Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the present invention relates to certain compounds that function as inhibitors of BCL6 (13- cell lymphoma 6) activity.
• the present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which BCL6 activity is implicated.
• BCL6 is a zinc finger transcription repressor that plays a key role in the formation and development of germinal centres, in which B cells undergo somatic hypermutation and recombination of the immunoglobulin genes, in order to generate diversity in antibodies against a variety of foreign antigens (Dent et al., Science, 1997, 276, 589-592). BCL6 allows the proliferation of antibody producing B cells by repressing genes involved in DNA damage response, cell cycle arrest and apoptosis.
• BCL6 mediates this repression by recruiting the corepressor proteins SMRT, NCoR and BCoR to an extended groove motif that forms along the dimer interface of the BCL6 BTB (BR-C, Ttk and Bab) domain (Ahmad et al., Mol Cell, 2003, 12, 1551-1564; Ghetu et al., Mol Cell, 2008, 29, 384-391).
• BR-C, Ttk and Bab BCL6 BTB domain
• a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
• a method of inhibiting BCL6 activity comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.
• a method of inhibiting cell proliferation, in vitro or in vivo comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
• a method of treating a disease or disorder in which BCL6 activity is implicated in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
• a method of treating a proliferative disorder in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
• a method of treating cancer in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy is provided.
• the cancer is human cancer.
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of BCL6 activity is provided.
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which BCL6 activity is implicated such as cancer, HIV, sepsis, graft-versus-host disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis or auto-immune diseases.
• the proliferative disorder is cancer, suitably a human cancer (for example haematological cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML)) and multiple myeloma, and solid tumours (including glioma, breast cancer, non-small cell lung cancer (NSCLC) and squamous cell carcinomas (SCC) (including SCC of the head and neck, oesophagus, lung and ovary)).
• haematological cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof obtainable by, or obtained by, or directly obtained by a process of preparing a compound as defined herein.
• references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e.
• a “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
• the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
• the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, selected from the following compounds: (S)-10-((5-chloro-2-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7- methyl-1, 2, 3, 4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one (Example 1a);
• Particular compounds of the present invention include any of the following compounds, or a pharmaceutically acceptable salt or solvate thereof:
• Particular compounds of the present invention include any of the following compounds, or a pharmaceutically acceptable salt or solvate thereof: (S)-10-((5-chloro-2-(4-cyclopropyl-3-oxopiperazin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3- difluoro-7-methyl-1 ,2,3,4-tetrahydro-[1 ,4]oxazepino[2,3-c]quinolin-6(7H)-one (Example 1 b);
• Particular compounds of the present invention include any of the following compounds, or a pharmaceutically acceptable salt or solvate thereof:
• Particular compounds of the present invention include any of the following compounds, or a pharmaceutically acceptable salt or solvate thereof: N-((3R,5S)-1-(5-chloro-4-(((S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-
• Particular compounds of the present invention include any of the following compounds, or a pharmaceutically acceptable salt or solvate thereof:
• Particular compounds of the present invention include any of the following compounds, or a pharmaceutically acceptable salt or solvate thereof:
• a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric, methane sulfonate or maleic acid.
• an inorganic or organic acid for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric, methane sulfonate or maleic acid.
• a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
• an alkali metal salt for example a sodium or potassium salt
• an alkaline earth metal salt for example a calcium or magnesium salt
• an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
• isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
• An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. , as (+) or (-)-isomers respectively).
• a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
• the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
• the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form.
• Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess antiproliferative activity.
• the present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions.
• H may be in any isotopic form, including 1 H, 2H(D), and 3H (T);
• C may be in any isotopic form, including 12C, 13C, and 14C;
• O may be in any isotopic form, including 16O and 18O ; and the like.
• certain compounds of the invention may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess antiproliferative activity. [0038] It is also to be understood that certain compounds of the invention may exhibit polymorphism, and that the invention encompasses all such forms that possess antiproliferative activity.
• tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro. keto enol enolate
• the compounds of the invention may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention.
• a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
• a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
• Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of invention, and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the invention.
• the present invention includes those compounds of the invention, as defined hereinbefore, when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the invention that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the invention may be a synthetically- produced compound or a metabolically-produced compound.
• a suitable pharmaceutically acceptable pro-drug of a compound of the invention is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
• pro-drug Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and
• H. Bundgaard Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al. , Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987; and i) J. Rautio, et al., Nature Reviews Drug Discov., 17, 559-587 (2016).
• a suitable pharmaceutically acceptable pro-drug of a compound of the invention that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
• An in vivo cleavable ester of a compound of the invention containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid.
• esters for carboxy include (1-6C)alkyl esters such as methyl, ethyl and tert- butyl, (1-6C)alkoxymethyl esters such as methoxymethyl esters, (1-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3- 8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1- cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-
• a suitable pharmaceutically acceptable pro-drug of a compound of the invention that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
• An in vivo cleavable ester or ether of a compound of the invention containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
• Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
• ester forming groups for a hydroxy group include (1-10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1-10C)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(1-6C) 2 carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
• Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
• a suitable pharmaceutically acceptable pro-drug of a compound of the invention that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a (1-4C)alkylamine such as methylamine, a [(1- 4C)alkyl] 2 amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a (1- 4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(1-4C)alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
• an amine such as ammonia
• a (1-4C)alkylamine such as methylamine
• a [(1- 4C)alkyl] 2 amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine
• a suitable pharmaceutically acceptable pro-drug of a compound of the invention that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
• Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with (1-10C)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
• Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin- 1-ylmethyl and
• the in vivo effects of a compound of the invention may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the invention. As stated hereinbefore, the in vivo effects of a compound of the invention may also be exerted by way of metabolism of a precursor compound (a pro-drug).
• the compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.
• reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
• a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
• the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
• an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
• a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
• a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
• the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
• an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
• a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
• an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
• a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. Resins may also be used as a protecting group.
• an esterifying group for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a
• the compounds of the invention demonstrate a pICso of 7.0 or more, in the HTRF assay described in the Examples section.
