WO2023055763A2 - Inhibiteurs à petites molécules de chd1l oncogènes présentant une activité préclinique contre le cancer colorectal - Google Patents

Inhibiteurs à petites molécules de chd1l oncogènes présentant une activité préclinique contre le cancer colorectal Download PDF

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WO2023055763A2
WO2023055763A2 PCT/US2022/044974 US2022044974W WO2023055763A2 WO 2023055763 A2 WO2023055763 A2 WO 2023055763A2 US 2022044974 W US2022044974 W US 2022044974W WO 2023055763 A2 WO2023055763 A2 WO 2023055763A2
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chd1l
compound
group
inhibitor
solvate
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WO2023055763A3 (fr
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Daniel V. LABARBERA
Joshua M. ABBOTT
Qiong ZHOU
Adedoyin D. ABRAHAM
Hector ESQUER
Brett Joseph PRIGARO
Laura Anne PIKE
Paul AWOLADE
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The Regents Of The University Of Colorado, A Body Corporate
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Priority claimed from US17/953,221 external-priority patent/US20230103444A1/en
Application filed by The Regents Of The University Of Colorado, A Body Corporate filed Critical The Regents Of The University Of Colorado, A Body Corporate
Priority to CA3233398A priority Critical patent/CA3233398A1/fr
Priority to AU2022354855A priority patent/AU2022354855A1/en
Publication of WO2023055763A2 publication Critical patent/WO2023055763A2/fr
Publication of WO2023055763A3 publication Critical patent/WO2023055763A3/fr

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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • BACKGROUND The integrity of the genome is maintained by conformational changes to chromatin structure that regulate accessibility to DNA for gene expression and replication. Chromatin structure is maintained by post-translational modifications of histones and rearrangement of nucleosomes.
  • ATP-dependent chromatin remodelers are enzymes that alter chromatin by changing histone composition, and by evicting or translocating nucleosomes along DNA. Their activity plays a critical role in cellular function by regulating gene expression and the accessibility of DNA for replication, transcription, and DNA repair.
  • CHD1L chromodomain helicase/ATPase DNA binding protein 1-like
  • ALC1 amplified in liver cancer 1
  • CHD1L is also involved in multi-drug resistance, ranging from upregulation of drug resistance efflux pumps (e.g., ABCB1) [Li et al., 2019] to PARP1 mediated DNA repair [Pines et al., 2012; Tsuda et al., 2017], and anti-apoptotic activity.
  • CHD1L overexpression has also been implicated in tumor progression and as a predictor of poor patient survival.
  • the multifunctional oncogenic mechanisms of CHD1L make it an attractive therapeutic target in cancer.
  • CRC colorectal cancer
  • TCF4 a.k.a. TCFL2
  • CBP CREB Binding protein
  • TCF transcription functions as a master regulator of epithelial- mesenchymal transition (EMT) [Sánchez-Tillá et al., 2011; Zhou et al., 2016; Abraham et al., 2019].
  • EMT epithelial- mesenchymal transition
  • CSC cancer stem cell
  • TCF4 is reported to be a specific driver of mCRC.
  • CRC can metastasize in early adenomas (i.e., polyps [see also Magri & Bardelli, 2019] which is likely caused by TCF-driven EMT.
  • TCF-transcription is a driving force at all stages of CRC progression and metastasis.
  • EMT is a major driving force in numerous human diseases, especially solid tumor progression, drug and radiation therapy resistance, evasion of the immune response and immunotherapy, and promotion of metastasis [Chaffer et al 2016; Chaffer & Weinberg 2011; Scheel & Weinberg Due to the significance of the Wnt signaling pathway and TCF-transcription in cancer and other diseases [Clevers, 2006], small molecule drugs that inhibit the Wnt signaling pathway and TCF- transcription have been examined.
  • Therapeutic strategies considered include receptor targets (e.g., Frizzled); preventing Wnt ligand secretion (e.g., porcupine); inhibiting ⁇ -catenin destruction complex (e.g., tankyrases); and protein-protein inhibition (PPI) with ⁇ -catenin and co-activators (e.g., CBP). While clinical trials may be underway, no drug has as yet been clinically approved that targets the Wnt/TCF pathway.
  • receptor targets e.g., Frizzled
  • Wnt ligand secretion e.g., porcupine
  • ⁇ -catenin destruction complex e.g., tankyrases
  • PPI protein-protein inhibition
  • CBP co-activators
  • the present invention describes a new therapeutic strategy, particularly for identifying small molecule drugs, for treatment of Wnt/TCF driven CRC in which CHD1L is identified as a DNA binding factor required for TCF-transcription regulating the malignant phenotype in CRC.
  • CHD1L is identified as a DNA binding factor required for TCF-transcription regulating the malignant phenotype in CRC.
  • U.S. Patent 9,616,047 reports small molecule inhibitors of ⁇ -catenin or disruptors of a ⁇ -catenin/TCF-4 complex which are said to attenuate colon carcinogenesis.
  • Inhibitors of ⁇ - catenin reported therein include esculetin, as well as, compounds designated HI-B1–HI-B20, HI- B22–-HI-B-24, HI-B26, HI-B32 and HI-B34, the structures of each of which is provided in the patent.
  • the patent further describes, in a number of generic chemical formulae therein, compounds said to be useful as ⁇ -catenin inhibitors and for the treatment of colon carcinogenesis.
  • This patent is incorporated by reference herein in its entirety for the structures of specific compounds, generic formulae and variable definitions of compounds said therein to be useful in the invention therein.
  • the compounds identified herein are structurally distinct from those described herein.
  • R 1 is mes-trimethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, naphthyl, 2,3,4,5,- tetramethylphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 2,4-dimethoxyphenyl, 2,5- dimethoxyphenyl or 4-phenoxyphenyl;
  • R 2 is hydrogen, methyl acetate, acetate, aminoacetyl, 4-formic acid benzyl, 4-isopropylbenzyl, 4- chlorobenzyl or 4-methoxybenzyl; and
  • R 3 is chlorine, -ORa or –NRbRc, where, Ra is a chain C1-3 alkyl, C5-6 cycloalkyl, C1-2 alkoxy, mono- or di-C1-2 alkylamino, or C5-6 nitrogen-containing or oxygen-containing heterocyclic group; and Rb
  • R 3 is chlorine, 2- hydroxytetrahydropyrrolyl, ethanolamino, 2,3-dihydroxy-1-methylpropylamino, 2,3- dihydroxypropylamino, piperazinyl, N-methylpiperazinyl, azepyl, piperidinyl, 2-methylpropylamino, propoxy, methylamino, ethylamino, cyclopropylamino, 1-ethylpropylamino, tetrahydropyran-4- ylmethoxy or 2-methoxyethoxy.
  • the reference also refers to a compound of formula I-5:
  • This published application is incorporated by reference herein in its entirety for the structures of specific compounds, generic formulae and variable definitions of compounds said therein to be useful in the invention therein. Structures disclosed in this published application can be excluded from any chemical formula of the present application.
  • the present invention examines the clinicopathological characteristics of CHD1L in CRC, and the results herein indicate that CHD1L is a druggable target involved in TCF-transcription. A mechanism for CHD1L-mediated TCF-transcription is also proposed herein.
  • CHD1L Small molecule inhibitors of CHD1L are identified herein which are able to prevent TCF transcription, reverse EMT, and other malignant properties in a variety of cell models including tumor organoids and patient derived tumor organoids (PDTOs).
  • Certain CHD1L inhibitors identified herein display drug-like pharmacological properties, including in vivo pharmacokinetic (PK) and pharmacodynamic (PD) profiles, important for translational development towards the treatment of CRC and other cancers.
  • PK in vivo pharmacokinetic
  • PD pharmacodynamic
  • CHD1L is found to be an essential component of the TCF transcription complex.
  • Small molecule inhibitors of CHDL1 which inhibit CHD1L ATPase and inhibit CHD1L-dependent TCF-transcription have been identified.
  • CHD1L inhibitors are believed to prevent the TCF-complex from binding to Wnt response elements and promoter sites. More specifically, CHD1L inhibitors induce the reversion of EMT.
  • CHD1L inhibitors are useful in the treatment of various cancers and particularly CRC and m-CRC.
  • CHD1L inhibitors are shown in embodiments to inhibit cancer stem cell (CSC) stemness and invasive potential.
  • CHD1L inhibitors induce cytotoxicity in CRC PDTOs.
  • the CHD1L-driven cancer is CRC, breast cancer, including BRCA-mutated breast cancer and metastatic breast cancer, ovarian cancer, including BRCA-mutated ovarian cancer, pancreatic cancer, including BRCA-mutated pancreatic cancer, glioma, liver cancer, lung cancer, prostate cancer, or gastrointestinal (GI) cancers.
  • the TCF transcription-driven cancer is CRC, including mCRC.
  • the EMT-driven cancer is CRC, including mCRC.
  • the cancer that is treated is breast cancer, including BRCA-mutated breast cancer and metastatic breast cancer.
  • the cancer that is treated is ovarian cancer.
  • the cancer that is treated is pancreatic cancer.
  • the invention provides a method for treatment of CHD1L-driven cancers, more specifically TCF transcription-driven cancers and yet more specifically EMT-driven cancers, including GI cancer, particularly CRC and mCRC, which comprises administration to a patient in need thereof of an amount of a CHD1L inhibitor which is effective for CHD1L inhibition, effective inhibition of aberrant TCF transcription or effective for induction of EMT reversion.
  • the CHD1L inhibitor is a compound of any one of formulas I- XXIII or XXX-XVII. In embodiments, the CHD1L inhibitor is a compound of any one of formulas I, II, or XX-XXIII. In embodiments, the CHD1L inhibitor is a compound of either of formulas XLV or XLVI. In an embodiment, the CHD1L inhibitor is any one of compounds 1-177. In an embodiment, the CHD1L inhibitor is any one of compounds 8-177 or any one of compounds 9-117. In an embodiment, the CHD1L inhibitor is any one of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169.
  • the compound is selected from compounds 52, 118, 126, 131, 150, or 169.
  • the compound is selected from compounds 28, 31, 54, 57, or 75.
  • the compound is one or more of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169.
  • the compound is one of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169.
  • the invention provides a method of inhibiting aberrant TCF-transcription, particularly in CRC, by administration of an effective amount of a CHD1L inhibitor. Yet more specifically, the invention an effective amount of a CHD1L inhibitor.
  • the invention provides a method of inhibiting Cancer Stem Cell (CSC) stemness and/or invasive potential, particularly in CRC, by administration of an effective amount of a CHD1L inhibitor.
  • CSC Cancer Stem Cell
  • the invention provides a method for treatment of cancerous tumors of CHD1L-driven cancers, or TCF transcription-driven cancers or EMT-driven cancers, particularly in CRC, by administration of an effective amount of a CHD1L inhibitor.
  • the invention provides a method for treatment of cancerous solid tumors of CHD1L-driven cancers, or TCF transcription-driven cancers or EMT-driven cancers, particularly in CRC, by administration of an effective amount of a CHD1L inhibitor.
  • the invention provides a method for treatment of breast cancer, including BRCA-mutated breast cancer, by administration of an effective amount of a CHD1L inhibitor.
  • the invention provides a method for treatment of ovarian cancer by administration of an effective amount of a CHD1L inhibitor.
  • the invention provides a method for treatment of pancreatic cancer by administration of an effective amount of a CHD1L inhibitor.
  • CHD1L inhibitors are selective for inhibition of CHD1L.
  • CHD1L inhibitors herein are not PARP inhibitors.
  • CHD1L inhibitors herein are not inhibitors of topoisomerases.
  • CHD1L inhibitors herein are not inhibitors of DNA topoisomerase.
  • CHD1L inhibitors herein are not inhibitors of topoisomerase type II ⁇ .
  • CHD1L inhibitors herein are not inhibitors of ⁇ -catenin, particularly inhibitors such as described in U.S. Patent 9,616,047.
  • CHD1L inhibitors herein are not inhibitors of Hsp90-Cdc37 interactive client protein expression, particularly inhibitors as described in CN109761909.
  • invention also provides a method to prevent tumor growth, invasion and/or metastasis in CHD1L-driven, TCF-transcription, or EMT-driven cancers by administering to a patient in need thereof of an amount of a CHD1L inhibitor of this invention which is effective for CHD1L inhibition, inhibition of aberrant TCF transcription, or effective for reversion of EMT.
  • tumors are solid tumors.
  • tumors are those associated with GI cancer.
  • tumors are those associated with CRC.
  • tumors are those associated with mCRC.
  • tumors are those associated with breast cancer.
  • tumors are those associated with BRAC-mutated breast cancer.
  • tumors are those associated with ovarian cancer. In embodiments, tumors are those associated with pancreatic cancer. In embodiments, tumors are those associated with lung cancer. In embodiments, tumors are those associated with liver cancer.
  • the invention provides a method for treatment of CRC, including mCRC, which comprises administration to a patient in need thereof of an amount of a CHD1L inhibitor method for treatment of CRC, including mCRC, which comprises administration to a patient in need thereof of an amount of a CHD1L inhibitor which is effective for inhibition of aberrant TCF transcription.
  • the invention provides a method for treatment of CRC, including mCRC, which comprises administration to a patient in need thereof of an amount of a CHD1L inhibitor which is effective for induction of reversion of EMT.
  • the invention provides a method for inducing apoptosis in cancer cells which comprises contacting a cancer cell with an effective amount of a CHD1L inhibitor.
  • the CHD1L inhibitor is provided in an amount effective for inhibition of aberrant TCF transcription.
  • the CHD1L inhibitor is provided in an amount effective for induction of reversion of EMT.
  • the cancer cells are CRC cancer cells.
  • the cancer cells are mCRC cancer cells.
  • the cancer cells are breast cancer cells. In an embodiment, the cancer cells are breast cancer cells carry a BRCA mutation. In an embodiment, the cancer cells are ovarian cancer cells. In an embodiment, the cancer cells are pancreatic cancer cells. In an embodiment, the cancer cells are lung cancer cells. In an embodiment, the cancer cells are liver cancer cells.
  • the method is applied in vivo. In an embodiment, the method is applied in vivo in a patient. In an embodiment, the method is applied in vitro. In embodiments of the methods herein comprising administration of the CHD1L inhibitor, the CHD1L inhibitor is administered by any known administration method and dosing schedule to achieve desired benefits. In an embodiment, administration is oral administration. In an embodiment, administration is by intravenous injection.
  • oral administration employs oral dosage forms comprising pharmaceutically acceptable polyethylene glycol (PEG).
  • the pharmaceutically acceptable PEG may be combined with a pharmaceutically acceptable organic solvent, particularly a pharmaceutically acceptable polar, aprotic solvent.
  • the organic solvent is pharmaceutically acceptable DMSO.
  • oral administration employs oral dosage forms comprising low molecular weight polyethylene glycol having molecular weight less than 600 g/mole.
  • oral administration employs PEG 400.
  • oral administration employs PEG 200.
  • the invention in addition1i provides a method of treatment of drug-resistant cancer which comprises administering to a patient in need thereof of an amount of a CHD1L inhibitor, which is effective for CHD1L inhibition, inhibition of aberrant TCF transcription or become resistant.
  • the treatment to which the cancer has become resistant is conventional chemotherapy and other targeted therapies.
  • the invention provides a method of increasing the efficacy of a DNA-damaging drug in cancer which comprises combined treatment of the cancer with the DNA damaging drug and a CHD1L inhibitor where the CHD1L is administered in an amount effective for decreasing resistance to the DNA- damaging drug.
  • the DNA-damaging drug is a topoisomerase inhibitor.
  • the DNA-damaging drug is a DNA topoisomerase inhibitor.
  • the DNA- damaging drug is a topoisomerase type II ⁇ inhibitor.
  • the DNA-damaging drug is etoposide or teniposide.
  • the DNA-damaging drug is SN38 or a prodrug thereof.
  • the DNA-damaging drug is a thymidylate synthase inhibitor.
  • the thymidylate synthase inhibitor is a folate analogue.
  • the thymidylate synthase inhibitor is a nucleotide analogue.
  • the thymidylate synthase inhibitor is raltitrexed, pemetrexed, nolatrexed or ZD9331.
  • the DNA-damaging drug is 5-fluorouracil or capecitabine.
  • the drug-resistant cancer is a CHD1L-driven cancer.
  • the drug-resistant cancer is a TCF transcription-driven cancer.
  • the drug-resistant cancer is an EMT-driven cancer.
  • the treatment is for drug-resistant CRC.
  • the treatment is for drug-resistant mCRC.
  • the treatment is for drug- resistant breast cancer, drug-resistant ovarian cancer, drug-resistant pancreatic cancer, drug- resistant lung cancer or drug-resistant liver cancer.
  • the DNA-damaging drug and the CHD1l inhibitor are administered by any known method on a dosing schedule appropriate for realizing the combined therapeutic benefit.
  • the CHD1L inhibitor is administered orally and the DNA-damaging drug is administered by any known administration method and dosing schedule.
  • the CHD1L inhibitor is administered prior to administration of the DNA-damaging drug.
  • the CHD1L inhibitor is administered prior to and optionally after administration of the DNA-damaging drug.
  • the CHD1L inhibitor is administered orally prior to and optionally after administration of the DNA-damaging drug by intravenous injection.
  • the invention provides methods for treatment of CHD1L-driven cancer, TCF-transcription-driven cancer, or EMT-driven cancer which comprises administration to a patient in need thereof of an amount of a CHD1L inhibitor which is effective for CHD1L inhibition or inhibition of aberrant TCF transcription or induction of reversion of EMT in combination with an alternative method of treatment for the cancer.
  • the cancer is GI cancer or more specifically CRC cancer and yet more specifically is mCRC.
  • the alternative method for treatment is administration of one or more of 5-fluorouracil, 5-fluorouracil in combination with folinic acid (also known as leucovorin), a topoisomerase inhibitor, or a cytotoxic or antineoplastic agent.
  • the CHD1L inhibitor is administered in combination with 5-fluorouracil or in combination with 5-fluorouracil and folinic acid.
  • the CHD1L inhibitor is administered in combination with a topoisomerase inhibitor and in particular with irinotecan (a prodrug of SN38 also known as camptothecin) or any other known prodrug of SN38.
  • the combined treatment using a CHD1L inhibitor and a topoisomerase inhibitor exhibits at least additive activity against the cancer.
  • the combined treatment of a CHD1L inhibitor with a topoisomerase inhibitor exhibits synergistic activity (greater than additive activity) against the cancer.
  • the CHD1L inhibitor is administered in combination with a cytotoxic or antineoplastic agent, in particular a platinum-based antineoplastic agent and more particularly cisplatin, carboplatin or oxaliplatin.
  • the combined treatment using a CHD1L inhibitor and a platinum-based antineoplastic agent exhibits at least additive activity against the cancer.
  • the combined treatment of a CHD1L inhibitor with a platinum-based antineoplastic agent exhibits synergistic activity (greater than additive activity) against the cancer.
  • the platinum-based antineoplastic agent and the CHD1l inhibitor are administered by any known method on a dosing schedule appropriate for realizing the combined therapeutic benefit.
  • the CHD1L inhibitor is administered orally and the platinum-based neoplastic agent is administered by any known administration method and dosing schedule.
  • the CHD1L inhibitor is administered prior to administration of the platinum-based neoplastic agent.
  • the CHD1L inhibitor is administered prior to and optionally after administration of the platinum-based antineoplastic agent.
  • the CHD1L inhibitor is administered orally prior to and optionally after administration of the platinum-based neoplastic agent by intravenous injection.
  • the CHD1L inhibitor is administered in combination with a chemotherapy regimen (administration of an alternative cancer cytotoxic agent or antineoplastic agent or adminintration of an antineoplastic procedure) for treatment of cancer, including without limitation GI cancer, particularly CRC, and mCRC.
  • the CHD1L inhibitor is administered in combination with the chemotherapy regimen designated FOLFOX.
  • the CHD1L inhibitor is administered in combination with the chemotherapy regimen designated FOLFIRI.
  • the chemotherapy regime and the CHD1l inhibitor are administered by any known method on a dosing schedule appropriate for realizing the combined therapeutic benefit.
  • the CHD1L inhibitor is administered orally and the chemotherapy regime is administered by any known administration method and dosing schedule. In embodiments, the CHD1L inhibitor is administered prior to administration of the chemotherapy regime. In embodiments, the CHD1L inhibitor is administered prior to and optionally after administration of the chemotherapy regime. In embodiments, the CHD1L inhibitor is administered orally prior to and optionally after administration of the PARP inhibitor by intravenous injection.
  • the invention provides a method for treatment of cancers that are sensitive to Poly(ADP)-ribose) polymerase I (PARPI) in which a CHD1L inhibitor is used in combination with a PARP inhibitor.
  • PARPI Poly(ADP)-ribose) polymerase I
  • an amount of a CHD1L inhibitor effective for CHD1L inhibition, inhibition of aberrant TCF transcription or induction of reversion of EMT is used in combination with an amount of a PARP inhibitor effective for treating cancer to at least enhance the effectiveness of the cancer treatment.
  • the combined treatment using a CHD1L inhibitor and a PARP inhibitor exhibits at least additive activity against the cancer.
  • the combined treatment of a CHD1L inhibitor with a PARP inhibitor exhibits synergistic activity (greater than additive activity) against the cancer.
  • the cancer is a cancer sensitive to treatment by a PARP inhibitor.
  • the cancer is a cancer that is or has become resistant to treatment by a PARP inhibitor.
  • the cancer is a cancer sensitive to treatment by a PARP inhibitor or which has become resistant to treatment by a PARP inhibitor and which is a CHD1L-driven, a TCF-driven or an EMT-driven cancer.
  • the cancer is a homologous recombination deficient cancer (see, for example, Zhou et al. BioRxiv 2020).
  • the cancer treated is a cancer sensitive to a PARP inhibitor and more particularly is breast or ovarian cancer.
  • the cancer is a BRCA-deficient cancer (BRCA-mutated cancer), for example, BRCA-deficient breast cancer (BRCA-mutated breast cancer), BRCA-deficient ovarian cancer (BRCA-mutated ovarian cancer or BRCA-defcient pancreatic cancer (BRCA-mutated pancreatic cancer).
  • BRCA-mutated cancer BRCA-deficient breast cancer
  • BRCA-mutated ovarian cancer BRCA-mutated ovarian cancer or BRCA-defcient pancreatic cancer
  • the cancer is pancreatic cancer.
  • the cancer is lung or liver cancer.
  • the cancer is prostate cancer.
  • the cancer treated is GI cancer, stomach cancer, CRC or mCRC.
  • combined treatment of the CHD1L inhibitor with the PARP inhibitor reverses resistance of the cancer to treatment by the PARP inhibitor.
  • the PARP inhibitor is olaparib, veliparib or talozoparib. In embodiments, the PARP inhibitor is rucaparib or niraparib.
  • the invention also provides a method for treating a cancer which comprises administration of an amount of a PARP inhibitor effective for treatment of the cancer combined with administration of an amount of a CHD1L inhibitor effective for inhibiting CHD1L.
  • the PARP inhibitor and the CHD1L inhibitor are administered by any known method on a dosing schedule appropriate for realizing the combined therapeutic benefit.
  • the CHD1L inhibitor is administered orally and the PARP inhibitor is administered by intravenous injection. In embodiments, the CHD1L inhibitor and the PARP inhibitor are both administered by intravenous injection.
  • the CHD1L inhibitor is administered prior to administration of the PARP inhibitor. In embodiments, the CHD1L inhibitor is administered prior to and optionally after administration of the PARP inhibitor. In embodiments, the CHD1L inhibitor is administered after administration of the PARP inhibitor. In embodiments, the CHD1L inhibitor is administered orally prior to and optionally after administration of the PARP inhibitor by intravenous injection. In embodiments, CHD1L inhibitors are combined with one or more agent that induces DNA damage to treat neoplastic disease, including various cancers. In specific embodiments, CHD1L inhibitors exhibit more than additivity anticancer activity when combined with one or more agent that induces DNA damage.
  • CHD1L inhibitors exhibit synergistic anticancer activity when combined with one or more agent that induces DNA damage.
  • This combined axtivity of CHD1L inhibitors can be assessed in combination with methylmethane sulfonate (an alkylating agent), which is an exemplary agent that induces DNA damage.
  • the invention also provides a method for identifying a CHD1L inhibitor, which inhibits CHD1L- dependent TCF transcription which comprises determining if a selected compound inhibits a CHD1L ATPase, as described in examples herein. In specific embodiments, inhibition of cat- CHD1L ATPase is determined.
  • compounds exhibiting % inhibition of 30% or greater are selected as inhibiting a CHD1L ATPase. In embodiments, compounds exhibiting % inhibition of 80% or greater are selected as inhibiting a CHD1L ATPase.
  • CHD1L inhibitors exhibit IC 50 less than 10 ⁇ M in dose response assays against CHD1L ATPase, particularly cat-CHD1L ATPase. In specific embodiments, CHD1L inhibitors exhibit IC 50 less than 5 ⁇ M in dose response assays against CHD1L ATPase, particularly cat-CHD1L ATPase.
  • CHD1L inhibitors exhibit IC 50 less than 5 ⁇ M in dose response assays against CHD1L ATPase, particularly cat-CHD1L ATPase. In specific embodiments, CHD1L inhibitors exhibit IC 50 less than 5 ⁇ M. In specific embodiments, CHD1L inhibitors exhibit IC 50 less than 3 ⁇ M. In specific embodiments, CHD1L inhibitors exhibit IC 50 less than 1 ⁇ M. In specific embodiments, CHD1L inhibitors are assessed for inhibition of TCF-transcription in a 2D cancer cell model, particularly using one or more CRC cell lines, such as described in examples herein.
  • inhibition of TCF-transcription is determined using a TOPflash reporter construct and more specifically a TOPflash luciferase reporter construct as described herein.
  • inhibition of TCF-transcription by CHD1L inhibitors in the cell model is dose-dependent.
  • inhibition of TCF-transcription by CHD1L inhibitors in the cell model is dose-dependent in the range of 1 to 50 ⁇ M.
  • a CHD1L inhibitor exhibits % TCF-transcription normalized to cell viability of 75% or less at 20 ⁇ M.
  • a CHD1L inhibitor exhibits % TCF-transcription normalized to cell viability of 50% or less at 40 ⁇ M.
  • CHD1L inhibitors exhibit dose dependent inhibition of TCF-transcription with IC 50 less than 10 ⁇ M assayed with TOPflash reporter in a cancer cell line. In specific embodiments, CHD1L inhibitors exhibit dose dependent inhibition of TCF-transcription with IC 50 less than 5 ⁇ M assayed with TOPflash reporter in a cancer cell line. In specific embodiments, CHD1L inhibitors exhibit dose dependent inhibition of TCF-transcription with IC 50 less than 3 ⁇ M assayed with TOPflash reporter in a cancer cell line.
  • the cancer cell line is a CRC cancer cell, a breast cancer cell, a glioma cell, a liver cancer cell, a lung cancer cell or a GI cancer cell.
  • the cancer cell line is a CRC cancer cell line. In a specific embodiment, the CRC cancer cell line is SW620.
  • CHD1L inhibitors are assessed for their ability to reverse or inhibit EMT. In specific embodiments, CHD1L inhibitors are assessed for their ability to reverse EMT in tumor organoids. In embodiments, reversion or inhibition of EMT is assessed in tumor organoids expressing vimentin where dose-dependent decrease in vimentin expression indicates reversion or inhibition of EMT. In embodiments, reversion of EMT is assessed in tumor organoids expressing E-cadherin where dose-dependent increase in E-cadherin expression indicates reversion or inhibition of EMT.
  • reversion of EMT is assessed in tumor organoids expressing E-cadherin, vimentin or both, where dose-dependent decrease in vimentin and dose-dependent increase in E-cadherin expression indicates reversion or inhibition of EMT.
  • dose-dependent reversion or inhibition of EMT is measured over a compound concentration of 0.1 to 100 ⁇ M.
  • dose-dependent reversion of EMT is measured over a compound concentration of 0.3 to 50 ⁇ M.
  • CHD1L inhibitors are assessed for their ability to inhibit clonogenic colony formation which is a well-established assay to measure cancer stem cell stemness.
  • cells are pretreated with a selected concentration of CHD1L inhibitors prior to plating.
  • cells are cultured at low density such that only CSC will form colonies over 10 days in culture.
  • cells are pretreated for 12-36 h.
  • cells are pretreated for 24 h.
  • cells are pretreated with CHD1L inhibitors at concentration in the range of 0.5-50 ⁇ M with appropriate controls.
  • CHD1L inhibitors exhibit 40% or more inhibition of clonogenic colony counts, compared to no compound control, for CHD1L concentration of 40 ⁇ M.
  • CHD1L inhibitors exhibit 40% or more inhibition of clonogenic colony counts, compared to no compound control, for CHD1L concentration of 20 ⁇ M.
  • CHD1L inhibitors exhibit 40% or more inhibition of clonogenic colony counts, compared to no compound control, for CHD1L concentration of 2 ⁇ M. In embodiments, inhibition of clonogenic colony formation lasts over 10 days in culture. In specific embodiments, CHD1L inhibitors are further assessed for loss of invasive potential employing any known method and particularly employing a method as described in the examples herein. In specific embodiments, CHD1L inhibitors are further assessed for antitumor activity as measured by induction of cytotoxicity in tumor organoids. In embodiments, cells are treated for a selected time (e.g., 24-96 h, preferably 72 h) with selected concentration of CHD1L inhibitor (1-100 ⁇ M).
  • a selected time e.g., 24-96 h, preferably 72 h
  • cytotoxicity is measured using any of a variety of cytotoxicity reagents known in the art, such as small molecules which, enter damaged cells and exhibit a measurable change on entry (e.g., fluorescence, such as, CellToxTM Green reagent (Promega, Madison, WI) or IncuCyteCytotox reagents (Sartorius, France).
  • cytotoxicity is measured by measurement of LDH (lactate dehydrogenase) released from dead cells.
  • the CHD1L inhibitors useful in methods of treatment, pharmaceutical compositions and pharmaceutical combinations herein are those of formulas I- XXIII, XXX-XLII and XLV-XLVI or pharmaceutically acceptable salts or solvates thereof.
  • the invention provides novel compounds of any formula herein and in particular of of formulas I-XXIII, XXXV-XLII or salts or solvates thereof.
  • the CHD1L inhibitors are those of formula I, II, XX- XXIII.
  • the CHD1L inhibitors are those of formula XX.
  • the CHD1L inhibitors are those of formulas I-IX, XI-XIX, XX, XXI, XXII, XXIII or XXXV-XLII. In embodiments, the CHD1L inhibitors are those of formula XLV or XLVI.
