WO2022155172A1 - Conjugués peptidiques d'agents thérapeutiques - Google Patents

Conjugués peptidiques d'agents thérapeutiques Download PDF

Info

Publication number
WO2022155172A1
WO2022155172A1 PCT/US2022/012079 US2022012079W WO2022155172A1 WO 2022155172 A1 WO2022155172 A1 WO 2022155172A1 US 2022012079 W US2022012079 W US 2022012079W WO 2022155172 A1 WO2022155172 A1 WO 2022155172A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
cancer
acceptable salt
pharmaceutically acceptable
mmol
Prior art date
Application number
PCT/US2022/012079
Other languages
English (en)
Inventor
Robert John Maguire
Johanna Marie CSENGERY
Original Assignee
Cybrexa 3, 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 Cybrexa 3, Inc. filed Critical Cybrexa 3, Inc.
Publication of WO2022155172A1 publication Critical patent/WO2022155172A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to conjugates of therapeutic molecules (e.g., cytotoxic agents) and targeting moieties (e.g., peptides), which are useful in the treatment of diseases such as cancer.
  • therapeutic molecules e.g., cytotoxic agents
  • targeting moieties e.g., peptides
  • Cancer is a group of diseases characterized by aberrant control of cell growth. The annual incidence of cancer is estimated to be in excess of 1.6 million in the United States alone. While surgery, radiation, chemotherapy, and hormones are used to treat cancer, it remains the second leading cause of death in the U.S., and additional strategies of treatment are needed. Drug conjugates have emerged as a viable and continuously explored approach to target malignant tumors.
  • Drug conjugates comprised of a drug (e.g., a cytotoxic agent) linked to a targeting moiety (e.g., a peptide, protein, or antibody) have been developed for use in tumor targeted therapy.
  • Drug conjugates can provide for the preferential delivery of drug to diseased tissue, reducing undesired side effects such as damage to non-cancerous tissue. See, for example, Vrettos, V., “On the design principles of peptide—drug conjugates for targeted drug delivery to the malignant tumor site,” Beilstein J. Org.
  • linkers groups which join the drug to the targeting moiety, has emerged as an important aspect in the design of new drug conjugates.
  • Some linkers may rely on the local physiological environment to release the drug component of the conjugate (e.g., a high glutathione concentration can lead to cleavage of a disulfide linker).
  • some linkers are more stable to these physiological conditions, providing higher stability of the conjugate in plasma.
  • certain linkers with higher plasma stability provide conjugates that exhibit reduced off-target toxicity compared to analogous, more cleavable linker conjugates. See Lu, J., “Linkers Having a Crucial Role in Antibody- Drug Conjugates,” Int.
  • the present disclosure provides, inter alia, a compound of Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein constituent variables are defined herein.
  • the present disclosure further provides a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • the present disclosure also provides methods of treating a disease or condition (e.g., cancer) by administering to a human or other mammal in need of such treatment a therapeutically effective amount of a compound of the disclosure.
  • FIG.1A shows a plot of efficacy (in terms of mean tumor volume) of nude mice bearing HCT116 colorectal carcinoma flank tumors after the indicated intraperitoneal doses of Compound 2 dosed for four total doses.
  • FIG.1B shows a plot of the percent change in body weight of nude mice bearing HCT116 colorectal carcinoma flank tumors after the indicated intraperitoneal doses of Compound 2 dosed for four total doses.
  • FIG.2A shows a plot of efficacy (in terms of mean tumor volume) of nude mice bearing HCT116 colorectal carcinoma flank tumors after the indicated intraperitoneal doses of Compound 11 dosed for four total doses.
  • FIG.2B shows a plot of the percent change in body weight of nude mice bearing HCT116 colorectal carcinoma flank tumors after the indicated intraperitoneal doses of Compound 11 dosed for four total doses.
  • FIG.3A shows a plot of efficacy (in terms of mean tumor volume) of nude mice bearing MKN45 gastric cancer tumors after the indicated intraperitoneal doses of Compound 1 dosed for four total doses.
  • FIG.3B shows a plot of the percent change in body weight of nude mice bearing MKN45 gastric cancer tumors after the indicated intraperitoneal doses of Compound 1 dosed for four total doses.
  • R 1 is a peptide
  • R 2 is a therapeutic moiety
  • L is selected from -(CH 2 ) p1 -Cy 1 -(CH 2 ) p2 - and -X-Y-Z-
  • Cy 1 is selected from C6-10 aryl and 5-10 membered heteroaryl, wherein the C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1
  • L is -(CH2)p1-Cy 1 -(CH2)p2-.
  • Cy 1 is C 6-10 aryl optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 .
  • Cy 1 is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 .
  • Cy 1 is phenyl.
  • R z is H.
  • o is 0.
  • o is an integer from 1 to 4.
  • o is 1.
  • L is selected from the following: , O , d . ents, L has the following structure: , n.
  • peptide refers to a targeting moiety comprising a 10-50 amino acid sequence, made up of naturally-occurring amino acid residues and optionally one or more non-naturally-occurring amino acids.
  • the peptide of R 1 is a peptide of 20 to 40 amino acid residues, 20 to 30 amino acid residues, or 30 to 40 amino acid residues.
  • the peptide is capped.
  • the peptide may include an N- terminal cap at the amino terminus such as an N-terminal acetyl group.
  • the peptide is capped at the carboxy terminus, for example, the carboxylic acid group can be converted to a carboxy ester or amide group.
  • the peptide may contain amino acids in which one or more amino acid side chains includes a protecting group.
  • the targeting moiety is a conformationally restricted peptide.
  • a conformationally restricted peptide can include, for example, macrocyclic peptides and stapled peptides.
  • a stapled peptide is a peptide constrained by a covalent linkage between two amino acid side-chains, forming a peptide macrocycle.
  • Conformationally restricted peptides are described, for example, in Guerlavais et al., Annual Reports in Medicinal Chemistry 2014, 49, 331-345; Chang et al., Proceedings of the National Academy of Sciences of the United States of America (2013), 110(36), E3445-E3454; Tesauro et al., Molecules 2019, 24, 351-377; Dougherty et al., Journal of Medicinal Chemistry (2019), 62(22), 10098-10107; and Dougherty et al., Chemical Reviews (2019), 119(17), 10241- 10287, each of which is incorporated herein by reference in its entirety.
  • the targeting moiety is an environmentally sensitive peptide described, for example, in U.S. Pat. Nos.8,076,451 and 9,289,508 and U.S. Pat. Pub. No. 2019/209580 (each of which are incorporated herein by reference in their entirety), although other peptides capable of such selective insertion could be used.
  • Other suitable peptides are described, for example, in Weerakkody, et al., PNAS 110 (15), 5834-5839 (April 9, 2013), which is also incorporated herein by reference in its entirety. Without being bound by theory, it is believed that the environmentally sensitive peptide undergoes a conformational change and inserts across cell membranes in response to physiological changes (e.g., pH).
  • R 1 is a peptide capable of selectively delivering R 2 L- across a cell membrane having an acidic or hypoxic mantle.
  • the peptide is capable of selectively delivering molecules across a cell membrane having an acidic or hypoxic mantle having a pH less than about 6.0.
  • the peptide is capable of selectively delivering a molecule across a cell membrane having an acidic or hypoxic mantle having a pH less than about 6.5.
  • the peptide is capable of selectively delivering a molecule across a cell membrane having an acidic or hypoxic mantle having a pH less than about 5.5. In some embodiments, the peptide is capable of selectively delivering a molecule across a cell membrane having an acidic or hypoxic mantle having a pH between about 5.0 and about 6.0.