• Preferred compounds of the invention demonstrate a pIC50 of 7.5 or more.
• the more preferred compounds of the invention demonstrate a pICso of 8.0 or more.
• the most preferred compounds of the invention demonstrate a pICso of 8.5 or more.
• the compounds of Formula I may also demonstrate a pDCso of 7.0 or more (preferably 8.0 or more).
• a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
• compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
• oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
• compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
• compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
• An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
• a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
• the size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
• a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
• a parenteral route is employed.
• a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
• a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
• Oral administration may also be suitable, particularly in tablet form.
• unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
• the present invention provides compounds that function as inhibitors of BCL6 activity.
• the present invention therefore provides a method of inhibiting BCL6 activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
• the present invention also provides a method of treating a disease or disorder in which BCL6 activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.
• the present invention provides a method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
• the present invention provides a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.
• the present invention provides a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.
• the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
• the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a proliferative condition.
• the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer.
• the cancer is human cancer.
• the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of BCL6 activity (i.e. in the inhibition of BCL6 transcriptional repression and/or co-repressor binding).
• the present invention also provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the degradation of BCL6.
• the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which BCL6 activity is implicated.
• the present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.
• the present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.
• the medicament is for use in the treatment of human cancers.
• the present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of BCL6 activity (i.e. in the inhibition of BCL6 transcriptional repression and/or co repressor binding).
• the present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the degradation of BCL6.
• the present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which BCL6 activity is implicated.
• proliferative disorder and “proliferative condition” are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.
• proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumours, cancers (including breast cancer, non-small cell lung cancer (NSCLC) and squamous cell carcinomas (SCC) (including SCC of the head and neck, oesophagus, lung and ovary), leukemias (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)), lymphomas (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)), psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis.
• Any type of cell may be treated, including but not limited to, lymphatic, blood, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin.
• the anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death).
• the compounds disclosed herein, or pharmaceutically acceptable salts thereof, being inhibitors of BCL6, have potential therapeutic uses in a variety of BCL6-mediated disease states.
• BCL6 expression has been linked to a variety of lymphomas (Wagner et al. , British J Haematology, 2010, 152, 3-12).
• BCL6 is involved in chromosomal translocations in diffuse large B-cell lymphoma (DLBCL) and inhibitors of BCL6 have been reported to kill DLBCL cells (Cerchietti et al., Cancer Cell, 2010, 17, 400-411), primary low grade follicular lymphoma cells (Cardenas et al.
• BCL6 is required for the formation of follicular helper T cells (Hatzi et al., J Exp. Med., 2015, 212(4), 539-553), which raises the possibility that BCL6 inhibitors may be used to treat angioimmunoblastic T-cell lymphoma (AITL), in which BCL6 is strongly expressed (Cortes & Palomero, CurrOpin Hematol, 2016, 23, 434-443).
• AITL angioimmunoblastic T-cell lymphoma
• BCL6 has also been implicated in leukaemia cells which have acquired resistance to tyrosine kinase inhibitors (TKIs). TKIs typically fail to eradicate leukaemia-initiating cells, which may often cause recurrence of leukaemia after initial treatment. BCL6 has been identified as an important component of the TKI drug-resistance pathway in both Ph+ acute lymphoblastic leukaemia (ALL) (Duy et al., Nature, 2011, 473, 384-388) and Ph+ chronic myeloid leukaemia (CML) (Hurtz et al., J Exp Med, 2011, 208(11), 2163-2174). Inhibitors of BCL6 may therefore be used to treat ALL and CML in combination with a TKI.
• ALL Ph+ acute lymphoblastic leukaemia
• CML Ph+ chronic myeloid leukaemia
• BCL6 non-haematological, solid tumours may be treated with an inhibitor of BCL6.
• BCL6 is amplified in approximately 50% of breast tumours and is expressed in many breast cancer cell lines, including triple negative breast cancer cell lines (Walker et al., Oncogene, 2015, 34, 1073-1082).
• BCL6 is also important for the survival and proliferation of non-small cell lung cancer (NSCLC) cells, primarily due to repression of genes involved in DNA damage repair (Marullo et al., Proc 107 th Annual Meeting AACR, 2016, Abstract nr 1271 and Deb et al., Cancer Res., 2017, Apr. 4, doi: 10.1158/0008-5472.CAN-15-3052).
• NSCLC non-small cell lung cancer
• BCL6 amplification may also be prevalent in squamous cell carcinomas (SCC) (including SCC of the head & neck, oesophagus, lung and ovary). Furthermore, inhibition of BCL6 has recently been reported to be a suitable therapeutic target for glioma and glioblastoma (Xu et al., Proc. Natl. Acad. Sci. U.S.A, 2017, 114(15), 3981-3986; Fabre et al., PLoS One, 2020, 15(4): e0231470).
• a compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of haematological cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), and chronic myeloid leukaemia (CML)) and multiple myeloma, and of solid tumours (including glioma, breast cancer, non-small cell lung cancer (NSCLC) and squamous cell carcinomas (SCC) (including SCC of the head and neck, oesophagus, lung and ovary)).
• haematological cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt
• a compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of DLBCL and FL is provided.
• a compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of solid tumours including glioma, breast cancer, NSCLC and SCC.
• a method for treating haematological cancers such as lymphomas (including DLBCL, FL, BL and AITL), leukaemias (including ALL, AML and CML) and multiple myeloma, and of solid tumours (including glioma, breast cancer, NSCLC and SCC (including SCC of the head and neck, oesophagus, lung and ovary)) in a warm-blooded animal such as man that is in need of such treatment, which comprises administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.
• haematological cancers such as lymphomas (including DLBCL, FL, BL and AITL), leukaemias (including ALL, AML and CML) and multiple myeloma
• solid tumours including glioma, breast cancer, NSCLC and SCC (including SCC of the head and neck, oesophagus, lung and ovary)
• a warm-blooded animal such as
• lymphomas including DLBCL, FL, BL and AITL
• a method for treating lymphomas comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.
