alkyloxy.
  • R 14 is G-C4 acyloxy or G-C4 alkyloxy.
  • Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-.
  • Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-;
  • R 8 is aryl optionally substituted with one substituent selected from amino and hydroxyl.
  • Z is absent.
  • R 1 is selected from: H and C1-C4 alkyl
  • R 4 is C1-C4 alkyl or cyclopropyl
  • R 5 is C1-C4 alkyl optionally substituted with C1-C4 acyloxy
  • R 6 is selected from: C1-C4 alkyl, aryl, aryl-Ci-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, wherein the C1 -C4 alkyl is substituted with a substituent selected from: amino -aryl, amino-C3-C?
  • cycloalkyl amino-heteroaryl or amino-heterocyclyl
  • the aryl, aryl-Ci-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from: amino, amino-G-C4 alkyl, amino -aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, C1-C4 haloacyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, hydroxyl, nitro, thio, and thio-Ci-C6 alkyl;
  • R 8 is selected from: aryl, heteroaryl, and C5-C7 cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl;
  • R 9 and R 10 are each independently H or C1-C4 alkyl
  • R 14 is selected from: G-C6 acyloxy, C1-C6 alkyloxy, hydroxyl and -OC(0)NR 9 R 10 ; Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-, or Z is absent; and n is 0, 1, or 2.
  • R 1 is selected from: H and C1-C4 alkyl;
  • R 4 is C1-C4 alkyl or cyclopropyl;
  • R 5 is C1-C4 alkyl optionally substituted with C1-C4 acyloxy
  • R 6 is selected from: C1-C4 alkyl, aryl, aryl-Ci-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, wherein the C1 -C4 alkyl is substituted with a substituent selected from: amino -aryl, amino-C3-C?
  • cycloalkyl, amino-heteroaryl or amino-heterocyclyl and the aryl, aryl-Ci-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from: amino, amino-G-C4 alkyl, amino -aryl, amino-C3-C?
  • cycloalkyl amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, C1-C4 haloacyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, hydroxyl, nitro, thio, and thio-Ci-C6 alkyl;
  • R 8 is selected from: aryl, heteroaryl, and C5-C7 cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl;
  • R 9 and R 10 are each independently H or C1-C4 alkyl
  • R 14 is selected from: C1-C6 acyloxy, C1-C6 alkyloxy, hydroxyl and -OC(0)NR 9 R 10 ; Z is absent; and n is 0, 1, or 2.
  • R 1 is selected from: H and G-C6 alkyl
  • R 2 is C1-C6 alkyl
  • R 3 is selected from: H, R 15 , and R 7 -CH(CH 3 ) 2 -; or
  • R 2 and R 3 taken together with the atoms to which they are each bonded form a heterocyclyldiyl
  • R 6 is selected from: G-C6 alkyl, aryl, aryl-G-C6 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more substituents selected from: G- G alkyloxy, G-G alkoxycarbonyl, G-G alkyl, G-G alkylamino, amino, amino-G-G alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl, amino-heterocyclyl, aryl, carboxamide, carboxyl, G-G cycloalkyl, cyano, G-C6 haloalkyl, G-C6 haloalkoxy, halo, hydroxyl, nitro, thio, and thio-G-G alkyl;
  • R 7 is selected from: H, aryl, G-G cycloalkyl, and heteroaryl, each of which is optionally substituted with one or more substituents selected from: G-G acylthio, G-G alkenyl, G-G alkyl, G-G alkylamino, G-G alkyloxy, amino, amino-G-G alkyl, halo, G-G haloalkyl, hydroxyl, hydroxy-G-G alkyl, and thio, wherein G-G alkenyl, G-G alkylamino and G-G alkyloxy are further optionally substituted with one substituent selected from G-G alkylaryl, hydroxyl, and thio;
  • R 8 is selected from: aryl, heteroaryl, and G-G cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl;
  • R 9 and R 10 are each independently H or G-G alkyl
  • R 11 is selected from: H, G-G acyl, G-G alkyl, and -C(0)NR 9 R 10 ;
  • R 15 is G-G alkyl
  • Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-, or Z is absent.
  • R 1 is G-G alkyl.
  • R 1 and R 2 are each independently C1-C6 alkyl; and R 3 is H or R 15 .
  • R 2 and R 3 taken together with the atoms to which they are each bonded form a heterocyclyldiyl.
  • R 6 is selected from: C1-C4 alkyl, aryl, aryl-Ci-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, wherein the C1 -C4 alkyl is substituted with a substituent selected from: amino -aryl, amino-C3-C?
  • cycloalkyl, amino-heteroaryl or amino-heterocyclyl and the aryl, aryl-Ci-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from: amino, amino-G-C4 alkyl, amino -aryl, amino-C3-C?
  • cycloalkyl amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, C1-C4 haloacyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, hydroxyl, nitro, thio, and thio-Ci-C6 alkyl.
  • R 1 is H or C1-C4 alkyl
  • R 6 is selected from: C1-C4 alkyl, aryl, aryl-Ci-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, wherein the C1 -C4 alkyl is substituted with a substituent selected from: amino -aryl, amino-C3-C?
  • cycloalkyl, amino-heteroaryl or amino-heterocyclyl and the aryl, aryl-Ci-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from: amino, amino-G-C4 alkyl, amino -aryl, amino-C3-C?
  • cycloalkyl amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, C1-C4 haloacyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, hydroxyl, nitro, thio, and thio-Ci-C6 alkyl.
  • Z is absent.
  • Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-.
  • R 1 is selected from: H, methyl, and isopropyl; R 2 is methyl; and R 3 is R 7 -CH(CH 3 ) 2 -; or
  • R 2 and R 3 taken together with the atoms to which they are each bonded form a heterocyclyldiyl selected from: pyrrolidinyldiyl, piperidinyldiyl, and azepanyldiyl;
  • R 6 is selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4- aminophenyl, 3-aminobenzyl, 3-(aminomethyl)benzyl, 3-(aminomethyl)phenyl, 3- aminophenyl, benzyl, phenyl, 3-mercaptopropyl, 2-mercaptoethyl, 4- (mercaptomethyl)phenyl, 7-tolyl, methyl, 2,4,6-trimethylphenyl, 4- (trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-fert-butylphenyl, 4-chlorophenyl,
  • R 7 is selected from: H, lH-indol-3-yl, l-methyl-lH-indol-3-yl, 2-methoxyphenyl, 3-((2- hydroxyethyl)amino)phenyl, 3 -((2-mercaptoethyl)amino)phenyl, 3 -(2-
  • R 8 is selected from: lH-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin- 2-yl, cyclohexyl, and phenyl;
  • R 11 is selected from: ⁇ , acetyl, propyl, ethyl, and methyl; and Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-, or Z is absent.
  • R 1 is H or C1 -C4 alkyl
  • R 5 is selected from: H and C1-C4 alkyl optionally substituted with one substituent selected from: C1-C4 alkyloxy and C1-C4 acyloxy;
  • R 6 is selected from: G-C6 alkyl, aryl, aryl-Ci-C6 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more substituents selected from: G- G alkyloxy, G-G alkoxycarbonyl, G-G alkyl, G-G alkylamino, amino, amino-G-C6 alkyl, amino-aryl, amino-G-G cycloalkyl, amino-heteroaryl, amino-heterocyclyl, aryl, carboxamide, carboxyl, G-G cycloalkyl, cyano, G-G haloalkyl, G-G haloalkoxy, halo, hydroxyl, nitro, thio, and thio-G-G alkyl;
  • R 9 and R 10 are each independently H or G-G alkyl
  • R 11 is selected from: H, G-G acyl, G-G alkyl, and -C(0)NR 9 R 10 .
  • R 1 is H, methyl or propyl.
  • R 1 is H or methyl
  • R 5 is G-G alkyl optionally substituted with one substituent selected from: G-G alkyloxy and G-G acyloxy. [00209] In certain embodiments, in compounds of Formula Ik', R 5 is G-G alkyl optionally substituted with G-G acyloxy.
  • R 6 is selected from: G-G alkyl, aryl, aryl -G-G alkyl, G-G cycloalkyl, heteroaryl, and heterocyclyl, wherein the G-G alkyl is substituted with a substituent selected from: amino-aryl, amino-G-G cycloalkyl, amino-heteroaryl or amino-heterocyclyl, and the aryl, aryl-G-G alkyl, G-G cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from: amino, amino-G-G alkyl, amino-aryl, amino-G-G cycloalkyl, amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, G-G haloacyl, G-G haloalkyl, G-G haloalk
  • R 6 is aryl or aryl-G-G alkyl, each optionally substituted with one or more substituents selected from: amino, amino-G-G alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, C1-C4 haloacyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, hydroxyl, nitro, thio, and thio- C1-C6 alkyl.
  • R 6 is benzyl or phenyl, each optionally substituted with one or more substituent selected from amino and aminomethyl.
  • R 11 is C1-C4 acyl or C1-C4 alkyl.
  • R 1 is methyl
  • R 5 is -CH2OR 12 , where R 12 is selected from: C1-C4 acyl and C1-C4 alkyl.
  • R 1 is H;
  • R 5 is -CH2OR 12 , where R 12 is selected from: C1-C4 acyl and C1-C4 alkyl. [00216] In certain embodiments in compounds of Formula Ik': R 1 is H; and R 5 is H or methyl; and
  • R 11 is selected from: H, acetyl, propyl, ethyl, and methyl.
  • R 1 is H or C1-C4 alkyl
  • R 5 is selected from: H and C1-C4 alkyl optionally substituted with one substituent selected from: C1-C4 alkyloxy and C1-C4 acyloxy;
  • R 6 is selected from: G-C6 alkyl, aryl, aryl-Ci-C6 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more substituents selected from: G- alkyloxy, G-G alkoxycarbonyl, G-G alkyl, G-G alkylamino, amino, amino-G-G alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl, amino-heterocyclyl, aryl, carboxamide, carboxyl, G-G cycloalkyl, cyano, G-C6 haloalkyl, G-G haloalkoxy, halo, hydroxyl, nitro, thio, and thio-G-G alkyl;
  • R 8 is selected from: aryl, heteroaryl, and G-G cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl;
  • R 9 and R 10 are each independently H or G-G alkyl
  • R 11 is selected from: H, G-G acyl, G-G alkyl, and -C(0)NR 9 R 10 .
  • R 1 is H, methyl or propyl.
  • R 1 is H or methyl.
  • R 5 is G-G alkyl optionally substituted with one substituent selected from: G-G alkyloxy and G-G acyloxy.
  • R 5 is G-G alkyl optionally substituted with G-G acyloxy.
  • R 6 is selected from: G-G alkyl, aryl, aryl -G-G alkyl, G-G cycloalkyl, heteroaryl, and heterocyclyl, wherein the G-G alkyl is substituted with a substituent selected from: amino-aryl, amino-G-G cycloalkyl, amino-heteroaryl or amino-heterocyclyl, and the aryl, aryl-Ci-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from: amino, amino-G-C4 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, C1-C4 haloacyl, C1-C4 haloalky
  • R 6 is aryl or aryl-Ci-C4 alkyl, each optionally substituted with one or more substituents selected from: amino, amino-G-C4 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, C1-C4 haloacyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, hydroxyl, nitro, thio, and thio- Ci-Ce alkyl.
  • R 6 is benzyl or phenyl, each optionally substituted with one or more substituent selected from amino and aminomethyl.
  • R 11 is C1-C4 acyl or C1-C4 alkyl.
  • R 1 is methyl
  • R 5 is -CH2OR 12 , where R 12 is selected from: C1-C4 acyl and C1-C4 alkyl. [00227] In certain embodiments in compounds of Formula ⁇ :
  • R 1 is H
  • R 5 is -CH2OR 12 , where R 12 is selected from: C1-C4 acyl and C1-C4 alkyl.
  • R 1 is selected from: H and G-C6 alkyl
  • R 2 is C1-C6 alkyl
  • R 3 is R 7 -CH(CH 3 ) 2 -;
  • R 2 and R 3 taken together with the atoms to which they are each bonded form a heterocyclyldiyl
  • R 6 is selected from: G-C6 alkyl, aryl, aryl-G-C6 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more substituents selected from: G- G alkyloxy, G-G alkoxycarbonyl, G-G alkyl, G-G alkylamino, amino, amino-G-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl, amino-heterocyclyl, aryl, carboxamide, carboxyl, G-G cycloalkyl, cyano, G-G haloalkyl, G-G haloalkoxy, halo, hydroxyl, nitro, thio, and thio-G-G alkyl;
  • R 7 is selected from: H, aryl, G-G cycloalkyl, and heteroaryl, each of which is optionally substituted with one or more substituents selected from: G-G acylthio, G-G alkenyl, G-G alkyl, G-G alkylamino, G-G alkyloxy, amino, amino-G-G alkyl, halo, G-G haloalkyl, hydroxyl, hydroxy-G-G alkyl, and thio, wherein G-G alkenyl, G-G alkylamino and G-G alkyloxy are further optionally substituted with one substituent selected from G-G alkylaryl, hydroxyl, and thio;
  • R 8 is selected from: aryl, heteroaryl, and G-G cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl;
  • R 11 is selected from: H, G-G acyl, and G-G alkyl
  • Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-, or Z is absent. In certain embodiments in compounds of Formula lo, Z is absent. [00230] In certain embodiments in compounds of Formula Io, Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-.
  • R 1 is selected from: H, methyl, and isopropyl; R 2 is methyl; and R 3 is R 7 -CH(CH 3 ) 2 -; or
  • R 2 and R 3 taken together with the atoms to which they are each bonded form a heterocyclyldiyl selected from: pyrrolidinyldiyl, piperidinyldiyl, and azepanyldiyl;
  • R 6 is selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4- aminophenyl, 3-aminobenzyl, 3-(aminomethyl)benzyl, 3-(aminomethyl)phenyl, 3- aminophenyl, benzyl, phenyl, 3-mercaptopropyl, 2-mercaptoethyl, 4- (mercaptomethyl)phenyl, /j>-tolyl, methyl, 2,4,6-trimethylphenyl, 4- (trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-fert-butylphenyl, 4-chlorophenyl,
  • R 7 is selected from: H, lH-indol-3-yl, l-methyl-lH-indol-3-yl, 2-methoxyphenyl, 3-((2- hydroxyethyl)amino)phenyl, 3 -((2-mercaptoethyl)amino)phenyl, 3 -(2- (acetylthio)ethoxy)phenyl, 3-(2-hydroxyethoxy)phenyl, 3-(2-mercaptoethoxy)phenyl, 3- (4-methylstyryl)phenyl, 3-(aminomethyl)phenyl, 3-(hydroxymethyl)phenyl, 3- hydroxyphenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3-aminophenyl, 3-chlorophenyl, 3-mercaptophenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 4-((2- hydroxyethyl)amino)phenyl
  • R 8 is selected from: lH-indol-3-yl, 4-aminophenyl, 4-hydroxyphenyl, 5-hydroxypyridin- 2-yl, cyclohexyl, and phenyl;
  • R 11 is selected from: ⁇ , acetyl, propyl, ethyl, and methyl; and Z is -C(0)NHCH(CH 2 R 8 )CH 2 CH(CH 3 )-, or Z is absent.
  • R 1 is H or C1-C4 alkyl
  • R 5 is selected from: H and C1-C4 alkyl optionally substituted with one substituent selected from: C1-C4 alkyloxy and C1-C4 acyloxy;
  • R 6 is selected from: G-C6 alkyl, aryl, aryl-Ci-C6 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more substituents selected from: G- G alkyloxy, G-G alkoxycarbonyl, G-G alkyl, G-G alkylamino, amino, amino-G-C6 alkyl, amino-aryl, amino-G-G cycloalkyl, amino-heteroaryl, amino-heterocyclyl, aryl, carboxamide, carboxyl, G-G cycloalkyl, cyano, G-G haloalkyl, G-G haloalkoxy, halo, hydroxyl, nitro,
  • R 9 and R 10 are each independently H or G-G alkyl
  • R 11 is selected from: H, G-G acyl, G-G alkyl, and -C(0)NR 9 R 10 .
  • R 1 is H, methyl or propyl.
  • R 1 is H or methyl.
  • R 5 is G-G alkyl optionally substituted with one substituent selected from: G-G alkyloxy and G-G acyloxy.
  • R 5 is G-G alkyl optionally substituted with G-G acyloxy.
  • R 6 is selected from: G-G alkyl, aryl, aryl -G-G alkyl, G-G cycloalkyl, heteroaryl, and heterocyclyl, wherein the G-G alkyl is substituted with a substituent selected from: amino-aryl, amino-G-G cycloalkyl, amino-heteroaryl or amino-heterocyclyl, and the aryl, aryl-G-G alkyl, G-G cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from: amino, amino-G-G alkyl, amino-aryl, amino-G-G cycloalkyl, amino-heteroaryl, amino-heterocycly
  • R 6 is aryl or aryl-G-G alkyl, each optionally substituted with one or more substituents selected from: amino, amino-G-G alkyl, amino-aryl, amino-G-G cycloalkyl, amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, G-G haloacyl, G-G haloalkyl, G-G haloalkoxy, hydroxyl, nitro, thio, and thio- G-G alkyl.
  • R 6 is benzyl or phenyl, each optionally substituted with one or more substituent selected from amino and aminomethyl.
  • R 11 is C1-C4 acyl or C1-C4 alkyl.
  • R 1 is methyl
  • R 5 is -CH2OR 12 , where R 12 is selected from: C1-C4 acyl and C1-C4 alkyl.
  • R 1 is H;
  • R 5 is -CH2OR 12 , where R 12 is selected from: C1-C4 acyl and C1-C4 alkyl.
  • R 1 is H or C1-C4 alkyl
  • R 5 is selected from: H and C1-C4 alkyl optionally substituted with one substituent selected from: C1-C4 alkyloxy and C1-C4 acyloxy;
  • R 6 is selected from: G-C6 alkyl, aryl, aryl-Ci-C6 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more substituents selected from: G- G alkyloxy, G-G alkoxycarbonyl, G-G alkyl, G-G alkylamino, amino, amino-G-C6 alkyl, amino-aryl, amino-G-G cycloalkyl, amino-heteroaryl, amino-heterocyclyl, aryl, carboxamide, carboxyl, G-G cycloalkyl, cyano, G-G haloalkyl, G-G haloalkoxy, halo, hydroxyl, nitro,
  • R 8 is selected from: aryl, heteroaryl, and G-G cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl;
  • R 9 and R 10 are each independently H or G-G alkyl
  • R 11 is selected from: H, G-G acyl, G-G alkyl, and -C(0)NR 9 R 10 .
  • R 1 is H, methyl or propyl.
  • R 1 is H or methyl.
  • R 5 is G-G alkyl optionally substituted with one substituent selected from: G-G alkyloxy and G-G acyloxy. [00247] In certain embodiments, in compounds of Formula Is', R 5 is G-G alkyl optionally substituted with G-G acyloxy.
  • R 6 is selected from: G-G alkyl, aryl, aryl -G-G alkyl, G-G cycloalkyl, heteroaryl, and heterocyclyl, wherein the G-G alkyl is substituted with a substituent selected from: amino-aryl, amino-G-G cycloalkyl, amino-heteroaryl or amino-heterocyclyl, and the aryl, aryl-G-G alkyl, G-G cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from: amino, amino-G-G alkyl, amino-aryl, amino-G-G cycloalkyl, amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, G-G haloacyl, G-G haloalkyl, G-G haloalkyl, G-G haloal
  • R 6 is aryl or aryl-G-G alkyl, each optionally substituted with one or more substituents selected from: amino, amino-G-G alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl, amino-heterocyclyl, carboxamide, carboxyl, cyano, C1-C4 haloacyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, hydroxyl, nitro, thio, and thio-
  • R 6 is benzyl or phenyl, each optionally substituted with one or more substituent selected from amino and aminomethyl.
  • R 11 is C1-C4 acyl or C1-C4 alkyl.
  • R 1 is methyl
  • R 5 is -CH2OR 12 , where R 12 is selected from: C1-C4 acyl and C1-C4 alkyl. [00253] In certain embodiments in compounds of Formula Is': R 1 is H; and
  • R 5 is -CH2OR 12 , where R 12 is selected from: C1-C4 acyl and C1-C4 alkyl.
  • R is selected from: amino-G-C6 alkyl, amino-aryl, amino-G-G cycloalkyl , amino- heterocyclyl, and heterocyclyl, each optionally substituted with one or more substituents selected from aryl, aryl-G-C6 alkyl, G-C6 alkyl, G-C6 alkylthio, carboxyl, carboxamide, C3-C7 cycloalkyl, C3-C7 cycloalkyl -C1-C6 alkyl, guanidino, halo, G-C6 haloalkyl, heterocyclyl, heterocyclyl-G-G alkyl, hydroxyl, and thio; or R is R ⁇ NCHCR 3 )-;
  • R 1 is selected from: H and G-C6 alkyl;
  • R 2 is C1-C6 alkyl; and
  • R 3 is R 7 -CH(CH 3 ) 2 -; or
  • R 2 and R 3 taken together with the atoms to which they are each bonded form a heterocyclyldiyl
  • R 4 is selected from: C1-C4 alkyl and C3-C6 cycloalkyl
  • R 5 is selected from: H and C1-C4 alkyl optionally substituted with one substituent selected from: C1-C4 alkyloxy and C1-C4 acyloxy;
  • R 6 is selected from: G-C6 alkyl, aryl, aryl-Ci-C6 alkyl, C3-C7 cycloalkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more substituents selected from: G- G alkyloxy, G-G alkoxycarbonyl, G-G alkyl, G-G alkylamino, amino, amino-G-G alkyl, amino-aryl, amino-C3-C7 cycloalkyl, amino-heteroaryl, amino-heterocyclyl, aryl, carboxamide, carboxyl, G-G cycloalkyl, cyano, G-G haloacyl, G-G haloalkyl, G-G haloalkoxy, halo, hydroxyl, nitro, thio, and thio-G-G alkyl;
  • R 7 is selected from: H, aryl, G-G cycloalkyl, and heteroaryl, each of which is optionally substituted with one or more substituents selected from: G-G acylthio, G-G alkenyl, G-G alkyl, G-G alkylamino, G-G alkyloxy, amino, amino-G-G alkyl, halo, G-G haloalkyl, hydroxyl, hydroxy-G-G alkyl, and thio, wherein G-G alkenyl, G-G alkylamino and G-G alkyloxy are further optionally substituted with one substituent selected from G-G alkylaryl, hydroxyl, and thio;
  • R 8 is selected from: aryl, heteroaryl, and G-G cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl;
  • R 9 and R 10 are each independently selected from: H, G-G alkyl, aryl, aryl-G-G alkyl, C3-C7 cycloalkyl-G-G alkyl, and hydroxy-G-G alkyl;
  • X is selected from C2-C3 alkenyldiyl and G alkyldiyl, wherein G alkyldiyl is substituted with one substituent selected from: G-C6 acyloxy, G-C6 alkyloxy, hydroxyl, oxo, -OC(0)NR 9 R 10 , -OC(S)NR 9 R 10 , -OC(0)OR 9 , and -OC(S)OR 9 ;
  • R 13 is selected from: C3-C6 alkyl and C3-C6-cycloalkyl;
  • Y is heteroaryldiyl, or Y is absent
  • compounds of general Formula I and sub- formulae described above may be generated from a precursor molecule in which one or more functional groups in the compound are protected with an appropriate protecting group.
  • compounds of general Formula I or sub-formulae having a free amino, hydroxyl or carboxyl group may be generated from a precursor molecule in which the amino, hydroxyl or carboxyl group is protected with a standard protecting group, such as those defined above.
  • Such precursor molecules comprising one or more protecting groups may themselves have cyctotoxic activity.
  • certain embodiments of the present disclosure relate to precursors of compounds of general Formula I and sub-formulae that comprise one or more protecting groups. Some embodiments relate to precursors of compounds of general Formula I and sub-formulae in which one or more functional groups are present in protected form. Some embodiments relate to precursors of compounds of general Formula I and sub-formulae in which one or more amino, hydroxyl or carboxyl functional groups are present in protected form.
  • the compounds of general Formula I and sub-formulae may be prepared according to relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions are provided in the Examples section herein. In certain embodiments, the present disclosure relates to methods of making a compound described herein.
  • compounds of general Formula I and sub-formulae used throughout this disclosure are intended to represent all individual enantiomers and mixtures thereof, unless stated or shown otherwise. Certain embodiments of the present disclosure encompass all such enantiomers, diastereoisomers and mixtures thereof, including but not limited to racemates. Certain embodiments relate to compounds of general Formula I and sub-formulae in a substantially pure enantiomeric, diastereomeric or isomeric form.
  • substantially pure is intended to mean that the compound is in a form that is at least 80% optically pure, that is, a form that comprises at least 80% of a single isomer.
  • chiral compounds may be in a form that is at least 85% optically pure, for example, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% optically pure.
  • Certain embodiments of the present disclosure encompass compounds of general Formula I and sub-formulae that are isotopically-labelled (i.e. have one or more atoms replaced by an atom having a different atomic mass or mass number).
  • isotopes that can be incorporated into the compounds described herein in some embodiments include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I, and 125 I.
  • radiolabeled compounds may be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action.
  • Isotopically-labelled compounds for example, those incorporating a radioactive isotope, may also be useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium ( 3 H) and carbon-14 ( 14 C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium ( 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.
  • Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples provided herein using an appropriate isotopically-labeled reagent in place of the noted non-labeled reagent.
  • the present disclosure encompasses any in vivo metabolic products of the compounds described herein. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, or the like, of the administered compound, primarily due to enzymatic processes. Accordingly, in some embodiments, the present disclosure includes compounds produced by a process comprising administering a compound of general Formula I or a sub-formula described herein to a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Such products are typically identified by administering a radiolabeled version of the compound in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.