  • the term acidic and/or hypoxic mantle refers to the environment of the cell in the diseased tissue in question having a pH lower than 7.0 and preferably lower than 6.5. An acidic or hypoxic mantle more preferably has a pH of about 5.5 and most preferably has a pH of about 5.0.
  • the compounds of formula (I) insert across a cell membrane having an acidic and/or hypoxic mantle in a pH dependent fashion to insert R 2 - into the cell. Since the compounds of formula (I) are pH-dependent, they preferentially insert across a cell membrane only in the presence of an acidic or hypoxic mantle surrounding the cell and not across the cell membrane of “normal” cells, which do not have an acidic or hypoxic mantle.
  • An example of a cell having an acidic or hypoxic mantle is a cancer cell.
  • pH-sensitive or “pH-dependent” as used herein to refer to the peptide R 1 or to the mode of insertion of the peptide R 1 or of the compounds of the invention across a cell membrane, means that the peptide has a higher affinity to a cell membrane lipid bilayer having an acidic or hypoxic mantle than a membrane lipid bilayer at neutral pH.
  • the compounds of the invention preferentially insert through the cell membrane to insert R 2 - to the interior of the cell (and thus deliver R 2 H as described above) when the cell membrane lipid bilayer has an acidic or hypoxic mantle (a “diseased” cell) but does not insert through a cell membrane when the mantle (the environment of the cell membrane lipid bilayer) is not acidic or hypoxic (a “normal” cell). It is believed that this preferential insertion is achieved as a result of the peptide R 1 forming a helical configuration, which facilitates membrane insertion.
  • the environmentally sensitive peptide comprises at least one of the following sequences: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO.1; Pv1), AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO.2; Pv2); ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO.3; Pv3); Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG (SEQ ID NO. 4; Pv4); and AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC (SEQ ID No.5; Pv5).
  • the environmentally sensitive peptide comprises at least one of the following sequences: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO.1; Pv1), AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO. 2; Pv2), and ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO.3; Pv3).
  • the environmentally sensitive peptide comprises the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO.1; Pv1).
  • the environmentally sensitive peptide comprises the sequence AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO.2; Pv2). In some embodiments, the environmentally sensitive peptide comprises the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO.3; Pv3). In some embodiments, the environmentally sensitive peptide comprises the sequence Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG (SEQ ID NO.4; Pv4). In some embodiments, the environmentally sensitive peptide comprises the sequence AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC (SEQ ID NO.5; Pv5).
  • the environmentally sensitive peptide consists essentially of the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO.1; Pv1). In some embodiments, the environmentally sensitive peptide consists essentially of the sequence AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO.2; Pv2). In some embodiments, the environmentally sensitive peptide consists essentially of the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO.3; Pv3). In some embodiments, the environmentally sensitive peptide consists essentially of the sequence AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG (SEQ ID NO. 4; Pv4).
  • the environmentally sensitive peptide consists essentially of the sequence AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC (SEQ ID NO.5; Pv5). Additional environmentally sensitive peptides are disclosed in in U.S. Patent Publication No. US 2019/209580, U.S. Patent Application No.16/925,094, U.S. Patent Application No.16/924,445, and WO 2020/160009 each of which is incorporated herein in its entirety.
  • the term “therapeutic moiety” refers to a moiety (e.g., R 2 -) derived from a therapeutic molecule or agent.
  • Suitable therapeutic molecules for use in the invention include cytotoxic agents (e.g., PARP inhibitors, topoisomerase I inhibitors, and maytansinoids) which have undesirable side effects when delivered systemically because of their possible deleterious effect on normal tissue.
  • cytotoxic agents e.g., PARP inhibitors, topoisomerase I inhibitors, and maytansinoids
  • PARP inhibitors are disclosed in (for example) United States patents 6,100,283; 6,310,082; 6,495,541; 6,548,494; 6,696,437; 7,151,102; 7,196,085; 7,449,464; 7,692,006; 7,781,596; 8,067,613; 8,071,623; and 8,697,736, which patents are incorporated herein by reference in their entirety.
  • Compounds of Formula (I) containing a PARP inhibitor moiety are described in U.S. Patent Publication No. US 2019/209580.
  • the term “small molecule topoisomerase I targeting moiety” or “topoisomerase I inhibitor” refers to a chemical group that binds to topoisomerase I.
  • the small molecule topoisomerase I targeting moiety can be a group derived from a compound that inhibits the activity of topoisomerase I.
  • Topoisomerase inhibitors include camptothecin and derivatives and analogues thereof such as opotecan, irinotecan (CPT-11), silatecan (DB- 67, AR-67), cositecan (BNP-1350), lurtotecan, gimatecan (ST1481), belotecan (CKD- 602), rubitecan, topotecan, deruxtecan, and exatecan.
  • Topoisomerase inhibitors are described in, for example, Ogitani, Bioorg. Med. Chem.
  • R 2 is camptothecin, opotecan, irinotecan (CPT-11), silatecan (DB-67, AR-67), cositecan (BNP-1350), lurtotecan, gimatecan (ST1481), belotecan (CKD-602), rubitecan, topotecan, deruxtecan, or exatecan.
  • R 2 is exatecan.
  • Suitable small molecule microtubule targeting moieties e.g., R 2
  • R 2 can be cytotoxic compounds like maytansinoids that may have undesirable side effects when delivered systemically because of their possible deleterious effect on normal tissue.
  • Small molecule microtubule targeting agents include, but are not limited to, maytansinoids, aclitaxel, docetaxel, epothilones, discodermolide, the vinca alkaloids, colchicine, combretastatins, and derivatives and analogues of the aforementioned.
  • Microtubule targeting agents are described in Tangutur, A. D., Current Topics in Medicinal Chemistry, 201717(22): 2523- 2537.
  • Microtubule-targeting agents also include maytansinoids, such as maytansine (DM1) and derivatives and analogues thereof, which are described in Lopus, M, Cancer Lett., 2011, 307(2): 113-118; and Widdison, W., J.
  • R 2 is a maytansinoid.
  • R 2 is DM1 or DM4.
  • R 2 is DM1.
  • R 2 is DM4.
  • R 2 is: .
  • the compound of the invention has the formula:
  • the compound of the invention has the formula: , , , , y acceptable salt of any of the aforementioned. In some embodiments, the compound of the invention has the formula: ,
  • the compound of formula (I) is selected from: ,
  • the peptide of R 1 includes a N-terminal cap, a C-terminal cap, an amino acid side chain protecting group, or a combination thereof.
  • R 2 is a therapeutic moiety
  • L’ is selected from -(CH2)p1-Cy 1 -(CH2)p2R LG and -X-Y-Z’-
  • Cy 1 is selected from C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,
  • the molecules of the invention can be tagged, for example, with a probe such as a fluorophore, radioisotope, and the like.
  • the probe is a fluorescent probe, such as LICOR.
  • a fluorescent probe can include any moiety that can re-emit light upon light excitation (e.g., a fluorophore).
  • the Amino acids are represented by the IUPAC abbreviations, as follows: Alanine (Ala; A), Arginine (Arg; R), Asparagine (Asn; N), Aspartic acid (Asp; D), Cysteine (Cys; C), Glutamine (Gln; Q), Glutamic acid (Glu; E), Glycine (Gly; G), Histidine (His; H), Isoleucine (Ile; I), Leucine (Leu; L), Lysine (Lys; K), Methionine (Met; M), Phenylalanine (Phe; F), Proline (Pro; P), Serine (Ser; S), Threonine (Thr; T), Tryptophan (Trp; W), Tyrosine (Tyr; Y), Valine (Val; V).
  • Pv1 means ADDQNPWRAYLDLLFPTDTLLLDLLWCG, which is the peptide of SEQ ID No.1.
