EP4598901A1 - Inhibiteurs d'adn polymérase thêta à base de pyrrolidine et d'imidazolidine et utilisation associée - Google Patents

Inhibiteurs d'adn polymérase thêta à base de pyrrolidine et d'imidazolidine et utilisation associée

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Publication number
EP4598901A1
EP4598901A1 EP23875684.5A EP23875684A EP4598901A1 EP 4598901 A1 EP4598901 A1 EP 4598901A1 EP 23875684 A EP23875684 A EP 23875684A EP 4598901 A1 EP4598901 A1 EP 4598901A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
haloci
deuterium
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23875684.5A
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German (de)
English (en)
Inventor
Richard T. POMERANTZ
Mercy Ramanjulu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Recombination Therapeutics LLC
Thomas Jefferson University
Original Assignee
Recombination Therapeutics LLC
Thomas Jefferson University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Recombination Therapeutics LLC, Thomas Jefferson University filed Critical Recombination Therapeutics LLC
Publication of EP4598901A1 publication Critical patent/EP4598901A1/fr
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/36—One oxygen atom with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/40—Two or more oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—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
    • C07D409/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

Definitions

  • Homology directed repair also known as homologous recombination (HR) is an important DNA repair pathway due to its necessary role in promoting genome integrity and the completion of replication (Moynahan ME et al., 2010, Nat. Rev. Mol. Cell. Biol., 11 : 196-207; Li X et al., 2008, Cell Research, 18:99-113; Sung P et al., 2008, Nature Reviews. Molecular Cell Biology, 7:739-750). Mutations in proteins that play a central role HDR, such as BRCA1 or BRCA2 (BRCA), strongly predispose women to breast and ovarian cancer (Moynahan ME et al., 2010, Nat. Rev. Mol. Cell.
  • PARP-1 plays an important role in DNA base excision repair (BER) and cells that become deficient in BER due to PARP-1 inhibition undergo a high frequency of ssDNA breaks and PARP-1 :DNA adducts which are converted to potentially lethal double-strand breaks (DSBs) during DNA replication. Since the BRCA proteins play a major role in repairing DSBs during S-phase, BRCA deficient cells are highly susceptible to DSBs and protein-DNA adducts caused by PARP-1 inhibitors as compared to normal cells. PARP-1 inhibitors have therefore shown promise in the clinic due to their ability to cause synthetic lethality in BRCA deficient cells (Sonnenblick A et al., 2015, Nat. Rev. Clin.
  • Polq DNA polymerase theta
  • PolO DNA polymerase theta
  • POLQ DNA polymerase theta
  • Polq promotes extension of singlestrand DNA (ssDNA)(Hogg M et al., 2012, Nucleic Acids Res., 40:2611-2622; Kent T et al., 2015, Nature Structural & Molecular Biology, 22). Polq also exhibits low-fidelity DNA synthesis and translesion synthesis (TLS) activities (Hogg M et al., 2011, J. Mol. Biol., 405:642-652; Arana ME et al., 2008, Nucleic Acids Res., 36:3847-3856; Zahn KE et al., 2015, Nature Structural & Molecular Biology, 22:304-311).
  • TLS translesion synthesis
  • MMEJ microhomology -mediated end-joining
  • BRCA deficient ovarian cancer cells were shown to be dependent on Polq for their survival in the presence of genotoxic agents (Ceccaldi RL et al., 2015, Nature, 517). This synthetic lethal relationship between Polq and HDR was further demonstrated in mouse models (Ceccaldi RL et al., 2015, Nature, 517). Most importantly, the DNA synthesis activity of Polq was shown to promote the survival of BRCA deficient cells (Mateos-Gomez PA et al., 2015, Nature, 518:254-257), which strongly suggests that pharmacological inhibition of the polymerase domain expressed by POLQ selectively kills BRCA deficient cancer cells.
  • compositions and methods for inhibiting Polq for preventing or treating various diseases or disorders, such as cancer satisfies this unmet need.
  • U represents CH2, O, S, or NR U ;
  • W represents C(R 4 ) or N;
  • Q represents O or S
  • R’ and R u independently represent hydrogen, deuterium, C1-6 alkyl, C2-6 alkenyl, alkynyl, hydroxy, thiol, C1-6 alkoxy, halogen, haloCi-6 alkyl, haloCi-6 alkoxy,
  • X represents C(R 15 )(R 16 ), N(R 17 ) or O;
  • R 15 , R 16 , and R 17 independently represent hydrogen, deuterium, Ci-6 alkyl, haloCi-6 alkyl, -OR 15a , -SR 15a , nitrile, -COCi-6 alkyl, -COOCi-6 alkyl, hydroxy, Ci-6 alkoxy, Ci-6 alkanol, C3-8 cycloalkyl, halogen, carbonyl, -NR V R W , -CH2-NR V R W , -OSO2NH2, -P(0)0H2, aryl, heteroaryl, heterocyclyl, and combinations thereof; wherein R 15 , R 16 , and R 17 may further comprise one or more divalent linkers L selected from the group consisting alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate,
  • R B and R B independently represents hydrogen, deuterium, Ci-6 alkyl, hydroxy, C1-6 alkoxy, C1-6 alkanol, halogen, -OR 15b , CO2H, CO2R 15b , haloCi-6 alkyl, and combinations thereof; or R B and the carbon to which it is bound together form a carbonyl group and R B is not present;
  • R 15a and R 15b independently represent hydrogen, deuterium, or C1-6 alkyl; wherein two groups R 13a and R 13b , or two groups R 15b , may join together to form a 5 to 7 membered saturated ring system which may be optionally substituted by one or more C1-6 alkyl groups;
  • R v , R w , R x and R Y independently represent hydrogen, deuterium, C1-6 alkyl, haloCi-6 alkyl, C3-8 cycloalkyl, -COC1-6 alkyl or heterocyclyl; wherein said alkyl groups may be optionally substituted with or more deuterium, hydroxy, amino or sulfone groups; and said heterocyclyl ring may be optionally substituted by one or more deuterium, oxo, hydroxy, C1-6 alkanol or -COC1-6 alkyl groups.
  • the present invention relates to a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I) or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.
  • the present invention relates to a method of inhibiting the activity of DNA polymerase theta (Polq), the method comprising the step of contacting Polq with a compound of Formula (I) or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.
  • Figure 1 depicts representative results from experiments showing that examples of Polq inhibitors (Polqi) selectively kill BRCA-mutant cancer cells.
  • Figures 1A-1E depict scatter plots showing that the survival of BRCA2-mutant DLD-1 cells is significantly reduced by treatment with the indicated Polqi as compared to BRCA2-WT DLD-1 cells which are mostly resistant to Polqi.
  • Figure 2 depicts representative results from experiments showing that Example 4 of a Polq inhibitor exhibits synergistic activity with the PARP inhibitor olaparib in reducing the survival of BRC A2-mutant cancer cells.
  • a scatter plot is depicted showing the survival of BRCA2-mutant DLD1 cells in the presence of olapraib alone at the indicated concentrations compared to olaparib with two different concentrations of Polq inhibitor Example 4 (left).
  • Synergy plot generated with ComBenefit software (right).
  • Figure 3, comprising Figure 3A through Figure 3E, depicts representative experimental data demonstrating that Polq inhibitors act synergistically with PARP inhibitors.
  • Figure 3A depicts a representative scatter plot and synergy plot showing clongenic survival of HCT116 BRCA2-null cells treated with varying concentrations of olaparib with DMSO or various concentrations of Example 6.
  • Figure 3B depicts a representative scatter plot synergy plot showing clongenic survival of DLD1 BRCA2-null cells treated with varying concentrations of olaparib with DMSO or various concentrations of Example 6.
  • Figure 3C depicts a representative scatter plot synergy plot showing clongenic survival of PE01 cells treated with varying concentrations of olaparib with DMSO or various concentrations of Example 6.
  • the present invention is based, in part, on the discovery that novel pyrrolidine and imidazolidine based compounds inhibited Polq DNA synthesis activity.
  • the present invention is directed, in part, to compositions comprising said pyrrolidine and imidazolidine based compounds and methods for inhibiting Polq in vitro and in vivo.
  • the Polq e.g., the activity of Polq, the level of Polq, etc.
  • the present invention also provides, in part, compounds and methods for preventing or treating cancer with pyrrolidine and imidazolidine based compounds.
  • the invention also provides a kit for modifying or inhibiting Polq (e.g., the activity of Polq, the level of Polq, etc.).
  • stabilizers refers to either, or both, primary particle and/or secondary stabilizers, which may be polymers or other small molecules.
  • primary particle and/or secondary stabilizers for use with the present invention include, e.g., starch, modified starch, and starch derivatives, gums, including but not limited to polymers, polypeptides, albumin, amino acids, thiols, amines, carboxylic acid and combinations or derivatives thereof.
  • xanthan gum alginic acid, other alginates, benitoniite, veegum, agar, guar, locust bean gum, gum arabic, quince psyllium, flax seed, okra gum, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, etc., cross-linked polyvinylpyrrolidone, ion-exchange resins, potassium polymethacrylate, carrageenan (and derivatives), gum karaya and biosynthetic gum.
  • useful primary particle and/or secondary stabilizers include polymers such as: polycarbonates (linear polyesters of carbonic acid); microporous materials (bisphenol, a microporous poly(vinylchloride), micro-porous polyamides, microporous modacrylic copolymers, microporous styrene-acrylic and its copolymers); porous polysulfones, halogenated poly (vinylidene), poly chloroethers, acetal polymers, polyesters prepared by esterification of a dicarboxylic acid or anhydride with an alkylene polyol, poly(alkylenesulfides), phenolics, polyesters, asymmetric porous polymers, cross-linked olefin polymers, hydrophilic microporous homopolymers, copolymers or interpolymers having a reduced bulk density, and other similar materials, poly(urethane), cross-linked chain-extended poly(urethane), poly(mides), poly(mides
  • the term “specific binding” refers to that binding which occurs between such paired species as enzyme/substrate, receptor/agonist, antibody/antigen, and lectin/carbohydrate which may be mediated by covalent or non-covalent interactions or a combination of covalent and non-covalent interactions.
  • the binding which occurs is typically electrostatic, hydrogen-bonding, or the result of lipophilic interactions. Accordingly, “specific binding” occurs between a paired species where there is interaction between the two which produces a bound complex having the characteristics of an antibody/antigen or enzyme/substrate interaction.
  • the specific binding is characterized by the binding of one member of a pair to a particular species and to no other species within the family of compounds to which the corresponding member of the binding member belongs.
  • an antibody preferably binds to a single epitope and to no other epitope within the family of proteins.
  • peptide As used herein, the terms “peptide”, “polypeptide”, and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds.
  • a protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein’s or peptide’s sequence.
  • Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds.
  • the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types.
  • Polypeptides include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others.
  • the polypeptides include natural peptides, recombinant peptides, synthetic peptides, or any combination thereof.
  • patient refers to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein.
  • the patient, subject or individual is a human.
  • the subject is a human subject, and may be of any race, ethnicity, sex, and age.
  • a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.
  • a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.