  • Compounds of general Formula I may be prepared from known starting materials by standard synthetic chemistry methods. Representative examples of suitable synthetic routes are described in detail in the Examples provided herein. One skilled in the art will recognize that alternative methods may be employed to synthesize compounds of general Formula I, and that the approaches described herein are therefore not intended to be exhaustive, but rather to provide the skilled person with examples of some broadly applicable and practical routes to representative compounds.
  • the compounds of general Formula I and sub-formulae described herein may be used to form conjugates, in which the compound is conjugated, either directly or via a linker, to a targeting moiety.
  • the conjugates may be represented by general Formula II:
  • (T) is a targeting moiety
  • (L) is an optional linker
  • (D) is a monovalent radical of a compound of Formula I.
  • conjugates of the present disclosure may comprise multiple compounds of general Formula I conjugated to the targeting moiety, for example, by attaching the compounds at different sites on the targeting moiety and/or by employing a linker that allows for attachment of multiple compounds to a single site on the targeting moiety.
  • T is the targeting moiety
  • L is an optional linker
  • D is a monovalent radical of a compound of general Formula I
  • m is an integer between 1 and about 10
  • n is an integer between 1 and about 20.
  • m is between about 1 and about 5, or between 1 and 2.
  • m is 1.
  • n is between 1 and 10, for example, between 1 and 8, between 2 and 8, between 2 and 6, or between 2 and 4.
  • L may be absent.
  • L is present.
  • compounds of general Formula I are peptide- based and thus may be considered to have a C-terminus and an N-terminus.
  • a compound of general Formula I may be conjugated to the targeting moiety or linker via a suitably reactive group at either the C- or N-terminus of the molecule. Such a reactive group may already be present in the compound, or the compound may be modified by standard techniques to introduce a suitable reactive group.
  • the compound of general Formula I is conjugated via the C-terminus of the molecule.
  • the compound of general Formula I is conjugated via the N-terminus of the molecule.
  • (T) is an antibody. Accordingly, certain embodiments of the present disclosure relate to antibody-drug conjugates (ADCs) comprising compounds of Formula I (D).
  • the Targeting moiety (T) of the conjugates described herein includes within its scope any unit of a (T) that binds or reactively associates or complexes with a receptor, antigen or other receptive moiety associated with a given target-cell population.
  • (T) acts to deliver the compound of general Formula I (D) to the particular target cell population with which (T) reacts.
  • Such (T) moities include, but are not limited to, large molecular weight proteins such as, for example, full-length antibodies, antibody fragments, smaller molecular weight proteins, polypeptide or peptides, lectins, glycoproteins, non-peptides, vitamins, nutrient-transport molecules (such as, but not limited to, transferrin), and other molecules or substances capable of binding to a target cell.
  • large molecular weight proteins such as, for example, full-length antibodies, antibody fragments, smaller molecular weight proteins, polypeptide or peptides, lectins, glycoproteins, non-peptides, vitamins, nutrient-transport molecules (such as, but not limited to, transferrin), and other molecules or substances capable of binding to a target cell.
  • a (T) may form a bond to a linker unit (L) or the compound (D).
  • a (T) can form a bond to a (L) unit via a heteroatom of the (T).
  • Heteroatoms that may be present on a (T) include sulfur (for example, from a sulfhydryl group of a (T)), oxygen (for example, from a carbonyl, carboxyl or hydroxyl group of a (T)) and nitrogen (for example, from a primary or secondary amino group of a (T)). These heteroatoms may be naturally present on (T), or may be introduced into (T) via chemical modification using techniques known in the art.
  • the conjugate includes a linker (L) and (T) is conjugated to the linker via a sulfhydryl group on (T).
  • a (T) may be selected that has a naturally occurring sulfhydryl group such that (T) bonds to (L) via the sulfur atom of the sulfhydryl group.
  • a (T) may be selected that has one or more lysine residues that can be chemically modified to introduce one or more sulfhydryl groups.
  • Reagents that can be used to modify lysines include, but are not limited to, N-succinimidyl S-acetylthioacetate (SAT A) and 2-iminothiolane hydrochloride (Traut's Reagent).
  • SAT A N-succinimidyl S-acetylthioacetate
  • T 2-iminothiolane hydrochloride
  • a (T) may also be selected that has one or more carbohydrate groups that can be chemically modified to include one or more sulfhydryl groups.
  • a (T) may be selected that has one or more carbohydrate groups that can be oxidized to provide an aldehyde (-CHO) group (see, for example, Laguzza et al, 1989, J. Med. Chem. 32(3):548-55).
  • the corresponding aldehyde can form a bond with a reactive site on a portion of a (L).
  • Reactive sites that can react with a carbonyl group on a (T) include, but are not limited to, hydrazine and hydroxylamine.
  • a surface lysine residue on (T) may be used to link (T) to (L).
  • attachment of (L) to (T) may be achieved by modification of (T) to include additional cysteine residues (see, for example, U.S. Patent Nos. 7,521,541; 8,455,622 and 9,000,130) or non-natural amino acids that provide reactive handles, such as selenomethionine, p- acetylphenylalanine, formylglycine or /j>-azidomethyl-L-phenylalanine (see, for example, Hofer et al, (2009) Biochemistry 48: 12047-12057; Axup et al, (2012) PNAS 109: 16101-16106; Wu et al, (2009) PNAS 106:3000-3005; Zimmerman et al, (2014) Bioconj. Chem. 25:351-361), to allow for site-specific conjugation.
  • additional cysteine residues see, for example, U.S. Patent Nos. 7,521,541; 8,455,622 and 9,000,130
  • non-natural amino acids
  • the (T) included in the conjugate may be a transferrin, an epidermal growth factor ("EGF”), bombesin, gastrin, a gastrin-releasing peptide, a platelet-derived growth factor, IL-2, IL- 6, a transforming growth factor ("TGF,” such as TGF-a or TGF- ⁇ ), a vaccinia growth factor (“VGF”), insulin, insulin-like growth factor I or II, a lectin or apoprotein from low density lipoprotein.
  • EGF epidermal growth factor
  • TGF transforming growth factor
  • VGF vaccinia growth factor
  • Other examples include engineered protein scaffolds such as those described in International Patent Publication Nos. WO 2012/116453 and WO 2014/012082.
  • ligands for cell surface receptors derived from various sources, including those derived from human cells, ligands derived from bacteria, and pathogen derived ligands, such as those described in International Patent Publication No. WO 2013/117705.
  • the (T) for inclusion in the conjugate compositions may be an antibody, such as a polyclonal antibody or monoclonal antibody.
  • the antibody may be directed to a particular antigenic determinant, such as for example, a cancer cell antigen, a viral antigen, a microbial antigen, a protein, a peptide, a carbohydrate, a chemical, nucleic acid, or fragments thereof.
  • a cancer cell antigen such as for example, a cancer cell antigen, a viral antigen, a microbial antigen, a protein, a peptide, a carbohydrate, a chemical, nucleic acid, or fragments thereof.
  • Methods of producing polyclonal antibodies are known in the art.
  • a monoclonal antibody (mAb) to an antigen of interest may also be prepared using various techniques well known in the art.
  • (T) may be a monoclonal antibody.
  • the monoclonal antibody may be, for example, a human monoclonal antibody, a humanized monoclonal antibody, an antibody fragment, or a chimeric antibody (for example, a human-mouse antibody).
  • Human monoclonal antibodies may be made by any of numerous techniques known in the art (see, for example, Teng et al, 1983, Proc. Natl. Acad. Sci.
  • the antibody included in the conjugate may be a bispecific antibody.
  • Methods for making bispecific antibodies are known in the art. For example, traditional production of full-length bispecific antibodies is based on the coexpression of two immunoglobulin heavy chain-light chain pairs, where the two chains have different specificities (see, for example, Milstein et al, 1983, Nature 305:537-539; International Patent Publication No. WO 93/08829, Traunecker et al, 1991, EMBO J. 10:3655-3659).
  • antibody variable domains with the desired binding specificities are fused to immunoglobulin constant domain sequences as described in International Patent Publication No. WO 94/04690.
  • the bispecific antibodies can have a hybrid immunoglobulin heavy chain with a first binding specificity in one arm, and a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) in the other arm.
  • This asymmetric structure facilitates the separation of the desired bispecific compound from unwanted immunoglobulin chain combinations, as the presence of an immunoglobulin light chain in only one half of the bispecific molecule provides for a facile way of separation.
  • bispecific antibodies include those described in International Patent Publication Nos. WO 2012/032080; WO 2012/058768 and WO 2013/063702, and in European Patent Publication No. EP 2 560 993.
  • Bifunctional antibodies are also described in European Patent Publication No. EP 0 105 360.
  • hybrid or bifunctional antibodies can be derived either biologically, i.e., by cell fusion techniques, or chemically, especially with cross-linking agents or disulfide-bridge forming reagents, and may comprise whole antibodies or fragments thereof. Methods for obtaining such hybrid antibodies are described for example, in International Patent Publication No. WO 83/03679, and European Patent Publication No. EP 0 217 577.
  • (T) may be a functionally active fragment, derivative or analog of an antibody that immunospecifically binds to a target antigen (for example, a cancer antigen, a viral antigen, a microbial antigen, or other antibodies bound to cells or matrix).
  • a target antigen for example, a cancer antigen, a viral antigen, a microbial antigen, or other antibodies bound to cells or matrix.
  • “functionally active” means that the fragment, derivative or analog is able to recognize the same antigen as that recognized by the antibody from which the fragment, derivative or analog is derived.
  • the antigenicity of the idiotype of the immunoglobulin molecule can be enhanced by deletion of framework and CDR sequences that are C-terminal to the CDR sequence that specifically recognizes the antigen.
  • synthetic peptides containing the CDR sequences can be used in binding assays with the antigen by any binding assay method known in the art (for example, the BIAcore assay) (see, for example, Kabat et al, 1991, Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md.; Kabat et al, 1980, J. Immunology 125(3):961-969).
  • Other useful antibody fragments include, but not limited to, F(ab')2 fragments, Fab fragments, Fab', Fv fragments and heavy chain and light chain dimers of antibodies, or any minimal fragment thereof such as Fvs or single chain antibodies (SCAs) (for example, as described in U.S. Patent No. 4,946,778; Bird, (1988) Science 242:423-42; Huston et al , (1988) Proc. Natl. Acad. Sci. USA 85 :5879-5883; and Ward et al, (1989) Nature 334:544-54).
  • Fvs or single chain antibodies SCAs
  • Antibodies suitable for inclusion in the conjugate compositions in some embodiments may be heavy chain only antibodies (such as those generated using the Humabody® VH platform from Crescendo Biologies, Cambridge, UK) or camelid-derived antibodies (see, for example, International Patent Publication No. WO 2010/001251).
  • recombinant antibodies such as chimeric or humanized monoclonal antibodies, comprising both human and non-human portions, may be used.
