Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—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
  • A61K31/496—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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/10—Spiro-condensed systems

Definitions

• the invention provides hetero-bifunctional compounds comprising a target protein binding moiety and a E3 ubiquitin ligase binding moiety, and associated methods of use.
• the bifunctional compounds are useful as modulators of targeted ubiquitination of leucine-rich repeat kinase 2 (LRRK2), which is then degraded and/or inhibited.
• LRRK2 leucine-rich repeat kinase 2
• E3 ubiquitin ligases (of which hundreds are known in humans) confer substrate specificity for ubiquitination, and therefore are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates.
• the development of ligands of E3 ligases has proven challenging, in part due to the fact that they must disrupt protein-protein interactions.
• recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of nutlins, the first small molecule E3 ligase inhibitors, additional compounds have been reported that target E3 ligases.
• Cereblon is a protein that in humans is encoded by the CRBN gene. CRBN orthologs are highly conserved from plants to humans, which underscores its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex ubiquitinates a number of other proteins. Through a mechanism which has not been completely elucidated, cereblon ubiquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates a number of developmental processes, such as limb and auditory vesicle formation. The net result is that this ubiquitin ligase complex is important for limb outgrowth in embryos. In the absence of cereblon, DDB1 forms a complex with DDB2 that functions as a DNA damage-binding protein.
• DDB1 forms a complex with
• Bifunctional compounds such as those described in U.S. Patent Application Publications 2015/0291562 and 2014/0356322 (incorporated herein by reference), function to recruit endogenous proteins to an E3 ubiquitin ligase for ubiquitination and subsequent degradation in the proteasome degradation pathway.
• the publications cited above describe bifunctional or proteolysis-targeting chimeric (PROTAC ® ) protein degrader compounds, which find utility as modulators of targeted ubiquitination of a variety of polypeptides and proteins, which are then degraded and/or inhibited by the bifunctional compounds.
• Eeucine-rich repeat kinase 2 (ERRK2) is a member of the leucine-rich repeat kinase family and is a large multi-domain protein with an N-terminal armadillo domain, ankryin repeat region, a leucine-rich repeat (ERR) domain, a tandem Roco type GTPase domain, a kinase domain containing a DFG-like motif, and a C-terminal WD40 domain.
• the LRRK2 protein is 2527 amino acids and a molecular weight of 280 kDa.
• G2019S is the most common LRRK2 mutation linked to Parkinson’s disease (PD), which is a progressive neurodegenerative disorder characterized by resting tremors, rigidity, decreased movement (bradykinesia), and postural instability.
• PD Parkinson’s disease
• the histological hallmarks of PD include neurodegeneration of the dopaminergic neurons in the substantia nigra pars compacta as well as intracellular inclusions called Lewy bodies and neurites consisting of the aggregated form of the alpha- sy nuclein protein.
• G2019S is associated with 1-2% of all PD patients and causes an increase in kinase activity of 2- fold in vitro ( West AB, et al: Parkinson’s diseaseassociated mutations in leucine-rich repeat kinase 2 augment kinase activity.
• LRRK2 was first described as having a link to autosomal dominant inherited Parkinson’s disease in 1978, where it was traced to a family in Japan ( Nukada H, et al: [A big family of paralysis agitans (author’s transl)]. Rinsho Shinkeigaku 1978, 18:627-634).
• the most common pathogenic LRRK2 mutation occurs in 4-8% of familial and 1-3% of sporadic PD cases.
• the G2019S mutation is common among PD patients of select ancestry, with 30-40% of North African Berber and 14% of Jewish patients harboring the mutation.
• LRRK2 kinase inhibitors have been proposed as having the potential to treat mutation-driven PD, where there is an increase in LRRK2 activity, such as G2019S, and idiopathic PD, where the activity of LRRK2 is increased ( Chen J, et al: Leucine-rich repeat kinase 2 in Parkinson’s disease: updated from pathogenesis to potential therapeutic target. Eur Neurol 2018, 79:256-265; Ales si DR, et al: LRRK2 kinase in Parkinson’s disease. Science 2018, 360:36-37; Di Maio R, et al: LRRK2 activation in idiopathic Parkinson’s disease. Sci Transl Med 2018, 10).