  • Pv2 means AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG, which is the peptide of SEQ ID No.2.
  • Pv3 means ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG, which is the peptide of SEQ ID No.3.
  • Pv4 means Ac- AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG, which is the peptide of SEQ ID NO.4.
  • Pv5 means AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC, which is the peptide of SEQ ID NO.5.
  • Pv6 means AAEQNPIYWWARYADWLFTTPLLLLDLALLVDADEGTCG, which is the peptide of SEQ ID NO.6.
  • the peptides R 1 are attached to L through a cysteine moiety of R 1 .
  • n-membered typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • pyrazolyl is an example of a 5-membered heteroaryl ring
  • pyridyl is an example of a 6-membered heteroaryl ring
  • 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
  • each linking substituent include both the forward and backward forms of the linking substituent.
  • -NR(CR'R'')n- includes both -NR(CR'R'') n - and -(CR'R'') n NR- and is intended to disclose each of the forms individually.
  • the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl” or "aryl” then it is understood that the "alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
  • substituted means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group.
  • substituted refers to any level of substitution, e.g., mono-, di-, tri-, tetra- or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. It is to be understood that substitution at a given atom results in a chemically stable molecule.
  • optionalally substituted means unsubstituted or substituted.
  • substituted means that a hydrogen atom is removed and replaced by a substituent.
  • a single divalent substituent e.g., oxo, can replace two hydrogen atoms.
  • Cn-m indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C 1-4 , C 1-6 and the like.
  • alkyl employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched.
  • C n-m alkyl refers to an alkyl group having n to m carbon atoms.
  • an alkyl group formally corresponds to an alkane with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound.
  • the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2- methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl and the like.
  • alkenyl employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds.
  • alkenyl group formally corresponds to an alkene with one C-H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound.
  • Cn-m alkenyl refers to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n- butenyl, sec-butenyl and the like.
  • alkylene employed alone or in combination with other terms, refers to a divalent alkyl linking group.
  • alkylene group formally corresponds to an alkane with two C-H bond replaced by points of attachment of the alkylene group to the remainder of the compound.
  • C n-m alkylene refers to an alkylene group having n to m carbon atoms.
  • alkylene groups include, but are not limited to, ethan-1,2-diyl, ethan-1,1-diyl, propan-1,3-diyl, propan-1,2-diyl, propan-1,1-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2- diyl, 2-methyl-propan-1,3-diyl and the like.
  • amino refers to a group of formula –NH2.
  • cyano or “nitrile” refers to a group of formula –C ⁇ N, which also may be written as -CN.
  • halo or “halogen”, used alone or in combination with other terms, refers to fluoro, chloro, bromo and iodo. In some embodiments, “halo” refers to a halogen atom selected from F, Cl, or Br. In some embodiments, halo groups are F.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen atom.
  • C n-m haloalkyl refers to a Cn-m alkyl group having n to m carbon atoms and from at least one up to ⁇ 2(n to m)+1 ⁇ halogen atoms, which may either be the same or different.
  • the halogen atoms are fluoro atoms.
  • the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CCl 3 , CHCl 2 , C 2 Cl 5 and the like.
  • the haloalkyl group is a fluoroalkyl group.
  • haloalkoxy employed alone or in combination with other terms, refers to a group of formula -O-haloalkyl, wherein the haloalkyl group is as defined above.
  • C n-m haloalkoxy refers to a haloalkoxy group, the haloalkyl group of which has n to m carbons.
  • Example haloalkoxy groups include trifluoromethoxy and the like.
  • the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • oxo refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to carbon, or attached to a heteroatom forming a sulfoxide or sulfone group, or an N-oxide group.
  • oxidized in reference to a ring-forming N atom refers to a ring-forming N-oxide.
  • oxidized in reference to a ring-forming S atom refers to a ring-forming sulfonyl or ring-forming sulfinyl.
  • aromatic refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n + 2) delocalized ⁇ (pi) electrons where n is an integer).
  • aryl employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2 fused rings).
  • Cn-m aryl refers to an aryl group having from n to m ring carbon atoms.
  • Aryl groups include, e.g., phenyl, naphthyl, and the like. In some embodiments, aryl groups have from 6 to about 10 carbon atoms. In some embodiments aryl groups have 6 carbon atoms. In some embodiments aryl groups have 10 carbon atoms. In some embodiments, the aryl group is phenyl.
  • any ring-forming N in a heteroaryl moiety can be an N-oxide.
  • the heteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl has 5-10 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl is a five-membered or six-membered heteroaryl ring.
  • the heteroaryl is an eight-membered, nine-membered or ten-membered fused bicyclic heteroaryl ring.
  • a five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S.
  • a six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S.
  • cycloalkyl employed alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.
  • Cn-m cycloalkyl refers to a cycloalkyl that has n to m ring member carbon atoms.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C 3-7 ).
  • the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C3-6 monocyclic cycloalkyl group. Ring- forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes.
  • cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of cyclopentane, cyclohexane and the like.
  • a cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, and the like.
  • the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded.
  • an azetidine ring may be attached at any position of the ring, whereas an azetidin-3-yl ring is attached at the 3-position.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.
  • Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. One method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ - camphorsulfonic acid.
  • optically active acids such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ - camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of ⁇ -methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and the like.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • the compounds of the invention have the (R)-configuration. In other embodiments, the compounds have the (S)-configuration. In compounds with more than one chiral centers, each of the chiral centers in the compound may be independently (R) or (S), unless otherwise indicated.
  • Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone – enol pairs, amide - imidic acid pairs, lactam – lactim pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4- triazole, 1H- and 2H- isoindole and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance.
  • the compound includes at least one deuterium atom.
  • one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium.
  • the compound includes two or more deuterium atoms.
  • the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms.
  • the term is also meant to refer to compounds of the inventions, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof. All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.
  • the compounds described herein and salts thereof may occur in various forms and may, e.g., take the form of solvates, including hydrates.
  • the compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compound.