  • Such recombinant antibodies can be made using standard recombinant DNA techniques (see, for example, U.S. Patent Nos. 4,816,567 and 4,816,397).
  • Humanized antibodies are antibody molecules from non-human species having one or more complementarity determining regions (CDRs) from the non-human species and a framework region from a human immunoglobulin molecule (see, for example, U.S. Patent No. 5,585,089).
  • Chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in International Patent Publication Nos. WO 87/02671 and WO 86/01533; European Patent Publication Nos. 012 023; 0 184 187; 0 171 496 and 0 173 494; U.S. Patent Nos.
  • human antibodies may be used.
  • Human antibodies can be prepared, for example, using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which can express human heavy and light chain genes.
  • the transgenic mice are immunized in the normal fashion with a selected antigen and monoclonal antibodies directed against the antigen can be obtained using conventional hybridoma technology.
  • the human immunoglobulin transgenes harbored by the transgenic mice rearrange during B cell differentiation, and subsequently undergo class switching and somatic mutation.
  • Human antibodies that recognize a selected epitope also can be generated using a technique referred to as "guided selection.”
  • a selected non-human monoclonal antibody for example a mouse antibody
  • is used to guide the selection of a completely human antibody recognizing the same epitope see, for example, Jespers et al , (1994) Biotechnology 12:899-903.
  • Other methods of generating human antibodies include the use of phage display libraries (see, for example, Hoogenboom and Winter, (1991) J. Mol. Biol. 227:381; Marks et al, (1991) J. Mol. Biol.
  • (T) may be a fusion protein of an antibody or a functionally active antibody fragment thereof.
  • an antibody or antibody fragment can be fused via a covalent bond (for example, a peptide bond) at either the N-terminus or the C-terminus to an amino acid sequence of another protein (or portion thereof, such as at least a 10, 20 or 50 amino acid portion of the protein) that is not an antibody.
  • Analogs and derivatives of antibodies that may be useful in the conjugate compositions in some embodiments include antibodies modified by additional of further binding motifs (for example, ZybodiesTM, Zygenia, Gaithersburg, MD), and those that have been modified by, for example, one or more of formylation, glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, or linkage to a cellular antibody unit or other protein. Additionally, an analog or derivative may contain one or more unnatural amino acids.
  • Antibodies for use in the conjugate compositions include in some embodiments antibodies having amino acid modifications (for example, substitutions, deletions or additions) in a region that interacts with an Fc receptor (see, for example, International Patent Publication Nos. WO 97/34631 and WO 2013/004842, and European Patent Publication No. EP 2 552 957).
  • Antibodies immunospecific for a target antigen can be obtained commercially or other source or produced by various methods known to one of skill in the art such as, for example, chemical synthesis or recombinant expression techniques.
  • the nucleotide sequence encoding antibodies immunospecific for a cancer cell antigen can be obtained, for example, from the GenBank database or a similar database, scientific publications, or by routine cloning and sequencing.
  • the targeting moiety comprised by the conjugate is an antibody or fragment thereof that binds to a cancer antigen.
  • antibodies that target cancer antigens and which are useful in the treatment of cancer include, but are not limited to, humanized anti-HER2 monoclonal antibody, HERCEPTIN® (trastuzumab; Genentech); RITUXAN® (rituximab; Genentech), a chimeric anti-CD20 monoclonal antibody for the treatment of patients with non-Hodgkin' s lymphoma; OvaRex (AltaRex Corporation, MA), a murine antibody for the treatment of ovarian cancer; Panorex (Glaxo Wellcome, NC), a murine IgG2a antibody for the treatment of colorectal cancer; Cetuximab Erbitux (Imclone Systems Inc., NY), an anti-EGFR IgG chimeric antibody for the treatment of epidermal growth factor positive cancers, such as head
  • BR96 mAb Trail et al , (1993) Science 261 :212-215
  • BR64 Trail et al, (1997) Cancer Research 57: 100-105
  • mAbs against the CD40 antigen such as S2C6 mAb (Francisco et al, (2000) Cancer Res.
  • mAbs against the CD33 antigen mAbs against the EphA2 antigen
  • mAbs against the CD70 antigen such as 1F6 mAb and 2F2 mAb and chimeric and humanized variants thereof
  • mAbs against the CD30 antigen such as AC10 (Bowen et al, (1993) J. Immunol. 151 :5896-5906; Wahl et al, (2002) Cancer Res. 62(13):3736-42) and chimeric and humanized variants thereof.
  • cancer antigens or tumor-associated antigens (TAAs)
  • TAAs tumor-associated antigens
  • Other cancer antigens include, but are not limited to, CA125 (ovarian), CA15-3 (carcinomas), CA19-9 (carcinomas), L6 (carcinomas), Lewis Y (carcinomas), Lewis X (carcinomas), alpha fetoprotein (carcinomas), CA 242 (colorectal), placental alkaline phosphatase (carcinomas), prostate specific membrane antigen (prostate), prostatic acid phosphatase (prostate), epidermal growth factor (carcinomas), MAGE-1 (carcinomas), MAGE-2 (carcinomas), MAGE-3 (carcinomas), MAGE-4 (carcinomas), anti transferrin receptor (carcinomas), p97 (melanoma), MUC1-KLH (breast cancer), CEA (colorectal), gplOO (melanoma), MARTI (melanoma), prostate specific antigen (PSA)
  • the targeting moiety comprised by the conjugate is an antibody or fragment thereof that binds to an antigen associated with an immunological disease.
  • antibodies that target antigens associated with immunological diseases and which are useful in the treatment of autoimmune and rheumatologic diseases include those that target cytokines, B cells or co-stimulation molecules.
  • Anti-cytokine antibodies include, for example, anti-tumor necrosis factor (TNF)-a, anti-interleukin (IL)-l, and anti-IL-6 antibodies.
  • TNF tumor necrosis factor
  • IL interleukin
  • anti-IL-6 antibodies anti-IL-6 antibodies.
  • antibodies which target B cells include, for example, anti-CD20 antibodies, which are useful for B-cell depletion, and anti-B lymphocyte stimulator (BLyS) antibodies, which are useful for B cell receptor (BCR) modulation.
  • Examples of antibodies that target such antigens and are used in the treatment of autoimmune and rheumatologic diseases include, but are not limited to, abatacept (Orencia), a CTLA-4 IgGl fusion that binds to CD80/86; adalimumab (Humira), a human anti-TNF-a antibody; anakinra (Kineret), an anti-IL-1 antibody; belimumab (Benlysta), a human monoclonal anti -BLyS antibody; canakinumab (Ilaris), an anti-IL-1 antibody; certolizumab pegol (Cimzia), a pegylated Fab fragment of a humanized anti-TNF-a monoclonal antibody; efalizumab (Raptiva), a humanized anti-CDl la antibody; epratuzumab, an IgGl monoclonal anti-CD22 antibody; golimumab (Simponi), a fully
  • the conjugate compositions optionally include a linker moiety (L), which is a bifunctional or multifunctional moiety capable of linking one or more compounds of general Formula I to targeting moiety (T).
  • the linker may be bifunctional (or monovalent) such that it links a single compound to a single site on (T).
  • the linker may be multifunctional (or polyvalent) such that it links more than one compound to a single site on (T). Multifunctional linkers may also be used to link one compound to more than one site on (T) in some embodiments.
  • the linkers include a functional group capable of reacting with the target group or groups on (T) and one or more functional groups capable of reacting with a target group on the compound of general Formula I (D).
  • Suitable functional groups are known in the art and include those described, for example, in Bioconjugate Techniques (G.T. Hermanson, 2013, Academic Press).
  • Non-limiting examples of functional groups for reacting with free cysteines or thiols include maleimide, haloacetamide, haloacetyl, activated esters such as succinimide esters, 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates.
  • maleimide haloacetamide
  • haloacetyl activated esters such as succinimide esters, 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates.
  • Non-limiting examples of functional groups for reacting with surface lysines and amines include activated esters such as N-hydroxysuccinamide (NHS) esters or sulfo-NHS esters, imido esters such as Traut's reagent, isothiocyanates, aldehydes and acid anhydrides such as diethylenetriaminepentaacetic anhydride (DTP A).
  • activated esters such as N-hydroxysuccinamide (NHS) esters or sulfo-NHS esters, imido esters such as Traut's reagent, isothiocyanates, aldehydes and acid anhydrides such as diethylenetriaminepentaacetic anhydride (DTP A).
  • Other examples include succinimido-l, l,3,3-tetra-methyluronium tetrafluoroborate (TSTU) and benzotriazol-l-yl-oxytripyrrolidinophosphonium hexaflu
  • Non-limiting examples of functional groups capable of reacting with an electrophilic group on (T) or (D) include hydrazide, oxime, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate and arylhydrazide.
  • a linker that includes a functional group that allows for bridging of two interchain cysteines on the antibody binding construct may be used, such as a ThioBridgeTM linker (Badescu et al, (2014) Bioconjug. Chem.
  • linkers for linking drugs to antibodies and other targeting moieties are known in the art, including hydrazone-, disulfide- and peptide-based linkers.
  • Suitable linkers typically are more chemically stable to conditions outside the cell than to conditions inside the cell, although less stable linkers may be contemplated in certain situations, such as when (D) has a low toxicity to normal cells.
  • Suitable linkers include, for example, cleavable and non-cleavable linkers.
  • a cleavable linker is typically susceptible to cleavage under intracellular conditions, for example, through lysosomal processes. Examples include linkers that are protease-sensitive, acid-sensitive or reduction-sensitive.
  • Non-cleavable linkers by contrast, rely on the degradation of the antibody in the cell, which typically results in the release of an amino acid-linker-cytotoxin moiety.
  • Suitable cleavable linkers include, for example, peptide-containing linkers cleavable by an intracellular protease, such as lysosomal protease or an endosomal protease.
  • the linker may be a dipeptide-containing linker, such as a valine-citrulline (Val-Cit) or a phenylalanine-lysine (Phe-Lys) linker.
  • Suitable dipeptides for inclusion in cleavable linkers include Val-Lys, Ala-Lys, Phe-Lys, Val-Cit, Phe-Cit, Leu-Cit, Ile-Cit, Trp-Cit, Phe-Arg, Ala-Phe, Val-Ala, Met-Lys, Asn-Lys, lie-Pro, Ile-Val, Asp-Val, His-Val, Met-(D)Lys, Asn-(D)Lys, Val-(D)Asp, NorVal-(D)Asp, Ala-(D)Asp, Me 3 Lys-Pro, PhenylGly-(D)Lys, Met- (D)Lys, Asn-(D)Lys, Pro-(D)Lys and Met-(D)Lys.
  • Linkers may also include longer peptide sequences in some embodiments, such as the tripeptides Met-Cit-Val, Gly-Cit-Val, (D)Phe-Phe- Lys or (D)Ala-Phe-Lys, or the tetrapeptides Gly-Phe-Leu-Gly or Ala-Leu-Ala-Leu.
  • Additional suitable cleavable linkers include disulfide-containing linkers.
  • disulfide-containing linkers include, but are not limited to, N-succinimydyl-4-(2-pyridyldithio) butanoate (SPDB) and N-succinimydyl-4-(2-pyridyldithio)-2-sulfo butanoate (sulfo-SPDB).
  • Disulfide-containing linkers may optionally include additional groups to provide steric hindrance adjacent to the disulfide bond in order to improve the extracellular stability of the linker, for example, inclusion of a geminal dimethyl group.
  • linkers include linkers hydrolyzable at a specific pH or within a pH range, such as hydrazone linkers.
  • Linkers comprising combinations of these functionalities may also be useful, for example, linkers comprising both a hydrazone and a disulfide are known in the art.
