[go: up one dir, main page]

WO2024245578A1 - Combinaisons thérapeutiques d'un inhibiteur de btk irréversible et d'un inhibiteur de btk réversible macrocyclique - Google Patents

Combinaisons thérapeutiques d'un inhibiteur de btk irréversible et d'un inhibiteur de btk réversible macrocyclique Download PDF

Info

Publication number
WO2024245578A1
WO2024245578A1 PCT/EP2023/064844 EP2023064844W WO2024245578A1 WO 2024245578 A1 WO2024245578 A1 WO 2024245578A1 EP 2023064844 W EP2023064844 W EP 2023064844W WO 2024245578 A1 WO2024245578 A1 WO 2024245578A1
Authority
WO
WIPO (PCT)
Prior art keywords
combination
btk
btk inhibitor
formula
subject
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
PCT/EP2023/064844
Other languages
English (en)
Inventor
Erik ENSING
Rogier Christian Buijsman
Martine Berendina Wilhemina PRINSEN
Winfried Robert Mulder
Michelle MULLER
Yvonne Gertruda Theodora Hendrika VAN MIL
Adrianus Petrus Antonius De Man
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.)
Netherlands Translational Research Center BV
Original Assignee
Netherlands Translational Research Center BV
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 Netherlands Translational Research Center BV filed Critical Netherlands Translational Research Center BV
Priority to PCT/EP2023/064844 priority Critical patent/WO2024245578A1/fr
Publication of WO2024245578A1 publication Critical patent/WO2024245578A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to therapeutic combinations of an irreversible BTK inhibitor and a macrocyclic reversible BTK inhibitor and relates to a method for treating a subject having a hyperproliferative disease, in particular a B-cell hematological malignancy, which subject receives or has received a Bruton’s tyrosine kinase (BTK) inhibitor for treatment of the hyperproliferative disease, using said therapeutic combinations.
  • the present invention further relates to a method of treating a subject diagnosed with or at risk of a recurrent or refractory form of a hyperproliferative disease, in particular a B-cell hematological malignancy, which subject has previously been treated with an irreversible BTK inhibitor, using said therapeutic combinations.
  • the method comprises: a) monitoring the patient over the course of therapy to determine whether the subject has a C481 mutation in BTK and b) co- administering to the patient an irreversible and a macrocyclic reversible BTK inhibitor if the patient has a C481 mutation in BTK.
  • the invention further relates to a method for treating a subject having a hyperproliferative disease, in particular a B-cell hematological malignancy, wherein the treatment comprises administering said therapeutic combinations.
  • Kinases are enzymes that transfer a phosphate group from ATP to a protein. Kinases play an important role in regulating cellular functions such as cell proliferation, subcellular translocation, apoptosis, inflammation and metabolism (Attwood M.M. et al (2021 ) Nat Rev Drug Discov).
  • the human kinome is composed of over 500 kinases. The development of small- molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy.
  • BTK tyrosine kinase
  • BCR B-cell receptor
  • BTK small molecule inhibitors
  • small molecule inhibitors such as the FDA approved covalent, irreversible, BTK inhibitors ibrutinib, acalabrutinib, zanubrutinib and tirabrutinib
  • CLL Chronic Lymphocytic Leukemia
  • MCL Mantle Cell Lymphoma
  • WM Macroglobulinemia
  • SLL Small Lymphocytic Lymphoma SLL.
  • a drawback of the first generation BTK inhibitor, ibrutinib is that drug resistance in 13- cell malignancies can develop when BTK acquires mutations at the cysteine at position C481 of the kinase domain. This mutation abrogates the covalent binding of ibrutinib hampering its efficacy.
  • Quinquenel et al. performed a ‘snapshot’ screening to determine the prevalence of resistance mutations and found that the presence of the BTK mutation was significantly associated with subsequent CLL progression. The correlation between disease progression, and the emergence and temporal dynamics of the most common resistance inducing C481S BTK mutation have been determined for CLL patients receiving single-agent ibrutinib treatment (Bodor et al.
  • Second-generation covalent, irreversible, BTK inhibitors which include acalabrutinib, zanubrutinib, and tirabrutinib, offer greater BTK selectivity and therefore limited off-target toxicity. These inhibitors, however, do not overcome resistance by C481 mutation.
  • BTK inhibitors include LOXO-305 (pirtobrutinib) and ARQ-531 (nemtabrutinib) and vecabrutinib. These agents do not require binding to the BTK C481 residue and effectively inhibit both wild type and mutant BTK with C481 substitutions.
  • non-covalent BTK inhibitors including pirtobrutinib (LOXO-305), ARQ-351 and vecabrutinib, inhibited B-cell-receptor signaling in BTK C481 -mutant cell and animal models.
  • phase 1 -2 clinical trial of pirtobrutinib showed promising efficacy for patients with B-cell cancer who had previously been treated with covalent BTK inhibitors (with 62% of patients with CLL having a response), including patients with or without BTK C481 mutations (with a response occurring in 71 % and 66% of the patients, respectively) (Wang et al. (2022) N. Engl. J. Med. 386, 735-43).
  • Pirtobrutinib was first disclosed in WO2017/10361 1 , ARQ-531 was disclosed in WO2017/111787 and vecabrutinib is disclosed in WO2013/185084. Further reversible BTK inhibitors are disclosed in WO2017/046604, , W02020/015735, WO2020/239124, WO2021/093839, W02020/043638, WO2013/067274, WO2018097234, WO2013/010380, W02016/161570, W02016/161571 , W02016/106624, W02016/106625, W02016/106626, W02016106623, W02016/106628 and W02016/109222.
  • reversible BTK inhibitors in development are fenebrutinib (Crawford et al. 2018 and Reiff et al. 2018), BMS-986142 (Watterson et al. 2016), luxeptinib (Thieme et al. 2022 and WO2014/104757, AS-0871 (Kawahata et al. 2018 and W02015/012149), AS-1763 (Kawahata et al. 2021 and WO2018/097234) and BIIB091 (Hopkins et al. 2021 and WO2018/191577). These reversible BTK inhibitors are being developed not only for B-cell hematological malignancies, but also for immunological and inflammatory diseases.
  • a general desire of combination drug treatment in cancer therapy is to improve response rate and to decrease the probability of the development of drug resistance (Al-Lazikani et al. 2012; Yap et al. 2013 and Li et al. 2014)
  • drug combinations are synergistic rather than additive, and, ideally, drug combinations work synergistically only in cancer cells and not in non-malignant cells.
  • Cancer cell lines are an attractive model to investigate new drug combinations because they can be used to determine whether new combinations are truly synergistic, as opposed to additive (Zhao et al. 2004 and Chou 2010).
  • cancer cell lines provide a good representation of the diversity of genetic changes that drive human cancers (Garnett et al. 2012 and Barretina et al. 2013).
  • a method for treating a subject having a hyperproliferative disease preferably a B-cell hematological malignancy, which subject receives or has received a Bruton’s tyrosine kinase (BTK) inhibitor for treatment of the hyperproliferative disease, preferably an irreversible BTK inhibitor
  • the method comprising the steps: a) monitoring the subject, preferably at predetermined intervals of time, over the course of the therapy for treatment of the hyperproliferative disease to determine whether the subject has a mutation in an endogenous gene encoding BTK that results in or provides a risk of resistance of the subject to the therapy, preferably resistance of the subject to the irreversible BTK inhibitor of the (mono) therapy, preferably the subject has a mutation in an endogenous gene encoding BTK that results in expression of a BTK protein with a modification at an amino acid position corresponding to amino acid position 481 of the amino acid sequence according to SEQ ID NO: I;
  • step a) if the subject has shown said mutation, administering to the subject a therapeutically combinatory amount of an irreversible BTK inhibitor and a reversible BTK inhibitor, in particular if the subject has the BTK modification corresponding to amino acid position 481 identified in step a), wherein the reversible BTK inhibitor is a compound of Formula (l-a) to (l-h) or a pharmaceutically acceptable salt and/or solvate thereof.
  • a method for treating a subject diagnosed with or at risk of a recurrent or refractory form of a hyperproliferative disease, preferably a B-cell hematological malignancy, which subject receives or has previously been treated with an irreversible BTK inhibitor comprises administering to said subject a therapeutic combinatory amount of an irreversible BTK inhibitor and a reversible BTK inhibitor, wherein the reversible BTK inhibitor is a compound of Formula (l-a) to (l-h) or a pharmaceutically acceptable salt and/or solvate thereof.
  • a method for treating a subject having a hyperproliferative disease preferably a B-cell hematological malignancy
  • the method comprising: administering to the subject a therapeutic combinatory amount of an irreversible BTK inhibitor and a reversible BTK inhibitor, wherein the reversible BTK inhibitor is a compound of Formula (l-a) to (l-h) or a pharmaceutically acceptable salt and/or solvate thereof.
  • step b) if the subject has shown said mutation, administering to the subject a therapeutically combinatory amount of said irreversible BTK inhibitor and said reversible BTK inhibitor, in particular if the subject has the BTK modification corresponding to amino acid position 481 identified in step a) wherein the reversible BTK inhibitor is a compound of Formula (l-a) to (l-h) or a pharmaceutically acceptable salt and/or solvate thereof.
  • a combination of an irreversible BTK inhibitor and a reversible BTK inhibitor for use in a method for treating a subject diagnosed with or at risk of a recurrent or refractory form of a hyperproliferative disease, preferably a B-cell hematological malignancy, which subject receives or has previously been treated with an irreversible BTK inhibitor, and wherein the method comprises administering to said subject a therapeutic combinatory amount of said irreversible BTK inhibitor and said reversible BTK inhibitor wherein the reversible BTK inhibitor is a compound of Formula (l-a) to (l-h) or a pharmaceutically acceptable salt and/or solvate thereof.
  • a combination of an irreversible BTK inhibitor and a reversible BTK inhibitor for use in a method for treating a subject having a hyperproliferative disease, preferably a B-cell hematological malignancy comprising: administering to the subject a therapeutic combinatory amount of said irreversible BTK inhibitor and said reversible BTK inhibitor, wherein the reversible BTK inhibitor is a compound of Formula (l-a) to (l-h) or a pharmaceutically acceptable salt and/or solvate thereof.
  • the present inventors have surprisingly found that a combination of an irreversible BTK inhibitor and a reversible BTK inhibitor, in particular a macrocyclic BTK inhibitor according to the invention, is more effective than an irreversible or reversible BTK inhibitor alone.
  • a combination of an irreversible BTK inhibitor and a reversible BTK inhibitor, in particular the macrocyclic BTK inhibitor according to the invention is more effective than an irreversible or reversible BTK inhibitor alone in inhibiting B-cell lymphoma cells comprising two separate cell pools each containing a different mutation in BTK.
  • combinations of a macrocyclic reversible BTK inhibitor compound according to the invention and an irreversible, covalent, inhibitor is synergistically effective in inhibiting B-cell lymphoma cells.
  • a synergistic effect of inhibition has been shown in a B- cell lymphoma cell line in which BTK has at least a C481S modification.
  • a pharmaceutical composition comprising a combination of an irreversible BTK inhibitor and a macrocyclic reversible BTK inhibitor, wherein the macrocyclic reversible BTK inhibitor is a compound according to any one of Formula (l-a) to (l-h), in a particular example according to a compound of Formula (A).
  • composition as used herein has its conventional meaning and refers to a composition which is pharmaceutically acceptable.
  • pharmaceutically acceptable has its conventional meaning and refers to compounds, material, compositions and/or dosage forms, which are, within the scope of sound medical judgment suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
  • effective amount refers to an amount of the compound of the invention, and/or an additional therapeutic agent, or a composition thereof, that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventive effect when administered to a subject suffering from a BTK-mediated disease or disorder.
  • effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
  • therapeutically combinatory amount has its meaning in the context of combination therapy of the compounds according to the invention, or a composition thereof, that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventive effect when administered to a subject suffering from a hyperproliferative disease, in particular a B-cell hematological malignancy .
  • the therapeutically combinatory amount is the total amount of the two (or more) compounds selected of an irreversible BTK inhibitor and a reversible BTK inhibitor used for treating the hyperproliferative disease, in particular a B-cell hematological malignancy.
  • the term “combination” as used herein, means a product that results from the mixing or combining of an irreversible BTK inhibitor and a reversible BTK inhibitor (and any additional therapeutic agents) and includes both fixed and non-fixed combinations.