  • the compounds of the invention, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, e.g., a composition enriched in the compounds of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the expressions, "ambient temperature” and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g., a temperature from about 20 oC to about 30 oC.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, e.g., from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
  • suitable salts are found in Remington's Pharmaceutical Sciences, 17 th Ed., (Mack Publishing Company, Easton, 1985), p.1418, Berge et al., J. Pharm.
  • the compounds described herein include the N- oxide forms.
  • Synthesis Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, such as those in the Schemes below. The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • a base e.g., DIEA
  • Compound 1-2 can be treated with R 1 H (e.g., a peptide described herein such as, for example, Pv1) to provide Compound 1-3.
  • Scheme 2 O H N CH CH O CH R1 in the presence of a base (e.g., DBU) to provide Compound 2-2.
  • Compound 2-2 can be coupled with Compound 2-3 in the presence of a base (e.g., triethylamine) to provide Compound 2-4.
  • a base e.g., triethylamine
  • Compound 2-4 can be treated with R 1 H (e.g., a peptide described herein such as, for example, Pv1) in the presence of a base (e.g., triethylamine) to provide Compound 2-5.
  • R 1 H e.g., a peptide described herein such as, for example, Pv1
  • a base e.g., triethylamine
  • the peptides R 1 may be prepared using the solid-phase synthetic method first described by Merrifield in J.A.C.S., Vol.85, pgs.2149-2154 (1963), although other art- known methods may also be employed. The Merrifield technique is well understood and is a common method for preparation of peptides. Useful techniques for solid-phase peptide synthesis are described in several books such as the text "Principles of Peptide Synthesis" by Bodanszky, Springer Verlag 1984.
  • This method of synthesis involves the stepwise addition of protected amino acids to a growing peptide chain which was bound by covalent bonds to a solid resin particle.
  • reagents and by-products are removed by filtration, thus eliminating the necessity of purifying intermediates.
  • the general concept of this method depends on attachment of the first amino acid of the chain to a solid polymer by a covalent bond, followed by the addition of the succeeding protected amino acids, one at a time, in a stepwise manner until the desired sequence is assembled. Finally, the protected peptide is removed from the solid resin support and the protecting groups are cleaved off.
  • the amino acids may be attached to any suitable polymer.
  • the polymer must be insoluble in the solvents used, must have a stable physical form permitting ready filtration, and must contain a functional group to which the first protected amino acid can be firmly linked by a covalent bond.
  • Various polymers are suitable for this purpose, such as cellulose, polyvinyl alcohol, polymethylmethacrylate, and polystyrene.
  • Methods of Use Provided herein is the use of the compounds of formula (I) in the treatment of diseases, such as cancer or neurodegenerative disease.
  • Another aspect of the present invention is the use of the compounds of formula (I) in the treatment of diseases involving acidic or hypoxic diseased tissue, such as cancer. Hypoxia and acidosis are physiological markers of many disease processes, including cancer.
  • hypoxia is one mechanism responsible for development of an acid environment within solid tumors.
  • hydrogen ions must be removed from the cell (e.g., by a proton pump) to maintain a normal pH within the cell.
  • cancer cells have an increased pH gradient across the cell membrane lipid bilayer and a lower pH in the extracellular milieu when compared to normal cells.
  • One approach to improving the efficacy and therapeutic index of cytotoxic agents is to leverage this physiological characteristic to afford selective delivery of compound to hypoxic cells over healthy tissue.
  • a therapeutically-effective amount of a compound of formula (I) or a pharmaceutically-acceptable salt thereof may be administered as a single agent or in combination with other forms of therapy, such as ionizing radiation or cytotoxic agents in the case of cancer.
  • the compound of formula (I) may be administered before, at the same time as, or after the other therapeutic modality, as will be appreciated by those of skill in the art.
  • Either method of treatment single agent or combination with other forms of therapy
  • cancers treatable with compounds of the present disclosure include bladder cancer, bone cancer, glioma, breast cancer (e.g., triple-negative breast cancer), cervical cancer, colon cancer, colorectal cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, gastrointestinal tumors, head and neck cancer (upper aerodigestive cancer), intestinal cancers, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, adenocarcinoma), melanoma, prostate cancer, rectal cancer, renal clear cell carcinoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.
  • breast cancer e.g., triple-negative breast cancer
  • cervical cancer e.g., cervical cancer, colon cancer
  • colorectal cancer endometrial cancer
  • cancers treatable with compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormone refractory prostate adenocarcinoma), breast cancer, triple-negative breast cancer, colon cancer and lung cancer (e.g. non-small cell lung cancer and small cell lung cancer). Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.
  • melanoma e.g., metastatic malignant melanoma
  • renal cancer e.g. clear cell carcinoma
  • prostate cancer e.g. hormone refractory prostate adenocarcinoma
  • breast cancer triple-negative breast cancer
  • colon cancer e.g. non-small cell lung cancer and small cell lung cancer
  • lung cancer e.g. non-small cell lung cancer and small cell lung cancer.
  • the disclosure includes refractory or recurrent malignancies whose growth may
  • cancers that are treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myeloma) and combinations
  • a compound of formula (I) or a pharmaceutically-acceptable salt thereof may be used in combination with a chemotherapeutic agent, a targeted cancer therapy, an immunotherapy or radiation therapy.
  • the agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
  • the chemotherapeutic agent, targeted cancer therapy, immunotherapy or radiation therapy is less toxic to the patient, such as by showing reduced bone marrow toxicity, when administered together with a compound of formula (I), or a pharmaceutically acceptable salt thereof, as compared with when administered in combination with the corresponding microtubule targeting agent (e.g., R 2 -H).
  • Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan TM ), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitros
  • Suitable agents for use in combination with the compounds of the present invention include: dacarbazine (DTIC), optionally, along with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; the “Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin and tamoxifen; a combination of cisplatin, vinblastine, and DTIC; or temozolomide.
  • DTIC dacarbazine
  • BCNU carmustine
  • cisplatin the “Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin and tamoxifen
  • a combination of cisplatin, vinblastine, and DTIC or temozolomide.
  • Compounds according to the invention may also be combined with immunotherapy drugs, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF).
  • cytokines such as interferon alpha, interleukin 2, and tumor necrosis
  • Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.
  • antimetabolites including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • methotrexate including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • methotrexate including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara- C, paclitaxel (TAXOL TM ), mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide.
  • certain natural products and their derivatives for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins
  • vinblastine vincristine, vindesine
  • bleomycin dactinomycin
  • daunorubicin da
  • cytotoxic agents that can be administered in combination with the compounds of the invention include, for example, navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.