  • cancer or “neoplasm” as used herein, include, but are not limited to, benign and malignant cancers of the oral cavity (e.g., mouth, tongue, pharynx, etc.), digestive system (e.g., esophagus, stomach, small intestine, colon, rectum, liver, bile duct, gall bladder, pancreas, etc.), respiratory system (e.g., larynx, lung, bronchus, etc.), bones, joints, skin (e.g., basal cell, squamous cell, melanoma, etc.), breast, genital system, (e.g., uterus, ovary, prostate, testis, etc.), urinary system (e.g, bladder, kidney, ureter, etc.), eye, nervous system (e.g., brain, etc.), endocrine system (e.g., thyroid, etc.), and hematopoietic system (e.g., lymphoma,
  • the terms “therapy” or “therapeutic regimen” refer to those activities taken to alleviate or alter a disorder or disease state, e.g., a course of treatment intended to reduce or eliminate at least one sign or symptom of a disease or disorder using pharmacological, surgical, dietary and/or other techniques.
  • a therapeutic regimen may include a prescribed dosage of one or more drugs or surgery. Therapies will most often be beneficial and reduce or eliminate at least one sign or symptom of the disorder or disease state, but in some instances the effect of a therapy will have non-desirable or sideeffects. The effect of therapy will also be impacted by the physiological state of the subject, e.g., age, gender, genetics, weight, other disease conditions, etc.
  • modulating mediating a detectable increase or decrease in the level of a mRNA, polypeptide, or a response in a subject compared with the level of a mRNA, polypeptide or a response in the subject in the absence of a treatment or compound, and/or compared with the level of a mRNA, polypeptide, or a response in an otherwise identical but untreated subject.
  • the term encompasses perturbing and/or affecting a native signal or response thereby mediating a beneficial therapeutic response in a subject, preferably, a human.
  • alteration refers to a mutation in a gene in a cell that affects the function, activity, expression (transcription or translation) or conformation of the polypeptide that it encodes.
  • Mutations encompassed by the present invention can be any mutation of a gene in a cell that results in the enhancement or disruption of the function, activity, expression, or conformation of the encoded polypeptide, including the complete absence of expression of the encoded protein and can include, for example, missense and nonsense mutations, insertions, deletions, frameshifts, and premature terminations.
  • mutations encompassed by the present invention may alter splicing the mRNA (splice site mutation) or cause a shift in the reading frame (frameshift).
  • Gene expression encompasses the transcription of genomic DNA into mRNA and the translation of mRNA into protein.
  • a “genome” is all the genetic material of an organism.
  • the term genome may refer to the chromosomal DNA.
  • Genome may be multichromosomal such that the DNA is cellularly distributed among a plurality of individual chromosomes. For example, in human there are 22 pairs of chromosomes plus a gender associated XX or XY pair.
  • DNA derived from the genetic material in the chromosomes of a particular organism is genomic DNA.
  • the term genome may also refer to genetic materials from organisms that do not have chromosomal structure.
  • the term genome may refer to mitochondria DNA.
  • a genomic library is a collection of DNA fragments representing the whole or a portion of a genome. Frequently, a genomic library is a collection of clones made from a set of randomly generated, sometimes overlapping DNA fragments representing the entire genome or a portion of the genome of an organism.
  • Encoding refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for Synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (z.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom.
  • a gene encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system.
  • Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA.
  • a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. Nucleotide sequences that encode proteins and RNA may include introns. “Homologous, homology” or “identical, identity” as used herein, refer to comparisons among amino acid and nucleic acid sequences.
  • nucleic acid molecules When referring to nucleic acid molecules, “homology,” “identity,” or “percent identical” refers to the percent of the nucleotides of the subject nucleic acid sequence that have been matched to identical nucleotides by a sequence analysis program. Homology can be readily calculated by known methods. Nucleic acid sequences and amino acid sequences can be compared using computer programs that align the similar sequences of the nucleic or amino acids and thus define the differences. In preferred methodologies, the BLAST programs (NCBI) and parameters used therein are employed, and the ExPaSy is used to align sequence fragments of genomic DNA sequences. However, equivalent alignment assessments can be obtained through the use of any standard alignment software.
  • homologous refers to the subunit sequence similarity between two polymeric molecules, e.g., between two nucleic acid molecules, e.g., two DNA molecules or two RNA molecules, or between two polypeptide molecules.
  • two nucleic acid molecules e.g., two DNA molecules or two RNA molecules
  • two polypeptide molecules e.g., two amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino
  • the homology between two sequences is a direct function of the number of matching or homologous positions, e.g., if half (e.g., five positions in a polymer ten subunits in length) of the positions in two compound sequences are homologous then the two sequences are 50% homologous, if 90% of the positions, e.g., 9 of 10, are matched or homologous, the two sequences share 90% homology.
  • the DNA sequences 5’ATTGCC 3’ and 5’TATGGC 3’ share 50% homology.
  • fragment refers to a subsequence of a larger nucleic acid.
  • a “fragment” of a nucleic acid can be at least about 15 nucleotides in length; for example, at least about 50 nucleotides to about 100 nucleotides; at least about 100 to about 500 nucleotides, at least about 500 to about 1000 nucleotides, at least about 1000 nucleotides to about 1500 nucleotides.
  • about 1500 nucleotides to about 2500 nucleotides In one embodiment, about 1500 nucleotides to about 2500 nucleotides.
  • “Variant” as the term is used herein, is a nucleic acid sequence or a peptide sequence that differs in sequence from a reference nucleic acid sequence or peptide sequence respectively, but retains essential properties of the reference molecule. Changes in the sequence of a nucleic acid variant may not alter the amino acid sequence of a peptide encoded by the reference nucleic acid, or may result in amino acid substitutions, additions, deletions, fusions and truncations.
  • a variant of a nucleic acid or peptide can be a naturally occurring such as an allelic variant, or can be a variant that is not known to occur naturally. Non-naturally occurring variants of nucleic acids and peptides may be made by mutagenesis techniques or by direct synthesis.
  • purified or “to purify” refers to the removal of components (e.g., contaminants) from a sample.
  • components e.g., contaminants
  • nucleic acids are purified by removal of contaminating cellular proteins or other undesired nucleic acid species. The removal of contaminants results in an increase in the percentage of desired nucleic acid in the sample.
  • label when used herein refers to a detectable compound or composition that is conjugated directly or indirectly to a probe to generate a “labeled” probe.
  • the label may be detectable by itself (e.g. radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition that is detectable (e.g., avidin-biotin).
  • primers can be labeled to detect a PCR product.
  • nucleic acid refers to both naturally-occurring molecules such as DNA and RNA, but also various derivatives and analogs.
  • probes, hairpin linkers, and target polynucleotides of the present teachings are nucleic acids, and typically comprise DNA. Additional derivatives and analogs can be employed as will be appreciated by one having ordinary skill in the art.
  • nucleotide base refers to a substituted or unsubstituted aromatic ring or rings.
  • the aromatic ring or rings contain at least one nitrogen atom.
  • the nucleotide base is capable of forming Watson-Crick and/or Hoogsteen hydrogen bonds with an appropriately complementary nucleotide base.
  • nucleotide bases and analogs thereof include, but are not limited to, naturally occurring nucleotide bases adenine, guanine, cytosine, 6 methylcytosine, uracil, thymine, and analogs of the naturally occurring nucleotide bases, e.g., 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, N6 delta 2-isopentenyladenine (6iA), N6-delta 2-isopentenyl-2-methylthioadenine (2 ms6iA), N2-dimethylguanine (dmG), 7methylguanine (7mG), inosine, nebularine, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine,
  • nucleotide refers to a compound comprising a nucleotide base linked to the C-l’ carbon of a sugar, such as ribose, arabinose, xylose, and pyranose, and sugar analogs thereof.
  • a sugar such as ribose, arabinose, xylose, and pyranose, and sugar analogs thereof.
  • nucleotide also encompasses nucleotide analogs.
  • the sugar may be substituted or unsubstituted.
  • Substituted ribose sugars include, but are not limited to, those riboses in which one or more of the carbon atoms, for example the 2’ -carbon atom, is substituted with one or more of the same or different Cl, F, — R, —OR, — NR2 or halogen groups, where each R is independently H, C1-C6 alkyl or C5-C14 aryl.
  • Exemplary riboses include, but are not limited to, 2’-(Cl- C6)alkoxyribose, 2’-(C5-C14)aryloxyribose, 2’, 3 ’-didehydroribose, 2’-deoxy-3’- haloribose, 2’ -deoxy-3’ -fluororibose, 2’-deoxy-3’-chlororibose, 2’-deoxy-3’- aminoribose, 2’ -deoxy-3 ’-(Cl-C6)alkylribose, 2’-deoxy-3’-(Cl-C6)alkoxyribose and 2’- deoxy-3’-(C5-C14)aryloxyribose, ribose, 2’ -deoxyribose, 2’, 3 ’-dideoxyribose, 2’- haloribose, 2’ -fluororibose, 2
  • nucleotide analogs refers to modified or non-naturally occurring nucleotides including, but not limited to, analogs that have altered stacking interactions such as 7-deaza purines (i.e., 7-deaza-dATP and 7-deaza-dGTP); base analogs with alternative hydrogen bonding configurations (e.g., such as Iso-C and Iso-G and other non-standard base pairs described in U.S. Pat. No. 6,001,983 to S. Benner and herein incorporated by reference); non-hydrogen bonding analogs (e.g., non-polar, aromatic nucleoside analogs such as 2,4-difluorotoluene, described by B. A.
  • 7-deaza purines i.e., 7-deaza-dATP and 7-deaza-dGTP
  • base analogs with alternative hydrogen bonding configurations e.g., such as Iso-C and Iso-G and other non-standard base pairs described in U.S. Pat
  • Nucleotide analogs include nucleotides having one or more modification son the phosphate moiety, base moiety or sugar moiety, such as dideoxy nucleotides and 2'-O-methyl nucleotides. Nucleotide analogs include modified forms of deoxyribo-nucleotides as well as ribonucleotides.
  • sequences on the left-hand end of a single-stranded polynucleotide sequence is the 5 ’-end.
  • the DNA strand having the same sequence as an mRNA is referred to as the “coding strand”; sequences on the DNA strand which are located 5’ to a reference point on the DNA are referred to as “upstream sequences”; sequences on the DNA strand which are 3’ to a reference point on the DNA are referred to as “downstream sequences.”
  • A adenine
  • G guanine
  • T thymine
  • C cytosine
  • U uracil
  • H A, C or T/U
  • R A or G
  • M A or C
  • K G or T/U
  • S G or C
  • Y C or T/U
  • W A or T/U
  • V A or G or C
  • N A or G or C or T/U.
  • nucleic acid sequences set forth herein throughout in their forward orientation are also useful in the compositions and methods of the invention in their reverse orientation, as well as in their forward and reverse complementary orientation, and are described herein as well as if they were explicitly set forth herein.
  • “Instructional material”, as that term is used herein, includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the nucleic acid, peptide, and/or compound of the invention in the kit for identifying, diagnosing or alleviating or treating the various diseases or disorders recited herein.