  • the term “fixed combination” means that the irreversible BTK inhibitor and the reversible BTK inhibitor are both administered in a single entity or dosage form.
  • the term “non-fixed combination” means that the irreversible BTK inhibitor and the reversible BTK inhibitor are administered as separate entities or dosage forms either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.
  • a "subject' is a human or non-human mammal. In one embodiment, a subject is a human.
  • controlling is intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of the diseases and conditions affecting the mammal. However, “controlling” does not necessarily indicate a total elimination of all disease and condition symptoms, and is intended to include prophylactic treatment.
  • excipient as used herein has its conventional meaning and refers to a pharmaceutically acceptable ingredient, which is commonly used in the pharmaceutical technology for preparing a granulate, solid or liquid oral dosage formulation.
  • salt as used herein has its conventional meaning and includes the acid addition and base salts of the compound of the invention.
  • solvate as used herein has its conventional meaning.
  • One or more compounds of the invention or the pharmaceutically acceptable salts thereof may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association Involves varying degrees of ionic and covalent bonding. Including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • “Solvate” encompasses both solution-phase and isolatable solvates. Examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O and includes any hydrate of the compound or the salt of said compound.
  • treatment has its conventional meaning and refers to curative, disease controlling, palliative and prophylactic treatment.
  • unit dosage form has its conventional meaning and refers to a dosage form which has the capacity of being administered to a subject, preferably a human, to be effective, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising the therapeutic agent, i.e. the compound of the invention.
  • BTK Bruton's Tyrosine Kinase
  • BTK Bruton's tyrosine kinase
  • Src-related Tec family of protein kinases which are a large subset of kinases which play a central role in the regulation of a wide variety of cellular signaling processes.
  • BTK plays a key role in the B-cell receptor signaling and a critical role in the regulation of survival, proliferation, activation and differentiation of B- lineage cells.
  • BTK small molecule inhibitors
  • small molecule inhibitors such as the FDA approved irreversible BTK inhibitors ibrutinib, acalabrutinib, zanubrutinib and tirabrutinib
  • CLL Chronic Lymphocytic Leukemia
  • MCL Mantle Cell Lymphoma
  • WM Macroglobulinemia
  • SLL Small Lymphocytic Lymphoma
  • BTK inhibitor as used herein has its conventional meaning and refers to an inhibitor for BTK.
  • a BTK inhibitor may be a small molecule inhibitor.
  • Inhibitors may be irreversible inhibitors, such as by forming a covalent bond, and may be reversible inhibitors, which may form a reversible interaction with BTK.
  • covalent BTK inhibitor has its conventional meaning and refers to a BTK inhibitor that reacts with its target protein (BTK) to form a covalent complex in which the protein has lost its function.
  • Covalent inhibitors can be reversible or irreversible, depending on the rate of the reverse reaction.
  • the terms 'covalent inhibitor' and 'irreversible inhibitor' are often used and are considered the same for the purpose of this patent application .
  • irreversible BTK inhibitor has its conventional meaning and refers to a BTK inhibitor that, after formation of a covalent complex with the protein, possesses an off-rate that is slow relative to the rate of re-synthesis of the target protein (BTK) in vivo, so that once the target protein is inhibited, it does not regain activity.
  • rate of re-synthesis has its conventional meaning and refers to the rate at which a cell and/or organism replaces a protein target with freshly synthesized functional protein.
  • the re-synthesis rate defines the rate at which an irreversibly inhibited protein target will recover activity in vivo, once the inhibitor is no longer present.
  • reversible BTK inhibitor has its conventional meaning and refers to a BTK inhibitor that inactivates the BTK enzyme through non-covalent, reversed, interactions. Unlike an irreversible inhibitor, a reversible inhibitor can dissociate from the enzyme.
  • mutant-BTK has its conventional meaning and refers to mutations of BTK. Mutations of BTK may be referred to by an altered or modified amino acid target (such as C as single-letter amino acid code for cysteine) at a certain position of the BTK structure (such as 481). Additionally, the amino acid substitution at the modification position may be referred to by an additional amino acid single-letter amino acid code, such as C481S for serine substitution and C481 T for threonine substitution of cysteine at the 481 position.
  • an altered or modified amino acid target such as C as single-letter amino acid code for cysteine
  • an additional amino acid single-letter amino acid code such as C481S for serine substitution and C481 T for threonine substitution of cysteine at the 481 position.
  • modification has its conventional meaning and refers to modification of a sequence of amino acids of a polypeptide, protein or a sequence of nucleotides in a nucleic acid molecule and includes deletions, insertions, and replacements of amino acids and nucleotides, respectively.
  • the term "resistance to BTK inhibitor” as used herein has its conventional meaning and refers to a BTK inhibitor, which shows a reduction in effectiveness, after being effective initially in treating a hyperproliferative disease, in particular a B-cell hematological malignancy.
  • a drawback of the currently approved irreversible inhibitors is that patients treated with these inhibitors can develop drug resistance when proteins with variations at the catalytic site are not able to bind efficiently to irreversible inhibitors in patients. This is a rather common event in patients treated with irreversible inhibitors and who experience relapse.
  • a major mechanism for the acquired resistance is the emergence of BTK cysteine 481 (C 481) mutations. These mutations hamper binding of irreversible inhibitors such as ibrutinib, acalabrutinib, zanubrutinib and tirabrutinib which form a covalent bond with this amino acid.
  • valine 416 V416)
  • A428 alanine 428
  • M437 methionine 437
  • T474 threonine 474
  • L528 leucine 528
  • drug resistance is meant the major cause of cancer treatment failure. While a treatment may be effective initially, the heterogeneity of cancer and its ability to adapt can allow the cancer to become resistant to the treatment and regrow.
  • relapse as used herein has the conventional meaning and refers to evidence of disease progression in a patient who has previously achieved criteria of a complete response or partial remission.
  • disease progression has the conventional meaning and refers to a measured increase in tumor size or tumor burden.
  • recurrent or refractory form of a hyperproliferative disease has the conventional meaning and refers to a particular cancer that is resistant, or non-responsive to therapy with a particular therapeutic agent.
  • a cancer can be refractory to therapy with a particular therapeutic agent either from the onset of treatment (i.e., non-responsive to initial exposure to the therapeutic agent), or as a result of developing resistance to the therapeutic agent, either over the course of a first treatment period with the therapeutic agent or during a subsequent treatment period with the therapeutic agent.
  • the term "acquired drug resistance” as used herein has the conventional meaning and refers to resistance of a drug caused by mutations in the target protein following treatment.
  • the mutations in the target protein hamper the binding of drug resulting in a regrowth of the tumor
  • Clinical drug resistance as used herein has the conventional meaning and refers to growth of a tumour while the patient is on treatment, that develops following after an initial clinical benefit (a clinical response or prolonged stable disease).
  • wt-BTK or “WT-BTK” or “BTK WT” as used herein has its conventional meaning and refers to wild-type Bruton’s Tyrosine Kinase.
  • a wild-type BTK has the regular meaning of a phenotype of the typical form of BTK as it occurs in nature. Originally, the wild-type was conceptualized as a product of the standard "normal” allele at a locus, in contrast to that produced by a non-standard, "mutant” allele.
  • microcycle as used herein has its conventional meaning and refers to a part of a molecule containing a ring consisting of 12 or more ring atoms forming said ring. In an example, a twelve membered ring consist of 12 atoms forming said ring.
  • binding affinity as used herein has its conventional meaning and refers to the equilibrium dissociation constant which is an inverse measure of the affinity of a protein- ligand (small molecule) pair under equilibrium conditions.
  • the value of K D is mathematically equivalent to the ratio k off /k on (or k d /k a ) measured using Surface Plasmon Resonance (SPR).
  • association rate constant or “on-rate (k on or k a )” as used herein has its conventional meaning and refers to a second-order rate constant that quantifies the rate at which a free ligand and free protein combine (through collisional encounters) to form a binary proteinligand complex.
  • dissociation rate constant or “off-rate ( k off or k d )” as used herein has its conventional meaning and refers to a first-order rate constant that quantifies the rate at which a binary protein-ligand complex dissociates to the free ligand and free protein.
  • Target residence time tau ( ⁇ ) has its conventional meaning and refers to the time a compound resides on its target.
  • Target residence time ( ⁇ ) can be determined according to the method as described below in the experimental section.
  • IC 50 has its conventional meaning and refers to the concentration of a substance that results in a 50% effect on some measure of biochemical and/or cellular function or substance-target binding interaction.
  • pIC 50 has its conventional meaning and refers to the negative logarithm of the IC 50 in molar concentration.
  • GI 50 refers to the concentration of a substance that inhibits cell growth by 50%.
  • LD 50 refers to the concentration of a substance that results in 50% cell death.
  • a bicyclic ringsystem refers to heterocyclic (heterocyclyl) groups, to cyclic groups having carbon groups only, i.e. without hetero atoms, within the cycle, and to combinations of a heterocyclic (heterocyclyl) group and a cyclic group having carbon groups only, i.e. without hetero atoms, within the cycle.
  • a monocylic ringsystem refers both to a heterocyclic (heterocyclyl) group, and to a cyclic group having carbon groups only, i.e. without hetero atoms, within the cycle.
  • heterocyclic (heterocyclyl) group refers to both heteroaryl groups and heterocycloalkyl groups.
  • a heterobicyclic group refers to a bicyclic group having one or more heteroatoms, which is saturated, partially unsaturated or unsaturated.
  • aromatic groups include aromatic carbocyclic ring systems (e.g. phenyl) and fused polycyclic aromatic ring systems (e.g. naphthyl and 1 , 2,3,4- tetrahydronaphthyl).
  • alkyl refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond having the specified number of carbon atoms.
  • an alkyl group contains, for example, from 1 to 6 carbon atoms (1 - 6C) Alkyl or from 1 to 3 carbon atoms (1 -3C)Alkyl.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl.
  • an alkyl group is linear. In another embodiment, an alkyl group is branched.
  • alkyl includes both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbon atoms; for example, “(1 -6C)Alkyl” includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
  • Alkylene refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbons, and having two terminal end chain attachments; for example, the term “A-C 4 alkylene-B” represents, for example, A-CH 2 -CH 2 -CH 2 -CH 2 -B, A-CH 2 - CH 2 -CH(CH 3 )-CH 2 -B, A-CH 2 -CH(CH 2 CH 3 )-B, A-CH 2 -C(CH 3 )(CH 3 )-B, and the like.
  • alkylcarbonyl refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond attached to a carbonyl group, wherein the aliphatic hydrocarbon group has the specified number of carbon atoms.
  • an alkyl group or aliphatic hydrocarbon group contains, for example, from 1 to 6 carbon atoms (1 -6C)Alkyl or from 1 to 3 carbon atoms (1 -3C)Alkyl.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl.
  • an alkyl group is linear. In another embodiment, an alkyl group is branched.
  • Cycloalkyl means a cycloalkyl group having the recited number of carbon atoms, with the same meaning as previously defined, such as cyclopropyl, cyclobutyl, or cyclopentyl.
  • Cycloalkyl refers to a cycloalkyl-group represented by an indicated number of carbon atoms; for example "(3-6C)cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • Heterocycloalkyl means a cycloalkyl group having the recited number of carbon atoms, and 1 -3 heteroatoms selected from N, O and/or S, with the same meaning as previously defined.
  • Haloalkyl means a branched or unbranched alkyl group having the recited number of carbon atoms, in which one and up to all hydrogen atoms are replaced by a halogen; halogen is as defined herein.
  • branched or straight chained haloalkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n- butyl substituted independently with one or more halogens, e.g., fluoro, chloro, bromo and iodo.