  • cytotoxic agents such as, for example, epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cis-platin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and haematopoietic growth factors.
  • anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-10, TGF- ⁇ , etc.).
  • Other anti-cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4.
  • Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.
  • Anti-cancer vaccines that can be administered in combination with the compounds of the invention include, for example, dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.
  • Suitable agents for use in combination with the compounds of the present invention include chemotherapy combinations such as platinum-based doublets used in lung cancer and other solid tumors (cisplatin or carboplatin plus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin or carboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed) or gemcitabine plus paclitaxel bound particles (Abraxane®).
  • chemotherapy combinations such as platinum-based doublets used in lung cancer and other solid tumors (cisplatin or carboplatin plus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin or carboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed) or gemcitabine plus paclitaxel bound particles (Abraxane®).
  • Compounds of this invention may be effective in combination with anti-hormonal agents for treatment of breast cancer and other tumors.
  • Suitable examples are anti-estrogen agents including but not limited to tamoxifen and toremifene, aromatase inhibitors including but not limited to letrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g. prednisone), progestins (e.g. megastrol acetate), and estrogen receptor antagonists (e.g. fulvestrant).
  • Suitable anti-hormone agents used for treatment of prostate and other cancers may also be combined with compounds of the present invention.
  • anti- androgens including but not limited to flutamide, bicalutamide, and nilutamide, luteinizing hormone-releasing hormone (LHRH) analogs including leuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists (e.g. degarelix), androgen receptor blockers (e.g. enzalutamide) and agents that inhibit androgen production (e.g. abiraterone).
  • LHRH luteinizing hormone-releasing hormone
  • LHRH antagonists e.g. degarelix
  • androgen receptor blockers e.g. enzalutamide
  • agents that inhibit androgen production e.g. abiraterone.
  • Compounds of the present invention may be combined with or administered in sequence with other agents against membrane receptor kinases especially for patients who have developed primary or acquired resistance to the targeted therapy.
  • These therapeutic agents include inhibitors or antibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3 and against cancer-associated fusion protein kinases such as Bcr-Abl and EML4-Alk.
  • Inhibitors against EGFR include gefitinib and erlotinib, and inhibitors against EGFR/Her2 include but are not limited to dacomitinib, afatinib, lapitinib and neratinib.
  • Antibodies against the EGFR include but are not limited to cetuximab, panitumumab and necitumumab.
  • Inhibitors of c-Met may be used in combination with the compounds of the invention.
  • Agents against Abl include imatinib, dasatinib, nilotinib, and ponatinib and those against Alk (or EML4-ALK) include crizotinib.
  • Angiogenesis inhibitors may be efficacious in some tumors in combination with compounds of the invention. These include antibodies against VEGF or VEGFR or kinase inhibitors of VEGFR. Antibodies or other therapeutic proteins against VEGF include bevacizumab and aflibercept.
  • Inhibitors of VEGFR kinases and other anti-angiogenesis inhibitors include but are not limited to sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib Activation of intracellular signaling pathways is frequent in cancer, and agents targeting components of these pathways have been combined with receptor targeting agents to enhance efficacy and reduce resistance.
  • agents that may be combined with compounds of the present invention include inhibitors of the PI3K-AKT-mTOR pathway, inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway, and inhibitors of protein chaperones and cell cycle progression.
  • Agents against the PI3 kinase include but are not limited topilaralisib, idelalisib, buparlisib.
  • Inhibitors of mTOR such as rapamycin, sirolimus, temsirolimus, and everolimus may be combined with compounds of the invention.
  • Other suitable examples include but are not limited to vemurafenib and dabrafenib (Raf inhibitors) and trametinib, selumetinib and GDC-0973 (MEK inhibitors).
  • Inhibitors of one or more JAKs e.g., ruxolitinib, baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin dependent kinases (e.g., palbociclib), HDACs (e.g., panobinostat), PARP (e.g., olaparib), and proteasomes (e.g., bortezomib, carfilzomib) can also be combined with compounds of the present invention.
  • a further example of a PARP inhibitor that can be combined with a compound of the invention is talazoparib.
  • a therapeutically effective amount of a compound refers to an amount of the compound to be administered to a subject in need of therapy or treatment which alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions, according to clinically acceptable standards for the disorder or condition to be treated.
  • a therapeutically effective amount can be an amount which has been demonstrated to have a desired therapeutic effect in an in vitro assay, an in vivo animal assay, or a clinical trial.
  • the therapeutically effective amount can vary based on the particular dosage form, method of administration, treatment protocol, specific disease or condition to be treated, the benefit/risk ratio, etc., among numerous other factors.
  • a therapeutically-effective amount of a compound of formula (I) may be administered to a patient suffering from cancer as part of a treatment regimen also involving a therapeutically-effective amount of ionizing radiation or a cytotoxic agent.
  • the term “therapeutically-effective” amount should be understood to mean effective in the combination therapy. It will be understood by those of skill in the cancer-treatment field how to adjust the dosages to achieve the optimum therapeutic outcome. Similarly, the appropriate dosages of the compounds of the invention for treatment of non-cancerous diseases or conditions (such as cardiovascular diseases) may readily be determined by those of skill in the medical arts.
  • treating includes the administration of a compound or composition which reduces the frequency of, delays the onset of, or reduces the progression of symptoms of a disease involving acidic or hypoxic diseased tissue, such as cancer, stroke, myocardial infarction, or long-term neurodegenerative disease, in a subject relative to a subject not receiving the compound or composition.
  • This can include reversing, reducing, or arresting the symptoms, clinical signs, or underlying pathology of a condition in a manner to improve or stabilize a subject's condition (e.g., regression of tumor growth, for cancer or decreasing or ameliorating myocardial ischemia reperfusion injury in myocardial infarction, stroke, or the like cardiovascular disease).
  • inhibiting or “reducing” are used for cancer in reference to methods to inhibit or to reduce tumor growth (e.g., decrease the size of a tumor) in a population as compared to an untreated control population.
  • All publications (including patents) mentioned herein are incorporated herein by reference for the purpose of describing and disclosing, for example, the constructs and methodologies that are described in the publications, which might be used in connection with the disclosure herein described.
  • the publications discussed throughout the text are provided solely for their disclosure prior to the filing date of the present application. Disclosed herein are several types of ranges.
  • the intent is to disclose or claim individually each possible number that such a range could reasonably encompass, including end points of the range as well as any sub-ranges and combinations of sub-ranges encompassed therein.