  • the instructional material may describe one or more methods of identifying, diagnosing or alleviating the diseases or disorders in a cell or a tissue of a subject.
  • the instructional material of the kit may, for example, be affixed to a container that contains one or more components of the invention or be shipped together with a container that contains the one or more components of the invention. Alternatively, the instructional material may be shipped separately from the container with the intention that the recipient uses the instructional material and the components cooperatively.
  • ranges throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range, such as from 1 to 6, should be considered to have specifically disclosed subranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
  • the present invention relates, in part, to the discovery that various novel pyrrolidine and imidazolidine derivatives selectively inhibited the polymerase domain of the POLQ gene product DNA polymerase theta (Polq).
  • the present invention also relates, in part, to pharmaceutical formulations comprising said pyrrolidine and imidazolidine derivatives as well as methods of treating diseases or disorders, such as cancers defective in homology directed repair (HDR)(or homologous recombination), non-homologous end-joining, or other DNA damage response pathways by inhibiting Polq (e g., the activity of Polq, the level of Polq, etc.) with disclosed pyrrolidine and imidazolidine derivatives and analogs thereof.
  • HDR homology directed repair
  • Polq e g., the activity of Polq, the level of Polq, etc.
  • Polq is highly expressed in many types of cancer cells, confers resistance to ionizing radiation and various chemotherapy agents including etoposide, camptothecin and cisplatin, and promotes the survival of cancer cells, such as those deficient in HDR or other DNA repair or DDR pathways. High expression levels of Polq corresponds to a poor clinical outcome for cancer patients. Accordingly, another aspect of the invention provides a method of treating cancer in a subject by administering a composition of the invention.
  • the present invention provides compounds that modulate or inhibit the level or activity of at least one A family polymerase (e.g., Polq).
  • the present invention provides compounds useful for preventing or treating a disease or disorder (e.g., cancer).
  • the compound of the present invention is a functionalized pyrrolidine or imidazolidine based compound or derivative thereof.
  • the present invention relates to a functionalized pyrrolidine or imidazolidine derivative such as compounds having the structure of Formula (I), or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof:
  • U represents CH2, O, S, or NR U ;
  • W represents C(R 4 ) or N
  • Y represents C(R 6 ) or N
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , and R 10 independently represent hydrogen, deuterium, C1-6 alkyl, C2-6 alkenyl, alkynyl, hydroxy, thiol, C1-6 alkoxy, halogen, haloCi-6 alkyl, haloCi-6 alkoxy, C3-8 cycloalkyl, nitrile, NR X R Y , and combinations thereof; wherein two adjacent groups R 1 to R 4 or R 6 to R 10 optionally join to form a 5- to 7-membered saturated or unsaturated ring optionally containing one or more heteroatoms selected from O, N or S;
  • X represents C(R 15 )(R 16 ), N(R 17 ) or O;
  • R 15 , R 16 , and R 17 independently represent hydrogen, deuterium, Ci-6 alkyl, haloCi-6 alkyl, -OR 15a , -SR 15a , nitrile, -COCi-6 alkyl, -COOCi-6 alkyl, hydroxy, Ci- 6 alkoxy, Ci-6 alkanol, C3-8 cycloalkyl, halogen, carbonyl, -NR V R W , -CH2-NR V R W , -OSO2NH2, -P(0)0H2, aryl, heteroaryl, heterocyclyl, and combinations thereof; wherein R 15 , R 16 , and R 17 may further comprise one or more divalent linkers L selected from the group consisting alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene
  • R B and R B independently represents hydrogen, deuterium, C1-6 alkyl, hydroxy, C1-6 alkoxy, C1-6 alkanol, halogen, -OR 13b , CO2H, CChR 15b , haloCi-6 alkyl, and combinations thereof; or R B and the carbon to which it is bound together form a carbonyl group and R B is not present;
  • R v , R w , R x and R Y independently represent hydrogen, deuterium, C1-6 alkyl, haloCi-6 alkyl, C3-8 cycloalkyl, -COC1-6 alkyl or heterocyclyl; wherein said alkyl groups may be optionally substituted with or more deuterium, hydroxy, amino or sulfone groups; and said heterocyclyl ring may be optionally substituted by one or more deuterium, oxo, hydroxy, C1-6 alkanol or -COC1-6 alkyl groups.
  • the compound of Formula (I) is represented by Formula (la):
  • the compound of Formula (I) is represented by Formula (lb): Formula (lb).
  • the compound of Formula (I) is represented by Formula (Ic)
  • Formula (Ic) Formula (Ic’)
  • the compound of Formula (I) is represented by Formula (Id) or Formula (Id’):
  • the compound of Formula (I) is represented by Formula (le) or Formula (le’):
  • U is O. In one embodiment, U is CH2. In one embodiment, U is S. In one embodiment, Q is O. In one embodiment, Q is S.
  • R 7 and R 8 or R 8 and R 9 join to form a pyrrolyl ring which is optionally substituted.
  • Y is N.
  • R A and R A each represent hydrogen or deuterium.
  • Z represents CR Z R Z .
  • R z and R z each represent hydrogen or deuterium.
  • R 17 represents hydrogen, deuterium, C1-6 alkyl, haloCi- 6 alkyl, -OR 15a , -SR 15a , nitrile, -COC1-6 alkyl, -COOC1-6 alkyl, hydroxy, C1-6 alkoxy,
  • halogen carbonyl, -NR V R W , -CH2-NR V R W , -OSO2NH2, -P(O)OH2, aryl, heteroaryl, heterocyclyl, and combinations thereof.
  • R 17 further comprises a divalent linker selected from the group consisting alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof.
  • R 17 comprises one or more divalent linkers.
  • R 17 has the structure -CH2CH2O-L-R 17 , wherein R 17 represents hydrogen, deuterium, C1-6 alkyl, haloCi-6 alkyl, -OR 13a , -SR 13a , nitrile, -COC1-6 alkyl, -COOC1-6 alkyl, hydroxy, C1-6 alkoxy, C1-6 alkanol, C3-8 cycloalkyl, halogen, carbonyl, -NR V R W , -CH2-NR V R W , -OSO2NH2, aryl, heteroaryl, heterocyclyl, and combinations thereof.
  • R 17 represents a substituent selected from the following:
  • W represents C(R 4 ). In an alternative embodiment, W represents N. In one embodiment, W represents C(H), C(CN), or N. In one embodiment, W represents C(C1) or C(F). In one embodiment, at least one of R 1 and R 3 represents halogen or haloCi-6 alkyl.
  • R 1 and R 3 independently represent halogen or haloCi-6 alkyl. In one embodiment, at least one of R 1 and R 3 represents haloCi-6 alkyl. In one embodiment, at least one of R 1 and R 3 represents halogen. In one embodiment, R 1 and R 3 each represent haloCi-6 alkyl. In one embodiment, R 1 and R 3 each independently represent halogen. In one embodiment, R 1 represents hydrogen, deuterium, methyl, CD3, haloCi-6 alkyl (such as CF3, CHF2, or CH2F), haloCi-6 alkoxyl (such as OCF3, OCHF2, or OCH2F), or halogen (such as fluorine or chlorine).
  • R 2 represents hydrogen; deuterium C1-6 alkyl (such as methyl or ethyl); C2-6 alkenyl (such as ethenyl); C1-6 alkoxy (such as methoxy); halogen (such as chlorine).
  • R 2 represents NR X R Y (such as N(Me)2 or N(Me)(Et)).
  • R 2 represents: hydrogen; C1-6 alkyl (such as methyl); C1-6 alkoxy (such as methoxy).
  • R 2 represents -NR X R Y (such as -N(Me)2 or -N(Me)(Et)).
  • R 2 represents C1-6 alkyl (such as methyl).
  • R 2 represents: hydrogen; halogen (such as chlorine).
  • R 2 represents Ci-6 alkyl (such as methyl).
  • R 2 represents hydrogen.
  • R 3 represents hydrogen, deuterium, methyl, CD3, haloCi-6 alkyl (such as CF3, CHF2, or CH2F), haloCi-6 alkoxy (such as OCF3, OCHF2, or OCH2F), or halogen (such as fluorine or chlorine).
  • R 3 represents haloCi-6 alkoxy (such as difluoromethoxy).
  • Rf represents C1-6 alkyl (such as methyl, ethyl or isopropyl).
  • R 3 represents haloCi-6 alkyl (such as trifluoromethyl). In one embodiment, R 3 represents haloCi-6 alkyl (such as trifluoromethyl).
  • R 4 represents hydrogen, deuterium, C1-6 alkyl (such as methyl, ethyl or isopropyl), CD3, C2 alkynyl, or nitrile. In one embodiment, R 4 represents hydrogen.
  • R 5 represents CH3 or CD3. In one embodiment, R 5 represents the following structure: wherein R 5 is selected from the group consisting of hydrogen, deuterium,
  • R 5 represents one of the following substituents:
  • R x and R Y represent Ci-6 alkyl (such as methyl or ethyl). In one embodiment, R x and R Y both represent Ci-6 alkyl (such as methyl or ethyl). In one embodiment, R x and R Y both represent methyl or one represents methyl and the other represents ethyl.
  • W represents C(R 4 );
  • R 1 represents Ci-6 alkyl (such as methyl),
  • R 2 represents hydrogen,
  • R 3 represents haloCi-6 alkyl (such as trifluoromethyl) and
  • R 4 represents nitrile.
  • R 1 represents Ci-6 alkyl (such as methyl)
  • R 2 represents hydrogen
  • R 3 represents Ci-6 alkyl (such as methyl or isopropyl)
  • R 4 represents nitrile
  • R 1 represents Ci-6 alkyl (such as methyl or ethyl)
  • R 2 represents hydrogen
  • R 3 represents haloCi-6 alkyl (such as trifluoromethyl or -CH(Me)-CF3)
  • R 4 represents hydrogen
  • R 1 represents Ci-6 alkyl (such as methyl)
  • R 2 represents hydrogen
  • R 3 represents Ci-6 alkyl (such as isopropyl)
  • R 4 represents hydrogen.
  • R 1 represents Ci-6 alkyl (such as methyl)
  • R 2 represents halogen (such as chlorine)
  • R 3 represents Ci-6 alkyl (such as methyl)
  • R 4 represents hydrogen
  • R 1 represents Ci-6 alkoxy (such as methoxy)
  • R 2 represents hydrogen
  • R.’ represents haloCi-6 alkyl (such as trifluoromethyl)
  • R 4 represents nitrile.
  • R 1 represents -NR X R Y (such as -N(Me)2 or -N(Me)(Et))
  • R 2 represents hydrogen
  • R 3 represents haloCi-6 alkyl (such as trifluoromethyl)
  • R 4 represents nitrile.