  • a halo(1 -3C)alkyl means a branched or unbranched alkyl group having 1 ,2, or 3 carbon atoms, in which at least one hydrogen atom is replaced by a halogen.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 1 - fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and perfluoro-n-propyl.
  • Alkoxy means an alkoxy group having the recited number of carbon atoms, the alkyl moiety having the same meaning as previously defined, e.g., "Alkoxy” refers to an alkyl-O-group represented by a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge; for example "(1 -6C)Alkoxy” includes -OCH 3 , -O-CH 2 CH 3 , - OCH(CH 3 ) 2 , -O(CH 2 ) 5 CH 3 , and the like.
  • Cycloalkoxy means a cycloalkyl group having the recited number of carbon atoms, with the same meaning as previously defined, attached via a ring carbon atom to an exocyclic oxygen atom, such as cyclopropoxyl, cyclobutoxyl.or cyclopentoxyl.
  • Cycloalkoxy refers to a cycloalkyl- O-group represented by a cycloalkyl group of indicated number of carbon atoms attached through an oxygen bridge; for example "(3-6C)cycloalkoxy” includes cyclopropyl-O-, cyclobutyl- O-, cyclopentyl-O-, or cyclohexyl-O-.
  • Heterocycloalkoxy means a cycloalkyl group having the recited number of carbon atoms, and 1 -3 heteroatoms selected from N, O and/or S, with the same meaning as previously defined, attached via a ring carbon atom to an exocyclic oxygen atom.
  • alkyl groups are unsubstituted or substituted with 1 to 3 substituents on each carbon atom.
  • a method comprising steps A and B should not be limited to a method consisting only of steps A and B, rather with respect to the present invention, the only enumerated steps of the method are A and B, and further the claim should be interpreted as including equivalents of those method steps.
  • a composition comprising components A and B should not be limited to a composition consisting only of components A and B, rather with respect to the present invention, the only enumerated components of the composition are A and B, and further the claim should be interpreted as including equivalents of those components.
  • indefinite article “a” or “an” does not exclude the possibility that more than one of the element or component are present, unless the context clearly requires that there is one and only one of the elements or components.
  • the indefinite article “a” or “an” thus usually means “at least one”.
  • Figure 1 Map of clinically documented BTK mutants.
  • Figure 2 Proliferation assay of single compounds (monotherapy) in wt-BTK TMD8 cells.
  • Figure 3 Proliferation assay of single compounds (monotherapy) in BTK C481S TMD8 cells.
  • Figure 4 Proliferation assay of single compounds (monotherapy) in BTK T474I TMD8 cells.
  • Figure 5 Proliferation assay of single compounds (monotherapy) in BTK T474I/C481S TMD8 cells.
  • Figure 6 Proliferation assay of single compounds (monotherapy) in BTK V416L TMD8 cells.
  • Figure 7 Proliferation assay of single compounds (monotherapy) in BTK L528W TMD8 cells.
  • Figure 8 Proliferation assay of single compounds (monotherapy) in a mixture of BTK C481S TMD8 cells and BTK V416L TMD8 cells.
  • Figure 9 Proliferation assay of single compounds (monotherapy) in a mixture of BTK C481S TMD8 cells and BTK T474I TMD8 cells.
  • Figure 10 Proliferation assay of single compounds (monotherapy) in a mixture of BTK C481S TMD8 cells and BTK L528W TMD8 cells.
  • Figure 1 1 Proliferation assay of ibrutinib and Compound A (combination therapy) in a mixture of BTK C481S TMD8 cells and BTK V416L TMD8 cells.
  • Figure 12 Proliferation assay of ibrutinib and Compound A (combination therapy) in a mixture of BTK C481S TMD8 cells and BTK T474I TMD8 cells.
  • Figure 13 Proliferation assay of ibrutinib and Compound A (combination therapy) in a mixture of BTK C481S TMD8 cells and BTK L528W TMD8 cells.
  • Figure 14 Proliferation assay of acalabrutinib and Compound A (combination therapy) in a mixture of BTK C481S TMD8 cells and BTK V416L TMD8 cells.
  • Figure 15 Proliferation assay of acalabrutinib and Compound A (combination therapy) in a mixture of BTK C481S TMD8 cells and BTK T474I TMD8 cells.
  • Figure 16 Proliferation assay of acalabrutinib and Compound A (combination therapy) in a mixture of BTK C481S TMD8 cells and BTK L528W TMD8 cells.
  • Figure 17A - 17G Proliferation assay of ibrutinib and Compound A (combination therapy) in BTK C481S TMD8 cells (curve shift analysis).
  • Figure 18 Excess over Bliss score matrix of Compound A and ibrutinib in BTK C481S TMD8 cells.
  • Figure 19A - 19G Proliferation assay of acalabrutinib and Compound A (combination therapy) in BTK C481S TMD8 cells (curve shift analysis).
  • Figure 20 Excess over Bliss score matrix of Compound A and acalabrutinib in BTK C481S TMD8 cells.
  • FIG. 21 Ibrutinib resistance mutations can be detected before clinical relapse.
  • samples before relapse were analyzed retrospectively to determine the interval of time between mutation detection and clinical relapse.
  • An initial clone could be detected at an estimated median of 9.3 months before relapse.
  • UPN unique patient number (Woyach et al. 2017).
  • the inventors have established that a combination of an irreversible BTK inhibitor and a reversible BTK inhibitor, in particular a macrocyclic reversible BTK inhibitor having any one of Formula (l-a) to (l-h) as defined below, is more effective than an irreversible or reversible BTK inhibitor alone.
  • a combination of an irreversible BTK inhibitor and a reversible BTK inhibitor in particular a compound having any one of Formula (l-a) to (l-h), as defined above, is more effective than an irreversible or reversible BTK inhibitor alone in inhibiting B-cell lymphoma cells comprising two separate cell pools each containing a different mutation in BTK.
  • combinations of a reversible BTK inhibitor compound according to Formula (l-a) to (l-h) and an irreversible, covalent, BTK inhibitor is synergistically effective in inhibiting B-cell lymphoma cells.
  • the reversible BTK inhibition compounds according to the invention have any one of Formula (l-a) to (l-h), which are extensively described in co-pending PCT application PCT/EP2021/085641 and in PCT application PCT/EP2022/085765.
  • the reversible BTK inhibitors according to the present invention include the (macrocyclic) BTK inhibition compounds of the co-pending PCT application PCT/EP2021/085641 and of the PCT application PCT/EP2022/085765 and are incorporated by reference, including the exemplary compounds having sub-formula 1 - 226 and the described syntheses routes for manufacturing the compounds having any one of Formula (l-a) to (l-h).
  • macrocyclic reversible BTK inhibitiors according to the invention provide an improved reversible binding activity towards wild-type BTK and/or BTK mutants than what is typically obtained with reversible BTK inhibitors.
  • the compounds according to the invention have any one of Formula (l-a) to (l-h), which contains a macrocyclic moiety, in combination with BTK specific pharmacophores (e.g. based on ligands for binding to BTK) to provide a binding activity towards wild-type BTK and/or BTK mutants through improved reversible binding.
  • BTK specific pharmacophores e.g. based on ligands for binding to BTK
  • the reversible BTK inhibitor is a compound according to any one of Formula (l-a) to (l-h), or pharmaceutically acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof:
  • R 1 is , wherein :
  • W is an aryl group having 6-10 carbon or a heteroaryl group having 1 -5 carbon; wherein any said aryl group and heteroaryl group is optionally and independently substituted with one or more substituents selected from halogen, (1 -2C)alkyl, (1 -2C)alkoxy; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro;
  • V is any one of O, -C(O)-NH-, -NH-C(O)-, -CH(R 1v )-NH-C(O)-, -CH(R 1v )- ;
  • R 1v is hydrogen or (1 -2C)alkyl
  • U is an aryl group having 6-10 carbon or an heteroaryl group having 1 -5 carbon; wherein any of said aryl group and heteroaryl group is optionally and independently substituted with one or more substituents selected from halogen, cyano, (1 -4C)alkyl, (1 -5C)alkoxy, (3-6C)cycloalkyl or (3-6C)heterocycloalkyl; wherein any of said alkyl, alkoxy, cycloalkyl and heterocycloalkyl group is optionally and independently substituted with one, two or three halogen; wherein R 2 is of Formula (ll-a) to (ll-f) selected from the group consisting of:
  • any of said linkers is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, CD 3 , (1 -4C)alkyl, (1 - 5C)alkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkoxy and (1 -6C)alkylcarbonyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen.
  • the reversible BTK inhibitor is a compound according to Formula (l-a) or (l-b) or a pharmaceutically acceptable salt and/or solvate thereof, wherein the compound comprises a bicyclic scaffold selected from: and
  • R 1 is any one of: and wherein R 2w is selected from hydrogen, halogen, (1 -2C)alkyl, (1-2C)alkoxy; wherein any said alkyl or alkoxy group is optionally and independently substituted with one, two or three fluoro; wherein R 3u is selected from hydrogen, halogen, cyano, (1 -4C)alkyl, (1 -5C)alkoxy, (3- 6C)cycloalkyl or (3-6C)heterocycloalkyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro; wherein R 2 is selected from the group consisting of:
  • the reversible BTK inhibitor is a compound according to Formula (A):
  • Formula (A) or pharmaceutically acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof.
  • the irreversible BTK inhibitor of the combination is selected from the group consisting of: ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, spebrutinib, branebrutinib, evobrutinib, remibrutinib, tolebrutinib, orelabrutinib, elsubrutinib, edralbrutinib, ACP-5862, and pharmaceutically acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof.
  • the irreversible BTK inhibitor of the combination is ibrutinib, and pharmaceutically acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof.
  • the irreversible BTK inhibitor of the combination is acalabrutinib, and pharmaceutically acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof.
  • the irreversible BTK inhibitor of the combination is zanubrutinib, and pharmaceutically acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof.
  • the irreversible BTK inhibitor of the combination is tirabrutinib, and pharmaceutically acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof.
  • the subject is identified as having a mutation in a gene that results in expression of a BTK protein with a modification at amino acid position 481 of the amino acid sequence according to SEQ ID NO: I, more preferably wherein the protein modification is C481S.
  • the subject is identified as having a mutation in a gene that results in expression of a BTK protein with a modification at amino acid position 481 of the amino acid sequence according to SEQ ID NO: I, wherein the modification is a substitution of cysteine to an amino acid selected from leucine, isoleucine, valine, alanine, glycine, methionine, serine, threonine, phenylalanine, tryptophan, lysine, arginine, histidine, proline, tyrosine, asparagine, glutamine, aspartic acid and glutamic acid at amino acid position 481 of the BTK protein.
  • the modification is a substitution of cysteine to an amino acid selected from leucine, isoleucine, valine, alanine, glycine, methionine, serine, threonine, phenylalanine, tryptophan, lysine, arginine, histidine, proline, tyros
  • the modification is a substitution of cysteine to serine at amino acid position 481 of the BTK protein.
  • the subject is identified as having a mutation in a gene that results in expression of a BTK protein with a modification at amino acid position 416 of the amino acid sequence according to SEQ ID NO: I, more preferably wherein the protein modification is V416L.
  • the subject is identified as having a mutation in a gene that results in expression of a BTK protein with a modification at amino acid position 416 of the amino acid sequence according to SEQ ID NO: I, wherein the modification is a substitution of valine to an amino acid selected from leucine, isoleucine, cysteine, alanine, glycine, methionine, serine, threonine, phenylalanine, tryptophan, lysine, arginine, histidine, proline, tyrosine, asparagine, glutamine, aspartic acid and glutamic acid at amino acid position 416 of the BTK protein.
  • the modification is a substitution of valine to an amino acid selected from leucine, isoleucine, cysteine, alanine, glycine, methionine, serine, threonine, phenylalanine, tryptophan, lysine, arginine, histidine, proline, tyros
  • the modification is a substitution of valine to leucine at amino acid position 416 of the BTK protein.
  • the subject is identified as having a mutation in a gene that results in expression of a BTK protein with a modification at amino acid position 428 of the amino acid sequence according to SEQ ID NO: I, more preferably wherein the protein modification is A428D.
  • the subject is identified as having a mutation in a gene that results in expression of a BTK protein with a modification at amino acid position 428 of the amino acid sequence according to SEQ ID NO: I, wherein the modification is a substitution of alanine to an amino acid selected from leucine, isoleucine, valine, cysteine, glycine, methionine, serine, threonine, phenylalanine, tryptophan, lysine, arginine, histidine, proline, tyrosine, asparagine, glutamine, aspartic acid and glutamic acid at amino acid position 428 of the BTK protein.