  • a further example of a cleavable linker is a linker comprising a ⁇ -glucuronide, which is cleavable by ⁇ -glucuronidase, an enzyme present in lysosomes and tumor interstitium (see, for example, De Graaf et al, (2002) Curr. Pharm. Des. 8: 1391-1403).
  • Cleavable linkers may optionally further comprise one or more additional functionalities such as self-immolative and self-elimination groups, stretchers or hydrophilic moieties.
  • Self-immolative and self-elimination groups that find use in linkers include, for example, /j>-aminobenzyloxycarbonyl (PABC) and /j>-aminobenzyl ether (PABE) groups, and methylated ethylene diamine (MED).
  • PABC /j>-aminobenzyloxycarbonyl
  • PABE /j>-aminobenzyl ether
  • MED methylated ethylene diamine
  • Other examples of self-immolative groups include, but are not limited to, aromatic compounds that are electronically similar to the PABC or PABE group such as heterocyclic derivatives, for example 2-aminoimidazol-5 -methanol derivatives as described in U.S. Patent No. 7,375,078.
  • linker may include one or more self-immolative and self- elimination groups, for example, a PABC group, a PABE group, or a combination of a PABC or PABE group and an MED.
  • Stretchers that find use in linkers for drug conjugates include, for example, alkylene groups and stretchers based on aliphatic acids, diacids, amines or diamines, such as diglycolate, malonate, caproate and caproamide.
  • Other stretchers include, for example, glycine based stretchers and polyethylene glycol (PEG) or monomethoxy polyethylene glycol (mPEG) stretchers.
  • PEG and mPEG stretchers also function as hydrophilic moieties and may be particularly useful with hydrophobic drugs
  • the linker included in the conjugate compositions of the present disclosure is a peptide-based linker of general Formula VII:
  • Z is a functional group capable of reacting with the target group on (T);
  • Str is a stretcher
  • AAi and AA2 are each independently an amino acid, wherein AAi-[AA2] m forms a protease cleavage site;
  • X is a self-immolative group
  • D is a monovalent radical of a compound of general Formula I; n is 0 or 1; m is 1, 2 or 3, and o is 0, 1 or 2.
  • R is H or C1-C6 alkyl; p is an integer between 2 and 10, and q is an integer between 1 and 10.
  • R is H or optionally substituted G-C6 alkyl.
  • Examples of substituents when R is substituted Ci -Ce alkyl include various hydrophilic groups, such as hydroxyl or a PEG group.
  • Str is — (CH2) p -C- — (CH 2 CH 2 0) q — C—
  • s tr is — (CH 2 ) p -C- or — (CH 2 CH 2 0) q — (CH2) p -C- 5 wherein p is an integer between 2 and 6, and q is an integer between 2 and 8.
  • AAi-[AA2]m is selected from Val-Lys, Ala-Lys, Phe-Lys, Val-Cit, Phe-Cit, Leu-Cit, Ile- Cit, Trp-Cit, Phe-Arg, Ala-Phe, Val-Ala, Met-Lys, Asn-Lys, lie-Pro, Ile-Val, Asp-Val, His-Val, Met-(D)Lys, Asn-(D)Lys, Val-(D)Asp, NorVal-(D)Asp, Ala-(D)Asp, Me 3 Lys-
  • m is 1 (i.e. AAi-[AA 2 ] m is a dipeptide). [00325] In some embodiments, in general Formula VII:
  • AAi-[AA2]m is a dipeptide selected from Val-Lys, Ala-Lys, Phe-Lys, Val-Cit, Phe-Cit, Leu-Cit, Ile-Cit and Trp-Cit.
  • each X is independently selected from /j>-aminobenzyloxycarbonyl (PABC), p- aminobenzyl ether (PABE) and methylated ethylene diamine (MED).
  • n is 1.
  • o is 1 or 2.
  • o is 0 (i.e. X is absent).
  • the linker is a disulfide-containing linker and the conjugate has general Formula VIII:
  • T is the targeting moiey
  • Y is -(01 ⁇ 4) ⁇ - or -( ⁇ 1 ⁇ 4 ⁇ 1 ⁇ 40) 3 ⁇ 4 -, wherein p and q are each independently an integer between 1 and 10; each R is independently H or G-C6 alkyl; n is 1, 2 or 3, and
  • N C represents an amide bond formed between the linker and the ⁇ -amino group of a surface lysine on (T).
  • Examples of commonly used cleavable linkers that may find use in the conjugate compositions of the present disclosure in some embodiments include, but are not limited to, linkers comprising SPDB, sulfo-SPDB, hydrazone, Val-Cit, maleidocaproyl (MC or mc), mc -Val-Cit, mc- Val-Cit-PABC, Phe-Lys, mc-Phe-Lys or mc-Phe-Lys-PABC.
  • Various non-cleavable linkers are known in the art for linking drugs to targeting moieties and may be useful in the conjugate compsitions of the present disclosure in certain embodiments.
  • non-cleavable linkers include linkers having an N-succinimidyl ester or N- sulfosuccinimidyl ester moiety for reaction with the cell binding agent, as well as a maleimido- or haloacetyl-based moiety for reaction with the drug, or vice versa.
  • An example of such a non- cleavable linker is based on sulfosuccinimidyl-4-[N-maleimidomethyl]cyclohexane-l-carboxylate (sulfo-SMCC).
  • Sulfo-SMCC conjugation typically occurs via a maleimide group which reacts with sulfhydryls (thiols,— SH) on the drug moiety, while the sulfo-NHS ester is reactive toward primary amines (as found in lysine and the protein or peptide N-terminus).
  • linkers include those based on N-succinimidyl 4- (maleimidomethyl)cyclohexanecarboxylate (SMCC), N-succinimidyl-4-(N-maleimidomethyl)- cyclohexane-l-carboxy-(6-amidocaproate) ("long chain" SMCC or LC-SMCC), ⁇ - maleimidoundecanoic acid N-succinimidyl ester (KMUA), ⁇ -maleimidobutyric acid N- succinimidyl ester (GMBS), ⁇ -maleimidocaproic acid N-hydroxysuccinimide ester (EMCS), m- maleimidobenzoyl -N-hydroxysuccinimide ester (MBS), N-(a-maleimidoacetoxy)-succinimide ester (AMAS), succinimidyl-6-(P-maleimidopropionamido)hexano
  • SMCC N
  • haloacetyl-based functional group such as N-succinimidyl-4- (iodoacetyl)-aminobenzoate (SIAB), N-succinimidyl iodoacetate (SIA), N-succinimidyl bromoacetate (SBA) and N-succinimidyl 3-(bromoacetamido)propionate (SBAP).
  • a haloacetyl-based functional group such as N-succinimidyl-4- (iodoacetyl)-aminobenzoate (SIAB), N-succinimidyl iodoacetate (SIA), N-succinimidyl bromoacetate (SBA) and N-succinimidyl 3-(bromoacetamido)propionate (SBAP).
  • non-cleavable linkers include maleimidocarboxylic acids, such as maleimidocaproyl (MC).
  • (T) is conjugated to a compound of general Formula I (D) via a linker (L) that comprises a linker moiety as described in International Patent Publication No. WO 2015/095953. Accordingly, certain embodiments of the present disclosure relate to conjugate compositions of general Formula III:
  • R 6a is selected from: d-Ce alkyldiyl, aryldiyl, C3-C7 cycloalkyldiyl, heteroaryldiyl, and heterocyclyldiyl, each optionally substituted with one or more substituents selected from: G-C6 alkyloxy, G-C6 alkoxycarbonyl, G-C6 alkyl, G-C6 alkylamino, amino, amino-G-C6 alkyl, amino-aryl, amino-C3-C7 cycloalkyl, aryl, carboxamide, carboxyl, C3-C7 cycloalkyl, cyano, G-C6 haloalkyl, G-C6 haloalkoxy, halo, hydroxyl, nitro, thio, and thio-G-C6 alkyl;
  • each AA is independently an amino acid; p is an integer from 0 to 25; (L 2 ) is optionally the remaining portion of linker (L 1 ), and wherein the -NH- group bonded to R 6a in Formula IV forms a peptide bond (JPB) with (AA)i in Formula V, wherein the JPB is enzymatically cleavable, and wherein (AA)i-(AA)n, taken together comprises an amino acid sequence capable of facilitating enyzmatic cleavage of the JPB.
  • linker moieties known in the art, and particularly those known to be useful in the context of drug delivery, may be used in the conjugates described herein.
  • Such linkers include, but are not limited to those described in International Patent Publication Nos. WO 2012/171020; WO 2012/113847; WO 2010/138719; WO 2007/103288; WO 2008/083312; WO 2003/068144; WO 2004/016801; WO 2009/134976; WO 2009/134952; WO 2009/134977; WO 2002/08180; WO 2004/043493; WO 2007/018431; WO 2003/026577; WO 2005/077090; WO 2005/082023; WO 2007/011968; WO 2007/038658; WO 2007/059404; WO 2006/110476; WO 2005/112919, and WO 2008/103693; U.S.
  • (D) is a compound of Formula I as described herein. It will be recognized by a worker skilled in the art that compounds described herein may be appropriately modified to facilitate a conjugation reaction with (L), or if (L) is not present, with (T). The skilled person will also appreciate that, depending on the exact structure of (D), various points of attachment on (D) may be used, for example, the C-terminus, the N-terminus or a side chain of (D) may form the point of attachment.
  • compounds of general Formula I for inclusion in the conjugate compositions have, or can be modified to include, a suitable functional group at the N- or C- terminus for conjugation to the linker or targeting moiety.
  • compounds of general Formula I for inclusion in the conjugate compositions have, or can be modified to include, a suitable functional group at the C-terminus for conjugation to the linker or targeting moiety.
  • suitable functional groups include, but are not limited to, hydroxyls, thiols, amino groups, carboxylic acid groups, acyl halides, halide groups, amides, esters, cyano groups, azide groups, and the like.
  • the conjugate compositions may be prepared by one of several routes known in the art, employing organic chemistry reactions, conditions, and reagents known to those skilled in the art (see, for example, Bioconjugate Techniques (G.T. Hermanson, 2013, Academic Press).
  • conjugation may be achieved by reaction of the targeting moiety (T) with a bivalent linker reagent to form a T-L intermediate via a covalent bond, followed by reaction with an activated (D) moiety; or reaction of (D) with a linker reagent to form a D-L intermediate via a covalent bond, followed by reaction with (T).
  • Such conjugation methods may be employed with a variety of compounds, targeting moieties and linkers to prepare the conjugate compositions described herein.
  • Various prepared linkers and linker components are commercially available or may be prepared using standard synthetic organic chemistry techniques (see, for example, March's Advanced Organic Chemistry (Smith & March, 2006, Sixth Ed., Wiley); Toki et al, (2002) J. Org. Chem. 67: 1866-1872; Frisch et al, (1997) Bioconj. Chem. 7: 180-186; Bioconjugate Techniques (G.T. Hermanson, 2013, Academic Press)).
  • the average number of drugs conjugated to the targeting moiety may be determined by standard techniques such as UV7VIS spectroscopic analysis, ELISA -based techniques, chromatography techniques such as hydrophobic interaction chromatography (HIC), UV-MALDI mass spectrometry (MS) and MALDI-TOF MS.
  • DAR drug- to-antibody ratio
  • chromatography techniques such as hydrophobic interaction chromatography (HIC), UV-MALDI mass spectrometry (MS) and MALDI-TOF MS.
  • distribution of drug-linked forms for example, the fraction of targeting moieties containing zero, one, two, three, etc. drugs
  • the fraction of targeting moieties containing zero, one, two, three, etc. drugs may also optionally be analyzed.
  • the compounds of general Formula I and/or the conjugate compositions may be tested for activity using standard techniques.
  • suitable testing methods are provided in the Examples section.
  • the cytotoxicity of the compounds or conjugates can be assayed in vitro using a suitable cell line, typically a cancer cell line.
  • a suitable cell line typically a cancer cell line.
  • cells of the selected test cell line are grown to an appropriate density and the candidate compound is added. After an appropriate incubation time (for example, about 48 to 72 hours), cell survival is assessed.
  • Methods of determining cell survival are well known in the art and include, but are not limited to, the resazurin reduction test (see Fields & Lancaster (1993) Am. Biotechnol. Lab. 11 :48-50; O'Brien et al, (2000) Eur. J. Biochem. 267:5421-5426 and U.S. Patent No.
  • Cytotoxicity is determined by comparison of cell survival in the treated culture with cell survival in one or more control cultures, for example, untreated cultures and/or cultures pre-treated with a control compound (typically a known therapeutic).
  • a control compound typically a known therapeutic.
  • a variety of cancer cell-lines suitable for testing candidate compounds are known in the art and many are commercially available (for example, from the American Type Culture Collection, Manassas, VA).