  • R 1 represents hydrogen
  • R 2 represents hydrogen
  • R 3 represents haloCi-6 alkyl (such as trifluoromethyl)
  • R 4 represents nitrile
  • R 1 represents hydrogen
  • R 2 represents Ci-6 alkyl (such as methyl)
  • R 3 represents Ci-6 alkyl (such as ethyl)
  • R 4 represents hydrogen
  • R 1 represents halogen (such as chlorine)
  • R 2 represents hydrogen
  • R 3 represents haloCi-6 alkyl (such as trifluoromethyl)
  • R 4 represents hydrogen
  • R 1 represents halogen (such as chlorine)
  • R 2 represents hydrogen
  • R 3 represents haloCi-6 alkoxy (such as difluoromethoxy)
  • R 4 represents hydrogen
  • R 1 represents C1-6 alkyl (such as methyl)
  • R 2 represents hydrogen
  • R 3 represents haloCi-6 alkoxy (such as difluoromethoxy)
  • R 4 represents hydrogen
  • R 1 represents C1-6 alkyl (such as methyl)
  • R 2 represents hydrogen
  • R 4 represents hydrogen
  • R 1 represents C1-6 alkyl (such as methyl), R 2 represents hydrogen, R 3 represents halogen (such as bromine) and R 4 represents hydrogen.
  • R 1 represents Ci-6 alkyl (such as methyl)
  • R 2 represents hydrogen
  • R 3 represents haloCi-6 alkyl (such as trifluoromethyl) and R 4 represents nitrile;
  • R 1 represents Ci-6 alkyl (such as methyl)
  • R 2 represents hydrogen
  • R 3 represents Ci-6 alkyl (such as methyl or isopropyl)
  • R 4 represents nitrile
  • R 1 represents Ci-6 alkyl (such as methyl)
  • R 2 represents hydrogen
  • R 3 represents haloCi-6 alkyl (such as trifluoromethyl)
  • R 4 represents hydrogen
  • R 1 represents Ci-6 alkoxy (such as methoxy)
  • R 2 represents hydrogen
  • R 3 represents haloCi-6 alkyl (such as trifluoromethyl)
  • R 4 represents nitrile.
  • R 1 represents -NR x R y (such as -N(Me)2 or -N(Me)(Et))
  • R 2 represents hydrogen
  • R 3 represents haloCi-6 alkyl (such as trifluoromethyl)
  • R 4 represents nitrile.
  • R 1 represents hydrogen
  • R 2 represents hydrogen
  • R 3 represents haloCi-6 alkyl (such as trifluoromethyl)
  • R 4 represents nitrile
  • R 1 represents Ci-6 alkyl (such as methyl)
  • R 2 represents hydrogen
  • R 3 represents haloCi-6 alkyl (such as trifluoromethyl)
  • R 4 represents hydrogen
  • R 15 and R 16 independently represent hydrogen; -OR 15a (such as hydroxy); halogen (such as fluorine); C1-6 alkanol (such as CH2OH);
  • C1-6 alkoxy such as methoxy
  • -NR V R W (such as -NH2, -NMe2, -N(H)(Me), -N(H)(COMe), -N(H)((CH 2 ) 2 OH), - N(H)((CH 2 )2SO 2 Me), N(Me)((CH 2 )2SO2Me), -N(H)(pyrrolidinyl), -N(Me)(pyrrolidinyl), - N(H)(azetidinyl), -N(H)(oxetanyl), -N(Me)(oxetanyl), -N(H)(cyclopentyl), -N(Me)(cyclopentyl), -N(H)(tetrahydropyranyl), -N(Me)(tetrahydropyranyl) or -N(H)(((CH2)2NH2), wherein said pyr
  • heterocyclyl such as azetidinyl, pyrrolidinyl, morpholinyl or piperazinyl
  • heterocyclyl optionally substituted by one or more hydroxy or C1-6 alkanol (such as CH2OH) groups.
  • R 15 and R 16 indepenently represent hydrogen; hydroxy; halogen (such as fluorine); C1-6 alkoxy (such as methoxy); -NR V R W (such as -NH2, -NMe 2 , -N(H)(Me), -N(H)(COMe), -N(H)((CH 2 ) 2 OH), - N(H)((CH2)2SO 2 Me), N(Me)((CH2)2SO2Me), -N(H)(pyrrolidinyl), -N(Me)(pyrrolidinyl), - N(H)(azetidinyl), -N(H)((CH2)2NH 2 ), wherein said pyrrolidinyl ring may be optionally substituted by an oxo or -COC1-6 alkyl (such as -COMe) group.
  • pyrrolidinyl ring may be optionally substituted by an oxo or -COC
  • heterocyclyl such as morpholinyl or piperazinyl
  • R 13 represents hydroxy
  • R A , R A , R B , and R B each represents hydrogen or -OR 16b (such as hydroxy).
  • R A , R A , R B , and R B each represents hydrogen or hydroxy.
  • R B represents -OR 13b (such as hydroxy).
  • X represents -C(H)(R 16 )- and R z , R z , R 16 , R A , R A , R B , and R B , each represent hydrogen.
  • X represents -C(H)(R 16 )- and R 16 represents -OR 15a (such as hydroxy).
  • X represents -C(H)(R 16 )-, R z , R z , R 15 , and R 16 represent hydrogen, and R B represents -OR 15b (such as hydroxy).
  • R 16 represents halogen (such as fluorine).
  • R 16 represents Ci-6 alkoxy (such as methoxy).
  • R 16 represents -NR V R W (such as -NH 2 , -NMe 2 , -N(H)(Me), -N(H)((CH 2 ) 2 OH), -N(H)((CH 2 ) 2 SO 2 Me), N(Me)((CH 2 ) 2 SO 2 Me), -N(H)(pyrrolidinyl), -N(Me)(pyrrolidinyl), -N(H)(azetidinyl), -N(H)(oxetanyl), -N(Me)(oxetanyl), -N(H)(cyclopentyl), -N(Me)(cyclopentyl), -N(H)(tetrahydropyranyl), -N(Me)(tetrahydropyranyl) or - N(H)((CH 2 ) 2 NH 2 ), wherein said pyrrolidinyl, tetrafluorany
  • R 16 represents heterocyclyl (such as azetidinyl, pyrrolidinyl, morpholinyl or piperazinyl optionally substituted by one or more hydroxy or Ci-6 alkanol (i.e. CH 2 OH) groups).
  • R 16 and R B each represent OR 15b (such as hydroxy).
  • X represents CR 15 R 16 , and R 13 , R 16 , R A , R A , R B , and R B each represent hydrogen.
  • X represents CHR 16
  • R 16 represents -NR V R W (such as -NH 2 or -N(H)(COMe)) and R A , R A , R B , and R B each represent hydrogen.
  • X represents CR 15 R 16 , R 15 , R 16 , R A , R A , R B , and R B each represent hydrogen
  • R 16 represents heterocyclyl (such as morpholinyl).
  • X represents CR 15 R 16 , and R 15 , R A , R A , and R B each represent hydrogen
  • R 16 represents -OR 15a (such as hydroxy)
  • R B represents OR 15b (such as hydroxy).
  • X represents CR i5 R i6
  • R 15 , R A , R A , R B , and R B each represent hydrogen
  • R 16 represents -OR 15a (such as hydroxy).
  • X represents CR 13 R 16 , and R 15 , R A , R A , R B , and R B each represent hydrogen
  • R 16 represents -L-aryl (such as -CH 2 -O-CH 2 -phenyl).
  • X represents CR 15 R 16 , and R 15 , R A , R A , R B , and R B each represent hydrogen
  • R 16 represents Ci-6 alkanol (such as CH 2 OH).
  • represents C O
  • X represents CR 15 R 16 , and R 15 , R 16 , R A , R A , and R B each represent hydrogen
  • R B represents -OR 15b (such as hydroxy).
  • X represents CR 15 R 16 , and R 13 , R A , R A , R B , and R B each represent hydrogen
  • R 16 represents CH 2 -NR V R W (such as -CH 2 -N(Me) 2 ).
  • X represents CR 15 R 16 ; R 15 , R A , R A , and R B each represent hydrogen; R 16 represents -OR 15a ; R B represents -OR 15b ; and R 15a and R 15b join together to form a 5 to 7 (such as 5) membered saturated ring system (such as dioxolanyl) which may be optionally substituted by one or more Ci-6 alkyl groups (such as two methyl groups).
  • R z , R z , R A , R A , R B , and R B represent hydrogen and R 16 represents represents -NR V R W (such as -NH2, -NMe 2 , -N(H)(Me), -N(H)((CH 2 ) 2 OH), -N(H)((CH 2 ) 2 SO 2 Me), N(Me)((CH 2 ) 2 SO 2 Me) -N(H)(pyrrolidinyl), -N(Me)(pyrrolidinyl), -N(H)(azetidinyl), -N(H)(oxetanyl), -N(Me)(oxetanyl), -N(H)(cyclopentyl), -N(Me)(cyclopentyl), -N(H)(tetrahydropyranyl), -N(Me)(tetrahydropyranyl) or - N(H)
  • R z , R z , R A , R A , R B , and R B represent hydrogen and R 16 represents represents heterocyclyl (such as azetidinyl, pyrrolidinyl, morpholinyl or piperazinyl optionally substituted by one or more hydroxy or C1-6 alkanol (i.e. CH2OH) groups).
  • R z , R z , R A , R A , and R B represent hydrogen; R 16 represents -OR 15a (such as hydroxy); and R B represents OR 15b (such as hydroxy).
  • Z represents C O; X represents -C(H)(R 16 )-; and R 16 , R A , R A , R B , and R B each represent hydrogen.
  • X represents -C(H)(R 16 )-;
  • R A , R A , R B , and R B each represent hydrogen;
  • R 16 represents -CH2-NR V R W (such as -CH2-N(Me)2).
  • X represents -C(H)(R 16 )-;
  • R A , R A , and R B each represent hydrogen;
  • R 16 represents -OR 15a and R B represents -OR 15b (such as hydroxy) wherein R 15a and R 15b join together to form a 5 to 7 (such as 5) membered saturated ring system (such as dioxolanyl) which may be optionally substituted by one or more Ci-6 alkyl groups (such as two methyl groups).
  • R 16 represents -NR V R W (such as -NH2, -NMe 2 , -N(H)(Me), -N(H)((CH 2 ) 2 OH), -N(H)((CH 2 )2SO 2 Me), N(Me)((CH 2 )2SO 2 Me), -N(H)(pyrrolidinyl), -N(Me)(pyrrolidinyl), -N(H)(azetidinyl), -N(H)((CH 2 ) 2 NH 2 ), wherein said pyrrolidinyl ring may be optionally substituted by an oxo or -COC1-6 alkyl (such as -COMe) group.
  • R 16 represents heterocyclyl (such as morpholinyl or piperazinyl).
  • R 16 and R B both represent hydroxy.
  • R 16 represents -NR V R W (such as -NH2 or -N(H)(COMe)).
  • R 16 represents heterocyclyl (such as morpholinyl).
  • R 16 and R B both represent hydroxy.
  • R 17 represents C1-6 alkanol (such as -CH 2 -CH(OH)Me).
  • R 17 represents -SO 2 -Ci-6 alkyl (such as -SO 2 -Me).
  • R v and R w represent hydrogen, C1-6 alkyl (such as methyl), -COC1-6 alkyl (such as -COMe) or heterocyclyl (such as azetidinyl or pyrrolidinyl), wherein said alkyl groups may be optionally substituted with or more hydroxy (such as (Chb A OH), amino (such as (CH 2 ) 2 NH 2 ) or sulfone (such as (CH 2 ) 2 SO 2 Me) groups and said heterocyclyl ring may be optionally substituted by one or more oxo or -COCi-6 alkyl (such as -COMe) groups.
