WO2022081512A1 - Compositions and methods of treatment of neuroinflammatory diseases with bruton's tyrosine kinase inhibitors - Google Patents

Compositions and methods of treatment of neuroinflammatory diseases with bruton's tyrosine kinase inhibitors Download PDF

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WO2022081512A1
WO2022081512A1 PCT/US2021/054482 US2021054482W WO2022081512A1 WO 2022081512 A1 WO2022081512 A1 WO 2022081512A1 US 2021054482 W US2021054482 W US 2021054482W WO 2022081512 A1 WO2022081512 A1 WO 2022081512A1
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btk
cas
amino
compound
formula
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French (fr)
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Maria Morabito
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Synubi Pharmaceuticals Llc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • A61K31/505—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
    • A61K31/505—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

Definitions

  • the present invention relates to pharmaceutical compositions encompassing a variety of Bruton ’s tyrosine kinase (BTK) inhibitors which are suitable in the treatment of a variety of neuroinflammatory disorders, including a number of neurological and psychiatric diseases.
  • BTK tyrosine kinase
  • Neuroinflammation has a pathological role in a number of neurological and psychiatric diseases. Neuroinflammation has been observed in but not limited to disorders such Alzheimer’s, Parkinson’s, major depression, bipolar, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders, anxiety, neuropathic and chronic pain, addiction and ADHD (Prata et al., (2017) J.
  • AD Alzheimer’ s disease
  • a ⁇ amyloid-p
  • NFTs intraneuronal tau-containing neurofibrillary tangles
  • NTs neuropil threads
  • glial activation neuroinflammation
  • synapse elimination neuronal degeneration and neuron cell death.
  • WHO World Health Organization (2017) Dementia factsheet: www.who.int/mediacentre/factsheets/fs362/en/.
  • the incidence of AD increases with age, and the prevalence is growing as a result of the ageing of the population. It is expected that by the year 2050, the number of Americans aged 65 and older with AD is projected to reach 12.7 million (Alzheimer Association, 2021).
  • AD progression with neuroinflammation in particular with aspects of the innate immune response that are overactivated in AD.
  • Persistent activation of microglia is a component of the innate immune response that is stimulated by chronic deposition of A ⁇ (see, Hansen et al., (2016) “Microglia in Alzheimer’s disease” J. Cell Biol., 217 (2): 459-472).
  • Accumulating evidence demonstrates that a component of the innate immune response, the inflammasome, plays an important role in the inflammatory response in AD.
  • Several drugs are approved by the U.S. Food and Drug Administration (FDA) to treat symptoms of AD. These drugs work by regulating neurotransmitters and may help reduce symptoms and help with certain behavioral problems. For example, donepezil (Aricept®), rivastigmine (Exelon'®), and galantamine (Razadyne®) are used to treat mild to moderate AD (donepezil can be used for severe AD as well). Similarly, memantine (Namenda®), the Exelon®patch, and Namzaric® (a combination of memantine and donepezil) are used to treat moderate to severe AD. However, these drugs may help only for a limited time and are not effective in slowing or halting the underlying disease process.
  • FDA U.S. Food and Drug Administration
  • a number of BTK inhibitors can also be effective agents in controlling neuroinflammation, and therefore, can be used in the treatment of a number of disease conditions associated with the inflammasome pathway.
  • Ibrutinib alleviates LPS-induced neuroinflammation and synaptic defects in a mouse model of depression, Brain Behavior and Immunity, 92, 2021, 10-24).
  • modulating the inflammasome pathway is a potential strategy for suppressing inflammation in the CNS and mitigate the effect of disease states, such as and not limited to AD, Parkinson’s, major depression, bipolar, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders, anxiety, neuropathic and chronic pain, addiction and ADHD (See Figure 1).
  • AD progression has linked AD progression with neuroinflammation, in particular with aspects of the innate immune response that are overactivated in AD.
  • Accumulating evidence demonstrates that chronic deposition of A ⁇ stimulates persistent activation of microglia, particularly of the pro-inflammatory type, A ⁇ activates the NLRP3 inflammasome (a component of the innate immune response) in microgli a, and upregulation of NLRP3 plays an important role in the inflammatory response in AD.
  • BTK is essential for NLRP3 activation, which is upregulated in AD (Saresella M et al., 2016) and is also required for the release of proinflammatory cytokines, such as IL-1 ⁇ (Ito M et al., 2015; Liu X et al., 2017). .Inhibition of BTK is expected to ameliorate neuroinflammatory pathophysiology in these neurological and psychiatric disorders.
  • compositions are provided herein which can be used in a method of treating a vari ety of neurological and psychiatri c disorders associ ated with BTK activity by inhibiting as low about ten percent up to about ninety five percent of the target kinase activity measured as occupancy of the kinase by the inhibitor in peripheral blood mononuclear cells (PBMCs).
  • PBMCs peripheral blood mononuclear cells
  • BTK inhibitors, derivatives or analogs thereof are provided as modulators of kinase activity in the brain to treat neurological and psychiatric disorders associated with BTK activity at lower doses than used to treat a variety of cancers and/or autoimmune disorders as such inhibitors are used in current medical treatments.
  • the doses used in cancer/oncological or autoimmune disorder treatment methods are to be considered “standard” dose/amount of the BTK inhibitor for comparative values.
  • kinase activity of BTK or another kinase is lowered by the presence of, or contact with, the inhibitor relative to the activity of the kinase prior to the presence of, or contact with, the inhibitor under suitable in vivo or in vitro conditions.
  • compositions containing a suitable BTK inhibitor as defined herein wherein the BTK inhibitor concentration/dose is sufficient to target and modulate the tyrosine kinase activity of BTK, thereby lowering or reducing or suppressing the kinase activity of BTK by at least about 10-90 percent, or lower, as compared to the kinase activity of BTK as determined prior to the presence of, or contact with, the inhibitor.
  • a neuroinflammatory disorder which leads to a number of neurological and/or psychiatric disease conditions, including AD, among others, as described herein.
  • Such treatment can also be prophylactic treatment.
  • BTK inhibitors also referred to herein as tyrosine kinase inhibitor agents or BTK inhibitor agents
  • salts or derivatives or analogs thereof as modulators of kinase activity, albeit at much lower doses than standard use doses, to treat a variety of neurodegenerative and psychiatric disorders.
  • a pharmaceutical composition comprises a therapeutically effective amount of BTK inhibitor, including all stereoisomers and enantiomers thereof, or a pharmaceutically acceptable salt or a solvate thereof or a prodrug thereof in combination with a pharmaceutically acceptable carrier, wherein said BTK inhibitor is present in an amount sufficient to inhibit at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or up to about 90 or 95 percent of a target kinase activity as measured as occupancy of the target kinase by inhibitor, and inhibition of enzyme activity, in peripheral blood mononuclear cells (PBMCs) using methods described herein and as known to one skilled in the art.
  • PBMCs peripheral blood mononuclear cells
  • each BTK inhibitor described herein varies with each specific inhibitor and the blood brain barrier allows only a fraction of inhibitor to cross into the brain to effect kinase modulation activity.
  • the measurement of kinase inhibition activity or inhibitor target occupancy in PCMBs of blood are standard methods of measuring the activity of, and therefore efficacy of such kinase inhibitors.
  • the percentage of inhibition can vary for effective treatment of a di sease or disorder associated with BTK activity, and that the percentage of inhibition of BTK activity can fall within a gradient of percentages within the range of percentages described above. For example, a percentage of about 45 % will also encompass a percentage of about 41% to about 49% inhibition, or 41%, 42%, 43% 44%, 46%, 47%, 48% or 49% and so forth for each percentage point described herein.
  • Also encompassed by the present invention are methods of identifying and/or evaluating or assessing the biological activity of molecular inhibitory agents such as drugs that can target the inflammasome pathway for the treatment of a neuroinfl ammatory disorders, including mild to moderate AD.
  • molecular inhibitory agents such as drugs that can target the inflammasome pathway for the treatment of a neuroinfl ammatory disorders, including mild to moderate AD.
  • Such methods include the first step of evaluating the tyrosine kinase activity of BTK or another target kinase at a specific amount, concentration or dose using known suitable conditions and standard laboratory methods. This determined amount would be deemed the control or standard dose for that particular kinase.
  • BTK/kinase inhibitor candidate (or analog or derivative thereof) under the same suitable laboratory conditions as the first step and determining the amount/concentration or dose of inhibitor to partially inhibit tyrosine kinase activity relative to the tyrosine kinase activity prior to the presence of, or contact with, the candidate inhibitor. If the candidate inhibitor inhibits the biological kinase activity by at least about 10 to about 90 percent, the candidate inhibitor is determined to be suitable for the pharmaceutical compositions of this invention.
  • the pharmaceutical compositions according to this invention contains a BTK inhibitor at a dose lower than standard use dose selected from the group consisting of but not limited to: a compound of formula (I), including enantiomers and stereoisomers thereof: a compound of formula (II), including enantiomers and stereoisomers thereof: and a compound of formula (III), including enantiomers and stereoisomers thereof: wherein:
  • X represents CH 2 , O, S, NH, CO, COO or CONH; each of Ari, An and An independently is selected from the group consisting of substituted or unsubstituted (C 6 -C 10 )aryl and substituted or unsubstituted (C 5 -C 10 )heteroaryl, wherein each of said substituents are independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 6 -C 10 )aryloxy; each of R 1 , R 2 and R 3 independently is selected from the group consisting of substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 3 -C 8 )cycloalkyl, substituted or unsubstituted (C 3 -C 8 )heterocycloalkyl, substituted or unsubstituted (C 6 -C 10 )aryl
  • representative examples of Ar1, Ar2 and Ar3 include without any limitation phenyl, 2-, 3- or 4-methylphenyl, pyridyl, 2-, 3- or 4-methylpyridl, and the like.
  • Non-limiting examples of X include O or CONH.
  • Representative examples of R 1 , R 2 R 3 without any limitation include five or six membered heterocycle rings, such as substituted pyrrolidine or piperidine among others. Suitable substituents include without any limitation acryloyl, butynoyl, and the like.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Ibrutinib also known as PCI-32765
  • PCI-32765 l-[(3R)-3-[4-amino-3-(4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidin-l-yl]prop-2-en-l-one
  • Ibrutinib commercially available as a drug under the tradename IMBRUVICA® (Pharmacyclics/Janssen).
  • BTK inhibitors such as ibrutinib and zanubrutinib, bind covalently to the active site, while other BTK inhibitors, such as fenebrutinib and RN486, bind non-covalently. Whether covalent or non-covalent binding results in inhibition, it is noted that the inhibitors still interact with certain key amino acid residues within the BTK catalytic domain.
  • BTK inhibitors include a variety of BTK inhibitors, or analogs or derivatives thereof, which are suitable in the prevention and/or treatment of a variety of neuroinflammatory disorders, including a number of neurological and psychiatric diseases. More specifically, the BTK inhibitors of the present invention modulate/inhibit the inflammasome complex in neurological diseases such as AD. Inhibition of BTK is reasonably expected to ameliorate neuroinflammatory pathophysiology in these neurological and psychiatric diseases.
  • compositions provided herein can be used in a method of preventing or treating a variety of neurological and psychiatric diseases by modulating/partially inhibiting as low as ten to twenty-five percent or up to fifty or ninety, or even ninety-five percent of the target kinase activity as measured in the blood.
  • FIG. 1 is a diagram showing how neuroinflammation plays an important role in AD pathology. Recognition of a damage signal leads to microglia activation and release of pro-inflammatory cytokines. Activation of NLRP3 inflammasome by microglia and Intraneuronal neurofibrillary tangles results in nucleation of new A0 plaques, thus amplifying AP-associated pathology and enhancing tau-associated pathology. BTK regulates activation of the NLRP3 inflammasome and production of pro-inflammatory cytokines. The BTK inhibitor (for example ibrutinib) acts on this process by reducing A
  • the BTK inhibitor for example ibrutinib
  • FIG. 2 shows the amino acid sequence of the catalytic domain of BTK (SEQ ID NO:1) with interacting amino acids highlighted in red. Crosses indicate amino acids interacting with four BTK inhibitors.
  • SEQ ID NO:1 BTK
  • Crosses indicate amino acids interacting with four BTK inhibitors.
  • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [ 0025]
  • the term “and/or” includes any and all combinations of one or more of the associated listed items. Further, the singular forms and the articles “a”, “an” and “the” are intended to include the plural forms as well, unless expressly stated otherwise. It will be further understood that the terms: includes, comprises, including and/or comprising, when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. Further, it will be understood that when an element, including component or subsystem, is referred to and/or shown as being connected or coupled to another element, it can be directly connected or coupled to the other element or intervening elements may be present.
  • alkyl means a saturated, straight-chain or branched-chain hydrocarbon substituent having the specified number of carbon atoms. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, tert-butyl, and so on. Derived expressions such as “alkoxy”, “thioalkyl”, “alkoxyalkyl”, “hydroxyalkyl”, “alkylcarbonyl”, “alkoxycarbonylalkyl”, “alkoxycarbonyl”, “diphenylalkyl”, “phenylalkyl”, “phenylcarboxyalkyd” and “phenoxyalkyl” are to be construed accordingly.
  • cycloalkyl includes all of the known cyclic groups.
  • Representative examples of “cycloalkyl” includes without any limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • Derived expressions such as “cycloalkoxy”, “cycloalkylalkyl”, “cycloalkylaryl”, “cycloalkyl carbonyl” are to be construed accordingly.
  • perhaloalkyl represents the alkyl, as defined above, wherein all of the hydrogen atoms in said alkyd group are replaced with halogen atoms selected from fluorine, chlorine, bromine or iodine.
  • Illustrative examples include trifluoromethyl, trichloromethyl, tri bromomethyl, triiodomethyl, pentafluoroethyl, pentachloroethyl, pentabromoethyl, pentaiodoethyl, and straight-chained or branched heptafluoropropyl, heptachloropropyl, heptabromopropyl, nonafluorobutyl, nonachlorobutyl, undecafluoropentyl, undecachloropentyl, tri decafluorohexyl, tridecachlorohexyl, and the like.
  • alkyl may partially be fluorinated, that is, only portions of the hydrogen atoms in said alkyl group are replaced with fluorine atoms and shall be construed accordingly.
  • acyl shall have the same meaning as “alkanoyl”, which can also be represented structurally as “R-CO-,” where R is an “alkyl” as defined herein having the specified number of carbon atoms. Additionally, “alkylcarbonyl” shall mean same as “acyl” as defined herein. Specifically, “(Ci-C4)acyl” shall mean formyl, acetyl or ethanoyl, propanoyl, n-butanoyl, etc. Derived expressions such as “acyloxy” and “acyloxyalkyl” are to be construed accordingly.
  • aryl means substituted or unsubstituted phenyl or naphthyl.
  • substituted phenyl or naphthyl include o-, p-, m-tolyl, 1,2-, 1,3-, 1,4-xylyl, 1 -methylnaphthyl, 2-methylnaphthyl, etc.
  • Substituted phenyl or “substituted naphthyl” also include any of the possible substituents as further defined herein or one known in the art.
  • arylalkyl means that the aryl as defined herein is further attached to alkyl as defined herein. Representative examples include benzyl, phenylethyl, 2-phenylpropyl, 1 -naphthylmethyl, 2 -naphthylmethyl and the like.
  • alkenyl means a non-cyclic, straight or branched hydrocarbon chain having the specified number of carbon atoms and containing at least one carbon-carbon double bond, and includes ethenyl, propenyl, and straight- chained or branched butenyl, pentenyl, hexenyl, and the like.
  • arylalkenyl and five membered or six membered “heteroarylalkenyl” is to be construed accordingly.
  • Illustrative examples of such derived expressions include furan-2-ethenyl, phenylethenyl, 4-methoxyphenylethenyl, and the like.
  • alkenoyl means an alkenyl group attached to a carbonyl group.
  • alkenyl group examples include propenoyl (acryloyl), butynoyl (methacryloyl), and the like.
  • alkynyl means a non-cyclic, straight or branched hydrocarbon chain having the specified number of carbon atoms and containing at least one carbon-carbon triple bond, and includes ethynyl, propynyl, and straight-chained or branched butynyl, pentynyl, hexynyl, and the like.
  • arylalkynyl and five membered or six membered “heteroarylalkynyl” is to be construed accordingly.
  • alkynoyl means an alkynyl group attached to a carbonyl group.
  • alkynoyl propynoyl (propiolyl), butynoyl, and the like.
  • heteroaryl includes all of the known heteroatom containing aromatic radicals.
  • Representative 5-membered heteroaryl radicals include furanyl, thienyl or thiophenyl, pyrrolyl, isopyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, and the like.
  • Representative 6-membered heteroaryl radicals include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like radicals.
  • bicyclic heteroaryl radicals include, benzofuranyl, benzothiophenyl, indolyl, quinolinyl, isoquinolinyl, cinnolyl, benzimidazolyl, indazolyl, pyridofuranyl, pyridothienyl, and the like radicals.
  • heterocycle includes all of the known reduced heteroatom containing cyclic radicals.
  • Representative 5-membered heterocycle radicals include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, 2-thiazolinyl, tetrahydrothiazolyl, tetrahydrooxazolyl, and the like.
  • Representative 6-membered heterocycle radicals include piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and the like.
  • Various other heterocycle radicals include, without limitation, aziridinyl, azepanyl, diazepanyl, diazabicyclo[2.2.1]hept-2-yl, and triazocanyl, and the like.
  • Halogen or “halo” means chloro, fluoro, bromo, and iodo.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • substituted means substituted with one or more substituents independently selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (Ci- C6)perfluoroalkyl, phenyl, hydroxy, -CO2II, an ester, an amide, (Ci-C6)alkoxy, (Ci- C 6 )thioalkyl and (Ci-C6)perfluoroalkoxy.
  • the term “patient” or “subj ect” refers to a warm blooded animal such as a mammal which is afflicted with a particular disease, disorder or condition. It is understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and primates such as humans are examples of animals within the scope of the meaning of the term.
  • treat or “treating” means any treatment, including but not limited to, alleviating symptoms, eliminating the causation of the symptoms either on a temporary or permanent basis, or to preventing or slowing the appearance of symptoms and progression of the named disease, disorder or condition.
  • the expression "pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant, or other material which is mixed with the compound of the present invention in order to permit the formation of a pharmaceuti cal composition, i.e., a dosage form capable of administration to the patient.
  • a carrier is pharmaceutically acceptable oil typically used for parenteral administration.
  • salts of the compounds of the present invention can be used in medicinal preparati ons. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, 2 -hydroxyethanesulfonic acid, p- toluenesulfonic acid, fumaric acid, maleic acid, hydroxymaleic acid, malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid, salicylic acid, cinnamic acid, 2- phenoxybenzoic acid, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanes
  • the acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate can also be formed.
  • the salts so formed may present either as mono- or di- acid salts and can exist substantially anhydrous or can be hydrated.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts, and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • prodrug shall have the generally accepted meaning in the art.
  • One such definition includes a pharmacologically inactive chemical entity that when metabolized or chemically transformed by a biological system such as a mammalian system is converted into a pharmacologically active substance.
  • stereoisomers is a general term used for all isomers of the individual molecules that differ only in the orientation of their atoms in space. Typically, it includes mirror image isomers that are usually formed due to at least one asymmetric center, (enantiomers). Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereoisomers, also certain individual molecules may exist as geometric isomers (cis/trans). Similarly, certain compounds of this invention may exist in a mixture of two or more structurally distinct forms that are in rapid equilibrium, commonly known as tautomers.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that all such i somers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
  • 'R' and 'S' are used as commonly used terms in organic chemistry to denote specific configuration of a chiral center.
  • 'R' rectus
  • 'S' sinister
  • 'R' rectus
  • 'S' sinister
  • 'R' chiral center with a counterclockwi se relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the priority of groups is based upon sequence rules wherein prioritization is first based on atomic number (in order of decreasing atomic number).
  • solvate as used herein means that an aggregate that consists of a solute ion or molecule with one or more solvent molecules.
  • hydrate means that a solute ion or molecule with one or more water molecules.
  • Inflammasomes are multiprotein complexes that can sense damage-associated molecular signals.
  • the NLR family which includes NLRP1, NLRP3, NLRP4, and NLRP12, have been shown to be involved in inflammasome assembly.