  • the modification is a substitution of alanine to an amino acid selected from leucine, isoleucine, valine, cysteine, glycine, methionine, serine, threonine, phenylalanine, tryptophan, lysine, arginine, histidine, proline, tyros
  • the modification is a substitution of alanine to aspartic acid at amino acid position 428 of the BTK protein.
  • the subject is identified as having a mutation in a gene that results in expression of a BTK protein with a modification at amino acid position 437 of the amino acid sequence according to SEQ ID NO: I, more preferably wherein the protein modification is M437R.
  • the subject is identified as having a mutation in a gene that results in expression of a BTK protein with a modification at amino acid position 437 of the amino acid sequence according to SEQ ID NO: I, wherein the modification is a substitution of methionine to an amino acid selected from leucine, isoleucine, valine, alanine, glycine, cysteine, serine, threonine, phenylalanine, tryptophan, lysine, arginine, histidine, proline, tyrosine, asparagine, glutamine, aspartic acid and glutamic acid at amino acid position 437 of the BTK protein.
  • the modification is a substitution of methionine to an amino acid selected from leucine, isoleucine, valine, alanine, glycine, cysteine, serine, threonine, phenylalanine, tryptophan, lysine, arginine, histidine, proline, tyros
  • the modification is a substitution of methionine to arginine at amino acid position 437 of the BTK protein.
  • the subject is identified as having a mutation in a gene that results in expression of a BTK protein with a modification at amino acid position 474 of the amino acid sequence according to SEQ ID NO: I, more preferably wherein the protein modification is T474I.
  • the subject is identified as having a mutation in a gene that results in expression of a BTK protein with a modification at amino acid position 474 of the amino acid sequence according to SEQ ID NO: I, wherein the modification is a substitution of threonine to an amino acid selected from leucine, isoleucine, valine, alanine, glycine, methionine, serine, cysteine, phenylalanine, tryptophan, lysine, arginine, histidine, proline, tyrosine, asparagine, glutamine, aspartic acid and glutamic acid at amino acid position 474 of the BTK protein.
  • the modification is a substitution of threonine to an amino acid selected from leucine, isoleucine, valine, alanine, glycine, methionine, serine, cysteine, phenylalanine, tryptophan, lysine, arginine, histidine, proline, tyros
  • the modification is a substitution of threonine to isoleucine at amino acid position 474 of the BTK protein.
  • the subject is identified as having a mutation in a gene that results in expression of a BTK protein with a modification at amino acid position 528 of the amino acid sequence according to SEQ ID NO: I, more preferably wherein the protein modification is L528W.
  • the subject is identified as having a mutation in a gene that results in expression of a BTK protein with a modification at amino acid position 528 of the amino acid sequence according to SEQ ID NO: I, wherein the modification is a substitution of leucine to an amino acid selected from cysteine, isoleucine, valine, alanine, glycine, methionine, serine, threonine, phenylalanine, tryptophan, lysine, arginine, histidine, proline, tyrosine, asparagine, glutamine, aspartic acid and glutamic acid at amino acid position 528 of the BTK protein.
  • the modification is a substitution of leucine to an amino acid selected from cysteine, isoleucine, valine, alanine, glycine, methionine, serine, threonine, phenylalanine, tryptophan, lysine, arginine, histidine, proline, tyros
  • the modification is a substitution of leucine to tryptophane at amino acid position 528 of the BTK protein.
  • prior therapy has been given to a subject having a hyperproliferative disease, preferably a B-cell hematological malignancy, where the subject has received a Bruton’s tyrosine kinase (BTK) inhibitor for treatment of the hyperproliferative disease, preferably an irreversible BTK inhibitor, more preferably, ibrutinib before starting a new treatment option for managing the same condition.
  • a hyperproliferative disease preferably a B-cell hematological malignancy
  • BTK tyrosine kinase
  • prior therapy has been given to a subject having a hyperproliferative disease, preferably a B-cell hematological malignancy, where the subject has received a Bruton’s tyrosine kinase (BTK) inhibitor for treatment of the hyperproliferative disease, preferably an irreversible BTK inhibitor, more preferably, acalabrutinib before starting a new treatment option for managing the same condition.
  • a hyperproliferative disease preferably a B-cell hematological malignancy
  • BTK tyrosine kinase
  • prior therapy has been given to a subject having a hyperproliferative disease, preferably a B-cell hematological malignancy, where the subject has received a Bruton’s tyrosine kinase (BTK) inhibitor for treatment of the hyperproliferative disease, preferably an irreversible BTK inhibitor, more preferably, zanubrutinib before starting a new treatment option for managing the same condition.
  • a hyperproliferative disease preferably a B-cell hematological malignancy
  • BTK tyrosine kinase
  • prior therapy has been given to a subject having a hyperproliferative disease, preferably a B-cell hematological malignancy, where the subject has received a Bruton’s tyrosine kinase (BTK) inhibitor for treatment of the hyperproliferative disease, preferably an irreversible BTK inhibitor, more preferably, tirabrutinib before starting a new treatment option for managing the same condition.
  • a hyperproliferative disease preferably a B-cell hematological malignancy
  • BTK tyrosine kinase
  • maintenance therapy is given to a subject having a hyperproliferative disease, preferably a B-cell hematological malignancy, where the subject has received and still is receiving a Bruton’s tyrosine kinase (BTK) inhibitor for treatment of the hyperproliferative disease, preferably an irreversible BTK inhibitor, more preferably, ibrutinib.
  • a hyperproliferative disease preferably a B-cell hematological malignancy
  • a Bruton’s tyrosine kinase (BTK) inhibitor for treatment of the hyperproliferative disease, preferably an irreversible BTK inhibitor, more preferably, ibrutinib.
  • BTK tyrosine kinase
  • maintenance therapy is given to a subject having a hyperproliferative disease, preferably a B-cell hematological malignancy, where the subject has received and still is receiving a Bruton’s tyrosine kinase (BTK) inhibitor for treatment of the hyperproliferative disease, preferably an irreversible BTK inhibitor, more preferably, acalabrutinib.
  • BTK Bruton’s tyrosine kinase
  • maintenance therapy is given to a subject having a hyperproliferative disease, preferably a B-cell hematological malignancy, where the subject has received and still is receiving a Bruton’s tyrosine kinase (BTK) inhibitor for treatment of the hyperproliferative disease, preferably an irreversible BTK inhibitor, more preferably, zanubrutinib.
  • maintenance therapy is given to a subject having a hyperproliferative disease, preferably a B-cell hematological malignancy, where the subject has received and still is receiving a Bruton’s tyrosine kinase (BTK) inhibitor for treatment of the hyperproliferative disease, preferably an irreversible BTK inhibitor, more preferably, tirabrutinib.
  • a hyperproliferative disease preferably a B-cell hematological malignancy
  • BTK tyrosine kinase
  • the methods for maintenance therapy comprise treating a B-cell hematological malignancy with a covalent and/or irreversible BTK inhibitor for an initial treatment period, followed by a maintenance therapy regimen.
  • the methods for maintenance therapy comprise treating a B-cell haematological malignancy with a covalent and/or irreversible BTK inhibitor for a period of six months or longer, such as, for example, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years or longer.
  • a covalent and/or irreversible BTK inhibitor for a period of six months or longer, such as, for example, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months
  • the subject is monitored over the course of the therapy with a BTK inhibitor for treatment of the hyperproliferative disease to determine whether the subject has a mutation in an endogenous gene encoding BTK that results in or provides a risk of resistance of the subject to the therapy, preferably resistance of the subject to the irreversible BTK inhibitor.
  • the subject is monitored at predetermined intervals of time over the course of the therapy for treatment of the hyperproliferative disease, wherein the predetermined interval of time is every week, every 2 weeks, every 3 weeks, every month, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every 8 months, every 9 months, every 10 months, every 1 1 months, every year following the first administration of the covalent and/or irreversible BTK inhibitor.
  • the treatment which is monitored is in particular a treatment of administration of an irreversible BTK inhibitor.
  • testing comprises performing polymerase chain reaction (PCR) amplification of nucleic acids that encode amino acid position 481 of the BTK protein.
  • PCR amplification comprises using a pair of oligonucleotide primers that flank the region encoding amino acid position 481 of the BTK protein.
  • the method comprises sequencing the amplified nucleic acids.
  • testing comprises performing deep sequencing of nucleic acids that encode amino acid position 481 of the BTK protein.
  • testing comprises contacting the nucleic acids with a sequence specific nucleic acid probe, wherein the sequence specific nucleic acid probe: (a) binds to nucleic acids encoding a modified BTK that is modified at amino acid position 481 ; and (b) does not bind to nucleic acids encoding the wild-type BTK having cysteine at amino acid position 481 .
  • testing comprises PCR amplification using the sequence specific nucleic acid probe.
  • testing comprises performing polymerase chain reaction (PCR) amplification of nucleic acids that encode amino acid position 416 of the BTK protein.
  • PCR amplification comprises using a pair of oligonucleotide primers that flank the region encoding amino acid position 416 of the BTK protein.
  • the method comprises sequencing the amplified nucleic acids.
  • testing comprises performing deep sequencing of nucleic acids that encode amino acid position 416 of the BTK protein.
  • testing comprises contacting the nucleic acids with a sequence specific nucleic acid probe, wherein the sequence specific nucleic acid probe: (a) binds to nucleic acids encoding a modified BTK that is modified at amino acid position 416; and (b) does not bind to nucleic acids encoding the wild-type BTK having valine at amino acid position 416.
  • testing comprises PCR amplification using the sequence specific nucleic acid probe.
  • testing comprises performing polymerase chain reaction (PCR) amplification of nucleic acids that encode amino acid position 428 of the BTK protein.
  • PCR amplification comprises using a pair of oligonucleotide primers that flank the region encoding amino acid position 428 of the BTK protein.
  • the method comprises sequencing the amplified nucleic acids.
  • testing comprises performing deep sequencing of nucleic acids that encode amino acid position 428 of the BTK protein.
  • testing comprises contacting the nucleic acids with a sequence specific nucleic acid probe, wherein the sequence specific nucleic acid probe: (a) binds to nucleic acids encoding a modified BTK that is modified at amino acid position 428; and (b) does not bind to nucleic acids encoding the wild-type BTK having alanine at amino acid position 428.
  • testing comprises PCR amplification using the sequence specific nucleic acid probe.
  • testing comprises performing polymerase chain reaction (PCR) amplification of nucleic acids that encode amino acid position 437 of the BTK protein.
  • PCR amplification comprises using a pair of oligonucleotide primers that flank the region encoding amino acid position 437 of the BTK protein.
  • the method comprises sequencing the amplified nucleic acids.
  • testing comprises performing deep sequencing of nucleic acids that encode amino acid position 437 of the BTK protein.
  • testing comprises contacting the nucleic acids with a sequence specific nucleic acid probe, wherein the sequence specific nucleic acid probe: (a) binds to nucleic acids encoding a modified BTK that is modified at amino acid position 437; and (b) does not bind to nucleic acids encoding the wild-type BTK having methionine at amino acid position 437.
  • testing comprises PCR amplification using the sequence specific nucleic acid probe.
  • testing comprises performing polymerase chain reaction (PCR) amplification of nucleic acids that encode amino acid position 474 of the BTK protein.
  • PCR amplification comprises using a pair of oligonucleotide primers that flank the region encoding amino acid position 474 of the BTK protein.
  • the method comprises sequencing the amplified nucleic acids.
  • testing comprises performing deep sequencing of nucleic acids that encode amino acid position 474 of the BTK protein.
  • testing comprises contacting the nucleic acids with a sequence specific nucleic acid probe, wherein the sequence specific nucleic acid probe: (a) binds to nucleic acids encoding a modified BTK that is modified at amino acid position 474; and (b) does not bind to nucleic acids encoding the wild-type BTK having threonine at amino acid position 474.
  • testing comprises PCR amplification using the sequence specific nucleic acid probe.
  • testing comprises performing polymerase chain reaction (PCR) amplification of nucleic acids that encode amino acid position 528 of the BTK protein.