• a method for treating DLBCL and FL, in a warm-blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.
• a method for treating leukaemias including ALL, AML and CML, in a warm-blooded animal such as man that is in need of such treatment, which comprises administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.
• a method for treating solid tumours comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.
• a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of haematological cancers such as lymphomas (including DLBCL, FL, BL and AITL), leukaemias (including ALL, AML and CML) and multiple myeloma, and of solid tumours (including glioma, breast cancer, NSCLC and SCC (including SCC of the head and neck, oesophagus, lung and ovary)).
• haematological cancers such as lymphomas (including DLBCL, FL, BL and AITL), leukaemias (including ALL, AML and CML) and multiple myeloma, and of solid tumours (including glioma, breast cancer, NSCLC and SCC (including SCC of the head and neck, oesophagus, lung and ovary)).
• BCL6 has also been linked to other disease states outside the cancer field. These include HIV (Cai et al, J. Virol., 2019, 93, e01073/1 -e01073/15), sepsis (Zhang et al., Int. Immunopharmacol., 2019, 75, 105789), graft-versus-host disease (Paz et al. Blood, 2019, 133, 94-99), non-alcoholic fatty liver disease including non-alcoholic steatohepatitis (Sommars et al., eLife, 2019, 8, e43922/1-e43922/25; Chikada et al., Sci.
• auto-immune diseases or conditions include rheumatoid arthritis, systemic lupus erythematosis, Graves’ disease, autoimmune haemolytic anaemia, multiple sclerosis, Type 1 diabetes, Goodpasture’s syndrome, Hashimoto’s thyroiditis, Guillain-Barre syndrome, immune thrombocytic purpura, atherosclerosis, Crohn’s disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, seronegative spondylarthropathies, autoimmune thyroiditis, Sjogren's syndrome, Hughes' syndrome, psoriasis, psoriatic arthritis, myasthenia gravis, thrombocytopenic purpura, Addison's disease, primary biliary cirrhosis, diffuse scleroderma, polymyositis, dermatomyositis, autoimmune hepatitis, autoimmune sclerosing cholangitis,
• the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of auto-immune diseases (such as rheumatoid arthritis, systemic lupus erythematosis, Graves’ disease, autoimmune haemolytic anaemia, multiple sclerosis, Type 1 diabetes, Goodpasture’s syndrome, Hashimoto’s thyroiditis, Guillain-Barre syndrome, immune thrombocytic purpura, atherosclerosis, Crohn’s disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, seronegative spondylarthropathies, autoimmune thyroiditis, Sjogren's syndrome, Hughes' syndrome, psoriasis, psoriatic arthritis, myasthenia gravis, thrombocytopenic purpura, Addison's disease, primary biliary cirrhosis,
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for use in the treatment of auto-immune diseases (such as rheumatoid arthritis, systemic lupus erythematosis, Graves’ disease, autoimmune haemolytic anaemia, multiple sclerosis, Type 1 diabetes, Goodpasture’s syndrome, Hashimoto’s thyroiditis, Guillain-Barre syndrome, immune thrombocytic purpura, atherosclerosis, Crohn’s disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, seronegative spondylarthropathies, autoimmune thyroiditis, Sjogren's syndrome, Hughes' syndrome, psoriasis, psoriatic arthritis, myasthenia gravis, thrombocytopenic purpura, Addison's disease, primary
• auto-immune diseases such as rheum
• a method of treating auto-immune diseases such as rheumatoid arthritis, systemic lupus erythematosis, Graves’ disease, autoimmune haemolytic anaemia, multiple sclerosis, Type 1 diabetes, Goodpasture’s syndrome, Hashimoto’s thyroiditis, Guillain-Barre syndrome, immune thrombocytic purpura, atherosclerosis, Crohn’s disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, seronegative spondylarthropathies, autoimmune thyroiditis, Sjogren's syndrome, Hughes' syndrome, psoriasis, psoriatic arthritis, myasthenia gravis, thrombocytopenic purpura, Addison's disease, primary biliary cirrhosis, diffuse scleroderma, polymyositis, dermatomyositis, autoimmune hepatitis
• auto-immune diseases such as
• the compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically, peripherally or topically (i.e. , at the site of desired action).
• Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intraderrmal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, sub
• the antiproliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
• Such chemotherapy may include one or more of the following categories of anti-tumour agents:-
• antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example cytarabine, gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like
• cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), steroid hormones, including progestogens (for example megestrol acetate) and corticosteroids (for example dexamethasone, prednisone and prednisolone), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;
• antioestrogens for example tamoxifen, fulvestrant, toremif
• anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquin- azoline (AZD0530; International Patent Application WO 01/94341), A/-(2-chloro-6-methylphenyl)- 2- ⁇ 6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino ⁇ thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem..
• inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et ai (Critical reviews in oncology/haematology, 2005, Vol.
• inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as A/-(3-chloro-4-fluorophenyl)-7- methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), A/-(3-ethynylphenyl)- 6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-/ ⁇ /-(3-chloro- 4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of
• antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1- ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide,
• an endothelin receptor antagonist for example zibotentan (ZD4054) or atrasentan;
• inhibitors of DNA damage response (DDR) pathways for example inhibitors of ATM (such as KU-60019, M3541, AZD0156 or AZD1390) and ATR (such as M6620, AZD6738 or BAY1895344);
• ATM such as KU-60019, M3541, AZD0156 or AZD1390
• ATR such as M6620, AZD6738 or BAY1895344
• antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
• (x) gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
• GDEPT gene-directed enzyme pro-drug therapy
• immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines, approaches using anti-idiotypic antibodies and approaches using checkpoint inhibitors (such as inhibitors targeting CTLA-4 (e.g. ipilimumab), PD-1 (e.g. nivolumab, pembrolizumab or cemiplimab) or PD-L1 (e.g. atezolizumab, avelumab or durvalumab)).
• cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
• the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more anti-tumour agents selected from procarbazine, carmustine, cytarabine, lomustine, irinotecan, temozolomide, cisplatin, carboplatin, doxorubicin, methotrexate, etoposide, cyclophosphamide, ifosfamide, and vincristine.
• the chemotherapy may include one or more anti-tumour agents selected from procarbazine, carmustine, cytarabine, lomustine, irinotecan, temozolomide, cisplatin, carboplatin, doxorubicin, methotrexate, etoposide, cyclophosphamide, ifosfamide, and vincristine.
• the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more chemotherapeutic agents selected from a BCL-2 family inhibitor (e.g. Venetoclax and/or navitoclax), a BTK inhibitor (e.g. Ibrutinib, Acalabrutinib, Tirabrutinib (ONO/GS-4059), BGB-3111 or Spebrutinib (CC-292), a TNF inhibitor (e.g. Lenalidomide), an EZH2 inhibitor (e.g.
• a BCL-2 family inhibitor e.g. Venetoclax and/or navitoclax
• a BTK inhibitor e.g. Ibrutinib, Acalabrutinib, Tirabrutinib (ONO/GS-4059), BGB-3111 or Spebrutinib (CC-292
• TNF inhibitor e.g. Le
• Tazemetostat CPI-0209, CPI-1205, DS- 3201, HH2853 PF-06821497, GSK126, GSK343, SHR2554 or EPZ011989), a corticosteroid (e.g. dexamethasone, prednisone or prednisolone), a HDAC inhibitor (e.g. panobinostat, entinostat, romidepsin, belinostat or vorinostat), an ATR or ATM kinase inhibitor and an EGFR tyrosine kinase inhibitor.
• a corticosteroid e.g. dexamethasone, prednisone or prednisolone
• HDAC inhibitor e.g. panobinostat, entinostat, romidepsin, belinostat or vorinostat
• ATR or ATM kinase inhibitor e.g., EGFR tyrosine kinase
• Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
• Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
• a combination for use in the treatment of a cancer comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and another anti-tumour agent.
• a combination for use in the treatment of a proliferative condition such as cancer (for example a cancer involving a solid tumour), comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and any one of the anti-tumour agents listed herein above.
• a combination for use in the treatment of a cancer comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a tyrosine kinase inhibitor.
• a combination for use in the treatment of leukaemia comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a tyrosine kinase inhibitor.
• a combination for use in the treatment of lymphomas comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and an EZH2 inhibitor.
• a combination for use in the treatment of cancer comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a corticosteroid.
• a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.
• a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of cancer in combination with a tyrosine kinase inhibitor, optionally selected from one listed herein above.
• a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of leukaemia (such as ALL or CML) in combination with a tyrosine kinase inhibitor, optionally selected from one listed herein above.
• leukaemia such as ALL or CML
• tyrosine kinase inhibitor optionally selected from one listed herein above.
• a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of cancer in combination with an EZH2 inhibitor, optionally selected from one listed herein above.
• a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of lymphomas in combination with an EZH2 inhibitor, optionally selected from one listed herein above.
• a pharmaceutical composition which comprises a compound of the invention, ora pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with an anti-tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.
• Figure 1 shows the flow cytometry splenocyte hierarchical gating strategy: GC B cells were gated according to the following hierarchical gating strategy: viable->single cell (doublet exclusion)-» lymphocytes-» CD19+CD20+ ->GL7+CD95+ (light squares); non-GC B cells were gated according to the following hierarchical gating strategy: viable-»single cell (doublet exclusion)-» lymphocytes-» CD19+CD20+ ->GL7-CD95- (dark squares).
• FIG. 2 shows the flow cytometry expression levels of BCL6 (geometric mean fluorescence intensity - GeoMFI) in non-GC B cells, without (vehicle) or with Example 4b at various concentrations. Stimulated and unstimulated B cell BCL6 expression is indicated with the upper and middle dashed lines respectively, while the lower dashed line represents the biological background expression for CD4 stimulated T cells.
• BCL6 geometric mean fluorescence intensity - GeoMFI
• Figure 3 shows the flow cytometry expression levels of Blimp (geometric mean fluorescence intensity - GeoMFI) in GC B cells, without (vehicle) or with Example 4b at various concentrations. Unstimulated and stimulated non-GC B cell Blimp expression is indicated with the dashed line.
• Figure 4 shows the number of GC B cells as defined by the expression of the lineage markers GL7 and CD95 on CD19+CD21+ spleen cells without (vehicle) or with Example 4b (at 10 ⁇ M).
• SCX-2 strong cation exchange e.g. Isolute® SCX-2 columns
• t triplet in NMR spectrum
• LC/MS and HRMS analysis was performed on an Agilent 1200 series HPLC and diode array detector coupled to a 6210 time of flight mass spectrometer with dual multimode APCI/ESI source.
• Analytical separation was carried out at 40°C on a Merck Chromolith Flash column (RP- 18e, 25 x 2 mm) using a flow rate of 1.5 mL/min in a 2 minute gradient elution with detection at 254 nm.
• the mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing formic acid at 0.1%.
• LC/MS and HRMS analysis was performed on a Waters Acquity UPLC and diode array detector coupled to a Waters G2 QToF mass spectrometer fitted with a multimode ESI/APCI source.
• Analytical separation was carried out at 30°C on a Phenomenex Kinetex C18 column (30 x 2.1 mm, 2.6u, 100A) using a flow rate of 0.5 mL/min in a 2 minute gradient elution with detection at 254 nm.
• the mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing formic acid at 0.1%.
• NMR data was collected on a Bruker Avance 500 spectrometer equipped with a 5 mm BBO/QNP probe, or on a Bruker Avance Neo 600 spectrometer equipped with a 5 mm TCI Cryo- Probe.
• the 1 H and 13 C spectra were referenced to the internal deuterated solvent. All NMR data were acquired at the temperature of 298 K. All data were acquired and processed using Bruker Topspin 2.1 or Bruker Topspin 4.