  • the NLRP3 NOD-, LRR- and pyrin domain-containing 3
  • inflammasome becomes activated by A ⁇ and in AD, NLRP1 and NLRP3 are upregulated; see, Saresella et al., (2016), “The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease,” Molecular Neurodegeneration, vol. 11, p. 23.
  • NLRP3 activation is required for tau pathology both directly and downstream of A ⁇ ; see, Ising et al., (2019), “NLRP3 inflammasome activation drives tau pathology,” Nature, 575 (7784):669-673. Further, genetic deletion of NLRP3 protects against A ⁇ pathology and cognitive dysfunction in AD mouse models; see, Heneka et al., (2013), “NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice,” Nature, vol. 493, no. 7434, pp. 674-678.
  • IL-ip interleukin- ip
  • TNF- ⁇ tumor necrosis factor- ⁇
  • IL-18 interleukin-18
  • NLRP1 pathway which induces caspase- 1 and caspase-6, is reported to be involved in the progression of AD; see, Kaushal et al., (2015), “Neuronal NLRP1 inflammasome activation of caspase- 1 coordinately regulates inflammatory interleukin- 1 -beta production and axonal degeneration-associated caspase-6 activation. Cell Death & Differentiation,” 22 (10): 1676-1686.
  • NLRP3 pathway is also involved in AD, since NLRP3 deletion reduces caspase- 1 and IL-1 ⁇ activities and enhances A ⁇ clearance (see above Heneka et al.) and NLRP3 regulates Caspase-8, see Antonopoulos et al., (2015), “Caspase-8 as an Effector and Regulator of NLRP3 Inflammasome Signaling,” J. Biol. Chem.
  • Tec Kinases pathway Four signaling pathways were identified to be shared by the three sets of pathways generated by IP A from the gene sets: Tec Kinases pathway, Neuroinflammation, PI3K signaling, and IL-8 signaling. These signaling pathways are interconnected, since IL-8 and neuroinflammation are downstream of Tec Kinases; see, Wang et al., (2009), “Tec Kinase Mediating IL-8 Transcription in Monocytes Stimulated with LPS,” Inflammation, 32(4):265-9; also see, Gottar-Guillier et al., (2011), “The Tyrosine Kinase BMX Is an Essenti al Mediator of Inflammatory Arthritis in a Kinase-Independent Manner,” J.
  • Tec Kinases are a family of mammalian non-receptor tyrosine kinases that include Bruton’s Tyrosine Kinase (BTK), Tec, BMX/ETK, ITK, and RLK/TXK and play important roles in the development or maintenance of the hematopoietic system and control many cellular functions essential to inflammation.
  • BTK Tyrosine Kinase
  • Tec BMX/ETK
  • ITK ITK
  • RLK/TXK RLK/TXK
  • BTK is expressed in the CNS and several studies have implicated BTK as a player in the molecular processes underlying AD. Recently, inhibition of BTK has been strongly implicated as a therapeutic intervention for AD; see, Keaney et al., (2019), “Inhibition of Bruton’s Tyrosine Kinase Modulates Microglial Phagocytosis: Therapeutic Implications for Alzheimer’s Disease,” J. Neuroimmune Pharmacol, pl -14; and several lines of evidence support BTK as a drug target for AD.
  • BTK protein was found in prefrontal cortex of post-mortem AD patients, see, Garranzo-Asensio et al., (2016), “Identification of prefrontal cortex protein alterations in Alzheimer's disease” Oncotarget, 9(13): 10847-10867; and upregulation of BTK transcript was observed in post-mortem AD patient brains (see above Keaney et al.), in temporal, see, Castillo et al., (2017), “Comparative profiling of cortical gene expression in Alzheimer's disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation” Sci. Rep.
  • mice 7(1): 17762, and prefrontal cortex see Garranzo-Asensio et al. above.
  • upregulation of BTK was observed in brains from the 5xF AD mouse model of AD (see above Keaney et al.) and in hippocampus of mice treated with A ⁇ (see Kobayashi et al. above).
  • BTK has been implicated in the regulation of several proteins involved in AD progression. Importantly, BTK is essential for NLRP3 inflammasome activation and IL-1 ⁇ release, see, Ito et al., (2015), “Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury,” Nat. Commun.
  • NLRP3 inflammasome is activated in AD, (see above Heneka et al.) by A ⁇ , see, Halle et al., (2008), “The NALP3 inflammasome is involved in the innate immune response to amyloid-beta,” Nat. Immunol.
  • NLRP3 is activated in response to Toll-like receptor 2 (TLR2) activation, which is upregulated in human AD tissues, see, Webster et al., (2009), “Genetic control of human brain transcript expression in Alzheimer disease,” Am. J. Hum. Genet. 84: 445-458; also see Friedman et al., (2016), “Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer's Disease Not Evident in Mouse Models,” Cell Rep.
  • TLR2 Toll-like receptor 2
  • AP-induced activation of TLRs and the NLRP3 inflammasome results in production and release of proinflammatory cytokines, such as IL-1 ⁇ .
  • BTK is critical for the full activation of phospholipase-C y2 (PLCy2), a genetic risk factor in AD, see, Bertram et al., (2008), “Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE,” Am. J. Hum. Genet. 83(5):623-32; also see, Sims et al., (2017), “Rare coding variants in PLCG2, ABB, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease,” Nat. Genet.
  • BTK inhibitors are reasonably expected to be effective against neurological diseases in which the NLRP3 inflammasome and neuroinflammation are involved such as AD (see above Ito et al.).
  • ibrutinib suppressed micro- and astrogliosis and proinflammatory cytokine levels, and downregulated tau phosphorylation (Lee H et al., 2021).
  • density of dendritic spines was increased in hippocampus of and PS I mice (Lee H et al., 2021).
  • Increase in dendritic spines density was also observed in cultured hippocampal neurons treated with ibrutinib (Lee H et al., 2021).
  • ibrutinib prevented the loss of brain functions and reduced anxiety-like behavior (Ekpenyong-Akiba AE et al., 2020).
  • these data support BTK inhibition and the selection of ibrutinib as a promising therapeutic intervention for AD (Ito M et al., 2015; Lee H et al., 2021).
  • compositions and methods of treating neurological and psychiatric disorders with BTK inhibitors include:
  • BTK inhibitors at low doses as compared to the standard dosage use for the treatment of cancers and/or autoimmune disorders, can be used to treat AD and other neurological and psychiatric disorders.
  • the present invention specifically encompasses methods for treating AD by partially inhibiting or modulating BTK activity in the brain by BTK inhibitors. Modulation vs complete inhibition of kinase activity has some advantages, for example, inhibition of a kinase that is dysregulated in one organ may prove harmful to other systems in which that kinase is not dysregulated but instead serves essential functions.
  • the present invention provides compositions and methods for modulation of kinase activity (by finding doses that inhibit only a percentage of kinase molecules) is a more efficacious and appropriate approach in AD to regulate inflammatory responses while limiting toxicity and improving specificity.
  • compositions comprising a therapeutically effective amount/dose of a BTK inhibitor, or an analog or derivative thereof, including all stereoisomers and enantiomers thereof, or a pharmaceutically acceptable salt or a solvate thereof or a prodrug thereof in combination with a pharmaceutically acceptable carrier, wherein said BTK inhibitor is present in an amount sufficient to inhibit at least about ten (10) percent to about ninety (90) percent of a target kinase activity.
  • the therapeutic dose of inhibitor is determined as described herein.
  • BTK inhibitors target the ATP-binding site of the kinase and the inhibitory mechanism (activity) of BTK inhibitors can be classified as either covalent (irreversible) or non-covalent (reversible) binding to the kinase.
  • covalent irreversible
  • non-covalent reversible binding to the kinase.
  • all BTK inhibitors bind to the ATP- binding site of BTK, and therefore share a common mechanism for the inhibition of kinase activity.
  • the BTK inhibitors share common residues that interact with the ATP binding sites.
  • Residues around 410, 430, 480 and 540 of BTK are involved in interactions with both types of inhibitors (See Zain above, Fig. 2A and Fig. 2 herein). Many of the residues involved in ATP binding are essential for inhibitor recognition. The reversible inhibitors interact with many amino acids that also interact with covalent inhibitors despite largely different binding orientation.
  • ibrutinib is one specific example of a BTK inhibitor suitable for use in the present invention.
  • Ibrutinib also known as PCI-32765
  • l-[(3R)-3-[4-amino-3-(4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidin-l-yl]prop-2-en-l-one (CAS No. 936563-96-1) is shown above.
  • Ibrutinib is commercially available as a drug under the tradename IMBRUVICA® (AbbVie/Pharmacyclics and Janssen).
  • Ibrutinib is an orally bioavailable, small-molecule inhibitor of BTK. Upon oral administration, ibrutinib binds to and irreversibly inhibits BTK activity.
  • BTK inhibitors suitable for use in the present invention are described below. Specifically encompassed by the present invention are analogs and derivatives of these compounds that also possess BTK inhibitory activity suitable for the pharmaceutical compositions and methods of the present invention as described herein.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula: [ 0072 ] Acalabrutinib (also known as Calquence) 4-[8-amino-3-[(2S)-l-but-2- ynoylpyrrolidin-2-yl]imidazo[l ,5-a]pyrazin-l-yl]-N-pyridin-2-ylbenzamide (CAS No.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Branebrutinib also known as BMS-986195
  • BMS-986195 4-[(3S)-3-(but-2- ynoylamino)piperidin-l-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (CAS No. 1912445-55-6).
  • Branebrutinib is a highly potent, selective covalent, irreversible inhibitor of BTK.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Evobrutinib (also known as M-2951) l-[4-[[[6-amino-5-(4- phenoxyphenyl)pyrimidin-4-yl]amino]methyl]piperidin-l-yl]prop-2-en-l-one (CAS No. 1415823-73-2).
  • Evobrutinib is an orally administered, irreversible antagonist of BTK which inhibits signal transduction until the protein is naturally degraded. Evobrutinib, functions chemically engaging irreversibly with the same cysteine residue on the BTK protein.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Orelabrutinib also known as ICP-022 2-(4-phenoxyphenyl)-6-(l -prop-2- enoylpiperidin-4-yl)pyridine-3-carboxamide (CAS No. 1655504-04-3).
  • Orelabrutinib is an orally available potent BTK inhibitor that irreversibly binds to BTK.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Remibrutinib (also known as LOU064) N-[3-[6-amino-5-[2-[methyl(prop-2- enoyl)amino]ethoxy]pyrimidin-4-yl]-5-fluoro-2-methylphenyl]-4-cyclopropyl-2- fluorobenzamide (CAS No. 1787294-07-8).
  • Remibrutinib is an oral BTK inhibitor developed by Novartis. The terminal acrylamide group binds covalently to C481.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Spebrutinib also known as AVL-292 N-[3-[[5-fluoro-2-[4-(2- methoxyethoxy)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide (CAS No. 1202757- 89-8). Spebrutinib is an orally bioavailable, selective inhibitor of BTK which targets and covalently binds to BTK, thereby irreversibly inhibiting BTK.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Tirabrutinib also known as Velexbru and GS-4059
  • 6-amino-9-[(3R)-l-but-2- ynoylpyrrolidin-3-yl]-7-(4-phenoxyphenyl)purin-8-one CAS No. 1351636-18-4.
  • Tirabrutinib is an orally available formulation containing an inhibitor of BTK. Upon administration, tirabrutinib covalently binds to BTK.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Tolebrutinib (also known as SAR442168) 4-amino-3-(4-phenoxyphenyl)-l- [(3R)-l-prop-2-enoylpiperidin-3-yl]imidazo[4,5-c]pyridin-2-one (CAS No. 1971920-73-6).
  • Tolebrutinib is an irreversible covalent agent with ability to cross the blood -brain barrier. In the cerebrospinal fluid, unbound tolebrutinib is found in the nanomolar concentration range, a pharmacologically relevant level .
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Zanubrutinib (7 S)-2-(4-phenoxyphenyl)-7-( 1 -prop-2-enoylpiperidin-4-yl)- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-3-carboxamide (CAS No. 1691249-45-2). Zanubrutinib inhibits BTK by forming a covalent bond with cysteine 481 residue.
  • Zanubrutinib was granted accelerated approval by the FDA in November 2019. It is currently marketed under the trade name BRUKINSATM.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Rilzabrutinib (also known as PRN1008) (E)-2-[(3R)-3-[4-amino-3-(2-fluoro-4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile (CAS No. 1575596-29-0).
  • Rilzabrutinib efficiently crosses the blood-brain barrier.
  • Rilzabrutinib is a small-molecule, reversible covalent inhibitor of BTK.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • ARQ 531 (2-chloro-4-phenoxyphenyl)-[4-[[(3R,6S)-6-(hydroxymethyl)oxan-3- yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (CAS No. 2095393-15-8).
  • ARQ 531 is a potent, reversible inhibitor of both wild-type and mutant BTK.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Fenebrutinib (also known as GDC-0853) 10-[3-(hydroxymethyl)-4-[l -methyl -
  • Fenebrutinib is a highly selective, reversible, non-covalent BTK inhibitor.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Pirtobrutinib also known as LOXO-305 5-amino-3-[4-[[(5-fluoro-2- methoxybenzoyl)amino]methyl]phenyl]- 1 -[(2 S)- 1,1,1 -trifl uoropropan-2-yl]pyrazole-4- carboxamide (CAS No. 2101700-15-4).
  • Pirtobrutinib is a highly selective and non- covalent next generation BTK inhibitor, which potently inhibits BTK with nanomolar potency and shows high selectivity with minimal off-target inhibition.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Vecabrutinib (3R,4S)-l-(6-amino-5-fluoropyrimidin-4-yl)-3-[(3R)-3-[3-chloro- 5-(trifluoromethyl)anilino]-2-oxopiperidin- 1 -yl]piperidine-4-carboxamide) (CAS No. 1510829-06-7).
  • Vecabrutinib is a selective, reversible, non-covalent BTK inhibitor with nanomolar potency.
  • the BTK inhibitor is present in an amount sufficient to inhibit or modulate the target kinase activity from about ten (10) percent to about twenty- five (25) percent . In yet some other embodiments the BTK inhibitor is present in an amount sufficient to inhibit or modulate the target kinase activity from about twenty-five (25) percent to about fifty (50) percent up to about ninety (90) percent. In yet some other embodiments the BTK inhibitor is present in an amount sufficient to inhibit or modulate the target kinase activity from about fifty (50) percent to about seventy-five (75) percent.
  • the BTK inhibitor is present in an amount sufficient to inhibit or modulate the target kinase activity from about seventy-five (75) percent to about ninety (90) percent.
  • such amounts may include at least ten (10) percent, at least fifteen (15) percent, at least twenty (20) percent, at least twenty -five (25) percent, at least thirty (30) percent, at least thirty-five (35) percent, at least forty (40) percent, at least forty-five (45) percent, at least fifty (50) percent, at least fifty-five (55) percent, at least sixty (60) percent, at least sixty (60) percent, at least sixty-five (65) percent, at least seventy (70) percent, at least seventy-five (75) percent, at least eighty (80) percent, at least eighty five (85) percent, at least ninety (90) percent, and so on.
  • Ibrutinib is a first-in- class, orally administered inhibitor of BTK. It is known in the art that it is brain penetrant, see above Ito et al., and also see, Goldwirt et al., (2016), “Ibrutinib brain distribution: a preclinical study,” Cancer Chemotherapy and Pharmacology, 81 : 783-789. Ibrutinib is also known to be an irreversible (covalent) inhibitor of BTK. It was co-developed by Pharmacyclics, LLC and Janssen Research & Development, LLC for the treatment of B- cell malignancies.
  • Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity.
  • Ibrutinib is an FDA-approved drug. The well-established safety, toxicity profile, and side effects of ibrutinib observed in humans were obtained at doses of 560-420 mg once daily [8-6 mg/kg/day, the recommended doses for Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Waldentrbm’s macroglobinemia (WM), Chronic Graft-versus-Host Disease (cGVHD)].
  • This 8-6 mg/kg/day dose is higher than the 2.5 mg/kg/day dose, which is necessary to achieve >95% BTK occupancy in blood cells.
  • Ibrutinib at high dosage 420-560 mg/day, 6- 8mg/kg, as FDA-approved doses
  • has been associated with adverse reactions see Imbruvica.com for complete listing) that include increased risk of infections (Williams AM, et al., 2017), leukostasis and bleeding complications (Kamel S et al., 2015; Murthy P et al., 2017), and increased rates of atrial fibrillation (Wiczer TE et al., 2017).
  • Doses of Ibrutinib as described herein as sufficient for the present methods are lower doses (3.2-12.8 fold less than the FDA-approved dose for MCL and MZL). Since the doses encompassed by the present invention are much lower than the FDA-approved ones, it is reasonable to predict corresponding higher inhibition specificity and reduced side effects.
  • ibrutinib suitable for the present invention are reasonably believed to be about: 0.625 mg/kg (predicted 25% occupancy), 1.25 mg/kg (predicted 50% occupancy), 2.5 mg/kg per day (95% occupancy), still well below the 560 mg/day (8mg/kg) approved for Mantle Cell Lymphoma (MCL) and Marginal Zone Lymphoma (MZL) and the 420 mg/day (6mg/kg) approved for 'Waldenstrom’s Maroglobinenima (WM). Similar methodology as that described herein can be used to determine suitable dosages of other BTK inhibitors as described herein.
  • Any BTK inhibitor having the described kinase inhibitory activity can be used in the pharmaceutical compositions of this invention.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor selected from the group comprising but not limited to, or consisting of : a compound of formula (I), including enantiomers and stereoisomers thereof: a compound of formula (II), including enantiomers and stereoisomers thereof: a compound of formula (III), including enantiomers and stereoisomers thereof: wherein:
  • X represents CH 2 , O, S, NH , CO, COO or CONH; each of Ar1, Ar2 and Ar3 independently is selected from the group consisting of substituted or unsubstituted (C 6 -C 10 )aryl and substituted or unsubstituted (C 5 -C 10 )heteroaryl, wherein each of said substituents are independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 6 -C 10 )aryloxy; each of R 1 , R 2 and R 3 independently is selected from the group consisting of substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 3 -C 8 )cycloalkyl, substituted or unsubstituted (C 3 -C 8 )heterocycloalkyl, substituted or unsubstituted (C 6 -C 10 )
  • representative examples of Ari, An and An indude without any limitation phenyl, 2-, 3- or 4-methylphenyl, pyridyl, 2-, 3- or 4-methylpyridl, and the like.
  • BTK inhibitors suitable for use in the present inventions indude: ibrutinib, acalabrutinib, tolebrutinib, zanubrutinib, bramebrutinib, evobrutinib, orelabrutinib, remibrutinib, sprebrutinib, tirabrutinib, rilzabrutinib, ARQ 531, BMS- 986142, fenebrutinib, pirtobrutinib, RN 486 or vecabrutinib.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Ibrutinib also known as PCI-32765) l-[(3R)-3-[4-amino-3-(4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidin-l-yl]prop-2-en-l-one (CAS No. 936563-96-1).
  • Ibrutinib is commercially available as a drug under the tradename IMBRUVICA® (AbbVie/Pharmacydics and Janssen).
  • Ibrutinib is an orally bioavailable, small-molecule inhibitor of BTK. Upon oral administration, ibrutinib binds to and irreversibly inhibits BTK activity.
  • Acalabrutinib (also known as Calquence) 4-[8-amino-3-[(2S)-l-but-2- ynoylpyrrolidin-2-yl]imidazo[l,5-a]pyrazin-l-yl]-N-pyridin-2-ylbenzamide (CAS No. 1420477-60-6), commercially availabl e as a drug under the tradename CalquenceTM (AstraZeneca).
  • acalabrutinib and its active metabolite, ACP-5862 act to form a covalent bond with a cysteine residue (Cys481) in the BTK active site, leading to inhibition of BTK enzymatic activity.
  • the reduced intrinsic reactivity of acalabrutinib helps to limit inhibition of off-target kinases having cysteine- mediated covalent binding potential.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Branebrutinib also known as BMS-986195
  • BMS-986195 4-[(3S)-3-(but-2- ynoylamino)piperidin-l-yl]-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide (CAS No. 1912445-55-6).