  • PCR amplification comprises using a pair of oligonucleotide primers that flank the region encoding amino acid position 528 of the BTK protein.
  • the method comprises sequencing the amplified nucleic acids.
  • testing comprises performing deep sequencing of nucleic acids that encode amino acid position 528 of the BTK protein.
  • testing comprises contacting the nucleic acids with a sequence specific nucleic acid probe, wherein the sequence specific nucleic acid probe: (a) binds to nucleic acids encoding a modified BTK that is modified at amino acid position 528; and (b) does not bind to nucleic acids encoding the wild-type BTK having tryptophane at amino acid position 528.
  • testing comprises PCR amplification using the sequence specific nucleic acid probe.
  • the sample for use in the methods contains one or more tumor cells from the subject. In some embodiments, the sample for use in the methods contains cell free DNA (cfDNA). In some embodiments, the sample for use in the methods contains circulating tumor DNA (ctDNA). In some embodiments, the sample for use in the methods contains tumor derived extracellular vesicles (EV). In some embodiments, the sample is a tumor biopsy sample, a blood sample, a serum sample, a plasma sample, a saliva sample, a urinary sample, a lymph sample, or a bone marrow aspirate.
  • cfDNA cell free DNA
  • ctDNA circulating tumor DNA
  • EV tumor derived extracellular vesicles
  • the sample is a tumor biopsy sample, a blood sample, a serum sample, a plasma sample, a saliva sample, a urinary sample, a lymph sample, or a bone marrow aspirate.
  • the nucleic acids used in the method is isolated from a tumor cell sample from the subject. In some embodiments of the methods, the nucleic acids used in the method are isolated from extracellular vesicles (EV) isolated from the subject. In some embodiments of the method the nucleic acids used in the method are isolated from a tumor biopsy sample, a blood sample, a serum sample, a plasma sample, a saliva sample, a urinary sample, a lymph sample, or a bone marrow aspirate from the subject. In some embodiments of the methods, the nucleic acids for use in the assay are RNA or DNA. In some embodiments of the methods, the nucleic acids for use in the assay are genomic DNA. In some embodiments of the methods, the nucleic acids for use in the assay are total RNA. In some embodiments of the methods, the nucleic acids for use in the assay are messenger RNA (mRNA).
  • mRNA messenger RNA
  • the nucleic acids for use in the assay are complementary DNA (cDNA).
  • the method further comprises isolating mRNA from the RNA sample. In some embodiments of the methods, the method further comprises reverse transcription of the total RNA, or mRNA, into cDNA.
  • testing comprises contacting the nucleic acids with a sequence specific nucleic acid probe, wherein the sequence specific nucleic acid probe: (a) binds to nucleic acids encoding a modified BTK that is modified at amino acid position 481 ; and (b) does not bind to nucleic acids encoding the wild-type BTK having cysteine at amino acid position 481 .
  • testing comprises PCR amplification using the sequence specific nucleic acid probe.
  • the sample for use in the methods contains one or more tumor cells from the subject. In preferred embodiments, the sample for use in the methods contains circulating tumor DNA (ctDNA). In preferred embodiments, the sample is a tumor biopsy sample, a blood sample, a serum sample, a plasma sample, a saliva sample, a urinary sample, a lymph sample, or a bone marrow aspirate.
  • ctDNA tumor DNA
  • the nucleic acids used in the method is isolated from a tumor cell sample from the subject.
  • the nucleic acids used in the method are isolated from a tumor biopsy sample, a blood sample, a serum sample, a plasma sample, a saliva sample, a urinary sample, a lymph sample, or a bone marrow aspirate from the subject.
  • the nucleic acids for use in the assay is genomic DNA.
  • the subject is diagnosed with or at risk of a recurrent or refractory form of a hyperproliferative disease, which subject has previously been treated with an irreversible BTK inhibitor.
  • At risk of a recurrent or refractory form of a hyperproliferative disease in the context of this invention is defined as the subject having a mutation in a gene that results in expression of a mutated BTK protein that is unable to bind a BTK inhibitor, preferably an irreversible BTK inhibitor.
  • the subject is diagnosed with recurrent or refractory form of a hyperproliferative disease, preferably a B-cell hematological malignancy that is resistant, or non-responsive to therapy with an irreversible BTK inhibitor.
  • a hyperproliferative disease preferably a B-cell hematological malignancy that is resistant, or non-responsive to therapy with an irreversible BTK inhibitor.
  • the subject is identified as having a mutation in a gene that results in expression of a mutated BTK protein that is unable to bind a BTK inhibitor, preferably an irreversible BTK inhibitor, which provides a risk of a recurrent or refractory form of a hyperproliferative disease, preferably a B-cell hematological malignancy.
  • a BTK inhibitor preferably an irreversible BTK inhibitor, which provides a risk of a recurrent or refractory form of a hyperproliferative disease, preferably a B-cell hematological malignancy.
  • the combination therapy is started when the B-cell hematological malignancy of the subject is relapsed or refractory, preferably wherein CLL/SLL is relapsed or refractory.
  • the combination therapy is started when the B-cell hematological malignancy of the subject is relapsed or refractory and the subject is identified as having a mutation in a gene that results in expression of a BTK protein with a modification at amino acid position 481 , of the amino acid sequence according to SEQ ID NO: I, more preferably wherein the mutant modification is C481S.
  • the irreversible BTK inhibitor of the combination therapy is the same as the irreversible BTK inhibitor of a prior (maintenance) therapy.
  • the irreversible BTK inhibitor of the combination therapy is ibrutinib, while the irreversible BTK inhibitor of a prior (maintenance) therapy is also ibrutinib.
  • the irreversible BTK inhibitor of the combination therapy is different from the irreversible BTK inhibitor of a prior (maintenance) therapy.
  • the irreversible BTK inhibitor of the combination therapy is acalabrutinib, while the irreversible BTK inhibitor of a prior (maintenance) therapy is ibrutinib.
  • the term "therapeutically combinatory amount” in preferred embodiments, is the total amount of the two (or more) compounds selected of an irreversible BTK inhibitor and a reversible BTK inhibitor, in particular the total amount of the irreversible BTK inhibitor and the macrocyclic reversible BTK inhibitor, used for treating the hyperproliferative disease, in particular a B-cell hematological malignancy.
  • the irreversible BTK inhibitor of the combination is administered in an amount in the range of 70 - 750 mg / day and / or wherein the irreversible BTK inhibitor of the combination is administered using one or more unit doses having an amount in the range of 70 - 750 mg / unit dose.
  • the irreversible BTK inhibitor of the combination is administered daily at a dose selected from the group consisting of 70 mg, 100 mg, 140 mg, 160 mg, 200 mg, 280 mg, 320 mg, 420 mg, 480 mg, and 560 mg per day and preferably wherein the reversible BTK inhibitor is administered at a dose in accordance to said therapeutically combinatory amount.
  • the irreversible BTK inhibitor of the combination is administered twice daily using a unit dose of 80 mg, 100 mg or 160 mg and preferably wherein the reversible BTK inhibitor is administered at a dose in accordance to said therapeutically combinatory amount.
  • the dose amount of the irreversible BTK inhibitor of the therapeutically combinatory amount of the combination is lower than the dose amount of the same irreversible BTK inhibitor administered during the prior therapy.
  • the therapeutically combinatory amount of the dose of the irreversible BTK inhibitor and the dose of the reversible BTK inhibitor of the combination is lower than the dose of the irreversible BTK inhibitor, which was administered during the prior therapy.
  • the irreversible BTK inhibitor and the reversible BTK inhibitor of the combination are in a combined dosage form.
  • the irreversible BTK inhibitor and the reversible BTK inhibitor of the combination are in separate dosage forms.
  • the pharmaceutical composition comprises a combination of an irreversible BTK inhibitor and a reversible BTK inhibitor, wherein the reversible BTK inhibitor is a compound according to any one of Formula (l-a) to (l-h), in a particular example a compound according to Formula A.
  • compositions in accordance with the present invention may comprise, as one of the active ingredients (‘API’), compound of Formula (l-a) to (l-h) or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • API active ingredients
  • a pharmaceutically acceptable salt includes any salt that retains the activity of the active agent(s) and is acceptable for pharmaceutical use.
  • a pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.
  • the pharmaceutically acceptable salt is the HCI-salt of the compound of the invention.
  • the pharmaceutically acceptable salt of the disclosed compounds may be prepared by methods of pharmacy well known to those skilled in the art.
  • compositions can comprise compounds according to the invention in the form of a solvate, comprising a pharmaceutically acceptable solvent, such as water (‘hydrate’), ethanol, and the like.
  • a pharmaceutically acceptable solvent such as water (‘hydrate’), ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • composition refers to a composition comprising a compound according to the invention or a salt or solvate thereof and, as the case may be, one or more additional, non-toxic ingredients, which composition is in a form suitable for administration to a (human) subject, through any route of administration, and which composition is physiologically tolerated upon such administration.
  • compositions of the invention may thus comprise one or more additional ingredients.
  • the composition comprises one or more carriers and/or excipients.
  • the appropriate choice of excipients is dependent on multiple factors, including the physicochemical properties of the API, the preferred pharmaceutical form, the preferred route of administration, the desired rate of release, etc.
  • the compositions of the invention can be formulated for a variety of routes of administration, oral administration being particularly preferred.
  • the composition is preferably provided in a unit dosage form.
  • unit dosage form refers to a physically discrete unit suitable as a unitary dosage for human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with any suitable pharmaceutical carrier(s) and/or excipient(s).
  • Exemplary, non-limiting unit dosage forms include a tablet (e.g., a chewable tablet), caplet, capsule (e.g., a hard capsule or a soft capsule), lozenge, film, strip, gelcap as well as any metered volume of a solution, suspension, syrup or elixir or the like, which may be contained, for instance in a vial, syringe, applicator device, sachet, spray, micropump etc.
  • the unit dosage form is a unit dosage form that is suitable for oral administration. Most preferably, it is a solid unit dosage form, such as a tablet.
  • pharmaceutically acceptable salts thereof may also be used.
  • Pharmaceutically acceptable salts of compounds of the invention include the acid addition and base salts thereof, such as preferably the calcium, potassium or sodium salts.
  • suitable salts reference is made “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • salts of compounds according to the invention may be readily prepared by mixing together solutions of compounds according to the invention and the desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the salt may vary from completely ionised to almost non-ionised.
  • the compounds and the pharmaceutical compositions of the present invention are useful as inhibitors of tyrosine kinases, in particular of BTK.
  • compounds of this invention are useful as inhibitors of tyrosine kinases that are important in hyper-proliferative diseases, especially in cancer, such as a B-cell hematological malignancy, and in the process of angiogenesis.
  • reversible BTK inhibitor compounds according to the invention having Formula (l-a) to (l-h) and pharmaceutical compositions comprising these, either alone or in combination with an irreversible BTK inhibitor, thereof can be used to treat or prevent a variety of conditions, diseases or disorders mediated by Bruton’s Tyrosine kinase (BTK).
  • BTK Tyrosine kinase
  • Such conditions, diseases or disorders include: cancers or tumors, including alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, breast and mammary cancer, ovarian cancer, prostate cancer, B-cell hematological malignancy, lymphoma and leukemia (including but not limited to acute myelogenous leukemia, chronic myelogenous leukemia, mantle cell lymphoma, NHL B cell lymphomas (e.g.
  • B-ALL marginal zone B-cell lymphoma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt lymphoma, mediastinal large B-cell lymphoma), Hodgkin lymphoma, NK and T cell lymphomas, TEL-Syk and ITK-Syk fusion driven tumors, myelomas including multiple myeloma, myeloproliferative disorders kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, Kaposi’s sarcoma, proliferative diabetic retinopathy, and angiogenic- associated disorders including solid tumors, and pancreatic cancer.