• the 1 H NMR spectra were acquired using a Bruker standard 1D zg30 pulse sequence with 16 scans.
• the sweep width was 20.5 ppm, and the FID contained 64k time-domain data points.
• Flash column chromatography was carried out using prepacked Biotage SNAP KP-Sil columns. Reverse phase chromatography was carried out using a Biotage SNAP Ultra C-18 12g and 30g columns as required.
• Example 1a (S)-10-((5-chloro-2-(3.3-difluoroazetidin-1-yl)pyrimidin-4-yl)amino)-2- cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)- one [00139] A mixture of (S)-2-cyclopropyl-10-((2,5-dichloropyrimidin-4-yl)amino)-3,3-difluoro-7- methyl-1, 2, 3, 4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one (Intermediate A1, 11.5 mg, 0.025 mmol), 3,3-difluoroazetidine hydrochloride (8 mg, 0.062 mmol) and DIPEA (80 ⁇ l , 0.46 mmol
• Example 1a The following tabulated examples were prepared by a method analogous to that used for the preparation of Example 1a, using the appropriate amine (as free base or as hydrochloride salt).
• the reaction mixtures were heated to 140 °C for 1 - 2h using microwave irradiation.
• examples 1f — 11 the reaction mixtures were heated to 80 °C for 1.5 - 3h. Purification was carried out by reverse-phase chromatography, and in some cases products were desalted using an SCX-2 column.
• Example 2a (S)-2-cyclopropyl-3,3-difluoro-10-((5-fluoro-2-((3R,5S)-3-hydroxy-5- methylpiperidin-1 -yl)pyrimidin-4-yl)amino)-7-methyl-1 ,2.3.4-tetrahydro-H ,41oxazepinor2,3- c1quinolin-6(7H)-one
• Example 2b (S)-2-cyclopropyl-10-((2-(4,4-difluoropiperidin-1 -yl)-5-fluoropyrimidin-4- vl)amino)-3,3-difluoro-7-methvl-1,2,3,4-tetrahvdro-M,4loxazepino[2,3-c]quinolin-6(7H)-one
• the resulting mixture was purified by reverse-phase flash chromatography (40% - 85% methanol in water (0.1% formic acid)). Fractions containing product were loaded onto an Isolute SCX-2 column (1 g), and the column was washed with methanol and then eluted with 20% 1.4 M methanolic ammonia. The product was further purified by flash column chromatography (3-10% methanol in DCM), and the fractions containing product were combined, the solvent removed under reduced pressure to yield the title compound (18.5 mg).
• Example 3a (S)-10-((2-(3-oxa-8-azabicvclor3.2.noctan-8-yl)-5-chloropyrimidin-4- yl)amino)-2-cyclopropyl-3.3-difluoro-7-(methyl-d3)-1,2.3.4-tetrahydro-[1,4]oxazepinor2.3- c][1,8]naphthyridin-6(7H)-one [00143] A mixture of 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (13.4 mg, 0.09 mmol), DIPEA (23 ⁇ L , 0.13 mmol) and (S)-2-cyclopropyl-10-((2,5-dichloropyrimidin-4-yl)amino)- 3,3-difluoro-7-(methyl-d3)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c][
• Example 4a (S)-10-((5-chloro-2-(3-methyl-1.2.4-oxadiazol-5-yl)pyridin-4-yl)amino)-2- cyclopropyl-3.3-difluoro-7-methyl-1.2.3.4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)- one
• Example 4b (S)-10-((3-chloro-2-fluoropyridin-4-yl)amino)-2-cyclopropyl-3.3-difluoro-7- methyl-1.2.3.4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one
• Example 4b was also prepared by the following procedure; (S)-10-amino-2-cyclopropyl- 3,3-difluoro-7-methyl-1 ,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one (Intermediate B1 , 1.7 g, 5.3 mmol), 4-bromo-3-chloro-2-fluoropyridine (1.41 g, 6.7 mmol), palladium (II) acetate (0.143 g, 0.64 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.456 g, 0.79 mmol) and cesium carbonate (2.7 g, 8.29 mmol) were combined under N 2 in 1,4-dioxane (50mL) and the resulting mixture was heated at reflux for 2 h.
• the resulting mixture was heated to 80°C for 1 h, then cooled to rt. Water (15 mL) was added and the aqueous mixture was extracted with DCM (4 x 10 mL). The organic extracts were combined, washed with brine (10 mL), dried (Na 2 SO 4 ), and stirred overnight with MP-TMT to remove residual Pd. The beads were removed by filtration, washing with DCM, and the combined filtrate was concentrated under reduced pressure.
• Example 4d (S)-10-((2-chloro-3-fluoropyridin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7- methyl-1.2.3.4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one v00148]
• Example 4d was prepared by a method analogous to that used for the synthesis of example 4b, using 2-chloro-3-fluoro-4-iodo-pyridine.
• the resulting mixture was heated at 140°C under microwave irradiation for 90 min, then further heated at 100 °C for 6 h, then again at 140 °C for 3 hours.
• the reaction mixture was cooled to rt, concentrated under reduced pressure, redissolved in DCM ( ⁇ 20 mL) and washed with water (2 x 10 mL).
• the solvent was removed under reduced pressure and the reaction was purified by column chromatography (0% to 10% methanol in DCM) affording a dark orange oil.
• the product was loaded onto an Isolute SCX-2 column (2 g), and the column was washed with methanol and then eluted with 20% 1.4 M methanolic ammonia.