• LRRK2 kinase inhibitors that will directly affect phosphorylation of downstream targets
• ASO oligonucleotides
• Lewy bodies are the main histological hallmark of PD. Lewy bodies are composed primarily of alpha- synuclein aggregates, and mutations in alpha-synuclein that increase this aggregation also increase the risk of developing PD ( Meade RM, et al: Alpha-synuclein structure and Parkinson’s disease lessons and emerging principles. Mol Neurodegener 2019, 14. 29-29). Depletion of LRRK2 with ASOs ⁇ Zhao HT, et al. : LRRK2 antisense oligonucleotides ameliorate a-synuclein inclusion formation in a Parkinson’s disease mouse model. Molecular therapy.
• Nucleic acids 2017, 8:508-519) and deletion of LRRK2 at a genomic level have been shown to reduce alpha-synuclein mediated pathology in mouse models of PD ⁇ Lin X, et al. : Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkin son ’ s-di sease-related mutant alpha-synuclein. Neuron 2009, 64:807-827).
• Mutations increasing LRRK2 activity, such as G2019S increase the aggregation of alpha-synuclein in neurons and mouse models of PD.
• LRRK2 is highly expressed in the immune system in neutrophils, monocytes and macrophages, as well as in brain microglia, and is a modulator of the intrinsic regulation of microglial activation and of lysosomal degradation processes ( Ma et al. Genetic comorbidities in Parkinson's disease. Hum Mol Genet. 2014 Feb 1 ;23(3):831-41. doi: 10.1093/hmg/ddt465. Epub 2013 Sep 20, which was reviewed in Schapansky et al. The complex relationships between microglia, alpha- synuclein, and LRRK2 in Parkinson's disease. Neuroscience. 2015 Aug 27;302:74-88. doi: 10.1016/j.neuroscience.2014.09.049.
• the respective positions of the PTM and ULM moieties (e.g., CLM), as well as their number as illustrated herein, is provided by way of example only and is not intended to limit the compounds in any way.
• the bifunctional compounds as described herein can be synthesized such that the number and position of the respective functional moieties can be varied as desired.
• the bifunctional compound further comprises a chemical linker (“L”).
• the compounds as described herein comprise multiple independently selected ULMs, multiple PTMs, multiple chemical linkers or a combination thereof.
• “L” is a bond.
• the linker “L” is a connector with a linear non-hydrogen atom number in the range of 1 to 20.
• the connector “L” can contain, but is not limited to, one or more functional groups such as ether, amide, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, thioether, sulfoxide, and sulfone.
• the linker can contain aromatic, heteroaromatic, cyclic, bicyclic or tricyclic moieties. Substitution with halogen, such as Cl, F, Br and I can be included in the linker. In the case of fluorine substitution, single or multiple fluorines can be included.
• CLM is a derivative of piperidine-2, 6-dione, where piperidine-2, 6-dione can be substituted at the 3-position, and the 3-substitution can be bicyclic hetero-aromatics with the linkage as C-N bond or C-C bond.
• Examples of CLM can be, but are not limited to, pomalidomide, lenalidomide and thalidomide and their analogs.
• poly-ubiquitination of the LRRK2 wild-type or mutant protein will occur when it is placed in proximity to the E3 ubiquitin ligase via use of the hetero-bifunctional compound, thereby triggering subsequent degradation of the LRRK2 or mutant protein via the proteasomal pathway and control or reduction of LRRK2 protein levels in cells, such as cells of a subject in need of such treatment.
• the description provides methods for treating or ameliorating a disease, condition, or symptom thereof causally related to LRRK2 or mutated form thereof in a subject or a patient, e.g., an animal such as a human, comprising administering to a subject in need thereof a composition comprising an effective amount, e.g., a therapeutically effective amount, of a hetero-bifunctional compound as described herein or salt form thereof, and a pharmaceutically acceptable carrier, wherein the composition is effective for treating or ameliorating the disease or disorder or symptom thereof in the subject.
• a composition comprising an effective amount, e.g., a therapeutically effective amount, of a hetero-bifunctional compound as described herein or salt form thereof, and a pharmaceutically acceptable carrier, wherein the composition is effective for treating or ameliorating the disease or disorder or symptom thereof in the subject.
• the description provides methods for identifying the effects of the degradation of LRRK2 protein in a biological system using compounds according to the present disclosure.
• the ULM (triangle) recognizes and binds to a specific E3 ubiquitin ligase
• the PTM large rectangle binds and recmits a target protein bringing it into close proximity to the E3 ubiquitin ligase.
• the E3 ubiquitin ligase is complexed with an E2 ubiquitin-conjugating protein (E2), and either alone or via the E2 protein catalyzes attachment of multiple ubiquitin molecules ( black circles) to a lysine on the target protein via an isopeptide bond.
• E2 ubiquitin-conjugating protein E2 ubiquitin-conjugating protein
• the poly-ubiquitinated protein (far right) has thereby been targeted for degradation by the proteosomal machinery of the cell.