  • Branebrutinib is a highly potent, selective covalent, irreversible inhibitor ofBTK.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Evobrutinib also known as M-2951 1 -[4-[[[6-amino-5-(4- phenoxyphenyl)pyrimidin-4-yl]amino]methyl]piperidin-l-yl]prop-2-en-l-one (CAS No. 1415823-73-2).
  • Evobrutinib is an orally administered, irreversible antagonist of BTK which inhibits signal transduction until the protein is naturally degraded. Evobrutinib, functions chemically engaging irreversibly with the same cysteine residue on the BTK protein.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Orelabrutinib also known as ICP-022 2-(4-phenoxyphenyl)-6-(l-prop-2- enoylpiperidin-4-yl)pyridine-3-carboxamide (CAS No. 1655504-04-3).
  • Orelabrutinib is an orally available potent BTK inhibitor that irreversibly binds to BTK.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Remibrutinib (also known as LOU064) N-[3-[6-amino-5-[2-[methyl(prop-2- enoyl)amino]ethoxy]pyrimidin-4-yl]-5-fluoro-2-methylphenyl]-4-cyclopropyl-2- fluorobenzamide (CAS No. 1787294-07-8).
  • Remibrutinib is an oral BTK inhibitor developed by Novartis. The terminal acrylamide group binds covalently to C481.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Spebrutinib also known as AVL-292 N-[3-[[5-fluoro-2-[4-(2- methoxyethoxy)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide (CAS No. 1202757- 89-8). Spebrutinib is an orally bioavailable, selective inhibitor of BTK which targets and covalently binds to BTK, thereby irreversibly inhibiting BTK.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Tirabrutinib also known as Velexbru and GS-4059
  • 6-amino-9-[(3R)-l-but-2- ynoylpyrrolidin-3-yl]-7-(4-phenoxyphenyl)purin-8-one CAS No. 1351636-18-4.
  • Tirabrutinib is an orally available formulation containing an inhibitor of BTK. Upon administration, tirabrutinib covalently binds to BTK.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Tolebrutinib also known as SAR442168, 4-amino-3-(4-phenoxyphenyl)-l- [(3R)-l-prop-2-enoylpiperidin-3-yl]imidazo[4,5-c]pyridin-2-one (CAS No. 1971920-73-6).
  • Tolebrutinib is an irreversible covalent agent with ability to cross the blood-brain barrier.
  • unbound tolebrutinib is found in the nanomolar concentration range, a pharmacologically relevant level.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Zanubrutinib (7S)-2-(4-phenoxyphenyl)-7-(l-prop-2-enoylpiperidin-4-yl)- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-3-carboxamide (CAS No. 1691249-45-2). Zanubrutinib inhibits BTK by forming a covalent bond with cysteine 481 residue.
  • Zanubrutinib was granted accelerated approval by the FDA in November 2019. It is currently marketed under the trade name BRUKINSATM.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Rilzabrutinib (also known as PRN1008) (E)-2-[(3R)-3-[4-amino-3-(2-fluoro-4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile (CAS No. 1575596-29-0).
  • Rilzabrutinib efficiently crosses the blood-brain barrier.
  • Rilzabrutinib is a small -molecule, reversible covalent inhibitor of BTK.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • ARQ 531 (2-chloro-4-phenoxyphenyl)-[4-[[(3R,6S)-6-(hydroxymethyl)oxan-3- yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (CAS No. 2095393-15-8).
  • ARQ 531 is a potent, reversible inhibitor of both wild-type and mutant BTK.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Fenebrutinib (also known as GDC-0853) 10-[3-(hydroxymethyl)-4-[l-methyl- 5-[[5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-l-yl]pyridin-2-yl]amino]-6-oxopyridin-3- yl]pyridin-2-yl]-4,4-dimethyl-l,10-di azatri cyclo[6.4.0.02, 6]dodeca-2(6),7-dien-9-one (CAS No. 1434048-34-6).
  • Fenebrutinib is a highly selective, reversible, non-covalent BTK inhibitor.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Pirtobrutinib also known as LOXO-305 5-amino-3-[4-[[(5-fluoro-2- methoxybenzoyl)amino]methyl]phenyl]- 1 -[(2 S)- 1,1,1 -trifluoropropan-2-yl]pyrazole-4- carboxamide (CAS No. 2101700-15-4).
  • Pirtobrutinib is a highly selective and non- covalent next generation BTK inhibitor, which potently inhibits BTK with nanomolar potency and shows high selectivity with minimal off-target inhibition.
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • RN486 6-cyclopropyl-8-fluoro-2-[2-(hydroxymethyl)-3-[l-methyl-5-[[5-(4- methylpiperazin- 1 -yl)pyridin-2-yl]amino]-6-oxopyridin-3-yl]phenyl]isoquinolin- 1 -one (CAS No. 1242156-23-5).
  • the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
  • Vecabrutinib (3R,4S)-l-(6-amino-5-fluoropyrimidin-4-yl)-3-[(3R)-3-[3-chloro- 5-(trifluoromethyl)anilino]-2-oxopiperidin- 1 -yl]piperidine-4-carboxamide) (CAS No. 1510829-06-7).
  • Vecabrutinib is a selective, reversible, non-covalent BTK inhibitor with nanomolar potency.
  • BTK is a potential novel drug target for treating a variety of neuroinflammation disorders, such as in AD.
  • BTK has been an actively -researched target in oncology with several compounds in development and currently three FDA-approved BTK inhibitors as mentioned above. More specifically: ibrutinib (Imbruvica) was approved in 2013, acalabrutinib (Calquence) approved in 2017, and zanubrutinib (Brukinsa) approved in 2019.
  • Acalabrutinib has a minimal penetration of blood-brain barrier (AstraZeneca Pty Ltd - PM-2019-03536-1-6) and zanubrutinib has had the least follow-up time and is known to penetrate of blood-brain barrier.
  • the BTK inhibitors as used in the pharmaceutical composition of this invention are known in the literature and can be synthesized by any of the procedures known to one skilled in the art.
  • ibrutinib can be synthesized following the procedures as disclosed in U. S. Patent No. 7,514,444, pertinent portions of which is incorporated herein by reference.
  • acalabrutinib can be synthesized following the procedures as disclosed in U. S. Patent No. 7,459,554, pertinent portions of which is incorporated herein by reference.
  • Zanubrutinib can be synthesized following the procedures as disclosed in U. S. Patent No. 9,447,106, pertinent portions of which is incorporated herein by reference.
  • Tolebrutinib can be synthesized following the procedures as disclosed in U. S. Patent No. 9,688,676, pertinent portions of which is incorporated herein by reference.
  • this invention provides BTK. inhibitors, such as ibrutinib and others described herein, for methods of treating a number of CNS disorders, thus providing a new channel for unmet needs in treating such disease conditions.
  • BTK has been identified as a novel inflammasome regulator and blocking BTK is likely to inhibit inflammasome activity
  • Ibrutinib could be a novel therapeutic that suppresses inflammation in the CNS and mitigate the effect of AD slowing the cognitive decline.
  • other novel BTK inhibitors can be identified and evaluated that would be suitable for use in the methods of the present invention.
  • a method of treating a neurological disease or a psychiatric disorder by administering to a patient in need thereof a therapeutically effective amount of a brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor.
  • BTK tyrosine kinase
  • the methods encompass administering to a subject in need thereof a therapeutic dose of a BTK inhibitor wherein the dosage of BTK inhibitor is sufficient to partially inhibit the activity of the BTK by at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 % as measured as inhibitor occupancy of the kinase in peripheral blood mononuclear cells (PBMCs).
  • PBMCs peripheral blood mononuclear cells
  • the present invention provides the significant advantage of using low dosages of the BTK inhibitors for the treatment of a variety of CNS disorders in order to mitigate any potential side effects yet treat the patient suffering from such disorders. It is reasonable to believe that the low dosages of BTK inhibitors as described herein not only will mitigate any side toxic effects of the inhibitor but also effectively modulate the kinase activity of the target enzyme.
  • an important aspect of the dosage is that, while Ibrutinib has been approved at doses as high as 560 mg/day for MCL and MZL, it is now provided that a lower daily dosage of approximately 43.75, 87.5 mg/day, and 175 mg/day (0.625 mg/kg, 1.25 mg/kg, and 2.5 mg/kg), can reasonably reduce the side effects as well as affinity and unwanted inhibition of other kinases, while controlling the level of neuroinflammation and thereby alleviating the associated conditions, such as mild to moderate AD, schizophrenia, and autism spectrum disorders (ASD), among other conditions.
  • AD Alzheimer's disease
  • Approved treatments for alleviation of symptoms of AD include the following: AChE inhibitors: donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne) which offer modest symptomatic relief (in terms of cognitive test scores and global functioning) for some patients but do not constitute standard treatment for the disease.
  • Memantine (Namenda) is an approved treatment of moderate to severe AD.
  • methods of preventing or treating AD by modulating/partially inhibiting BTK activity in a subject are described herein.
  • the methods of prevention or treating AD encompass administering to a subject in need thereof a therapeutic dose of a BTK inhibitor wherein the dosage of BTK inhibitor is sufficient to partially inhibit the activity of BTK by at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 %.
  • any of the known neurologi cal di seases can be treated by the BTK inhibitors as described hereinabove.
  • Non-limiting examples of such neurological disease is selected from the group consisting of AD, Parkinson’s disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, neuropathic and chronic pain, human immunodeficiency virus (HIV)-associated dementia and Creutzfeldt-Jakob disease.
  • Other neurological conditions or diseases may also include traumatic brain injury (TBI) and brain ischemia, among others.
  • any of the known psychiatric diseases can be treated by the BTK inhibitors as described hereinabove.
  • Non-limiting examples of such psychiatric disease is selected from the group consisting of major depression, bipolar, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders, anxiety, addiction and ADHD.
  • any of the therapeutically effective amounts of BTK inhibitors as described herein can be used in the methods of preventing or treating either the neurological disease or the psychiatric diseases. Accordingly, in some embodiments such a therapeutically effective amount of BTK inhibitor is an amount sufficient to inhibit at least 10 (ten) percent of target kinase activity. In yet some other embodiments such therapeutically effective amount of BTK inhibitor is an amount sufficient to inhibit at least 25 percent of target kinase activity. In further embodiments of the present invention, the percentage of BTK inhibition can be up to about 90 or even 95% as measured in the blood and correlated to BTK inhibition in the brain after penetrating the blood brain barrier.
  • compositions containing a therapeutically effective amounts of a BTK inhibitor as described herein and a therapeutically effective amount of another drug used to treat a CNS condition as described herein.
  • the pharmaceutical composition of this invention can be administered by any of the methods known in the art.
  • the pharmaceutical composition of this invention can be administered by oral, intramuscular, subcutaneous, rectal, intratracheal, intranasal, intraperitoneal or topical route.
  • the pharmaceutical compositions of this invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • An erodible polymer containing the active ingredient may be envisaged.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g.
  • a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • pre-formulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid pre-formulation composition is then subdivided into unit dosage forms of the type described above containi ng from 0.1 to about 500 mg of the active ingredient of the present invention.
  • Flavored unit dosage forms contain from about 1 to 100 mg, for example about 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • the li qui d forms in which the pharmaceutical composi tions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • three doses of the BTK inhibitor can be tested that are predicted to inhibit BTK by approximately 25%, 50%, and 95% (measured as enzyme occupancy in blood) and are well below FDA-approved doses (3.2- 12.8 fold less as by example for ibrutinib) in a patient population with AD.
  • This clinical study can be randomized and double-blind, testing three doses of BTK inhibitor to be administered daily for 14 days in 3 cohorts of patients, each receiving one of BTK inhibitor low dose regimen or placebo. Patients enlisted in such clinical trials can exhibit mild or moderate symptoms of AD.
  • Ibrutinib is a first-in-class, orally administered inhibitor of BTK. It is known in the art that it is brain penetrant, see above Ito et al., and also see, Goldwirt et al., (2016), “Ibrutinib brain distribution: a preclinical study,” Cancer Chemotherapy and Pharmacology, 81 : 783-789. Ibrutinib is also known to be an irreversible (covalent) inhibitor of BTK. It was co-developed by Pharmacy dies, LLC and Janssen Research & Development, LLC for the treatment of B-cell malignancies. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity.
  • Ibrutinib levels in excess of the ICso for BTK inhibition were also recognized in the CSF of patients with mantle cell lymphoma that received 560 mg/day of Ibrutinib, see Bernard S. et al., (2015), “Activity of Ibrutinib in mantle cell lymphoma patients with central nervous system relapse,” Blood, 126, 1695-98; and in patients with primary CNS lymphoma that received Ibrutinib at 560-840 mg/day (see Dunleavy K et al., 2015, “Phase I study of dose-adjusted Teddi-R with Ibrutinib in untreated and relapsed/refractory primary CNS lymphoma. Blood, 126, Abstract 472).
  • ibrutinib is a suitable drug for the treatment of a number of CNS indications, including the treatment of AD.
  • An exemplary clinical study to assess the safety and tolerability of ibrutinib will include a 2-week Phase I multiple ascending doses, randomized, double-blind, placebo controlled clinical trial, which is characterized by small groups is described herein. The doses will be much lower than the maximum dose approved by FDA for the oncological indications mentioned above.
  • the primary enrollment criteria will be a diagnosis of AD dementia as determined by the National Institute on Aging and Alzheimer’s Association core clinical criteria (see McKhann GM et al., 2011, “The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging- Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease,” Alzheimer’s Dement. 2011;7:263-9). Additional criteria include age 50 to 75 years and scores of 4 or lower on a modified Hachinski Ischemia Scale (see Rosen WG et al., 1980, “Pathological verification of ischemic score in differentiation of dementias,” Ann. Neurol.
  • subj ects will be excluded if with current and concurrent use of systemic anticoagulation with warfarin or other Vitamin K antagonists, or strong CYP3A4 inhibitors or inducers, or evidence of bleeding diathesis or coagulopathy, or any history of symptomatic intracranial hemorrhage, or non-healing wound, ulcer, or bone fracture, or vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug, or known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV). Investigational agents will be prohibited one month prior to entry and for the duration of the trial. Also exclusionary is previous treatment with an investigational small molecule with anti-amyloid properties or passive immunization against amyloid within 1 year of entry or previous treatment with an active immunization against amyloid.
  • HCV human immunodeficiency virus
  • HCV hepatitis C virus
  • HBV he
  • the study is a 2-week Phase I with multiple ascending doses, randomized, double-blind, placebo controlled trial of Ibrutinib in AD patients with mini-mental state examination (MMSE) scores ranging from 20 to 26.
  • MMSE mini-mental state examination
  • a total of 24 subjects will be recruited in three sequential groups, with each randomized to receive oral ibrutinib at doses of 0.625 mg/kg, 1.25 mg/kg, or 2.5 mg/kg, or placebo daily for 2 weeks (each cohort: 6 participants receiving Ibrutinib dose, 2 receiving placebo).
  • Subjects will be seen for safety visits at weeks 1, 2, and 3. Outcome measures will be collected after 2 weeks on ibrutinib or placebo. Study medication compliance will be measured throughout the study.
  • a final safety visit will be completed after the participant had been off ibrutinib or placebo for approximately 2 weeks.
  • a primary objective of the exemplified study is to assess the safety and tolerability of the drug in patients with AD and determine dose levels that provide 50% and lower target occupancy of the acti ve site in blood cells and to characterize the pharmacokinetic profiles and target occupancy for these doses.
  • low daily ibrutinib doses (0.625 mg/kg, 1.25 mg/kg, and 2.5 mg/kg) will be evaluated to assess the safety and tolerability of these doses and characterize their pharmacokinetic profiles in blood and CSF and determine the target occupancy of the BTK active site as measured in blood.
  • ADAS-cog Alzheimer's Disease Assessment Scale
  • MMSE Mini-Mental State Examination
  • NPI Neuropsychiatric Inventory
  • Another objective is to assess levels of inflammatory biomarkers (IL-lp, IL-6, IL-12, IL-18, TNF- ⁇ , and TGF- ⁇ ) and neurodegeneration biomarkers [P-taul81/tau, A ⁇ 42/A ⁇ 4O, neurofilament light (NfL), neurogranin] in CSF and blood.
  • the biomarker analyses would allow assessment of AD pathologies and neuroinfiammation in these patients.
  • Primary endpoints are to assess the safety and tolerability of ibrutinib in patients with AD and determine dose levels that provide lower occupancy of the BTK active site in blood cells.
  • a secondary endpoint is the evaluation of safety using clinical efficacy measures (Alzheimer's Disease Assessment Scale - Cognitive Subscale, MMSE, Neuropsychiatric Inventory,).
  • Another secondary endpoint is the measurement of inflammatory and neurodegenerative biomarkers in CSF and blood.
  • the patient will be administered with the medication in the morning with or without food.
  • the ibrutinib treatment groups will receive 0.625 mg/kg, or 1.25 mg/kg, or 2.5 mg/kg daily for 2 weeks.
  • the dosage will be terminated if serious adverse events or any other unanticipated serious problem are detected.
  • the control group will receive the placebo for the entire study.
  • Safety assessments will include physical and neurological examinations, MMSE examinations, vital signs (including blood pressure, pulse, oral temperature, respiration rate, and weight), electrocardiograms, and laboratory measurements, such as complete blood cell counts, basic metabolic panel, including renal function and electrolyte levels, coagulations factors, and liver function tests. Physical and neurological examination and laboratory measurements will be assessed at the baseline visit, on day 1 (pre-dose), 8, 14, 15, 28 as shown in the Table below:
  • Lymphoma 11:1-8 leukostasis and bleeding complications (see Kamel S et al., 2015, “Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation” Leukemia 29:783-7; also see Murthy P et al., 2017, “The NLRP3 inflammasome and Bruton’s tyrosine kinase in platelets co-regulate platelet activation, aggregation, and in vitro thrombus formation,” Biochem. Biophys. Res. Commun.
  • PKs pharmacokinetics
  • BTK occupancy Blood samples for pharmacokinetics (PKs) and BTK occupancy will be collected on day 1 (pre-dose and up to 6 hours after dosing), day 8 (pre-dose), and Day 15.
  • CSF samples for PKs will be collected on day 1 day 1 (pre-dose and up to 6 hours after dosing), day 15.
  • Samples will be analyzed for ibrutinib concentrations by high- performance liquid chromatography with tandem mass spectrometric detection.
  • PK assessments and drug exposure derived from area under the concentration-time curve [AUG] will be performed on the plasma concentration-time data obtained on day 1.
  • BTK occupancy in peripheral blood mononuclear cell s will be measured using a fluorescent affinity probe assay (see Honigberg et al., 2010, “The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy,” Proc. Natl. Acad. Sci. U S A 107:13075-80) within 4 hours of treatment after the first dose and the last dose (at 4 weeks).
  • the probe fluorescently tagged derivative of ibrutinib
  • the BTK-bound fluorescent probe is inversely proportional to the occupancy of the binding site by Ibrutinib.
  • Total BTK and actin protein levels in each sample will be used to normalize protein in each lane.
  • the relative density of each band will be quantified using volume integration and local average background correction. Normalized intensity of BTK-bound fluorescent probe will be a measure of ibrutinib-free BTK.
  • Pharmacokinetic and pharmacodynamic relationship of BTK active-site occupancy and Ibrutinib exposure will be calculated using the percentage of BTK occupancy before dosing and averaged post-dose for each patient in each group. These values will be plotted against the drug exposure (AUCO-24) achieved in the patient after administration of Ibrutinib on day 1.
  • ADAS-cog Alzheimer's Disease Assessment Scale
  • MMSE Mini-Mental State Examination
  • NPI Neuropsychiatric Inventory
  • CSF biomarkers AP42 and the AP42/40 ratio reflecting brain amyloidosis
  • T-tau total tau
  • P-taul81 phosphoiylated tau
  • CSF levels of neurofilament light (NfL) and synaptic protein neurogranin are significantly elevated in AD compared to healthy controls, correlating with cognitive impairment and brain neuropathology (Blennow K, 2017).
  • This core AD biomarkers can also be measured in blood samples (Blennow K and Zetterberg H, 2019). Elevated concentrations of peripheral inflammatory biomarkers were reported in AD patients (Lai KSP et al., 2017; Su C et al., 2019; Park J-C et al., 2020).
  • peripheral concentrations of IL-1 ⁇ , IL-6, IL-12 and IL-18, TNF- ⁇ , and TGF- ⁇ were detected in peripheral blood of AD subjects compared with control subjects (Swardfager W et al., 2010; Park J-C et al., 2020).