• Example 5a (S)-2-cyclopropyl-3.3-difluoro-10-((5-fluoro-2-((1R,5S.7R)-7-hydroxy-3-oxa-9- azabicvclo[3.3.1]nonan-9-yl)pyrimidin-4-yl)amino)-7-methyl-1.2.3.4-tetrahydro-
• Step 2 (1R,5S, 7s)-9-(5-fluoro-4-(methylthio)pyrimidin-2-yl)-3-oxa-9-azabicyclo[3.3. 1lnonan-7-ol fendo isomer 1
• Step 3 ( 1R.5S, 7s)-9-(5-fluoro-4-(methylsulfonyl)pyrimidin-2-yl)-3-oxa-9-azabicyclo[3.3. 11- nonan-7-ol fendo isomer 1
• Reaction mixture was diluted with DCM (30 mL) and the organic mixture was washed with 1 M sodium sulfite (30 mL) and sat. aq. NaHCOs (20 mL). The aq. washings were combined and extracted with DCM (20 mL). The organic extracts were combined, dried (Na 2 S0 4 ) and concentrated in vacuo. Purification by flash chromatography (10 g KP-sil; 0% to 10% MeOH in DCM) afforded the title compound (0.25 g, 106%) as a sticky yellow solid, which was used without further purification in the subsequent steps.
• Step 4 (S)-2-cvclopropyl-3,3-difluoro-10-((5-fluoro-2-(( 1R,5S, 7R)-7-hydroxy-3-oxa-9- azabicyclo[3.3. nnonan-9-yl)pyrimidin-4-yl)amino)-7-methyl-1 ,2,3,4-tetrahydro-
• Example 7a (2S)-10-((2-(3-acetyl-3.8-diazabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4- yl)amino)-2-cyclopropyl-3,3-difluoro-7-methvl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3- c]quinolin-6(7H)-one and;
• Example 7b (2S)-10-((2-(8-acetyl-3.8-diazabicyclo[3.2.1]octan-3-yl)-5-chloropyrimidin-4- yl)amino)-2-cyclopropyl-3.3-difluoro-7-methyl-1.2.3.4-tetrahydro-[1,4]oxazepinor2,3- c]quinolin-6(7H)-one
• Step 1 tert-butyl 3-acetyl-3,8-diazabicyclo[3.2. 1loctane-8-carboxylate
• Step 2 1 -(3,8-diazabicyclo[3.2. 1loctan-3-yi)ethan-1-one hydrochloride
• 4 M HCI in 1,4-dioxane (3.50 mL, 14 mmol) was added dropwise to a solution of tert- butyl 3-acetyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (from Step 1, 266 mg, 1.05 mmol) in DCM (5 mL) at 0 °C.
• Step 3 (2S)-10-((2-(8-acetyl-3, 8-diazabicyclo[3.2.1loctan-3-yl)-5-chloropyrimidin-4-yl)amino)-2- cyclopropyl-3, 3-difluoro-7-methyl-1 ,2, 3, 4-tetrahydro-[1,4]oxazepino[2, 3-clquinolin-6(7H)-one and (2S)-10-((2-(3-acetyl-3, 8-diazabicyclo[3.2.
• reaction mixture was dissolved in DMSO (0.8 mL) and purified by reverse-phase chromatography (Biotage 12 g Ultra C-18 column; 10-60-80-100% methanol in water (0.1% formic acid modifier)). Fractions containing product were combined and passed through an SCX-2 (2g) column, washing with methanol (10 mL) and eluting with 2M methanolic ammonia (30 mL). The ammonia fractions were combined and evaporated under reduced pressure to give a mixture of regioisomers.
• Example 8a (S)-10-((5-chloro-2-(dimethylamino)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3- difluoro-7-methvl-1,2,3,4-tetrahvdro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one
• Example 9a (S)-10-((5-chloro-2-((3S.5R)-3-fluoro-5-hydroxypiperidin-1 -yl)pyrimidin-4- yl)amino)-2-cyclopropyl-3.3-difluoro-7-methyl-1,2.3.4-tetrahydro-[1,4]oxazepino[2.3- c]quinolin-6(7H)-one: (S)-10-((5-chloro-2-((3R.5S)-3-fluoro-5-hydroxypiperidin-1 - yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3.3-difluoro-7-methyl-1,2.3.4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one(1 :1) [00159] A mixture of (S)-2-cyclopropyl-10-((2,5-dichloropyrimidin
• Example 9a-1 (S)-10-((5-chloro-2-((3S,5R)-3-fluoro-5-hydroxypiperidin-1-yl)pyrimidin-4- yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1 ,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin- 6(7H)-one, and
• Example 9a-2 (S)-10-((5-chloro-2-((3R,5S)-3-fluoro-5-hydroxypiperidin-1- yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1 ,2,3,4-tetrahydro- [1,4]oxazepino[2,3-c]quinolin-6(7H)-one
• example 9a The preparation of example 9a was repeated on larger scale to provide a further 21 mg of this mixture of diastereoisomers, which was separated by preparative HPLC (column and conditions as above, over a 30 minute isocratic elution with 55% methanol in water (modified with 0.1% formic acid). Fractions containing only the earlier-running diastereoisomer were combined and evaporated to give example 9a-1 as a beige solid (6.5 mg). Fractions containing only the later-running diastereoisomer were combined and evaporated to give example 9a-2 as a beige solid (4.5 mg). Both compounds are c/s-piperidine diastereoisomers, but absolute stereochemistry has not been unambiguously determined and is provisionally assigned as shown above.
• Example 9a The following tabulated examples were prepared by a method analogous to that used for the preparation of Example 9a. 1-1.5 eq of the appropriate amine (as free base or as hydrochloride salt) was used. Amines used were racemic, leading to a mixture of isomers as shown. Potassium carbonate (3 - 4 eq) was used in place of DI PEA, and acetonitrile was used as solvent. Heating times were 4 - 5h at 140 - 150 °C in the microwave.
• Example 10d used (S)- 10-((2-chloro-5-fluoropyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1, 2,3,4- tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one (Intermediate A2), and was heated to 140 °C for 16 hours.
• Example 11a (2S)-10-rr5-chloro-2-(4-methyl-1.4-diazepan-1-yl)pyrimidin-4-vnamino1-2- cyclopropvl-3,3-difluoro-7-methvl-2,4-dihvdro-1H-M,4loxazepino[2,3-c]quinolin-6(7H)-one
• Example 11a The following tabulated examples were prepared by a method analogous to that used for the preparation of Example 11a.