  • the methods, pharmaceutical compositions and pharmaceutical combinations of the invention employ CHD1L inhibitors that are selected from one or more of compounds 1-177 or pharmaceutically acceptable salts or solvates thereof. Two or more CHD1L inhibitors can be employed in combination in the methods herein. In specific embodiments, the CHD1L inhibitors employed in the invention are selected from one or more of compounds 6-39 or pharmaceutically acceptable salts thereof.
  • the CHD1L inhibitors employed in the methods of the invention are selected from one or more of compounds 40-51 or pharmaceutically acceptable salts or solvates thereof. In specific embodiments, the CHD1L inhibitors employed in the methods of the invention are selected from one or more of compounds 52-68 or pharmaceutically acceptable salts or solvates thereof. In specific embodiments, the CHD1L inhibitors employed in the methods of the invention are selected from one or more of compounds 70-73 or pharmaceutically acceptable salts or solvates thereof. In specific embodiments, the CHD1L inhibitors employed in the methods of the invention are selected from one or more of compounds 74-101 or pharmaceutically acceptable salts or solvates thereof.
  • the CHD1L inhibitors employed in the methods of the invention are selected from one or more of compounds 102-103 or pharmaceutically acceptable salts or solvates thereof. In specific embodiments, the CHD1L inhibitors employed in the methods of the invention are selected from one or more of compounds 104-116 or pharmaceutically acceptable salts or solvates thereof. In specific embodiments, the CHD1L inhibitors employed in the methods of the invention are selected from one or more of compounds 117-142 or pharmaceutically acceptable salts or solvates thereof. In specific embodiments, the CHD1L inhibitors employed in the methods of the invention are selected from one or more of compounds 143-177 or pharmaceutically acceptable salts or solvates thereof.
  • the CHD1L inhibitors employed in the methods of the invention are selected from one or more of compounds 150-154 or pharmaceutically acceptable salts or solvates thereof. In specific embodiments, the CHD1L inhibitors employed in the methods of the invention are selected from one or more of compounds 155-159 or pharmaceutically acceptable salts or solvates thereof. In specific embodiments, the CHD1L inhibitors employed in the methods of the invention are selected from one or more of compounds 28-39, 74-75, 52, 54, 62-66 or 74-75 or pharmaceutically acceptable salts or solvates thereof.
  • the compound is selected from compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169 or pharmaceutically acceptable salts or solvates thereof. In more specific embodiments, the compound is selected from compounds 52, 118, 126, 131, 150, or 169 or pharmaceutically acceptable salts or solvates thereof. In embodiments, the compound is selected from compounds 28, 31, 54, 57, or 75 or pharmaceutically acceptable salts or solvates thereof. In embodiments, the compound is one or more of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169 or pharmaceutically acceptable salts or solvates thereof.
  • the compound is one of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169 or pharmaceutically acceptable salts or solvates thereof.
  • the CHD1L inhibitors employed in the methods of the invention are selected from compound 52 or pharmaceutically acceptable salts or solvates thereof.
  • the forgoing specifically recited CHD1L inhibitors can be combined with one or more alternative cancer cytoxic or antineoplastic agents for treatment or pharmaceutical combination. More specifically the alternative cancer cytoxic or antineoplastic agents include, without limitation, one or more PARP inhibitor, one or more topoisomerase inhibitor, one or more thymidylate synthase inhibitor or one or more platinum-based antineoplastic agent.
  • the CHD1L inhibitors employed in methods of this invention are compounds 6, 8, 52, 54, 56, 61, 62, 65 or 66 or pharmaceutically acceptable salts or solvates thereof.
  • the CHD1L inhibitors employed in methods of this invention are compounds 6, 8 or pharmaceutically acceptable salts or solvates thereof.
  • the CHD1L inhibitors employed in methods of this invention are compounds 52, 54 or pharmaceutically acceptable salts or solvates thereof.
  • the CHD1L inhibitors employed in methods of this invention are compounds 22, 23, 26 or 27 or pharmaceutically acceptable salts thereof.
  • the methods of the invention employ CHD1L inhibitors of formula II and include all embodiments described herein for formula II.
  • the invention also provides novel compounds of formula II, salts thereof and pharmaceutical compositions contains such compounds and salts.
  • the methods of the invention employ CHD1L inhibitors of formula XX and include all embodiments described herein for formula XX.
  • the invention also provides novel compounds of formula XX, salts thereof and pharmaceutical compositions containing such compounds and salts.
  • the methods of the invention employ CHD1L inhibitors of formula XXI and include all embodiments described herein for formula XXI.
  • the invention also provides novel compounds of formula XXI, salts thereof and pharmaceutical compositions containing such compounds and salts.
  • the methods of the invention employ CHD1L inhibitors of formula XXII and include all embodiments described herein for formula XXII.
  • the invention also provides novel compounds of formula XXII, salts thereof and pharmaceutical compositions containing such compounds and salts.
  • the methods of the invention employ CHD1L inhibitors of formula XXIII and include all embodiments described herein for formula XXIII.
  • the invention also provides novel compounds of formula XXII, salts thereof and pharmaceutical compositions containing such compounds and salts.
  • the methods of the invention employ CHD1L inhibitors of formula XLV and include all embodiments described herein for formula XXIII.
  • the invention also provides novel compounds of formula XLV salts thereof and pharmaceutical compositions containing such compounds and salts.
  • the methods of the invention employ CHD1L inhibitors of formula XLVI and include all embodiments described herein for formula XLVI.
  • the invention also provides novel compounds of formula XXII, salts thereof and pharmaceutical compositions containing such compounds and salts.
  • the invention is also directed to CHD1L inhibitors of this invention and pharmaceutically-acceptable compositions comprising any such inhibitors.
  • pharmaceutically-acceptable compositions comprise one or more CHD1L inhibitors and a pharmaceutically-acceptable excipient.
  • the invention is directed to any compound or pharmaceutically acceptable salt or solvate thereof as described in chemical formulas herein which is novel.
  • the invention is directed to CHD1L inhibitors and pharmaceutically acceptable salts thereof as described in formulas herein with the exception that the CHD1L inhibitor is other than compounds 1-8 or salts or solvates thereof.
  • the invention is directed to CHD1L inhibitors and pharmaceutically acceptable salts thereof as described in formulas herein with the exception that the CHD1L inhibitor is other than compounds 1-9 or salts thereof.
  • the invention is directed to any one of compounds 9-39, 40-68, 69-73, 74-101, 102-103, 104-116, 117-142, or 143-177 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically acceptable compositions that contains such compounds or salts or solvates.
  • the invention is directed to any one of compounds 10-39, 40-73, 74-116, 117-142 or 43-177 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically acceptable compositions that contains such compounds or salts or solvates.
  • the invention is directed to any one of compounds 52-73 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically acceptable compositions that contains such compounds or salts or solvates.
  • the invention is directed to any one of compounds 28-39, 74,75, 52, 54, 62-66, or 74-75 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically acceptable compositions that contains such compounds or salts or solvates.
  • the invention is directed to any one of compounds 10-39 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically acceptable compositions that contains such compounds or salts or solvates.
  • the invention is directed to any one of compounds 40-73 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically acceptable compositions that contains such compounds or salts or solvates.
  • the invention is directed to any one of compounds 74-116 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically acceptable compositions that contains such compounds or salts or solvates. In embodiments, the invention is directed to any one of compounds 117-142 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically acceptable compositions that contains such compounds or salts or solvates. In embodiments, the invention is directed to any one of compounds 143-177 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically acceptable compositions that contains such compounds or salts or solvates. In embodiments, the invention is directed to one or more of compounds 10-177 of Scheme 1 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically-acceptable compositions that contains such compounds or salts or solvates.
  • the invention is directed to one or more of compounds 150-154 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically acceptable compositions that contains such compounds or salts or solvates. In embodiments, the invention is directed to one or more of compounds 155-159 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically acceptable compositions that contains such compounds or salts or solvates. In embodiments, the compound is selected from compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically acceptable compositions that contains such compounds or salts or solvates.
  • the compound is selected from compounds 52, 118, 126, 131, 150, or 169 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically acceptable compositions that contains such compounds or salts or solvates.
  • the compound is selected from compounds 28, 31, 54, 57, or 75 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically acceptable compositions that contains such compounds or salts or solvates.
  • the compound is one or more of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically acceptable compositions that contains such compounds or salts or solvates.
  • the compound is one of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169 or pharmaceutically acceptable salts or solvates thereof or pharmaceutically acceptable compositions that contains such compounds or salts or solvates.
  • the CHD1L inhibitors employed in the methods of the invention are selected from compound 52 or pharmaceutically acceptable salts or solvates thereof.
  • a CHD1L inhibitor of the invention has Clog P of 5 or less.
  • a CHD1L inhibitor of the invention has Clog P of 3-4.
  • the invention is directed to the following compounds and to methods herein employing these compounds for the treatment of cancer, particularly CRC and mCRC: any one of compounds 52-73; compound 52 or 53; compounds 54, 55 or 67; compounds 57, 58 or 59; or pharmaceutically acceptable salts or solvates thereof; any one of compound 8, compound 52, compound 53, compound 54, compound 55, compound 56, compound 57, compound 58, compound 59, compound 61, compound 62, compound 65, compound 66, or compound 67 or pharmaceutically acceptable salts or solvates thereof.
  • the invention is directed to the following compounds and to methods herein employing these compounds for the treatment of cancer, particularly CRC and mCRC: any one of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169; any one of compounds 52, 118, 126, 131, 150, or 169;.any one of compounds 28, 31, 54, 57, or 75; any one of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169; one or more of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169.
  • the invention provides a pharmaceutical combination of one or more CHD1L inhibitor and one or more alternative cancer cytotoxic or antineoplastic agent.
  • the components of the pharmaceutical combination can be together or separate.
  • the pharmaceutical combination is a pharmaceutical compositions containing one or more CHDL1 inhibitor and one or more PARP inhibitor or one or more topoisomerase inhibitor or one or more thymidylate synthase inhibitor.
  • the pharmaceutical combination is a pharmaceutical compositions containing one or more CHDL1 inhibitor and one or more platinum- based antineoplastic agent.
  • the pharmaceutical combination is two or more separate pharmaceutical compositions each containing different components of the pharmaceutical combination.
  • the pharmaceutical combination is two separate pharmaceutical compositions, one containing one or more CHD1L inhibitors and one containing one or more PARP inhibitors or one or more topoisomerase inhibitor or one or more thymidylate synthase inhibitor. In embodiments, the pharmaceutical combination is two separate pharmaceutical compositions, one containing one or more CHD1L inhibitors and one containing one or more platinum-based antineoplastic agent. In embodiments, the pharmaceutical combination is a single pharmaceutical composition, containing one or more CHD1L inhibitors and one containing one or more PARP inhibitor. In embodiments, the pharmaceutical combination is a single pharmaceutical composition, containing one or more CHD1L inhibitors and one containing one or more topoisomerase inhibitor.
  • the pharmaceutical combination is a single pharmaceutical composition, containing one or more CHD1L inhibitors and one containing one or more thymidylate synthase inhibitor. More specifically, the invention relates to pharmaceutical combinations as described herein which comprise one or more CHD1L inhibitor of any one of formulas I- XXIII, XXX-XLII anf XLV-XLVI or pharmaceutically acceptable salts or solvates thereof. More specifically, the invention relates to pharmaceutical combinations as described herein which comprise one or more CHD1L inhibitor of any one of formulas I, II, XX-XXIII or pharmaceutically acceptable salts or solvates thereof.
  • the invention relates to pharmaceutical combinations as described herein which comprise one or more CHD1L inhibitor of any one of formulas XLV -XLVI or pharmaceutically acceptable salts or solvates thereof. More specifically, the invention relates to pharmaceutical combinations as described herein which comprise one or more of CHDL1 inhibitors of any of compounds 1-177 or any one of compounds 9-177 or pharmaceutically acceptable salts or solvates thereof.
  • the CHD1L inhibitors of the pharmaceutical combination are compounds 52-73; compound 52 or 53; compounds 54, 55 or 67; or compounds 57, 58 or 59; or pharmaceutically acceptable salts or solvates thereof; any one of compound 8, compound 52, compound 53, compound 54, compound 55, compound 56, compound 57, compound 58, compound 59, compound 61, compound 62, compound 65, compound 66, or compound 67 or pharmaceutically acceptable salts or solvates thereof.
  • the CHD1L inhibitors of the pharmaceutical combination are any one of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169; any one of compounds 52, 118, 126, 131, 150, or 169;.any one of compounds 28, 31, 54, 57, or 75; any one of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169; one or more of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169.
  • the invention also relates to the use of a CHD1L inhibitor in the manufacture of a medicament for the treatment of cancer, particularly for the treatment of CHD1L-driven cancer, TCF-driven cancer, or EMT-driven cancer, particularly GI cancer, and more particularly CRC or mCRC.
  • the cancer to be treated is breast cancer, particularly BRCA-mutated breast cancer, ovarian cancer, particularly BRCA-mutated ovarian cancer, pancreatic cancer, particularly BRCA-mutated pancreatic cancer, lung cancer, prostate cancer or liver cancer.
  • the invention relates to the use of a CHD1L inhibitor of any one of formulas I- XX, XXI, XXII, XXIII, XXX-XLII and XLV-XLVI or pharmaceutically acceptable salts or solvates thereof in the manufacture of a medicament for the treatment of cancer, CHD1L-driven cancer, TCF-driven cancer, or EMT-driven cancer, particularly GI cancer, and more particularly CRC or mCRC.
  • the CHD1L inhibitors are those of formulas I-IX, XI-XIX, XX, XX1, XXII, XXIII, XXXV- XLII and XLV-XLVI.
  • the CHD1L inhibitors are those of formula I, formula II, formula XX, formula XXI, formula XXII or formula XXIII. In embodiments, the CHD1L inhibitors are those of formula XLVor XLVI. In embodiments, the CHD1L inhibitor is one or more of the compounds 1-117 of Scheme 1. In embodiments, the CHD1L inhibitor is one or more of the compounds 118-177 of Scheme 1.
  • the CHD1L inhibitors are compounds 52-73; compound 52 or 53; compounds 54, 55 or 67; or compounds 57, 58 or 59; or pharmaceutically acceptable salts or solvates thereof; any one of compound 8, compound 52, compound 53, compound 54, compound 55, compound 56, compound 57, compound 58, compound 59, compound 61, compound 62, compound 65, compound 66, or compound 67 or pharmaceutically acceptable salts or solvates thereof.
  • the CHD1L inhibitors of the pharmaceutical combination are any one of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169; any one of compounds 52, 118, 126, 131, 150, or 169;.any one of compounds 28, 31, 54, 57, or 75; any one of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169; one or more of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169 or pharmaceutically acceptable salts or solvates thereof.
  • the invention also relates to the use of a CHD1L inhibitor in combination with an alternative cancer cytooxic or antineoplastic agent in ithe manufacture of a medicament for the combination treatment of cancer, particularly for the treatment of CHD1L-driven cancer, TCF- driven cancer, or EMT-driven cancer, particularly GI cancer, and more particularly CRC or mCRC.
  • the cancer to be treated is breast cancer, particularly BRCA-mutated breast cancer or metastatic breast cancer, ovarian cancer, particularly BRCA-mutatedovarian cancer, pancreatic cancer, particularly BRCA-mutated pancreatic cancer, lung cancer, prostate cancer, or liver cancer.
  • the invention relates to the use of a CHD1L inhibitor of any one of formulas I- XXIII, XXX-XLII and XLV-XLVI or pharmaceutically acceptable salts or solvates thereof in the manufacture of a medicament for the combination treatment of cancer, CHD1L-driven cancer, TCF-driven cancer, or EMT-driven cancer, particularly GI cancer, and more particularly CRC or mCRC.
  • the CHD1L inhibitors are those of formula I, formula II, formula XX, formula XXI, formula XXII or formula XXIII.
  • the CHD1L inhibitors are those of formula XLV-XLVI.
  • the CHD1L inhibitors are those of formulas I-IX, XI-XIX, XX, XXI, XXII, XXIII, XXII, XXIII, XXXV-XLII or XLV-XLVI.
  • the CHD1L inhibitor is one or more of the compounds 1-117 or one or more of compounds 8-177, compounds 9-177 or compounds 118-177 of Scheme 1.
  • the CHD1L inhibitors are compounds 52-73; compound 52 or 53; compounds 54, 55 or 67; or compounds 57, 58 or 59; or pharmaceutically acceptable salts or solvates thereof; any one of compound 8, compound 52, compound 53, compound 54, compound 55, compound 56, compound 57, compound 58, compound 59, compound 61, compound 62, compound 65, compound 66, or compound 67 or pharmaceutically acceptable salts or solvates thereof.
  • the CHD1L inhibitors of the pharmaceutical combination are any one of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169; any one of compounds 52, 118, 126, 131, 150, or 169;.any one of compounds 28, 31, 54, 57, or 75; any one of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169; one or more of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169 or pharmaceutically acceptable salts or solvates thereof.
  • the one or more CHD1L inhibitors are combined in the medicament with one or more PARP inhibitors, one or more topoisomerase inhibitors, one or more thymidylate synthase inhibitors or one or more platinum-based antineoplastic agents.
  • the invention further relates to a CHD1L inhibitor in combination with one or more alterntive cancer cytotoxic or antineoplastic agent for use in the treatment of cancer, CHD1L-driven cancer, TCF-driven cancer, or EMT-driven cancer, particularly GI cancer, and more particularly CRC or mCRC.
  • the cancer to be treated is breast cancer, ovarian cancer, and pancreatic cancer, particularly BRCA-mutated breast cancer, BRCA-mutated ovarian cancer, BRCA-mutated pancreatic cancer, prostate cancer, stomach cancer, lung cancer, or liver cancer. More specifically, the invention relates to the use of a CHD1L inhibitor of any one of formulas I- XXIII, XXX-XLII and XLV-XLVI or pharmaceutically acceptable salts or solvates thereof in the manufacture of a medicament for the combination treatment of cancer, CHD1L-driven cancer, TCF-driven cancer, or EMT-driven cancer, particularly GI cancer, and more particularly CRC or mCRC.
  • the CHD1L inhibitors are those of formula I, formula II, formula XX, formula XXI, formula XXII or formula XXIII. In embodiments, the CHD1L inhibitors are those of formula XLV-XLVI. In embodiments, the CHD1L inhibitors are those of formulas I-IX, XI-XIX, XX, XXI, XXII, XXIII, XXII, XXIII, XXXV-XLII or XLV-XLVI. In embodiments, the CHD1L inhibitor is one or more of the compounds 1-117 or one or more of compounds 8-177, compounds 9-177 or compounds 118-177 of Scheme 1.
  • the CHD1L inhibitors are compounds 52-73; compound 52 or 53; compounds 54, 55 or 67; or compounds 57, 58 or 59; or pharmaceutically acceptable salts or solvates thereof; any one of compound 8, compound 52, compound 53, compound 54, compound 55, compound 56, compound 57, compound 58, compound 59, compound 61, compound 62, compound 65, compound 66, or compound 67 or pharmaceutically acceptable salts or solvates thereof.
  • the CHD1L inhibitors of the pharmaceutical combination are any one of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169; any one of compounds 52, 118, 126, 131, 150, or 169;.any one of compounds 28, 31, 54, 57, or 75; any one of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169; one or more of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169 or pharmaceutically acceptable salts or solvates thereof.
  • the alternitve cancer cytotoxic or antineoplastic agent is one or more PARP inhibitors, one or more topoisomerase inhibitors, one or more thymidylate synthase inhibitors or one or more platinum-based antineoplastic agents.
  • PARP inhibitors one or more PARP inhibitors
  • topoisomerase inhibitors one or more thymidylate synthase inhibitors
  • platinum-based antineoplastic agents platinum-based antineoplastic agents.
  • FIG.1B SW620, HCT-16, and DLD1CHD1L- OE cells with TOPflash reporter were used to measure inhibition of TCF transcription using 3 doses over 24h.
  • Figures 2A-2D CHD1L inhibitors reverse EMT and the malignant phenotype in CRC. Dose responses for CHD1L inhibitors that modulate EMT measured by high-content imaging of (FIG.2A) downregulation of VimPro-GFP reporter and (FIG.2B) upregulation of EcadPro-RFP reporter.
  • FIG.2C Mean EC 50 values ⁇ SEM are calculated from three independent experiments (FIG.2C) CSC stemness measured by clonogenic colony formation after pretreatment with CHD1L inhibitors in DLD1CHD1L-OE and HCT-116 cells.
  • Figures 3A-C Compound 6 induces apoptosis in CRC cell lines and PDTOs.
  • FIG.3A Time course evaluation of the induction E-cadherin expression using Ecad-ProRFP reporter assay and cytotoxicity using Cell-ToxTM Green cytotoxicity assay (Promega, Madison, WI).
  • FIG.3B Annexin V-FITC staining analysis of apoptosis after treatment of SN-38 and 6 for 12 hours.
  • FIG.3C Cytotoxicity of 6 in PDTO CRC102 using CellTiter-Blue® cell viability assay (Promega, Madison, WI). Mean EC 50 values ⁇ s.d. are calculated from six independent experiments and representative graph is shown with inset of a representative PDTO.
  • CHD1L is activated through binding TCF-complex members PARP1 and TCF4 [Abbott et al., 2020] (1) Once activated, CHD1L is directed to hindered WREs localized on chromatin. (2) Chromatin remodeling and DNA translocation occurs exposing WRE sites. (3) TCF-complex binds to exposed WREs facilitated by CHD1L, promoting EMT genes and other genes associated with mCRC. CHD1L ATPase inhibitors effectively prevent step 1, leading to the reversion of EMT and other malignant properties of CRC. Figures 6A-E Evaluation of Compound 8.
  • FIG.6A Compound 8 displays potent low ⁇ M dose- dependent inhibition of TCF-transcription based on TOPFlash reported in SW260 cells cultures in 2D and over a 24 h time course.
  • Compound 8 effectively reverses EMT in dual reporter SW620 tumor organoids over 72 h evidenced by downregulation of vimentin (FIG.6B) and (FIG.6C) upregulation of E-cadherin promoter activity in a dose-dependent manner.
  • Compound 8 significantly inhibits (FIG.6D) clonogenic colony formation over 10 days after pre-treatment for 24 h and (FIG.6E) HCT116 invasive potential over 48 h.
  • FIG.7A Treatment with Compound 6.9
  • FIG.7B Treatment with Compound 6.11
  • Alternative compound numbers as used in Scheme 1 are given in parenthesis.
  • IC 50 in some cases average IC 50 , are provided in each figure. Viability data for a number of exemplary compounds are provided in Table 3.
  • FIGS 8A-B Assessment of CHD1L-mediated DNA repair and “on target” effects of CHD1L inhibitor 6 alone and in combination with irinotecan (prodrug of SN38).
  • CHD1L is known to be essential for PARP-1-mediated DNA repair, causing resistance to DNA damaging chemotherapy [Ahel et al., 2009; Tsuda et al., 2017].
  • DLD1 CRC cells that have low level expression of CHD1L (DLD1 Empty Vector, EV) compared to DLD1 cells that were engineered to overexpress CHD1L (DLD1 Overexpressing, OE) were used.
  • FIG.8A is a Western blot comparing expression of CHD1L in DLD1(EV) to DLD1(OE) in view of control expression of --tubulin in these cells.
  • FIG.8B presents a graph of --H2AX intensity (relative to DMSO) for compound alone, SN38 alone, and a combination of the two in DLD1 empty vector cells and DLD1 overexpressing cells.
  • Compound 6.0 alone does not induce significant DNA damage, nor does it synergize with SN38 in DLD1 cells with low expression of CHD1L.
  • This graph demonstrates CHD1L inhibitor “on target” effects that synergize with SN38 inducing DNA damage in DLD1 cells overexpressing CHD1L.
  • FIG.9A Synergy studies with exemplary CHD1L inhibitors and irinotecan (Prodrug of SN38).
  • FIG.9B Synergy studies with compound 6.9 in SW620 Colorectal Cancer (CRC) Tumor Organoids.
  • FIG.9C Synergy studies with compound 6.11 in SW620 Colorectal Cancer (CRC) Tumor Organoids.
  • SN38 combinations of 6, and 6.3 are 50-fold, and 150-fold more potent, respectively, than SN38 alone in killing colon SW620 tumor organoids.
  • SN38 combination of 6.9 and 6.11 are both over 100-fold more potent than SN38 alone.
  • Each of compounds 6, 6.3, 6.9 and 6.11 exhibit synergism with irinotecan (and SN38) for killing SW620 tumor organoids.
  • Figure 10 In vivo synergy studies of compound 6 in combination with irinotecan in mice.
  • Figure 10 includes a graph of tumor volume (fold) SW620 tumor xenografts as a function of days (up to 28 days) of treatment with compound 6 alone (2), irinotecan alone (3) or a combination thereof (4), compared to control (1).
  • a data Table is also provided showing data statistical significance.
  • Figure 11 In vivo synergy of CHD1L inhibitor compound 6 and irinotecan continues post treatment.
  • Figure 11 includes a graph of tumor volume (fold) SW620 tumor xenografts as a function of days (up to 41 days) of treatment with irinotecan alone (1) or a combination of compound 6 and irinotecan (2).
  • a data Table is also provided showing data statistical significance.
  • the combination of irinotecan and compound 6 significantly inhibits colon SW620 tumors to almost no tumor volume beyond the last treatment (day 28) compared to irinotecan alone.
  • Figure 12 Compound 6 alone and in combination with irinotecan significantly increases the survival of CRC tumor-bearing mice compared to vehicle and irinotecan alone.
  • Figure 12 includes a graph of survival (%) as a function of time up to 52 days after last treatment on day 28 with compound 6 alone (2), irinotecan alone (3) or a combination thereof (4), compared to control (1).
  • a data Table is also provided showing data statistical significance. Survival rate was significantly higher with the combination treatment compared to single dosage compounds or control.
  • Figure 13 In vivo synergy studies of compound 6.11 incombination with irinotecan in mice.
  • Figure 13 includes a graph of tumor volume (fold) SW620 tumor xenografts as a function of days (up to 20 days) of treatment with compound 6.11 alone (2), irinotecan alone (3) or a combination thereof (4), compared to control (1).
  • a data Table is also provided showing data statistical significance.
  • the combination of irinotecan and compound 6.11 significantly inhibit colon SW620 tumor xenografts to almost no tumor volume within 20 days of treatment compared to the irinotecan alone.
  • Figure 14 In vivo synergy of CHD1L inhibitor compound 6.11 and irinotecan continues post treatment.
  • Figure 14 includes a graph of tumor volume (fold) SW620 tumor xenografts as a function of days (up to 41 days) of treatment with irinotecan alone (1) or a combination of compound 6 and irinotecan (2). Treatment was stopped at day 33 (Tx released). The combination of irinotecan and compound 6.11 significantly inhibits colorectal SW620 tumors beyond the last treatment (day 33) compared to irinotecan alone.
  • Figure 15 In vivo synergy of CHD1L Inhibitor 6.11 and irinotecan significantly increases survival benefit. Compound 6.11 in combination with irinotecan significantly Increases the survival of CRC tumor-bearing mice compared to vehicle and irinotecan alone.
  • Figure 15 includes a graph of survival (%) as a function of time up to 50 days after last treatment on day 33 with compound 6 alone (2), irinotecan alone (3) or a combination thereof (4), compared to control (1).
  • a data Table is also provided showing data statistical significance. Survival rate was significantly higher with the combination treatment compared to irinotecan alone or control.
  • Figures 16A and 16B Enzymatic inhibition of CHD1L and SW620 tumor organoid cytotoxicity.
  • FIG.16A Quantification of the catalytic domain of CHD1L recombinant protein.
  • FIG.16B Dose- response of CHD1L inhibitor compounds measuring SW620 tumor organoid viability.
  • FIG.17A TCF-transcriptional activity in isolated SW620 and HCT116 EMT phenotypes. P-values were calculated by one-way ANOVA where *P ⁇ 0.05.
  • FIGs.18A-18D CHD1L inhibitors are potent cytotoxic agents in CRC cell line and patient tumor organoids.
  • FIGs.18A and 18B Dose-response graphs of lead CHD1Li, measuring cell viability after 72 h of treatment of isolated M-phenotype SW620 and HCT116 tumor organoids.
  • FIGs.18C and 18D Dose-response graphs of lead CHD1Li, measuring cell viability after 72 h of treatment of CRC042 and CRC102 patient-derived tumor organoids (PDTO).
  • PDTO patient-derived tumor organoids
  • FIGs.19A and 19C Dose-response graphs of the downregulation of VimPro-GFP promoter activity measured by EGFP fluorescence of SW620 and HCT116 tumor organoids treated with lead CHD1L inhibitors.
  • FIGs.19B and 19D Fold change upregulation of EcadPro-RFP promoter activity measured through RFP fluorescent signal in SW620 and HCT116 tumor organoids after treatment with lead CHD1L inhibitors.
  • FIG.19E Representative maximum projection confocal images of HCT116 tumor organoids after treatment with compound 6.5 for both VimPro-GFP and EcadPro-RFP promoter activity. Data is shown in mean ⁇ SEM of duplicate experiments.
  • Figures 20A-20B Cancer cell stemness is greatly reduced by CHD1L inhibitors.
  • FIG.20A Number of clonogenic colonies formed after continuous lead CHD1Li treatment in SW620 cells.
  • FIG.20B Number of clonogenic colonies formed after continuous treatment with lead CHD1L inhibitors in HCT116 cells. The data is represented as the mean ⁇ SEM of duplicate experiments using triplicate technical replicates.
  • Figures 21A and 21B The data is represented as the mean ⁇ SEM of duplicate experiments using triplicate technical replicates.
  • FIG.21A is a graph of tumor volume as a function of days after initiation of treatment for control vehicle only ( -, closed circles), 6.1175 mg/kg (squares) and 6.11125 mg/kg. Data point significance assessed using 2-Way ANOVA (multiple comparison), where *P ⁇ 0,05, **P ⁇ 0.01, ***P ⁇ 0.001, ****P ⁇ 0.0001, # P ⁇ 0.05, #### P ⁇ 0.0001.
  • FIG. 21B is a graph of average mouse body weight as a function of days after initiation of treatment.
  • the invention relates generally to the characterization of a relatively new oncogene, CHD1L, as a tumorigenic factor associated with poor prognosis and survival in CRC.
  • CHD1L a relatively new oncogene
  • a new biological function for CHD1L as a DNA binding factor for the TCF transcription complex required for promoting TCF- driven EMT and other malignant properties has been demonstrated.