  • the hyperproliferative disease is a B-cell hematological malignancy.
  • the B-cell hematological malignancy is any one of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center diffuse large B-cell lymphoma (GCB DLBCL), primary mediastinal B-cell lymphoma (PMBL), non- Hodgkin lymphoma, Burkitt’s lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, precursor B-cell acute lymphoblastic leukemia, hairy cell leukemia, mantle cell lymphoma, B cell prolymphocytic leukemia, lym- phoplasmacytic lymphoma/Walden
  • the B-cell hematological malignancy is mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), diffuse large 13- cell lymphoma (DLBCL), Waldenstrom macroglobulinemia (WM), follicular lymphoma (FL) and marginal zone lymphoma (MZL).
  • MCL mantle cell lymphoma
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • DLBCL diffuse large 13- cell lymphoma
  • WM Waldenstrom macroglobulinemia
  • FL follicular lymphoma
  • MZL marginal zone lymphoma
  • the B-cell malignancy is Mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).
  • MCL Mantle cell lymphoma
  • CLL chronic lymphocytic leukemia
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • compositions for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or aa nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds can be formulated for parenteral administration by injection, e.g. bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly or by intramuscular injection).
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be the VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co- solvent system (VPD:5W) consists of VPD diluted 1 :1 with a 5% dextrose in water solution.
  • This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • salts may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.
  • the compounds of the present invention can be prepared by methods well known in the art of organic chemistry. See, for example, J. March, ‘Advanced Organic Chemistry' 4 th Edition, John Wiley and Sons. During synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is achieved by means of conventional protecting groups, such as those described in T.W. Greene and P.G.M. Wutts ‘Protective Groups in Organic Synthesis’ 3 rd Edition, John Wiley and Sons, 1999. The protective groups are optionally removed at a convenient subsequent stage using methods well known in the art.
  • the products of the reactions are optionally isolated and purified, if desired, using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography and the like. Such materials are optionally characterized using conventional means, including physical constants and spectral data.
  • Methyl (1 R,3R)-3-aminocyclohexanecarboxylate hydrochloride (1 .06 g, 5.47 mmol) was suspended in 10 mL water.
  • Sodium bicarbonate (1 .38 g, 16.4 mmol) in 10 mL water was added followed by a drop-wise addition of a solution N-(benzyloxycarbonyloxy)succinimide (1 .50 g, 6.01 mmol) in dioxane (30 mL).
  • the reaction mixture was stirred at room temperature o/n.
  • the mixture was diluted with ethyl acetate (50 mL) and water (50 mL) and the bi-phasic system was stirred 30 minutes at room temperature.
  • Triethylamine (10.4 mL, 74.62 mmol), 4-dimethylaminopyridine (605 mg, 4.95 mmol) and di-tert-butyl dicarbonate (13.5 g, 61 .86 mmol) were added sequentially to a solution of 4- nitrobenzene sulfonamide (10 g, 49.46 mmol) in dichloromethane (100 mL).
  • the reaction mixture was stirred for 30 minutes at room temperature.
  • hydrochloric acid (1 N aqueous solution) until it becomes acidic.
  • the organic layer was separated and washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered and then concentrated under reduced pressure.
  • Example A Compound A Example A
  • the reaction mixture was stirred for 3 h. allowing the temperature to come to room temperature.
  • the mixture was quenched with 10% aq. Na2S2O4-solution/5% aq. NaHSO 3 -solution/brine and ethyl acetate.
  • the phases were separated and the water layer was extracted with ethyl acetate.
  • the combined organic phases were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • E Ethyl (E)-8-[1 -bromo-3-[(1 R,3R)-3-(tert-butoxycarbonylamino)cyclohexyl]-8-[(2,4-dime- thoxyphenyl)methylamino]imidazo[1 ,5-a]pyrazin-5-yl]oct-7-enoate (18.85 g, 25.86 mmol) was dissolved in dichloromethane (129 mL). Trifluoroacetic acid (19.2 mL) was added and the mixture was stirred at rroooomm temperature for 2 h.
  • Lithium (E)-8-[3-[(1 R,3R)-3-aminocyclohexyl]-1 -bromo-8-[(2,4-dimethoxyphenyl)- methylamino]imidazo[1 ,5-a]pyrazin-5-yl]oct-7-enoate (9.14 g, 15.07 mmol) was suspended dissolved in DMF (520 mL) and N-ethylmorpholine (3.83 mL, 30.14 mmol) was added.
  • Compound A as described herein is the same compound as compound having subformula 184 of co-pending PCT application PCT/EP2022/085765. Said compound having subformula 184 is also incorporated by reference.
  • TMD8 diffuse large B-cell lymphoma cells were purchased from Tokyo Medical and Dental University. TMD8 cells expressing mutant BTK were created at Synthego Corporation. TMD8 cell lines expressing BTK C481S, BTK T474I, BTK T474I/C481S, BTK V416L and BTK L528W were generated via CRISPR/Cas9. BTK T474I/C481S expressing cells were generated by re- editing BTK C481S cells. TMD8 mutant cell pools were enriched to obtain a 100% mutant genotype. The mutation status of all cell lines was confirmed via sequencing. Cells were cultured in MEM-alpha cell culture medium (cat. no. 22571038, Life Technologies), supplemented with 10% (v/v) heat-inactivated fetal bovine calf serum (Avantor, cat. no. 97068085) and 1 % penicillin/streptomycin.
  • Inhibition of proliferation in response to compound was measured using the ATPIite 1 StepTM assay (cat. no. 6016736, Perkin Elmer).
  • Percentage viability was used as the main y-axis signal.
  • IC 50 s were fitted by non-linear regression using IDBS XLfitTM 5 using a 4-parameter logistic curve, yielding a maximum signal, minimum signal, hill-parameter and IC 50 .
  • efficacy, Gl 50 and LD 50 were also determined.
  • WT-BTK, BTK C481S, BTK T474I, BTK T474I/C481S, BTK V416L and BTK L528W TMD8 cell lines were seeded at 800 cells per well in a white 384-well culture plate (cat. no. 781080, Greiner Bio-One) and allowed to rest for at least 4 hours at 37 °C, 95 % humidity, and 5 % CO 2 .
  • Compound A pirtobrutinib, ibrutinib, acalabrutinib and nemtabrutinb were diluted in 3.16-fold dilution steps in 100% DMSO and further diluted in 20 mM Hepes, generating a dose response range from 316 nM to 0.0316 nM in the assay.
  • DMSO was used as a vehicle control.
  • Luminescence was recorded at 96 hours.
  • BTK C481S TMD8 cells were seeded at 800 cells per well in a white 384-well culture plate (cat. no. 781080, Greiner Bio-One) and allowed to rest for at least 4 hours at 37 °C, 95 % humidity, and 5 % CO 2 .
  • Compound A was diluted in 3.16-fold dilution steps in 100% DMSO and further diluted in 20 mM Hepes, generating a dose response range from 316 nM to 0.0316 nM in the assay.
  • Ibrutinib or acalabrutinib was added in a fixed, inactive concentration to each concentration of Compound A, ranging from 316 nM to 0.316 nM.
  • DMSO was used as a vehicle control.
  • Luminescence was recorded at 96 hours. Anti-proliferative responses were assessed by 1 ) determining IC 50 shifts of the combinations at 96 hours compared to the single compounds, in which an leftward IC 50 shift of factor 2 is indicative of synergy; 2) calculating excess over Bliss scores (Lui et al. 2018).
  • the BTK C481S TMD8 cell line was combined with either BTK T474I, BTK V416L or BTK L528W TMD8 cell lines and seeded at 800 cells per well for each cell line (1600 cells/well total) in white 384-well culture plates (cat. no. 781080, Greiner Bio-One). Cells were allowed to rest for at least 4 hours at 37 °C, 95 % humidity and 5 % CO 2 . Ibrutinib or acalabrutinib were diluted in 3.16-fold dilution steps in 100% DMSO and further diluted in 20 mM Hepes, generating a 9-point dose response range from 316 nM to 0.0316 nM in the assay.
  • Compound A was added in a fixed concentration to each concentration of ibrutinib or acalabrutinib, ranging from 316 nM to 0.316 nM.
  • DMSO was used as a vehicle control.
  • Luminescence was recorded at 96 hours.
  • Anti- proliferative responses were assessed 1 ) calculating efficacy of the single compounds and the combination compounds, compared to vehicle control at 96h, and 2) calculating the gain in efficacy of the combination compared to the single compounds.
  • Binding kinetics measurements on wt-BTK, BTK C481S, BTK T474I (Surface Plasmon Resonance) Streptavidin-coated chips (Cat. No. BR100531 ), disposables and maintenance kits for Biacore were purchased from Cytiva (Eindhoven, The Netherlands). Biotinylated BTK WT enzym (Carna Biosciences, cat. no. 08-480-20N), BTK C481S (Carna Biosciences, cat. no. 08- 417-20N), BTK T474I (Carna Biosciences, cat. no.
  • the kinetic constants of the compounds were determined with single cycle kinetics with five consecutive injections with an increasing 15 compound concentration with ranges of 3.16 - 316 nM. Experiments were performed with an association time of 100 s per concentration and a dissociation time of 1200 s, except for compounds with a long target residence time, such as irreversible inhibitors, where dissociation time was increased. To circumvent problems of mass transport limitation, a flow rate of 30 ⁇ l/min was used. A blank run with the same conditions was performed before the compound was 20 injected. The SPR sensorgrams were analyzed with Biacore Evaluation Software by using a method of double referencing. First the reference channel was subtracted from the channel containing immobilized protein.
  • Table 7 Proliferation data for compounds in a mixture of BTK C481S TMD8 cells + BTK V416L TMD8 cells.
  • each concentration of ibrutinib contained the indicated concentration of Compound A.
  • Vehicle treated cells represent 100% viability.
  • each concentration of ibrutinib contained the indicated concentration of Compound A.
  • Vehicle treated cells represent 100% viability.
  • each concentration of ibrutinib contained the indicated concentration of Compound A.
  • Vehicle treated cells represent 100% viability.
  • each concentration of acalabrutinib contained the indicated concentration of Compound A.
  • Vehicle treated cells represent 100% viability.
  • each concentration of acalabrutinib contained the indicated concentration of Compound A.
  • Vehicle treated cells represent 100% viability. Efficacy was calculated by subtracting % viability of the indicated concentrations from vehicle treated cells.
  • each concentration of acalabrutinib contained the indicated concentration of Compound A.
  • Vehicle treated cells represent 100% viability. Efficacy was calculated by subtracting % viability of the indicated concentrations from vehicle treated cells.
  • Compound A was tested in combination with fixed concentrations of ibrutinib in BTK C481S TMD8 cells, see Figure 17A - 17G.
  • IC 50 shifts were determined by comparing the individual IC 50 s of Compound A and ibrutinib with the IC 50 of the combination. In the combination each concentration of compound A contained the indicated concentration of ibrutinib. A leftward IC 50 shift of factor >2 is indicative of synergy (pIC 50 (M) of >0.30).
  • IC 50 shifts were determined by comparing the individual IC 50 s of Compound A and acalabrutinib with the IC 50 of the combination. In the combination each concentration of compound A contained the indicated concentration of acalabrutinib.
  • a leftward IC 50 shift of factor >2 is indicative of synergy (pIC 50 (M) of >0.30).
  • Table 18 KD and Target residence times (T (h)) for BTK inhibitors on wt-BTK, BTK C481S, BTK T474I measured with SPR.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des combinaisons thérapeutiques d'un inhibiteur de BTK irréversible et d'un inhibiteur de BTK réversible macrocyclique et un procédé de traitement d'un sujet ayant une maladie hyperproliférative, en particulier une malignité hématologique des lymphocytes B, lequel sujet reçoit ou a reçu un inhibiteur de tyrosine kinase de Bruton (BTK) pour le traitement de la maladie hyperproliférative, à l'aide desdites combinaisons thérapeutiques. La présente invention concerne en outre un procédé de traitement d'un sujet diagnostiqué avec ou présentant un risque d'une forme récurrente ou réfractaire d'une maladie hyperproliférative, en particulier une malignité hématologique des lymphocytes B, ledit sujet ayant été préalablement traité avec un inhibiteur irréversible de BTK, à l'aide desdites combinaisons thérapeutiques. Dans des modes de réalisation particuliers, le procédé comprend : a) la surveillance du patient au cours d'une thérapie pour déterminer si le sujet a une mutation C481 dans BTK et b) la co-administration au patient d'un inhibiteur de BTK irréversible et d'un inhibiteur de BTK réversible macrocyclique si le patient a une mutation C481 dans la BTK. L'invention concerne en outre un procédé de traitement d'un sujet ayant une maladie hyperproliférative, en particulier une malignité hématologique des lymphocytes B, le traitement comprenant l'administration desdites combinaisons thérapeutiques.
PCT/EP2023/064844 2023-06-02 2023-06-02 Combinaisons thérapeutiques d'un inhibiteur de btk irréversible et d'un inhibiteur de btk réversible macrocyclique Pending WO2024245578A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP2023/064844 WO2024245578A1 (fr) 2023-06-02 2023-06-02 Combinaisons thérapeutiques d'un inhibiteur de btk irréversible et d'un inhibiteur de btk réversible macrocyclique