• an E3 ubiquitin ligase e.g., a cereblon E3 ubiquitin ligase
• ubiquitinates the LRRK2 protein or mutated form thereof once the E3 ubiquitin ligase and the LRRK2 protein are placed in proximity via a bifunctional compound that binds both the E3 ubiquitin ligase and the LRRK2 protein.
• the present disclosure provides hetero -bifunctional compounds which comprise a ligand, e.g., a small molecule ligand (i.e., having a molecular weight of below 2,000, 1,000, 500, or 200 Daltons), which is capable of binding to an E3 ubiquitin ligase, such as cereblon.
• a ligand e.g., a small molecule ligand (i.e., having a molecular weight of below 2,000, 1,000, 500, or 200 Daltons)
• E3 ubiquitin ligase such as cereblon.
• the compounds also comprise a small molecule moiety that is capable of binding to the LRRK2 protein or mutated form thereof in such a way that the LRRK2 protein or mutated form is placed in proximity to the ubiquitin ligase to effect ubiquitination and degradation (and/or inhibition) of the LRRK2 protein or mutated form.
• Small molecule means, in addition to the above, that the molecule is non-peptidyl, that is, it is not considered a peptide, e.g., comprises fewer than 4, 3, or 2 amino acid residues.
• each of the PTM, ULM and hetero-bifunctional molecule is a small molecule.
• LRRK2 as used throughout the Specification, unless specifically indicated to the contrary, is intended to include both wild-type LRRK2 and mutant forms therefore, such as a LRRK2 mutant protein including one or more mutation selected from G2019S, I2020T, N1437H, R1441G/C/H, and Y1699C.
• co-administration and “co-administering” or “combination therapy” refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time-varied administration (administration of one or more therapeutic agents at a time different from that of the administration of an additional therapeutic agent or agents), as long as the two or more therapeutic agents are present in the patient to some extent, preferably at effective amounts, at the same time.
• one or more of the hetero bifunctional compounds described herein are coadministered with at least one additional bioactive agent, e.g., an anticancer agent.
• the co-administration of such compounds results in synergistic activity and/or therapy such as, e.g., anticancer activity.
• Alkylene groups may also be substituted as otherwise disclosed herein, preferably with optionally substituted C1-C6 alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl is preferred, thus providing a chiral center), a sidechain of an amino acid group as otherwise described herein, an amido group as described hereinabove, or a urethane group 0-C(0)-NRiR 2 group where Ri and R 2 are as otherwise described herein, although numerous other groups may also be used as substituents.
• Various optionally substituted moieties may be substituted with 3 or more substituents, preferably no more than 3 substituents and preferably with 1 or 2 substituents.
• R ss is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted 0-(Ci-C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted -C(0)(Ci-C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
• arylalkyl refers to an aryl group as defined above appended to an alkyl group defined above The arylalkyl group is attached to the parent moiety through an alkyl group wherein the alkyl group is one to six carbon atoms. The aryl group in the arylalkyl group may be substituted as defined above.
• heterocyclic also includes bicyclic groups in which any of the heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, and the like).
• lower alkyl refers to methyl, ethyl or propyl
• lower alkoxy refers to methoxy, ethoxy or propoxy.
• a of Formulas (al) through (e) is independently selected from the group H, optionally substituted linear or branched alkyl, cycloalkyl, Cl and F; n of Formulas (al) through (e) represent an integer from 1 to 10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);
• the CLM or ULM is selected from the structure of Formula (g):
• a of Formula (g) is selected from a H, methyl, or optionally substituted linear or branched alkyl; n is an integer from 1 to 4;
• w of Formula (g) represents a bond that may be stereospecific ((R) or (S)) or non stereo specific.
• R is selected from: H, 0, OH, N,
• Q1-Q4, and A of Formulas (a) through (g) can independently be covalently coupled to a linker and/or a linker to which is attached one or more PTM, ULM, or CLM groups.
• n is an integer from 1 to 4, and each R is independently selected functional groups or atoms, for example, O, OH, N, -Cl, -F, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., an -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy, on the aryl or heteroaryl of the CLM, and optionally, one of which is modified to be covalently joined to a PTM, a chemical linker group (L), a ULM, CLM or combination thereof.
• R is independently selected functional groups or atoms, for example, O, OH, N, -Cl, -F, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (
• R 2 is H or a C1-C3 alkyl
• R 3 is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;
• R, R’, R”, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 of the CLM can be a bond.