• Amines were obtained from commercial vendors and used as free base or hydrochloride salt. Some amines were used as racemates, leading to a mixture of isomers as shown.
• the reactions were heated to 140 °C in the microwave.
• examples 12b and 12c (3S,5R)-3-(Boc-amino)-5- methylpiperidine or (3R,5S)-3-(Boc-amino)-5-methylpiperidine were used. Boc groups were removed by treatment with TFA in DCM at room temperature to give the products shown.
• Example 12e was further heated to 160 °C in the microwave for 4 hours.
• examples 12x01-12x50 may be prepared by methods analogous to those previously described for examples 9a, 11a or 12a.
• Amines may be obtained from commercial vendors or prepared by known methods, and used as free base or hydrochloride salt. Some amines were used as racemates, leading to a mixture of isomers as shown.
• Protecting groups may be used to mask reactive functionality; for example in the preparation of example 12x14 tert- butyl 6-hydroxy-1,4-diazepane-1-carboxylate was used, and the Boc group was removed by treatment with TFA in DCM at room temperature.
• Example 13a (S)-10-((5-chloro-2-((3R.5S)-3-hydroxy-5-methylpiperidin-1-yl)Pyridin-4- yl)amino)-2-cyclopropyl-3.3-difluoro-7-methyl-1.2.3.4-tetrahydro-[1,4]oxazepino[2,3- c]quinolin-6(7H)-one
• Step 2 (S)- 10-((5-chloro-2-((3R, 5S)-3-hydroxy-5-methylpiperidin- 1 -yl)pyridin-4-yl)amino)-2- cyclopropyl-3, 3-difluoro-7-methyl- 1,2, 3, 4-tetrahydro-[ 1, 4]oxazepino[2, 3-c]quinolin-6(7H)-one
• Reaction mixture loaded directly onto a reverse phase column and purified (30 - 60% MeOH in water, 0.1% formic acid), then further purified by flash column chromatography ( (1 - 10% MeOH in DCM, 10 g KP Sil) to give the title compound (3 mg).
• Example 13b ((S)-10-((5-chloro-2-(4.4-difluoropiperidin-1-yl)Pyridin-4-yl)amino)-2- cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)- one [00170]
• Example 13b was prepared by a two-step procedure analogous to that used to prepare example 12a.
• Example 13p01 was prepared by analogy to example 2a, with heating to 120 °C for 4 days.
• LCMS (method X4) rt 3.46min, m/z calculated 565.2350 for C 27 H 30 F 5 N 6 O 2 [M+H]+, found 565.2383.
• Example 13p06 was prepared by analogy to example 2a, with heating to 120 °C for 4 days.
• LCMS (method T4) rt 2.37min, m/z calculated 503.2013 for C 24 H 26 F 3 N 6 O 3 [M+H] + , found 503.2014.
• Example 13p08 was prepared by analogy to example 2a, with heating to 120 °C for 4 days.
• Example 13p11 was prepared by analogy to example 9a, with additional heating to 160 °C for 8h, then to 180 °C for 3h.
• LCMS (method X4) rt 2.71 min; m/z calculated 529.2175 for C 26 H 28 CIF 3 N 6 0 3 + [M+H] + , found 529.2155.
• Example 13p12 was prepared by analogy to example 9a.
• LCMS (method T4) rt 2.00 min; m/z calculated 461.1907 for C 22 H 24 F 3 N 6 O 2 [M+H] + , found 461.1909.
• Example 13c06 was prepared by analogy to example 4a: To a mixture of (S)-10-amino-2- cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one (Intermediate B1, 16.5 mg, 0.051 mmol), 4-(5-fluoro-4-iodopyridin-2-yl)morpholine (Intermediate C4, 24.5 mg, 0.076 mmol), dicesium carbonate (126 mg, 0.39 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.7 mg, 0.005 mmol), and xantphos (18.7 mg, 0.032 mmol) under argon was added DMF (0.3 mL) and toluene (0.3 mL).
• Example 13c08 was prepared by analogy to example 4a: To a mixture of (S)-10-amino-2- cyclopropyl-3,3-difluoro-7-methyl-1 ,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one (Intermediate B1, 16.5 mg, 0.051 mmol), (S)-4-(5-fluoro-4-iodopyridin-2-yl)-2-methylmorpholine (Intermediate C5, 25.7 mg, 0.076 mmol), dicesium carbonate (126 mg, 0.39 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.7 mg, 0.005 mmol), and xantphos (18.7 mg, 0.032 mmol) under argon was added DMF (0.3 mL) and toluene (0.3 mL).
• Example 13c12 was prepared by analogy to example 4a: To a mixture of (S)-10-amino-2- cyclopropyl-3,3-difluoro-7-methyl-1 ,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one (Intermediate B1, 16.5 mg, 0.051 mmol), 5-chloro-4-iodo-N,N-dimethylpyridin-2-amine
• Example 13f04 was prepared as mono-formic acid salt by analogy to example 4a: To a mixture of (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1 ,2,3,4-tetrahydro-[1 ,4]oxazepino[2,3- c]quinolin-6(7H)-one (Intermediate B1, 10 mg, 0.031 mmol), 2-(4,4-difluoropiperidin-1-yl)-5- fluoro-4-iodopyridine (Intermediate C2, 10.7 mg, 0.031 mmol), dicesium carbonate (41 mg, 0.125 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.7 mg, 0.004 mmol), and xantphos (4.5 mg, 0.008 mmol) under argon was added DMF (0.3 mL) and Toluene (0.3 mL).
• Example 13f05 was prepared by analogy to example 13f04 from (3R,5S)-1-(5-fluoro-4- iodopyridin-2-yl)-5-methylpiperidin-3-ol (prepared by analogy to intermediate C2).
• Examples 14a and 14b represent epimers at the 3-methylpiperidine centre. Each is a single compound, resulting from chiral separation of an intermediate at an earlier stage of the synthesis, but the stereochemistry of each has not been determined.