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2023/064844 WO2024245578A1 (fr) 2023-06-02 2023-06-02 Combinaisons thérapeutiques d'un inhibiteur de btk irréversible et d'un inhibiteur de btk réversible macrocyclique

Publications (1)

Publication Number Publication Date
WO2024245578A1 true WO2024245578A1 (fr) 2024-12-05

Family

ID=86776532

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/064844 Pending WO2024245578A1 (fr) 2023-06-02 2023-06-02 Combinaisons thérapeutiques d'un inhibiteur de btk irréversible et d'un inhibiteur de btk réversible macrocyclique

Country Status (1)

Country Link
WO (1) WO2024245578A1 (fr)

Citations (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013010380A1 (fr) 2011-07-19 2013-01-24 Merck Sharp & Dohme Corp. Inhibiteurs de btk
WO2013067274A1 (fr) 2011-11-03 2013-05-10 Genentech, Inc. Composés hétéroaryl pyridones et aza-pyridones en tant qu'inhibiteurs de l'activité btk
WO2013185084A1 (fr) 2012-06-08 2013-12-12 Biogen Idec Ma Inc. Inhibiteurs de tyrosine kinase au pyrimidinyle
WO2014018567A1 (fr) * 2012-07-24 2014-01-30 Pharmacyclics, Inc. Mutations associées à la résistance à des inhibiteurs de la tyrosine kinase de bruton (btk)
WO2014104757A1 (fr) 2012-12-28 2014-07-03 크리스탈지노믹스(주) Dérivé 2,3-dihydro-isoindole-1-one utilisé comme suppresseur de kinase btk, et composition pharmaceutique associée
WO2015012149A1 (fr) 2013-07-26 2015-01-29 カルナバイオサイエンス株式会社 Nouveau dérivé triazine
WO2016109222A1 (fr) 2014-12-31 2016-07-07 Merck Sharp & Dohme Corp. Composés alcool tertiaire imidazopyrazine inhibiteurs de la btk
WO2016106628A1 (fr) 2014-12-31 2016-07-07 Merck Sharp & Dohme Corp. Inhibiteurs de btk
WO2016106625A1 (fr) 2014-12-31 2016-07-07 Merck Sharp & Dohme Corp. Inhibiteurs de btk
WO2016106623A1 (fr) 2014-12-31 2016-07-07 Merck Sharp & Dohme Corp. Composés benzamides et imidazopyrazines utilisés comme inhibiteurs de la btk
WO2016106626A1 (fr) 2014-12-31 2016-07-07 Merck Sharp & Dohme Corp. Analogues de l'imidazopyrazine avec substitutions sur carbone tertiaire 3 en tant qu'inhibiteurs de btk
WO2016161570A1 (fr) 2015-04-08 2016-10-13 Merck Sharp & Dohme Corp. Inhibiteurs azacarbazole de la btk
WO2016161571A1 (fr) 2015-04-08 2016-10-13 Merck Sharp & Dohme Corp. Inhibiteurs de la btk de type indazole et azaindazole
WO2017046604A1 (fr) 2015-09-16 2017-03-23 Redx Pharma Plc Dérivés de pyrazolopyrimidine comme inhibiteurs de btk pour le traitement du cancer
WO2017103611A1 (fr) 2015-12-16 2017-06-22 Redx Pharma Plc Composés utilisés comme inhibiteurs de kinase
WO2017111787A1 (fr) 2015-12-23 2017-06-29 Arqule, Inc. Tétrahydropyranyl-amino-pyrrolopyrimidinone et procédés d'utilisation associés
WO2018097234A1 (fr) 2016-11-25 2018-05-31 カルナバイオサイエンス株式会社 Nouveau dérivé d'oxoisoquinoline
WO2018191577A1 (fr) 2017-04-14 2018-10-18 Biogen Ma Inc. Analogues de benzoazépine utilisés en tant qu'agents inhibiteurs de la tyrosine kinase de bruton
WO2020015735A1 (fr) 2018-07-20 2020-01-23 正大天晴药业集团股份有限公司 Inhibiteurs de la tyrosine kinase de bruton
WO2020043638A1 (fr) 2018-08-28 2020-03-05 Merck Patent Gmbh Imidazopyridines condensées utilisées comme inhibiteurs réversibles de la tyrosine kinase de bruton (btk)
WO2020239124A1 (fr) 2019-05-31 2020-12-03 Fochon Pharmaceuticals, Ltd. Dérivés de pyrrolo [2, 3-b] pyridine et de pyrazolo [3,4-b] pyridine substitués en tant qu'inhibiteurs de protéine kinase
WO2021093839A1 (fr) 2019-11-13 2021-05-20 南京明德新药研发有限公司 Composé pyrrolopyrimidine utilisé comme inhibiteur de btk et son utilisation
WO2023110970A1 (fr) * 2021-12-14 2023-06-22 Netherlands Translational Research Center Holding B.V Inhibiteurs macrocycliques de btk
WO2023110936A1 (fr) * 2021-12-14 2023-06-22 Netherlands Translational Research Center Holding B.V Inhibiteurs de kinase réversibles macrocycliques

Patent Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013010380A1 (fr) 2011-07-19 2013-01-24 Merck Sharp & Dohme Corp. Inhibiteurs de btk
WO2013067274A1 (fr) 2011-11-03 2013-05-10 Genentech, Inc. Composés hétéroaryl pyridones et aza-pyridones en tant qu'inhibiteurs de l'activité btk
WO2013185084A1 (fr) 2012-06-08 2013-12-12 Biogen Idec Ma Inc. Inhibiteurs de tyrosine kinase au pyrimidinyle
WO2014018567A1 (fr) * 2012-07-24 2014-01-30 Pharmacyclics, Inc. Mutations associées à la résistance à des inhibiteurs de la tyrosine kinase de bruton (btk)
WO2014104757A1 (fr) 2012-12-28 2014-07-03 크리스탈지노믹스(주) Dérivé 2,3-dihydro-isoindole-1-one utilisé comme suppresseur de kinase btk, et composition pharmaceutique associée
WO2015012149A1 (fr) 2013-07-26 2015-01-29 カルナバイオサイエンス株式会社 Nouveau dérivé triazine
WO2016109222A1 (fr) 2014-12-31 2016-07-07 Merck Sharp & Dohme Corp. Composés alcool tertiaire imidazopyrazine inhibiteurs de la btk
WO2016106628A1 (fr) 2014-12-31 2016-07-07 Merck Sharp & Dohme Corp. Inhibiteurs de btk
WO2016106625A1 (fr) 2014-12-31 2016-07-07 Merck Sharp & Dohme Corp. Inhibiteurs de btk
WO2016106623A1 (fr) 2014-12-31 2016-07-07 Merck Sharp & Dohme Corp. Composés benzamides et imidazopyrazines utilisés comme inhibiteurs de la btk
WO2016106626A1 (fr) 2014-12-31 2016-07-07 Merck Sharp & Dohme Corp. Analogues de l'imidazopyrazine avec substitutions sur carbone tertiaire 3 en tant qu'inhibiteurs de btk
WO2016106624A1 (fr) 2014-12-31 2016-07-07 Merck Sharp & Dohme Corp. Inhibiteurs de la btk comprenant une imidazopyrazine d'alcool tertiaire
WO2016161570A1 (fr) 2015-04-08 2016-10-13 Merck Sharp & Dohme Corp. Inhibiteurs azacarbazole de la btk
WO2016161571A1 (fr) 2015-04-08 2016-10-13 Merck Sharp & Dohme Corp. Inhibiteurs de la btk de type indazole et azaindazole
WO2017046604A1 (fr) 2015-09-16 2017-03-23 Redx Pharma Plc Dérivés de pyrazolopyrimidine comme inhibiteurs de btk pour le traitement du cancer
WO2017103611A1 (fr) 2015-12-16 2017-06-22 Redx Pharma Plc Composés utilisés comme inhibiteurs de kinase
WO2017111787A1 (fr) 2015-12-23 2017-06-29 Arqule, Inc. Tétrahydropyranyl-amino-pyrrolopyrimidinone et procédés d'utilisation associés
WO2018097234A1 (fr) 2016-11-25 2018-05-31 カルナバイオサイエンス株式会社 Nouveau dérivé d'oxoisoquinoline
WO2018191577A1 (fr) 2017-04-14 2018-10-18 Biogen Ma Inc. Analogues de benzoazépine utilisés en tant qu'agents inhibiteurs de la tyrosine kinase de bruton
WO2020015735A1 (fr) 2018-07-20 2020-01-23 正大天晴药业集团股份有限公司 Inhibiteurs de la tyrosine kinase de bruton
WO2020043638A1 (fr) 2018-08-28 2020-03-05 Merck Patent Gmbh Imidazopyridines condensées utilisées comme inhibiteurs réversibles de la tyrosine kinase de bruton (btk)
WO2020239124A1 (fr) 2019-05-31 2020-12-03 Fochon Pharmaceuticals, Ltd. Dérivés de pyrrolo [2, 3-b] pyridine et de pyrazolo [3,4-b] pyridine substitués en tant qu'inhibiteurs de protéine kinase
WO2021093839A1 (fr) 2019-11-13 2021-05-20 南京明德新药研发有限公司 Composé pyrrolopyrimidine utilisé comme inhibiteur de btk et son utilisation
WO2023110970A1 (fr) * 2021-12-14 2023-06-22 Netherlands Translational Research Center Holding B.V Inhibiteurs macrocycliques de btk
WO2023110936A1 (fr) * 2021-12-14 2023-06-22 Netherlands Translational Research Center Holding B.V Inhibiteurs de kinase réversibles macrocycliques