  • Blood samples will be evaluated for levels of IL-1 ⁇ , IL- 6, IL-12 and IL-18, TNF- ⁇ , and TGF- ⁇ , P-tau181/tau, A ⁇ 42/A ⁇ 40, and neurofilament light (NfL); CSF samples will be evaluated for levels of IL-1 ⁇ , IL -6, IL-12 and IL-18, TNF- ⁇ , and TGF- ⁇ , P-taul81/tau, A ⁇ 42/A ⁇ 40, neurofilament light (NfL), and neurogranin.
  • Standardized methods such as automated electrochemiluminescence immunoassay will be used for the quantitation of the biomarkers and each assay will be run in triplicate. Although the treatment may be too short to see changes in biomarkers, any difference we may observe after dosage would be interpreted as potentially associated with the treatment and will be considered in future clinical development including dose selection, biomarker requirement in patient selection and/or potentially stratification of future clinical trials.
  • Alzheimer's disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation.
  • Sci Rep. 7 17762. PMC5736730.
  • NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493 (7434) : 674-678. PMC3812809.
  • GDS Geriatric Depression Scale

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Abstract

Compositions and methods are described herein for use in preventing or treating a variety of neurological and psychiatric disorders by partially inhibiting targeted Bruton tyrosine kinase activity in a subject.

Description

COMPOSITIONS AND METHODS OF TREATMENT OF NEUROINFLAMMATORY DISEASES WITH BRUTON'S TYROSINE KINASE INHIBITORS
RELATED APPLICATIONS
[ 0001 ] This application claims the benefit under 35 U.S.C. § 1 19(e) of U.S. Provisional Application No. 63/090,481, filed on October 12, 2020, which is incorporated herein by reference in its entirety.
SEQUENCE LISTING
[ 0001 . 1 ] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on November 15, 2021, is named 0404 0002WQl SL.txt and is 1,888 bytes in size.
FIELD OF THE INVENTION
[ 0002] The present invention relates to pharmaceutical compositions encompassing a variety of Bruton ’s tyrosine kinase (BTK) inhibitors which are suitable in the treatment of a variety of neuroinflammatory disorders, including a number of neurological and psychiatric diseases.
BACKGROUND OF THE INVENTION
[ 0003 ] Recent studies show that neuroinflammation has a pathological role in a number of neurological and psychiatric diseases. Neuroinflammation has been observed in but not limited to disorders such Alzheimer’s, Parkinson’s, major depression, bipolar, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders, anxiety, neuropathic and chronic pain, addiction and ADHD (Prata et al., (2017) J.
Neuroinflammation 14 (1): 179; Dunna et al. (July 2019) Pharmacol. Biochem. Behavior: vol.182:22-34; Erickson et al., (February 2019) Pharmacol. Biochem. Behavior: vol.177:34-60; Friesa et al., (February 2019)Pharmacol. Biochem. Behavior: vol. 177:12- 19; Kohnoa et al. (April 2019) Pharmacol. Biochem. Behavior: vol. 179:34-42; Luri, D.I., (2018) J. Exper. Neuroscience: vol. 12: 1-11; Najjar et al. (2013) J. Neuroinflammation: vol.10:43; Radtke et al. (2017) BioMed Research International: pages 1-21; Article ID 5071786. [ 0004 ] Alzheimer’ s disease (AD) is a progressive and devastating neurological disorder and the most common cause of dementia. AD is characterized clinically by cognitive decline and behavioral disturbances and pathologically by extracellular plaque deposits of amyloid-p (Aβ) peptides, intraneuronal tau-containing neurofibrillary tangles (NFTs), neuropil threads (NTs), glial activation, neuroinflammation, synapse elimination, neuronal degeneration and neuron cell death. See for example, World Health Organization (2017) Dementia factsheet: www.who.int/mediacentre/factsheets/fs362/en/. The incidence of AD increases with age, and the prevalence is growing as a result of the ageing of the population. It is expected that by the year 2050, the number of Americans aged 65 and older with AD is projected to reach 12.7 million (Alzheimer Association, 2021).
[ 0005 ] Many studies have linked AD progression with neuroinflammation, in particular with aspects of the innate immune response that are overactivated in AD. Persistent activation of microglia, particularly of the pro-infl ammatory type, is a component of the innate immune response that is stimulated by chronic deposition of Aβ (see, Hansen et al., (2018) “Microglia in Alzheimer’s disease” J. Cell Biol., 217 (2): 459-472). Accumulating evidence demonstrates that a component of the innate immune response, the inflammasome, plays an important role in the inflammatory response in AD.
[ 0006] Several drugs are approved by the U.S. Food and Drug Administration (FDA) to treat symptoms of AD. These drugs work by regulating neurotransmitters and may help reduce symptoms and help with certain behavioral problems. For example, donepezil (Aricept®), rivastigmine (Exelon'®), and galantamine (Razadyne®) are used to treat mild to moderate AD (donepezil can be used for severe AD as well). Similarly, memantine (Namenda®), the Exelon®patch, and Namzaric® (a combination of memantine and donepezil) are used to treat moderate to severe AD. However, these drugs may help only for a limited time and are not effective in slowing or halting the underlying disease process. Recently, the conditionally FDA-approved aducanumab (Aduhelm), which targets the Aβ aggregates, was added to the list of treatments to slow cognitive decline, albeit marginally, without reversing the disease progression. Therefore, novel therapeutic approaches are still necessary to address the underlying biological causes of the disease.
SUMMARY OF THE INVENTION
[ 0007 ] A number of BTK inhibitors, some of which are FDA approved for the treatment of a number of cancers, can also be effective agents in controlling neuroinflammation, and therefore, can be used in the treatment of a number of disease conditions associated with the inflammasome pathway. (See e.g., Weifen Li, et al. Ibrutinib alleviates LPS-induced neuroinflammation and synaptic defects in a mouse model of depression, Brain Behavior and Immunity, 92, 2021, 10-24). Therefore, modulating the inflammasome pathway is a potential strategy for suppressing inflammation in the CNS and mitigate the effect of disease states, such as and not limited to AD, Parkinson’s, major depression, bipolar, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders, anxiety, neuropathic and chronic pain, addiction and ADHD (See Figure 1).
[ 0008] Studies have linked AD progression with neuroinflammation, in particular with aspects of the innate immune response that are overactivated in AD. Accumulating evidence demonstrates that chronic deposition of Aβ stimulates persistent activation of microglia, particularly of the pro-inflammatory type, Aβ activates the NLRP3 inflammasome (a component of the innate immune response) in microgli a, and upregulation of NLRP3 plays an important role in the inflammatory response in AD.
[ 0009] BTK is essential for NLRP3 activation, which is upregulated in AD (Saresella M et al., 2016) and is also required for the release of proinflammatory cytokines, such as IL-1β (Ito M et al., 2015; Liu X et al., 2017). .Inhibition of BTK is expected to ameliorate neuroinflammatory pathophysiology in these neurological and psychiatric disorders. Accordingly, pharmaceutical compositions are provided herein which can be used in a method of treating a vari ety of neurological and psychiatri c disorders associ ated with BTK activity by inhibiting as low about ten percent up to about ninety five percent of the target kinase activity measured as occupancy of the kinase by the inhibitor in peripheral blood mononuclear cells (PBMCs). As described herein, BTK inhibitors, derivatives or analogs thereof, are provided as modulators of kinase activity in the brain to treat neurological and psychiatric disorders associated with BTK activity at lower doses than used to treat a variety of cancers and/or autoimmune disorders as such inhibitors are used in current medical treatments. As used herein, the doses used in cancer/oncological or autoimmune disorder treatment methods are to be considered “standard” dose/amount of the BTK inhibitor for comparative values.
[ 0010] Accordingly, described herein are compounds and pharmaceutical compositions that can function effectively to modulate BTK activity. The compounds and pharmaceutical compositi ons provided herein can be used in methods of treating a variety of neurological and psychiatric disorders by modulating the BTK activity. “Modulating” as used herein means that the kinase activity of BTK or another kinase is lowered by the presence of, or contact with, the inhibitor relative to the activity of the kinase prior to the presence of, or contact with, the inhibitor under suitable in vivo or in vitro conditions.
[ 0011] In accordance with this invention is provided compositions containing a suitable BTK inhibitor as defined herein, wherein the BTK inhibitor concentration/dose is sufficient to target and modulate the tyrosine kinase activity of BTK, thereby lowering or reducing or suppressing the kinase activity of BTK by at least about 10-90 percent, or lower, as compared to the kinase activity of BTK as determined prior to the presence of, or contact with, the inhibitor. Also provided herein are methods of treating a patient/ subject suffering from a neuroinflammatory disorder, which leads to a number of neurological and/or psychiatric disease conditions, including AD, among others, as described herein. Such treatment can also be prophylactic treatment.
[ 0012 ] Specifically encompassed by the present invention are BTK inhibitors (also referred to herein as tyrosine kinase inhibitor agents or BTK inhibitor agents), or salts or derivatives or analogs thereof as modulators of kinase activity, albeit at much lower doses than standard use doses, to treat a variety of neurodegenerative and psychiatric disorders. A pharmaceutical composition, as described herein, comprises a therapeutically effective amount of BTK inhibitor, including all stereoisomers and enantiomers thereof, or a pharmaceutically acceptable salt or a solvate thereof or a prodrug thereof in combination with a pharmaceutically acceptable carrier, wherein said BTK inhibitor is present in an amount sufficient to inhibit at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or up to about 90 or 95 percent of a target kinase activity as measured as occupancy of the target kinase by inhibitor, and inhibition of enzyme activity, in peripheral blood mononuclear cells (PBMCs) using methods described herein and as known to one skilled in the art. The blood brain barrier permeability of each BTK inhibitor described herein varies with each specific inhibitor and the blood brain barrier allows only a fraction of inhibitor to cross into the brain to effect kinase modulation activity. The measurement of kinase inhibition activity or inhibitor target occupancy in PCMBs of blood are standard methods of measuring the activity of, and therefore efficacy of such kinase inhibitors.
[ 0013] One skilled in the art will understand that the percentage of inhibition can vary for effective treatment of a di sease or disorder associated with BTK activity, and that the percentage of inhibition of BTK activity can fall within a gradient of percentages within the range of percentages described above. For example, a percentage of about 45 % will also encompass a percentage of about 41% to about 49% inhibition, or 41%, 42%, 43% 44%, 46%, 47%, 48% or 49% and so forth for each percentage point described herein.
[ 0014] Also encompassed by the present invention are methods of identifying and/or evaluating or assessing the biological activity of molecular inhibitory agents such as drugs that can target the inflammasome pathway for the treatment of a neuroinfl ammatory disorders, including mild to moderate AD. Such methods include the first step of evaluating the tyrosine kinase activity of BTK or another target kinase at a specific amount, concentration or dose using known suitable conditions and standard laboratory methods. This determined amount would be deemed the control or standard dose for that particular kinase. Subsequently contacting the BTK or other target kinase with a BTK/kinase inhibitor candidate (or analog or derivative thereof) under the same suitable laboratory conditions as the first step and determining the amount/concentration or dose of inhibitor to partially inhibit tyrosine kinase activity relative to the tyrosine kinase activity prior to the presence of, or contact with, the candidate inhibitor. If the candidate inhibitor inhibits the biological kinase activity by at least about 10 to about 90 percent, the candidate inhibitor is determined to be suitable for the pharmaceutical compositions of this invention.
[ 0015] In some embodiments, the pharmaceutical compositions according to this invention contains a BTK inhibitor at a dose lower than standard use dose selected from the group consisting of but not limited to: a compound of formula (I), including enantiomers and stereoisomers thereof:
Figure imgf000006_0001
a compound of formula (II), including enantiomers and stereoisomers thereof: and
Figure imgf000007_0001
a compound of formula (III), including enantiomers and stereoisomers thereof:
Figure imgf000007_0002
wherein:
X represents CH2, O, S, NH, CO, COO or CONH; each of Ari, An and An independently is selected from the group consisting of substituted or unsubstituted (C6-C10)aryl and substituted or unsubstituted (C5-C10)heteroaryl, wherein each of said substituents are independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, and (C6-C10)aryloxy; each of R1, R2 and R3 independently is selected from the group consisting of substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C3-C8)cycloalkyl, substituted or unsubstituted (C3-C8)heterocycloalkyl, substituted or unsubstituted (C6-C10)aryl, and substituted or unsubstituted (C5-C10)heteroaryl, wherein each of said substituents are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C2-C6)acyl, substituted or unsubstituted acryloyl, and substituted or unsubstituted (C3-C6)alkynoyl.
[0016] In some embodiments, representative examples of Ar1, Ar2 and Ar3 include without any limitation phenyl, 2-, 3- or 4-methylphenyl, pyridyl, 2-, 3- or 4-methylpyridl, and the like. Non-limiting examples of X include O or CONH. Representative examples of R1, R2 R3 without any limitation include five or six membered heterocycle rings, such as substituted pyrrolidine or piperidine among others. Suitable substituents include without any limitation acryloyl, butynoyl, and the like. [ 0017 ] In some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000008_0001
[ 0018 ] Ibrutinib (also known as PCI-32765) l-[(3R)-3-[4-amino-3-(4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidin-l-yl]prop-2-en-l-one (CAS No. 936563-96-1) (Ibrutinib, commercially available as a drug under the tradename IMBRUVICA® (Pharmacyclics/Janssen).
[ 0019 ] Structures of other suitabl e BTK inhibitors are described herein. It is important to note that functional BTK inhibitors bind to/act on the catalytic domain of BTK. (See Zain and Vihinen (2021) Structure-Function Relationship of Covalent and Non-Covalent BTK Inhibitors. Front Immunol. 12:694853. PMC832433). In Figure 2 (reproduced from Zain and Vihinen), the amino acid sequence of the catalytic domain of BTK with interacting amino acids highlighted in red are shown. Crosses indicate amino acids interacting with four BTK inhibitors. Some BTK inhibitors such as ibrutinib and zanubrutinib, bind covalently to the active site, while other BTK inhibitors, such as fenebrutinib and RN486, bind non-covalently. Whether covalent or non-covalent binding results in inhibition, it is noted that the inhibitors still interact with certain key amino acid residues within the BTK catalytic domain.
[ 0020 ] Additional embodiments in accordance with the present invention are described herein and relate generally to a pharmaceutical composition encompassing a variety of BTK inhibitors, or analogs or derivatives thereof, which are suitable in the prevention and/or treatment of a variety of neuroinflammatory disorders, including a number of neurological and psychiatric diseases. More specifically, the BTK inhibitors of the present invention modulate/inhibit the inflammasome complex in neurological diseases such as AD. Inhibition of BTK is reasonably expected to ameliorate neuroinflammatory pathophysiology in these neurological and psychiatric diseases. Accordingly, the pharmaceutical compositions provided herein can be used in a method of preventing or treating a variety of neurological and psychiatric diseases by modulating/partially inhibiting as low as ten to twenty-five percent or up to fifty or ninety, or even ninety-five percent of the target kinase activity as measured in the blood.
[ 0021 ] The above and other features of the invention including various novel details of construction and combinations of parts, and other advantages, will now be more particularly described with reference to the accompanying drawings and pointed out in the claims. It will be understood that the particular method and device embodying the invention are shown by way of illustration and not as a limitation of the invention. The principles and features of this invention may be employed in various and numerous embodiments wi thout departing from the scope of the invention .
BRIEF DESCRIPTION OF THE DRAWINGS
[ 0022 ] In the accompanying drawings, reference characters refer to the same parts throughout the different view's. The drawings are not necessarily to scale; emphasis has instead been placed upon illustrating the principles of the invention. The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings(s) will be provided by the Office upon request and payment of the necessary fee. Of the drawings:
[ 0023 ] FIG. 1 is a diagram showing how neuroinflammation plays an important role in AD pathology. Recognition of a damage signal leads to microglia activation and release of pro-inflammatory cytokines. Activation of NLRP3 inflammasome by microglia and Intraneuronal neurofibrillary tangles results in nucleation of new A0 plaques, thus amplifying AP-associated pathology and enhancing tau-associated pathology. BTK regulates activation of the NLRP3 inflammasome and production of pro-inflammatory cytokines. The BTK inhibitor (for example ibrutinib) acts on this process by reducing A|3 plaques, proinflammatory cytokines, and Tau phosphorylation in mouse models of AD.
[ 0024 ] FIG. 2 (reproduced from Zain and Vihinen) shows the amino acid sequence of the catalytic domain of BTK (SEQ ID NO:1) with interacting amino acids highlighted in red. Crosses indicate amino acids interacting with four BTK inhibitors. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [ 0025] The invention now will be described more fully hereinafter with reference to the accompanying drawings, in which illustrative embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
Definitions
[ 0026] As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items. Further, the singular forms and the articles "a", "an" and "the" are intended to include the plural forms as well, unless expressly stated otherwise. It will be further understood that the terms: includes, comprises, including and/or comprising, when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. Further, it will be understood that when an element, including component or subsystem, is referred to and/or shown as being connected or coupled to another element, it can be directly connected or coupled to the other element or intervening elements may be present.
[ 0027 ] It will be understood that although terms such as “first” and “second” are used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another element. Thus, an element discussed below could be termed a second element, and similarly, a second element may be termed a first element without departing from the teachings of the present invention.
[ 0028] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein. [ 0029 ] Since all numbers, values and/or expressions referring to quantities of ingredients, reaction conditions, etc., used herein and in the claims appended hereto, are subject to the various uncertainties of measurement encountered in obtaining such values, unless otherwise indicated, all are to be understood as modified in all instances by the term “about/’
[ 0030 ] Where a numerical range is disclosed herein such range is continuous, inclusive of both the minimum and maximum values of the range as well as every value between such minimum and maximum values. Still further, where a range refers to integers, every integer between the minimum and maximum values of such range is included. In addition, where multiple ranges are provided to describe a feature or characteristic, such ranges can be combined. That is to say that, unless otherwise indicated, all ranges disclosed herein are to be understood to encompass any and all sub-ranges subsumed therein. For example, a stated range of from “10% to 90%” should be considered to include any and all sub-ranges between the minimum value of 10 and the maximum value of 90. Exemplary sub-ranges of the range 10% to 90% include, but are not limited to any dose of inhibitor with an occupancy with values between 10% and 90%.
[ 0031 ] As used herein, the expression “alkyl” means a saturated, straight-chain or branched-chain hydrocarbon substituent having the specified number of carbon atoms. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, tert-butyl, and so on. Derived expressions such as “alkoxy”, “thioalkyl”, “alkoxyalkyl”, “hydroxyalkyl”, “alkylcarbonyl”, “alkoxycarbonylalkyl”, “alkoxycarbonyl”, “diphenylalkyl”, “phenylalkyl”, “phenylcarboxyalkyd” and “phenoxyalkyl” are to be construed accordingly.
[ 0032 ] As used herein, the expression “cycloalkyl” includes all of the known cyclic groups. Representative examples of “cycloalkyl” includes without any limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Derived expressions such as “cycloalkoxy”, “cycloalkylalkyl”, “cycloalkylaryl”, “cycloalkyl carbonyl” are to be construed accordingly.
[ 0033 ] As used herein, the expression “perhaloalkyl” represents the alkyl, as defined above, wherein all of the hydrogen atoms in said alkyd group are replaced with halogen atoms selected from fluorine, chlorine, bromine or iodine. Illustrative examples include trifluoromethyl, trichloromethyl, tri bromomethyl, triiodomethyl, pentafluoroethyl, pentachloroethyl, pentabromoethyl, pentaiodoethyl, and straight-chained or branched heptafluoropropyl, heptachloropropyl, heptabromopropyl, nonafluorobutyl, nonachlorobutyl, undecafluoropentyl, undecachloropentyl, tri decafluorohexyl, tridecachlorohexyl, and the like. Derived expression, “perhaloalkoxy”, is to be construed accordingly. It should further be noted that certain of the alkyl groups as described herein, such as for example, “alkyl” may partially be fluorinated, that is, only portions of the hydrogen atoms in said alkyl group are replaced with fluorine atoms and shall be construed accordingly.