  • R v and R w both represent hydrogen or Ci-6 alkyl (such as methyl) or one represents hydrogen and the other represents Ci-6 alkyl (such as methyl) or one represents hydrogen or Ci-6 alkyl (such as methyl) and the other represents -COCi-6 alkyl (such as -COMe), C3-8 cycloalkyl (such as cyclopentyl) or heterocyclyl (such as azetidinyl, tetrahydropyranyl or pyrrolidinyl), wherein said alkyl groups may be optionally substituted with or more hydroxy (such as (Chb A OH), amino (such as (Chb A Nhb) or sulfone (such as (CHz ⁇ SChMe) groups and said heterocyclyl ring may be optionally substituted by one or more oxo or -COC1-6 alkyl (such as -COMe) groups.
  • R 5 represents C1-6 alkyl (such as CH3, CD3, ethyl or isopropyl) or C3-8 cycloalkyl (such as cyclopropyl). In one embodiment, R 5 represents C1-6 alkyl (such as methyl, ethyl or isopropyl). In one embodiment, R 5 represents Ci-6 alkyl (such as CH3, CD3 or ethyl). In one embodiment, R 3 represents C1-6 alkyl (such as methyl or ethyl). In a yet further embodiment, R’ represents C1-6 alkyl (such as CHs or CDs).
  • R 6 represents C1-6 alkoxy (such as methoxy). In one embodiment, R 6 represents: hydrogen; halogen (such as fluorine). In one embodiment, R 6 represents C1-6 alkoxy (such as methoxy). In one embodiment, R 6 represents: hydrogen. In one embodiment, R 6 represents halogen (such as fluorine). In one embodiment, R 6 represents hydrogen.
  • R x and R Y represent C1-6 alkyl (such as methyl). In one embodiment, R 7 represents halogen (such as chlorine). In one embodiment, R x and R Y independently represent hydrogen or methyl. In one embodiment, both of R x and R Y represent hydrogen or both of R x and R Y represent methyl or one of R x and R Y represents hydrogen and the other represents methyl.
  • R 8 , R 9 , and R 10 each represent halogen. In one embodiment, R 8 represents fluorine. In one embodiment, R 9 represents chlorine. In one embodiment, R 10 represents fluorine.
  • R 8 represents: hydrogen; halogen (such as fluorine, bromine or chlorine); C1-6 alkyl (such as methyl or ethyl); C2-6 alkenyl (such as ethenyl);
  • R 8 represents: hydrogen; halogen (such as fluorine, bromine or chlorine); C1-6 alkyl (such as methyl or ethyl); C2-6 alkenyl (such as ethenyl); haloCi-6 alkyl (such as trifluoromethyl).
  • R 8 and R 7 join to form a 5 to 7 membered saturated or unsaturated ring optionally containing one or more heteroatoms selected from O, N or S (such as a pyrrolinyl or tetrahydropyranyl ring).
  • R 8 represents: hydrogen; halogen (such as fluorine or chlorine).
  • R 8 represents haloCi-6 alkyl (such as trifluoromethyl). In one embodiment, R 8 represents halogen (such as fluorine).
  • R 7 and R 8 join to form a 5 to 7 membered saturated or unsaturated ring optionally containing one or more heteroatoms selected from O, N or S (such as a benzyl, pyridinyl, purinyl, pyrimidinyl, diazinyl, pyrrolyl, pyrrolinyl, tetrahydropyranyl, pyrazolyl, morpholinyl, pyridyl, furanyl or thiophenyl ring optionally substituted by one or more methyl or fluorine groups).
  • heteroatoms selected from O, N or S (such as a benzyl, pyridinyl, purinyl, pyrimidinyl, diazinyl, pyrrolyl, pyrrolinyl, tetrahydropyranyl, pyrazolyl, morpholinyl, pyridyl, furanyl or thiophenyl ring optionally substituted by one or more
  • R 8 and R 7 join to form a 5 to 7 membered saturated or unsaturated ring optionally containing one or more heteroatoms selected from O, N or S (such as a benzyl, pyridinyl, purinyl, pyrimidinyl, diazinyl, pyrrolyl, pyrrolinyl, tetrahydropyranyl, pyrazolyl, morpholinyl, pyridyl, furanyl or thiophenyl ring optionally substituted by one or more methyl or fluorine groups).
  • heteroatoms selected from O, N or S (such as a benzyl, pyridinyl, purinyl, pyrimidinyl, diazinyl, pyrrolyl, pyrrolinyl, tetrahydropyranyl, pyrazolyl, morpholinyl, pyridyl, furanyl or thiophenyl ring optionally substituted by one or more
  • R 9 represents: hydrogen; halogen (such as fluorine or chlorine); Ci-6 alkyl (such as methyl); haloCi-6 alkyl (such as fluoromethyl, difluoromethyl or trifluoromethyl). In one embodiment, R 9 represents Ci-6 alkoxy (such as methoxy). In one embodiment, R 9 represents hydrogen.
  • R 10 represents: hydrogen
  • R 10 represents halogen (such as fluorine). In one embodiment, R 10 represents hydrogen.
  • each of R 6 , R 7 and R 10 represent hydrogen and R 8 and R 9 both represents halogen (such as fluorine or chlorine).
  • each of R 6 , R 7 and R 10 represent hydrogen, R 8 represents halogen (such as fluorine) and R 9 represents Ci-6 alkyl (such as methyl).
  • each of R 6 , R 7 , R 8 and R 10 represent hydrogen and R 9 represents haloCi-6 alkyl (such as fluoromethyl or difluorom ethyl).
  • each of R 6 , R 7 and R 10 represent hydrogen, R 8 represents halogen (such as fluorine) and R 9 represents Ci-6 alkoxy (such as methoxy).
  • each of R 6 , R 8 and R 10 represent hydrogen and R 7 and R 9 both represent halogen (such as fluorine or chlorine). In one embodiment, each of R 6 , R 7 and R 10 represent hydrogen, R 8 represents haloCi-6 alkyl (such as trifluoromethyl) and R 9 represents halogen (such as fluorine).
  • each of R 6 , R 8 , R 9 and R 10 represent hydrogen and R 7 represents Ci-6 alkyl (such as methyl, ethyl, CD3, or C2D5); each of R 6 , R 8 , R 9 and R 10 represent hydrogen and R 7 represents halogen (such as chlorine); each of R 6 , R 9 and R 10 represent hydrogen and R 7 and R 8 both represent halogen (such as fluorine, bromine or chlorine); each of R 6 , R 9 , and R 10 represent hydrogen, R 7 represents C1-6 alkyl (such as methyl, ethyl, CDs, or C2D5), and R 8 represents halogen (such as fluorine); each of R 6 , R 7 and R 10 represent hydrogen, R 8 represents C1-6 alkyl (such as methyl) and R 9 represents halogen (such as chlorine); each of R 6 , R 9 and R 10 represent hydrogen, R 7 represents Ci-6 alkyl (such as methyl or ethyl) and R 8 represents halogen
  • each of R 6 , R 9 and R 10 represent hydrogen, R 7 represents halogen (such as chlorine) and R 8 represents C3-8 cycloalkyl (such as cyclopropyl).
  • each of R 6 , R 7 , R 8 and R 10 represent hydrogen and R 9 represents Ci-6 alkyl (such as methyl).
  • each of R 6 , R 7 , R 8 and R 10 represent hydrogen and R 9 represents haloCi-6 alkyl (such as fluoromethyl or difluoromethyl).
  • each of R 6 , R and R 10 represent hydrogen, R 8 represents halogen (such as fluorine) and R 9 represents C1-6 alkoxy (such as methoxy).
  • each of R 6 , R 7 and R 10 represent hydrogen, R 8 represents haloCi-6 alkyl (such as trifluoromethyl) and R 9 represents halogen (such as fluorine).
  • each of R 6 , R 8 , R 9 and R 10 represent hydrogen and
  • R 7 represents Ci-6 alkyl (such as methyl, ethyl, CD3, or C2D5); each of R 6 , R 8 , R 9 and R 10 represent hydrogen and R 7 represents halogen (such as chlorine); each of R 6 , R 9 and R 10 represent hydrogen and R 7 and R 8 both represent halogen (such as fluorine, bromine or chlorine); each of R 6 , R 9 , and R 10 represent hydrogen, R 7 represents Ci-6 alkyl (such as methyl, ethyl, CD3, or C2D5); each of R 6 , R 7 and R 10 represent hydrogen, R 8 represents C1-6 alkyl (such as methyl) and R 9 represents halogen (such as chlorine); each of R 6 , R 9 and R 10 represent hydrogen, R 7 represents C1-6 alkyl (such as methyl or ethyl) and R 8 represents halogen (such as chlorine or fluorine); each of R 6 , R 9 and R 10 represent hydrogen, R 7 represents C1-6 alkoxy (such as meth
  • both of R 7 and R 10 represent hydrogen and each of R 6 , R 8 and R 9 represent halogen (such as chlorine or fluorine).
  • each of R 6 , R 7 , R 8 and R 10 represent hydrogen and R 9 represents Ci-6 alkyl (such as methyl).
  • each of R 6 , R 7 and R 10 represent hydrogen and R 8 and R 9 both represents halogen (such as fluorine or chlorine).
  • each of R 6 , R 7 and R 10 represent hydrogen, R 8 represents halogen (such as fluorine) and R 9 represents Ci-6 alkyl (such as methyl).
  • each of R 6 , R 7 and R 10 represent hydrogen, R 8 represents halogen (such as fluorine) and R 9 represents haloCi-6 alkyl (such as fluoromethyl or trifluorom ethyl).
  • each of R 6 , R 7 , R 8 and R 10 represent hydrogen and R 9 represents haloCi-6 alkyl (such as fluoromethyl or difluoromethyl).
  • each of R 6 , R 7 , R 8 and R 10 represent hydrogen and R 9 represents halogen (such as chlorine).
  • each of R 6 , R 7 and R 10 represent hydrogen, R 8 represents halogen (such as fluorine) and R 9 represents Ci-6 alkoxy (such as methoxy).
  • each of R 6 , R 7 and R 10 represent hydrogen, R 8 represents haloCi-6 alkyl (such as trifluoromethyl) and R 9 represents halogen (such as fluorine).
  • R 7 and R 8 join to form a pyrrolinyl ring and R 9 and R 10 both represent hydrogen.
  • R 9 and R 10 both represent hydrogen, R 7 represents Ci-6 alkyl (such as methyl) and R 8 represents halogen (such as fluorine); each of R 8 , R 9 and R 10 represent hydrogen and R 7 represents -NR m R n (such as - NH2, -NHMe or -NMei).
  • R 9 and R 10 both represent hydrogen and R 7 and R 8 join to form a pyrrolinyl, morpholinyl, furanyl or thiophenyl ring optionally substituted by a methyl, fluorine or chlorine group.