Non-Patent Citations (34)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 2000, MEADE PUBLISHING CO.
AL-LAZIKANI BBANERJI UWORKMAN P: "Combinatorial drug therapy for cancer in the post-genomic era", NATURE BIOTECH, vol. 30, 2012, pages 679 - 682
ATTWOOD M.M. ET AL.: "Trends in kinase drug discovery targets, indications and inhibitor design", NAT REV DRUG DISCOV, vol. 20, 2021, pages 839 - 861, XP037602806, DOI: 10.1038/s41573-021-00252-y
BODOR ET AL., BRITISH JOURNAL OF HAEMATOLOGY, 2021
BODOR, C., KOTMAYER, L., LASZLΔ, T., TAKACS, F., BARNA, G., KISS, R., SEBESTYEN, E., NAGY, T., HEGYI, L., MIKALA, G., FEKETE, S. P: "Screening and monitoring of the BTK C481 S mutation in a real-world cohort of patients with relapsed/refractory chronic lymphocytic leukaemia during ibrutinib therapy", JOURNAL OF HAEMATOLOGY, vol. 194, no. 2, 2021, pages 355 - 364
BORISY AAELLIOTT PJHURST NWLEE MSLEHAR JPRICE ER ET AL.: "Systematic discovery of multicomponent therapeutics", PROC NATL ACAD SCI USA, vol. 100, 2003, pages 7977 - 7982, XP009061663, DOI: 10.1073/pnas.1337088100
CHOU TC: "Drug combination studies and their synergy quantification using the Chou-Talalay method", CANCER RES, vol. 70, 2010, pages 440 - 446, XP055169871, DOI: 10.1158/0008-5472.CAN-09-1947
COKOL M, CHUA HN, TASAN M, MUTLU B, WEINSTEIN ZB, SUZUKI Y: "Systematic exploration of synergistic drug pairs", MOLECULAR SYSTEMS BIOLOGY, vol. 7, 2011, pages 544
CRAWFORD, J.JOHNSON, A. R.MISNER, D.BELMONT, L. D.CASTANEDO, G.CHOY, R.CORAGGIO, M.DONG, L.EIGENBROT, C.ERICKSON, R. J.: "Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development", JOURNAL OF MEDICINAL, vol. 61, no. 6, 2018, pages 2227 - 1145, XP055685494, DOI: 10.1021/acs.jmedchem.7b01712
GARNETT MJEDELMAN EJHEIDORN SJGREENMAN CDDASTUR ALAU KW ET AL.: "Systematic identification of genomic markers of drug sensitivity in cancer cells", NATURE, vol. 483, 2012, pages 570 - 575, XP055186003, DOI: 10.1038/nature11005
GU DANLING ET AL: "Targeting Bruton tyrosine kinase using non-covalent inhibitors in B cell malignancies", JOURNAL OF HEMATOLOGY & ONCOLOGY, vol. 14, no. 1, 6 March 2021 (2021-03-06), pages 40, XP055861303, Retrieved from the Internet <URL:https://jhoonline.biomedcentral.com/track/pdf/10.1186/s13045-021-01049-7.pdf> DOI: 10.1186/s13045-021-01049-7 *
HOPKINS, B.BAME, E.BAJRAMI, B.BLACK, C. A.BOHNERT, T.BOISELLE, C.BURDETTE, D.BURNS, J. C.DELVA, L.DONALDSON, D.: "Discovery and Preclinical Characterization of BIIB091, a Reversible, Selective BTK Inhibitor for the Treatment of Multiple Sclerosis", JOURNAL OF MEDICINAL CHEMISTRY, vol. 65, no. 2, 2021, pages 1206 - 1224, XP093034944, DOI: 10.1021/acs.jmedchem.1c00926
KAWAHATA, W., ASAMI, T., KIYOI, T., IRIE, T., KASHIMOTO, S., FURUICHI, H., SAWA, M.: "Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton's Tyrosine Kinase", JOURNAL OF MEDICINAL CHEMISTRY, vol. 64, no. 19, 2021, pages 14129 - 14141, XP055930428, DOI: 10.1021/acs.jmedchem.1c01279
KAWAHATA, W., ASAMI, T., KIYOI, T., IRIE, T., TANIGUCHI, H., ASAMITSU, Y., INOUE, T., MIYAKE T, SAWA M: "Design and Synthesis of Novel Amino-triazine Analogues as Selective Bruton's Tyrosine Kinase Inhibitors for Treatment of Rheumatoid Arthritis", JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, no. 19, 2018, pages 8917 - 8933
LI FZHAO CWANG L: "Molecular-targeted agents combination therapy for cancer: developments and potentials", INT J CANCER, vol. 134, 2014, pages 1257 - 1269, XP055517584, DOI: 10.1002/ijc.28261
LIU, Q.YIN, X.LANGUINO, L. R.ALTIERI, D. C.: "Evaluation of Drug Combination Effect Using a Bliss Independence Dose-Response Surface Model", STATISTICS IN BIOPHARMACEUTICAL RESEARCH, vol. 10, no. 2, 2018, pages 112 - 122, XP093053632, DOI: 10.1080/19466315.2018.1437071
MATHEWS GRINER LAGUHA RSHINN PYOUNG RMKELLER JMLIU D ET AL.: "High throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells", PROC NATL ACAD SCI USA, vol. 111, 2014, pages 2349 - 2354, XP055218384, DOI: 10.1073/pnas.1311846111
NAKHODA, S.VISTAROP, A.WANG, Y. L: "Resistance to Bruton tyrosine kinase inhibition in chronic lymphocytic leukaemia and non-Hodgkin lymphoma", BRITISH JOURNAL, vol. 200, no. 2, 2022, pages 137 - 149
R. BAROUCH-BENTOV, K. SAUER: "Mechanisms of drug resistance in kinases", EXP. OPIN. INVEST. DRUGS, vol. 20, 2011, pages 153 - 208
REIFF, S. D.MANTEL, R.SMITH, L.GREENE, J. E.MUHOWSKI, E. M.FABIAN, C. A.GOETTL, V. M.TRAN, M. T.HARRINGTON, B. K.ROGERS, K. A.: "The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation", CANCER DISCOVERY, vol. 8, no. 10, 2018, pages 1300 - 1315, XP055939114, DOI: 10.1158/2159-8290.CD-17-1409
REIFF, S. D.MUHOWSKI, E. M.GUINN, D.LEHMAN, A.FABIAN, C. A.CHENEY, C.MANTEL, R.SMITH, L.JOHNSON, A. J.YOUNG, W. B.: "Noncovalent inhibition of C481S Bruton tyrosine kinase by GDC-0853: a new treatment strategy for ibrutinib-resistant CLL", BLOOD, vol. 132, no. 10, 2018, pages 1039 - 1049
STAHLWERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH
STRAETEMANS RO'BRIEN TWOUTERS LVAN DUN JJANICOT M ET AL.: "Design and analysis of drug combination experiments", BIOMETRICAL J, vol. 47, 2005, pages 299 - 308, XP071616797, DOI: 10.1002/bimj.200410124
T.W. GREENEP.G.M. WUTTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY AND SONS
THIEME, E.LIU, T.BRUSS, N.ROLEDER, C.LAM, V.WANG, X.NECHIPORUK, T.SHOUSE, G.DANILOVA, O. V.BOTTOMLY, D.: "Dual BTK/SYK inhibition with CG-806 (luxeptinib) disrupts B-cell receptor and Bcl-2 signaling networks in mantle cell lymphoma", CELL DEATH AND DISEASE, vol. 13, no. 3, 2022
THOMPSON PHILIP A ET AL: "Pirtobrutinib: a new hope for patients with BTK inhibitor-refractory lymphoproliferative disorders", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 141, no. 26, 10 May 2023 (2023-05-10), pages 3137 - 3142, XP087346928, ISSN: 0006-4971, [retrieved on 20230510], DOI: 10.1182/BLOOD.2023020240 *
WANG ET AL., N. ENGL. J. MED., vol. 386, 2022, pages 735 - 43
WANG, E. W., MI, X., THOMPSON, M. C., MONTOYA, S., NOTTI, R. Q., AFAGHANI, J.,DURHAM, B. H., PENSON, A. V., WITKOWSKI, M. T., LU, : "Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 386, no. 8, 2022, pages 735 - 743
WATTERSON, S. H.DE LUCCA, G. V.SHI, Q.LANGEVINE, C. M.LIU, Q.BATT, D. G.BERTRAND, M. B.GONG, H.DAI, J.YIP, S.: "Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142", JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, no. 19, 2016, pages 9173 - 9200, XP055449340, DOI: 10.1021/acs.jmedchem.6b01088
WEI, L.SU, Y.LIN, C. MCHAO, T. Y.HUANG, S.HUYNH, T. D.JAN, H. J.WHANG-PENG, J.CHIOU, J. F.WU, A. T.: "Preclinical investigation of ibrutinib, a Bruton's kinase tyrosine (Btk) inhibitor, in suppressing glioma tumorigenesis and stem cell phenotypes", ONCOTARGET, vol. 7, no. 43, 2016, pages 69961 - 69975, XP055649279, DOI: 10.18632/oncotarget.11572
WOYACH, J. A.RUPPERT, A. S.GUINN, D.LEHMAN, A.BLACHLY, J. S.LOZANSKI, A.HEEREMA, N. A.ZHAO, W.COLEMAN, J. T.JONES, D. B.: "BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia", JOURNAL OF CLINICAL ONCOLOGY, vol. 35, no. 13, 2017, pages 1437 - 1443
WOYACH, J. CLIN. ONCOL., vol. 35, 2017, pages 1437 - 1443
YAP TAOMLIN ADE BONO JS: "Development of therapeutic combinations targeting major cancer signaling pathways", J CLINICAL INVEST, vol. 20, 2013, pages 1592 - 1605, XP009184619, DOI: 10.1200/JCO.2011.37.6418
ZHAO L, WIENTJES MG, AU JLS: "Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram and combination index analyses", CLIN CANC RES, vol. 10, 2004, pages 7994 - 8004

Similar Documents

Publication Publication Date Title
US12310968B2 (en) Chiral diaryl macrocycles and uses thereof
TWI859406B (zh) 化合物及其用途
US12441726B2 (en) Compounds and uses thereof
TWI837478B (zh) 用於治療ｂｒａｆ相關的疾病和病症之化合物
EP3843850B1 (fr) Composés pyrazolo[3,4-b]pyridine utilisés en tant qu&#39;inhibiteurs de kinases tam et met
DK2663564T3 (en) IMIDAZO [4,5-C] QUINOLIN-2-ON COMPOUND AND ITS USE AS PI3-KINASE / MTOR DUAL INHIBITOR
KR102460362B1 (ko) 자가면역 질환의 치료 및 예방을 위한 2-치환된 인다졸의 용도
WO2022109426A1 (fr) Composés et utilisations associées
TWI864749B (zh) 化合物及其用途
US12264151B2 (en) Substituted diamino heterocyclic carboxamide compound and a composition containing the compound and use thereof
AU2022409472A1 (en) Macrocyclic btk inhibitors
WO2024245578A1 (fr) Combinaisons thérapeutiques d&#39;un inhibiteur de btk irréversible et d&#39;un inhibiteur de btk réversible macrocyclique
WO2024246287A1 (fr) Utilisation médicale d&#39;un inhibiteur de btk réversible macrocyclique
TW201504239A (zh) 蛋白酪氨酸激酶抑制劑及其應用
WO2024245577A1 (fr) Combinaisons thérapeutiques d&#39;un inhibiteur irréversible de btk et d&#39;un inhibiteur réversible de btk
RU2814662C1 (ru) Соединения 4-оксо-3,4-дигидрохиназолинона для лечения braf-ассоциированных заболеваний и нарушений
WO2025222132A1 (fr) Composés et leurs utilisations
WO2025222125A1 (fr) Composés et leurs utilisations
WO2025222187A1 (fr) Composés et leurs utilisations
WO2025222158A1 (fr) Composés et leurs utilisations
EA047636B1 (ru) Соединения и способы их применения
BR112018074919B1 (pt) Uso de indazóis 2-substituídos para preparação de medicamento para tratamento e profilaxia de doenças autoimunes

Legal Events

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

Ref document number: 23731158

Country of ref document: EP

Kind code of ref document: A1