  • tumour growth or proliferation in vivo can be determined in an appropriate animal model using standard techniques known in the art (see, for example, Enna, et al, Current Protocols in Pharmacology, J. Wiley & Sons, Inc., New York, NY).
  • current animal models for screening anti -tumour compounds are xenograft models, in which a human tumour has been implanted into an animal.
  • xenograft models of human cancer include, but are not limited to, human solid tumour xenografts, implanted by sub-cutaneous injection or implantation and used in tumour growth assays; human solid tumour isografts, implanted by fat pad injection and used in tumour growth assays; human solid tumour orthotopic xenografts, implanted directly into the relevant tissue and used in tumour growth assays; experimental models of lymphoma and leukaemia in mice, used in survival assays, and experimental models of lung metastasis in mice.
  • the compounds or conjugates can be tested in vivo on solid tumors using mice that are subcutaneously grafted bilaterally with 30 to 60 mg of a tumor fragment, or implanted with an appropriate number of cancer cells, on day 0.
  • the animals bearing tumors are mixed before being subjected to the various treatments and controls.
  • tumors are allowed to develop to the desired size, animals having insufficiently developed tumors being eliminated.
  • the selected animals are distributed at random to undergo the treatments and controls. Animals not bearing tumors may also be subjected to the same treatments as the tumor- bearing animals in order to be able to dissociate the toxic effect from the specific effect on the tumor.
  • Chemotherapy generally begins from 3 to 22 days after grafting, depending on the type of tumor, and the animals are observed every day.
  • Test articles can be administered to the animals, for example, by i.p. injection or bolus infusion.
  • the different animal groups are weighed about 3 or 4 times a week until the maximum weight loss is attained, after which the groups are weighed at least once a week until the end of the trial.
  • Tumors can be measured after a pre-determined time period, or monitored continuously by measuring about 2 or 3 times a week until the tumor reaches a predetermined size and/or weight, or until the animal dies if this occurs before the tumor reaches the pre-determined size/weight.
  • the animals are then sacrificed and the tissue histology, size and/or proliferation of the tumor assessed.
  • the animals are grafted with a particular number of cells, and the anti-tumor activity is determined by the increase in the survival time of the treated mice relative to the controls.
  • tumor cells are typically treated with the compound/conjugate ex vivo and then injected into a suitable test animal. The spread of the tumor cells from the site of injection is then monitored over a suitable period of time.
  • In vivo toxic effects of the compounds/conjugates can be evaluated by measuring their effect on animal body weight during treatment and by performing haematological profiles and liver enzyme analysis after the animal has been sacrificed.
  • the compounds or conjugates of the present disclosure are typically formulated as pharmaceutical compositions.
  • Certain embodiments of the present disclosure thus relate to pharmaceutical compositions comprising a compound or conjugate described herein and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compound or conjugate is typically present in the composition in an amount which is effective to treat the particular disease or condition of interest with acceptable toxicity to the patient.
  • the activity of compounds described herein can be determined by one skilled in the art using standard techniques, for example, as described in the Examples below.
  • the compounds or conjugates described herein in an appropriate pharmaceutical composition may be administered via various accepted modes of administration for the disease to be ttreated.
  • the pharmaceutical compositions may, for example, be formulated in solid, semi solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the pharmaceutical compositions are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • Compositions that will be administered to a patient may take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container comprising the pharmaceutical composition in aerosol form may hold a plurality of dosage units.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy (22nd ed.) eds. Loyd V. Allen, Jr., et al, Pharmaceutical Press, 2012.
  • compositions to be administered will, in any event, contain a therapeutically effective amount of a compound or conjugate described herein, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest.
  • a pharmaceutical composition described herein may be in the form of a solid or liquid.
  • the carrier(s) may be particulate, so that the compositions are, for example, in tablet or powder form, or the carrier(s) may be liquid, with the compositions being, for example, an oral syrup, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration.
  • the pharmaceutical compositions When intended for oral administration, typically are either solid or liquid form, including semi solid, semi liquid, suspension and gel forms.
  • the pharmaceutical compositions may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form.
  • a solid composition will typically contain one or more inert diluents or edible carriers.
  • binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch, and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.
  • excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch, and the like
  • lubricants such as magnesium stearate or Sterotex
  • glidants such as colloidal silicon dioxide
  • sweetening agents such as sucrose or saccharin
  • a flavoring agent such as peppermint,
  • the pharmaceutical composition when in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.
  • a liquid carrier such as polyethylene glycol or oil.
  • the pharmaceutical compositions may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension.
  • the liquid may be, for example, for oral administration or for delivery by injection.
  • the pharmaceutical compositions typically contain, in addition to the active compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
  • a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
  • Liquid pharmaceutical compositions may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution (such as physiological saline), Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • Parenteral preparations can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • An injectable pharmaceutical composition is preferably sterile.
  • compositions may be formulated for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base.
  • the base for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
  • Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device.
  • compositions may be formulated for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drug.
  • Compositions for rectal administration may contain an oleaginous base as a suitable nonirritating excipient.
  • bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.
  • compositions may include various materials, which modify the physical form of a solid or liquid dosage unit.
  • the composition may include materials that form a coating shell around the active ingredients.
  • the materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.
  • the active ingredients may be encased in a gelatin capsule.
  • compositions may be prepared in dosage units that can be administered as an aerosol.
  • aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of compounds described herein may be delivered in single phase, bi phasic, or tri phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. [00362] The pharmaceutical compositions described herein may be prepared by methodology well known in the pharmaceutical art.
  • a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound described herein with sterile, distilled water so as to form a solution.
  • a surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are compounds that non covalently interact with the compound described herein so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.
  • the compounds and conjugates described herein are administered in a therapeutically effective amount, which one skilled in the art will appreciate will vary depending upon a variety of factors understood such as the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; any drug combination and/or the severity of the particular disorder or condition. Appropriate dosages and concentrations of the compounds or conjugates can be readily determined by one skilled into the art taking into account factors such as those outlined above.
  • compounds and conjugates as described herein may be administered as part of a combination therapy.
  • a pharmaceutical composition comprising a compound or conjugate may also be administered simultaneously with, prior to, or after administration of one or more other therapeutic agents.
  • Such combination therapy includes administration of a single pharmaceutical dosage formulation which contains the compound or conjugate and one or more additional active agents, as well as administration of the compound or conjugate and each active agent in its own separate pharmaceutical dosage formulation.
  • the formulation comprising the compound or conjugate and the formulation comprising the additional active agent(s) may be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially.
  • Certain embodiments of the present disclosure relate to the use of the compounds and conjugates described herein as cytotoxic agents. Accordingly, in certain embodiments, the compounds and conjugates may be used to inhibit proliferation of a target cell population, such as a cancer cell population, either in vitro or in vivo. [00366] Certain embodiments of the present disclosure relate to the use of the compounds and conjugates described herein in therapy. Some embodiments relate to methods of using a compound or conjugate described herein in the treatment of a disease or disorder.
  • the compounds and conjugates may be indicated for use to treat various diseases where exertion of a cytotoxic or cytostatic effect on a target cell is desirable.
  • diseases that may be treated in some embodiments include benign and malignant tumors; leukemia and lymphoid malignancies; neuronal, glial, astrocytal, hypothalamic and other glandular, macrophagal, epithelial, stromal and blastocoelic disorders; autoimmune disease; inflammatory disease; fibrosis, and infectious disease.
  • Certain embodiments of the present disclosure relate to methods of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound or conjugate described herein.
  • a therapeutically effective amount of compound or conjugate in respect of cancer treatment may exert one or more of the following effects: reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and potentially stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and potentially stop) tumor metastasis; inhibit, to some extent, tumor growth; increase survival time; and/or relieve to some extent one or more of the symptoms associated with the cancer.
  • the compound may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic.
  • efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR).
  • Certain embodiments relate to the use of a compound or conjugate as described herein in a method of inhibiting tumor growth in a subject. Some embodiments relate to the use of a compound or conjugate as described herein in a method of killing cancer cells in vitro. Some embodiments relate to the use of a compound or conjugate as described herein in a method of killing cancer cells in vivo in a subject having a cancer. Some embodiments relate to the use of a compound or conjugate as described herein in a method of increasing the survival time of a subject having cancer, comprising administering to the subject a therapeutically effective amount of the compound or conjugate.