  • R 10 represents hydrogen
  • R 9 represents halogen (such as chlorine)
  • R 7 and R 8 join to form a pyrrolinyl ring optionally substituted by a methyl group.
  • the compound of Formula (I) is represented by one of the following compounds:
  • references to compounds of the Formula (I) include the salt forms of the compounds.
  • the salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.
  • All of these salts may be prepared by conventional means from the corresponding compound according to Formula I by reacting, for example, the appropriate acid or base with the compound according to Formula I.
  • the salts are in crystalline form, and preferably prepared by crystallization of the salt from a suitable solvent.
  • suitable salt forms for example, as described in Handbook of Pharmaceutical Salts: Properties, Selectin and Use by P. H. Stahl and C. G. Wermuth (Wiley-VCH 2002).
  • the present invention includes within its scope all possible enantiomers and diastereoisomers, including mixtures thereof.
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • the invention also extends to any tautomeric forms or mixtures thereof.
  • the subject invention also includes all pharmaceutically acceptable isotopically- labelled compounds which are identical to those recited in formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.
  • Compounds of Formula I may be prepared according to the general methods of Schemes 4-5. Certain compounds of Formula /, identified as having the structure of Formula la, may be prepared using the general method shown in Scheme 4. Other compounds of Formula I, identified as having the structure of Formula lb, may be prepared using the general method shown in Scheme 5. It may be appreciated that the compounds of formula la are compounds of Formula I wherein U is O while compounds of Formula lb are compounds of Formula I wherein U is CH2. Intermediates 2, 5 and X may be prepared using the general methods shown in Schemes 1-3.
  • Compounds of Formula 5 may be prepared as shown in Scheme 2.
  • Compound 3, a known compound or a compound prepared using known methods, is treated with a carbamoylation agent 4 such as phosgene, diphosgene, triphosgene, carbonyldiimidazole, disuccinimidyl carbonate and the like where LG is a suitable leaving group sue as halogen, imidazole, succinimide and the like, in the presence of a suitable base such as pyridine, N,N-dimethylpyridine, triethylamine, diisopropylethylamine, diazabicyclononene, diazabicycloundecene, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium tert- butoxide, potassium tert-butoxide, N-butyllithium, lithium diisopropylamide and the like, optionally in the presence of a suitable solvent such as water
  • a compound of Formula 2 is reacted with a compound of Formula 5 in the presence of in the presence of a suitable base such as pyridine, N,N- dimethylpyridine, triethylamine, diisopropylethylamine, diazabicyclononene, diazabicycloundecene, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium tert-butoxide, potassium tert-butoxide, N-butyllithium, lithium diisopropylamide and the like, optionally in the presence of a suitable solvent such as water, hexane, heptane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, ethylacetate, tetrahydrofuran, benzene, toluene, diethylether,
  • a suitable base such as pyridine, N,N- dimethylpyr
  • a compound of Formula 6 is then reacted with a compound of Formula 7, a known compound or a compound prepared by known methods, in the presence of a suitable catalyst such as copper (I) bromide, copper (I) iodide, nickel bromide and the like, a suitable coordinating agent such as N,N- dimethylethylenediamine, a suitable base such as potassium carbonate, potassium phosphate, cesium carbonate, sodium tert-butoxide and the like, a suitable ligand such as cesium fluoride, a suitable solvent such as water, tetrahydrofuran, 1,4-di oxane, dimethylsulfoxide, dimethylformamide, acetonitrile, optionally in the presence of molecular sieves, optionally with heating, optionally with microwave irradiation, to provide a compound of Formula I.
  • a suitable catalyst such as copper (I) bromide, copper (I) iodide, nickel bromide and the like
  • a compound of Formula 8 a known compound or a compound prepared using known methods wherein PG represents a suitable protecting group such as benzyl, tert-butyldimethylsilyl, methoxymethyl, tetrohydropyranyl and the like and LG 2 represents a suitable leaving group such as chloro, bromo, iodo, mesyl, trifluoromesyl, p-toleuensulfonyl and the like, is treated with a compound of Formula 7, a known compound or a compound prepared using known methods, in the presence of a suitable base such as sodium tert-butoxide, lithium hexamethyldisylazide, cesium carbonate, potassium phosphate and the like, a suitable catalyst such as palladium (0) bis(dibenzylidineacetone), palladium acetate, (DPPF)PdCh and the like, a suitable ligand such
  • a compound of Formula 9 is then reacted under suitable conditions to remove the protecting group such as catalytic hydrogenation in the presence of a suitable catalyst such as palladium on carbon, palladium hydroxide and the like, hydrogen fluoride/pyridine, diaminoethylsulfur trifluoride, aqueous acid and the like to provide a compound of Formula 10.
  • a suitable catalyst such as palladium on carbon, palladium hydroxide and the like, hydrogen fluoride/pyridine, diaminoethylsulfur trifluoride, aqueous acid and the like to provide a compound of Formula 10.
  • a compound of Formula 10 is then reacted with a compound of Formula 5 in the presence of in the presence of a suitable base such as pyridine, N,N- dimethylpyridine, tri ethyl amine, diisopropylethylamine, diazabicyclononene, diazabicycloundecene, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium tert-butoxide, potassium tert-butoxide, N-butyllithium, lithium diisopropylamide and the like, optionally in the presence of a suitable solvent such as water, hexane, heptane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, ethylacetate, tetrahydrofuran, benzene, toluene, diethylether, methanol, ethanol, N-methylpyrrolidone, di
  • a protecting group is a derivative of a chemical functional group which would otherwise be incompatible with the conditions required to perform a particular reaction which, after the reaction has been carried out, can e removed to re-generate the original functional group, which is thereby considered to have been “protected”.
  • Any chemical functionality that is a structural component of any of the reagents used to synthesize compounds of this invention may be optionally protected with a chemical protecting group if such a protection group is useful in the Synthesis of compounds of this invention.
  • the compounds of Formula I and intermediates may be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization or chromatography.
  • the present invention when compounds of Formula I the present invention contain one or more chiral centers, the compounds may exist in, and may be isolated s pure enantiomeric or diasteromeric forms or as racemic mixtures.
  • the present invention therefore includes any possible enantiomers, diastereomers, racemates or mixtures thereof of the compounds of the invention which are biologically active in the treatment of cancer.
  • the compounds of the invention may possess one or more stereocenters, and each stereocenter may exist independently in either the R or S configuration.
  • compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In one embodiment, a mixture of one or more isomer is utilized as the therapeutic compound described herein.
  • the methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and/or pharmaceutically acceptable salts of compounds having the structure of any compound of the invention, as well as metabolites and active metabolites of these compounds having the same type of activity.
  • Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like.
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol.
  • the compounds described herein exist in unsolvated form.
  • the compounds of the invention may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
  • prodrugs are prepared as prodrugs.
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo.
  • a prodrug upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • sites on, for example, the aromatic ring portion of compounds of the invention are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In one embodiment, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group.
  • substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).
  • substitution with positron emitting isotopes, such as n C, 18 F, 15 O and 13 N is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • reactive functional groups such as hydroxyl, amino, imino, thio or carboxy groups
  • Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed.
  • each protective group is removable by a different means.
  • Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.
  • the invention also includes a method of treating or preventing pain or inflammation in a subject in need thereof.
  • the method comprises administering to the subject an effective amount of a therapeutic composition comprising a compound of the invention.
  • the inflammation is selected from the group consisting of arthritic disorders, psoriasis, allergies, opioid tolerance, Crohn’s Disease, migraine headaches, periarteritis nodosa, thyroiditis , aplastic anemia, Hodgkin ' s disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet ' s syndrome, polymyositis , gingivitis, nephritis, hypersensitivity, swelling occurring after injury including brain edema, and myocardial ischemia.
  • the arthritic disorder is selected from the group consisting of rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis , systemic lupus erythematosus and juvenile arthritis.
  • the method further comprises administering to the subject an additional therapeutic agent.
  • the compound of the invention can be administered alone or in combination with other anti-tumor agents, including cytotoxic/antineoplastic agents and anti -angiogenic agents.
  • Cytotoxic/anti -neoplastic agents are defined as agents which attack and kill cancer cells.
  • Some cytotoxic/anti-neoplastic agents are alkylating agents, which alkylate the genetic material in tumor cells, e.g., cis-platin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacabazine.
  • cytotoxic/anti-neoplastic agents are antimetabolites for tumor cells, e.g., cytosine arabinoside, fluorouracil, methotrexate, mercaptopuirine, azathioprime, and procarbazine.
  • Other cytotoxic/anti-neoplastic agents are antibiotics, e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin.
  • doxorubicin e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin.
  • mitotic inhibitors (vinca alkaloids).
  • cytotoxic/anti-neoplastic agents include taxol and its derivatives, L-asparaginase, anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.
  • anti-cancer agents that can be used in combination with the disclosed compounds include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedef
  • anticancer drugs include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5- ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PT
  • the compounds of the invention may be administered to a subject in conjunction with (e.g. before, simultaneously, or following) an antiinflammatory agent selected from the group consisting of nonsteroidal agents (“NSAIDS”) such as salicylates (e.g., salsalate, mesalamine, diflunisal, choline magnesium tri salicylate), diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, mefenamic acid, nabumetone, naproxen, piroxicam, phenyl butazone, ketoprofen, S-ketoprofen, ketorolac tromethamine, sulindac, tolmetin).
  • NSAIDS nonsteroidal agents
  • anti-inflammatory drugs include steroidal agents such as beclomethasone, betamethasone, cortisone, dexamethasone, fluocinolone, flunisolide, fluticasone proprionate, fluorinated- corticoids, triamcinolone-diacetate, hydorcortisone, prednisolone, methylprednisolone, and prednisone.
  • Immunosuppressive agents e.g., adenocorticosteroids, cyclosporin
  • antihistamines and decongestants e.g.
  • compositions of the present invention may be carried out using known procedures, at dosages and for periods of time effective to treat cancer in the patient.
  • An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a cancer in the patient.
  • Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily. In another example, the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 1 mg/kg to about 5,000 mg/kg of body weight/per day.
  • One of ordinary skill in the art would be able to assess the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.
  • the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.
  • dosage unit form refers to a physically discrete unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect, in association with the required pharmaceutical vehicle.
  • the dosage unit forms of the invention can be selected based upon (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound for the treatment of cancer in a patient.
  • compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.
  • Doses of the compound of the invention for administration may be in the range of from about 1 pg to about 10,000 mg, from about 20 pg to about 9,500 mg, from about 40 pg to about 9,000 mg, from about 75 pg to about 8,500 mg, from about 150 pg to about 7,500 mg, from about 200 pg to about 7,000 mg, from about 3050 pg to about 6,000 mg, from about 500 pg to about 5,000 mg, from about 750 pg to about 4,000 mg, from about 1 mg to about 3,000 mg, from about 10 mg to about 2,500 mg, from about 20 mg to about 2,000 mg, from about 25 mg to about 1,500 mg, from about 30 mg to about 1,000 mg, from about 40 mg to about 900 mg, from about 50 mg to about 800 mg, from about 60 mg to about 750 mg, from about 70 mg to about 600 mg, from about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.