• R’ is a halogen and R 1 is as described herein.
• ULM indicates the point of attachment with a linker group or a PTM
• the linker group is optionally substituted an optionally substituted C 1 -C50 alkyl (e.g., Ci, C 2 , C3, C 4 , C5, Ce, C7, C 8 , C 9 , C 10 , Cn, C12, Cn, CM, Ci5, CM, Cn, Ci8, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 alkyl, and including all implied subranges, e.g., C1-C10, C1-C20; C2-C10, C2-20; C10-C20, C10-C50 etc.).
• C1 -C10, C1-C20 e.g., Ci, C
• the unit A L of the linker (L) comprises a structure selected from the group consisting of:
• Q L is a 3-6 membered heterocyclic, heterobicyclic, or heteroaryl ring, optionally substituted with 0-6 R Q , each R Q is independently H, or optionally substituted linear or branched Ci- 6 alkyl (e.g., optionally substituted by 1 or more halo, Ci- 6 alkoxyl);
• R’ is hydrogen, halogen (e.g., F, Cl, or Br), C1-C3 alkyl, or C1-C3 fluoroalkyl;
• R4 is H or linear or branched C1-C3 alkyl (e.g., methyl or ethyl); indicates the point of attachment of the (i.e., the point of attachment with the 6-membered heteroaryl of the PTM); and indicates the point of attachment of the PTM with the L or ULM, and where not present, the may be attached to the L or ULM via an atom of the 6- membered heterocycloalkyl (e.g., a carbon or nitrogen of the 6-membered heterocycloalkyl), R3, or R4.
• the 6- membered heterocycloalkyl e.g., a carbon or nitrogen of the 6-membered heterocycloalkyl
• the PTM has the chemical structure: wherein:
• Ri a , Rib, and Ric are each independently a H or a linear or branched C1-C2 alkyl, each optionally substituted with one or more halogen or nitrile group; or Ri a or Ri b together with the carbon to which they are attached form a C3-C6 cycloalkyl that is optionally substituted with one or more C1-C3 alkyl, nitrile group, or halogen.
• the R 2 is H or F.
• the present invention further provides pharmaceutical compositions comprising therapeutically effective amounts of at least one bifunctional compound as described herein, in combination with a pharmaceutically acceptable carrier, additive or excipient.
• parenteral includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
• Enteric coated oral tablets may also be used to enhance bioavailability of the compounds from an oral route of administration.
• the most effective dosage form will depend upon the pharmacokinetics of the particular agent chosen as well as the type, location and severity of disease, condition or symptom, and the health of the patient.
• Administration of compounds according to the present disclosure as sprays, mists, or aerosols for intra-nasal, intra tracheal or pulmonary administration may also be used.
• Sterile injectable forms of the compositions as described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1, 3-butanediol.
• the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides.
• the active ingredient is preferably administered to achieve peak plasma concentrations of the active compound of about 0.00001-30 millimole (mM), preferably about 0.1-30 micromole (mM). This may be achieved, for example, by the intravenous injection of a solution or formulation of the active ingredient, optionally in saline, or an aqueous medium or administered as a bolus of the active ingredient. Oral administration may also be appropriate to generate effective plasma concentrations of active agent.
• mM millimole
• mM micromole
• Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
• the present disclosure provides a method of treating a human patient in need of said treatment of a disease state, condition, or symptom causally related to Tau expression, over-expression, mutation, aggregation, misfolding or dysregulation where the degradation of the LRRK2 protein and/or mutated form thereof will produce a therapeutic effect in the patient, the method comprising administering to the patient an effective amount of a compound according to the present disclosure, optionally in combination with another bioactive agent.
• X represents a suitable leaving group (e.g. OTs, OMs, Cl, Br, etc.)
• Y represents either a primary or secondary amine or alcohol
• M represents a metalated version of the TLM (Na + , Cs + , Li + , etc)
• PG represents a suitable protecting group
• Exemplary Compounds 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, and 19 were prepared in a manner analogous to Exemplary Compound 2.
• Step 8 To a mixture of 5-tert-butoxy-3-[6-[(3S)-3-methylpiperazin-l-yl]pyrimidin-4-yl]-lH-indazole (140 mg, 382.03 umol, 1 eq), KI (317.09 mg, 1.91 mmol, 5 eq) and 2-[2-[2-[2-[2-[2-(2,6-dioxo-3- piperidyl)- 1 ,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (254.09 mg, 420.24 umol, 1.1 eq) in MeCN (5 mL) was added DIPEA (246.87 mg, 1.91 mmol, 332.71 uL, 5 eq) in one portion.