  • cancers which may be may be treated or stabilized in certain embodiments include hematologic neoplasms, including leukemias, myelomas and lymphomas; carcinomas, including adenocarcinomas and squamous cell carcinomas; melanomas and sarcomas.
  • Carcinomas and sarcomas are also frequently referred to as "solid tumors," examples of commonly occurring solid tumors include, but are not limited to, cancer of the bladder, brain, breast, cervix, colon, endometrium, head and neck, kidney, lung, ovary, pancreas, prostate, salivary gland, stomach or uterus, non-small cell lung cancer and colorectal cancer.
  • Various forms of lymphoma also may result in the formation of a solid tumor and, therefore, are also often considered to be solid tumors.
  • Solid tumors include, but are not limited to, sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer (for example, gastrointestinal cancer), oral cancer, nasal cancer, throat cancer, squamous cell carcinoma (for example, of the lung), basal cell carcinoma, adenocarcinom
  • sweat gland carcinoma sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung carcinoma, bladder carcinoma, lung cancer, non-small cell lung cancer, epithelial carcinoma, glioma, glioblastoma, multiforme astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, and retinoblastoma.
  • Blood-borne cancers include, but are not limited to, acute lymphoblastic leukemia "ALL”, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia "AML”, acute promyelocyte leukemia "APL”, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia "CML”, chronic lymphocytic leukemia "CLL”, hairy cell leukemia, and multiple myeloma.
  • ALL acute lymphoblastic leukemia
  • ALL acute lymphoblastic B-cell leukemia
  • acute lymphoblastic T-cell leukemia acute myeloblastic leukemia
  • AML acute promyelocyte leukemia
  • APL acute monoblastic leukemia
  • Lymphomas include, but are not limited to, Hodgkin disease, non- Hodgkin lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, and polycythemia vera.
  • Certain embodiments relate to the use of a compound or conjugate as described herein in methods for treating or preventing cancer in combination with an additional method of treatment.
  • the additional method of treatment may be, for example, treatment with chemotherapeutic or other anti -cancer agent(s), radiation or surgery.
  • chemotherapeutic agents commonly used alone or in combination in the treatment of cancers include, but are not limited to, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, treosulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; TLK 286 (TELCYTATM); acetogenins (especially bullatacin and bullatacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betul
  • anthracyclines such as annamycin, AD 32, alcarubicin, daunorubicin, dexrazoxane, DX-52-1, epirubicin, GPX-100, idarubicin, KRN5500, menogaril, dynemicin, including dynemicin A, an esperamicin, neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins (for example, A2 and B2), cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, detorubicin, 6-diazo-5-oxo-L-norle
  • TAXOL® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANETM Cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine; platinum; platinum analogs or platinum-based analogs such as cisplatin, oxaliplatin and carboplatin; vinblastine (VELBAN®); etoposide (VP-16); ifosfamide; mitoxantrone; vincristine (ONCOVIN®); vinca alkaloid; vinorelbine (NAVELBINE®); velcade; revlimid; thalidomide; IMiD3; lovastatin;
  • anti-cancer agents include anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti -estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX® tamoxifen), raloxifene, megastrol, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and FARESTON® toremifene; aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® megestrol acetate, AROMASIN® exemestane, formestanie, fadrozole, RTVISOR® vorozole, FEMARA® letrozole, and ARIMIDEX® anastrozole; and anti-hormonal agents that act to regulate
  • Certain embodiments relate to the use of a compound or conjugate described herein in a method of treating an immunological disease.
  • Immunological diseases are characterized by inappropriate activation of immune cells and can be classified, for example, by the type(s) of hypersensitivity reaction(s) that underlie the disorder. These reactions are typically classified into four types: anaphylactic reactions, cytotoxic (cytolytic) reactions, immune complex reactions, or cell-mediated immunity (CMI) reactions (also referred to as delayed-type hypersensitivity (DTH) reactions).
  • CMI cell-mediated immunity
  • DTH delayed-type hypersensitivity
  • immunological diseases include the following: rheumatoid arthritis, autoimmune demyelinative diseases (for example, multiple sclerosis, allergic encephalomyelitis), endocrine ophthalmopathy, uveoretinitis, systemic lupus erythematosus, myasthenia gravis, Grave's disease, glomerulonephritis, autoimmune hepatological disorder, inflammatory bowel disease (e.g.
  • the immunological disease may be a disorder of B lymphocytes (for example, systemic lupus erythematosus, Goodpasture's syndrome, rheumatoid arthritis, and type I diabetes), Thl -lymphocytes (for example, rheumatoid arthritis, multiple sclerosis, psoriasis, Sjorgren's syndrome, Hashimoto's thyroiditis, Grave's disease, primary biliary cirrhosis, Wegener's granulomatosis, tuberculosis, or acute graft versus host disease), or Th2 -lymphocytes (for example, atopic dermatitis, systemic lupus erythematosus, atopic asthma, rhinoconjunctivitis, allergic rhinitis, Omenn's syndrome, systemic sclerosis, or chronic graft versus host disease).
  • B lymphocytes for example, systemic lupus erythematosus, Goodpasture
  • the immunological disease may be T cell-mediated, which may include activated T cells.
  • Fibrosis can occur in many tissues within the body, typically as a result of inflammation or damage, examples include but are not limited to; lungs (for example, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis), liver (for example, cirrhosis), and heart (for example, endomyocardial fibrosis, old myocardial infarction, atrial fibrosis).
  • lungs for example, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis
  • liver for example, cirrhosis
  • heart for example, endomyocardial fibrosis, old myocardial infarction, atrial fibrosis.
  • fibrosis disorders include mediastinal fibrosis (soft tissue of the mediastinum), myelofibrosis (bone marrow), retroperitoneal fibrosis (soft tissue of the retroperitoneum), progressive massive fibrosis (lungs), nephrogenic systemic fibrosis (skin), Crohn's disease (intestine), keloid (skin), scleroderma/systemic sclerosis (skin, lungs), arthrofibrosis (knee, shoulder, other joints), Peyronie's disease (penis), Dupuytren's contracture (hands, fingers) and some forms of adhesive capsulitis (shoulder).
  • Certain embodiments relate to the use of a compound or conjugate described herein in a method of treating an infectious disease.
  • the compound or conjugate may be used directly on certain infectious agents or pathogens, or may be used to exert a cytostatic or cytotoxic effect on a host cell that harbors or otherwise provides for the infectious agent or pathogen.
  • the following Examples illustrate various methods of making compounds described herein, i.e., compounds of Formula I and related formulae. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art.
  • starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described herein.
  • EXAMPLE 1 SYNTHESIS OF COMPOUNDS OF GENERAL FORMULA I
  • An example of a synthetic protocol that may be used to prepare certain compounds of general Formula I is provided as Scheme 1 in FIG. 1 and described in the following Example.
  • Example 1.1 Methyl 2-formylthiazole-4-carboxylate (Compound 1). [00391] Compound 1 was synthesized according to the procedures described for the ethyl ester analog in U.S. Patent No. 8,476,451 in comparable yield. 3 ⁇ 4 NMR (400 MHz, DMSO) ⁇ 9.99 (s, 1H), 8.99 (s, 1H), 3.90 (s, 3H).
  • Example 1.4 Methyl 2-((LR,3i?)-3-((S)-l,l-Dimethylethylsulfinamido)-l-hydroxy-4- methylpentyl)thiazole-4-carboxylate (Compound 4).
  • Example 1.11 2-((lR,3R)-3-((2S,3S)-7V,3-Dimethyl-2-((i?)-l-methylpiperidine-2- carboxamido)pentanamido)-l-hydroxy-4-methylpentyl)- J V-(4-(2,2,2- trifluoroacetamido)phenylsulfonyl)thiazole-4-carboxamide (Compound 12).
  • Example 1.14 (S,£)-4-((2S,3S)-7V,3-Dimethyl-2-((S)-3-methyl-2-(methylamino)-3- phenylbutanamido)pentanamido)-2,5-dimethylhex-2-enoic Acid (Compound 17).
  • Example 1.16 (i?)-N-((2S,3S)-l-(((S ⁇ )-2,5-Dimethyl-6-oxo-6-(4-(2,2,2- trifluoroacetamido)phenylsulfonamido)hex-4-en-3-yl)(methyl)amino)-3-methyl-l-oxopentan- 2-yl)-l-isopropylpiperidine-2-carboxamide (Compound 24).
  • DIPEA (4.0 eq) was added to a stirring mixture of (i?)-l-methylpiperidine-2-carboxylic acid (1.5 eq) and HATU (2.0 eq) in DMF. The yellow solution was stirred at ambient temperature for 5-10 minutes. The resulting activated acid was added to a stirring mixture of an appropriate amine (1.0 eq) in DMF. After stirring for 30 minutes at ambient temperature, the mixture was purified by silica gel column chromatography with 100% EtOAc, followed by 2-20% MeOH/GrbC to afford the desired amide as a white solid.
  • Acetic anhydride 35 eq was added dropwise to a cold (0°C) stirring solution of an appropriate secondary alcohol (1.0 eq) in pyridine (0.1 M). The resulting mixture was stirred at ambient temperature for 17 h, concentrated in vacuo and co-evaporated with PhMe (3x). The oily residue was purified by silica gel column chromatography with 100% EtOAc, follow by 5-20% MeOH/CEbC to afford the desired acetate as an off-white solid.
  • EXAMPLES 2.1 TO 2.5 describe the preparation of certain compounds of general Formula I and drug-linkers comprising these compounds.
  • the synthetic scheme is provided as Scheme 2 in FIG. 2 and employs the following general intermediates.
  • Trifluoroacetic anhydride (0.45 mL, 3.24 mmol) was added to a stirring suspension of (3- aminophenyl)methanesulfonamide (0.5 g, 2.56 mmol) in 1,4-dioxane (5 mL). The resulting tan- coloured suspension was stirred at ambient temperature for 22 h. The mixture filtered and washed with CH2CI2 to afford the desired product as a white solid in 98% (0.7 g) yield.
  • Compound 30 2-((li?,3i?)-3-((2S,3S)-N,3-Dimethyl-2-((i?)-l-methylpiperidine-2- carboxamido)pentanamido)-l-ethoxy-4-methylpentyl)- ⁇ -((2i?,4S)-5-((4-((14S,17S)-l-(2,5- dioxo-2,5-dihydro-lH-pyrrol-l-yl)-14-isopropyl-12,15-dioxo-17-(3-ureidopropyl)-3,6,9-trioxa-
  • EXAMPLES 2.6 TO 2.9 describe the preparation of certain compounds of general Formula I and drug-linkers comprising these compounds.
  • the synthetic scheme is provided as Scheme 3 in FIG. 3.
  • EXAMPLES 2.10 AND 2.11 describe the preparation of certain compounds of general Formula I and drug-linkers comprising these compounds.
  • the synthetic scheme is provided as Scheme 4 in FIG. 4 and employs the following general intermediates.
  • EXAMPLE 2.12 describes the preparation of a compound of general Formula I and a drug-linker comprising the compound. The synthetic scheme for these compounds is provided as Scheme 5 in FIG. 5.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule générale (I) ayant une activité cytotoxique et/ou antimitotique et des procédés d'utilisation desdits composés, ainsi que des compositions pharmaceutiques comprenant lesdits composés. Les composés peuvent également être conjugués avec une fraction de ciblage, telle qu'un anticorps. De telles compositions de conjugués peuvent être utilisées dans le traitement du cancer et d'autres maladies. (I)
PCT/CA2016/051135 2015-09-29 2016-09-29 Composés cytotoxiques et antimitotiques et leurs procédés d'utilisation WO2017054080A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562234452P 2015-09-29 2015-09-29
US62/234,452 2015-09-29