  • Abbott et al., 2020 and the supplementary information for this article, which is available from the journal web site (mct.aacrjournals.org) provide description of a portion of the experiments and data presented herein and are each incorporated by reference herein in its entirety.
  • CHD1L is amplified (Chr1q21) and overexpressed in many types of cancer (e.g., breast, bladder, colorectal, esophageal, fibrosarcoma, liver, ovarian, and gastrix cancer).
  • CHD1L expression was correlated with poor survival, with low-CHD1L patients living significantly longer than high-CHD1L patients.
  • Marisa et al., 2013 identified six distinct subtypes for improved clinical stratification of CRC and CHD1L is universally expressed in all six subtypes, indicating its potential as a therapeutic target for CRC.
  • CHD1L also correlated with tumor node metastasis, with increased expression moving from N0 (no regional spread) to N3 (distant regional spread).
  • CHD1L is an oncogene promoting malignant CRC and its high expression correlates with poor prognosis and survival of CRC patients.
  • a new biological function for CHD1L as a DNA binding factor for the TCF-transcription complex required for promoting TCF-driven EMT and other malignant properties is demonstrated herein.
  • the first known inhibitors of CHD1L have been identified and characterized which display good pharmacological efficacy in cell-based models of CRC, including PDTOs.
  • CHD1L inhibitors effectively prevent CHD1L-mediated TCF-transcription, leading to the reversion of EMT and other malignant properties, including CSC stemness and invasive potential.
  • CHD1L inhibitor 6 displays the ability to induce cell death that is consistent with the reversion of EMT and induction of cleaved E-cadherin mediated extrinsic apoptosis through death receptors. Furthermore, compound 6 synergizes with SN38 (i.e., irinotecan) displaying potent DNA damage induction compared to SN38 alone, which is consistent with the inhibition of PARP1/CHD1L mediated DNA repair. CHD1L inhibitors having drug-like physicochemical properties and favorable in vivo PK/PD disposition with no acute liver toxicity have been identified.
  • CHD1L-mediated TCF-driven EMT involved in CRC tumor progression and metastasis is presented (FIG.5).
  • TCF- complex specifically recruits CHD1L to dynamically regulate metastatic gene expression.
  • CHD1L binds to nucleosome hindered WREs when directed by the TCF-complex via protein interactions with PARP1 and TCF4.
  • PARP1 is characterized as the major cellular activator of CHD1L through macro domain binding that releases auto inhibition.
  • CHD1L inhibitors have a unique mechanism of action by inhibiting CHD1L ATPase activity, which prevents exposure of WREs to the TCF-complex, inhibiting transcription of TCF-target genes associated with EMT and particularly with mCRC.
  • Small molecule inhibitors of CHD1L as described herein, have been identified in screens based on inhibition of CHD1L ATPase activity. Certain inhibitors identified exhibit drug-like physicochemical properties and favorable in vivo PK/PD disposition with no acute liver toxicity. Such inhibitors are effective as a treatment for CRC and mCRC (metastatic CRC) among other CHD1L-driven cancers.
  • drugability relates to pharmaceutical properties of a prospective drug for administration, distribution, metabolism and excretion. Drugability is assessed in various ways in the art. For example, the “Lipinski Rule of 5" for determining drug-like characteristics in a molecule related to in vivo absorption and permeability can be applied [Lipinski et al., 2001; Ghose, et al., 1999]
  • the invention provides methods for combination therapy in which administration of CHD1L inhibitor is combined with administration of one or more anticancer agent which is not a CHD1L inhibitor.
  • the other anticancer agents is a topoisomerase inhibitor, a platinum-based antineoplastic agent, a PARP inhibitor or combinations of two or more of such inhibitors and agents.
  • the combination therapy combines administration of a CHD1L inhibitor with a topoisomerase inhibitor.
  • the combination therapy combines administration of a CHD1L inhibitor with a platinum-based antineoplastic agent.
  • the combination therapy combines administration of a CHD1L inhibitor with a PARP inhibitor.
  • the combination therapy combines administration of a CHD1L inhibitor with a topoisomerase inhibitor and administration of a PARP inhibitor.
  • the combination therapy combines administration of a CHD1L inhibitor with chemotherapy for the specific cancer being treated.
  • the combination of a CHD1L inhibitor and the other antineoplastic agent exhibits synergistic activity in combination.
  • therapy employing CHD1L can be combined with radiation therapy suitable for a given cancer.
  • Various PARP inhibitors are known in the art.
  • PARP-resistance cancer is treated with a combination of a CHD1L inhibitor and the PARP inhibitor.
  • Various topoisomerase inhibitors are known in the art and have been employed clinically.
  • topoisomerase inhibitors useful in methods and compositions hereinare topoisomerase I inhibitors.
  • topoisomerase inhibitors useful in methods and compositions herein include camptothecin and prodrugs thereof, irinotecan, topotecan, belotecan, indotecan, or indimitecan.
  • topoisomerase inhibitors useful in methods and compositions herein include etoposide or teniposide.
  • topoisomerase inhibitors useful in methods, pharmaceutical combinaions and combined cancer therapy herein include namitecan, silatecan, vosaroxin, aldoxorubicin, doxorubicin, becatecarin, or edotecarin.
  • topoisomerase inhibitors useful in methods and compositions herein are topoisomerase I inhibitors.
  • topoisomerase II-alpha inhibitors are, for example, reported in Published PCT application WO2020/0205991, published October 8, 2020, and its priority document U.S. provisional application 62/827,818, filed April 1, 2019.
  • Each of these references is incorporated by reference herein in its entirety for descriptions of types of topoisomerase inhibitors, specific topoisomerase inhibitors, mechanisms of topoisomerase inhibition, cancers treated using topoisomerase inhibitors and combination therapies using topoisomerase inhibitors.
  • Various platinum-based antineoplastic agents also called platins
  • platins platinum-based antineoplastic agents
  • platinum-based antineoplastic agents useful in methods and compostions herein include cisplatin, carbon platin, oxaliplatin, nedaplatin, lobaplatin, or heptaplatin.
  • platinum-based antineoplastic agents include satraplatin, or picoplatin.
  • Platinum-based antineoplastic agents may be liposomally encapsulated (e.g., LypoplatinTM) or bound in nanopolymers (e.g., ProLindac TM ).
  • Various thymidylate synthase inhibitors are known in the art and have been employed clinically particularly in the treatment of CRC [Papamichael, 2009; Lehman, 2002].
  • Thymidylate synthase inhibitors useful in the methods and compositons herein include without limitation folate analogues and nucleotide analogues.
  • the thymidylate synthase inhibitor is raltitrexed, pemetrexed, nolatrexed or ZD9331.
  • the thymidylate synthase inhibitor is 5-fluorouracil or capecitabine.
  • the invention provides CHD1L inhibitors of the following formulas: Compounds useful in the methods, pharmaceutical compositions or pharmaceutical combinations of this invention include those of formula I: or salts, or solvates thereof, where: the B ring is an optionally-substituted at least divalent heteroaryl ring or ring system having one, two or three 5- or 6-member rings, any two or three of which can be fused rings, where the rings are carbocyclic, heterocyclic, aryl or heteroaryl rings and at least one of the rings is heteroaryl; in the B ring, each X is independently selected from N or CH and at least one X is N; R P is an optionally-substituted primary or secondary amine group [–N(R 2 )(R 3 )] or is a –(M) x -P group, where P is –N(R 2 )(R 3 ) or
  • C1-C3 alkoxy, C1-C6 acyl each of which groups is optionally substituted with one or more halogen, nitro, cyano, amino, mono- or di-C1-C3 alkyl substituted amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6-cycloalkenyl, C1-C3 haloalkyl, C6-C12 aryl, C5-C12 heteroaryl, C3-C12 heterocyclyl.
  • R 1 -R 3 are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl, each of which groups is optionally substituted;
  • One or more of R 1 -R 3 is cycloalkyl substituted alkyl, for example, a cyclopropylmethyl, a cyclopentylmethyl, or a cyclohexylmethyl;
  • R is hydrogen or a C1-C3 alkyl; each R’
  • the A ring is divalent and is a single 6-member aromatic ring which can contain 1 or 2 heteroatoms, particularly 1 or 2 nitrogen.
  • the divalent Aring is 1,4-phenylene or 2, 5-pyridylene.
  • the divalent B ring is substituted with at least one electronegative substituent.
  • the electronegative substituent is a halogen.
  • the electronegative substituent is a haloalkyl group having 1-3 carbon atoms.
  • the electronegative substituent is fluorine.
  • the electronegative substituent is tifluoromethyl (CF 3 -).
  • x is 1.
  • the B ring is substituted with at least one halogen, and x is 1 and L 1 is – CH 2 –. In related embodiments of formula I, the B ring is substituted with at least one fluorine, x is 1 and L 1 is –CH 2 –. In an embodiment of formula I, the divalent B ring is substituted with at least one C1-C3 alkyl group. In an embodiment of formula I, the B ring is substituted with at least one methyl group.
  • Ring A is an optionally substituted phenylene; Ring A is an optionally substituted 1,4-disubstituted phenylene Ring A is an optionally substituted naphthylene; Ring A is an optionally substituted 2,6-disubstituted naphthylene; Ring A is an optionally substituted pyridylene; Ring A is an optionally substituted 2,5-pyridylene; Ring B is an optionally substituted pyridylene, Ring B is an optionally substituted pyrimidylene; Ring B is an optionally substituted pyrazinylene; Ring B is an optionally substituted triazinylene; Ring B is an optionally substituted quinazolinylene; Ring B is an optionally substituted pteridinylene; Ring B is an optionally substituted quinolinylene; Ring B is an optionally substituted isoquinolinyenel; Ring B is an optionally substituted naphthyridinylene; Ring B
  • R A represents H at all available ring positions. In embodiments, R A represents one C1-C3 alkyl substituebt at an available ring position. In embodiments, R A represents one methyl substituebt at an available ring position. In embodiments, R A represents one halogen substituted at an available ring position. In embodiments, R A represents one fluorine substituted at an available ring position. In embodiments, R A represents one C1-C3 haloalkyl substituted at an available ring position; In embodiments, R A represents one trifluoromethyl group at an available ring position. In embodiments, R B represents H at all available ring positions.
  • Preferred A and B ring substitution includes one or more C1-C3 alkyl, C3-C7 cycloalkyl, C4-C10 cycloalkyl substituted alkyl, C2-C4 alkenyl, C1-C3 alkoxy, C1-C3 acyl, a C1-C4 alkoxycarbonyl, a C1-C4 acyloxy, carboxyl, halogen, hydroxyl, C1-C3 haloalkyl, mono- or disubstituted phenyl or mono- or disubstituted benzyl.
  • More specific A and B ring substitution includes methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, phenyl, benzyl, halophenyl, halobenzyl, Cl, Br, F, CF 3 -, HO-, CF 3 O-, CH 3 CO- , HOOC-, CH 3 OCO-and CHCO-.
  • the divalent A ring is other than a phenyl ring or a benzyl ring.
  • the A ring is other than a phenyl ring.
  • the A ring is other than an unsubstituted phenyl ring or an unsubstituted benzyl ring. In an embodiment, the A ring is other than an unsubstituted phenyl ring.
  • the divalent B ring has one of the structures illustrated in Scheme 4, RB1-RB17. In embodiments, the divalent B ring has structrure RB2-RB5, wherein R B represents optional substitution as described for formula I. The ring is bonded to R P or Y at positions indicated.
  • R B represents optional substitution at ring carobns with one or more of C1-C3 alkyl, halogen or C1-C3 haloalkyl and more specifically C1-C3 fluoroalkyl and more specifically with one or more methyl, trifluoromethyl or fluorine.
  • the divalent B ring has structrure RB6, which is bonded to R P or Y are the positions indicated and wherein R B represents optional substitution as described for formula I.
  • R B represents optional substitution at ring carobns with one or more of C1-C3 alkyl, halogen or C1-C3 haloalkyl and more specifically C1-C3 fluoroalkyl and more specifically with one or more methyl, trifluoromethyl or fluorine.
  • the B ring is as illustrated in RB7-RB17 which is bonded to RP and bonded to Y at the position indicated and wherein R B represents optional substitution as described for formula I.
  • R B represents optional substitution at ring carobns with one or more of C1-C3 alkyl, halogen or C1-C3 haloalkyl and more specifically C1-C3 fluoroalkyl and more specifically with one or more methyl, trifluoromethyl or fluorine.
  • the B ring is as shown in RB14-17.
  • the divalent B ring has structure as shown in Scheme 4, formula RB1, where X 1 and X 2 are selected from CH and N and at least one of X 1 and X 2 is N and X 3 -X 6 are selected from CH, CH 2 , O, S, N and NH where the illustrated B ring is saturated, unsaturated or aromatic, dependent upon choice of 1-X 6 and R B represents optional substitution as defined for formula I.
  • R B represents hydrogens and the B ring is unsubstituted.
  • R B represents one or more halogen, C1-C3 alkyl, C1-C3 acyl, C1-C3 alkoxy.
  • R B represents one or more F, Cl or Br, methyl, ethyl, acetyl or methoxy or combinations thereof.
  • the B ring is selected from any of RB2-RB5, as shown in Scheme 4.
  • Y is –O–, –S–, –N(R 1 )–, –CON(R 1 )–, –N(R 1 )CO– or –N(R 1 )CON(R 1 )–;
  • Y is –O–, –S–, –NH–, –CONH–, or –NHCO— or –N(R 1 )CON(R 1 )–;
  • Y is –N(R 1 )–, –CON(R 1 )–,–N(R 1 )CO— or –N(R 1 )CON(R 1 )–;
  • Y is –N(R 1 )–, –CON(R 1 )–, or –N(R 1 )CO—
  • Y is –N(R 1 )CON(R 1 )–;
  • Y is –N(H)–, –CON(H)–,–N(H)CO– or –N(H)CON(
  • both x and y are 0 and Y is –N(R 1 ) -. In embodiments of formula I, both x and y are 0 and Y is —NH -. In embodiments of formula I, both x and y are 0 and Y is —CONH-. In embodiments of formula 1, both x and y are 0 and Y is –NHCO-. In embodiments of formala 1, both x and y are 0 and Y is –NHCONH-.
  • Z is –N(R ⁇ ) -, –CON(R ⁇ ) -, or –N(R ⁇ )CO -;
  • Z is -CH(CF 3 )N(R ⁇ ) -;
  • Z is —SO 2 N(R ⁇ ) -;
  • Z is -N(R ⁇ )CON(R ⁇ ) -;
  • Z is -N(R ⁇ )CH 2 CON(R ⁇ )CH 2 -;
  • Z is particularly a C1-C3 fluoroalkyl;
  • R' is hydrogen or a C1-C3 alkyl;
  • R’ is hydrogen, methyl or CF 3 -;
  • R’ is hydrogen or methyl;
  • R’ is hydrogen;
  • Z is –N(R ⁇ ) -, –CON(R ⁇ ) -, or –N(R ⁇ )CO - and
  • R’ is hydrogen or methyl;
  • Z is –N(R ⁇ ) -, –CON(R ⁇ ) -, –
  • x is 0; x is 1 and L 2 is –(CH 2 ) n –, where n is 1-3; y is 0, x is 1 and L 2 is –(CH 2 ) n –, where n is 1-3; x is 0 and Z is –N(R ⁇ ) -, –CON(R ⁇ ) -,–N(R ⁇ )CO - or –N(R ⁇ )CON(R’) -; x is 0, and Z is –N(R ⁇ ) -, –CON(R ⁇ ) -,–N(R ⁇ )CO - or –N(R ⁇ )CON(R’) - and R’ is hydrogen or methyl; x is 0, and Z is –N(H) -, –CON(H) -,–N(H)CO - or –N(H)CON(H) -; x is 0 and Z is–CON(R
  • x is 1, L 2 is –(CH 2 ) n -, where n is 1-3, and Z is –N(R 1 ) -, –CON(R ⁇ ) -, –N(R ⁇ )CO - or –N(R ⁇ )CON(R’) - ;
  • x is 1, L 2 is –(CH 2 ) n -, where n is 1-3, and Z is —NH -, –CONH -, –NHCO - or –NHCONH - ;
  • x is 1, L 2 is –CH 2 - and Z is –NH -, –CONH -, –NHCO - or –NHCONH -;
  • x is 1, L 2 is –CH 2 -CH 2 -, and Z is –NH -, –CONH -, –NHCO - or –NHCONH -;
  • x is 1, L 2 is –CH 2 -CH 2 -,
  • R P is: –N(R 2 )(R 3 ); –(M)-N(R 2 )(R 3 ), where M is an optionally substituted linker -(CH 2 ) n - or -N(R)(CH 2 ) n -, where each n is independently an integer from 1-6 (inclusive) and R is hydrogen or an optionally substituted alkyl group having 1-3 carbon atoms; –(M)-N(R 2 )(R 3 ), M is an optionally substituted linker -(CH 2 ) n -, where each n is independently an integer from 1-6 (inclusive) and R is hydrogen or an optionally substituted alkyl group having 1-3 carbon atoms; –(M)-N(R 2 )(R 3 ), M is an optionally substituted linker -(CH 2 ) n -, where each n is independently an integer from 1-6 (inclusive) and R is hydrogen or an optionally substituted alkyl group having 1-3
  • R P or -N(R 2 )(R 3 ) is: any one of R N 1-R N 39 of Scheme 2; R N 1; R N 3; R N 2 or R N 4; R N 5 or R N 6; R N 7 or R N 8; R N 9; R N 10; R N 11; R N 12; R N 13; R N 14; R N 15; R N 16; R N 17 or R N 18; R N 19 or R N 20; R N 21; R N 22; R N 23 or R N 24; R N 25; R N 26-R N 29; R N 27-R N 32; R N 30; R N 31; R N 33-R N 36; R N 37; R N 38; R N 39; or RN1, RN2, RN3, RN4, RN11, RN13, or RN14; or R N 1-R N 31 which is unsubstituted.
  • R H is: optionally substituted phenyl; other than optionally substituted pheny; unsubstituted phenyl; other than unsubsttuted pheny; optionally substituted naphthyl; unsubstituted naphthyl; optionally substituted naphthy-2-yl; optionally substituted naphthy-1-yl; naphthy-2-yl; naphthy-1-yl; optionally substituted thiophenyl; halogen substituted thiophenyl; bromine substituted thiophenyl; optionally substituted thiophen-2-yl; halogen substituted thiophen-2-yl; bromine substituted thiophen-2-yl; 4- halothiophen-2-yl; 4-bromothiophen-2-yl; optionally substituted furyl; optionally substituted fur-2-yl; optionally substituted indolyl; unsubstituted indoly
  • optional substitution of R H is substitution with one or more halogen, C1- C3 alkyl, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 fluoroalkyl, C4-C7 cycloalkylalkyl, OH, amino, C1- C6 acyl, -COOR E , -OCOR E , -CONR E R F , -OCONR E R D , -NR E COR F , -SR E , -SOR E , -SO 2 R E ,and -SO 2 NR E R F , where R E and R e are as defined above and in particular are hydrogen, C1-C3 alkyl, phenyl or benzyl.
  • R H is substitution with one or more halogen (particularly Br or Cl), C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 fluoroalkyl (particularly CF 3 -).
  • R H has formula: where: X 11 is CH, CR T or N; R T is optional R H ring substitution as described above and R and R’ are independently hydrogen, C1-C6 alkyl group, C4-C10 cycloalkylalkyl group, aryl group, heterocyclyl group, or heteroaryl group each of which groups are optionally substituted.
  • R T is hydrogen or substitution with one or more of halogen, OH, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 alkyl substituted with a C3-C6 cycloalkyl;
  • R’ is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 alkyl substituted with a C3-C6 cycloalkyl; and
  • R is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 alkyl substituted with a C3-C6 cycloalkyl.
  • R H has formula: X 11 is CH, CR T or N; X 10 is CH, CR T or N; R T is R H ring optional substitution as described above and R’ are independently hydrogen, C1-C6 alkyl group, C4-C10 cycloalkylalkyl group, aryl group, heterocyclyl group, or heteroaryl group each of which groups are optionally substituted.
  • R T is hydrogen or substitution with one or more of halogen, OH, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 alkyl substituted with a C3-C6 cycloalkyl;
  • R’ is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 alkyl substituted with a C3-C6 cycloalkyl; and
  • R is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 alkyl substituted with a C3-C6 cycloalkyl.
  • R H in formula I or R12 in formula XX is selected from any one of formulas R12-1 to R12-84.
  • R H is selected from the following formulas in Scheme 3: R12-79 or R12-80; or R12-81-R12-84; or R12-70, R12-71, or R12-75-R12-78; or R12-3, R12-4, R12-5, R12-7, R12-8, R12-10, R12-23, R12-25, R12-27, R12-29, or R12-31; or R12-12, R12-13, R2-145, R12-15, R12-16, R12-17, R12-18, R12-19, R12-20, R12-21, R12-21 or R12-22, where p is 0; or R12-33, R12-34, R12-35, R12-36, R12-37, R12-38, R12-39 R12-40, R12-41, R12-42, where p is 0; or R12-
  • R H is selected from 5-membered heterocyclic groups of general formula: where: T, U, V, and W are selected from O, S, C(R ⁇ )(R ⁇ ), C(R ⁇ ) - /, C(R ⁇ ), C - /, N(R ⁇ ), or N - /; where the group contains one or two double bonds dependent upon choice of T, U, V, and W; where the R H group is bonded to the -(L 2 )y-Z -moiety in the compound of formula I through C-/, C(R ⁇ ) - /, or N - /; and where R ⁇ indicates optional substitution on N or C.
  • R H is selected from 5-membered heterocyclic groups of formula: T is C(R ⁇ ), C - /, or N; or U is O, S, C(R ⁇ )(R ⁇ ), C(R ⁇ ) - /, N(R ⁇ ), or N - /; V is CR ⁇ , C - /, or N and W is CR ⁇ , C ⁇ ⁇ , N, where the RH group is bonded to the ⁇ (L2)y-Z ⁇ moiety in the compound of formula I through C-/, C(R ⁇ ) - /, or N - /, where the R H group is bonded to the -(L 2 )y-Z -moiety in the compound of formula I through C -/, C(R ⁇ ) - /, or N - /; and where R ⁇ indicates optional substitution on N or C.
  • the symbol “ -/” indicates a monovalent bond through which the heterocyclic group is bonded in the compounds herein e.g., C -/ indicates a monovalent bond from a ring carbon through which the heterocyclic group is bonded into compounds herein.
  • R H is a fused ring heterocyclic group of formula: U, V and W are selected from O, S, N, C(R ⁇ )(R ⁇ ), C(R ⁇ ) - /, C(R ⁇ ), C - /, N(R ⁇ ), or N - /; T ⁇ , U', V ⁇ and W are selected from C(R ⁇ ), C - /, N(R ⁇ ), or N - /; where the R H group is bonded to the -(L 2 )y-Z -moiety in the compound of formula I through C-/, C(R ⁇ ) - /, or N - / in the indicated ring; where the group contains bonds dependent upon choice of, U, V, and W; and where R ⁇ indicates optional substitution on N or C.
  • R H is a fused heterocyclic group of formula: U, and V are selected from N, C(R ⁇ ), or C - /, /; W is selected from O, S, C(R ⁇ )(R ⁇ ), C(R ⁇ ) - /, N(R ⁇ ), or N - /; T ⁇ , U', V ⁇ and W' are selected from C(R ⁇ ), C - /, N(R ⁇ ), or N - /; where the R H group is bonded to the -(L 2 )y-Z -moiety in the compound of formula I through C-/, C(R ⁇ ) - /, or N - / in the indicated ring; and where R ⁇ indicates optional substitution on N or C.
  • Each R'' is selected from hydrogen, halogen, nitro, cyano, amino, mono- or di-C1- C3 alkyl substituted amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6-cycloalkenyl, C1- C3 haloalkyl, C6-C12 aryl, C5-C12 heteroaryl, C3-C12 heterocyclyl.
  • C1- C3 alkoxy, C1-C6 acyl each of which groups is optionally substituted with one or more halogen, nitro, cyano, amino, mono- or di-C1-C3 alkyl substituted amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6-cycloalkenyl, C1-C3 haloalkyl, C6-C12 aryl, C5-C12 heteroaryl, C3-C12 heterocyclyl. C1-C3 alkoxy, and C1-C6 acyl.
  • R H is selected from any one of: R T is R H ring optional substitution as described above and R and R’ are independently hydrogen, C1-C6 alkyl group, C4-C10 cycloalkylalkyl group, aryl group, heterocyclyl group, or heteroaryl group each of which groups are optionally substituted.
  • R T is hydrogen or substitution with one or more of halogen, OH, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 alkyl substituted with a C3-C6 cycloalkyl;
  • R’ is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 alkyl substituted with a C3-C6 cycloalkyl; and
  • R is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 alkyl substituted with a C3-C6 cycloalkyl.
  • R and R’ are independently hydrogen, C1-C3 alkyl or C4-C7 cycloalkylalkyl.
  • R T represents hydrogens or substitution with one halogen, particularly Br.
  • R H is a 6-member optionally substituted heterocyclic or heteroaryl group having 1-3 nitrogen in the ring, 1 or 2 oxygens, sulfurs or both in the ring, or 1 or 2 nitrogens and one oxygen or sulfur in the ring, where optional substitution is defined as in formula I.
  • the heterocyclic group can be unsaturated, partially unsaturated or a heteroaryl group.
  • R H is an optionally substituted fused heterocyclic or heteroaryl group having two fused 6-member rings having 1-5 nitrogens in the fused rings, 1-3 oxygens, sulfurs or both in the fused rings or 1-4 nitrogens and 1 or 2 oxygens, sulfurs or both in the fused rings, where optional substitution is defined as in formula I.
  • the fused rings have 1, 2, 3 or 4 nitrogens in the fused rings.
  • the fused rings have 1 or 2 oxygens or sulfurs in the fused rings.
  • the fused rings have 1 or 2 nitrogens and one oxygen or sulfur in the fused rings.
  • the fused ring heterocyclic group can be unsaturated, partially unsaturated or a heteroaryl group.
  • the R H group is selected from phenyl, oxazinyl, pyridinyl, pyrimidinyl, thionyl, pyranyl, thiazinyl, 4H-pyranyl, naphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, purinyl and chromanyl, where the R H group is attached to the -(L 2 )y-Z -moiety in the compound of formula I at any available ring position.
  • R H group is attached to the -(L 2 )y-Z -moiety in the compound of formula I at a carbon in the ring.
  • R P is selected from the group of moieties R N 1, R N 2, R N 3, R N 9, R N 10, R N 11, R N 13, R N 14, R N 36, R N 37, R N 38 or R N 39 and R H is selected from the group of moieties R12- 3, R12-5, R12-44. R13-45, R12-48, R12-58, R12-70, R12-72, R12-73, R12-75, R12-79, R12-80, R12-82, R12-83, or R12-84.
  • R P is selected from the group of moieties R N 1, R N 2, R N 3, R N 9, R N 10, R N 11, R N 13, R N 14, R N 36, R N 37, R N 38 or R N 39
  • R H is selected from the group of moieties R12-3, R12-5, R12-44. R13-45, R12-48, R12-58, R12-70, R12-72, R12- 73, R12-75, R12-79, R12-80, R12-82, R12-83, or R12-84, and the A ring is unsubstituted 1,4- phenylene or 2,5-pyridylene.
  • R P is selected from the group of moieties R N 1, R N 2, R N 3, R N 9, R N 10, R N 11, R N 13, R N 14, R N 36, R N 37, R N 38 or R N 39
  • R H is selected from the group of moieties R12-3, R12-5, R12-44.
  • the A ring is unsubstituted 1,4- phenylene or 2,5-pyridylene
  • Y is —NH-, -CONH, -NH-CO- or –NH-CO-NH- and x is 0 or 1 and L 1 , if present, is –(CH 2 )-.
  • R P is selected from the group of moieties R N 1, R N 2, R N 3, R N 9, R N 10, R N 11, R N 13, R N 14, R N 36, R N 37, R N 38 or R N 39
  • R H is selected from the group of moieties R12-3, R12-5, R12-44.
  • the A ring is unsubstituted 1,4-phenylene or 2,5- pyridylene
  • Y is —NH-, -CONH, -NH-CO- or –NH-CO-NH-
  • x is 0 or 1
  • L 1 if present, is –(CH 2 )-
  • Z is -CONH, -NH-CO- or –NH-CO-NH-
  • y is 0 or 1 and L 2 , if present is –(CH 2 )-.
  • the A ring is unsubstituted 1,4-phenylene.
  • Y is –NH-.
  • Z is –CONH-.
  • y is 1.
  • x is 1.
  • -Z-(L 2 )y-R H is a group other than –NH-SO 2 -R W , where R W is R 1 is mes-trimethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, naphthyl, 2,3,4,5,- tetramethylphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 2,4-dimethoxyphenyl, 2,5- dimethoxyphenyl or 4-phenoxypheny.
  • -Z-(L 2 )y- is a moiety other than –NR X -SO 2 -, where R X is H, hydrogen, methyl acetate, acetate, aminoacetyl, 4-formic acid benzyl, 4-isopropylbenzyl, 4-chlorobenzyl or 4-methoxybenzyl.
  • - Z- is other than –NR X -SO 2 -, where R X is H, hydrogen, methyl acetate, acetate, aminoacetyl, 4- formic acid benzyl, 4-isopropylbenzyl, 4-chlorobenzyl or 4-methoxybenzyl.
  • R H is other than a phenyl group or an optionally substituted phenyl group.
  • R H is a heterocyclic group that is substituted with a single halogen, particularly a Br.
  • R P or –N(R 2 )(R 3 ) are optionally substituted amine groups illustrated in Scheme 2, R N 1-R N 39. Exemplary optional substitution of groups is illustrated in Scheme 2. The illustrated R substituent groups can be positioned on any available ring position.
  • preferred alkyl are C1-C3 alkyl
  • acyl includes formyl
  • preferred acyl are C1-C6 acyl and more preferably acetyl
  • acyloxy are preferably C1-C4 acyloxy
  • alkoxycarbonyl are preferably C2-C5 alkoxycarbonyl
  • hydroxyalkyl are C1-C6 hydroxyalkyl and preferably are –CH 2 -CH 2 -OH
  • preferred alkyl are C1-C3 alkyl
  • preferred alkyl for –SO 2 alkyl are C1-C3 alkyl and more preferred is methyl.
  • -N(R 2 )(R 3 ) is R N 1. In specific embodiments, -N(R 2 )(R 3 ) is R N 3. In specific embodiments, -N(R 2 )(R 3 ) is R N 2 or R N 4. In specific embodiments, -N(R 2 )(R 3 ) is R N 5 or R N 6. In specific embodiments, -N(R 2 )(R 3 ) is R N 7 or R N 8. In specific embodiments, -N(R 2 )(R 3 ) is R N 9. In specific embodiments, -N(R 2 )(R 3 ) is R N 10. In specific embodiments, -N(R 2 )(R 3 ) is R N 11.