[ 0034 ] As used herein the expression “acyl” shall have the same meaning as “alkanoyl”, which can also be represented structurally as “R-CO-,” where R is an “alkyl” as defined herein having the specified number of carbon atoms. Additionally, “alkylcarbonyl” shall mean same as “acyl” as defined herein. Specifically, “(Ci-C4)acyl” shall mean formyl, acetyl or ethanoyl, propanoyl, n-butanoyl, etc. Derived expressions such as “acyloxy” and “acyloxyalkyl” are to be construed accordingly.
[ 0035] As used herein, the expression “aryl” means substituted or unsubstituted phenyl or naphthyl. Specific examples of substituted phenyl or naphthyl include o-, p-, m-tolyl, 1,2-, 1,3-, 1,4-xylyl, 1 -methylnaphthyl, 2-methylnaphthyl, etc. “Substituted phenyl” or “substituted naphthyl” also include any of the possible substituents as further defined herein or one known in the art.
[ 0036] As used herein, the expression “arylalkyl” means that the aryl as defined herein is further attached to alkyl as defined herein. Representative examples include benzyl, phenylethyl, 2-phenylpropyl, 1 -naphthylmethyl, 2 -naphthylmethyl and the like.
[ 0037 ] As used herein, the expression "alkenyl" means a non-cyclic, straight or branched hydrocarbon chain having the specified number of carbon atoms and containing at least one carbon-carbon double bond, and includes ethenyl, propenyl, and straight- chained or branched butenyl, pentenyl, hexenyl, and the like. Derived expression, “arylalkenyl” and five membered or six membered “heteroarylalkenyl” is to be construed accordingly. Illustrative examples of such derived expressions include furan-2-ethenyl, phenylethenyl, 4-methoxyphenylethenyl, and the like. Similarly, other derived expression, “alkenoyl” means an alkenyl group attached to a carbonyl group. Illustrative examples of such group include propenoyl (acryloyl), butynoyl (methacryloyl), and the like.
[ 0038 ] As used herein, the expression "alkynyl" means a non-cyclic, straight or branched hydrocarbon chain having the specified number of carbon atoms and containing at least one carbon-carbon triple bond, and includes ethynyl, propynyl, and straight-chained or branched butynyl, pentynyl, hexynyl, and the like. Derived expression, “arylalkynyl” and five membered or six membered “heteroarylalkynyl” is to be construed accordingly. Illustrative examples of such derived expressions include furan-2-ethynyl, phenylethynyl, 4-methoxyphenylethynyl, and the like. Similarly, other derived expression, “alkynoyl” means an alkynyl group attached to a carbonyl group. Illustrative examples of such group include propynoyl (propiolyl), butynoyl, and the like.
[ 0039] As used herein, the expression “heteroaryl” includes all of the known heteroatom containing aromatic radicals. Representative 5-membered heteroaryl radicals include furanyl, thienyl or thiophenyl, pyrrolyl, isopyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, and the like. Representative 6-membered heteroaryl radicals include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like radicals. Representative examples of bicyclic heteroaryl radicals include, benzofuranyl, benzothiophenyl, indolyl, quinolinyl, isoquinolinyl, cinnolyl, benzimidazolyl, indazolyl, pyridofuranyl, pyridothienyl, and the like radicals.
[ 00401 As used herein, the expression “heterocycle” includes all of the known reduced heteroatom containing cyclic radicals. Representative 5-membered heterocycle radicals include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, 2-thiazolinyl, tetrahydrothiazolyl, tetrahydrooxazolyl, and the like. Representative 6-membered heterocycle radicals include piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and the like. Various other heterocycle radicals include, without limitation, aziridinyl, azepanyl, diazepanyl, diazabicyclo[2.2.1]hept-2-yl, and triazocanyl, and the like.
[ 0041 ] “Halogen” or “halo” means chloro, fluoro, bromo, and iodo.
[ 0042 ] In a broad sense, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a few of the specific embodiments as disclosed herein, the term “substituted” means substituted with one or more substituents independently selected from the group consisting of (Ci-C6)alkyl, (C2-C6)alkenyl, (Ci- C6)perfluoroalkyl, phenyl, hydroxy, -CO2II, an ester, an amide, (Ci-C6)alkoxy, (Ci- C6)thioalkyl and (Ci-C6)perfluoroalkoxy. However, any of the other suitable substituents known to one skilled in the art can also be used in these embodiments. [ 0043] It should be noted that any atom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the appropriate number of hydrogen atom(s) to satisfy such valences.
[ 0044] As described herein, the term “patient” or “subj ect” refers to a warm blooded animal such as a mammal which is afflicted with a particular disease, disorder or condition. It is understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and primates such as humans are examples of animals within the scope of the meaning of the term.
[ 0045] As used herein, “treat” or “treating” means any treatment, including but not limited to, alleviating symptoms, eliminating the causation of the symptoms either on a temporary or permanent basis, or to preventing or slowing the appearance of symptoms and progression of the named disease, disorder or condition.
[ 00461 As used herein, the expression "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant, or other material which is mixed with the compound of the present invention in order to permit the formation of a pharmaceuti cal composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is pharmaceutically acceptable oil typically used for parenteral administration.
[ 0047 ] The term "pharmaceutically acceptable salts" as used herein means that the salts of the compounds of the present invention can be used in medicinal preparati ons. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, 2 -hydroxyethanesulfonic acid, p- toluenesulfonic acid, fumaric acid, maleic acid, hydroxymaleic acid, malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid, salicylic acid, cinnamic acid, 2- phenoxybenzoic acid, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, carbonic acid or phosphoric acid. The acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate can also be formed. Also, the salts so formed may present either as mono- or di- acid salts and can exist substantially anhydrous or can be hydrated. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts, and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
[ 0048] As used herein, the term “prodrug” shall have the generally accepted meaning in the art. One such definition includes a pharmacologically inactive chemical entity that when metabolized or chemically transformed by a biological system such as a mammalian system is converted into a pharmacologically active substance.
[ 0049] The expression " stereoisomers" is a general term used for all isomers of the individual molecules that differ only in the orientation of their atoms in space. Typically, it includes mirror image isomers that are usually formed due to at least one asymmetric center, (enantiomers). Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereoisomers, also certain individual molecules may exist as geometric isomers (cis/trans). Similarly, certain compounds of this invention may exist in a mixture of two or more structurally distinct forms that are in rapid equilibrium, commonly known as tautomers. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that all such i somers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
[ 0050] As used herein, 'R' and 'S' are used as commonly used terms in organic chemistry to denote specific configuration of a chiral center. The term 'R' (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term 'S' (sinister) refers to that configuration of a chiral center with a counterclockwi se relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon sequence rules wherein prioritization is first based on atomic number (in order of decreasing atomic number). A listing and discussion of priorities is contained in Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Mander, editors, Wiley- Interscience, John Wiley & Sons, Inc., New York, 1994. [ 0051 ] In addition to the (R)-(S) system, the older D-L system may also be used herein to denote absolute configuration, especially with reference to amino acids. In this system a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top. The prefix 'D' is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon at the chiral center and 'L', that of the isomer in which it is on the left.
[ 0052 ] The term “solvate” as used herein means that an aggregate that consists of a solute ion or molecule with one or more solvent molecules. Similarly, a “hydrate” means that a solute ion or molecule with one or more water molecules.
[ 0053 ] Neuroinflammation and the inflammasome have been associated with AD
[ 0054 ] Inflammasomes are multiprotein complexes that can sense damage-associated molecular signals. The NLR family, which includes NLRP1, NLRP3, NLRP4, and NLRP12, have been shown to be involved in inflammasome assembly. In brain microglia, the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome becomes activated by Aβ and in AD, NLRP1 and NLRP3 are upregulated; see, Saresella et al., (2016), “The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease,” Molecular Neurodegeneration, vol. 11, p. 23. NLRP3 activation is required for tau pathology both directly and downstream of Aβ; see, Ising et al., (2019), “NLRP3 inflammasome activation drives tau pathology,” Nature, 575 (7784):669-673. Further, genetic deletion of NLRP3 protects against Aβ pathology and cognitive dysfunction in AD mouse models; see, Heneka et al., (2013), “NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice,” Nature, vol. 493, no. 7434, pp. 674-678. Inflammasomes regulate the processing and secretion of proinflammatory cytokines such as interleukin- ip (IL-ip), tumor necrosis factor TNF-α, and IL-18; see, Latz et al., (2013), “Activation and regulation of the inflammasomes,” Nat. Rev. Immunol. 13(6): 397-4.11 . The NLRP1 pathway, which induces caspase- 1 and caspase-6, is reported to be involved in the progression of AD; see, Kaushal et al., (2015), “Neuronal NLRP1 inflammasome activation of caspase- 1 coordinately regulates inflammatory interleukin- 1 -beta production and axonal degeneration-associated caspase-6 activation. Cell Death & Differentiation,” 22 (10): 1676-1686. The NLRP3 pathway is also involved in AD, since NLRP3 deletion reduces caspase- 1 and IL-1β activities and enhances Aβ clearance (see above Heneka et al.) and NLRP3 regulates Caspase-8, see Antonopoulos et al., (2015), “Caspase-8 as an Effector and Regulator of NLRP3 Inflammasome Signaling,” J. Biol. Chem.
290(33):20167-84; which is also reportedly involved in AD, see Rohn et al., (2001), “Activation of caspase-8 in the Alzheimer's disease brain. Neurobiol. Dis. 8(6): 1006-16.”
[ 0055] Several studies indicate that the gut microbiome can influence neuroinflammation, raising the possibility that microbiome-based therapies could be an effective strategy for neurodegenerative disorders; see Sochocka et al., (2019), “The Gut Microbiome Alterations and Inflammation -Driven Pathogenesis of Alzheimer’s Disease- a Critical Review. Mol. Neurobiology 56 (3): 1841-1851. A recent study has shown that administration of the bacteria Bifidobacterium breve Al reversed the behavior impairm en t and prevented cognitive dysfunction in an AD mouse model; see Kobayashi et al., (2017), “Therapeutic potential of Bifidobacterium breve strain Al for preventing cognitive impairment in Alzheimer’s disease,” Sci. Rep.7(l):13510.
[ 0056] BTK as a drug target for AD
[0057] Identification of novel potential drug targets for AD were determined by investigating signaling pathways involving APP interactors and genes regulated by Aβ and reversed by the microbiome. Using the Ingenuity Pathway Analysis (IP A, Qiagen) program, the following gene sets were analyzed: a) 147 genes encoding APP protein interactors in humans (UniProtKB - P05067 (A4 HUMAN)); b) 300 genes regulated by Aβ and expressed in hippocampus in mice (see above Kobayashi et al.); c) 221 genes in hippocampus whose transcription is reversed by Bifidobacterium treatment in Aβ-treated mice (see above Kobayashi et al.).
[ 0058 ] Four signaling pathways were identified to be shared by the three sets of pathways generated by IP A from the gene sets: Tec Kinases pathway, Neuroinflammation, PI3K signaling, and IL-8 signaling. These signaling pathways are interconnected, since IL-8 and neuroinflammation are downstream of Tec Kinases; see, Wang et al., (2009), “Tec Kinase Mediating IL-8 Transcription in Monocytes Stimulated with LPS,” Inflammation, 32(4):265-9; also see, Gottar-Guillier et al., (2011), “The Tyrosine Kinase BMX Is an Essenti al Mediator of Inflammatory Arthritis in a Kinase-Independent Manner,” J. Immunol., 186:6014-6023; and PI3K regulates Tec Kinases signaling, see, Yang et al., (2001) “Tec Kinase Signaling in T Cells Is Regulated by Phosphatidylinositol 3-Kinase and the Tec Pleckstrin Homology Domain,” J. Immunol. 166:387-395. This suggests that the Tec Kinases signaling pathway as a potential novel drug target for AD. Tec Kinases are a family of mammalian non-receptor tyrosine kinases that include Bruton’s Tyrosine Kinase (BTK), Tec, BMX/ETK, ITK, and RLK/TXK and play important roles in the development or maintenance of the hematopoietic system and control many cellular functions essential to inflammation.
[ 0059 ] BTK is expressed in the CNS and several studies have implicated BTK as a player in the molecular processes underlying AD. Recently, inhibition of BTK has been strongly implicated as a therapeutic intervention for AD; see, Keaney et al., (2019), “Inhibition of Bruton’s Tyrosine Kinase Modulates Microglial Phagocytosis: Therapeutic Implications for Alzheimer’s Disease,” J. Neuroimmune Pharmacol, pl -14; and several lines of evidence support BTK as a drug target for AD. Increased BTK protein was found in prefrontal cortex of post-mortem AD patients, see, Garranzo-Asensio et al., (2018), “Identification of prefrontal cortex protein alterations in Alzheimer's disease” Oncotarget, 9(13): 10847-10867; and upregulation of BTK transcript was observed in post-mortem AD patient brains (see above Keaney et al.), in temporal, see, Castillo et al., (2017), “Comparative profiling of cortical gene expression in Alzheimer's disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation” Sci. Rep. 7(1): 17762, and prefrontal cortex (see Garranzo-Asensio et al. above). In mice, upregulation of BTK was observed in brains from the 5xF AD mouse model of AD (see above Keaney et al.) and in hippocampus of mice treated with Aβ (see Kobayashi et al. above).
[ 0060 ] BTK has been implicated in the regulation of several proteins involved in AD progression. Importantly, BTK is essential for NLRP3 inflammasome activation and IL-1β release, see, Ito et al., (2015), “Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury,” Nat. Commun.
6:7360; also see, Liu et al., (2017), “Human NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activity is regulated by and potentially targetable through Bruton tyrosine kinase” J. Allergy Clin. Immunol. 140(4): 1054-1067. NLRP3 inflammasome is activated in AD, (see above Heneka et al.) by Aβ, see, Halle et al., (2008), “The NALP3 inflammasome is involved in the innate immune response to amyloid-beta,” Nat. Immunol. 9(8):857-65; and genetic deletion of NLRP3 protects against Aβ pathology and cognitive dysfunction in AD mouse models (see above Heneka et al.). NLRP3 is activated in response to Toll-like receptor 2 (TLR2) activation, which is upregulated in human AD tissues, see, Webster et al., (2009), “Genetic control of human brain transcript expression in Alzheimer disease,” Am. J. Hum. Genet. 84: 445-458; also see Friedman et al., (2018), “Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer's Disease Not Evident in Mouse Models,” Cell Rep. 22(3):832-847; and AD mouse models, see, Wes et al., (2014), “Tau overexpression impacts a neuroinflammation gene expression network perturbed in Alzheimer's disease,” PLoS One. 9(8):el06050; also see, Holtman et al., (2015), “Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis,” Acta Neuropathol.
Commun. 3:31. AP-induced activation of TLRs and the NLRP3 inflammasome results in production and release of proinflammatory cytokines, such as IL-1β.
[ 0061] BTK is critical for the full activation of phospholipase-C y2 (PLCy2), a genetic risk factor in AD, see, Bertram et al., (2008), “Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE,” Am. J. Hum. Genet. 83(5):623-32; also see, Sims et al., (2017), “Rare coding variants in PLCG2, ABB, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease,” Nat. Genet. 49(9): 1373-1384; and a substrate of BTK, see, Watanabe et al., (2001), “Four tyrosine residues in phospholipase C-gamma 2, identified as Btk-dependent phosphorylation sites, are required for B cell antigen receptor-coupled calcium signaling” J. Biol. Chem. 276(42):38595-601 . Blockade of BTK activity (pharmacological or siRNA) decreased activation of PLCy2 and reduced microglial phagocytosis (see above Keaney et al., 2019).
[ 0062] Furthermore, consistent with a role for BTK inhibition in decreasing neuroinflammation and maintaining normal brain function, treatment with Ibrutinib, a BTK inhibitor, significantly reduced microglial and astrocyte activation and decreased levels of IL-ip in mice, see, Nam et al., (2018), “Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice,” J.
Neuroinflammation 15: 271, and prevented the loss of brain functions and reduced anxietylike behavior in a senescence mouse model, see, Ekpenyong-Akiba et al., (2020) “Amelioration of Age-Related Brain Function Decline by Bruton's Tyrosine Kinase Inhibition,” Aging Cell. 19(l):el3079. Therefore, BTK inhibitors are reasonably expected to be effective against neurological diseases in which the NLRP3 inflammasome and neuroinflammation are involved such as AD (see above Ito et al.).
[ 0063] Also consistent with a role for BTK inhibition in decreasing neuroinflammation and maintaining normal brain function, in 5xFAD mice (a model of AD overexpressing Aβ), treatment with ibrutinib, a BTK inhibitor, significantly reduced microglial and astrocyte activation and decreased levels of IL-lp (Nam HY et al., 2018). Importantly, in 5xFAD mice, two weeks treatment with ibrutinib reduced the numbers of Aβ plaques and Aβ plaque-associated gliosis, downregulated tau phosphorylation and reduced proinflammatory cytokine levels (Lee H et al., 2021). In PS19 mice (a model of tauopathy), ibrutinib suppressed micro- and astrogliosis and proinflammatory cytokine levels, and downregulated tau phosphorylation (Lee H et al., 2021). After two weeks of ibrutinib treatment, density of dendritic spines was increased in hippocampus of and PS I mice (Lee H et al., 2021). Increase in dendritic spines density was also observed in cultured hippocampal neurons treated with ibrutinib (Lee H et al., 2021). In addition, in a senescence mouse model, ibrutinib prevented the loss of brain functions and reduced anxiety-like behavior (Ekpenyong-Akiba AE et al., 2020). Taken together, these data support BTK inhibition and the selection of ibrutinib as a promising therapeutic intervention for AD (Ito M et al., 2015; Lee H et al., 2021).
[ 0064] Compositions and methods of treating neurological and psychiatric disorders with BTK inhibitors
[ 0065] As described herein, BTK inhibitors, at low doses as compared to the standard dosage use for the treatment of cancers and/or autoimmune disorders, can be used to treat AD and other neurological and psychiatric disorders. The present invention specifically encompasses methods for treating AD by partially inhibiting or modulating BTK activity in the brain by BTK inhibitors. Modulation vs complete inhibition of kinase activity has some advantages, for example, inhibition of a kinase that is dysregulated in one organ may prove harmful to other systems in which that kinase is not dysregulated but instead serves essential functions. While in most cancer therapies the aim of standard use dosage of a BTK inhibitor is to completely eliminate/inhibit kinase activity, the present invention provides compositions and methods for modulation of kinase activity (by finding doses that inhibit only a percentage of kinase molecules) is a more efficacious and appropriate approach in AD to regulate inflammatory responses while limiting toxicity and improving specificity.
[ 0066] Thus, encompassed by the present invention, are compounds and pharmaceutical compositions comprising a therapeutically effective amount/dose of a BTK inhibitor, or an analog or derivative thereof, including all stereoisomers and enantiomers thereof, or a pharmaceutically acceptable salt or a solvate thereof or a prodrug thereof in combination with a pharmaceutically acceptable carrier, wherein said BTK inhibitor is present in an amount sufficient to inhibit at least about ten (10) percent to about ninety (90) percent of a target kinase activity. The therapeutic dose of inhibitor is determined as described herein.
[ 0067 ] Most BTK inhibitors target the ATP-binding site of the kinase and the inhibitory mechanism (activity) of BTK inhibitors can be classified as either covalent (irreversible) or non-covalent (reversible) binding to the kinase. (See Zain and Vihinen (2021) Structure-Function Relationships of Covalent and Non-Covalent BTK Inhibitors. Front Immunol. 12:694853. PMC832433.) However, all BTK inhibitors bind to the ATP- binding site of BTK, and therefore share a common mechanism for the inhibition of kinase activity. Moreover, the BTK inhibitors share common residues that interact with the ATP binding sites. Residues around 410, 430, 480 and 540 of BTK are involved in interactions with both types of inhibitors (See Zain above, Fig. 2A and Fig. 2 herein). Many of the residues involved in ATP binding are essential for inhibitor recognition. The reversible inhibitors interact with many amino acids that also interact with covalent inhibitors despite largely different binding orientation.
[ 0068 ] As described above, ibrutinib is one specific example of a BTK inhibitor suitable for use in the present invention.
Figure imgf000022_0001
[ 0069 ] The structure of Ibrutinib (also known as PCI-32765) l-[(3R)-3-[4-amino-3-(4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidin-l-yl]prop-2-en-l-one (CAS No. 936563-96-1) is shown above. Ibrutinib is commercially available as a drug under the tradename IMBRUVICA® (AbbVie/Pharmacyclics and Janssen). Ibrutinib is an orally bioavailable, small-molecule inhibitor of BTK. Upon oral administration, ibrutinib binds to and irreversibly inhibits BTK activity.