  • the dosage of a second compound as described elsewhere herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.
  • the compounds for use in the method of the invention may be formulated in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.
  • the compositions of the invention are administered to the patient from about one to about five times per day or more.
  • the compositions of the invention are administered to the patient, 1-7 times per day, 1-7 times every two days, 1-7 times every 3 days, 1-7 times every week, 1-7 times every two weeks, and 1-7 times per month.
  • the frequency of administration of the various combination compositions of the invention will vary from individual to individual depending on many factors including, but not limited to, age, the disease or disorder to be treated, the severity of the disease or disorder to be treated, gender, overall health, and other factors.
  • the invention should not be construed to be limited to any particular dosing regime and the precise dosage and composition to be administered to any patient is determined by the medical professional taking all other factors about the patient into account.
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced to a level at which the improved disease is retained. In some embodiments, a patient may require intermittent treatment on a long-term basis, or upon any recurrence of the disease or disorder.
  • the liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agent e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • preservatives e.g., methyl or propyl p-hydroxy benzoates or sorbic acid
  • Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient.
  • the powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a “granulation.”
  • solvent-using “wet” granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated.
  • Polq inhibitors (Polqi)
  • HDR homology-directed repair
  • HDR high-density lipoprotein
  • factors important for HDR may be defective and/or downregulated in cancer cells, including but not limited to Mrel 1, Rad50, Nbsl, CtIP, Exol, PALB2, BARD1, RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3. Therefore, in one embodiment, cancer cells defective or downregulated in one or more of these HDR factors will be susceptible to the Polq inhibitors described herein.
  • Polq inactivation in combination with DDR factors RAD54 or FANCJ also results in synthetic lethality.
  • Polqi described herein will preferentially kill cancer cells with defects or downregulation of RAD54 and/or FANCJ.
  • Polqi described herein will show preferential killing of cancer cells defective in or downregulated in ATR or ATM DDR factors. In one embodiment, it is also expected that Polqi described herein will exhibit synergistic or additive anti-proliferation effects when combined with ATR inhibitors or ATM inhibitors.
  • Polqi described herein will show effective killing of cancer cells exhibiting replicative stress, especially when combined with other anti -cancer agents that exacerbate replicative stress, including but not limited to gemcitabine, ATR inhibitors, cytarabine, topoisomerase inhibitors (i.e. etoposide), cisplatin, etc.
  • Polq was also shown to confer resistance to ionizing radiation (JR), bleomycin, cisplatin, mitomycin C, and topoisomerase inhibitors (etoposide, campt othecin). Therefore, in another embodiment it is expected that Polqi described herein will promote cancer cell sensitivity to a variety of anti-cancer agents including but not limited to IR, bleomycin, cisplatin, mitomycin C and topoisomerase inhibitors.
  • JR ionizing radiation
  • bleomycin bleomycin
  • cisplatin mitomycin C
  • topoisomerase inhibitors etoposide, campt othecin
  • PARP inhibitors PARPi
  • Polq inactivation both reduce cancer cell resistance to IR.
  • PARPi PARP inhibitors
  • combining Polqi described herein with PARPi will sensitize cancer cells to IR and overcome cancer cell resistance to IR.
  • suppression of Polq combined with a DNApk inhibitor causes cancer cell sensitivity to IR.
  • Polqi described here in will show synergistic anti-proliferation effects when combined with DNApk inhibitors and IR or other anti-cancer agents that cause DNA double-strand breaks.
  • Polqi described herein will act synergistically with PARP inhibitors (PARPi), especially in HDR defective cells.
  • PARPi PARP inhibitors
  • Polqi combined with PARPi including but not limited to Lynparza (olaparib), talazoparib, niraparib, and rucaparib will potentiate the effects of PARPi in solid tumors and hematological malignancies.
  • Polqi described herein when combined with PARPi will suppress cancer cell resistance to PARPi.
  • Polqi described herein are expected to induce synthetic lethality in cancer cells with defects in or suppression of the expression of non- homologous end-joining NHEJ factors such as LIG4 or KU70/80.
  • said non-homologous end-joining genes are selected from any one or more of: LIG4, NHEJ1 , POLL, POLM, PRKDC, XRCC4, XRCC5, XRCC6, and DCLRE1C.
  • a compound of formula (I) as defined herein for use in the treatment of tumours which have elevated ligase Ilia levels, reduced ligase IV levels and increased dependence upon MMEJ (altEJ) DSB repair.
  • Polqi described herein will benefit CRISPR-Cas9 based genome engineering by reducing off-target effects and thus increase the fidelity and safety of CRISPR-Cas9 type RNA-guided genome engineering for therapeutics and basic research applications.
  • combining Polqi described herein with DNApk inhibitors will have an even greater effect on increasing the fidelity and safety of CRISPR-Cas9 type RNA-guided genome engineering for therapeutic and basic research applications.
  • Step 4 Synthesis of l-(2-morpholinoethyl)imidazolidin-2-one
  • Step 2 Synthesis of 2-(3-(2-(4-cyanopiperidin-l-yl)ethyl)-2-oxoimidazolidin-l- yl)-4,6-bis(trifluoromethyl)phenyl (4-fluorophenyl)(methyl)carbamate
  • Step 5 Synthesis of 2-iodo-6-methyl-4-(trifluoromethyl)phenyl (3-chloro-4- fluorophenyl)(methyl) carbamate
  • Step 6 Synthesis of 2-methyl-6-(2-oxoimidazolidin-l-yl)-4- (trifluoromethyl)phenyl (3-chloro-4-fluorophenyl)(methyl)carbamate
  • 2-iodo-6-methyl-4-(trifluoromethyl)phenyl (3-chloro-4- fluorophenyl)(methyl) carbamate 0.1 g, 0.0002 mol
  • imidazolidin-2-one 0.035 g, 0.0004 mol
  • potassium carbonate 0.055 g, 0.0004 mol
  • caesium fluoride (0.06 g, 0.0004 mol
  • reaction mixture was heated at 90 °C in an oil-bath for 24 h. After completion of the reaction by TLC (Rr 0.4, 5% MeOH in DCM) the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by column chromatography (100-200 silica gel, 1-2% MeOH in DCM as eluent) to afford title compound as off-white solid (15 mg, 17%).
  • Step 1 Synthesis of 4,4,5, 5-tetramethyl-2-(2-methyl-4-(trifluoromethyl)phenyl)- 1,3,2-dioxaborolane
  • a solution of l-bromo-2-methyl-4-(trifluoromethyl)benzene (1 g, 0.0041 mol) in 1,4 dioxane (20 mb) was purged with N2 in a sealed tube for 30 min and then added bispinacolato diboron ( 2.12 g, 0.00837 mol), potassium acetate (0.82 g, 0.00836 mol) and Pd(dppf)C12.DCM (0.34 g, 0.00042 mol) with stirring under inert atmosphere.
  • Step 6 Synthesis of 2-methyl-6-(2-oxooxazolidin-3-yl)-4- (trifluoromethyl)phenyl(4-fluorophenyl) (methyl)carbamate
  • 2-iodo-6-methyl-4-(trifluoromethyl)phenyl (4- fluorophenyl) (methyl) carbamate 0.1 g, 0.00022 mol
  • oxazolidin-2-one 0.0383 g, 0.00044 mol
  • potassium carbonate (0.91 g, 0.00066 mol
  • caesium fluoride 0.066 g, 0.00044 mol
  • reaction mixture was heated at 100 °C in an oil-bath for 24 h. After completion of the reaction by TLC (Rf 0.5, 60% EtOAc in Hexane) the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by column chromatography (100-200 silica gel, 30-35% EtOAc in Hexane as eluent) to afford title compound as off-white solid (20 mg, 22%).
  • Step 1 Synthesis of l-(2-hydroxy-3,5-bis(trifluoromethyl)phenyl)-l,3-dihydro-
  • Step 2 Synthesis of tert-butyl 3-(2-hydroxy-3,5-bis(trifluoromethyl)phenyl)-2- oxo-2, 3-dihydro- 1 H-imidazole- 1 -carboxylate
  • Step 3 Synthesis of tert-butyl 3-(2-(((4-fluorophenyl)(methyl)carbamoyl)oxy)- 3,5-bis(trifluoromethyl)phenyl)-2-oxo-2,3-dihydro-lH-imidazole-l -carboxylate
  • Step 1 Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane
  • Step 4 Synthesis of (A)-l-(2-hydroxy-3,5-bis(trifluoromethyl)phenyl)-5- methylpyrrolidin-2-one
  • Step 6 Synthesis of 2-[(2R)-2-methyl-5-oxopyrrolidin-l-yl]-4,6- bis(trifluoromethyl)phenyl N-(4-fluorophenyl)-N-methylcarbamate
  • Step 3 Synthesis of 2-(2-oxo-4-(trifluoromethyl)imidazolidin-l-yl)-4,6- bis(trifluoromethyl)phenyl (4-fluorophenyl)(methyl)carbamate
  • Step 1 Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane
  • Step 6 Synthesis of (S)-2-(3-hydroxy-2-oxopyrrolidin-l-yl)-4,6- bis(trifluoromethyl)phenyl (4-fluorophenyl)(methyl)carbamate
  • Step 2 Synthesis of 2,4-bis(trifluoromethyl)phenol To a cold (0 °C) solution of 2-(2,4-bis(trifluoromethyl)phenyl)-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (crude 6 g ) in EtOH (120 mL), added hydrogen peroxide 30% aq. solution (6.0 mL) under inert atmosphere with stirring. The reaction mixture was stirred at ambient temperature for 16h. After completion of the reaction confirmed by TLC (Rr 0.2, 10% EtOAc in Hexane), the reaction mixture was cooled to 0 °C and quenched with aq.
  • TLC Rr 0.2, 10% EtOAc in Hexane
  • Step 4 Synthesis of (4-fluorophenyl)(methyl)carbamic chloride To a cold (0 °C) solution of triphosgene (1.6 g, 0.0128 mol) in DCM (40 mL) added a solution ofN-methyl-4-fluoro aniline (1.89 g, 0.0064 mol) and pyridine (2.52 g, 2.6 mL, 0.032 mol) dropwise for over a period of 10 min. After that continued stirring at RT for 16h. Progress of the reaction was monitored by TLC (Rr - 0.7, 10% EtOAc in Hexane(> ⁇ 4)).
  • Step 6 Synthesis of 2-(2-oxoimidazolidin-l-yl)-4,6-bis(trifluoromethyl)phenyl (4-fluorophenyl)(methyl) carbamate
  • 2-iodo-4,6-bis(trifluoromethyl)phenyl (4-fluorophenyl)(methyl)carbamate (0.2 g, 0.00039 mol), 2-imidazilidinone (0.064 g, 0.0007 mol), copper (I)-iodide (0.037 g, 0.00019 mol), N,N’ -dimethylethylenediamine (0.07 mL, 0.00039 mol), cesium fluoride (0.12 g, 0.00079 mol) and potassium carbonate (0.1 g, 0.00072 mol) were suspended in 1,4-di oxane priorly purged with N2 for 30 minutes (16 mL).