  • -N(R 2 )(R 3 ) is R N 12. In specific embodiments, -N(R 2 )(R 3 ) is R N 13. In specific embodiments, -N(R 2 )(R 3 ) is R N 14. In specific embodiments, -N(R 2 )(R 3 ) is R N 15. In specific embodiments, -N(R 2 )(R 3 ) is R N 16. In specific embodiments, -N(R 2 )(R 3 ) is R N 17 or R N 18. In specific embodiments, -N(R 2 )(R 3 ) is R N 19 or R N 20. In specific embodiments, -N(R 2 )(R 3 ) is R N 21.
  • -N(R 2 )(R 3 ) is R N 22. In specific embodiments, -N(R 2 )(R 3 ) is R N 23 or R N 24. In specific embodiments, -N(R 2 )(R 3 ) is R N 25. In an embodiment, -N(R 2 )(R 3 ) is R N 1, R N 2, R N 3, R N 4, R N 11, R N 13, or R N 14. In an embodiment, -N(R 2 )(R 3 ) is R N 26-R N 29. In an embodiment, -N(R 2 )(R 3 ) is R N 30. In an embodiment, -N(R 2 )(R 3 ) is R N 31.
  • R H is a moiety illustrated in Scheme 3 R12-1 to R12-78. In embodiments of formula I, R H is a moiety illustrated in Scheme 3 R12-1 to R12-69. In embodiments of formula I, R H is a moiety illustrated in Scheme 3 R12-1 to R12-71. In embodiments of formula I, R H is a moiety illustrated in Scheme 3 R12-72 to R12-78. In an embodiment, R H is R12-35-R12-42. In embodiments, R H is any of R12-43-R12-69. In embodiments, R H is any of R12-43-R12-45. In embodiments, R H is any of R12-46-R12-48.
  • R H is any of R12- 49-R12-51. In embodiments, R H is any of R12-52-R12-54. In embodiments, R H is any of R12-55- R12-58. In embodiments, R H is any of R12-59-R12-62 In embodiments, R H is any of R12-63- R12-66. In embodiments, R H is any of R12-67-R12-69. In embodiments, R H is R12-72 or R12-73. In embodiments, R H is R12-74. In embodiments, R H is t12-75 or R12-76. In embodiments, R H is R12-77. In embodiments, R H is R12-78.
  • preferred alkyl groups are C-C6 alkyl groups or more preferred C1-C3 alkyl groups
  • preferred halogen are F, Cl and Br
  • acyl includes formyl and preferred acyl are –CO-C1-C6 alky and more preferred is acetyl
  • phenyl is optionally substituted with one or more halogen, alkyl or acyl.
  • More preferred alkyl are methyl, ethyl. Methyl cyclopropyl and cyclopropyl. More preferred halogen are Cl and Br.
  • compounds useful in the methods herein include those of formula II:
  • R 4 and R 5 are independently selected from hydrogen, halogen, alkyl group, alkenyl group, cycloalkyl group, cycloalkenyl group, or heterocyclyl group, each of which groups is optionally substituted or R 4 and R 5 together form an optionally substituted 5- or 6-member heterocyclic ring which can contain one or two double bonds or be aromatic; and the dotted line is a single or double bond dependent upon choice of R 4 and R 5 .
  • x is 1, and y is 1.
  • both X are nitrogens.
  • R P is –N(R 2 )(R 3 ).
  • L 1 and L 2 are –(CH 2 )n -, where n are independently is 1, 2 or 3.
  • R H is a heterocyclic or heteroaryl group.
  • Y is -N(R 1 ) -, -CON(R 1 ) -, or -N(R 1 )CO -.
  • Z is –CON(R ⁇ ) - or –N(R ⁇ )CO -.
  • R' is hydrogen, a C1-C3 alkyl or a Ci-C3 haloalky.
  • R' is hydrogen, methyl or trifluoromethyl.
  • R A is hydrogen, halogen C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 acyl, or C1-C3 haloalkyl.
  • R' is hydrogen, methyl, methoxy or trifluoromethyl.
  • R 4 and R 5 are selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxyl, or C1-C3 haloalkyl.
  • R 4 and R 5 together form a 5- or 6-member carbocyclic or heterocyclic ring which is saturated, partially unsaturated or is heteroaromatic.
  • R H is any one of RH1- RH12.
  • Y is NH. In embodiments of formula II, Y is NH, and x is 0. In embodiments of formula II, Y is NH, x is 0 and R 5 is other than an electronegative group. In embodiments of formula II, Y is NH, x is 0 and R 5 is hydrogen. In embodiments of formula II, Y is NH, x is 0, R 5 is hydrogen and R 4 is a C1-C3 alkyl. In embodiments of formula II, Y is NH, x is 0, R 5 is hydrogen and R 4 is methyl. In embodiments of formula II, Y is NH, x is 1 and L 1 is –(CH 2 )n-, where n is 1 or 2.
  • Y is NH, x is 1 and L 1 is –(CH 2 )n-, where n is 1 or 2, and R 5 is an electronegative group.
  • Y is NH, x is 1 and L 1 is –(CH 2 )n-, where n is 1 or 2, and R 5 is a halogen.
  • Y is NH, x is 1 and L 1 is –(CH 2 )-, and R 5 is a halogen.
  • Y is NH, x is 1 and L 1 is –(CH 2 )n-, where n is 1 or 2, and R 5 is a fluorine.
  • Y is NH, x is 1 and L 1 is –(CH 2 )-, and R 5 is a fluorine.
  • Y is NH, x is 1 and L 1 is –(CH 2 )-, R 5 is a halogen and R 4 is C1-C3 alkyl.
  • Y is NH, x is 1 and L 1 is –(CH 2 )-, R 5 is a halogen and R 4 is methyl.
  • Y is NH, x is 1 and L 1 is –(CH 2 )-, R 5 is a fluorine and R 4 is C1-C3 alkyl.
  • Y is NH, x is 1 and L 1 is –(CH 2 )-, R 5 is a fluorine and R 4 is methyl.
  • compounds useful in the methods herein include those of formula III: or salts, or solvates thereof, where variables are as defined in formula I and II and the dotted line represent a single or double bond.
  • y is 1.
  • y is 0.
  • both X are nitrogens.
  • R P is –N(R 2 )(R 3 ).
  • L 2 is –(CH 2 )n -, where n is 1, 2 or 3.
  • R H is a heterocyclyl or heteroaryl group.
  • Y is -N(R 1 ) -, -CON(R 1 ) -, or -N(R 1 )CO -.
  • Z is –CON(R ⁇ ) - or –N(R ⁇ )CO -.
  • R' is hydrogen, a C1-C3 alkyl or a C1-C3 haloalky.
  • R' is hydrogen, methyl or trifluoromethyl.
  • R A is hydrogen, halogen C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 acyl, or C1-C3 haloalkyl.
  • R' is hydrogen, methyl, methoxy or trifluoromethyl.
  • R 4 and R 5 are selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxyl, or C1-C3 haloalkyl.
  • R 4 and R 5 together form a 5- or 6-member carbocyclic or heterocyclic ring which is saturated, partially unsaturated or is heteroaromatic.
  • R H is any one of RH1-RH12.
  • compounds useful in the methods herein include those of formula IV: or salts or solvates thereof; where variables are as defined in formula I and II and the dotted line represents a single or double bond.
  • y is 1.
  • y is 0. In embodiments, both X are nitrogens.
  • R P is –N(R 2 )(R 3 ).
  • L 2 is –(CH 2 )n -, where n is 1, 2 or 3.
  • R H is a heterocyclyl or heteroaryl group.
  • R 1 is hydrogen
  • R1 is hydrogen, methyl or trifluoromethyl.
  • Z is –CON(R ⁇ ) - or – N(R ⁇ )CO -.
  • R' is hydrogen, a C1-C3 alkyl or a Ci-C3 haloalky.
  • R' is hydrogen, methyl or trifluoromethyl.
  • R A is hydrogen, halogen C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 acyl, or C1-C3 haloalkyl.
  • R' is hydrogen, methyl, methoxy or trifluoromethyl.
  • R 4 and R 5 are selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxyl, or C1-C3 haloalkyl.
  • R 4 and R 5 together form a 5- or 6-member carbocyclic or heterocyclic ring which is saturated, partially unsaturated or is heteroaromatic.
  • R H is any one of RH1-RH12.
  • compounds useful in the methods herein include those of formula V: or salts or solvates thereof; where variables are as defined in formula I and II and the dotted line represents a single or double bond.
  • y is 1.
  • y is 0.
  • both X are nitrogens.
  • R P is –N(R 2 )(R 3 ).
  • L 2 is –(CH 2 )n -, where n is 1, 2 or 3.
  • R H is a heterocyclyl or heteroaryl group.
  • R 1 is hydrogen
  • R1 is hydrogen, methyl or trifluoromethyl.
  • Rs is hydrogen, C1-C3 alkyl, optionally substituted C1-C3 alkyl, or aryl.
  • R A is hydrogen, halogen C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 acyl, or C1-C3 haloalkyl.
  • R' is hydrogen, methyl, methoxy or trifluoromethyl.
  • R 4 and R 5 are selected from hydrogen, halogen, C1- C3 alkyl, C1-C3 alkoxyl, or C1-C3 haloalkyl.
  • R 4 and R 5 together form a 5- or 6- member carbocyclic or heterocyclic ring which is saturated, partially unsaturated or is heteroaromatic.
  • R H is any one of RH1-RH12.
  • compounds useful in the methods herein include those of formula VI: or salts or solvates thereof; where variables are as defined in formula I and II and the dotted line represents a single or double bond.
  • y is 1.
  • y is 0.
  • both X are nitrogens.
  • x is 1 and -N-(CH 2 )n -, where n is 1, 2 or 3.
  • y is 0.
  • L 2 is –(CH 2 )n -, where n is 1, 2 or 3.
  • R H is a heterocyclyl or heteroaryl group.
  • R 1 is hydrogen
  • R 1 is hydrogen, methyl or trifluoromethyl.
  • Rs is hydrogen, C1-C3 alkyl, optionally substituted C1-C3 alkyl, or aryl.
  • R A is hydrogen, halogen C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 acyl, or C1- C3 haloalkyl.
  • R' is hydrogen, methyl, methoxy or trifluoromethyl.
  • R 4 and R 5 are selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxyl, or C1- C3 haloalkyl. In embodiments, R 4 and R 5 together form a 5- or 6-member carbocyclic or heterocyclic ring which is saturated, partially unsaturated or is heteroaromatic.
  • R H is any one of RH1-RH12.
  • compounds useful in the methods herein include those of formula VII: or salts or solvates thereof; where variables are as defined in formula I and II and the dotted line represents a single or a double bond.
  • y is 1. In embodiments, y is 0. In embodiments, both X are nitrogens.
  • x is 1 and -N-(CH 2 )n -, where n is 1, 2 or 3.
  • y is 0.
  • L 2 is –(CH 2 )n -, where n is 1, 2 or 3.
  • R H is a heterocyclyl or heteroaryl group.
  • R 1 is hydrogen
  • R 1 is hydrogen, methyl or trifluoromethyl.
  • Rs is hydrogen, C1-C3 alkyl, optionally substituted C1-C3 alkyl, or aryl.
  • R A is hydrogen, halogen C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 acyl, or C1- C3 haloalkyl.
  • R' is hydrogen, methyl, methoxy or trifluoromethyl.
  • R 4 and R 5 are selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxyl, or C1- C3 haloalkyl.
  • R 4 and R 5 together form a 5- or 6-member carbocyclic or heterocyclic ring which is saturated, partially unsaturated or is heteroaromatic.
  • RH is any one of RH1-RH12.
  • compounds useful in the methods herein include those of formula VIII: or salts or solvates thereo where variables are as defined in formula I and II, the dotted line represents a single or a double bond, R 6 -R 9 are independently selected from hydrogen and R A groups defined in formula I.
  • R M represents optional substitution on the fused ring and R M takes the values of R A in formula I.
  • y is 1.
  • y is 0.
  • both X are nitrogens.
  • x is 1 and -N-(CH 2 )n -, where n is 1, 2 or 3.
  • x is 0.
  • L 2 is –(CH 2 )n -, where n is 1, 2 or 3.
  • R 1 is hydrogen In embodiments, R 1 is hydrogen, methyl or trifluoromethyl.
  • R 7 -R 9 are independently selected from hydrogen, C1-C3 alkyl, optionally substituted C1-C3 alkyl, or aryl.
  • R 7 -R 9 are independently selected from hydrogen, halogen C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 acyl, or C1-C3 haloalkyl. In embodiments, R 7 -R 9 are all hydrogens.
  • R 4 and R 5 are selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxyl, or C1-C3 haloalkyl. In embodiments, R 4 and R 5 together form a 5- or 6-member carbocyclic or heterocyclic ring which is saturated, partially unsaturated or is heteroaromatic.
  • R M is one or more hydrogen, halogen, C1-C3 alkyl group, C4-C7 cycloalkylalkyl group or C1-C3 haloalkyl group. In embodiments, R M is one or more hydrogen, halogen, particularly Br, methyl or trifluoromethyl. In embodiments, R M is hydrogen.
  • compounds useful in the methods herein include those of formula IX:
  • w here variables are as defined in formula I, the dotted line represents a single or a double bond.
  • R 6 -R 9 are independently selected from hydrogen and R A groups defined in formula I and R M represents optional substitution as defined in formula I.
  • y is 1.
  • y is 0.
  • both X are nitrogens.
  • x is 1 and M is -N-(CH 2 )n -, where n is 1, 2 or 3.
  • x is 1 and M is - (CH 2 )n -, where n is 1, 2 or 3.
  • x is 0.
  • L 2 is –(CH 2 )n -, where n is 1, 2 or 3.
  • R 1 is hydrogen In embodiments, R 1 is hydrogen, methyl or trifluoromethyl.
  • R 7 -R 9 are independently selected from hydrogen, C1-C3 alkyl, optionally substituted C1-C3 alkyl, or aryl.
  • R 7 -R 9 are independently selected from hydrogen, halogen C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 acyl, or C1-C3 haloalkyl. In embodiments, R 7 -R 9 are all hydrogens.
  • R 4 and R 5 are selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxyl, or C1-C3 haloalkyl. In embodiments, R 4 and R 5 together form a 5- or 6- member carbocyclic or heterocyclic ring which is saturated, partially unsaturated or is heteroaromatic.
  • RM is hydrogen, halogen, C1-C3 alkyl group or C1-C3 haloalkyl group.
  • R M is hydrogen, halogen, particularly Br, methyl or trifluoromethyl.
  • the invention provides a compound of formula XI:
  • each X is independently selected from N or CH and at least one X is N;
  • the A ring is a carbocyclic or heterocyclic ring having 3-10 carbon atoms and optionally 1-6 heteroatoms and which optionally is saturated, unsaturated or aromatic;
  • L 1 is an optional 1-3 carbon linker that is optionally substituted, where x is 0 or 1 to indicate the absence of presence of L 1 ;
  • R1 is selected from the group consisting of hydrogen, alkyl group.
  • R 2 and R 3 are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl, each of which groups is optionally substituted or R 2 and R 3 together form an optionally substituted 5- to 8-member heterocyclic ring which is a saturated, partially unsaturated or aromatic ring;
  • R 4 and R 5 are independently selected from hydrogen, halogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl, each of which groups is optionally substituted or R 4 and R 5 together form an optionally substituted 5- or 6-member ring which optionally contains one or two double bonds or is aromatic and optionally contains 1-3 heteroatoms; where the dotted line is a single or double bond dependent upon selection of R 4 and R 5
  • R 1 is H. In embodiments of formula XI, R 1 is H, and x is 0. In embodiments of formula XI, R 1 is H, x is 0 and R 5 is other than an electronegative group. In embodiments of formula XI, R 1 is H, x is 0 and R 5 is hydrogen. In embodiments of formula XI, R 1 is H, x is 0, R 5 is hydrogen and R 4 is a C1-C3 alkyl. In embodiments of formula XI, R 1 is H, x is 0, R 5 is hydrogen and R 4 is methyl.
  • R 1 is H, x is 1 and L 1 is –(CH 2 )n-, where n is 1 or 2. In embodiments of formula XI, R 1 is H, x is 1 and L 1 is –(CH 2 )n-, where n is 1 or 2, and R 5 is an electronegative group. In embodiments of formula XI, R 1 is H, x is 1 and L1 is –(CH 2 )n-, where n is 1 or 2, and R 5 is a halogen. In embodiments of formula XI, R 1 is H, x is 1 and L 1 is –(CH 2 )-, and R 5 is a halogen.
  • R 1 is H, x is 1 and L 1 is –(CH 2 )n-, where n is 1 or 2, and R 5 is a fluorine.
  • R 1 is H, x is 1 and L 1 is –(CH 2 )-, and R 5 is a fluorine.
  • R 1 is H, x is 1 and L 1 is –(CH 2 )-, R 5 is a halogen and R 4 is C1-C3 alkyl.
  • R 1 is H, x is 1 and L 1 is –(CH 2 )-, R 5 is a halogen and R 4 is methyl.
  • R 1 is H, x is 1 and L1 is –(CH 2 )-, R 5 is a fluorine and R 4 is C1-C3 alkyl.
  • R 1 is H, x is 1 and L 1 is –(CH 2 )-, R 5 is a fluorine and R 4 is methyl.
  • the compound has formula XII: or a salt or solvate thereof where variables are as defined for formula XI.
  • the compound has formula XIII: or a salt, or a solvate thereof, wherein variables are as defined in formula XI and where; each Y is independently selected from N or CH; R B represents hydrogens or 1-10 substituents on the indicated ring, wherein R A substituents are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, mono- or disubstituted amino, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, -OR 15 , -COR 15 , - COOR 15 , -OCOR 15 , -CO-NR 16 R 17 , -OCON R 16 R 17 , -NR 16 -CO-R 15 , -SR 15 , -SOR 15 , -SO 2 R 15 , -SO 2 - NR 16 R 17 , or -(L 2 ) y -R 10 , where L 2 is an organic radicals
  • R 1 is H. In embodiments of formula XIII, R 1 is H, and x is 0. In embodiments of formula XIII, R 1 is H, x is 0 and the B ring is substituted with other than an electronegative group. In embodiments of formula XIII, R 1 is H, x is 0 and the B ring is substituted with one or more hydrogens or C1-C3 alkyl groups. In embodiments of formula XIII, R 1 is H, x is 0, the B ring is substituted with one or more hydrogens or methyl groups. In embodiments of formula XIII, R 1 is H, x is 1 and L 1 is –(CH 2 )n-, where n is 1 or 2.
  • R 1 is H, x is 1 and L 1 is –(CH 2 )n-, where n is 1 or 2, and the B ring is substituted with an electronegative group.
  • R 1 is H, x is 1 and L 1 is –(CH 2 )n-, where n is 1 or 2, and the B ring is substituted with a halogen.
  • R 1 is H, x is 1 and L 1 is –(CH 2 )-, and the B ring is substituted with a halogen.
  • R 1 is H, x is 1 and L 1 is –(CH 2 )n-, where n is 1 or 2, and the B ring is substituted with a fluorine.
  • R 1 is H, x is 1 and L 1 is –(CH 2 )-, and the B ring is substituted with a fluorine.
  • R 1 is H, x is 1 and L 1 is – (CH 2 )-, the B ring is substituted a halogen and a C1-C3 alkyl.
  • R 1 is H, x is 1 and L 1 is –(CH 2 )-, and the B ring is substituted a halogen.
  • R 1 is H, x is 1 and L1 is –(CH 2 )-, the B ring is substituted with a fluorine and R 4 is C1-C3 alkyl.
  • R1 is H, x is 1 and L1 is –(CH2)-, the B ring is substituted a halogen and a methyl.
  • the compound has formula XIV or XV:
  • the compound has formula XVI or XVII: or a salt or solvate thereof, where variables are as defined in formula XI or XV, and R 11 and R 12 are independently selected from hydrogen, halogen, alkyl group, alkenyl group, cycloalkyl group, cycloalkenyl group, or heterocyclyl group, each of which groups is optionally substituted.
  • the compound has formula XVIII: or salts (or solvates) ther wherein: R 1 is selected from the group consisting of hydrogen, alkyl group. alkenyl group, cycloalkyl group, cycloalkenyl group, heterocyclyl group, or aryl group, each of which groups is optionally substituted (need to define substitution); R 2 and R 3 together form an optionally substituted 5- or 6-member heterocyclic ring which can contain one or two double bonds or be aromatic; R 4 and R 5 are independently selected from hydrogen, halogen, alkyl group, alkenyl group, cycloalkyl group, cycloalkenyl group, or heterocyclyl group, each of which groups is optionally substituted or R 4 and R 5 together form an optionally substituted 5- or 6-member heterocyclic ring which can contain one or two double bonds or be aromatic; the dotted line is a single or double bond dependent upon choice of R 4 and R 5 ; R 6 -R 9 are independently selected from hydrogen,
  • L is a 2-6 atom linker group; (e.g., --CH 2 -O-, -CH 2 -CH 2 -O-, -O-CH 2 -, -O-CH 2 -CH 2 -, - CO-NH-, --NH-CO-, -CH 2 -CO-NH-, -CH 2 -CH 2 -CO-NH-)
  • the compound is of formula XIX: where: R 1 -R 9 are as defined above; the dotted line represents a single or double bond dependent on choice of R 4 and R 5 ; y is 0 or an integer ranging from 1-3 inclusive; and R 10 is selected from alkyl group.
  • the CHD1L inhibitor is a compound of formula XX, XXI, XXII or XXIII:
  • R 1 -R 9 represent hydrogen or optional substituents
  • R 10 is a moiety believed to be associated with potency
  • R N is a moiety believed to be associated with physicochemical properties such as solubility.
  • L 1 is as defined for formula I above and x is 0 or 1 to show the absence of presence of the L 1 group.
  • R 5 is a substituent other than hydrogen which is believed to be associated with metabolic stability.
  • R 5 is a halogen, particularly F or Cl, a C1-C3 alkyl group, particularly a methyl group.
  • R 5 is an electronegative substituent, particularly a halogen, and more preferably F or Cl.
  • R 5 is a halogen, particularly F or Cl
  • R 4 is a C1- C3 alkyl group, particularly a methyl group.
  • R 5 is an electronegative substituent, particularly a halogen, and more preferably F or Cl.
  • R 4 is a substituent other than hydrogen and in particular is a C1-C3 alkyl group, and more particularly is a methyl group.
  • R 5 is F and R 4 is methyl.
  • L 1 is –(CH 2 )n-, where n is 1 or 2 and more specifically where n is 1.
  • R 6 -R 9 are selected from hydrogen, C1-C3-alkyl, halogen, hydroxyl, C1-C3 alkoxy, formyl, or C 1 -C 3 acyl. In embodiments, one or two of R 6 -R 9 are moieties other than hydrogen. In an embodiment, one of R 6 -R 9 is a halogen, particularly fluorine. In specific embodiments, all of R 6 - R 9 are hydrogen. In embodiments, R N is an amino moiety –N(R 2 )(R 3 ). In specific embodiments, R N is an optionally substituted heterocyclic group having a 5- to 7- member ring optionally containing a second heteroatoms (N, S or O).
  • R N is optionally substituted pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, piperazin-1-yl, or morpholino.
  • R N is substituted with one substituent selected from C1-C3 alkyl, formyl, C1-C3 acyl (particularly acetyl), hydroxyl, halogen (particularly F or Cl), hydroxyl, C1-C3 alkyl (particularly –CH 2 -CH 2 -OH).
  • R N is unsubstituted pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, piperazin-1-yl, or morpholino.
  • R 10 is –NRy-CO-(L 2 )y-R 12 or –CO-NRy--(L 2 )y-R 12 , where y is 0 or 1 to indicate the absence of presence of L 2 which is an optional 1-6 carbon atom linker group which linker is optionally substituted and wherein one or two, carbons of the linker are optionally replaced with O, NH, NRy or S, where Ry is hydrogen or a 1-3 carbon alkyl, and R 12 is an aryl group, cycloalkyl group, heterocyclic group, or heteroaryl group, each of which is optionally substituted.
  • y is 1.
  • L 2 is –(CH 2 )p-, where p is 0-3.
  • R 12 is thiophen-2-yl, thiophen-3-yl, furany-2-yl, furan-3-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-4-yl, oxazol-5-yl, oxazol-2-yl, indol-2-yl, indol-3-yl, benzofuran-2-yl, benzofuran-3-yl, benzo[b]thiophen-2-yl, benzo[b]thiophen-3- yl, isobenzofuran-1-yl, isoindol-1-yl, or benzo[c]thiophen-1-yl.
  • R 1 is hydrogen or methyl.
  • R 12 is thiophen-2-yl, furany-2-yl, pyrrol-2-yl, oxazol-4-yl, indol-2-yl, benzofuran-2-yl, or benzo[b]thiophen-2-yl.
  • R 12 is thiophen-2-yl or indol-2-yl.
  • R 1 is hydrogen or methyl.
  • R 1 is selected from the group consisting of hydrogen, alkyl group, alkenyl group, cycloalkyl group, cycloalkenyl group, heterocyclyl group, or aryl group, each of which groups is optionally substituted;
  • R N is –NR 2 R 3 , R 2 and R 3 are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl, each of which groups is optionally substituted or R 2 and R 3 together form an optionally substituted 5- to 8- member heterocyclic ring which is a saturated, partially unsaturated or aromatic ring;
  • R 4 –R 9 are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, mono- or dialkyl substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted cycloal
  • R N is an optionally substituted cyclic amine group selected from any of R N 1-R N 39 (Scheme 2). Exemplary optional substitution of groups is illustrated in Scheme 2. The illustrated R substituent groups can be positioned on any available ring position.
  • preferred alkyl are C1-C3 alkyl
  • acyl includes formyl
  • preferred acyl are C1-C6 acyl and more preferably acetyl
  • hydroxyalkyl are C1-C6 hydroxyalkyl and preferably are –CH 2 -CH 2 -OH
  • preferred alkyl are C1-C3 alkyl
  • preferred alkyl for –SO 2 alkyl are C1-C3 alkyl and more preferred is methyl.
  • R N is R N 1.
  • R N is R N 3.
  • R N is R N 2 or R N 4.
  • R N is R N 5 or R N 6. In specific embodiments, R N is R N 7 or R N 8. In specific embodiments, R N is R N 9. In specific embodiments, R N is R N 10. In specific embodiments, R N is R N 11. In specific embodiments, R N is R N 12. In specific embodiments, R N is R N 13. In specific embodiments, R N is R N 14. In specific embodiments, R N is R N 15. In specific embodiments, R N is R N 16. In specific embodiments, R N is R N 17 or R N 18. In specific embodiments, R N is R N 19 or R N 20. In specific embodiments, R N is R N 21. In specific embodiments, R N is R N 22. In specific embodiments, R N is R N 23 or R N 24.
  • R N is R N 25. In an embodiment, R N is R N 1, R N 2, R N 3, R N 4, R N 11, R N 13, or R N 14. In an embodiment, R N is R N 26-R N 29. In an embodiment, R N is R N 30. In an embodiment, R N is R N 31.
  • R 12 is an optionally-substituted thienyl, thienylmethyl, furyl, furylmethyl, indolyl or methylindolyl. In embodiments, R 12 is a moiety illustrated in Scheme 3 R12- 1 to R12-69, R12-1-R12-71 or R12-72-R12-78.
  • preferred alkyl groups are C-C6 alkyl groups or more preferred C1-C3 alkyl groups
  • preferred halogen are F, Cl and Br
  • acyl includes formyl and preferred acyl are –CO-C1-C6 alky and more preferred is acetyl
  • phenyl is optionally substituted with one or more halogen, alkyl or acyl.
  • R 12 is a methyl, ethyl group or propyl substituted with a moiety as illustrated in Scheme 3 R12-1 to R12-22.
  • R 12 is R12-1.
  • R 12 is R12-2.
  • R 12 is R12-3.
  • R 12 is R12-4.
  • R 12 is R12-5. In an embodiment, R 12 is R12-6. In an embodiment, R 12 is R12-7. In an embodiment, R 12 is R12-8. In an embodiment, R 12 is R12-9. In an embodiment, R 12 is R12-10. In an embodiment, R 12 is R12-11. In an embodiment, R 12 is R12-12. In an embodiment, R 12 is R12-13. In an embodiment, R 12 is R12-14. In an embodiment, R 12 is R12-15. In an embodiment, R12 is R12-16. In an embodiment, R12 is R12-17. In an embodiment, R 12 is R12-18 In an embodiment, R 12 is R12-19. In an embodiment, R 12 is R12-20. In an embodiment, R 12 is R12-21.
  • R 12 is R12-22. In an embodiment, R 12 is one of R12-23-R12-26. In an embodiment, R 12 is one of R12-27-R12-30. In an embodiment, R 12 is one of R12-31-R12-34. In an embodiment, R 12 is one of R12-35-R12-42. In embodiments, R12 is any one of R12-43-R12-69. In embodiments, R 12 is a methyl, ethyl group or propyl group substituted with a moiety R12-43-R12-69, as illustrated in Scheme 3. In embodiments, R12 is any one of R12- 43-R12-45.
  • R 12 is a methyl, ethyl group or propyl group substituted with a moiety R12-43-R12-45 as illustrated in Scheme 3.
  • R12 is any one of R12-46-R12-48.
  • R 12 is a methyl, ethyl group or propyl group substituted with a moiety R12-46-R12- 48 as illustrated in Scheme 3.
  • R12 is any one of 12-49-R12-51.
  • R 12 is a methyl, ethyl group or propyl group substituted with a moiety R12-49-R12- 51 as illustrated in Scheme 3.
  • R12 is any one of R12-52-R12-54.
  • R 12 is a methyl, ethyl group or propyl group substituted with a moiety R12-52-R12- 54 as illustrated in Scheme 3.
  • R12 is any one of R12-55-R12-58.
  • R 12 is a methyl, ethyl group or propyl group substituted with a moiety R12-55-R12- 58 as illustrated in Scheme 3.
  • R12 is any one of R12-59-R12-62
  • R 12 is a methyl, ethyl group or propyl group substituted with a moiety R12-59-R12- 62 as illustrated in Scheme 3.