  • a range of therapeutically effective amounts of an active ingredient is disclosed or claimed, for instance, the intent is to disclose or claim individually every possible number that such a range could encompass, consistent with the disclosure herein.
  • the therapeutically effective amount of a compound can be in a range from about 1 mg/kg to about 50 mg/kg (of body weight of the subject).
  • a compound of Formula (I) or a pharmaceutically-acceptable salt thereof is combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral.
  • any of the usual pharmaceutical media may be employed, such as for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations such as for example, suspensions, elixirs, and solutions; or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like in a case of oral solid preparations, such as for example, powders, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, although other ingredients, for example, to aid solubility or for preservative purposes, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents, and the like may be employed.
  • suitable dosage of the pharmaceutical compositions of the invention for the particular disease or condition to be treated.
  • the resultant solution was treated with DIEA (0.040 mL, 0.229 mmol), the ice-bath was removed, and the solution was stirred at ambient temperature overnight.
  • the solution was applied to a RediSep silica gel cartridge (24 g), using MeOH (gradient 1% to 20%) in DCM as the eluent (the product eluted at 6% MeOH).
  • MeOH grade 1% to 20%
  • the fractions were combined and evaporated in vacuo.
  • the product was further purified by pHPLC on a Kinetex C8, 100 ⁇ , 5 micron, 150x30 mm column eluted with acetonitrile (10% step to 45%) in water (solvents buffered with 0.05% TFA).
  • Step 2.1 1'-(octane-1,8-diyl)bis(1H-pyrrole-2,5-dione)
  • (2E,2' anediyl))bis(4-oxobut-2-enoic acid) from Step 1, 723 mg, 2.12 mmol
  • sodium acetate 139 mg, 1.69 mmol
  • acetonitrile 8 mL
  • triethylamine (0.192 mL, 1.38 mmol
  • acetic anhydride 1.2 mL, 12.7 mmol
  • Step 2 Compound 5 A solution of the compound of Step 1 (30 mg, 0.0085 mmol) and (1 4 S,1 6 S,3 2 S,3 3 S,2R,4S,10E,12E,14R)-8 6 -chloro-1 4 -hydroxy-8 5 ,14-dimethoxy-3 3 ,2,7,10- tetramethyl-1 2 ,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)- benzenacyclotetradecaphane-10,12-dien-4-yl N-(4-mercapto-4-methylpentanoyl)-N-methyl- L-alaninate (DM4, 13.2 mg, 0.017 mmol) in DMF (0.17 mL) was treated with aqueous sodium bicarbonate (1.14 M, 0.030 mL, 0.03
  • Compound 8 (1 4 S,1 6 S,3 2 S,3 3 S,2R,4S,10E,12E,14R)-8 6 -chloro-1 4 -hydroxy-8 5 ,14-dimethoxy- 3 3 ,2,7,10-tetramethyl-1 2 ,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)- benzenacyclotetradecaphane-10,12-dien-4-yl (S)-1-bromo-10,10,14,15-tetramethyl-2,7,13- trioxo-9-thia-3,6,14-triazahexadecan-16-oate (12.3 mg, 0.0123 mmol) was treated with a solution of 44.7 mg (0.0132 mmol) of Pv1 in anhydrous DMF (1.10 mL) at room temperature.
  • Tris buffer (1.1 mL) was added followed by the addition of NaHCO3 (17.2 mg, 0.205 mmol). The reaction mixture was sonicated for 1 minute and then allowed to stir at room temperature for 45 min. TFA (80 ⁇ L, 1.04 mmol) was added and the solution was loaded onto a 150x30 mm C8 Kinetex column and purified via a standard 10-100% B gradient (A: water w.0.1% TFA; B: MeCN w.0.1% TFA). Product containing fractions were lyophilized to afford 30.3 mg of product (white solid, 56% yield). HPLC purity at 254 nm: 99.3%. Retention time: 6.62 min (Method B).
  • the mixture was applied to a medium pressure reverse phase cartridge Biotage C18300 ⁇ (25 g) and eluted with acetonitrile (10% step to 30% gradient to 95%) in water (solvents buffered with AcOH 0.05%).
  • the purified fractions were combined, frozen and lyophilized to afford the crude product (30 mg).
  • the product was further purified by pHPLC, Kinetex C8, 5 micron, 100 ⁇ , 150 x 30 mm, using acetonitrile (10% step to 35% gradient to 95%) in water (solvents buffered with NH 4 OAc, 10 mM).
  • the purified fractions were combined, frozen and lyophilized to afford impure product.
  • the product was further purified by pHPLC, Kinetex C8, 5 micron, 100 ⁇ , 150 x 30 mm, using acetonitrile (10% step to 35% gradient to 95%) in water (solvents buffered with TFA, 0.05%).
  • the purified fractions were combined, frozen and lyophilized, to afford the product (15.6 mg) as the bis-TFA salt in 15% yield.
  • Example 10 Example 10
  • the resultant solution was treated with saturated aqueous sodium bicarbonate (1.0 mL). Within two minutes a heavy precipitate developed. The resultant mixture was stirred at room temperature for two hours. The precipitate was removed by filtration, and the mother liquor was applied to a medium pressure reverse phase RediSep C18 Gold cartridge (50 g). The product was eluted with acetonitrile (10% step to 40% and a gradient to 90%) in water (solvents buffered with acetic acid 0.05%). The product eluted at 71% acetonitrile. Purified fractions were combined, frozen and lyophilized to afford the product as a colorless glass (116 mg) in 62% yield. LC (method A): 3.599 min. (99%).
  • the mixture was stirred at room temperature until the starting materials were consumed (3 hours).
  • the mixture was made acidic with acetic acid (0.3 mL) and applied to a medium pressure reverse phase cartridge RediSep Aq C18 (100 g) and eluted with acetonitrile (10% step to 30% and a gradient to 90%) in water (solvents buffered with TFA 0.05%).
  • the product eluted at 59% acetonitrile.
  • the purified fractions were combined, frozen and lyophilized to afford the product as a white solid (321 mg) as the bis-TFA salt in 61% yield.
  • Step 1 (1 4 S,1 6 , , , , , , , )- -c oro- - y roxy- , -dimethoxy- 3 3 ,2,7,10-tetramethyl-1 2 ,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)- benzenacyclotetradecaphane-10,12-dien-4-yl N-(3-((2-((2-aminoethyl)amino)-2- oxoethyl)thio)propanoyl)-N-methyl-L-alaninate 2-((3-(( hydroxy-8 5 ,14- dimethoxy-3 3 ,2,7,10-tetramethyl-1 2 ,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)- benzenacyclotetradeca
  • HATU (23.9 mg) and NMM (7.0 ⁇ L) were added sequentially.
  • the reaction mixture was left to stir for 5 minutes and then 100 ⁇ L of a solution of N 1 -((4-methoxyphenyl)diphenylmethyl)ethane-1,2-diamine (0.8 M in 2:1 DMF/THF) was added.
  • the reaction mixture was left to stir at room temperature for 4 hours.
  • the solution was loaded on a 30 g C18 Aq column. It was purified via a standard 10-95% B gradient (A: water w.0.05% AcOH; B: MeCN w.0.05% AcOH). Product containing fractions were lyophilized.
  • IP intraperitoneal
  • FIG.1A shows efficacy (in terms of mean tumor volume) of nude mice bearing HCT116 colorectal carcinoma flank tumors after the indicated intraperitoneal doses of Compound 2 dosed for four total doses.
  • FIG.1B shows the percent change in body weight of nude mice bearing HCT116 colorectal carcinoma flank tumors after the indicated intraperitoneal doses of Compound 2 dosed for four total doses.
  • FIG.2A shows efficacy (in terms of mean tumor volume) of nude mice bearing HCT116 colorectal carcinoma flank tumors after the indicated intraperitoneal doses of Compound 11 dosed for four total doses.
  • FIG.2B shows the percent change in body weight of nude mice bearing HCT116 colorectal carcinoma flank tumors after the indicated intraperitoneal doses of Compound 11 dosed for four total doses.
  • Example C Efficacy of Compound 1 in a MKN45 HER2 Negative Gastric Cancer Model Six-week-old female athymic nude Foxn nu mice were obtained from Taconic Labs (Cat# NCRNU-F) and were housed 5 per cage on Alpha-Dri bedding in a disposable caging system. Human MKN45 cells derived from gastric carcinoma were diluted 1:1 in Phenol Red-free Matrigel and subcutaneously implanted into the left flank of each mouse at a density of 2x10 6 cells in 100 ⁇ L.
  • IP intraperitoneal
  • FIG.3A shows a plot of efficacy (in terms of mean tumor volume) of nude mice bearing MKN45 gastric cancer tumors after the indicated intraperitoneal doses of Compound 1 dosed for four total doses.
  • FIG.3B shows a plot of the percent change in body weight of nude mice bearing MKN45 gastric cancer tumors after the indicated intraperitoneal doses of Compound 1 dosed for four total doses.