  • the reaction mixture was heated at 90 °C in an oil-bath for 24 h. After completion of the reaction by TLC (Rf 0.4, 5% MeOH in DCM) the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by column chromatography (100-200 silica gel, 0- 3% MeOH in DCM as eluent) to afford the title compound as off-white solid (50 mg). The solid was re-purified by preparative TLC(solid phase: merck, 20 * 20 cm, silicagel 60 GF254, 1mm, PLC glass plate, 2% MeOH in DCM as eluent) to afford the title compound as white solid (28 mg, 15%).
  • Step 7 Synthesis of 2-(2-oxo-3-(2-oxopropyl)imidazolidin-l-yl)-4,6- bis(trifluoromethyl)phenyl (4-fluorophenyl) (methyl)carbamate
  • Step 8 Synthesis of 2-(3-(2-hydroxypropyl)-2-oxoimidazolidin-l-yl)-4,6- bis(trifluoromethyl)phenyl (4-fluorophenyl)(methyl)carbamate
  • Step 1 Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-
  • Step 6 Synthesis of 2-(3-(2-hydroxyethyl)-2-oxoimidazolidin-l-yl)-4,6- bis(trifluoromethyl)phenyl (4-fluorophenyl)(methyl)carbamate
  • Step 7 Synthesis of 2-(3-(2-(((4-fluorophenyl)(methyl)carbamoyl)oxy)-3,5- bis(trifluoromethyl)phenyl)-2-oxoimidazolidin-l-yl)ethyl sulfamate
  • Step 1 Synthesis of 2-(2,4-bis(trifhjoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane
  • Step 6 Synthesis of 2-(2-oxoimidazolidin-l-yl)-4,6-bis(trifluoromethyl)phenyl (4-fluorophenyl)(methyl) carbamate
  • 2-iodo-4,6-bis(trifhioromethyl)phenyl (4-fluorophenyl)(methyl)carbamate (0.2 g, 0.00039 mol), 2-imidazilidinone (0.064 g, 0.0007 mol), copper (I)-iodide (0.037 g, 0.00019 mol), N,N’ -dimethylethylenediamine (0.07 mL, 0.00039 mol), caesium fluoride (0.12 g, 0.00079 mol) and potassium carbonate (0.1 g, 0.00072 mol) were suspended in 1,4-di oxane priorly purged with N2 for 30 minutes (16 mL).
  • the reaction mixture was heated at 90 °C in an oil-bath for 24 h. After completion of the reaction by TLC (Rf 0.4, 5% MeOH in DCM) the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by column chromatography (100-200 silica gel, 0-3% MeOH in DCM as eluent) to afford the title compound as off-white solid (50 mg). The solid was re-purified by preparative TLC(solid phase: merck, 20 x 20 cm, silicagel 60 GF254, 1mm, PLC glass plate, 2% MeOH in DCM as eluent) to afford white solid (28 mg, 15%).
  • Step 7 Synthesis of tert-butyl 3-((3-(2-(((4- fluorophenyl)(methyl)carbamoyl)oxy)-3,5-bis(trifluoromethyl)phenyl)-2- oxoimidazolidin-l-yl)methyl)-3-hydroxyazetidine-l -carboxylate
  • Step 8 Synthesis of 2-(3-((3-hydroxyazetidin-3-yl)methyl)-2-oxoimidazolidin-l- yl)-4,6-bis(trifluoromethyl)phenyl (4-fluorophenyl)(methyl)carbamate
  • Step 1 Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane
  • Step 1 Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane
  • a solution of l-bromo-2,4-bis(trifluoromethyl)benzene (3 g, 0.01 mol) in 1,4 dioxane (90 mL) was purged with N2 in a sealed tube for 30 min and then added bispinacolato diboron ( 5.07 g, 0.02 mol), potassium acetate (1.96 g, 0.02 mol) and Pd(dppf)Ch.DCM (0.816 g, 0.001 mol) with stirring under inert atmosphere.
  • Step 6 Synthesis of 2-(2-oxoimidazolidin-l-yl)-4,6-bis(trifluoromethyl)phenyl (4-fluorophenyl)(methyl) carbamate 2-iodo-4,6-bis(trifluoromethyl)phenyl (4-fluorophenyl)(methyl)carbamate (0.2 g, 0.00039 mol), 2-imidazilidinone (0.064 g, 0.0007 mol), copper (I)-iodide (0.037 g, 0.00019 mol), N,N’-dimethylethylenediamine (0.07 mL, 0.00039 mol), caesium fluoride (0.12 g, 0.00079 mol) and potassium carbonate (0.1 g, 0.00072 mol) were suspended in 1,4-di oxane priorly purged with N2 for 30 minutes (16 mL).
  • Step 8 Synthesis of 2-(3-(3-(dimethylamino)-2-hydroxypropyl)-2- oxoimidazolidin-l-yl)-4,6-bis (trifluoromethyl)phenyl(4-fluorophenyl)(methyl)carbamate
  • the reaction mixture was heated at 90 °C in an oil-bath for 24 h. After completion of the reaction by TLC (Rr 0.4, 5% MeOH in DCM) the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by column chromatography (100-200 silica gel, 0-3% MeOH in DCM as eluent) to afford the title compound as off-white solid (50 mg). The solid was re-purified by preparative TLC(solid phase: merck, 20 x 20 cm, silicagel 60 GF254, 1mm, PLC glass plate, 2% MeOH in DCM as eluent) to afford white solid (28 mg, 15%).
  • Step 4 Synthesis of 2-(2-oxoimidazohdin-l-yl)-4,6-bis(trifluoromethyl)phenyl (4-(difluoromethoxy)phenyl)(methyl)carbamate
  • Step 1 Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane
  • a solution of l-bromo-2,4-bis(trifluoromethyl)benzene (1, 25.0 g, 85.3 mmol 1.0 eq) in 1,4 dioxane (300 mL) was purged with N2 in a sealed tube for 2 mins and then added bispinacolato diboron (43.4 g, 170 mmol, 2.0 eq), potassium acetate (16.8 g, 170 mmol) and Pd(dppf)C12.DCM (2.4 g, 3 mmol, 0.04 eq) with stirring under inert atmosphere.
  • Step 4 Synthesis of 1 -(2 -hydroxy-3, 5-bis(trifluoromethyl)phenyl)imidazolidine-
  • Step 5 Synthesis of tert-butyl (lH-pyrrolo[2,3-b]pyridine-6-yl)carbamate
  • Step 6 Synthesis of tert-butyl methyl(l-methyl-lH-pyrrolo[2,3-b]pyridine-6- yl)carbamate
  • Step 9 Synthesis of 2-(2-oxoimidazolidin-l-yl)-4,6-bis(trifluoromethyl)phenyl N- methyl-N- ⁇ 1 -methyl- lH-pyrrolo[2,3-b]pyridin-6-yl (carbamate
  • Step 1 Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane
  • a solution of l-bromo-2,4-bis(trifluoromethyl)benzene (25.0 g, 85.3 mmol, 1.0 eq) in dioxane (300 mb) was purged with Ni and then added bispinacolatodiboron (43.4 g, 170.6 mmol, 2.0 eq), potassium acetate (16.8 g, 170.6 mmol, 2.0 eq) and Pd(dppf)Ch.DCM (2.4 g, 8.53 mmol, 0.1 eq) with stirring under inert atmosphere.
  • Step 4 Synthesis of 1 -(2 -hydroxy-3, 5-bis(trifluoromethyl)phenyl)-3-(3- hydroxyethyl)imidazolidine-2-one
  • Step 5 Synthesis of l-(2-benzyloxy-3,5-bis(trifluoromethyl)phenyl)-3-(3- hydroxyethyl)imidazolidine-2-one
  • Step 6 Synthesis of l-(2-(benzyloxy)-3,5-bis(trifluoromethyl)phenyl)-3-(2-tert- butyldimethylsilyl)oxy)ethyl)imidazolidine-2-one
  • Step 9 Synthesis of 2-(3-(2-hydroxyethyl)-2-oxoimidazolidin-l-yl)-4,6- bis(trifluoromethyl)phenyl (4-fluorophenyl)(methyl)carbamate
  • Step 13 Synthesis of 2-(3-(2-(((4-fluorophenyl)(methyl)carbamoyl)oxy)-3, 5- bis(trifluoromethyl)phenyl)-2-oxoimidazolidin- 1 -y l)ethy 1 (2-(2-(2-(2- aminoehoxy)ethoxy)ethoxy)acetyl)sulfamate
  • Step 4 Synthesis of cyclopropyl(4-fluorophenyl)carbamic chloride
  • Step 5 Synthesis of 2-iodo-4,6-bis(trifluoromethyl)phenyl cyclopropyl(4- fluorophenyl)carbamate
  • 2-iodo-4,6-bis(trifluoromethyl)phenyl cyclopropyl(4-fluorophenyl)carbamate (0.2 g, 0.00037 mol), 2-imidazilidinone (0.064 g, 0.0007 mol), copper (I)-iodide (0.035 g, 0.00018 mol), N,N’ -dimethylethylenediamine (0.04 mL, 0.00037 mol), caesium fluoride (0.11 g, 0.00075 mol) and potassium carbonate (0.1 g, 0.00075 mol) were suspended in 1,4-dioxane priorly purged with N2 for 30 minutes (16 mL).
  • the reaction mixture was heated at 100 °C in an oil-bath for 8 h. After completion of the reaction by TLC (Rf 0.3, 5% MeOH in DCM) the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by column chromatography (100-200 silica gel, 50-60% EtOAc in Hexane as eluent) to afford the impure compound. The impure compound was re-purified by preparative TLC(solid phase: merck, 20 x 20 cm, silicagel 60 GF254, 1mm, PLC glass plate, 2% MeOH in DCM as eluent) to afford pure title compound as white solid (36 mg, 10%).
  • Step 1 Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane
  • Step 4 Synthesis of l-(2-(difluoromethoxy)ethyl)imidazolidine-2-one
  • Step 5 Synthesis of l-(2-(difluoromethoxy)ethyl)-3-(2-hydroxy-3,5- bis(trifluoromethyl)phenyl)imidazolidine-2-one
  • Step 6 Synthesis of 2-(3-(2-(difluoromethoxy)ethyl)-2-oxoimidazolidin-l-yl)- 4,6-bis(trifluoromethyl)phenyl (4-fluorophenyl)(methyl)carbamate
  • DCM dimethyl methyl-N-(2-(difluoromethoxy)ethyl)-2-oxoimidazolidin-l-yl)- 4,6-bis(trifluoromethyl)phenyl (4-fluorophenyl)(methyl)carbamate
  • reaction solution was concentrated under reduced pressure to remove the solvent, and dissolved in DCM (3 mL). The solution was used for next step without further purification.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des dérivés de pyrrolidine et d'imidazolidine, leur utilisation dans le traitement et la prophylaxie du cancer, des compositions contenant lesdits dérivés et des procédés pour leur préparation.
EP23875684.5A 2022-10-03 2023-10-03 Inhibiteurs d'adn polymérase thêta à base de pyrrolidine et d'imidazolidine et utilisation associée Pending EP4598901A1 (fr)

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