  • R 12 is any one of R12-63-R12-66. In embodiments, R 12 is a methyl, ethyl group or propyl group substituted with a moiety R12-63-R12- 66 as illustrated in Scheme 3. In embodiments, R 12 is any one of R12-67-R12-69. In embodiments, R 12 is a methyl, ethyl or propyl group substituted with a moiety R12-67-R12-69 as illustrated in Scheme 3. In embodiments, R 12 is a moiety R12-70 or R12-71 as illustrated in Scheme 3. In embodiments, R 12 is a moiety R12-72 or R12-73 as illustrated in Scheme 3.
  • R 12 is a moiety R12-74 as illustrated in Scheme 3. In embodiments, R 12 is a moiety R12-75 or R12-76 as illustrated in Scheme 3. In embodiments, R 12 is a moiety R12-75 or R12-76, where p is 1 or 2 as illustrated in Scheme 3. In embodiments, R 12 is a moiety R12-77 as illustrated in Scheme 3. In embodiments, R 12 is a moiety R12-77., where p is 1 or 2 as illustrated in Scheme 3. In embodiments, R 12 is a moiety R12-78 as illustrated in Scheme 3. In embodiments, R 12 is a moiety R12-78., where p is 1 or 2 as illustrated in Scheme 3.
  • R N is an optionally substituted cyclic amine group selected from any of R N 1-R N 25 or R N 26-R N 39 (Scheme 2) and R 12 is a thienyl, thienylmethyl, furyl, furylmethyl, indolyl or methylindoyl.
  • R N is R N 1, R N 2, R N 3, R N 4, R N 11, R N 13, R N 14 or R N 25 and R 12 is a thienyl, thienylmethyl, furyl, furylmethyl, indolyl or methylindoyl.
  • R N is R N 37 and R 12 is a thienyl, thienylmethyl, furyl, furylmethyl, indolyl or methylindoyl.
  • R N is R N 38 or R N 39 and R 12 is a thienyl, thienylmethyl, furyl, furylmethyl, indolyl or methylindoyl.
  • R N is R N 26 and R 12 is a thienyl, thienylmethyl, furyl, furylmethyl, indolyl or methylindoyl.
  • R N is R N 27-R N 32 and R 12 is a thienyl, thienylmethyl, furyl, furylmethyl, indolyl or methylindoyl.
  • R N is R N 33- R N 35 and R 12 is a thienyl, thienylmethyl, furyl, furylmethyl, indolyl or methylindoyl.
  • R N is R N 36 and R 12 is a thienyl, thienylmethyl, furyl, furylmethyl, indolyl or methylindoyl.
  • R N is an optionally substituted cyclic amine group of formula R N 37 (Scheme 2) and R 12 is a thienyl, thienylmethyl, furyl, furylmethyl, indolyl or methylindoyl.
  • R N is R N 38 and R 12 is a thienyl, thienylmethyl, furyl, furylmethyl, indolyl or methylindoyl.
  • R N is R N 39 and R 12 is a thienyl, thienylmethyl, furyl, furylmethyl, indolyl or methylindoyl.
  • R10 is —NHCOR12.
  • R10 is –CONHR 12 .
  • R 10 is –CO-NH-R 12 and R N is any one of R N 1-R N 25 and R 12 is any one of R12-1-R12-22.
  • R 10 is –CO-NH-R 12 and R N is any one of R N 1-R N 25 and R 12 is any one of R12-1-R12-69.
  • x is 1.
  • x is 1 and L 1 is –(CH 2 )n-.
  • x is 1 and L 1 is –(CH 2 )n- , where n is 1 or 2.
  • x is 1 and L 1 is –(CH 2 )n-, where n is 1. In further embodiments of the forgoing embodiments of formula XXI or XXIII, x is 1 and L 1 is –(CH 2 )-, and R 5 is an electronegative group. In further embodiments of the forgoing embodiments of formula XXI or XXIII, x is 1 and L 1 is –(CH 2 )-, and R 5 is a halogen. In further embodiments of the forgoing embodiments of formula XXI or XXIII, x is 1 and L 1 is –(CH 2 )-, and R 5 is a fluorine.
  • x is 1 and L 1 is –(CH 2 )-, R 5 is a fluorine and R 4 is a C1-C3 alkyl group.
  • x is 1 and L 1 is –(CH 2 )-, R 5 is a fluorine and R 4 is a methyl group.
  • the compound is of formula XXX: or salts (or solvates) thereof, wherein: R 1 is selected from the group consisting of hydrogen, alkyl group.
  • R 2 and R 3 together form an optionally substituted 5- or 6-member heterocyclic ring which can contain one or two double bonds or be aromatic;
  • R 6 -R 9 are independently selected from hydrogen, halogen, alkyl group, alkenyl group, cycloalkyl group, cycloalkenyl group, or heterocyclyl group, each of which groups is optionally substituted;
  • Y is 0 or an integer ranging from 1-3 inclusive;
  • R 10 is selected from alkyl group.
  • R 10 is any one of RH1-RH12.
  • compounds useful in the methods herein include those of formula XXXI: or salts or solvates there pendently selected from hydrogen and R A groups defined in formula I, R M represents optional substitution on the fused ring and R M takes the values of RA in formula I and W 1 is N or CH.
  • y is 1.
  • y is 0.
  • both X are nitrogens.
  • x is 1 and M is -N-(CH 2 )n -, where n is 1, 2 or 3.
  • x is 1 and M is - (CH 2 )n -, where n is 1, 2 or 3.
  • x is 0.
  • L 2 is –(CH 2 )n -, where n is 1, 2 or 3.
  • R 1 is hydrogen
  • R 1 is hydrogen, methyl or trifluoromethyl.
  • R 7 -R 9 are independently selected from hydrogen, C1-C3 alkyl, optionally substituted C1-C3 alkyl, or aryl.
  • R 7 -R 9 are independently selected from hydrogen, halogen C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 acyl, or C1-C3 haloalkyl.
  • R 7 -R 9 are all hydrogens.
  • R 4 and R 5 are selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxyl, or C1-C3 haloalkyl. In embodiments, R 4 and R 5 together form a 5- or 6- member carbocyclic or heterocyclic ring which is saturated, partially unsaturated or is heteroaromatic.
  • R M is one or more hydrogen, halogen, C1-C3 alkyl group or C1- C3 haloalkyl group. In embodiments, R M is one or more hydrogen, halogen, particularly Br, methyl or trifluoromethyl. In embodiments, R M is hydrogen.
  • compounds useful in the methods, pharmaceutical compositions and pharmaceutical combinations of this invention include compounds of formula XXXII:
  • R B represents optional substitution as defined in formula I and R 6 -R 9 are hydrogen or take values of R A from formula I.
  • y is 1. In embodiments, y is 0. In embodiments, both X are nitrogens.
  • x is 1 and M is -N-(CH 2 )n -, where n is 1, 2 or 3. In embodiments, x is 1 and M is - (CH 2 )n -, where n is 1, 2 or 3. In embodiments, x is 0. In embodiments, L 2 is –(CH 2 )n -, where n is 1, 2 or 3.
  • R 1 is hydrogen In embodiments, R 1 is hydrogen, methyl or trifluoromethyl.
  • R 6 -R 9 are independently selected from hydrogen, C1-C3 alkyl, optionally substituted C1-C3 alkyl, or aryl.
  • R 6 -R 9 are independently selected from hydrogen, halogen C1-C3 alkyl, C1-C3 alkoxyl, C1-C3 acyl, or C1-C3 haloalkyl.
  • R 7 -R 9 are all hydrogens.
  • R 4 and R 5 are selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxyl, or C1-C3 haloalkyl.
  • R B is one or more hydrogen, halogen, C1-C3 alkyl group or C1-C3 haloalkyl group.
  • R B is one or more hydrogen, halogen, particularly Br, methyl or trifluoromethyl.
  • R B is hydrogen.
  • R H is a heterocyclyl or heteroaryl group. In embodiments, R H is optionally substituted naphthyl, thiophene, indoyl, or pyridinopyrroyl.
  • y is 0.
  • L 2 is –(CH 2 )n- and n is 1, 2 or 3.
  • the A ring is a phenyl ring where R A is hydrogen.
  • R P is a group selected from any one of R N -1 to R N -31.
  • the B ring of formula XLII is that of formula RBI as shown in Scheme 4.
  • the B ring of formula XLII is that of RB2-RB5 of Scheme 4.
  • the invention provides salts, particularly pharmaceutically acceptable salts of each of the compounds of any of formulas I-IX, XI-XIX, XXX-XXXII, XXXV-XLII and formula XX below.
  • the invention provides solvates and salts thereof, particularly pharmaceutically acceptable solvates and salts of each of the compounds of any of formulas I-XIX, XXX-XXII, XXV, XXV-XLII and formula XX and XXI below.
  • a preferred solvate is a hydrate.
  • the invention provides pharmaceutical compositions comprising any compound of any one of the formulas herein.
  • compounds of formula XLV are useful in the methods, pharmaceutical compositions and pharmaceutical combinations herein:
  • X 1 and X 2 are independently CH or N;
  • R B is hydrogen, C1-C3 alkyl or C1-C3 fluoroalkyl; a, b, c or d are zero or integers, where a is 1 or 2, b is 0 or 1, c is 0 or 1, and d is 0 or 1; and
  • R H is selected from any one of the moieties of Scheme 3, R12-1 to R12-84.
  • X 1 is N and X 2 is CH or X 1 is CH and X 2 is N; X 1 is N and X 2 is CH; X 1 is CH and X 2 is N; a is 1 and X 1 is N and X 2 is CH or X 1 is CH and X 2 is N; a is 1 and X 1 is N and X 2 is CH; a is 1 and X 1 is CH and X 2 is N; a is 2 and X 1 is N and X 2 is CH or X 1 is CH and X 2 is N; a is 2 and X 1 is N and X 2 is CH; or a is 2 and X 1 is CH and X 2 is N.
  • b is 0 and c is 0, b is 0 and c is 1, b is 1 and c is 0, or b is 1 and c is 1; b is 0 and c is 0; b is 0 and c is 1; b is 1 and c is 0; or b is 1 and c is 1.
  • d is 0 or d is 1.
  • R H is one of moieties R12-1 to R12-84 of Scheme 3; or R H is one of moieties R12-5; R12-44; R12-45; R12-58; R12-62; R12-75, R12-79; or R12-80; or R H is: where: R 20 and R 21 are independently, a hydrogen, a C1-C3 alkyl, a C1-C3 fluoroalkyl or a halogen on the indicated carbon or represents substitution on the indicated ring with one or more of the listed atoms or groups.
  • R 20 and R 21 are both hydrogens or represent hydrogens at all available ring positions.
  • R 20 and R 21 are independently a hydrogen, methyl, trifluormethyl or halogen on the indicated carbon or represents substitution on the indicated ring with one or more of the listed atoms or groups.
  • R 20 and R 21 are independently a methyl, trifluormethyl or halogen on the indicated carbon above or represents substitution on the indicated ring with one or more of the listed atoms or groups.
  • R 21 is hydrogen or represents hydrogen at all available positions on the indicated ring and R 20 is a methyl, trifluormethyl or halogen on the indicated carbon above or represents substitution on the indicated ring with one or more of the listed atoms or groups.
  • R 20 is hydrogen or represents hydrogen at all available positions on the indicated ring and R 21 is a methyl, trifluormethyl or halogen on the indicated carbon above or represents substitution on the indicated ring with one or more of the listed atoms or groups.
  • the halogen of R 20 or R 21 is independently fluorine, chlorine or bromine.
  • R H is R12-79; R12-80; R12-44, wherein R’ represents hydrogens at all ring positions; R12-45, wherein R’ represents hydrogens at all ring positions; R12-58, wherein R’ represents hydrogens at all available ring positions; R12-62, wherein R’ represents hydrogens at all available ring positions; 2-haloquinolin-4-yl; 2- chloroquinolin-4-yl; R12-75, where both Rs are hydrogen and X is a halogen, R12-5, wherein R is hydrogen and R’ represents hydrogens on all ring positions; R12-5, where R is hydrogen and R’ represents a halogen at the 6-ring position; 6-chloroquinolin-4-yl, 2-C1-C3alkyl-1H-indol-3-yl or 2- methyl-1H-indol-3-yl..
  • R H is R12-80; R12-44, wherein R’ represents hydrogens at all ring positions; R12-58, wherein R’ represents hydrogens at all available ring positions; 2-haloquinolin-4-yl; 2-chloroquinolin-4-yl; R12-5, wherein R is hydrogen and R’ represents hydrogens on all ring positions; R12-5, where R is hydrogen and R’ represents a halogen at the 6-ring position; 6-chloroquinolin-4-yl, 2-C1-C3 alkyl-1H-indol-3-yl or 2-methyl-1H- indol-3-yl.
  • R H is naphth-1-yl. In embodiments of the foregoing embodiments of formula XLV, R H is 4-bromothiophen-2-yl. In embodiments of the foregoing embodiments of formula XLV, R H is thiophen-2-yl. In embodiments of the foregoing embodiments of formula XLV, R H is 1H-indol-3-yl. In embodiments of the forgoing embodiments of formula XLV, R H is 6-chloro-1H-indol-3-yl. In embodiments of the forgoing embodiments of formula XLV, R H is 2-methyl-1H-indol-3-yl.
  • R H is quinolin-4-yl. In embodiments of the foregoing embodiments of formula XLV, R H is 2-chloroquinolin-4-yl.
  • the compound is selected from compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169. In more specific embodiments, the compound is selected from compounds 52, 118, 126, 131, 150, or 169. In embodiments of formula XLV, the compound is selected from compounds 28, 31, 54, 57, or 75.
  • the compound is one or more of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169. In embodiments of formula XLV, the compound is one of compounds 28, 31, 52, 54, 57, 75, 118, 126, 131, 150, or 169.
  • the compounds of formula XLVI are useful in the method, pharmaceutical compositions and pharmaceutical combinations as described herein: or salts or solvates thereof; wherein variables are as defined for formula XLV and R H and R P are as defined in formula I and various embodiments thereof listed above. In embodiments, R P is any of the moieties RN1-RN39.
  • R P is any of R N 1; R N 3; R N 2 or R N 4; R N 5 or R N 6; R N 7 or R N 8; R N 9; R N 10; R N 11; R N 12; R N 13; R N 14; R N 15; R N 16; R N 17 or R N 18; R N 19 or R N 20; R N 21; R N 22; R N 23 or R N 24; R N 25; R N 26-R N 29; R N 27-R N 32; R N 30; R N 31; R N 33-R N 36; R N 37; R N 38; R N 39; or R N 1, R N 2, R N 3, R N 4, R N 11, R N 13, or R N 14; or R N 1-R N 31 which is unsubstituted or R N 32-R N -39; or R N 37; or R N 38 or R N 39.
  • An aliphatic compound is an organic compound containing carbon and hydrogen joined together in straight chains, branched chains, or non-aromatic rings and which may contain single, double, or triple bonds. Aliphatic compounds are distinguished from aromatic compounds.
  • the term aliphatic group herein refers to a monovalent group containing carbon and hydrogen that is not aromatic. Aliphatic groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl, as well as aliphatic groups substituted with other aliphatic groups, e.g., alkenyl groups substituted with alkyl groups, alkyl groups substituted with cycloalkyl groups.
  • alkyl or alkyl group refer to a monoradical of a straight-chain or branched saturated hydrocarbon.
  • Alkyl groups include straight-chain and branched alkyl groups. Unless otherwise indicated alkyl groups have 1-8 carbon atoms (C1-C8 alkyl groups) and preferred are those that contain 1-6 carbon atoms (C1-C6 alkyl groups) and more preferred are those that contain 1-3 carbon atoms (C1-C3 alkyl groups). Alkyl groups are optionally substituted with one or more non- hydrogen substituents as described herein.
  • alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, various branched-pentyl, n-hexyl, various branched hexyl, all of which are optionally substituted, where substitution is defined elsewhere herein.
  • Substituted alkyl groups include fully halogenated or semihalogenated alkyl groups, such as alkyl groups having one or more hydrogens replaced with one or more fluorine atoms, chlorine atoms, bromine atoms and/or iodine atoms.
  • Substituted alkyl groups include fully fluorinated or semifluorinated alkyl.
  • Cycloalkyl groups are alkyl groups having at least one 3- or higher member carbon ring. Cycloalkyl groups include those having 3-12-member carbon rings. Cycloalkyl groups include those having 3- 20 carbon atoms and those having 3-12 carbon atoms. More specifically, cycloalkyl groups can have at least one 3-10-member carbon ring. Cycloalkyl groups can have a single carbon ring having 3-10 carbons in the ring. Cycloalkyl groups are optionally substituted. Cycloalkyl groups can be bicyclic having 6-12 carbons.
  • Exemplary cycloalkyl groups include among others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl groups.
  • Bicyclic alkyl groups include fused bicyclci grouos and bridged bicyclic groups.
  • Exemplary bicycloalkyl groups include, among others, bicyclo[2.2.2]octyl, bicyclo[4.4.0] decyl (decalinyl), and bicyclo[2.2.2]heptyl (norbornyl).
  • Cycloalkylalkyl groups are alkyl groups as described herein which are substituted with a cycloalkyl group as dcribed herein. More specifically, the alkyl group is a methyl or an ethyl group and the cycloalkyl group is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. Cycloalkyl groups are optionally substituted.
  • optional substitution iincludes substitution with one or more halogens, alkyl groups having 1-3 carbon atoms, alkoxy groups having 1-3 carbo atoms, hydroxyl and nitro groups
  • alkylene refers to a divalent radical of a straight-chain or branched saturated hydrocarbon. Alkylene groups can have 1-12 carbon atoms unless otherwise indicated. Alkylene groups include those having 2-12, 2-8, 2-6 or 2-4 carbon atoms.
  • Linker groups (L1) herein include alkylene groups, particularly straight chain, unsubstituted alkylene groups, -(CH2)n-, where n is 1- 12, n is 1-10, n is 1-9, n is 1-8, n is 1-7, n is 1-6, n is 1-5, n is 1-4, n is 1-3, n is 2-10, n is 2-9, n is 2-8, n is 2-7, n is 2-6, n is 2-5 or n is 2-4.
  • An alkoxy group is an alkyl group, as broadly discussed above, linked to oxygen (Ralkyl-O-).
  • An alkoxy grou is monovalent.
  • An alkenylene group is a divalent radical of a straight-chain or branched alkylene group which has one or more carbon-carbon double bonds. In specific embodiments, the same carbon atom is not part of two double bonds. In an alkenylene group one or more CH2-CH2 moieties of the alkylene group are replaced with a carbon-carbon double bond. In specific embodiments, an alkenylene group contains 2-12 carbon atoms or more preferably 3-12 carbon atoms. In specific embodiments, an alkenylene group contains one or two double bonds. In specific embodiments, the alkenylene group contains one or two trans-double bonds. In specific embodiments, the alkenylene group contains one or two cis-double bonds.
  • An alkoxyalkyl group is an alkyl group in which one or more of the non-adjacent internal –CH 2 - groups are replaced with –O-, such a group may also be termed an ether group.
  • the alkoxyalkyl group is monovalent. These groups may be straight-chain or branched, but straight-chain groups are preferred.
  • Alkoxyalkyl groups include those having 2-12 carbon atoms and 1, 2, 3 or 4 oxygen atoms. More specifically, alkoxyalkyl groups include those having 3 or 4 carbons and 1 oxygen, or those having 4, 5 or 6 carbons and 2 oxygens. Each oxygen in the group is bonded to a carbon in the group. The group is bonded into a molecule via a bond to a carbon in the group.
  • An alkoxyalkylene group is a divalent alkoxyalkyl group. This group can be described as an alkylene group in which one or more of the internal –CH 2 - groups are replaced with an oxygen. These groups may be straight-chain or branched, but straight-chain groups are preferred.
  • Alkoxyalkylene groups include those having 2-12 carbon atoms and 1, 2, 3 or 4 oxygen atoms. More specifically, alkoxyalkylene groups include those having 3 or 4 carbons and 1 oxygen, or those having 4, 5 or 6 carbons and 2 oxygens. Each oxygen in the group is bonded to a carbon in the group. The group is bonded into a molecule via bonds to a carbon in the group.
  • Linker groups (L1) herein include alkoxyalkylene groups, particularly straight chain, unsubstituted alkoxyalkylene groups.
  • alkoxyalkylene groups include, among others, -CH 2 -O-CH 2 -, -CH 2- CH 2 -O-CH 2 - CH 2 -, -CH 2 -CH 2 -CH 2 -O-CH 2 -CH 2 -CH 2 -,-CH 2 -CH 2 -O-CH 2 -, -CH 2 -O-CH 2 -CH 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -O-CH 2 -CH 2 -, and - CH 2 -CH 2 -CH 2 -O-CH 2 -CH 2 -CH 2 -O-CH 2 -CH 2 -CH 2 -.
  • acyl group refers to the group –CO-R where R is hydrogen, an alkyl or aryl group as described herein.
  • Aryl groups include monovalent groups having one or more 5- or 6-member aromatic rings.
  • Aryl groups can contain one, two or three, 6-member aromatic rings.
  • Aryl groups can contain two or more fused aromatic rings.
  • Aryl groups can contain two or three fused aromatic rings.
  • Aryl groups are optionally substituted with one or more non-hydrogen substituents.
  • Substituted aryl groups include among others those which are substituted with alkyl or alkenyl groups, which groups in turn can be optionally substituted.
  • aryl groups include phenyl groups, biphenyl groups, and naphthyl groups, all of which are optionally substituted as described herein.
  • Substituted aryl groups include fully halogenated or semihalogenated aryl groups, such as aryl groups having one or more hydrogens replaced with one or more fluorine atoms, chlorine atoms, bromine atoms and/or iodine atoms.
  • Substituted aryl groups include fully fluorinated or semifluorinated aryl groups, such as aryl groups having one or more hydrogens replaced with one or more fluorine atoms.
  • Alkyl groups include arylalkyl groups in which an alkyl group is substituted with an aryl group.
  • Arylalkyl groups include benzyl and phenethyl groups among others. Arylalkyl groups are optionally substituted as described herein. Substituted arylalkyl groups include those in which the aryl group is substituted with 1-5 non-hydrogen substituents and particularly those substituted with 1, 2 or 3 non-hydrogen substituents. Useful substituents include among others, methyl, methoxy, hydroxy, halogen, and nitro. Particularly useful substituents are one or more halogens. Specific substituents include F. Cl, and nitro. An acyl group is an R-CO- groups where R is alkyl, cycloalkyl or aryl as defined herein each of which is optionally substituted.
  • An acyl oxy group is an R-COO- group where R is alkyl, cycloalkyl or aryl as defined herein each of which is optionally substituted.
  • An alkoxycarbonyl group is an RO-CO- group where R is an alkyl or cycloalkyl as defined herein each of which is optionally substituted.
  • a carboxyl group is a –COOH group which may be in the ionized form –COO-.
  • a heterocyclic group is a monovalent group having one or more saturated or unsaturated carbon rings and which contains one or more heteroatoms (e.g., N, O or S) per ring.
  • a heterocyclic group contains one to six heteroatoms (e.g., N, O or S).
  • a heterocyclic groups contains one to three heteroatoms. These groups optionally contain one, two or three double bonds.
  • a ring atom may be bonded to one or more hydrogens or be substituted as described herein.
  • One or more carbons in the heterocyclic ring can be –CO- groups.
  • the heteroatoms in the ring may be substituted with one or more substituents dependent upon valency or sbstituted with one or more oxygen atoms.
  • Heterocyclic groups include those having 3-12 carbon atoms, and 1-6, heteroatoms, wherein 1 or 2 carbon atoms are replaced with a –CO- group.
  • Heterocyclic groups include those having 3-12 or 3- 10 ring atoms of which up to three can be heteroatoms other than carbon.
  • Heterocyclic groups can contain one or more rings each of which is saturated or unsaturated.
  • Heterocyclic groups include bicyclic and tricyclic groups. Preferred heterocyclic groups have 5- or 6-member rings. Heterocyclic groups are optionally substituted as described herein.
  • heterocyclic groups can be substituted with one or more alkyl groups.
  • Heterocyclic groups include those having 5- and 6- member rings with one or two nitrogens and one or two double bonds.
  • Heterocyclic groups include those having 5- and 6-member rings with an oxygen or a sulfur and one or two double bonds.
  • Heterocyclic group include those having 5- or 6-member rings and two different heteroatoms, e.g., N and O, O and S or N and S.
  • heterocyclic groups include among others among others, pyrrolidinyl, piperidyl, piperazinyl, pyrrolyl, pyrrolinyl, furyl, thienyl, morpholinyl, oxazolyl, oxazolinyl, oxazolidinyl, indolyl, triazoly, triazinyl groups, sultam groups (e.g., 1,1-dioxidoisothiazolidin-2-yl, 1,1-dioxidothiazinan-2-yl)
  • Heterocycylalky groups are alkyl groups substituted with one or more heterocycyl groups wherein the alkyl groups optionally carry additional substituents and the heterocycyl groups are optionally substituted.
  • Heteroaryl groups are monovalent groups having one or more aromatic rings in which at least one ring contains a heteroatom (a non-carbon ring atom). Heteroaryl groups include those having one or two heteroaromatic rings carrying 1, 2 or 3 heteroatoms and optionally have one 6-member aromatic ring. Heteroaryl groups can contain 5-20, 5-12 or 5-10 ring atoms. Heteroaryl groups include those having one aromatic ring contains a heteroatom and one aromatic ring containing carbon ring atoms. Heteroaryl groups include those having one or more 5- or 6-member aromatic heteroaromatic rings and one or more 6-member carbon aromatic rings.
  • Heteroaromatic rings can include one or more N, O, or S atoms in the ring. Heteroaromatic rings can include those with one, two or three N, those with one or two O, and those with one or two S, or combinations of one or two or three N, O or S.
  • Specific heteroaryl groups include furyl, pyridinyl, pyrazinyl, pyrimidinyl, quinolinyl, purinyl, indolyl groups.
  • the heteroaryl group is an indolyl group and more specifically is an indol-3-yl group: Heteroatoms include O, N, S, P or B. More specifically heteroatoms are N, O or S.
  • one or more heteroatoms are substituted for carbons in aromatic or carbocyclic rings.
  • any heteroatoms in such aromatic or carbocyclic rings may be bonded to H or a substituent group, e.g., an alkyl group or other substituent.
  • Heteroarylalkyl groups are alkyl groups substituted with one or more heteroaryl groups wherein the alkyl groups optionally carry additional substituents and the aryl groups are optionally substituted.
  • Specific alkyl groups are methyl and ethyl groups.
  • the term amino group refers to the species –N(H) 2 .
  • alkylamino refers to the species - NHR′′ where R′′ is an alkyl group, particularly an alkyl group having 1-3 carbon atoms.
  • dialkylamino refers to the species –N(R′′) 2 where each R′′ is independently an alkyl group, particularly an alkyl group having 1-3 carbon atoms. Groups herein are optionally substituted.
  • any alky, cycloalkyl, aryl, heteroaryl and heterocyclic groups can be substituted with one or more halogen, hydroxyl group, nitro group, cyano group, isocyano group, oxo group, thioxo group, azide group, cyanate group, isocyanate group, acyl group, haloakyl group, alkyl group, alkenyl group or alkynyl group (particularly those having 1-4 carbons), a phenyl or benzyl group (including those that are halogen or alkyl substituted), alkoxy, alkylthio, or mercapto (HS-).
  • optional substitution is substitution with 1-12 non-hydrogen substituents.
  • optional substitution is substitution with 1-6 non-hydrogen substituents. In specific embodiments, optional substitution is substitution with 1-3 non-hydrogen substituents. In specific embodiments, optional substituents contain 6 or fewer carbon atoms. In specific embodiments, optional substitution is substitution by one or more halogen, hydroxy group, cyano group, oxo group, thioxo group, unsubstituted C1-C6 alkyl group or unsubstituted aryl group.
  • Specific substituted alkyl groups include haloalkyl groups, particularly trihalomethyl groups and specifically trifluoromethyl groups.
  • Specific substituted aryl groups include mono-, di-, tri, tetra- and pentahalo-substituted phenyl groups; mono-, di , tri-, tetra-, penta-, hexa-, and hepta-halo- substituted naphthalene groups; 3- or 4-halo-substituted phenyl groups, 3- or 4-alkyl-substituted phenyl groups, 3- or 4-alkoxy-substituted phenyl groups, 3- or 4-RCO-substituted phenyl, 5- or 6- halo-substituted naphthalene groups.
  • substituted aryl groups include acetylphenyl groups, particularly 4-acetylphenyl groups; fluorophenyl groups, particularly 3- fluorophenyl and 4-fluorophenyl groups; chlorophenyl groups, particularly 3-chlorophenyl and 4- chlorophenyl groups; methylphenyl groups, particularly 4-methylphenyl groups, and methoxyphenyl groups, particularly 4-methoxyphenyl groups.
  • aromatic as applied to cyclic groups refers to ring structures which contain double bonds that are conjugated around the entire ring structure, possibly through one or more heteroatoms such as an oxygen atom, sulfur atom or a nitrogen atom.
  • Aryl groups, and heteroaryl groups are examples of aromatic groups.
  • the conjugated system of an aromatic group contains a characteristic number of electrons, for example, 6 or 10 electrons that occupy the electronic orbitals making up the conjugated system, which are typically un-hybridized p-orbitals.
  • carbocyclic refers to a monovalent group having a carbon ring or ring system which comprises 3 to 12 carbon atoms and may be monocyclic, bicyclic or tricyclic. The ring does not contain any heteroatoms. The ring may be unsaturated, partially unsaturated or saturated. Compounds and substituent groups of formulas herein are optionally substituted.
  • a substituent refers to a single atom (for example, a halogen atom) or a group of two or more atoms that are covalently bonded to each other, which are covalently bonded to an atom or atoms in a molecule to satisfy the valency requirements of the atom or atoms of the molecule, typically in place of a hydrogen atom.
  • substituents include among others alkyl groups, hydroxyl groups, alkoxy groups, acyloxy groups, mercapto groups, and aryl groups. Substituent groups may themselves be substituted.
  • Substituted or substitution refer to replacement of a hydrogen atom of a molecule or of an chemical group or moiety with one or more additional substituents such as, but not limited to, halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, acyloxy, hydroxy, mercapto, carboxy, aryloxy, aryl, arylalkyl, heteroaryl, amino, alkylamino, dialkylamino, morpholino, piperidino, pyrrolidin-1-yl, piperazin-1-yl, nitro, sulfato, or other R-groups.
  • additional substituents such as, but not limited to, halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, acyloxy, hydroxy, mercapto, carboxy, aryloxy, aryl, arylalkyl, heteroaryl, amino, alkylamino, dialkylamino, morpholin
  • Carbocyclic or heterocyclic rings are optionally substituted as described generally for other groups, such as alkyl and aryl groups herein. Substitution if present is typically on ring C, ring N or both.