[ 0070 ] Examples of other BTK inhibitors suitable for use in the present invention are described below. Specifically encompassed by the present invention are analogs and derivatives of these compounds that also possess BTK inhibitory activity suitable for the pharmaceutical compositions and methods of the present invention as described herein.
[0071] In some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000022_0002
[ 0072 ] Acalabrutinib (also known as Calquence) 4-[8-amino-3-[(2S)-l-but-2- ynoylpyrrolidin-2-yl]imidazo[l ,5-a]pyrazin-l-yl]-N-pyridin-2-ylbenzamide (CAS No. 1420477-60-6), commercially available as a drag under the tradename Calquence™ (AstraZeneca).Both acalabrutinib and its active metabolite, ACP-5862, act to form a covalent bond with a cysteine residue (Cys481) in the BTK active site, leading to inhibition of BTK enzymatic activity. Relative to the other BTK. inhibitors, the reduced intrinsic reactivity of acalabrutinib helps to limit inhibition of off-target kinases having cysteine- mediated covalent binding potential.
[ 0073 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000023_0001
[ 0074 ] Branebrutinib (also known as BMS-986195) 4-[(3S)-3-(but-2- ynoylamino)piperidin-l-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (CAS No. 1912445-55-6). Branebrutinib is a highly potent, selective covalent, irreversible inhibitor of BTK.
[ 0075 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000024_0001
[ 0076] Evobrutinib (also known as M-2951) l-[4-[[[6-amino-5-(4- phenoxyphenyl)pyrimidin-4-yl]amino]methyl]piperidin-l-yl]prop-2-en-l-one (CAS No. 1415823-73-2). Evobrutinib is an orally administered, irreversible antagonist of BTK which inhibits signal transduction until the protein is naturally degraded. Evobrutinib, functions chemically engaging irreversibly with the same cysteine residue on the BTK protein.
[ 0077 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000024_0002
[ 0078 ] Orelabrutinib (also known as ICP-022) 2-(4-phenoxyphenyl)-6-(l -prop-2- enoylpiperidin-4-yl)pyridine-3-carboxamide (CAS No. 1655504-04-3). Orelabrutinib is an orally available potent BTK inhibitor that irreversibly binds to BTK.
[ 0079 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000025_0001
[ 0080 ] Remibrutinib (also known as LOU064) N-[3-[6-amino-5-[2-[methyl(prop-2- enoyl)amino]ethoxy]pyrimidin-4-yl]-5-fluoro-2-methylphenyl]-4-cyclopropyl-2- fluorobenzamide (CAS No. 1787294-07-8). Remibrutinib is an oral BTK inhibitor developed by Novartis. The terminal acrylamide group binds covalently to C481.
[ 0081 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000025_0002
[ 0082 ] Spebrutinib (also known as AVL-292) N-[3-[[5-fluoro-2-[4-(2- methoxyethoxy)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide (CAS No. 1202757- 89-8). Spebrutinib is an orally bioavailable, selective inhibitor of BTK which targets and covalently binds to BTK, thereby irreversibly inhibiting BTK.
[ 0083 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000026_0001
[ 0084 ] Tirabrutinib (also known as Velexbru and GS-4059) 6-amino-9-[(3R)-l-but-2- ynoylpyrrolidin-3-yl]-7-(4-phenoxyphenyl)purin-8-one (CAS No. 1351636-18-4).
Tirabrutinib is an orally available formulation containing an inhibitor of BTK. Upon administration, tirabrutinib covalently binds to BTK.
[0085] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000026_0002
[ 0086] Tolebrutinib (also known as SAR442168) 4-amino-3-(4-phenoxyphenyl)-l- [(3R)-l-prop-2-enoylpiperidin-3-yl]imidazo[4,5-c]pyridin-2-one (CAS No. 1971920-73-6). Tolebrutinib is an irreversible covalent agent with ability to cross the blood -brain barrier. In the cerebrospinal fluid, unbound tolebrutinib is found in the nanomolar concentration range, a pharmacologically relevant level .
[ 0087 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000027_0001
[ 0088 ] Zanubrutinib (7 S)-2-(4-phenoxyphenyl)-7-( 1 -prop-2-enoylpiperidin-4-yl)- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-3-carboxamide (CAS No. 1691249-45-2). Zanubrutinib inhibits BTK by forming a covalent bond with cysteine 481 residue.
Zanubrutinib was granted accelerated approval by the FDA in November 2019. It is currently marketed under the trade name BRUKINSA™.
[ 0089 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000027_0002
[ 0090 ] Rilzabrutinib (also known as PRN1008) (E)-2-[(3R)-3-[4-amino-3-(2-fluoro-4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile (CAS No. 1575596-29-0). Rilzabrutinib efficiently crosses the blood-brain barrier. Rilzabrutinib is a small-molecule, reversible covalent inhibitor of BTK. [ 0091] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000028_0001
[ 0092] ARQ 531 (2-chloro-4-phenoxyphenyl)-[4-[[(3R,6S)-6-(hydroxymethyl)oxan-3- yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (CAS No. 2095393-15-8). ARQ 531 is a potent, reversible inhibitor of both wild-type and mutant BTK.
[ 0093] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000028_0002
[ 0094] BMS-986142 (7S)-3-fluoix-4-[3-(8-fluoro-l-methyl-2,4-dioxoquinazolin-3-yl)-
2-methylphenyl]-7-(2-hydroxypropan-2-yl)-6,7,8,9-tetrahydro-5H-carbazole- 1 - carboxamide (CAS No. 1643368-58-4).
[ 0095] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000029_0001
[ 0096] Fenebrutinib (also known as GDC-0853) 10-[3-(hydroxymethyl)-4-[l -methyl -
5-[[5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-l-yl]pyridin-2-yl]amino]-6-oxopyri din-3- yl]pyridin-2-yl]-4,4-dimethyl-l,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-one (CAS No. 1434048-34-6). Fenebrutinib is a highly selective, reversible, non-covalent BTK inhibitor.
[ 0097 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000029_0002
[ 0098 ] Pirtobrutinib (also known as LOXO-305) 5-amino-3-[4-[[(5-fluoro-2- methoxybenzoyl)amino]methyl]phenyl]- 1 -[(2 S)- 1,1,1 -trifl uoropropan-2-yl]pyrazole-4- carboxamide (CAS No. 2101700-15-4). Pirtobrutinib is a highly selective and non- covalent next generation BTK inhibitor, which potently inhibits BTK with nanomolar potency and shows high selectivity with minimal off-target inhibition.
[ 0099 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000030_0001
[ 00100] RN486 6-cyclopropyl-8-fluoro-2-[2-(hydroxymethyl)-3-[l-methyl-5-[[5-(4- methylpiperazin-l-yl)pyridin-2-yl]amino]-6-oxopyridin-3-yl]phenyl]isoquinolin-l-one (CAS No. 1242156-23-5).
[ 00101] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000030_0002
[ 00102] Vecabrutinib (3R,4S)-l-(6-amino-5-fluoropyrimidin-4-yl)-3-[(3R)-3-[3-chloro- 5-(trifluoromethyl)anilino]-2-oxopiperidin- 1 -yl]piperidine-4-carboxamide) (CAS No. 1510829-06-7). Vecabrutinib is a selective, reversible, non-covalent BTK inhibitor with nanomolar potency.
[ 00103] BTK inhibitor dosage selection
[ 00104] In some embodiments the BTK inhibitor is present in an amount sufficient to inhibit or modulate the target kinase activity from about ten (10) percent to about twenty- five (25) percent . In yet some other embodiments the BTK inhibitor is present in an amount sufficient to inhibit or modulate the target kinase activity from about twenty-five (25) percent to about fifty (50) percent up to about ninety (90) percent. In yet some other embodiments the BTK inhibitor is present in an amount sufficient to inhibit or modulate the target kinase activity from about fifty (50) percent to about seventy-five (75) percent. In yet some other embodiments the BTK inhibitor is present in an amount sufficient to inhibit or modulate the target kinase activity from about seventy-five (75) percent to about ninety (90) percent. In other embodiments such amounts may include at least ten (10) percent, at least fifteen (15) percent, at least twenty (20) percent, at least twenty -five (25) percent, at least thirty (30) percent, at least thirty-five (35) percent, at least forty (40) percent, at least forty-five (45) percent, at least fifty (50) percent, at least fifty-five (55) percent, at least sixty (60) percent, at least sixty (60) percent, at least sixty-five (65) percent, at least seventy (70) percent, at least seventy-five (75) percent, at least eighty (80) percent, at least eighty five (85) percent, at least ninety (90) percent, and so on. All such ranges are wi thin the scope of the i nvention. More parti cularly, one of skill in the art readily appreciates these dosing ranges depend specifically upon the particular BTK inhibitor used, its activity at the BTK site and its absorption, distribution, metabolism and excretion (ADME) properties as well as the particular indication/neurological or psychiatric disorders.
[ 00105] One example of a suitable BTK inhibitor is ibrutinib. Ibrutinib is a first-in- class, orally administered inhibitor of BTK. It is known in the art that it is brain penetrant, see above Ito et al., and also see, Goldwirt et al., (2018), “Ibrutinib brain distribution: a preclinical study,” Cancer Chemotherapy and Pharmacology, 81 : 783-789. Ibrutinib is also known to be an irreversible (covalent) inhibitor of BTK. It was co-developed by Pharmacyclics, LLC and Janssen Research & Development, LLC for the treatment of B- cell malignancies. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. Ibrutinib is an FDA-approved drug. The well-established safety, toxicity profile, and side effects of ibrutinib observed in humans were obtained at doses of 560-420 mg once daily [8-6 mg/kg/day, the recommended doses for Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Waldentrbm’s macroglobinemia (WM), Chronic Graft-versus-Host Disease (cGVHD)]. This 8-6 mg/kg/day dose is higher than the 2.5 mg/kg/day dose, which is necessary to achieve >95% BTK occupancy in blood cells. Ibrutinib at high dosage (420-560 mg/day, 6- 8mg/kg, as FDA-approved doses) has been associated with adverse reactions (see Imbruvica.com for complete listing) that include increased risk of infections (Williams AM, et al., 2017), leukostasis and bleeding complications (Kamel S et al., 2015; Murthy P et al., 2017), and increased rates of atrial fibrillation (Wiczer TE et al., 2017). Doses of Ibrutinib as described herein as sufficient for the present methods are lower doses (3.2-12.8 fold less than the FDA-approved dose for MCL and MZL). Since the doses encompassed by the present invention are much lower than the FDA-approved ones, it is reasonable to predict corresponding higher inhibition specificity and reduced side effects.
[ 00106] Previous studies have shown that 95% BTK occupancy is achieved 4 hours post-dose in all patients at 2.5 mg/kg/day and partial occupancy at 1.25mg/kg/day with no evidence of accumulation of Ibrutinib exposure after repeated daily oral dosing (Advani RFI et al., 2013). The comparable half-life of ibrutinib and BTK. (4-8 h and 8 h, respectively; Advani RH et al., 2013; Bronson J et al., 2014; Hutchinson CV and Dyer MIS, 2014) predicts no accumulation of Ibrutinib BTK-bound in the system.
[ 00107 ] Based on these observations, and to achieve lower occupancy and partial inhibition of BTK, the following doses of ibrutinib suitable for the present invention are reasonably believed to be about: 0.625 mg/kg (predicted 25% occupancy), 1.25 mg/kg (predicted 50% occupancy), 2.5 mg/kg per day (95% occupancy), still well below the 560 mg/day (8mg/kg) approved for Mantle Cell Lymphoma (MCL) and Marginal Zone Lymphoma (MZL) and the 420 mg/day (6mg/kg) approved for 'Waldenstrom’s Maroglobinenima (WM). Similar methodology as that described herein can be used to determine suitable dosages of other BTK inhibitors as described herein.
[ 00108 ] Compounds and compositions of BTK inhibitors
[ 00109 ] Any BTK inhibitor having the described kinase inhibitory activity can be used in the pharmaceutical compositions of this invention.
[ oono] In some embodiments, the pharmaceutical composition according to this invention contains a BTK inhibitor selected from the group comprising but not limited to, or consisting of : a compound of formula (I), including enantiomers and stereoisomers thereof:
Figure imgf000033_0001
a compound of formula (II), including enantiomers and stereoisomers thereof:
Figure imgf000033_0002
a compound of formula (III), including enantiomers and stereoisomers thereof:
Figure imgf000033_0003
wherein:
X represents CH2, O, S, NH , CO, COO or CONH; each of Ar1, Ar2 and Ar3 independently is selected from the group consisting of substituted or unsubstituted (C6-C10)aryl and substituted or unsubstituted (C5-C10)heteroaryl, wherein each of said substituents are independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, and (C6-C10)aryloxy; each of R1, R2 and R3 independently is selected from the group consisting of substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C3-C8)cycloalkyl, substituted or unsubstituted (C3-C8)heterocycloalkyl, substituted or unsubstituted (C6-C10)aryl, and substituted or unsubstituted (C5-C10)heteroaryl, wherein each of said substituents are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C2-C6)acyl, substituted or unsubstituted acryloyl, and substituted or unsubstituted (C3-C6)alkynoyl.
[oom] In some embodiments, representative examples of Ari, An and An indude without any limitation phenyl, 2-, 3- or 4-methylphenyl, pyridyl, 2-, 3- or 4-methylpyridl, and the like. Non-limiting examples of X indude O or CONH. Representative examples of Ri, R2, RS without any limitation indude five or six membered heterocyde rings, such as substituted pyrrolidine or piperidine among others. Suitable substituents indude without any limitation acryloyl, butynoyl, and the like.
[ 00112 ] Some examples of BTK inhibitors suitable for use in the present inventions indude: ibrutinib, acalabrutinib, tolebrutinib, zanubrutinib, bramebrutinib, evobrutinib, orelabrutinib, remibrutinib, sprebrutinib, tirabrutinib, rilzabrutinib, ARQ 531, BMS- 986142, fenebrutinib, pirtobrutinib, RN 486 or vecabrutinib.
[00113] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000034_0001
[ 00114 ] Ibrutinib (also known as PCI-32765) l-[(3R)-3-[4-amino-3-(4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidin-l-yl]prop-2-en-l-one (CAS No. 936563-96-1). Ibrutinib is commercially available as a drug under the tradename IMBRUVICA® (AbbVie/Pharmacydics and Janssen). Ibrutinib is an orally bioavailable, small-molecule inhibitor of BTK. Upon oral administration, ibrutinib binds to and irreversibly inhibits BTK activity.
Figure imgf000035_0001
[ 00115 ] Acalabrutinib (also known as Calquence) 4-[8-amino-3-[(2S)-l-but-2- ynoylpyrrolidin-2-yl]imidazo[l,5-a]pyrazin-l-yl]-N-pyridin-2-ylbenzamide (CAS No. 1420477-60-6), commercially availabl e as a drug under the tradename Calquence™ (AstraZeneca).Both acalabrutinib and its active metabolite, ACP-5862, act to form a covalent bond with a cysteine residue (Cys481) in the BTK active site, leading to inhibition of BTK enzymatic activity. Relative to the other BTK inhibitors, the reduced intrinsic reactivity of acalabrutinib helps to limit inhibition of off-target kinases having cysteine- mediated covalent binding potential.
[ 00116] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000035_0002
[ 00117 ] Branebrutinib (also known as BMS-986195) 4-[(3S)-3-(but-2- ynoylamino)piperidin-l-yl]-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide (CAS No. 1912445-55-6). Branebrutinib is a highly potent, selective covalent, irreversible inhibitor ofBTK. [ 00118 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000036_0001
[ 00119] Evobrutinib (also known as M-2951) 1 -[4-[[[6-amino-5-(4- phenoxyphenyl)pyrimidin-4-yl]amino]methyl]piperidin-l-yl]prop-2-en-l-one (CAS No. 1415823-73-2). Evobrutinib is an orally administered, irreversible antagonist of BTK which inhibits signal transduction until the protein is naturally degraded. Evobrutinib, functions chemically engaging irreversibly with the same cysteine residue on the BTK protein.
[ 00120] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000036_0002
[ 00121] Orelabrutinib (also known as ICP-022) 2-(4-phenoxyphenyl)-6-(l-prop-2- enoylpiperidin-4-yl)pyridine-3-carboxamide (CAS No. 1655504-04-3). Orelabrutinib is an orally available potent BTK inhibitor that irreversibly binds to BTK.
[ 00122 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000037_0001
[00123] Remibrutinib (also known as LOU064) N-[3-[6-amino-5-[2-[methyl(prop-2- enoyl)amino]ethoxy]pyrimidin-4-yl]-5-fluoro-2-methylphenyl]-4-cyclopropyl-2- fluorobenzamide (CAS No. 1787294-07-8). Remibrutinib is an oral BTK inhibitor developed by Novartis. The terminal acrylamide group binds covalently to C481.
[00124] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000037_0002
[00125] Spebrutinib (also known as AVL-292) N-[3-[[5-fluoro-2-[4-(2- methoxyethoxy)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide (CAS No. 1202757- 89-8). Spebrutinib is an orally bioavailable, selective inhibitor of BTK which targets and covalently binds to BTK, thereby irreversibly inhibiting BTK.
[00126] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000038_0001
[ 00127 ] Tirabrutinib (also known as Velexbru and GS-4059) 6-amino-9-[(3R)-l-but-2- ynoylpyrrolidin-3-yl]-7-(4-phenoxyphenyl)purin-8-one (CAS No. 1351636-18-4).
Tirabrutinib is an orally available formulation containing an inhibitor of BTK. Upon administration, tirabrutinib covalently binds to BTK.
[ 00128 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000038_0002
[ 00129 ] Tolebrutinib (also known as SAR442168) 4-amino-3-(4-phenoxyphenyl)-l- [(3R)-l-prop-2-enoylpiperidin-3-yl]imidazo[4,5-c]pyridin-2-one (CAS No. 1971920-73-6).
Tolebrutinib is an irreversible covalent agent with ability to cross the blood-brain barrier. In the cerebrospinal fluid, unbound tolebrutinib is found in the nanomolar concentration range, a pharmacologically relevant level.
[ 00130 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000039_0001
[ 00131 ] Zanubrutinib (7S)-2-(4-phenoxyphenyl)-7-(l-prop-2-enoylpiperidin-4-yl)- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-3-carboxamide (CAS No. 1691249-45-2). Zanubrutinib inhibits BTK by forming a covalent bond with cysteine 481 residue.
Zanubrutinib was granted accelerated approval by the FDA in November 2019. It is currently marketed under the trade name BRUKINSA™.
[ 00132 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000039_0002
[ 00133 ] Rilzabrutinib (also known as PRN1008) (E)-2-[(3R)-3-[4-amino-3-(2-fluoro-4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile (CAS No. 1575596-29-0). Rilzabrutinib efficiently crosses the blood-brain barrier. Rilzabrutinib is a small -molecule, reversible covalent inhibitor of BTK. [ 00134 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000040_0001
[ 00135 ] ARQ 531 (2-chloro-4-phenoxyphenyl)-[4-[[(3R,6S)-6-(hydroxymethyl)oxan-3- yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (CAS No. 2095393-15-8). ARQ 531 is a potent, reversible inhibitor of both wild-type and mutant BTK.
[ 00136] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000040_0002
[ 00137 ] BMS-986142 (7S)-3-fluoro-4-[3-(8-fluoro-l-methyl-2,4-dioxoquinazolin-3-yl)-
2-methylphenyl]-7-(2-hydroxypropan-2-yl)-6,7,8,9-tetrahydro-5H-carbazole-l- carboxamide (CAS No. 1643368-58-4).
[ 00138 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000041_0001
[ 00139 ] Fenebrutinib (also known as GDC-0853) 10-[3-(hydroxymethyl)-4-[l-methyl- 5-[[5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-l-yl]pyridin-2-yl]amino]-6-oxopyridin-3- yl]pyridin-2-yl]-4,4-dimethyl-l,10-di azatri cyclo[6.4.0.02, 6]dodeca-2(6),7-dien-9-one (CAS No. 1434048-34-6). Fenebrutinib is a highly selective, reversible, non-covalent BTK inhibitor.