Abstract

La présente invention concerne des conjugués de molécules thérapeutiques (par exemple, des agents cytotoxiques) et des fractions de ciblage (par exemple, des peptides) qui sont utiles dans le traitement de maladies telles que le cancer.
PCT/US2022/012079 2021-01-13 2022-01-12 Conjugués peptidiques d'agents thérapeutiques WO2022155172A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163136881P 2021-01-13 2021-01-13
US63/136,881 2021-01-13

Publications (1)

Publication Number Publication Date
WO2022155172A1 true WO2022155172A1 (fr) 2022-07-21

Family

ID=80742286

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2022/012079 WO2022155172A1 (fr) 2021-01-13 2022-01-12 Conjugués peptidiques d'agents thérapeutiques

Country Status (1)

Country Link
WO (1) WO2022155172A1 (fr)

Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6100283A (en) 1995-08-02 2000-08-08 Newcastle University Ventures Limited Benzimidazole compounds
US6495541B1 (en) 1999-01-11 2002-12-17 Agouron Pharmaceuticals, Inc. Tricyclic inhibitors of poly(ADP-ribose) polymerases
US6548494B1 (en) 1999-08-31 2003-04-15 Agouron Pharmaceuticals, Inc. Tricyclic inhibitors of poly(ADP-ribose) polymerases
US6696437B1 (en) 1999-05-07 2004-02-24 Abbott Gmbh & Co. Kg Heterocyclically substituted benzimidazoles, the production and application thereof
US7151102B2 (en) 2000-10-30 2006-12-19 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7196085B2 (en) 2002-04-30 2007-03-27 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7449464B2 (en) 2003-03-12 2008-11-11 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7692006B2 (en) 2006-10-17 2010-04-06 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7781596B1 (en) 1998-11-03 2010-08-24 Abbott Laboratories Substituted 2-phenylbenzimidazoles, the production thereof and their use
US8067613B2 (en) 2007-07-16 2011-11-29 Abbott Laboratories Benzimidazole poly(ADP ribose)polymerase inhibitors
US8071623B2 (en) 2007-01-10 2011-12-06 Instituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Amide substituted indazoles as poly(ADP-ribose)polymerase(PARP) inhibitors
US8076451B2 (en) 2005-01-18 2011-12-13 Board Of Governors For Higher Education, State Of Rhode Island And Providence Plantations Selective delivery of molecules into cells or marking of cells in diseased tissue regions using environmentally sensitive transmembrane peptide
US8697736B2 (en) 2005-09-29 2014-04-15 Abbvie Inc. 1H-benzimidazole-4-carboxamides substituted with phenyl at the 2-position are potent PARP inhibitors
US9289508B2 (en) 2010-07-13 2016-03-22 University Of Rhode Island Environmentally sensitive compositions and methods of use in the treatment and diagnosis of tumors
WO2018227132A1 (fr) * 2017-06-09 2018-12-13 Rhode Island Council On Postsecondary Education Composés liés et autres composés activés par ph
US20190209580A1 (en) 2018-01-05 2019-07-11 Cybrexa, Inc. Compounds, compositions, and methods for treatment of diseases involving acidic or hypoxic diseased tissues
US20200237926A1 (en) * 2019-01-28 2020-07-30 Rhode Island Council On Postsecondary Education pHLIP® targeted delivery of potent cytotoxic compounds
US20200246420A1 (en) * 2019-01-28 2020-08-06 Rhode Island Council On Postsecondary Education pHLIP® peptide-mediated epitope tethering at cell surfaces
CA3133798A1 (fr) * 2019-03-18 2020-09-24 The Trustees Of Columbia University In The City Of New York Lieurs stables non hydrolysables, non clivables pour agents therapeutiques de precision et leurs utilisations