  • carbocyclic and heterocyclic ring can optionally contain a -CO-, -CO-O-, -CS- or –CS- O- moiety in the ring.
  • any of the chemical groups herein that are substituted, i.e., contain one or more non- hydrogen substituents it is understood, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the compounds of this invention include all stereochemical isomers arising from the substitution of these compounds.
  • Protected derivatives of the disclosed compounds also are contemplated.
  • a variety of suitable protecting groups for use with the disclosed compounds are disclosed in Greene and Wuts, Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999.
  • protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis, and the like.
  • One preferred method involves the removal of an ester, such as cleavage of a phosphonate ester using Lewis acidic conditions, such as in TMS-Br mediated ester cleavage to yield the free phosphonate.
  • a second preferred method involves removal of a protecting group, such as removal of a benzyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof.
  • a protecting group such as removal of a benzyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof.
  • a t-butoxy-based group, including t-butoxy carbonyl protecting groups can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as water, dioxane and/or methylene chloride.
  • Another exemplary protecting group, suitable for protecting amino and hydroxy functions amino is trityl.
  • CHD1L inhibitors which in an embodiment target TCF-driven EMT.
  • Reversion of EMT by CHD1L inhibitors may be an effective treatment when used in combination with cytotoxic chemotherapy and targeted antitumor drugs as well as radiation therapy.
  • EMT-targeting agents may also sensitize both primary tumors and metastatic lesions to clinically relevant therapies, and potentially inhibit tumor cell metastasis.
  • CHD1L inhibitors which can be used to treat or prevent metastasis of a wide variety of advanced solid tumors and blood cancers.
  • Pharmaceutically acceptable salts, prodrugs, stereoisomers, and metabolites of all the CHD1L inhibitor compounds of this invention also are contemplated.
  • the invention expressly includes pharmaceutically usable solvates of compounds according to formulas herein.
  • useful solvates are hydrates.
  • the compounds of formula I or salts thereof can be solvated (e.g., hydrated).
  • the solvation can occur in the course of the manufacturing process or can take place (e.g., as a consequence of hygroscopic properties of an initially anhydrous compound of formulas herein (hydration)).
  • Compounds of the invention can have prodrug forms.
  • Prodrugs of the compounds of the invention are useful in the methods of this invention. Any compound that will be converted in vivo to provide a biologically, pharmaceutically or therapeutically active form of a compound of the invention is a prodrug.
  • prodrugs are well known in the art.
  • a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into an active compound following administration of the prodrug to a subject.
  • the term prodrug as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds described herein.
  • Prodrugs preferably have excellent aqueous solubility, increased bioavailability, and are readily metabolized into the active TOP2A inhibitors in vivo.
  • Prodrugs of compounds described herein may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound.
  • the suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. Examples of prodrugs are found, inter alia, in Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985), Methods in Enzymology, Vol.42, at pp.309-396, edited by K. Widder, et. al. (Academic Press, 1985); A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H.
  • Bundgaard Chapter 5, "Design and Application of Prodrugs," by H. Bundgaard, at pp.113-191, 1991); H. Bundgaard, Advanced Drug Delivery Reviews, Vol.8, p.1- 38 (1992); H. Bundgaard, et al., Journal of Pharmaceutical Sciences, Vol.77, p.285 (1988); and Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).
  • Administration of and administering a compound or composition should be understood to mean providing a compound or salt thereof, a prodrug of a compound, or a pharmaceutical composition comprising a compound.
  • the compound or composition can be administered by another person to the patient (e.g., intravenously) or it can be self-administered by the subject (e.g., tablets or capsules).
  • patient refers to mammals (for example, humans and veterinary animals such as dogs, cats, pigs, horses, sheep, and cattle).
  • Administration of CHD1L inhibitors herein in combination with other agents, such as alternative anti-cancer, antineoplastic or cancer cytotoxic agents is contemplated.
  • Such combined administration includes administration of two or more active ingredients at the same time or at times separated by minutes, hours or days as is found to be effective and consistent with the administration of any known alternative treatments with which the CHD1L inhibitor is to be combined.
  • Combined administration further includes administration by the same method and/or location of the patient’s body or by different methods at different locations, again as is consistent with and consistent with the administration of known alternative treatments with which the CHD1L inhibitor is to be combined.
  • the CHD1L inhibitors are administered together with an alternative cancer cytotoxic or cancer cytotoxic or antineoplastic agent or antineoplastic procedure (e.g., radiation treatment) in one or more acceptable pharmaceutical dosage forms or are administered separately within a selected time period to provide synergistic effect.
  • the CHD1L inhibitor(s) is (are) administered by the same route as the alternative cancer cytotoxic or cancer cytotoxic or antineoplastic agent.
  • the CHD1L inhibitor(s) is administered by a route different from the alternative cancer cytotoxic or antineoplastic agent. In embodiments, the CHD1L inhibitor(s) are administered orally or by injection. In embodiments, the alternative cancer cytotoxic or antineoplastic agent are administered orally or by injection. In embodiments, the CHD1L inhibitor(s) are administered locally to tumors or systemically or a combination of both forms of administration. In embodiments, the alternative neoplastic agent is administered locally to tumors or systemically or a combination of both forms of administration.
  • components of the pharmaceutical combination are administered to a subject in need thereof in a joint therapeutic amount to provide synergistic therapeutic effect.
  • components of the pharmaceutical combination are administered by any appropriate mode of administration to a subject in need thereof in a joint therapeutic amount to provide synergistic therapeutic effect.
  • components of the pharmaceutical combination are administered by local or systemic administration or by a combination of local and systemic administration to a subject in need thereof in a joint therapeutic amount to provide synergistic therapeutic effect. If a patient is to receive or is receiving multiple pharmaceutically active compounds, the compounds can be administered simultaneously or sequentially.
  • the active compounds may be found in one tablet or in separate tablets, which are administered at once or sequentially in any order.
  • the compositions may be in different dosage forms.
  • one or more compounds may be delivered via a tablet, while another is administered via injection or orally as a syrup. All combinations, delivery methods and administration sequences are contemplated.
  • the combination therapy herein comprises administration of one or more CHD1L inhibitor and administration of one or more alternative cancer cytotoxic or antineoplastic agent to a patient in need of treatment. Administration includes any form or forms of administration which achieves synergistic therapeutic action of the CHD1L inhibitor(s) and the alternative cancer cytotoxic or antineoplastic agent.
  • Administration includes simultaneous, concurrent, sequential, successive, alternate or separate administration of inhibitor(s) CHD1L with the alternative cancer cytotoxic or antineoplastic agent.
  • oral administration of CHD1L inhibitor(s) may be combined with administration of the alternative cancer cytotoxic or antineoplastic agent orally or by injection.
  • the order (sequence) and relative timing of administration of CHD1L inhibitor(s) and administration of the alternative cancer cytotoxic or antineoplastic agent is adjusted to achieve synergistic therapeutic action.
  • administration of CHD1L inhibitor(s) is at the same time (i.e., within up to 2 hours of each other) as administration of alternative cancer cytotoxic or antineoplastic agent.
  • administration of CHD1L inhibitor(s) is separate from administration of the alternative cancer cytotoxic or antineoplastic agent within a selected time period of more than 2 hours of each other. In embodiments, administration of CHD1L inhibitor(s) is separate from administration of the alternative cancer cytotoxic or antineoplastic agent, but within a selected time period of ⁇ 24 hours to 1 week. In embodiments, the invention provides a pharmaceutical combination of one or more CHD1L inhibitor and one or more alternative cancer cytotoxic or antineoplastic agent. In embodiments, the components of the pharmaceutical combination can be together or separate.
  • the pharmaceutical combination is a pharmaceutical compositions containing one or more CHDL1 inhibitor and one or more topoisomerase inhibitor, PARP inhibitor, or thymidylate synthase inhibitor. In embodiments, the pharmaceutical combination is two or more separate pharmaceutical compositions each containing different components of the pharmaceutical combination. In embodiments, the pharmaceutical combination is two separate pharmaceutical compositions, one containing one or more CHD1L inhibitors and one containing one or more topoisomerase inhibitor, one or more PARP inhibitor and/or one or more thymidylate synthase inhibitor. In embodiments, the pharmaceutical combination is a single pharmaceutical composition, containing one or more CHD1L inhibitors and one containing one or more inhibitor of PARP.
  • the pharmaceutical combination is a single pharmaceutical composition, containing one or more CHD1L inhibitors and one containing one or more inhibitor of topoisomerase. In embodiments, the pharmaceutical combination is a single pharmaceutical composition, containing one or more CHD1L inhibitors and one containing one or more inhibitor of thymidylate synthase. In embodiments, the components of the pharmaceutical combination are administered together in a single dosage form appropriate for the selected mode of administration, e.g., oral or by injection. In embodiments, where the pharmaceutical combination is a single dosage form, the relative amount of the one or more CHD1L inhibitor and one or more alternative cancer cytotoxic or antineoplastic agent in the dosage form is fixed.
  • the pharmaceutical combination is administered as two separate pharmaceutical compositions or dosage forms, one containing one or more CHD1L inhibitors and one containing one or more alternative cancer cytotoxic or antineoplastic agent. Such separate administration may be in the same or different dosage form for appropriate for the selected mode of administration.
  • the components of the pharmaceutical combination are administered in one or more dosage form and may be administered at the same time or at different times.
  • the components of the pharmaceutical combination can be administered simultaneously, concurrently or sequentially with or without specific time limits where such administration provides therapeutically effective combined amounts of the one or more CHD1L inhibitor and the one or more alternative cancer cytotoxic or antineoplastic agent.
  • the combined therapeutically effective amount of the one or more CHD1L inhibitor and the one or more alternative cancer cytotoxic or antineoplastic agent exhibits greater than an additive therapeutic effect. In embodiments, the combined therapeutically effective amount of the one or more CHD1L inhibitor and the one or more alternative cancer cytotoxic or antineoplastic agent exhibits a synergistic therapeutic effect. In embodiments, the one or more CHD1L inhibitor and the one or more alternative cancer cytotoxic or antineoplastic agent are formulated separately and sold separately, but administered to a subject in need thereof as a pharmaceutical combination. In embodiments, the one or more CHD1L inhibitor and the one or more alternative cancer cytotoxic or antineoplastic agent are administered for treatment of the same disorder or disease state.
  • the disorder or disease state is a proliferative disorder and more specifically is cancer.
  • the components of the pharmaceutical combination may be sold together or separately in the same or different dosage forms, in combination with instructions for simultaneous, concurrent or sequential administration of the components of the pharmaceutical combination. Any forms of administration that achieve the desired combined therapeutic effect can be employed.
  • the combined administration can be local to the site of one or more tumors or can be systemically administered to the subject.
  • one or more components of the pharmaceutical combination can be administered locally to one or more tumor site and one or more other components of the pharmaceutical combination can be administered systemically to the subject.
  • Local or systemic administration can be by any appropriate mode of administration. Local administration can, for example, be by injection, infusion or by topical application.
  • Systemic administration can, for example, be oral, topical or by injection.
  • One or more CHD1L inhibitors as described herein can be administered in combination with chemotherapy, radiotherapy, immunotherapy, surgery or any combination of such therapies.
  • the combination therapy(ies) descibed herein can be administered in combination with chemotherapy, radiotherapy, immunotherapy, surgery or any combination of such therapies.
  • Pharmaceutical compositions herein comprise a named active ingredient or combination of named active ingredients in an amount effective for achieving the desired biological activity for a given form of administration to a given patient and optionally contain a pharmaceutically acceptable excipient or carrier.
  • compositions can include an amount (for example, a unit dosage) of one or more of the disclosed compounds together with one or more non-toxic pharmaceutically acceptable additives, including carriers, diluents, and/or adjuvants, and optionally other biologically active ingredients.
  • non-toxic pharmaceutically acceptable additives including carriers, diluents, and/or adjuvants, and optionally other biologically active ingredients.
  • Such pharmaceutical compositions can be prepared by standard pharmaceutical formulation techniques such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (19th Edition).
  • compositions herein comprise one or more compounds of any of formulas I-XIX, XXX-XXII, XXXV, XXXV-XLII, XLV, XLVI and formula XX and XXI or pharmaceutically acceptable salts, or solvates thereof and a pharmaceutically acceptable excipient.
  • excipient means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API) or another clearly designated active pharmaceutical ingredient, which is typically included for formulation and/or administration to a patient.
  • Pharmaceutically acceptable carriers are those carriers that are compatible with the other ingredients in the formulation and are biologically acceptable. Carriers can be solid or liquid.
  • carriers are solids, for example, in which oral dosage forms are pills.
  • carriers are liquids, for example, in which oral dosage forms are solutions or suspensions.
  • Carriers can include one or more substances that can also act as solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrating agents, or encapsulating materials. Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water (of appropriate purity, e.g., pyrogen-free, sterile, etc.), an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat.
  • a pharmaceutically acceptable liquid carrier such as water (of appropriate purity, e.g., pyrogen-free, sterile, etc.), an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat.
  • the liquid carrier can contain other suitable pharmaceutical additives such as, for example, solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • Compositions for oral administration can be in either liquid or solid form.
  • liquid carriers for oral and parenteral administration include water of appropriate purity, aqueous solutions (particularly containing additives, e.g., cellulose derivatives, sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g., glycols) and their derivatives, and oils.
  • liquid carriers for oral administration include solutions of active ingredients (i.e., CHD1L inhibitors preferably dissolved or suspended in a liquid carrier.
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • Liquid pharmaceutical compositions that are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • Compositions for oral administration can be in either liquid or solid form.
  • the carrier can also be in the form of creams and ointments, pastes, and gels.
  • the creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type.
  • administration of CHD1L inhibitors employs dosage forms comprising pharmaceutically acceptable polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • the pharmaceutically acceptable PEG may be combined with a pharmaceutically acceptable organic solvent, particularly a pharmaceutically acceptable polar, aprotic solvent.
  • the organic solvent is pharmaceutically acceptable DMSO.
  • oral administration employs oral dosage forms comprising low molecular weight polyethylene glycol having molecular weight of 600 g/mole or less.
  • oral administration employs PEG 400.
  • oral administration employs PEG 200.
  • PEG is described by its average Mn (number average) molecular weight. PEG having Mn of 600 or less are suitable for use in formulations of CHD1L inhibitors herein. More specifically, PEG having Mn of 400 or 200 are suitable for formulations herein.
  • administration employs oral formulations comprising PEG, preferably low molecular weight PEG and more specifically PEG having Mn of 600 or less.
  • oral formulations comprise a therapeutically effective amount of a CHD1L inhibitor in combination with PEG, particularly where the CHD1L inhibitor suspended or dissolved in the PEG.
  • a combination of PEG and an appropriate pharmaceutically acceptable polar aprotic solvent is pharmaceutically acceptable DMSO.
  • the oral formulation comprises PEG and DMSO.
  • the solvent combination of PEG and DMSO is miscible.
  • the combination of PEG and DMSO dissolves the therapeutically effective amount of the CHD1L inhibitor.
  • the volume ratio of PEG to DMSO in oral formulations ranges from 100 to 4. More specifically, the volume ratio of PEG to DMSO ranges from 20 to 4, or 9 to 4 or 12 to 6 or 10 to 8.
  • a solvent mixture of 90% by volume PEG, particularly low molecular weight PEG, and 10% by volume DMSO is employed in oral formulations.
  • a “therapeutically effective amount” of the disclosed compounds is a dosage of the compound that is sufficient to achieve a desired therapeutic effect, such as an anti-tumor or anti-metastatic effect. It will be understood that the therapeutically effective amount of a given compound depends upon the compound, the route of administration and the dosage form as well as the patient to be treated (age, weight, etc.).
  • a therapeutically effective amount is an amount sufficient to achieve tissue concentrations at the site of action that are similar to those that are shown to modulate TCF-transcription and/or epithelial-mesenchymal transition (EMT) in tissue culture, in vitro, or in vivo.
  • a therapeutically effective amount of a compound may be such that the subject receives a dosage of about 0.1 ⁇ g/kg body weight/day to about 1000 mg/kg body weight/day, for example, a dosage of about 1 ⁇ g/kg body weight/day to about 1000 ⁇ g/kg body weight/day, such as a dosage of about 5 ⁇ g/kg body weight/day to about 500 ⁇ g/kg body weight/day.
  • the therapeutically effect amount of the CHD1L inhibitor may depend upon the active ingredient, treatment or therapy with which it is combined.
  • modulate refers to the ability of a disclosed compound to alter the amount, degree, or rate of a biological function, the progression of a disease, or amelioration of a condition.
  • modulating can refer to the ability of a compound to elicit an increase or decrease in angiogenesis, to inhibit TCF-transcription and/or EMT, or to inhibit tumor metastasis or tumorigenesis.
  • Treatment refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop.
  • the term ameliorating refers to any observable beneficial effect of the treatment.
  • the beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease.
  • the phrase treating a disease is inclusive of inhibiting the full development of a disease or condition, for example, in a subject who is at risk for a disease, or who has a disease, such as cancer or a disease associated with a compromised immune system.
  • Preventing a disease or condition refers to prophylactically administering a composition to a subject who does not exhibit signs of a disease or exhibits only early signs of the disease, for the purpose of decreasing the risk of developing a pathology or condition, or diminishing the severity of a pathology or condition.
  • the CHD1l inhibitors herein can be used to treat cancer alone or in combination therapies as described herien.
  • Cancers which may generally be treated with compounds of the present invention include, without limitation, carcinomas such as cancer of the bladder, breast, colon, rectum, kidney, liver, lung (small cell lung cancer, and non-small-cell lung cancer), esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic le
  • All references throughout this application for example patent documents including issued or granted patents or equivalents; patent application publications; and non-patent literature documents or other source material; are hereby incorporated by reference herein in their entireties, as though individually incorporated by reference. All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains.
  • references cited herein are incorporated by reference herein in their entirety to indicate the state of the art, in some cases as of their filing date, and it is intended that this information can be employed herein, if needed, to exclude (e.g., to disclaim) specific embodiments that are in the prior art.
  • compounds known in the prior art including certain compounds disclosed in the references disclosed herein (particularly in referenced patent documents), are not intended to be included in the claim.
  • Esquer et al., 2021 and any supplementary information for that journal article are each incorporated by reference herein in its entirety for descriptions of biological and chemical methods useful in making and assessing the activities and properties of the CHD1L inhibitors herein.
  • Abbott et al., 2020 and the supplementary information for that journal article are each incorporated by reference herein in its entirety for descriptions of biological and chemical methods useful in making and assessing the activities and properties of the CHD1L inhibitors herein.
  • Esquer et al., 2020 and any supplementary information for that journal article are each incorporated by reference herein in its entirety for descriptions of biological and chemical methods useful in making and assessing the activities and properties of the CHD1L inhibitors herein.
  • Yang et al., 2020 and any supplementary information for that journal article are each incorporated by reference herein in its entirety for descriptions of biological and chemical methods useful in making and assessing the activities and properties of the CHD1L inhibitors herein.
  • any one or more hydrogens in a molecule disclosed can be replaced with deuterium or tritium.
  • Isotopic variants of a molecule are generally useful as standards in assays for the molecule and in chemical and biological research related to the molecule or its use. Isotopic variants, including those carrying radioisotopes, may also be useful in diagnostic assays and in therapeutics. Methods for making such isotopic variants are known in the art.
  • Molecules disclosed herein may contain one or more ionizable groups [groups from which a proton can be removed (e.g., -COOH) or added (e.g., amines) or which can be quaternized (e.g., amines)].
  • Salts can be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric
  • compounds of the invention can contain one or more negatively charged groups (free acids) which may be in the form of salts.
  • exemplary salts of free acids are formed with inorganic base include, but are not limited to, alkali metal salts (e.g., Li + , Na + , K + ), alkaline earth metal salts (e.g., Ca 2+ , Mg 2+ ), non-toxic heavy metal salts and ammonium (NH 4 + ) and substituted ammonium (N(R') 4 + salts, where R' is hydrogen, alkyl, or substituted alkyl, i.e., including, methyl, ethyl, or hydroxyethyl, specifically, trimethyl ammonium, triethyl ammonium, and triethanol ammonium salts), salts of cationic forms of lysine, arginine, N-ethylpiperidine, piperidine, and the like.
  • alkali metal salts e.g., Li + ,
  • Compounds of the invention can also be present in the form of zwitterions.
  • Compound herein can be in the form of pharmaceutically acceptable salts, which refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, and which are not biologically or otherwise undesirable.
  • the scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers and non-racemic mixtures thereof.
  • the compounds of the invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
  • the compounds can be, for example, racemates or optically active forms. The optically active forms can be obtained by resolution of the racemates or by asymmetric synthesis.
  • enantiomers of the invention exhibit specific rotation that is + (positive).
  • the (+) enantiomers are substantially free of the corresponding (-) enantiomer.
  • an enantiomer substantially free of the corresponding enantiomer refers to a compound which is isolated or separated via separation techniques or prepared free of the corresponding enantiomer. “Substantially free,” means that the compound is made up of a significantly greater proportion of one enantiomer. In preferred embodiments the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments of the invention, the compound is made up of at least about 99% by weight of a preferred enantiomer.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by methods described herein.
  • HPLC high performance liquid chromatography
  • Compounds of the invention, and salts thereof, may exist in their tautomeric form, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, that may exist, are included within the invention.
  • This example describes the pathogenic characterization and mechanisms of pathology for CHD1L in CRC patients.
  • the clinicopathological characteristics of 585 patients with CRC were analyzed from the Cartes d’Identite des Tumeurs (CIT) program with respect to CHD1L expression (GEO: GSE39582). [Marisa et al., 2013] These characteristics are summarized in Abbott et al., 2020, supplementary information. Additional data for this example are found in Abbott et al., 2020 and its supplementary information.
  • CHD1L in CRC molecular subtypes.
  • P ⁇ 0.001 CHD1L expression was high in C5, C4, and C3, and low in C2 and C6.
  • the C2 subtype is associated with a decrease in the WNT signaling pathway and deficient for mismatch repair.
  • the C4 and C6 subtypes are associated with poorer relapse-free survival compared to other subtypes.
  • the C4 subtype is associated with increased CSC stemness and the C5 subtype is associated with activated WNT signaling and deregulated EMT pathways.
  • CHD1L expression correlates with Wnt/TCF associated genes
  • the expression is quantified as FPKM (fragments per kilobase exon per million fragments mapped).
  • CHD1L expression with genes involved in KEGG WNT pathway using Spearman’s correlation a significant positive correlation with 65 of 125 genes was observed.
  • TOP2A topoisomerase II ⁇
  • CHD1L appears to be involved in TCF-transcription and EMT in CRC patients.
  • Example 2 CHD1L mediates TCF-transcription in CRC Based on the correlation of CHD1L with TCF-complex members, CHD1L may have a mechanistic role in TCF-transcription. To assess this role, SW620 and DLD1 cell lines, which have high and low endogenous CHD1L expression, respectively, were utilized. Additional data for this example are found in Abbott et al, 2020, and its Supplemetary Information. Small hairpin RNA (shRNA) was used to knockdown CHD1L in SW620 cells (SW620 CHD1L-KD ).
  • shRNA Small hairpin RNA
  • CHD1L was overexpressed in DLD1 cells (DLD1 CHD1L-OE ).
  • DLD1 CHD1L-OE DLD1 CHD1L-OE
  • TOPflash luciferase reporter [Morin et al., 1997; Zhou et al., 2016] transfected into SW620 CHD1L-KD or DLD1 CHD1L-OE
  • overexpression of CHD1L produced a significant increase in TCF-transcription (P ⁇ 0.0001) (Abbott et al., 2020).
  • CHD1L directly interacts with the TCF-transcription complex Activation of TCF-transcription is a dynamic process that involves the shedding of co-repressor proteins, binding of co-activator proteins, and remodeling of the chromatin landscape.
  • Co-IP Co-immunoprecipitation
  • CHD1L has been well characterized as a binding partner with PARP1 in DNA damage response.
  • PARP1 is also a component of the TCF-complex binding to TCF4 and ⁇ -catenin.
  • the results herein demonstrate that CHD1L binds to the TCF- complex, which is likely through interactions between TCF4 and PARP1.
  • ChIP chromatin immunoprecipitation
  • CHD1L was enriched at c-Myc, vimentin, slug, LEF1, and N-cadherin WREs, further supporting that CHD1L is functioning directly with the TCF- complex.
  • CHD1L mediated TCF-transcription promotes EMT and CSC stemness in CRC Previously, TCF-transcription was characterized as a master regulator of EMT in CRC. [Zhou et al., 2016]
  • CHD1L localizes at WREs of EMT effector genes.
  • CHD1L is an EMT effector gene involved in promoting the mesenchymal phenotype in CRC.
  • a hallmark of EMT is an increase in CSC stemness.
  • Example 3 Identification of Small Molecule Inhibitors of CHD1L As established in Examples 1 and 2, herein, CHD1L is a driver of TCF-mediated EMT. Based on this, an assay to identify small molecule inhibitors of CHD1L is described herein. The drug discovery goal was to target CHD1L DNA translocation or interactions with DNA, which are dependent on CHD1L’s catalytic domain ATPase activity. [Ryan & Owen-Hughes, 2011; Flaus et al., 2011] CHD1L belongs to the SNF2 (sucrose non-fermenter 2) ATPase superfamily of chromatin remodelers that contains a two-lobe ATPase domain.
  • SNF2 sucrose non-fermenter 2
  • ATPase superfamily of chromatin remodelers that contains a two-lobe ATPase domain.
  • CHD1L also has a macro domain that is unique relative to other chromatin remodelers, which promotes an auto-inhibited state through interactions between the macro and the ATPase domains. [Lehmann et al., 2017; Gottschalk et al., 2009] However, the macro domain binds to PARP1, the major activator of CHD1L, alleviating auto-inhibition.
  • Enzyme kinetics of cat-CHD1l versus fl-CHD1L were compared.
  • the cat- CHD1L provides for a more robust ATPase assay compared to fl-CHD1L, which is consistent with the report from Lehman et al., 2017. Therefore, to identify direct inhibitors of CHD1L ATPase, an exemplary High-through-put screening (HTS) assay in the context of TCF-transcription is described which includes: cat-CHD1L, c-Myc DNA, ATP, and phosphate-binding protein that fluoresces upon binding inorganic phosphate (Pi). This assay was validated and pilot screening was preformed against clinically relevant kinase inhibitors.
  • HTS High-through-put screening
  • This stringent hit limit identified 64 hits, of which 53 hits were confirmed against recombinant CHD1L ATPase activity.
  • Example 4 Exemplary Inhibitors A subset of seven confirmed hits (compounds 1-7, see Scheme 1) were purchased, representing a range of pharmacophores with greater than 50% inhibition against cat-CHD1L ATPase. Compounds 1-7 were subjected to dose response studies against cat-CHD1L ATPase, which validated these hits as potent CHD1L inhibitors with activity between 900 nM to 5 ⁇ M ( Figure 1A). Structures of additional exemplary compounds 8-73 are provided in Scheme 1, where SEM represents the protecting group trimethylsilylethoxy methyl.
  • E- cadherin and vimentin are putative biomarkers for the epithelial and mesenchymal phenotypes, respectively. [McDonald et al., 2015] Loss of E-cadherin and gain of vimentin are also clinical biomarkers of poor prognosis.
  • SW620 cells transduced with either EcadPro-RFP or VimPro- GFP were cultured as tumor organoids for 72 h, reaching a diameter of 600 ⁇ m. Tumor organoids were treated with compounds 5-7 for an additional 72 h to determine the effective concentration 50 percent (EC 50 ) for modulating promoter activity. Changes in promoter expression was quantified using a 3D confocal image 507 based high-content analysis algorithm ( Figure 2A-2B).
  • EMT EMT stemness and cell invasion. Therefore, the ability of compounds 5-7 to inhibit migration and invasion in HCT-116 and DLD1 CHD1L-OE cells was tested. All three compounds demonstrated a significant inhibition of CSC stemness ( Figure 2C). However, compounds 5 and 6.0 display more potent dose dependent inhibition. Note that DLD1 CHD1L-OE cells form two times more colonies than HCT-116 cells, which have moderate CHD1L expression. This observation is consistent with CHD1L’s oncogenic and tumorigenic properties.
  • CHD1L has been reported to confer anti-apoptotic activity by inhibiting activation of caspase- dependent apoptosis. [Li et al., 2013; Sun et al., 2016] Additionally, reversal or inhibition of EMT is known to restore apoptotic activity of cancer cells. [Lu et al., 2014] To determine if CHD1L inhibitors reverse EMT prior to induction of cell death, E-cadherin expression by EcadPro-RFP reporter activity was monitored and cytotoxicity was measured using the CellToxTM Green assay. Cells were treated with CHD1L inhibitors for 72 h and imaged every 2 h.
  • Cleavage of E-cadherin is a marker of apoptosis [Steinhusen et al., 2001]
  • These results indicate that compound 6 induces extrinsic apoptosis that is consistent with E-cadherin mediated apoptosis through death receptors.
  • annexin-V staining in SW620 cells over 12 h was examined.
  • Compound 6.0 induced significant apoptosis compared to DMSO alone and had similar activity to the positive control SN-38, the active metabolite of irinotecan (Figure 3B) CHD1L inhibitors are effective against patient-derived tumor organoids (PDTOs).
  • PDTOs patient-derived tumor organoids
  • the use of PDTOs in preclinical drug development has been established as a predictive in vitro cell model for clinical efficacy. [Drost J & Clevers H, 2018] After establishing the ability of compound 6 to reverse EMT and induce apoptosis using cell line based models, the efficacy of compound 6 was evaluated in PDTOs produced from patient sample CRC102 obtained from the University of Colorado Cancer Center (UCCC) gastrointestinal (GI) tissue bank (Figure 3C).
  • UCCC University of Colorado Cancer Center
  • GI gastrointestinal
  • Example 7 In vitro and in vivo PK, PD, and liver toxicity of Exemplary Inhibitor Compound 6.
  • CLogP consensus LogP
  • Compound 6.0 reaches a high plasma drug concentration C Max ( ⁇ 30,000 ng/mL) and AUC ( ⁇ 80,000 ng/mL/h) with a relatively long half-life (T 1/2 ⁇ ) of 3 h after intraperitoneal (i.p.) administration.
  • C Max ⁇ 30,000 ng/mL
  • AUC ⁇ 80,000 ng/mL/h
  • T 1/2 ⁇ half-life
  • compound 6 exhibited a half-life in liver microsomes of less than 20 minutes.