[ 00140 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000041_0002
[ 00141 ] Pirtobrutinib (also known as LOXO-305) 5-amino-3-[4-[[(5-fluoro-2- methoxybenzoyl)amino]methyl]phenyl]- 1 -[(2 S)- 1,1,1 -trifluoropropan-2-yl]pyrazole-4- carboxamide (CAS No. 2101700-15-4). Pirtobrutinib is a highly selective and non- covalent next generation BTK inhibitor, which potently inhibits BTK with nanomolar potency and shows high selectivity with minimal off-target inhibition.
[ 00142 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000042_0002
[ 00143] RN486 6-cyclopropyl-8-fluoro-2-[2-(hydroxymethyl)-3-[l-methyl-5-[[5-(4- methylpiperazin- 1 -yl)pyridin-2-yl]amino]-6-oxopyridin-3-yl]phenyl]isoquinolin- 1 -one (CAS No. 1242156-23-5).
[ 00144 ] In yet some embodiments the pharmaceutical composition according to this invention contains a BTK inhibitor which is a compound of formula:
Figure imgf000042_0001
[ 00145] Vecabrutinib (3R,4S)-l-(6-amino-5-fluoropyrimidin-4-yl)-3-[(3R)-3-[3-chloro- 5-(trifluoromethyl)anilino]-2-oxopiperidin- 1 -yl]piperidine-4-carboxamide) (CAS No. 1510829-06-7). Vecabrutinib is a selective, reversible, non-covalent BTK inhibitor with nanomolar potency.
[ 00146] It has now been identified that BTK is a potential novel drug target for treating a variety of neuroinflammation disorders, such as in AD. One of skill in the art readily appreciates that the BTK has been an actively -researched target in oncology with several compounds in development and currently three FDA-approved BTK inhibitors as mentioned above. More specifically: ibrutinib (Imbruvica) was approved in 2013, acalabrutinib (Calquence) approved in 2017, and zanubrutinib (Brukinsa) approved in 2019. Acalabrutinib has a minimal penetration of blood-brain barrier (AstraZeneca Pty Ltd - PM-2019-03536-1-6) and zanubrutinib has had the least follow-up time and is known to penetrate of blood-brain barrier.
[ 00147 ] Accordingly, the BTK inhibitors as used in the pharmaceutical composition of this invention are known in the literature and can be synthesized by any of the procedures known to one skilled in the art. Specifically, ibrutinib can be synthesized following the procedures as disclosed in U. S. Patent No. 7,514,444, pertinent portions of which is incorporated herein by reference. Similarly, acalabrutinib can be synthesized following the procedures as disclosed in U. S. Patent No. 7,459,554, pertinent portions of which is incorporated herein by reference. Zanubrutinib can be synthesized following the procedures as disclosed in U. S. Patent No. 9,447,106, pertinent portions of which is incorporated herein by reference. Tolebrutinib can be synthesized following the procedures as disclosed in U. S. Patent No. 9,688,676, pertinent portions of which is incorporated herein by reference.
[ 00148 ] Accordingly, this invention provides BTK. inhibitors, such as ibrutinib and others described herein, for methods of treating a number of CNS disorders, thus providing a new channel for unmet needs in treating such disease conditions. Even more advantageously, since BTK has been identified as a novel inflammasome regulator and blocking BTK is likely to inhibit inflammasome activity, Ibrutinib could be a novel therapeutic that suppresses inflammation in the CNS and mitigate the effect of AD slowing the cognitive decline. Additionally, using the methods detailed herein, other novel BTK inhibitors can be identified and evaluated that would be suitable for use in the methods of the present invention.
[ 00149 ] Methods of preventing or treating CNS disorders such as AD
[ 00150 ] Methods or preventing or treating neurological and psychiatric disorders are encompassed by the present invention. Accordingly, there is provided a method of treating a neurological disease or a psychiatric disorder by administering to a patient in need thereof a therapeutically effective amount of a brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor. In particular, the methods encompass administering to a subject in need thereof a therapeutic dose of a BTK inhibitor wherein the dosage of BTK inhibitor is sufficient to partially inhibit the activity of the BTK by at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 % as measured as inhibitor occupancy of the kinase in peripheral blood mononuclear cells (PBMCs).
[ 00151] The present invention provides the significant advantage of using low dosages of the BTK inhibitors for the treatment of a variety of CNS disorders in order to mitigate any potential side effects yet treat the patient suffering from such disorders. It is reasonable to believe that the low dosages of BTK inhibitors as described herein not only will mitigate any side toxic effects of the inhibitor but also effectively modulate the kinase activity of the target enzyme. Thus, an important aspect of the dosage is that, while Ibrutinib has been approved at doses as high as 560 mg/day for MCL and MZL, it is now provided that a lower daily dosage of approximately 43.75, 87.5 mg/day, and 175 mg/day (0.625 mg/kg, 1.25 mg/kg, and 2.5 mg/kg), can reasonably reduce the side effects as well as affinity and unwanted inhibition of other kinases, while controlling the level of neuroinflammation and thereby alleviating the associated conditions, such as mild to moderate AD, schizophrenia, and autism spectrum disorders (ASD), among other conditions.
[ 00152] Currently, there is no approved treatment to prevent progression of AD. Approved treatments for alleviation of symptoms of AD include the following: AChE inhibitors: donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne) which offer modest symptomatic relief (in terms of cognitive test scores and global functioning) for some patients but do not constitute standard treatment for the disease. Memantine (Namenda) is an approved treatment of moderate to severe AD. Also encompassed by the present invention are methods of preventing or treating AD by modulating/partially inhibiting BTK activity in a subject are described herein. In particular, the methods of prevention or treating AD encompass administering to a subject in need thereof a therapeutic dose of a BTK inhibitor wherein the dosage of BTK inhibitor is sufficient to partially inhibit the activity of BTK by at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 %.
[ 00153] It is contemplated that any of the known neurologi cal di seases can be treated by the BTK inhibitors as described hereinabove. Non-limiting examples of such neurological disease is selected from the group consisting of AD, Parkinson’s disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, neuropathic and chronic pain, human immunodeficiency virus (HIV)-associated dementia and Creutzfeldt-Jakob disease. Other neurological conditions or diseases may also include traumatic brain injury (TBI) and brain ischemia, among others.
[ 00154] It is further contemplated that any of the known psychiatric diseases can be treated by the BTK inhibitors as described hereinabove. Non-limiting examples of such psychiatric disease is selected from the group consisting of major depression, bipolar, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders, anxiety, addiction and ADHD.
[ 00155] As noted herein any of the therapeutically effective amounts of BTK inhibitors as described herein can be used in the methods of preventing or treating either the neurological disease or the psychiatric diseases. Accordingly, in some embodiments such a therapeutically effective amount of BTK inhibitor is an amount sufficient to inhibit at least 10 (ten) percent of target kinase activity. In yet some other embodiments such therapeutically effective amount of BTK inhibitor is an amount sufficient to inhibit at least 25 percent of target kinase activity. In further embodiments of the present invention, the percentage of BTK inhibition can be up to about 90 or even 95% as measured in the blood and correlated to BTK inhibition in the brain after penetrating the blood brain barrier.
[ 00156] Further it has been con tempi ated that a combination of BTK inhibitor and one, or more drugs currently used to treat such conditions may provide synergistic benefits in treating such disease conditions. Accordingly, there is further provided pharmaceutical compositions containing a therapeutically effective amounts of a BTK inhibitor as described herein and a therapeutically effective amount of another drug used to treat a CNS condition as described herein.
[ 00157] In another embodiment of the method of this invention, the pharmaceutical composition of this invention can be administered by any of the methods known in the art. Specifically, the pharmaceutical composition of this invention can be administered by oral, intramuscular, subcutaneous, rectal, intratracheal, intranasal, intraperitoneal or topical route. Generally, the pharmaceutical compositions of this invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. An erodible polymer containing the active ingredient may be envisaged. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these pre-formulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation composition is then subdivided into unit dosage forms of the type described above containi ng from 0.1 to about 500 mg of the active ingredient of the present invention. Flavored unit dosage forms contain from about 1 to 100 mg, for example about 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
[ 00158 ] The li qui d forms in which the pharmaceutical composi tions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
[ 00159 ] Exemplification: Clinical Trial Protocol for Evaluation of BTK Inhibitors [ 00160 ] To address the critical need for effective therapeutic approaches to AD, a clinical study as described below, can be used to assess the safety and tolerability of BIX inhibitors. For the initial study, ibrutinib is selected over other BIX inhibitors because of its known brain penetrance and preclinical efficacy data in animal models of AD. However, other BTK inhibitors can be assessed using the same, or very similar protocols, using doses suitable for each BTK inhibitor. For example, three doses of the BTK inhibitor can be tested that are predicted to inhibit BTK by approximately 25%, 50%, and 95% (measured as enzyme occupancy in blood) and are well below FDA-approved doses (3.2- 12.8 fold less as by example for ibrutinib) in a patient population with AD. This clinical study can be randomized and double-blind, testing three doses of BTK inhibitor to be administered daily for 14 days in 3 cohorts of patients, each receiving one of BTK inhibitor low dose regimen or placebo. Patients enlisted in such clinical trials can exhibit mild or moderate symptoms of AD.
[ 00161 ] Ibrutinib is a first-in-class, orally administered inhibitor of BTK. It is known in the art that it is brain penetrant, see above Ito et al., and also see, Goldwirt et al., (2018), “Ibrutinib brain distribution: a preclinical study,” Cancer Chemotherapy and Pharmacology, 81 : 783-789. Ibrutinib is also known to be an irreversible (covalent) inhibitor of BTK. It was co-developed by Pharmacy dies, LLC and Janssen Research & Development, LLC for the treatment of B-cell malignancies. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity.
[ 00162 ] In humans, ibrutinib rapidly crosses the blood brain barrier and in patients that received 560 mg/day of ibrutinib, Ibrutinib was observed in the cerebrospinal fluid (CSF) at concentrations that exceeded the ICso for BTK inhibition (0-5 nmol/1), see MacGlashan et al., (2011), “Inhibition of IgE-mediated secretion from human basophils with a highly selective Bruton's tyrosine kinase, Btk, inhibitor,” International Immunopharmacology, 11, 475-9. Similarly, Ibrutinib levels in excess of the ICso for BTK inhibition were also recognized in the CSF of patients with mantle cell lymphoma that received 560 mg/day of Ibrutinib, see Bernard S. et al., (2015), “Activity of Ibrutinib in mantle cell lymphoma patients with central nervous system relapse,” Blood, 126, 1695-98; and in patients with primary CNS lymphoma that received Ibrutinib at 560-840 mg/day (see Dunleavy K et al., 2015, “Phase I study of dose-adjusted Teddi-R with Ibrutinib in untreated and relapsed/refractory primary CNS lymphoma. Blood, 126, Abstract 472).
[ 00163] From the foregoing data and the well-established safety and toxicity profile, and the blood brain barrier penetration, it has now reasonable to believe that ibrutinib is a suitable drug for the treatment of a number of CNS indications, including the treatment of AD. An exemplary clinical study to assess the safety and tolerability of ibrutinib will include a 2-week Phase I multiple ascending doses, randomized, double-blind, placebo controlled clinical trial, which is characterized by small groups is described herein. The doses will be much lower than the maximum dose approved by FDA for the oncological indications mentioned above.
[ 00164 ] The rationale for use of lower dosage in CNS indications are as follows.
Previous studies have shown that 95% BTK occupancy is achieved 4 hours post-dose in all patients at 2.5 mg/kg per day and partial occupancy at 1.25 mg/kg per day; there is no evidence of accumulation of Ibrutinib exposure after repeated daily oral dosing (see Advani et al., 2013, “Bruton tyrosine kinase inhibitor Ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies,” J. Clin. Oncol. 31:88- 94). Based on these observations and to enable a partial inhibition of BTK (to limit toxicity while still obtaining efficacy in brain), it is now proposed to assess the safety and efficacy of Ibrutinib below or equal to 2.5 mg/kg per day dose to achieve lower BTK occupancy. The following doses will be used in this study: 0.625 mg/kg (predicted approximately 25% occupancy), 1.25 mg/kg (predicted approximately 50% occupancy), 2.5 mg/kg per day (95% occupancy, as control), still well below the 560 mg/day (8 mg/kg) approved for mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL) and the 420 mg/day (6 mg/kg) approved for Waldenstrom's macroglobulinemia (WM).
[ 00165] Elevated concentrations of peripheral inflammatory biomarkers such as interleukin- 10 (IL-10), IL-2, IL-6, IL-18 and soluble TNF receptors 1 and 2 were reported in AD patients (see Lai KSP et al., 2017, “Peripheral inflammatory markers in Alzheimer’s disease: a systematic review and meta-analysis of 175 studies,” J. Neurol. Neurosurg. Psychiatry, 88 (10), 876-882; and Su C et al., 2019, “Peripheral Inflammatory Biomarkers in Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review and MetaAnalysis/’ Psychogeriatrics 19 (4), 300-309. The concentration of these inflammatory biomarkers can be assessed in plasma of patients to see whether Ibrutinib treatment results in a decrease of these biomarkers.
[ 00166] The primary enrollment criteria will be a diagnosis of AD dementia as determined by the National Institute on Aging and Alzheimer’s Association core clinical criteria (see McKhann GM et al., 2011, “The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging- Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease,” Alzheimer’s Dement. 2011;7:263-9). Additional criteria include age 50 to 75 years and scores of 4 or lower on a modified Hachinski Ischemia Scale (see Rosen WG et al., 1980, “Pathological verification of ischemic score in differentiation of dementias,” Ann. Neurol. 7(5):486-488) (score range: 0-12, with the highest score indicating highest probability of vascular dementia), 6 or lower on the Geriatric Depression Scale (score range: 0-15, with the highest score indicating most depressive symptoms) (see Sheikh J et al., 1986, “Geriatric Depression Scale (GDS): recent evidence and development of a shorter version,” In: Brind TL, ed. Clinical Gerontology: A Guide to Assessment and Intervention. New York: Haworth Press: 165-173), and 18 to 26 on the Mini-Mental State Examination (MMSE) (see Folstein MF et al., 1975, “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician,” J. Psychiatric Res. 12:189 -98). Subjects will be required to have stable permitted medications for 4 weeks prior to study participation. Cholinesterase inhibitors and memantine hydrochloride will be permitted if stable for 12 weeks prior to screening.
[ 00167 ] Participants will be excluded from the study if they exhibited any significant neurologic disease other than AD. Additionally, subjects showing evidence of infection, with condition which could possibly interfere with inflammatory process, a clinically significant or unstable medical condition, any other severe concurrent disease, or history of serious organ dysfunction or disease, or with a history of schizophrenia or alcohol or substance abuse/dependence within the past 2 years (Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria) will be excluded.
[ 00168] Additionally, subj ects will be excluded if with current and concurrent use of systemic anticoagulation with warfarin or other Vitamin K antagonists, or strong CYP3A4 inhibitors or inducers, or evidence of bleeding diathesis or coagulopathy, or any history of symptomatic intracranial hemorrhage, or non-healing wound, ulcer, or bone fracture, or vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug, or known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV). Investigational agents will be prohibited one month prior to entry and for the duration of the trial. Also exclusionary is previous treatment with an investigational small molecule with anti-amyloid properties or passive immunization against amyloid within 1 year of entry or previous treatment with an active immunization against amyloid.
[ 00169 ] The study is a 2-week Phase I with multiple ascending doses, randomized, double-blind, placebo controlled trial of Ibrutinib in AD patients with mini-mental state examination (MMSE) scores ranging from 20 to 26. A total of 24 subjects will be recruited in three sequential groups, with each randomized to receive oral ibrutinib at doses of 0.625 mg/kg, 1.25 mg/kg, or 2.5 mg/kg, or placebo daily for 2 weeks (each cohort: 6 participants receiving Ibrutinib dose, 2 receiving placebo). Subjects will be seen for safety visits at weeks 1, 2, and 3. Outcome measures will be collected after 2 weeks on ibrutinib or placebo. Study medication compliance will be measured throughout the study. A final safety visit will be completed after the participant had been off ibrutinib or placebo for approximately 2 weeks.
[ 00170 ] A primary objective of the exemplified study is to assess the safety and tolerability of the drug in patients with AD and determine dose levels that provide 50% and lower target occupancy of the acti ve site in blood cells and to characterize the pharmacokinetic profiles and target occupancy for these doses. For ibrutinib, low daily ibrutinib doses (0.625 mg/kg, 1.25 mg/kg, and 2.5 mg/kg) will be evaluated to assess the safety and tolerability of these doses and characterize their pharmacokinetic profiles in blood and CSF and determine the target occupancy of the BTK active site as measured in blood.
[ 00171 ] Cognition and behavior as measures of safety using clinical measures such as Alzheimer's Disease Assessment Scale (ADAS-cog), Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory (NPI) will be assessed. Another objective is to assess levels of inflammatory biomarkers (IL-lp, IL-6, IL-12, IL-18, TNF-α, and TGF-β) and neurodegeneration biomarkers [P-taul81/tau, Aβ42/Aβ4O, neurofilament light (NfL), neurogranin] in CSF and blood. The biomarker analyses would allow assessment of AD pathologies and neuroinfiammation in these patients. [ 00172] Primary endpoints are to assess the safety and tolerability of ibrutinib in patients with AD and determine dose levels that provide lower occupancy of the BTK active site in blood cells. A secondary endpoint is the evaluation of safety using clinical efficacy measures (Alzheimer's Disease Assessment Scale - Cognitive Subscale, MMSE, Neuropsychiatric Inventory,). Another secondary endpoint is the measurement of inflammatory and neurodegenerative biomarkers in CSF and blood.
[ 00173] The patient will be administered with the medication in the morning with or without food. The ibrutinib treatment groups will receive 0.625 mg/kg, or 1.25 mg/kg, or 2.5 mg/kg daily for 2 weeks. The dosage will be terminated if serious adverse events or any other unanticipated serious problem are detected. The control group will receive the placebo for the entire study.
[ 00174 ] Patients will be followed closely for any adverse events. Safety assessments will include physical and neurological examinations, MMSE examinations, vital signs (including blood pressure, pulse, oral temperature, respiration rate, and weight), electrocardiograms, and laboratory measurements, such as complete blood cell counts, basic metabolic panel, including renal function and electrolyte levels, coagulations factors, and liver function tests. Physical and neurological examination and laboratory measurements will be assessed at the baseline visit, on day 1 (pre-dose), 8, 14, 15, 28 as shown in the Table below:
Figure imgf000052_0001
[ 00175] Patients will have cognitive assessment on Day 1 (pre-dose), day 15, day 28) , to ensure the absence of a prominent decline in function while on study drug. General daily function will be assessed, and any clinical symptoms, such as dizziness, headache or other symptoms will be addressed. All measures will be compared to baseline testing before drag therapy is started. [ 00176] It has been reported that ibrutinib has been associated with significant immunosuppression and increased risk of infections (see Williams AM, et al., 2017, “Analysis of the risk of infection in patients with chronic lymphocytic leukemia in the era of novel therapies,” Leuk. Lymphoma 11:1-8), leukostasis and bleeding complications (see Kamel S et al., 2015, “Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation” Leukemia 29:783-7; also see Murthy P et al., 2017, “The NLRP3 inflammasome and Bruton’s tyrosine kinase in platelets co-regulate platelet activation, aggregation, and in vitro thrombus formation,” Biochem. Biophys. Res. Commun.
483:230-6), and increased rates of atrial fibrillation (see Wiczer et aL, 2017, “Cumulative incidence, risk factors, and management of atrial fibrillation in patients receiving Ibrutinib,” Blood Adv. 1 : 1739-48). Particular attention will be devoted to the monitoring of these potential adverse events in patients receiving ibrutinib.
[00177] Blood samples for pharmacokinetics (PKs) and BTK occupancy will be collected on day 1 (pre-dose and up to 6 hours after dosing), day 8 (pre-dose), and Day 15. CSF samples for PKs will be collected on day 1 day 1 (pre-dose and up to 6 hours after dosing), day 15. Samples will be analyzed for ibrutinib concentrations by high- performance liquid chromatography with tandem mass spectrometric detection. PK assessments and drug exposure (derived from area under the concentration-time curve [AUG]) will be performed on the plasma concentration-time data obtained on day 1.