Publications (1)

Publication Number Publication Date
WO2017054080A1 true WO2017054080A1 (fr) 2017-04-06

Family

ID=58422528

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2016/051135 WO2017054080A1 (fr) 2015-09-29 2016-09-29 Composés cytotoxiques et antimitotiques et leurs procédés d'utilisation

Country Status (1)

Country Link
WO (1) WO2017054080A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10517958B2 (en) 2016-10-04 2019-12-31 Zymeworks Inc. Compositions and methods for the treatment of platinum-drug resistant cancer
CN111647040A (zh) * 2020-05-11 2020-09-11 深圳市老年医学研究所 一种天然活性多肽Tubulysin U的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013173393A1 (fr) * 2012-05-15 2013-11-21 Concortis Biosystems, Corp Conjugués médicamenteux, procédés de conjugaison et utilisations de ceux-ci

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013173393A1 (fr) * 2012-05-15 2013-11-21 Concortis Biosystems, Corp Conjugués médicamenteux, procédés de conjugaison et utilisations de ceux-ci

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10517958B2 (en) 2016-10-04 2019-12-31 Zymeworks Inc. Compositions and methods for the treatment of platinum-drug resistant cancer
CN111647040A (zh) * 2020-05-11 2020-09-11 深圳市老年医学研究所 一种天然活性多肽Tubulysin U的制备方法
CN111647040B (zh) * 2020-05-11 2022-02-22 深圳市老年医学研究所 一种天然活性多肽Tubulysin U的制备方法

Similar Documents

Publication Publication Date Title
US20230265173A1 (en) Sulfonamide-containing linkage systems for drug conjugates
US20190269785A1 (en) Cytotoxic and anti-mitotic compounds, and methods of using the same
AU2020230264C1 (en) Cytotoxic and anti-mitotic compounds, and methods of using the same
WO2017054080A1 (fr) Composés cytotoxiques et antimitotiques et leurs procédés d'utilisation
BR112015023415B1 (pt) Compostos citotóxicos e anti-mitóticos, composição, composição farmacêutica e uso dos mesmos

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16849982

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16849982

Country of ref document: EP

Kind code of ref document: A1