• Example 14a (S)-10-((5-chloro-2-((S).4-difluoro-3-methylpiperidin-1-yl)pyrimidin-4- yl)amino)-2-cyclopropyl-3.3-difluoro-7-methyl-1,2.3.4-tetrahydro-[1,4]oxazepino[2.3- c]quinolin-6(7H)-one or (S)-10-((5-chloro-2-((R)-4,4-difluoro-3-methylpiperidin-1 - yl)Pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro- [1,4]oxazepino[2.3-c]quinolin-6(7H)-one [00174] A vial containing (S)-4,5-dichloro-2-(4,4-difluoro-3-methylpiperidin
• reaction mixture was added to water (5 mL) and a beige precipitate formed. Additional water (10 mL) was added and the aq. mixture was stirred for 5 min. The precipitate was filtered, washed with water (100 mL) and dried, then purified by flash column chromatography (10 g KP-Sil, 0-10% methanol in DCM) affording the title compound (2.16 g, 88%) as a beige solid.
• reaction mixture was cooled to rt and 3 M HCI (0.5 mL) was added.
• the mixture was stirred at rt for 2 h, then filtered through a pad of Celite onto an SCX-2 (2 g) column, which was eluted with water (10 mL), MeOH (20 mL) and 2 N methanolic ammonia (20 mL).
• Step 1 (S)-4-((1-cvclopropyl-2,2-difluoro-3-hvdroxypropyl)amino)-1-methyl-6-nitroquinolin- 2(1H)-one
• Step 2 (S)-3-bromo-4-((1-cvclopropyl-2,2-difluoro-3-hvdroxypropyl)amino)-1 -methyl-6- nitroquinolin-2( 1H)-one
• Trifluoroacetic acid (8.83 mL) was added to a stirred mixture of (S)-4-((1 -cyclopropyl-2, 2- difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitroquinolin-2(1H)-one (from step 1; 8.15 g, 23 mmol) and freshly recrystallised N-bromosuccinimide (4.1 g, 23 mmol) in anhydrous CH2CI2 (150 mL) at 0 °C under Ar. The reaction mixture was stirred at 0 °C for 15 min. The reaction mixture was diluted with CH2CI2 (100 mL) and washed with saturated aq.
• Step 3 ( S) -2-cyclopropyl-3, 3-difluoro- 7-methyl- 10-nitro- 1,2,3, 4-tetrahydro-[1,4]oxazepino-[2, 3- c]quinolin-6(7H)-one
• the product was found to be -88% ee by chiral SFC [YMC Chiral ART Amylose-C, (4.6mm x 250mm, 5uM); 30:70 methanol:C02 (isocratic, 0.2% v/v ammonia modifier); flowrate 4 mL/min; 40 °C; detection at 210-400nm; 1 uL injection], Rt of desired (S) enantiomer 2.06min; (R) enantiomer 1.75min.
• Step 2 ethyl 4-hvdroxy-1-methyl-6-nitro-2-oxo-1,2-dihydrociuinoline-3-carboxylate
• Step 3 ethyl 4-chloro-1-methyl-6-nitro-2-oxo-1,2-dihydrociuinoline-3-carboxylate
• Phosphorus oxychloride 250 mL, 2700 mmol
• ethyl 4- hydroxy-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate 24.1 g, 82.5 mmol.
• the flask was fitted with a suba-seal and an argon balloon then heated to 80°C with stirring for 2.5 h.
• the mixture was concentrated in vacuo.
• the residue was diluted with water and extracted with EtOAc.
• Step 1 methyl 5-chloro-2-((methyl-d 3 )amino)nicotinate
• Step 2 ethyl 6-chloro-4-hvdroxy-1-(methyl-d 3 )-2-oxo-1,2-dihydro-1,8-naphthyridine-3- carboxylate
• a microwave vial (2.0-5.0 mL volume) was charged with methyl 5-chloro-2-((methyl- d3)amino)nicotinate (from step 1 ; 239 mg, 1.17 mmol).
• the reaction vial was flushed with Ar, sealed with a cap and then further flushed with Ar.
• DCM (4.5 mL) was added followed by triethylamine (0.98 mL, 7.0 mmol) and ethyl 3-chloro-3-oxopropanoate (0.6 mL, 4.7 mmol).
• the reaction mixture was heated at 60°C in a heating block for 2 h.
• Step 3 ethyl 4, 6-dichloro- 1-(methyl-d 3 )-2-oxo- 1,2-dihydro- 1, 8-naphthyridine-3-carboxylate
• Phosphorus oxychloride (3.5 mL, 37.4 mmol) was added to a flask containing ethyl 6- chloro-4-hydroxy-1-(methyl-d 3 )-2-oxo-1 ,2-dihydro-1 ,8-naphthyridine-3-carboxylate (from step 2; 335 mg, 1.2 mmol).
• the flash was fitted with a reflux condenser with a suba-seal and an argon balloon then heated to 80°C with stirring for 2.5 h. The reaction mixture was cooled to rt and concentrated in vacuo.
• Intermediate L1a and Intermediate L1b represent a pair of enantiomers where one is the ( R )- and the other is the (S)-methyl-piperidine. It has not been determined which is the ( R )- and which is the (S)-enantiomer.
• the compounds were separated by preparative chiral SFC during Step 3 using the method described below.
• Step 2 rac-5-chioro-2-(4, 4-difluoro-3-methylpiperidin- 1-yl)pyrimidin-4-ol
• a microwave vial (10-20 mL volume) was charged with 2,5-dichloropyrimidin-4-ol (from step 1 ; 502 mg, 3.0 mmol) and rac-4,4-difluoro-3-methylpiperidine hydrochloride (522 mg, 3.0 mmol).
• the reaction vial was flushed with Ar, sealed with a cap and then further flushed with Ar.
• Ethanol (5 mL) was added followed by DIPEA (1.4 mL, 8.0 mmol).
• the reaction mixture was heated at 80°C in a heating block for 10 h.
• the reaction mixture was concentrated in vacuo.

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