Patent Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6310082B1 (en) 1909-05-30 2001-10-30 Newcastle University Ventures Limited Benzimidazole compounds
US6100283A (en) 1995-08-02 2000-08-08 Newcastle University Ventures Limited Benzimidazole compounds
US7781596B1 (en) 1998-11-03 2010-08-24 Abbott Laboratories Substituted 2-phenylbenzimidazoles, the production thereof and their use
US6495541B1 (en) 1999-01-11 2002-12-17 Agouron Pharmaceuticals, Inc. Tricyclic inhibitors of poly(ADP-ribose) polymerases
US6696437B1 (en) 1999-05-07 2004-02-24 Abbott Gmbh & Co. Kg Heterocyclically substituted benzimidazoles, the production and application thereof
US6548494B1 (en) 1999-08-31 2003-04-15 Agouron Pharmaceuticals, Inc. Tricyclic inhibitors of poly(ADP-ribose) polymerases
US7151102B2 (en) 2000-10-30 2006-12-19 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7196085B2 (en) 2002-04-30 2007-03-27 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7449464B2 (en) 2003-03-12 2008-11-11 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US8076451B2 (en) 2005-01-18 2011-12-13 Board Of Governors For Higher Education, State Of Rhode Island And Providence Plantations Selective delivery of molecules into cells or marking of cells in diseased tissue regions using environmentally sensitive transmembrane peptide
US8697736B2 (en) 2005-09-29 2014-04-15 Abbvie Inc. 1H-benzimidazole-4-carboxamides substituted with phenyl at the 2-position are potent PARP inhibitors
US7692006B2 (en) 2006-10-17 2010-04-06 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US8071623B2 (en) 2007-01-10 2011-12-06 Instituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Amide substituted indazoles as poly(ADP-ribose)polymerase(PARP) inhibitors
US8067613B2 (en) 2007-07-16 2011-11-29 Abbott Laboratories Benzimidazole poly(ADP ribose)polymerase inhibitors
US9289508B2 (en) 2010-07-13 2016-03-22 University Of Rhode Island Environmentally sensitive compositions and methods of use in the treatment and diagnosis of tumors
WO2018227132A1 (fr) * 2017-06-09 2018-12-13 Rhode Island Council On Postsecondary Education Composés liés et autres composés activés par ph
US20190209580A1 (en) 2018-01-05 2019-07-11 Cybrexa, Inc. Compounds, compositions, and methods for treatment of diseases involving acidic or hypoxic diseased tissues
US20200237926A1 (en) * 2019-01-28 2020-07-30 Rhode Island Council On Postsecondary Education pHLIP® targeted delivery of potent cytotoxic compounds
US20200246420A1 (en) * 2019-01-28 2020-08-06 Rhode Island Council On Postsecondary Education pHLIP® peptide-mediated epitope tethering at cell surfaces
WO2020160009A1 (fr) 2019-01-28 2020-08-06 Rhode Island Council On Postsecondary Education Administration ciblée de phlip® de composés cytotoxiques puissants
CA3133798A1 (fr) * 2019-03-18 2020-09-24 The Trustees Of Columbia University In The City Of New York Lieurs stables non hydrolysables, non clivables pour agents therapeutiques de precision et leurs utilisations

Non-Patent Citations (30)

* Cited by examiner, † Cited by third party
Title
"Physicians' Desk Reference", 1996, MEDICAL ECONOMICS COMPANY
"Remington's Pharmaceutical Sciences,", 1985, MACK PUBLISHING COMPANY, pages: 1418
"The ACS Style Guide: A Manual for Authors and Editors", 1997, AMERICAN CHEMICAL SOCIETY
A. KEREKES, J. MED. CHEM., vol. 54, 2011, pages 201 - 210
BERGE ET AL., J. PHARM. SCI.,, vol. 66, no. 1, 1977, pages 1 - 19
CHANG ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 110, no. 36, 2013, pages E3445 - E3454
DOUGHERTY ET AL., CHEMICAL REVIEWS, vol. 119, no. 17, 2019, pages 10241 - 10287
DOUGHERTY ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 62, no. 22, 2019, pages 10098 - 10107
GUERLAVAIS ET AL., ANNUAL REPORTS IN MEDICINAL CHEMISTRY, vol. 49, 2014, pages 331 - 345
JENS ATZRODT, VOLKER DERDAUTHORSTEN FEYJOCHEN ZIMMERMANN, ANGEW. CHEM. INT., 2007, pages 7744 - 7765
KUMAZAWA, E, CANCER CHEMOTHER PHARMACOL, vol. 42, 1998, pages 210 - 220
LOPUS, M, CANCER LETT., vol. 307, no. 2, 2011, pages 113 - 118
LU, J.: "Linkers Having a Crucial Role in Antibody-Drug Conjugates", INT. J. MOL. SCI., vol. 17, 2016, pages 1 - 22
MERRIFIELD, J.A.C.S., vol. 85, 1963, pages 2149 - 2154
NAKADA, T., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 26, 2016, pages 1542 - 1545
OGITANI, BIOORG. MED. CHEM. LETT, vol. 26, 2016, pages 5069 - 5072
PETURSSION ET AL.: "Protecting Groups in Carbohydrate Chemistry", J. CHEM. EDUC.,, vol. 74, no. 11, 1997, pages 1297
R. XU, J. LABEL COMPD. RADIOPHARM, vol. 58, 2015, pages 308 - 312
REAGAN-SHAW ET AL., FASEB J., vol. 22, no. 3, 2008, pages 659 - 61
ROBERTSON: "Protecting Group Chemistry,", 2000, OXFORD UNIVERSITY PRESS
SMITH ET AL.: "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,", 2007, THIEME
STAHL ET AL.: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY
TAHARA, M, MOL CANCER THER, vol. 13, no. 5, 2014, pages 1170 - 1180
TANGUTUR, A. D., CURRENT TOPICS IN MEDICINAL CHEMISTRY, vol. 17, no. 22, 2017, pages 2523 - 2537
TESAURO ET AL., MOLECULES, vol. 24, 2019, pages 351 - 377
VRETTOS, V.: "On the design principles of peptide—drug conjugates for targeted drug delivery to the malignant tumor site", BEILSTEIN J. ORG. CHEM., vol. 14, 2018, pages 930 - 954
WEERAKKODY ET AL., PNAS, vol. 110, no. 15, 9 April 2013 (2013-04-09), pages 5834 - 5839
WIDDISON, W., J. MED. CHEM., vol. 49, 2006, pages 4392 - 4408
WUTS ET AL.: "Protective Groups in Organic Synthesis", 2006, WILEY
WYATT LINDEN C ET AL: "Applications of pHLIP Technology for Cancer Imaging and Therapy", TRENDS IN BIOTECHNOLOGY, ELSEVIER PUBLICATIONS, CAMBRIDGE, GB, vol. 35, no. 7, 21 April 2017 (2017-04-21), pages 653 - 664, XP085072583, ISSN: 0167-7799, DOI: 10.1016/J.TIBTECH.2017.03.014 *

Similar Documents

Publication Publication Date Title
TWI820077B (zh) 治療涉及酸性或缺氧性患病組織之疾病之化合物、組合物及方法
US11739102B2 (en) Fused pyrimidine compounds as KRAS inhibitors
US20240010755A1 (en) Peptide conjugates of cytotoxins as therapeutics
JP2022549375A (ja) 免疫調節剤としてのピリド［３，２－ｄ］ピリミジン化合物
US20240067616A1 (en) Peptide conjugates of microtubule-targeting agents as therapeutics
US11939331B2 (en) Tricyclic heterocycles as FGFR inhibitors
KR20130118731A (ko) 항증식성 질환 치료에 사용하기 위한 ｐｉ3ｋ 억제제로서 피페라지노트리아진
JPWO2021007435A5 (fr)
WO2022155172A1 (fr) Conjugués peptidiques d'agents thérapeutiques
US20230416331A1 (en) Peptide conjugates of peptidic tubulin inhibitors as therapeutics
WO2023147311A1 (fr) Inhibiteurs de protéase 1 de traitement spécifique de l'ubiquitine (usp1) à des fins de traitement de tumeurs solides

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: 22704029

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: 22704029

Country of ref document: EP

Kind code of ref document: A1