  • a second acute in vivo experiment was conducted using a maximum tolerated dose of 6.0 (50 mg/kg) administered to athymic nude mice by i.p. QD over five days.
  • the goals of this experiment were to (1) determine if compound 6.0 causes acute toxicity to livers, (2) accumulates in VimPro- GFP SW620 xenograft tumors, and (3) to determine PD effects.
  • Example 8 Biological Evaluation of Compound 8 Compound 8 was evaluated in a number of biological assays described above.
  • Results are presented in Figures 7A-E.
  • Compound 8 displays more potent dose dependent inhibition of CHD1L-mediated TCF-transcription (Fig.7A) compared to compound 6.
  • compound 8 reverses EMT, evidenced by the downregulation of vimentin and upregulation of E-cadherin promoter activity (Figs.7B and 7C, respectively).
  • Compound 8 significantly inhibits clonogenic colony formation over 10 days (Fig.7D).
  • Compound 8 significantly inhibits HCT116 invasive potential over 48 h (FIG.7E).
  • Example 9 Methods Applied in Examples herein Additional Materials and Methods Antibodies.
  • Monoclonal mouse anti-TCF4 antibody was purchased from EMD Millipore (Billerica, MA, USA) (catalog# 05-511), a 1:1000 dilution was used for Western blot and 2 ⁇ g antibody per 300 ⁇ g of protein was used for IP.
  • Monoclonal rabbit anti-CHD1L antibody was purchased from Abcam (Cambridge, MA, USA) (catalog #ab197019), a 1:5000 dilution was used for Western blot, and 1.5 ⁇ g antibody per 300 ⁇ g of protein was used for IP.
  • Monoclonal rabbit anti-Vimentin catalog# 5741
  • anti-Slug catalog #9585
  • anti-E-cadherin catalog #3195
  • anti-ZO-1 catalog #8193
  • anti-Histone H3 catalog #4620
  • Monoclonal rabbit anti- ⁇ -catenin catalog #9582
  • Monoclonal rabbit anti- ⁇ -catenin catalog #9582
  • Monoclonal rabbit anti- ⁇ -catenin catalog #9582
  • Monoclonal rabbit anti-phospho- ⁇ -catenin was purchased from Cell Signaling (catalog# 5651). Monoclonal rabbit anti-TCF4 (catalog #2569) and anti-Histone H3 (catalog #4620) were purchased from Cell Signaling and 2 ⁇ g antibody per 1 mg of protein was used for ChIP.
  • Anti-rabbit IgG HRP-linked secondary antibody (catalog #7074) was purchased from Cell Signaling and a 1:3000 dilution was used for Western blot.
  • Anti-goat and anti- mouse IgG HRP-linked secondary antibodies (catalog #805-035-180 and #115-035-003) were from Jackson ImmunoResearch (West Grove, PA), a 1:10,000 dilution was used for Western blot.
  • CHD1L Transcriptome expression data of 585 CRC patients from the CIT cohort (GEO: GSE39582) were used for in silico validation (GSE39582).
  • GSE39582 Gene expression analyses were performed by the Affymetrix GeneChipTM Human Genome U133 Plus 2.0 Array (Thermo Fisher Scientific, Waltham, MA).
  • Robust Multi-Array Analysis (RMA) was used for data preprocessing and ComBat (empirical Bayes regression) for batch correction. Signal intensity was log2 normalized.
  • the CHD1L cutoff for CRC risk stratification based on disease specific survival was determined by the receiver operating characteristic (ROC) curve. Cutoff for CHD1L expression was set to 6.45.
  • RNA-seq analysis RNA-seq data from CRC patient tumor xenograft explants were obtained from the UCCC (University of Colorado Cancer Center) GI tumor tissue bank, and analyzed as previously described.
  • CHD1L overexpression and shRNA knockdown Full length CHD1L was synthesized in a pGEX-6P-1 plasmid (GenScript, Piscataway, NJ).
  • the CHD1L sequence flanked by EcoRI and NotI was digested out and ligated to a lentiviral backbone to create pCDH1-CMV-CHD1L-EF1-puro plasmid for overexpression of CHD1L in human CRC cells.
  • Mission® shRNA Sigma-Aldrich Co. LLC, St.
  • TRCN0000013469 and TRCN0000013470 (sh69 and sh70) specific for CHD1L were purchased from Sigma-Aldrich (St. Louis, MO).
  • Virus was produced in HEK293T cells using TransIT®-293 reagent (Mirus, Madison, WI), and plasmids pHRdelta8.9 and pVSV-G.
  • CRC cells were transduced with overexpression or shRNA knockdown virus and selected with 2 ⁇ g/ml puromycin for 7 days.
  • the proteins were transferred to a nitrocellulose membrane.
  • the membranes were blocked at room temperature with 5% non-fat milk in TBS/Tween® 20 (TBST contains 20 mM Tris, 150 mM NaCl, and 0.1% Tween® 20 (Croda International PLC, Snaith, UK) for 1 hour at room temperature.
  • TBS/Tween® 20 TBS/Tween® 20
  • Tween® 20 Cellular PLC, Snaith, UK
  • Membranes were washed three times with TBST. Blots were incubated with the appropriate primary antibody in 5% nonfat milk in TBST overnight at 4 °C.
  • Membranes were washed three times with TBST and then incubated with appropriate secondary antibody for one hour.
  • Membranes were washed again with TBST three times.
  • IP ImmunoPreciptation
  • DynabeadsTM Protein A IP Kit ThermoScientific, Waltham, MA. Briefly, 300 ⁇ g of lysate incubated with 2 ⁇ g of the anti-TCF4 and anti-CHD1L IP antibody, anti-rabbit IgG and anti- mouse IgG were used as nonspecific binding controls and were rotated at 4 °C for 2 h. After preincubation, 50 ⁇ L of beads were transferred to the preincubated antibody/lysate mixture followed by overnight incubation at 4 °C. The flow through was collected and the beads were washed 3x with PBST.
  • Chromatin Immunoprecipitation (ChIP) Using detailed methods previously described [Zhou et al., 2016], cells were cross-linked with 1.42% formaldehyde for 15 min and quenching with 125 mM glycine for 5 min. Cells were lysed with Szak’s RIPA (Radioimmunoprecipitation assay buffer) buffer and sonicated.
  • ChIP Chromatin Immunoprecipitation
  • IP steps were conducted at 4 °C as follows: 50 ⁇ L of protein A/G agarose beads were prewashed with cold Szak’s RIPA buffer and incubated with 1 mg of lysate for 2 h.0.3 mg/mL of salmon sperm DNA was added and incubated for 2 h. Lysate (100 ⁇ L) was set aside as the input control. Anti-CHD1L (2 ⁇ g) was added to the remainder and incubated overnight.
  • the IP product was amplified with PowerUpTM SYBRTM Green Master Mix (Applied Biosystems, Austin, TX) using known published primers.
  • PowerUpTM SYBRTM Green Master Mix Applied Biosystems, Austin, TX
  • Clonogenic Assay Colony formation was assessed after CHD1L knockdown in SW620 cells or overexpression in DLD1 cells as previously described.
  • HCT-116 or CHD1L overexpressing DLD1 cell lines were pre-treated in monolayer cultures for 24 h with vehicle control (0.5% DMSO) or CHD1L inhibitors at the concentrations indicated in FIG.2C.
  • Pretreated viable cells were plated at 1,000 cells/well in 6-well plates or 200 cells/well in a 24-well plates.
  • Tumor organoid Culture Cell lines were cultured [Zhou et al., 2016; Abraham et al., 2019] as tumor organoids using phenol red free RPMI-1640 containing 5% FBS and by seeding 5,000 cells/well into un-coated 96-well U- bottom Ultra Low Attachment Microplates (Perkin-Elmer, Hopkinton, MA) followed by centrifugation for 15 min at 1,000 rpm to promote cells aggregation. A final concentration of 2% Matrigel® matrix (Corning Incorporated, Corning, New York) was added and tumor organoids were allowed to self- assemble over 72 h under incubation (5% CO 2 , 37 °C, humidity) before treatment, and maintained under standard cell culture conditions during treatment time courses.
  • VimPro-GFP and EcadPro-RFP reporter 3D high-content imaging assays Stable VimPro-GFP or EcadPro-RFP SW620 reporter cells were generated using pCDH imPro- GFP-EF1-puro virus or pCDH-EcadPro-mCherry-EF1-puro virus as previously reported. [Zhou et al., 2016; Abraham et al., 2019] The stable fluorescently labeled reporter cells were used to generate tumor organoids as described herein. Tumor organoids were treated with CHD1L inhibitors at 10 ⁇ M for an additional 72 h. Following treatment, tumor organoids were stained with 16 ⁇ M of Hoechst 33342 for 1 h (nuclei stain).
  • CellToxTM Green cytotoxicity assay solution was prepared per manufacturer’s protocol (Promega, Madison, WI). Briefly, tumor organoids were treated for 72 h with CellToxTM Green reagent (0.5X) and various doses of CHD1L inhibitors over a range of 0-to-100 ⁇ M. Organoids were imaged using the Opera PhenixTM 207 screening system (PerkinElmer Cellular Technologies, Hamburg, Germany) with excitation at 488 nm and emission at 500-550 nm. Mean intensity of the whole well was utilized for calculating cytotoxicity with Lysis Buffer (Promega, Madison, WI) as the 100% cytotoxicity control and 0.5% DMSO as the 0% cytotoxicity control.
  • Lysis Buffer Promega, Madison, WI
  • Intensity values were normalized to these controls using Prism8 (GraphPad, San Diego, CA). Invasion assays. HCT116 cells were plated at 60,000 cells/well into an IncuCyte ® ImageLock 96-well plate (Sartorius, France) and allowed to attach overnight. A wound was created in all wells using the IncuCyte® WoundMaker then washed 2x with PBS. The plate was brought to 4 ⁇ C using a Corning XT Cool Core to avoid polymerization of the Matrigel® matrix (Corning Life Sciences, Corning, NY) during the preparation of the invasion conditions. Wells were coated with 50 ⁇ L of 50% Matrigel® matrix in RPMI-1640 media.
  • Plates were centrifuged at 150 rpm at 4 ⁇ C for 3 min, using a swing bucket rotor to ensure even matrix coating with no air bubbles. Afterwards, plates were placed on a Corning XT CoolSink module prewarmed inside a cell culture incubator (5% CO 2 , 37 °C, humidity) for 10 min to evenly polymerize the matrix, followed by the addition of CHD1L inhibitors dissolved in 50 ⁇ L of RPMI-1640 media containing 5% FBS. Finally, the plate was placed in an IncuCyte® S3 live cell imager (Sartorius, France) for 48 h. The wound was imaged every hour using the phase contrast channel and 10x objective in wide mode.
  • Cells were harvested and resuspended in buffer-A, containing 20 mM HEPES, pH 7.5, 500 mM NaCl, 50 mM KCl, 20 mM imidazole, 10 mM MgCl 2 , 1 mM TCEP (tris(2-carboxyethyl)phosphine), 10% glycerol and 500 ⁇ M PMSF. Cells were lysed by sonication and cellular debris was removed by centrifugation. The supernatant was loaded onto a Ni-NTA resin column (Qiagen, Hilden, Germany).
  • Protein bound to the column was washed with 1x with buffer-A, 1x with buffer-A containing 10 mM ATP, and washed an additional time with buffer-A. Proteins were eluted using buffer-B (buffer-A with 500 mM imidazole) with a gradient from 20 to 500 mM imidazole.
  • buffer-B buffer-A with 500 mM imidazole
  • cat-CHD1L was dialyzed overnight into 50 mM Tris, pH 7.5, 200 mM NaCl, and 1 mM DTT.
  • fl-CHD1L was dialyzed overnight into 20 mM MES, pH 6.0, 300 mM NaCl, 10% glycerol, and 1 mM DTT.
  • Protein was then purified by ion- exchange chromatography.
  • cat-CHD1L was bound to a Q-sepharose column (GE Healthcare, Chicago, IL) and fl-CHD1L was bound to a S-sepharose column (GE Healthcare, Chicago, IL), and proteins were eluted using a NaCl gradient of 0.2 – 1M for cat-CHD1L and 0.3 -1M for fl-CHD1L. Pure fractions were pooled, concentrated, and further purified by size-exclusion chromatography using a SuperdexTM 200 column (GE Healthcare, Chicago, IL) with 20 mM HEPES, pH 7.5, 100 mM NaCl, 1 mM TCEP, and 10% Glycerol.
  • Protein purifications were conducted using an ⁇ CTA Start FPLC (GE Healthcare, Chicago, IL). CHD1L ATPase assay All reactions were carried out using low volume non-binding surface 384-well plates (Corning Inc., Corning NY).
  • ATPase activity was assayed by adding 500 nM of Phosphate Sensor (Life Technologies, Carlsbad, CA), containing labeled phosphate-binding protein, specifically labeled with the fluorophore MDCC, and measuring excitation (430 nm) and emission (450 nm) immediately on an EnVision® plate reader (PerkinElmer, Hopkinton, MA). An inorganic phosphate standard curve was used to convert the fluorescence to [Pi], and enzyme kinetics were determined using Prism8 (GraphPad Software, San Diego, CA). HTS drug discovery for inhibitors of CHD1L Assay composition was the same as described above using cat-CHD1L, except that the reaction mixture volume was modified to accommodate addition of drug or DMSO.
  • a selected amount of compounds dissolved in 100% DMSO were mixed with 50 mM Tris pH 7.5, 50 mM NaCl, 1 mM DTT, 5% glycerol buffer to 200 ⁇ M in 10% DMSO.
  • 1 ⁇ L of each compound was added to the enzyme mixture to give a final concentration of 20 ⁇ M.
  • the negative control used was 1% DMSO and 10 mM EDTA was used as a positive control.
  • Reactions were initiated with the addition of 10 ⁇ M ATP and incubated at 37 °C for 1 h. ATPase activity was measured by fluorescence by adding 500 nM Phosphate Sensor.
  • cat- CHD1L was screened against a 20,000-compound diversity set from Life Chemicals (Woodbridge, CT) and a Kinase Inhibitor library from Selleck Chemicals (Houston, TX). Both libraries were prescreened before purchase to remove Pan-assay interference compounds (PAINS) which tend to react nonspecifically with many biological targets rather than selectively with a desired target.
  • PAINS Pan-assay interference compounds
  • PDTOs were treated with DMSO (0.5%) or compound 6.0 with various concentrations for an additional 72 h to obtain a dose response.
  • PDTO cell viability was measured using CellTiter- Blue® reagent (Promega, Madison, WI). Media (80 ⁇ L) was aspirated from wells and 80 ⁇ L of the reagent was added and incubated for 4 h and cell viability was measured by fluorescence intensity using excitation 560 excitation and 590 emission.
  • SW620 cells were plated at 30,000 cells/well in 96-well plates.
  • Cells were treated with DMSO (negative control), SN-38 (apoptosis positive control), and compound 6.0 at concentrations indicated for 12 h.
  • Cells were then rinsed 2x with cold PBS, 1x with cold Annexin-V staining buffer (10 mM HEPES, pH 7.4, 140 mM NaCl, 2.5 mM CaCl 2 ), and then incubated with Annexin-V FITC at 1:100 for 30 min in the dark.
  • Cells were then rinsed 2x with Annexin-V staining buffer and FITC intensity was measured using an EnVision® plate reader (PerkinElmer, Hopkinton, MA).
  • Example 10 Additional Experimental Methods for Assessment of Compound Activities Microsome stability. CD-1 mouse microsomes were commercially purchased and the reactions were performed as previously desribed.
  • a master mix was prepared as follows: Microsomes (0.5 mg/mL), 10 ⁇ M CHD1Li solubilized in DMSO (0.1%), 5 mM UDPGA, 25 ⁇ g alamethicin, and 1 mM MgCl2 in 100 mM phosphate buffer (pH 7.4).
  • the master mix was pre-incubated at 37°C for 5 min, then 1 mM NADPH was added to start the microsomal activity reaction and maintained at 37°C throughout the time course. Reactions were stopped at 0, 5, 15, 30, 45, and 60 min by adding 200 ⁇ L acetonitrile and analyzed by mass spectrometry.
  • the appropriate microsome controls were also performed in the same reaction conditions.
  • Cells were seeded into a 96-well plate as monolayers and treated with compound 6.0 at 10 -M (0.5% DMSO) or SN-38 (1 -M), or the combination of 6.0 and SN38 over 6 hours. Media was aspirated and cells were washed with cold PBS. Cells were then fixed with 3% paraformaldehyde for 15 min at room temperature and washed with PBS three times. Cells were blocked for 1 hour at room temperature in 5% BSA, 0.3% Triton X-100 in PBS.
  • CHD1L inhibitors and SN38 were assessed for antitumor activity against colorectal cancer cell lines alone or in combination.
  • Cell lines were cultured as monolayers or 3D tumor organoids using RPMI-1640 containing 5% fetal bovine serum as previously reported [Abbott et al. , 2020].
  • RPMI-1640 containing 5% fetal bovine serum as previously reported [Abbott et al. , 2020].
  • 3D SW620 tumor organoid cytotoxicity studies 2,000 cells in 100 ⁇ L were plated into each well of the 96-well U-bottom ultra-low attachment microplates (Corning Inc., Corning, NY, USA). Plates were centrifuged at 1,000 rpm for 15 minutes to promote cell aggregation.
  • a final 2% of Matrigel concentration was reached by coating the centrifuged cells with 25 ⁇ L of 10% Matrigel per well. Plates were then incubated for 3 days before treatment.3D organoids were treated with 25 ⁇ L of various concentrations of drugs.3 days after treatment, organoids with 40 ⁇ L of medium were manually transferred to 96-well white solid bottom plates. An equal amount of Celltiter-glo 3D (Promega) was added, and the plates were kept on a plate shaker for 45 minutes at 400 rpm before luminescence was read with Envision plate reader (PerkinElmer). For combination studies, synergy scores were determined using Combenefit analysis [De Veroli et al., 2016]. In vivo studies.
  • CHD1L inhibitors compound 6.0 and 6.11 were assessed pharmacokinetically to determine the plasma half-life in nine-week-old female CD-1 mice as previously reported [Abbott et al., 2020].
  • Compound 6 was further assessed for antitumor activity alone and in combination with irinotecan against SW620 tumor xenografts in athymic nude mice. Xenografts were generated using the methodology as previously reported [Zhou et al., 2016]. Briefly, compound 6 was administered at 5 mg/kg by intraperitoneal injection (i.p.) 2x/day 7 days/week for a total of 5 weeks. Irinotecan was administered i.p.
  • FIGs.7A and 7B illustrate representative single agent cytotoxicity dose response studies in SW620 colorectal cancer (CRC) tumor organoids and provide IC 50 for exemplary compounds as indicated.
  • Tables 4A and 4B below provides a summary of cytotoxicity data for exemplary compounds.
  • Table 4A provides cytotoxicity data for representative single compounds in several different CRC tumor organaoids.
  • Table 4A Tumor Organoid Cytotoxicity Tumor Organoid Cytotoxicity IC 50 ( ⁇ M) CHD1L SW620 HCT116 CRC042 CRC102 6.28 >30 3 ⁇ 4 3 ⁇ 4 3 ⁇ 4 L Inhibitors (CHD1Li) with SN38 or Olaparib. Treatments are performed in four different CRC tumor organoid types. The concentration of CHD1L inhibitor is varied as indicated. IC 50 for the combination treatment are generally decreased compared to SN38 and Olaparib alone.
  • FIG.8B presents a graph of --H2AX intensity (relative to DMSO) for compound 6 alone, irinotecan (SN38) alone, and a combination of the two in DLD1 empty vector (EV) cells and DLD1 (OE) overexpressing cells.
  • FIG.8A is a Western Blot showing relative expression of CHD1L in DLD1(EV) cells compared to DLD1(OE) cells compared to control expression of --tubulin in these cells.
  • CHD1L is known to be essential for PARP-1 Mediated DNA Repair, causing resistance to DNA damaging chemotherapy [Ahel et al., 2009; Tsuda et al., 2017].
  • FIG.8B demonstrate CHD1L inhibitor “on target” effects that synergize with SN38 inducing DNA damage.
  • FIGs.9A-9C illustrate the results of synergy studies with exemplary CHD1L Inhibitors 6, 6.3, 6.9 and 6.11 in SW620 Colorectal Cancer (CRC) Tumor Organoids.
  • SN38 combinations with 6, and 6.3 are 50-fold, and 150-fold more potent, respectively, than SN38 alone in killing colon SW620 tumor organoids.
  • SN38 combinations with 6.9 and 6.11 are both over 100-fold more potent than SN38 alone.
  • Each of compounds 6, 6.3, 6.9 and 6.11 shows synergism with irinotecan (and SN38) for killing SW620 tumor organoids.
  • Synergy scores for exemplary CHD1L inhibitors where scores are determined as described in De Veroli et al.2016 are provided in Table 5.
  • SynergyFinder has normalized input data as percentage inhibition, they can be directly interpreted as the proportion of cellular responses that can be attributed to the drug interactions. (e.g., synergy score 20 corresponds to 20% of response beyond expectation). According to our experience, the synergy scores near 0 gives limited confidence on synergy or antagonism.
  • FIG.10 includes a graph of tumor volume (fold) SW620 tumor xenografts as a function of days (up to 28 days) of treatment with Compound 6 alone, irinotecan alone or a combination thereof.
  • FIG.11 includes a graph of tumor volume (fold) SW620 tumor xenografts as a function of days (up to 28 days) of treatment with irinotecan alone (1) or a combination of Compound 6.0 and irinotecan (2).
  • the combination of irinotecan and Compound 6 significantly inhibits colon SW620 tumors to almost no tumor volume beyond the last treatment compared to irinotecan alone. Within 2-weeks of the last treatment of irinotecan alone tumor volume rose to above the volume of the last treatment, signifying tumor recurrence.
  • FIG.12 shows that Compound 6 alone and in combination with irinotecan (4) significantly increases the survival of CRC-tumor-bearing mice compared to vehicle (1), Compound 6 alone (2) and irinotecan alone (3).
  • FIG.13 includes a graph of tumor volume (fold) SW620 tumor xenografts as a function of days (up to 20 days) of treatment with Compound 6.11 alone, irinotecan alone or a combination thereof.
  • the combination of irinotecan and Compound 6.11 significantly inhibits colorectal cancer SW620 tumor xenografts compared to irinotecan alone or control.
  • FIG.14 includes a graph of tumor volume (fold) SW620 tumor xenografts as a function of days (up to 33 days) of treatment with irinotecan alone or a combination of compound 6.11 with irinotecan.
  • the combination of irinotecan and compound 6.11 significantly inhibits colorectal SW620 tumors beyond the last treatment (day 33) compared to irinotecan alone.
  • Eight days post treatment (Tx Released) tumor volume with irinotecan treatment alone rose ⁇ 3-fold, signifying tumor recurrence.
  • tumor volume with treatment of the combination of 6.11 and irinotecan continued to drop (by ⁇ 1.5-fold) post treatment.
  • Example 11 Summary of Currently Preferred Structure Activity Relationships for Inhibitors.
  • the currently preferred structure activity relationship based on formula I for CHD1L Inhibitors of this invention is as follows:
  • the B ring it is currently preferred th or fused 6, 6-member aromatic ring and that both X are N.
  • the B ring optionally contains a fused ring, which if present, can contain one or two additional N.
  • Preferred R B (B ring substitution), if present, include hydrogen, alkyl and fluoroalkyl groups. In certain embodiments, where x is 1 and L1 is present, and preferably L 1 is –CH 2 -, R B can be an electronegative group, such as a halogen and particularly F or a haloalkyl, particularly CF 3 -. Preferred R B are hydrogen or C1-C3 alkyl.
  • the preferred A ring is optionally substituted phenyl, with unsubstituted phenyl (where R A is hydrogen) more preferred.
  • the R P group is believed to be associated with water solubility, with -N(R 2 )(R 3 ) groups generally preferred and more particularly preferred optionally substituted N-containing heterocycles, where R 2 and R 3 together with the N to which they are attached form a 5- to 8-member ring which may contain one or more additional heteroatoms and which may be saturated (no double bond) or contain one or more double bonds.
  • R H is believed associated with activity and potency as well as metabolic stability.
  • R H is preferably an aromatic group and more particularly a heteroaromatic group with ring substitution that stabilizes the aromatic or heteroaromatic ring.
  • Preferred Y is NR with R that is hydrogen more preferred.
  • Preferably x is 0 except as noted above.
  • Preferred Z is — CO-NH-.
  • Preferred L 2 is –CH 2 - or –CH 2 -CH 2 -.
  • Preferred L 1 when present is –CH 2 -.
  • HTS screening for CHD1L identified a phenylamino pyrimidine pharmacophore illustrated in formula XX:
  • R 5 is a substituent other than hydrogen which is believed to be associated with metabolic stability.
  • R 5 is a halogen, particularly F or Cl, a C1-C3 alkyl group, particularly a methyl group.
  • R 4 is a substituent other than hydrogen and in particular is a C1-C3 alkyl group, and more particularly is a methyl group.
  • R 5 is F and R 4 is methyl.
  • R 6 -R 9 are selected from hydrogen, C1-C3-alkyl, halogen, hydroxyl, C1-C3 alkoxy, formyl, or C 1 -C 3 acyl. In embodiments, one or two of R 6 -R 9 are moieties other than hydrogen. In an embodiment, one of R 6 -R 9 is a halogen, particularly fluorine. In specific embodiments, all of R 6 - R 9 are hydrogen. In embodiments, R N is an amino moiety –N(R 2 )(R 3 ). In specific embodiments, R N is an optionally substituted heterocyclic group having a 5- to 7- member ring optionally containing a second heteroatoms (N, S or O).
  • R N is optionally substituted pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, piperazin-1-yl, or morpholino.
  • R N is substituted with one substituent selected from C1-C3 alkyl, formyl, C1-C3 acyl (particularly acetyl), hydroxyl, halogen (particularly F or Cl), hydroxyC1-C3 alkyl (particularly –CH 2 -CH 2 -OH).
  • R N is unsubstituted pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, piperazin-1-yl, or morpholino.
  • R 10 is –NRy-CO-(L 2 )y-R 12 or –CO-NRy--(L 2 )y-R 12 , where y is 0 or 1 to indicate the absence of presence of L 2 which is an optional 1-6 carbon atom linker group which linker is optionally substituted and wherein one or two, carbons of the linker are optionally replaced with O, NH, NRy or S, where Ry is hydrogen or a 1-3 carbon alkyl, and R 12 is an aryl group, cycloalkyl group, heterocyclic group, or heteroaryl group, each of which is optionally substituted.
  • y is 1.
  • L 2 is –(CH 2 )p-, where p is 0-3.
  • R 12 is thiophen-2-yl, thiophen-3-yl, 4-bromothiophen-2-yl, furany-2-yl, furan-3-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-4-yl, oxazol-5-yl, oxazol-2-yl, indol-2-yl, indol-3-yl, benzofuran-2-yl, benzofuran-3-yl, benzo[b]thiophen- 2-yl, benzo[b]thiophen-3-yl, isobenzofuran-1-yl, isoindol-1-yl, or benzo[c]thiophen-1-yl.
  • R 1 is hydrogen or methyl.
  • R 12 is thiophen-2-yl, furany-2-yl, pyrrol- 2-yl, oxazol-4-yl, indol-2-yl, benzofuran-2-yl, or benzo[b]thiophen-2-yl.
  • R 12 is thiophen-2-yl or indol-2-yl.
  • R 1 is hydrogen or methyl.
  • Exemplary compounds of the invention are illustrated in Scheme 1.
  • X is halogen and preferably Cl or Br.
  • R is C1-C5 alkyl or cycloalkyl, and preferably a C1-C3 alkyl or cyclopropyl and more specifically, methyl, ethyl, n-propyl or cyclopropyl.
  • Exemplary R P and -N(R 2 )(R 3 ) groups for any formulas herein are illustrated in Scheme 2.
  • Exemplary R 12 and R H groups for any formulas herein are illustrated in Scheme 3.
  • Exemplary B rings for formula I are illustrated in Scheme 4.
  • Scheme 1 Exemplary Compounds of Formula I or Formula XX-XXIII
  • Scheme 1 (continued) Scheme 1 (continued) Scheme 1 (continued) Scheme 2 (Exemplary R P and -N(R 2 )(R 3 ) groups) Scheme 2 (continued) Scheme 2 (continued) Scheme 3: Exemplary R 12 and R H Groups Scheme 3 (continued) Scheme 3 (continued) Scheme 3 (continued) Scheme 3 (continued) Scheme 3 (continued) R is H, alky, acyl, R is H, alky, acyl, R is H, alky, acyl, halogen halogen halogen halogen X 11 is CH or N; p is 0, 1 or 2; X 11 is CH or N; X 10 is CR or N; R is hydrogen, C1-C6 alkyl, C4-C7 p is 0, 1 or 2; 10 cycloalkylalkyl, -SO 2 -R’, phenyl, or R is hydrogen, C1-C6 alkyl,
  • X is halogen, particularly Cl and Br; X is halogen, particularly Cl and Br; p is 0, 1 or 2; p is 0, 1 or 2; X 11 is CH or N; each Rs, independently, is hydrogen, each Rs, independently, is hydrogen, halogen, hydroxide, C1-C6 alkyl, halogen, hydroxide, C1-C6 alkyl, C3-C7-cycloalkylalkyl, phenyl or C3-C7-cycloalkylalkyl, phenyl or benzyl or C1-C3 alkoxide, and benzyl or C1-C3 alkoxide, and particularly each Rs is independently particularly each Rs is independently H or C1-C3 alkyl or C3-cycloalkyl H or C1-C3 alkyl or C3-cycloalkyl R12-77, p is 0, 1 or 2; X 11 is CH or N; each Rs, independently, is hydrogen,
  • Halogen is particularly Cl or Br.
  • Scheme 3 (continued) R12-78, p is 0, 1 or 2; R is hydrogen or C1-C4 alkyl or cycloalkyl; each Rs, independently, is hydrogen, halogen, hydroxide, C1-C6 alkyl, C3-C7-cycloalkylalkyl, phenyl or benzyl or C1-C3 alkoxide, and particularly each Rs is independently H or C1-C3 alkyl or C3-cycloalkyl or halogen.
  • Halogen is particularly Cl or Br.
  • R is particularly hydrogen or methyl.
  • This three-step synthesis starts with selective aromatic nucleophilic substitution on the 4- position of a 2,4-dichloro-pyrimidine A (e.g., 2,4-dichloro-6-methylpyrimidine, where R 4 is methyl or 2,4-dichloro-5-fluoropyrimidine, where R 5 is fluorine) with a p-phenylenediamine B to form the intermediate C.