• the aqueous phase was extracted with ethyl acetate (100 mL * 3).
• the combined organic phase was washed with brine (100 mL * 2), dried with anhydrous NaiSCri, filtered and concentrated in vacuum.
• the residue was purified by silica gel chromatography (column height: 80 g, 100-200 mesh silica gel, 0-20% (30 min) of Ethyl acetate in Petroleum ether) to give ethyl 2-(4- benzylmorpholin-2-yl)acetate (16 g, 60.76 mmol, 54.04% yield) as a yellow oil.
• reaction solution was purified by prep- HPLC (FA condition: column: Phenomenex Luna 08 100*30mm*5um; mobile phase: [water (0.225%FA)-ACN]; B%: 5%-35%, 18min) to give 2-(2,6-dioxo-3-piperidyl)-5-[4-[2-[2-[(2S)-4- [6-(5-isopropoxy-lH-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-l- yl]ethoxy]ethyl]piperazin-l-yl]isoindoline-l,3-dione (27.70 mg, 34.88 umol, 15.29% yield, 96.3% purity) as a yellow solid.
• the aqueous phase was extracted with ethyl acetate (3 x 5 mL).
• the combined organic phase was washed with brine (3 x 5 mL), dried with anhydrous NaiSCL, filtered and concentrated in vacuum to give crude product (150 mg).
• the crude product was purified by silica gel chromatography (100-200 mesh silica gel, 0-100 % of MeOH in EtOAc) to give 5-(l-methylcyclopropoxy)-3-[6-[(3S)-3-methyl-4-(4-piperidylmethyl)piperazin-l- yl]pyrimidin-4-yl]-lH-indazole (100 mg, crude) as a yellow gum.
• reaction solution was diluted with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate in petroleum ether) to afford tert-butyl 4-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-l- carboxylate (490 mg, 1.23 mmol, 75.22% yield, 100% purity) as a colorless oil.
• reaction mixture was stirred at 25°C for lh. Then NaBFLCN (30.29 mg, 481.94 umol, 2 eq) was added. After addition, the reaction mixture was stirred at 25 °C for 16h. The reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (3 x lOmL). The organic layer was washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure.
• the solution was stirred at 100°C for 2 h to give yellow solution.
• the mixture was cooled to 20°C and concentrated in reduced pressure at 20°C.
• the residue was poured into water (10 mL).
• the aqueous phase was extracted with ethyl acetate (10 mL * 3).
• the combined organic phase was washed with brine (10 mL * 3), dried with anhydrous NaiSCL, filtered and concentrated in vacuum.
• Step 2 To a flame-dried three-neck 100 mL round-bottomed flask equipped with an argon inlet adapter, a septum, and a stir bar was added 4-(2,2-diethoxyethoxy)but-l-yne (600 mg, 3.22 mmol, 1 eq) and THF (10 mL) via syringe. The solution was cooled at -78°C (bath temperature) in a dry ice/acetone bath, and n-BuLi (2.5 M, 1.55 mL, 1.2 eq) was added dropwise via syringe turning the reaction brown.
• 4-(2,2-diethoxyethoxy)but-l-yne 600 mg, 3.22 mmol, 1 eq
• THF 10 mL
• the reaction was stirred at 100°C for 16hr.
• the reaction mixture was poured into H2O (20 mL).
• the mixture was extracted with ethyl acetate (20 mL*2).
• the organic phase was washed with brine (15 mL*3), dried over anhydrous NaiSCL, concentrated in vacuum to give a residue.
• the aqueous phase was extracted with ethyl acetate (5 mL * 3).
• the combined organic phase was washed with brine (5 mL * 2), dried with anhydrous NaaSCL, filtered and concentrated in vacuum.
• the residue was purified by silica gel chromatography (column height: 12 g, 100-200 mesh silica gel, 0-20% (10 min) of Ethyl acetate in Petroleum ether, 20% (5 min) of Ethyl acetate in Petroleum ether) to give 3-[tert- butoxycarbonyl(methyl)amino]propyl 4-methylbenzenesulfonate (670 mg, 1.95 mmol, 73.84% yield) as a colorless oil.
• the mixture was stirred at 80°C for 16 hr to give yellow suspension.
• the mixture was cooled to 20°C and concentrated in reduced pressure at 20°C.
• the residue was poured into water (5 mL).
• the aqueous phase was extracted with ethyl acetate (5 mL * 3).
• the combined organic phase was washed with brine (5 mL * 2), dried with anhydrous NaaSC , filtered and concentrated in vacuum.

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