[ 00178] BTK occupancy in peripheral blood mononuclear cell s (PBMCs) will be measured using a fluorescent affinity probe assay (see Honigberg et al., 2010, “The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy,” Proc. Natl. Acad. Sci. U S A 107:13075-80) within 4 hours of treatment after the first dose and the last dose (at 4 weeks). The probe (fluorescently tagged derivative of ibrutinib) binds to BTK with remarkably little specific labeling of other proteins. The BTK-bound fluorescent probe is inversely proportional to the occupancy of the binding site by Ibrutinib. Total BTK and actin protein levels in each sample will be used to normalize protein in each lane. The relative density of each band will be quantified using volume integration and local average background correction. Normalized intensity of BTK-bound fluorescent probe will be a measure of ibrutinib-free BTK. [ 00179] Pharmacokinetic and pharmacodynamic relationship of BTK active-site occupancy and Ibrutinib exposure will be calculated using the percentage of BTK occupancy before dosing and averaged post-dose for each patient in each group. These values will be plotted against the drug exposure (AUCO-24) achieved in the patient after administration of Ibrutinib on day 1. General daily function will be assessed as measure of safety, and any clinical symptoms, such as dizziness, headache or other symptoms will be addressed. All measures will be compared to baseline testing before drug dosing is started. Cognitive assessment measurements will be conducted at Day 1 (pre-dose), 15, and 28 and will include Alzheimer's Disease Assessment Scale (ADAS-cog, score range: 0-70) (Rosen WG et al., 1984), Mini-Mental State Examination (MMSE) (Folstein MF et al., 1975), and Neuropsychiatric Inventory (NPI, score range: 0-144) (Cummings JL, 1997).
[ 00180] CSF biomarkers AP42 and the AP42/40 ratio (reflecting brain amyloidosis), total tau (T-tau) and phosphoiylated tau (P-taul81) levels (related to tau pathology) have been validated clinically in numerous studies and are measures of disease severity or progression (Blennow K and Zetterberg H, 2019). In CSF of AD patients, levels of Aβ1-42 are significantly lower than in age-matched healthy elderly controls, whereas the levels of T-tau and P-taul81 are significantly higher than those of controls (Dubois B et al., 2007, 2010, Albert MS et al., 2011, McKhann GM et al., 2011). Furthermore, CSF levels of neurofilament light (NfL) and synaptic protein neurogranin are significantly elevated in AD compared to healthy controls, correlating with cognitive impairment and brain neuropathology (Blennow K, 2017). This core AD biomarkers can also be measured in blood samples (Blennow K and Zetterberg H, 2019). Elevated concentrations of peripheral inflammatory biomarkers were reported in AD patients (Lai KSP et al., 2017; Su C et al., 2019; Park J-C et al., 2020). Particularly higher peripheral concentrations of IL-1β, IL-6, IL-12 and IL-18, TNF-α, and TGF-β were detected in peripheral blood of AD subjects compared with control subjects (Swardfager W et al., 2010; Park J-C et al., 2020).
[ 00181 ] Data for neurodegenerative and inflammatory biomarkers will be collected predose and following ibrutinib dose regimen to establish their levels in patients with mild AD. CSF and blood samples will be collected from each group at Day 1 (pre-dose) and Day 15 (24 hour after treatment). Blood samples will be evaluated for levels of IL-1β, IL- 6, IL-12 and IL-18, TNF-α, and TGF-β, P-tau181/tau, Aβ42/Aβ40, and neurofilament light (NfL); CSF samples will be evaluated for levels of IL-1β, IL -6, IL-12 and IL-18, TNF-α, and TGF-β, P-taul81/tau, Aβ42/Aβ40, neurofilament light (NfL), and neurogranin.
Standardized methods such as automated electrochemiluminescence immunoassay will be used for the quantitation of the biomarkers and each assay will be run in triplicate. Although the treatment may be too short to see changes in biomarkers, any difference we may observe after dosage would be interpreted as potentially associated with the treatment and will be considered in future clinical development including dose selection, biomarker requirement in patient selection and/or potentially stratification of future clinical trials.
[ 00182 ] At completion of the study, the frequencies of adverse events or laboratory abnormalities between the participants who received each dose of ibrutinib (n = 6) and the pooled placebo subjects (n = 6) will be compared using Fisher’s exact test. Changes in clinical outcomes (MMSE, ADAS-cog, CDR-SOB, ADCS-ADL, NPI) will be examined using analysis of covariance or Kruskal -Wallis H test (for non-normally distributed NPI data).
[ 00183 ] This clinical study supports the development of a method for treating AD and other neurological diseases and psychiatric disorders by partial inhibition of BTK activity (by reducing the ratio of active BTK versus inhibitor-bound BTK) to “modulate” BTK activity in brain. It is reasonable to believe that these lower doses of BTK inhibitors will result in lower off-target BTK activity associated with side effects, increasing the tolerability of the drug, and potentially enabling the use of BTK inhibitor for long periods of time.
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Claims

CLAIMS What is claimed is:
1. A pharmaceutical composition comprising a therapeutically effective amount of a Bruton’s tyrosine kinase (BTK) inhibitor, including all stereoisomers and enantiomers thereof, or a pharmaceutically acceptable salt or a solvate thereof or a prodrug thereof in combination with a pharmaceutically acceptable carrier, wherein said BTK inhibitor is present in an amount sufficient to inhibit at least about 10 to about 90 percent of a target kinase activity.
2. The pharmaceutical composition according to claim 1, wherein the BTK. inhibitor is present in an amount sufficient to inhibit or modulate the target kinase activity of at least about 10% to 90% of activity.
3. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is selected from the group comprising: a compound of formula (I), including enantiomers and stereoisomers thereof:
Figure imgf000062_0001
a compound of formula (II), including enantiomers and stereoisomers thereof:
Figure imgf000062_0002
a compound of formula (III), including enantiomers and stereoisomers thereof:
Figure imgf000062_0003
wherein:
X represents CH2, O, S, NH, CO, COO or CONH; each of Ar1, Ar2 and Ar3 independently is selected from the group consisting of substituted or unsubstituted (C6-C10)aryl and substituted or unsubstituted (C5-C10)heteroaryl, wherein each of said substituents are independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, and (C6-C10)aryloxy; each of R1, R2 and R3 independently is selected from the group consisting of substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C3-C8)cycloalkyl, substituted or unsubstituted (C3-C8)heterocycloalkyl, substituted or un substituted (C6-C10)aryl, and substituted or unsubstituted (C5-C10)heteroaryl, wherein each of said substituents are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C2-C6)acyl, substituted or unsubstituted acryloyl, and substituted or unsubstituted (C3-C6)alkynoyl.
4. The pharmaceutical composition according to claim 1, wherein the BTK. inhibitor is selected from the group consisting of: ibrutinib, acalabrutinib, tolebrutinib, zanubrutinib, bramebrutinib, evobrutinib, orelabrutinib, remibrutinib, sprebrutinib, tirabrutinib, rilzabrutinib, ARQ 531, BMS-986142, fenebrutinib, pirtobrutinib, RN 486 or vecabrutinib.
5. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is a compound of formula:
Figure imgf000063_0001
Ibrutinib (also known as PCI-32765) l-[(3R)-3-[4-amino-3-(4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidin-l-yl]prop-2-en-1-one (CAS No. 936563-96-1).
6. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is a compound of formula:
Figure imgf000064_0001
Acalabrutinib (also known as Calquence) 4-[8-amino-3-[(2S)-l-but-2-ynoylpyrrolidin-2- yl]imidazo[l,5-a]pyrazin-l-yl]-N-pyridin-2-ylbenzamide (CAS No. 1420477-60-6).,
7. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is a compound of formula:
Figure imgf000064_0002
Branebrutinib (also known as BMS-986195) 4-[(3S)-3-(but-2-ynoylamino)piperidin-l-yl]- 5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide (CAS No. 1912445-55-6).
8. The pharmaceutical composition according to claim 1, wherein the BTK. inhibitor is a compound of formula :
Figure imgf000065_0001
Evobrutinib (also known as M-2951) l-[4-[[[6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl]amino]methyl]piperidin-l -yl]prop-2-en- 1-one (CAS No. 1415823-73-2).
9. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is a compound of formula:
Figure imgf000065_0002
Orelabrutinib (also known as ICP-022) 2-(4-phenoxyphenyl)-6-(l-prop-2-enoylpiperidin- 4-yl)pyridine-3 -carboxamide (CAS No. 1655504-04-3).
10. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is a compound of formula:
Figure imgf000066_0001
Remibrutinib (also known as LOU064) N-[3-[6-amino-5-[2-[methyl(prop-2- enoyl)amino]ethoxy]pyrimidin-4-yl]-5-fluoro-2-methylphenyl]-4-cyclopropyl-2- fluorobenzamide (CAS No. 1787294-07-8).
11. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is a compound of formula:
Figure imgf000066_0002
Spebrutinib (also known as AVL-292) N-[3-[[5-fluoro-2-[4-(2- methoxyethoxy)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide (CAS No. 1202757- 89-8).
12. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is a compound of formula:
Figure imgf000067_0001
Tirabrutinib (also known as Velexbru and GS-4059) 6-amino-9-[(3R)-l-but-2- ynoylpyrrolidin-3-yl]-7-(4-phenaxyphenyl)purin-8-one (CAS No. 1351636-18-4).
13. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is a compound of formula:
Figure imgf000067_0002
Tolebrutinib (also known as SAR442168) 4-amino-3-(4-phenoxyphenyl)-l-[(3R)-l-prop- 2-enoylpiperidin-3-yl]imidazo[4,5-c]pyridin-2-one (CAS No. 1971920-73-6).
14. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is a compound of formula:
Figure imgf000068_0001
Zanubrutinib (7S)-2-(4-phenoxyphenyl)-7-(l-prop-2-enoylpiperidin-4-yl)-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrimidine-3-carboxamide (CAS No. 1691249-45-2).
15. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is a compound of formula:
Figure imgf000068_0002
Rilzabrutinib (also known as PRN1008) (E)-2-[(3R)-3-[4-amino-3-(2-fluoro-4- phenoxyphenyl)pyrazolo[3 ,4-d]pyrimidin- 1 -yljpiperidine- 1 -carbonyl]-4-methyl-4-[4-
(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile (CAS No. 1575596-29-0).
16. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is a compound of formula:
Figure imgf000069_0001
ARQ 531 (2-chloro-4-phenoxyphenyl)-[4-[[(3R,6S)-6-(hydroxymethyl)oxan-3-yl]amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (CAS No. 2095393-15-8).
17. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is a compound of formula:
Figure imgf000069_0002
BMS-986142 (7S)-3-fluoro-4-[3-(8-fluoro-l-methyl-2,4-dioxoquinazolin-3-yl)-2- methylphenyl]-7-(2-hydroxypropan-2-yl)-6,7,8,9-tetrahydro-5H-carbazole-l-carboxamide (CAS No. 1643368-58-4).
18. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is a compound of formula:
Figure imgf000070_0001
Fenebrutinib (also known as GDC-0853) 10-[3-(hydroxymethyl)-4-[l-methyl-5-[[5-[(2S)- 2-methyl-4-(oxetan-3-yl)piperazin-l-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyri din-2- yl]-4,4-dimethyl-l , 10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-one (CAS No. 1434048-34-6).
19. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is a compound of formula:
Figure imgf000070_0002
Pirtobrutinib (also known as LOXO-305) 5-amino-3-[4-[[(5-fluoro-2- methoxybenzoyl)amino]methyl]phenyl]- 1 - [(2S)- 1,1,1 -trifluoropropan-2-yl]pyrazole-4- carboxamide (CAS No. 2101700-15-4).
20. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is a compound of formula:
Figure imgf000071_0001
RN486 6-cyclopropyl-8-fluoro-2-[2-(hydroxymethyl)-3-[l-methyl-5-[[5-(4- methylpiperazin- 1 -yl)pyridin-2-yl]amino]-6-oxopyridin-3-yl]phenyl]isoquinolin- 1 -one (CAS No. 1242156-23-5).
21. The pharmaceutical composition according to claim 1, wherein the BTK inhibitor is a compound of formula:
Figure imgf000071_0002
Vecabrutinib (3R,4S)-l-(6-amino-5-fluoropyrimidin-4-yl)-3-[(3R)-3-[3-chloro-5- (trifluoromethyl)anilino]-2-oxopiperidin-l-yl]piperidine-4-carboxamide) (CAS No. 1510829-06-7).
22. A pharmaceutical composition comprising a therapeutically effective amount of a Bruton’s tyrosine kinase (BTK) inhibitor according to any of claims 1-21, including all stereoisomers and enantiomers thereof, or a pharmaceutically acceptable salt or a solvate thereof or a prodrug thereof in combination with a pharmaceutically acceptable carrier, wherein said BTK inhibitor is present in an amount sufficient to inhibit at least about between 10 and 90 percent of BTK activity.
23. A method of treating a neurological disease associated with BTK activity by administering to a patient in need thereof a therapeutically effective amount of a brainpenetrant Bruton’s tyrosine kinase (BTK) inhibitor according to any of claims 1-22.
24. A method of treating a psychiatric disease associated with BTK activity by administering to a patient in need thereof a therapeutically effective amount of a brainpenetrant Bruton’s tyrosine kinase (BTK) inhibitor according to any of claims 1-22.
25. The method according to claim 23, wherein the neurological disease is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, human immunodeficiency virus (HIV)-associated dementia and Creutzfeldt-Jakob disease, neuropathic and chronic pain.
26. The method according to claim 24 wherein the psychiatric disease is selected from the group consisting of major depression, bipolar, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders, anxiety, addiction and ADHD. .
27. The method according to claim 23 or 25, wherein the neurological disease is Alzheimer’s Disease (AD).
28. The method according to claim 23 or 24 wherein the therapeutically effective amount of BTK inhibitor is an amount sufficient to inhibit at least about ten percent of target kinase activity.
29. The method according to claim 23 or 24, wherein the therapeutically effective amount of BTK inhibitor is an amount sufficient to inhibit at least about twenty-five percent of target kinase activity.
30. The method according to claim 23 or 24, wherein the BTK inhibitor is selected from the group consisting of: a compound of formula (I), including enantiomers and stereoisomers thereof:
Figure imgf000073_0001
a compound of formula (II), including enantiomers and stereoisomers thereof:
Figure imgf000073_0002
a compound of formula (III), including enantiomers and stereoisomers thereof:
Figure imgf000073_0003
wherein:
X represents CHi, O, S, NH, CO, COO or CONH; each of Ar1, Ar2 and Ar3 independently is selected from the group consi sting of substituted or unsubstituted (C6-C10)aryl and substituted or unsubstituted (C5-C10)heteroaryl, wherein each of said substituents are independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, and (C6-C10)aryloxy; each of R1, R2 and R3 independently is selected from the group consisting of substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C3-C8)cycloalkyl, substituted or unsubstituted (C3-C8)heterocycloalkyl, substituted or unsubstituted (C6-C10)aryl, and substituted or unsubstituted (C5-C10)heteroaryl, wherein each of said substituents are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C2-C6)acyl, substituted or unsubstituted acryloyl, and substituted or unsubstituted (C3-C6)alkynoyl.
31. The method according to claim 23 or 24, wherein the BTK inhibitor is selected from the group consisting of: ibrutinib, acalabrutinib, tolebrutinib, zanubrutinib, bramebrutinib, evobrutinib, orelabrutinib, remibrutinib, sprebrutinib, tirabrutinib, rilzabrutinib, ARQ 531, BMS-986142, fenebrutinib, pirtobrutinib, RN 486 or vecabrutinib.
32. The method according to claim 23 or 24, wherein, the BTK inhibitor is selected from the group comprising:
Figure imgf000074_0001
Ibrutinib (also known as PCI-32765) l-[(3R)-3-[4-amino-3-(4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l -yl]piperidin-l-yl]prop-2-en-l-one (CAS No. 936563-96-1);
Figure imgf000074_0002
Acalabrutinib (also known as Calquence) 4-[8-amino-3-[(2S)-l-but-2-ynoylpyrrolidin-2- yl]imidazo[l,5-a]pyrazin-l-yl]-N-pyridin-2-ylbenzamide (CAS No. 1420477-60-6) ;
Figure imgf000075_0001
Branebrutinib (also known as BMS-986195) 4-[(3S)-3-(but-2-ynoylamino)piperidin-l-yl]- 5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide (CAS No. 1912445-55-6);
Figure imgf000075_0002
Evobrutinib (also known as M-2951) l-[4-[[[6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl]amino]methyl]piperidin-l-yl]prop-2-en-l-one (CAS No. 1415823-73-2);
Figure imgf000075_0003
Orelabrutinib (also known as ICP-022) 2-(4-phenoxyphenyl)-6-(l-prop-2-enoylpiperidin- 4-yl)pyridine-3 -carboxamide (CAS No. 1655504-04-3) ;
Figure imgf000076_0001
Remibrutinib (also known as LOU064) N-[3-[6-amino-5-[2-[methyl(prop-2- enoyl)amino]ethoxy]pyrimidin-4-yl]-5-fluoro-2-methylphenyl]-4-cyclopropyl-2- fluorobenzamide (CAS No. 1787294-07-8) ;
Figure imgf000076_0002
Spebrutinib (also known as AVL-292) N-[3-[[5-fluoro-2-[4-(2- methoxyethoxy)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide (CAS No. 1202757- 89-8) ;
Figure imgf000076_0003
Tirabrutinib (also known as Velexbru and GS-4059) 6-amino-9-[(3R)-l-but-2- ynoylpyrrolidin-3-yl]-7-(4-phenoxyphenyl)purin-8-one (CAS No. 1351636-18-4) ;
Figure imgf000077_0001
Tolebrutinib (also known as SAR442168) 4-amino-3-(4-phenoxyphenyl)-l-[(3R)-l-prop- 2-enoylpiperidin-3-yl]imidazo[4,5-c]pyridin-2-one (CAS No. 1971920-73-6)
Figure imgf000077_0002
Zanubrutinib (7S)-2-(4-phenoxyphenyl)-7-(l-prop-2-enoylpiperidin-4-yl)-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrimidine-3-carboxamide (CAS No. 1691249-45-2) ;
Figure imgf000077_0003
Rilzabrutinib (also known as PRN1008) (E)-2-[(3R)-3-[4-amino-3-(2-fluoro-4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile (CAS No. 1575596-29-0) ;
Figure imgf000078_0001
ARQ 531 (2-chloro-4-phenoxyphenyl)-[4-[[(3R,6S)-6-(hydroxymethyl)oxan-3-yl]amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (CAS No. 2095393-15-8) ;
Figure imgf000078_0002
BMS-986142 (7 S)-3 -fluoro-4-[3 -(8-fluoro- 1 -methyl -2, 4-dioxoquinazolin-3 -yl)-2- methylphenyl]-7-(2-hydroxypropan-2-yl)-6,7,8,9-tetrahydro-5H-carbazole-l-carboxamide (CAS No. 1643368-58-4);
Figure imgf000079_0001
Fenebrutinib (also known as GDC-0853) 10-[3-(hydroxymethyl)-4-[l-methyl-5-[[5-[(2S)- 2-methyl-4-(oxetan-3-yl)piperazin-l-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2- yl]-4,4-dimethyl-l, 10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-one (CAS No. 1434048-34-6);
Figure imgf000079_0002
Pirtobrutinib (also known as LOXO-305) 5-amino-3-[4-[[(5-fluoro-2- methoxybenzoyl)amino]methyl]phenyl]- 1 - [(2 S)- 1,1/1 -trifluoropropan-2-yl]pyrazole-4- carboxamide (CAS No, 2101700-15-4) ;
Figure imgf000080_0002
RN4866-cyclopropyl-8-fluoro-2-[2-(hydroxymethyl)-3-[l-methyl-5-[[5-(4- methylpiperazin- 1 -yl)pyridin-2-yl]amino]-6-oxopyridin-3-yl]phenyl]isoquinolin- 1 -one (CAS No. 1242156-23-5); and
Figure imgf000080_0001
Vecabrutinib (3R,4S)-l-(6-amino-5-fluoropyrimidin-4-yl)-3-[(3R)-3-[3-chloro-5- (trifluoromethyl)anilino]-2-oxopiperidin-l-yl]piperidine-4-carboxamide) (CAS No. 1510829-06-7).
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