  • a 2,4-dichloro-pyrimidine A e.g., 2,4-dichloro-6-methylpyrimidine, where R 4 is methyl or 2,4-dichloro-5-fluoropyrimidine, where R 5 is fluorine
  • Scheme 5 Exemplary reaction conditions are shown in Scheme 5 where reactants are added with trimethylamine to ice cold ethanol and stirred at rt for 15 h. [Kumar et al., 2014; Odingo et al., 2014].
  • Chlorinated intermediate C is then reacted with any amine HNR 2 R 3 D by amination to generate intermediate E.
  • Exemplary amination conditions are shown in Scheme 5, where reactants are reacted in DMF in the presence of K 2 CO 3 at elevated temperature.
  • Step three couples the R 10 group employing acid F to intermediate E.
  • Various known synthetic methods can be employed to introduce a selected R 10 group, for example, cross coupling, click chemistry or substation reactions (e.g., SN2, aromatic, electrophilic) [Li et al., 2014a; Li et al., 2014b; LaBarbera et al., 2007].
  • Scheme 5 illustrates coupling of the amine group of E with a selected carboxylic acid F to form R 10 which is –NH-CO-R 12 in compound G.
  • R 12 are aryl, aryl-substituted alkyl, heteroaryl and heteroaryl-substituted alkyl.
  • Exemplary coupling conditions are illustrated in Scheme 5, where coupling proceeds in the presence of propylphosphonic anhydride (T3P) and triethyamine at room temperature to form the desired compound G.
  • T3P propylphosphonic anhydride
  • the illustrated method has been employed, for example to prepare compound 6, and compound 8 (see, Scheme 6).
  • Various substituted starting materials A, B, D and F are commercially available or can be prepared using known methods.
  • aniline derivatives already substituted with R 10 can be used in place of p-phenylenediamine derivatives B to form a corresponding R 10 -substituted intermediate C’.
  • Carrying out step 2 of the illustrated reaction, by reacting intermediate C’ with D will result in desired corresponding compound G’ (where R 10 replaces R 12 -CO-NH-).
  • R 10 replaces R 12 -CO-NH-
  • ring N in reactants F may be protected with appropriate amine protecting groups. Use of appropriate protecting groups is generally routine in the art.
  • a variety of primary or secondary amines (D) are commercially available or can be prepared by well-known methods.
  • chlorinated intermediate C can be reacted with an appropriate nucleophile to add a selected –NR 2 R 3 group at the 4-chloro position.
  • D can be a cyclic amine such as pyrrolidine.
  • Suzuki coupling may be used to install an amine containing group by C-C bond formation [Li et al., 2014a].
  • Buchwald-Hartwig cross coupling can be used to form carbon and amine bonds in such intermediates.
  • N-(4-aminophenyl)-2-chloro-6-methyl-pyrimidin-4-amine 102
  • TEA triethyl amine
  • Boc-protected indole-3-caboxylic acid 106-boc was used in a peptide coupling methodology with compound 104 in the presence of T3P and TEA to achieve the synthesis of boc-protected indole derivative 8-boc, which was converted to the indole derivative 8 in good yield via TFA deprotection of the boc-protecting group.
  • the boc protecting group is -COO-t-butylK2Co3,KI, EtOH N-(4- ⁇ [6-Methyl-2-(1-pyrrolidinyl)-4-pyrimidinyl]amino ⁇ phenyl)-1- ⁇ [(2-Methyl-2- propanyl)oxy]carbonyl ⁇ -1H-indole-3-carboxamide (8-boc).
  • Scheme 7 illustrates an alternative method of synthesis optimized for yield of compound 6.
  • a t-butyl protected carbamate for example, compound 35 is reacted with a selected aromatic carboxylic acid, for example, compound 36 to form a protected carbamate intermediate, for example, compound 37.
  • the intermediate is deprotected as known in the art, for example with trifluoroacetic acid (TFA) and the deprotected carbamate is reacted with a chlorinated heterocyclic group carrying a primary or secondary amine group (e.g., a pyrrolidinyl group), for example, compound 38 to form the desired compound of Formula XX, for example, compound 6.
  • TFA trifluoroacetic acid
  • This method can also be employed to prepare various compounds of formula XX by selection of starting aromatic carboxylic acids and chlorinated heterocyclic compound carrying a primary of secondary amine group.
  • Scheme 7 reagents employed for synthesis of compound 6 are shown, where in the first reaction DCC is N,N’-dicyclohexylcarbondiimide, DMAP is dimethylaminopyridine and the solvent is DCM dichloromethane.
  • DCC is N,N’-dicyclohexylcarbondiimide
  • DMAP dimethylaminopyridine
  • the solvent is DCM dichloromethane.
  • potassium carbonate, and potassium iodide in ethanol is employed.
  • One of ordinary skill in the art can readily adapt the reagents and reaction conditions employed to prepare desired compounds of formula XX.
  • Example 13 Biological Evaluation and Comparison of Inhibitors of Oncogenic CHD1L
  • CHD1L is unique from other chromatin remodelers and has a diverse repertoire of cellular functions.
  • CHD1L is essential for PARP-mediated DNA repair and knockdown of CHD1L sensitizes tumor cells to DNA damaging agents.
  • Two recent reports validate CHD1L as significant factor promoting drug resistance to PARP inhibitors via CHD1L mediated nucleosome sliding, alleviating PARP trapping.
  • CHD1L is a required component of the TCF/LEF-transcription factor complex (denoted henceforth as TCF-transcription) (see also, Abbott et al., 2020), which is linked as a driver of GI cancers and many other cancers.
  • N-(2-chloro-5-fluoro-6-methylpyrimidin-4-yl)benzene-1,4-diamine (3.2).2,4-dichloro-5-fluoro-6- methylpyrimidine (2.2) 250 mg, 1.381 mmol, 1.0 equiv
  • ethanol (10 mL) cooled in an ice bath.
  • Triethyl amine (231 ⁇ L, 1.657 mmol, 1.2 equiv) and p-phenylenediamine (1) 324.1 mg, 1.381 mmol, 1.0 equiv
  • N-(2-chloro-5-fluoropyrimidin-4-yl)benzene-1,4-diamine (3.3).
  • 2,4-dichloro-5-fluoropyrimidine (2.3) (500 mg, 2.995 mmol, 1.0 equiv) was dissolved in EtOH (20 mL) and cooled in an ice bath.
  • Triethyl amine (501.57 ⁇ L, 3.593 mmol, 1.2 equiv)
  • p-phenylenediamine (1) (323.88 mg, 2.995 mmol, 1.0 equiv) were added and the reaction was allowed to warm to RT and stir for 8h.
  • N-(6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4-yl)benzene-1,4-diamine (4.1).3.1 was dissolved in 5 mL of DCM and treated with 5 mL of TFA at 0 °C, resulting in a red colored solution. The reaction was warmed to RT and allowed to stir for 3h. The reaction was concentrated and redissolved in 10% methanol and DCM, then washed with bicarb and water. The organic later was dried over sodium sulfate and concentrated, purified via column chromatography using 10% methanol in DCM to produce 4.1 (2.09 g, 67% over two steps) as an orange solid.
  • N-(2-chloro-5-fluoro-6-methylpyrimidin-4-yl)benzene-1,4-diamine (4.2).3.2 (260 mg, 1.029 mmol, 1.0 equiv) was dissolved in DMF (29 mL) and treated with potassium carbonate (156.4 mg, 1.132 mmol, 1.1 equiv) and pyrrolidine (422.5 ⁇ L, 5.145 mmol, 5.0 equiv). The reaction was heated to 80 °C for 8h then diluted with ethyl acetate and washed with water and a 5% lithium chloride solution.
  • N-(5-fluoro-2-(pyrrolidin-1-yl)pyrimidin-4-yl)benzene-1,4-diamine (4.3).3.3 (310 mg, 1.30 mmol, 1.0 equiv) was dissolved in DMF (36 mL) and treated with potassium carbonate (197.6 mg, 1.43 mmol, 1.1 equiv) and pyrrolidine (533.8 ⁇ L, 6.5 mmol, 5.0 equiv). The reaction was heated to 80 °C for 8h then diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to provide 4.3 as a dark yellow solid, which was carried on crude.
  • N-(4-((6-methyl-2-(1-pyrrolidinyl)-4-pyrimidinyl)amino)phenyl)-2-(2-thienyl)acetamide (6.0) 4.1 (262.0 mg, 0.973 mmol, 1.0 equiv) was dissolved in DCM (40 mL, anhydrous) then treated with 5.1 (145.3 mg, 1.02 mmol, 1.05 equiv), DMAP (118.9 mg, 0.973 mmol, 1.0 equiv), and then DCC (251 mg, 1.22 mmol, 1.25 equiv) under nitrogen.
  • N-(4-((5-fluoro-6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4-yl)amino)phenyl)-2-(thiophen-2- yl)acetamide (6.1).4.2 (450 mg, 1.566 mmol, 1.0 equiv) was dissolved in DCM (15.0 mL, anhydrous) and treated with 2-thiopheneacetic acid (5.1) (244.9 mg, 1.723 mmol, 1.1 equiv), and triethylamine (546.4 ⁇ L, 3.915 mmol, 2.5 equiv). The reaction was allowed to stir for 5 min.
  • N-(4-((5-fluoro-2-(pyrrolidin-1-yl)pyrimidin-4-yl)amino)phenyl)-2-(thiophen-2-yl)acetamide (6.2).4.1 (50.0 mg, 0.183 mmol, 1.0 equiv) was dissolved in DCM (15.0 mL, anhydrous) and treated with 2-thiopheneacetic acid (5.1) (28.6 mg, 0.201 mmol, 1.1 equiv), and triethylamine (63.9 ⁇ L, 0.458 mmol, 2.5 equiv).
  • N-(4-((5-fluoro-6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4-yl)(methyl)amino)phenyl)-2-(thiophen- 2-yl)acetamide (6.3). 6.1 (13 mg, 0.0316 mmol, 1.0 equiv) was dissolved in THF (1.0 mL, anhydrous) and treated with sodium hydride (1.52 mg, 0.0379 mmol, 1.2 equiv) at 0 °C under nitrogen. The reaction was allowed to stir for 10 min. then iodomethane (3.0 ⁇ L, 0.047 mmol, 1.5 equiv) was added and the reaction was allowed to stir for 15h.
  • 2,4-dichloro-6- methylpyrimidine (2.1) (2.36g, 0.0145 mol, 1.05 equiv) was dissolved in 30 mL of absolute ethanol and cooled with an ice bath and triethyl amine (2.5 mL, 0.0179 mol, 1.3 equiv) was added.
  • tert- butyl (4-aminophenyl)carbamate (2.87g, 0.0138 mol, 1.0 equiv) was dissolved in 15 mL of absolute ethanol and transferred to an additional funnel.
  • tert-butyl (4-((6-methyl-2-morpholinopyrimidin-4-yl)amino)phenyl)carbamate (9.2).8 (199.0 mg, 0.594 mmol, 1.0 equiv) was dissolved in acetone (3.4 mL) and cooled with an ice bath. Sodium carbonate (69.3 mg, 0.653 mmol, 1.1 equiv) was added followed by morpholine (53.0 ⁇ L, 0.612 mmol, 1.03 equiv) in 1.0 mL of acetone, dropwise. The ice bath was removed and the reaction was heated to 80 °C for 8h.
  • reaction was allowed to stir for 12h at room temperature. Upon completion, the reaction was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated, then purified via column chromatography using 0-10% methanol in dichloromethane to produce the desired product 6.8 (20 mg, 63 % yield) as a yellow oil.
  • reaction was allowed to stir for 12h at room temperature. Upon completion, the reaction was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated, then purified via column chromatography using 0-10% methanol in dichloromethane to produce the desired product 6.9 (17.4 mg, 86 % yield) as a yellow solid.
  • N-(4-((6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4-yl)oxy)phenyl)-2-(thiophen-2-yl)acetamide (6.13).6.12 (44.3 mg, 0.123 mmol, 1.0 equiv) was dissolved in DMF (anhydrous, 1 mL) and then treated with potassium carbonate (20.3 mg, 0.148 mmol, 1.2 equiv) and pyrrolidine (20.6 mL, 0.247 mmol, 2.0 equiv). The mixture was heated to 80 °C for 8h, then diluted in dichloromethane and washed with water then brine.
  • N-(4-((6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4-yl)oxy)phenyl)-1H-indole-3-carboxamide (6.14). 11.2 (9.0 mg, 0.024 mmol, 1.0 equiv) was dissolved in 1.0 mL anhydrous DMF. Potassium Carbonate (4.3 mg, 0.0312 mol, 1.3 equiv) was added followed pyrroldine (10 mL, 0.119 mmol, 5.0 equiv) and the reaction was heated to 80 °C for 8h. The reaction was then diluted with ethyl acetate and washed with water then brine.
  • N-(4-((6-methyl-2-morpholinopyrimidin-4-yl)amino)phenyl)-2-(thiophen-2-yl)acetamide (6.15).
  • 4.1 (17.5 mg, 0.061 mmol, 1.0 equiv) was dissolved in anhydrous DCM (1.5 mL) then treated with DMAP (7.5 mg, 0.061 mmol, 1.0 equiv), DCC (19.9 mg, 0.0763 mmol, 1.25 equiv), and 5.1 (9.1 mg, 0.064 mmol, 1.05 equiv). The reaction was allowed to stir for 12h at room temperature. Upon completion, the reaction was filtered through a pad of celite and concentrated on to silica gel.
  • N-(4-((6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4-yl)amino)phenyl)-2-(naphthalen-1-yl)acetamide (6.16).4.1 (33.6 mg, 0.125 mmol, 1.0 equiv) was dissolved in anhydrous DCM (1.5 mL) then treated with DMAP (15.3 mg, 0.125 mmol, 1.0 equiv), DCC (32.2 mg, 0.156 mmol, 1.25 equiv), and 2-(naphthalen-1-yl)acetic acid (25.6 mg, 0.137 mmol, 1.1 equiv). The reaction was allowed to stir for 12h at room temperature.
  • N-(4-((6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4-yl)amino)phenyl)-2-(1H-pyrrolo[2,3-b]pyridin-3- yl)acetamide (6.20) 4.1 (25.2 mg, 0.0936 mmol, 1.0 equiv) was dissolved in dichloroemethane, anhydrous (1.5 mL) and treated with DMAP (12.6 mg, 0.103 mmol, 1.1 equiv), DCC (24.1 mg, 0.117 mmol, 1.25 equiv) and 2-(1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (39 mg, 0.223 mmol, 1.0 equiv).
  • Methyl 2-(1-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-indol-3-yl)acetate (I16).
  • Methyl 2-(1Hindol-3-yl)acetate (54.8 mg, 0.290 mmol, 1.0 equiv)
  • 4- (trifluoromethyl)benzenesulfonyl chloride (85.1 mg, 0.348 mmol, 1.2 equiv)
  • tetrabutylammonium hydrogen sulfate 9.85 mg, 0.029 mmol, 0.1 equiv) were dissolved in toluene (2 mL) and cooled in an ice bath (Scheme 10).
  • N-(4-((6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4-yl)amino)phenyl)-2-(2-oxoindolin-3-yl) acetamide (6.30).
  • 4.1 (22.0 mg, 0.0817 mmol, 1.0 equiv) was dissolved in dichloromethane, anhydrous (1.5 mL) and treated with HBTU (40.3 mg, 0.106 mmol, 1. equiv), 2-(2-oxoindolin-3- yl)acetic acid (17.2 mg, 0.090 mmol, 1.1 equiv) and then DIPEA (28.3 mL, 0.163 mmol, 1.0 equiv).
  • Scheme 8 The synthesis of compound 6.0 and analogs 6.1–6.4.
  • Schemes 9 A and 9B The optimized syntheses of certain 6.0 analogs.
  • Example 14 Additional Synthetic Examples Exemplary Synthesis of Benzyl Analogues of Compound 6
  • Scheme 10 illustrated an exemplary synthesis of benzyl analogues of compound 6. The compound numbers below refer to the compound numbers in Scheme 10.
  • Scheme 10 1.5 g of 4-aminobenzylamine, 1, (12.28 mmol) was added to 25 mL acetonitrile solution of 2,4- dichloro-6-methylpyrimidine, 2, (2.0 g, 1 eq) and triethylamine (3.43 mL, 2 eq).
  • Scheme 13 Exemplary Synthesis of amide and urea analogues (Scheme 14)
  • compound numbers are referenced to Scheme 14.
  • Compound 6 2-chloro-6-methylpyrimidin-4-amine (500 mg, 3.48 mmol) and pyrrolidine (3 eq) were added simultaneously to a flask containing K 2 CO 3 (1.05 eq) and DMF (2 mL). After refluxing at 75°C for 8 h, the reaction mixture was poured into crushed ice and stirred vigorously. The resulting precipitate was collected via vacuum filtration to give intermediate 4 as an off-white solid in 76% yield.
  • the required nitro precursor of 9 was prepared as follows; intermediate 4 (150 mg, 0.842 mmol), 4-nitrophenyl isocyanate (1.0 eq) and triethylamine (3 eq) were refluxed in 5 mL dioxane at 110°C for 16 h. After cooling to RT, the resulting precipitate was filtered while washing with 5mL cold diethyl ether to afford the desired nitro precursor as a yellow solid.
  • Scheme 16 The urea intermediate 11 was prepared as described for 9 while its conversion to 12 was achieved using the procedure for intermediate 4. Thereafter, 80 mg of 12 (0.177 mmol) in 3 mL n-BuOH was treated with pyrrolidine (3 eq) and refluxed at 120°C for 16 h.
  • EMT phenotypes can be isolated by FACS based on dual-reporter fluorescence and interrogated as individual cell populations in long- term culture, including stable xE/xM (RFP -/GFP -), and quasi-EMT populations E (RFP+), E/M (RFP+/GFP+), and M (GFP+). Isolated EMT phenotypes display unequivocal differences morphologically and metabolically, and these phenotypic differences are driven by TCF- transcription. The correlation between cytotoxicity and CHD1L inhibition are consistent with the inhibition of CHD1L mediated TCF-transcription in CRC.
  • CHD1L inhibitors displayed potent antitumor activity in SW620 and HCT116 M-Phenotype tumor organoids, inhibiting cell viability at low micromolar IC 50 values ( Figure 18A and 18B). Likewise, CHD1Li had potent cytotoxicity against CRC042 and CRC102 patient tumor organoids ( Figure 18C and 18D). These results underscore the potent antitumor activity of CHD1Li in a variety of CRC cell models, including CRC patient tumor organoids. CHD1L inhibitors were then evaluated for their ability to inhibit EMT and/or induce mesenchymal- epithelial transition (MET, i.e.
  • MET mesenchymal- epithelial transition
  • CHD1L inhibitor 6.31 was the most potent of the compounds assessed with an IC 50 value of 300 nM in SW620 cells and 200 nM in HCT116 cells.
  • CHD1L inhibitors prove to be effective antitumor agents that prevent CHD1L- mediated TCF-transcription that in turn inhibits EMT and induces MET, resulting in loss of CSC stemness while promoting cytotoxicity to tumor cells.
  • Example 16 In vivo Biological Evaluation of CHD1L Inhibitors. We described that CHD1Li 6.0 has a good in vivo disposition, including a plasma half-life of 3 h in mice.
  • 6.0 does not display any liver toxicity when treating mice at a maximum tolerated dose of 50 mg/kg by intraperitoneal (i.p.) administration daily over five days.
  • i.p. intraperitoneal
  • CHD1L inhibitor 6.11 Prior to conducting in vivo studies with CHD1L inhibitors, we conducted in vitro mouse microsomal stability studies with select compound, including 6.0, 6.4, 6.5, 6.11, and 6.31. CHD1L inhibitor 6.11 proved to be the most metabolically stable of these compounds when exposed to microsomes with a 2-fold longer half-life of 130.3 minutes compared to 67.2 minutes for compound 6.0. Therefore, 6.11 was prioritized for in vivo evaluation. As described in more detail above, using CD-1 mice, we administered 6.11 by i.p. injection at a dose of 50 mg/kg and assessed the pharmacokinetics (PK) of 6.11, including elimination half-life (t 1/2 ⁇ ) from plasma, and liver and fat tissues.
  • PK pharmacokinetics
  • the t 1/2 ⁇ of 6.11 in the plasma and tissues is 8 h, which is a 2.7-fold longer half-life than 6.0.
  • the in vivo half-life 6.11 is consistent with its in vitro microsomal stability, indicating that the bromothiophene moiety of 6.11 significantly improves the in vivo PK by increasing its stability to liver enzymes compared to 6.0.
  • Example 17 Experimental Methods General Experimental Methods. All commercial chemicals were used as supplied unless otherwise stated.
  • High resolution mass spectrometry were recorded using Q Exactive mass spectrometer (ThermoFisher, San Jose, CA) operated independently in positive or negative ion mode, scanning in full MS mode (2 ⁇ scans) from 150 to 1500 m/z at 140,000 resolution, with 4 kV spray voltage, 45 sheath gas, 15 auxiliary gas. Acquired data were then converted from raw to mzXML file format using Mass Matrix (Cleveland, OH). CHD1L Enzyme ATPase Assay. CHD1L enzyme inhibition assay was performed as described previously (Abbott et al., 2020).
  • the reaction was initiated by the addition of 10 ⁇ mol/L ATP (New England Biolabs, Ipswich, MA) to a total volume of 10 ⁇ L and incubated at 37°C for 1 hour.
  • ATPase activity was measured by adding 500 nmol/L of Phosphate Sensor (ThermoFisher, Waltham, MA) measuring excitation (430 nm) and emission (450 nm) immediately on an Envision plate reader (PerkinElmer, Waltham, MA). Background signal was determined by using all assay components excluding the enzyme.
  • Cell lines Cell lines were purchased directly from ATCC and used as indicated. Engineered cell lines previously reported were STR profiled for authenticity. All cell lines were tested for bacterial and mycoplasma contamination before use.
  • SW620 and HCT116 cell lines were obtained from American Type Culture Collection (ATCC) (Manassas, VA) and grown in RPMI-1640 media supplemented with 5% fetal bovine serum (FBS) in a humidified incubator at 37°C and 5% CO 2 . Cells were expanded in 10 cm 2 tissue culture-treated dishes (ThermoFisher) following ATCC protocols. Epithelial-Mesenchymal transition (EMT) dual reporter cell lines (SW620 and HCT116 E, E/M, and M) were generated, characterized, and maintained as previously outlined (PMID: 33742123).
  • EMT Epithelial-Mesenchymal transition
  • Both wildtype and dual reporter cell lines were harvested and prepared for experiments by aspirating media, washing with 10 mL PBS, detaching with 1 mL of Trypsin-EDTA at 0.25% (ThermoFisher), and neutralizing with 4 mL of complete growth medium.
  • Cells were counted using a Bio-Rad TC20 automated cell counter (Bio- Rad, Hercules, CA) by Trypan Blue (1:1) live/dead cell exclusion.
  • Cell Line Tumor Organoid Culture Tumor organoids were prepared by plating at 2,000 cells/well into CellCarrier Spheroid Ultra-Low Attachment (ULA) 96-well plates (Cat.
  • SW620 cells were plated into duplicate 96-well plates at 20,000 cells/well (HCT116 at 10,000 cells/well), one white solid bottom plate was used to assess TCF-transcriptional activity and one clear plate was used to measure total protein by BCA assay for normalization purpose.
  • Cell lines were allowed to attach overnight and then were transiently transfected with TOPflash plasmid (Millipore, Billerica, MA) using TransIT-LT1 transfection reagent (Mirus Bio, Madison, WI) for 72 h.
  • HCT116 cells were plated at an optimal cell concentration to avoid colonies merging over a growth period of 7-10 days.
  • PK studies were conducted using our previously published methods (Abraham et al., 2019) where CHD1Li 6.11 was administered by oral gavage (p.o.) at a dose of 50 mg/kg in a vehicle of 100% DMSO.
  • Statistical Analysis All statistical analyses were performed using GraphPad Prism v9.0 (GraphPad Software Inc., La Jolla, CA). The data were collected using experimental replicates unless otherwise noted. All P-value significant is represented as *, p ⁇ 0.05; **, p ⁇ 0.01; ***, p ⁇ 0.001; ****, p ⁇ 0.0001.
  • Chromodomain Helicase DNA Binding Protein 1 Like also known as Amplified in Liver Cancer 1 (ALC1); T cell factor/lymphoid enhancer factor (TCF/LEF); epithelial-mesenchymal transition (EMT), mesenchymal-epithelial transition (MET); epithelial-mesenchymal plasticity (EMP); cancer stem cell (CSC); gastrointestinal (GI); colorectal cancer (CRC).
  • Example 18 In Vivo Anti-Tumor Activity of Compound 6.11 Administered by Oral Gavage 11-week-old athymic nude mice (35) where inoculated in the flanks (Flk) with isolated SW620 EMT dual-reporter quasi-mesenchymal cells (GFP+). (Esquer et al., 2021) Five days after cell injection, injected mice were randomized into three groups for treatment (Tx). Group 1 (12 mice) received control treatment of gavage vehicle (10% DMSO, 90% PEG 400 (polyethylene glycol 400) by volume). Group 2 (11 mice) received oral gavage of compound 6.11 at 75 mg/kg dissolved in vehicle.
  • Fig.21A is a graph of tumor volume (mm3) starting at 3 days after treatment was initiated. This graph shows a significant dose dependent decrease in tumor volume on oral treatment of mice with compound 6.11 over 27 days of treatment.
  • Figure 21B is a graph of average mouse body weight (grams) by treatment group as a function of days after treatment was initiated. This graph indicates no significant difference in body weight among the mice of the three treatment groups. Body weight loss is a general measure of treatment toxicity. All animal studies were conducted in accordance with the animal protocol procedures approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Colorado Denver Anschutz Medical Campus (Aurora, CO).
  • IACUC Institutional Animal Care and Use Committee
  • Example 19 Summary Table of Selected Biological Activity of CHD1L Inhibitors Table 6 provides a summary of Cat-CHD1L activity, 3D cytotocxicity data and microsomal stability data for certain CHD1L inhibitors described herein. Methods for measuring these biological activities are described in the Examples above.
  • Table 6 Biological Activity Table cat- 3D Cytotoxicity Microsomal stability CHD1L 72hr IC 50 ( ⁇ M) Table 6 (continued) cat- 3D Cytotoxicity Microsomal stability CHD1L 72hr IC 50 ( ⁇ M) Table 6 (continued) cat- 3D Cytotoxicity Microsomal stability CHD1L 72hr IC 50 ( ⁇ M) Compounds 57 (6.5), 52 (6.11), 54 (6.16), 28 (6.18), 31 (6.21), 75 (6.31), 118 (6.33), 120 (6.35), 123 (6.38) and 150 (6.58) exhibit good enzyme inhibition and below 10uM IC50 of cytotoxicity in SW620 cells.
  • any one of compounds 57, 52, 54, 28, 31, 75, 118, 120, 123 and 150 is particularly useful in the methods of treatment, combination therapies, pharmaceutical compositions and pharmaceutical combinations of this invention.
  • CHD1L contributes to cisplatin resistance by upregulating the ABCB1-NF-kappaB axis in human non-small-cell lung cancer.
  • PARP1 promotes nucleotide excision repair through DDB2 stabilization and recruitment of ALC1. J Cell Biol 2012;199(2):235-49. 12.
  • ALC1/CHD1L a chromatin-remodeling enzyme, is required for efficient base excision repair.
  • SPOCK1 is regulated by CHD1L and blocks apoptosis and promotes HCC cell invasiveness and metastasis in mice. Gastroenterology 2013;144(1):179-91.
  • Chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like (CHD1l) gene suppresses the nucleus-to-mitochondria translocation of nur77 to sustain hepatocellular carcinoma cell survival.
  • Hepatology 2009;50(1):122-9. 15 He LR, Ma NF, Chen JW, Li BK, Guan XY, Liu MZ, et al.
  • Overexpression of CHD1L is positively associated with metastasis of lung adenocarcinoma and predicts patients’ poor survival. Oncotarget 2015;6(31):31181-90. 16.
  • CHD1L Is a marker for poor prognosis of hepatocellular carcinoma after surgical resection.
  • CHD1L is a novel independent prognostic factor for gastric cancer.
  • Clin Transl Oncol: 2014;16(8):702-7 (Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico).
  • ⁇ - catenin/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness.
  • EMT epithelial-to-mesenchymal transition
  • Zhou Q Abraham AD, Li L, Babalmorad A, Bagby, Arcaroli JJ, et al. Topoisomerase II ⁇ mediates TCF-dependent epithelial-mesenchymal transition in colon cancer. Oncogene 2016:35(38):4990-9.
  • Abraham AD Esquer H, Zhou Q, Tomlinson N, Hamill BD, Abbott JM, et al.
  • E-Cadherin and vimentin as biomarkers of clinical outcomes among patients with non-small cell lung cancer treated with erlotinib as second- or third-line therapy.
  • Dhanasekaran SM Barrette TR, Ghosh D, Shah R, Varambally S, Kurachi K, et al. Delineation of prognostic biomarkers in prostate cancer. Nature 2001;412(6849):822-6.
  • Kashiwagi S Yashiro M, Takashima T, Nomura S, Noda S, Kawajiri H, et al. Significance of E-cadherin expression in triple-negative breast cancer.
  • Thymidylate Synthase Inhibitors in the Treatment of Advanced Colorectal Cancer: Current Status, 2009, Stem Cells, 18(3):166-175.

Abstract

L'invention concerne le traitement de cancers induits par CHD1L, notamment des cancers induits par transcription de TCF et des cancers induits par EMT à l'aide d'inhibiteurs de CHD1L. Des inhibiteurs à petites molécules de CHD1L qui inhibent l'ATPase CHD1L et inhibent la transcription de TCF dépendante de CHD1L ont été identifiés. Les inhibiteurs de CHD1L empêchent le complexe de TCF de se lier à des éléments de réponse de Wnt et à des sites promoteurs. Plus particulièrement, les inhibiteurs de CHD1L induisent la réversion d'EMT. Les inhibiteurs de CHD1L sont utiles dans le traitement de divers cancers et en particulier du CCR et du CCRm. Le cancer induit par CHD1L est, entre autres, le CCR, le cancer du sein, le gliome, le cancer du foie, le cancer du poumon ou les cancers gastro-intestinaux (GI). L'invention concerne également des inhibiteurs de CHD1L de formules I et XX et des sels associés tels que définis dans la description, ainsi que des compositions pharmaceutiques contenant des inhibiteurs de CHD1L. L'invention concerne également des associations synergiques d'inhibiteurs de CHD1L avec d'autres agents antinéoplasiques.
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