Methods for treating symptoms and disorders associated with lysosomal storage diseases

Abstract

To provide pharmaceutical compositions for use in a method for treating or preventing certain symptoms and disorders associated with lysosomal storage diseases.SOLUTION: Disclosed is a pharmaceutical composition for use in a method for treating or preventing certain symptoms and disorders associated with a lysosomal storage disease in a subject in need thereof including (a) cognitive dysfunction and / or gait disorders including ataxia; or (b) supranuclear gaze palsies (e.g., associated with a lysosome storage disease), where the pharmaceutical composition comprises an effective amount of a compound of Formula (I) or pharmaceutically acceptable salt prodrug thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is an international application claiming priority to and benefit of U.S. Provisional Patent Application No. 62 / 800,996, filed February 4, 2019, No. 62 / 851,433, filed May 22, 2019, No. 62 / 894,167, filed August 30, 2019, No. 62 / 937,618, filed November 19, 2019, and No. 62 / 962,647, filed January 17, 2020, the contents of each of which are hereby incorporated in their entirety.

[0002] The present invention relates to a method for treating or preventing symptoms and disorders associated with, inter alia, lysosomal storage diseases, including supranuclear gaze palsy (Palsy), including horizontal and vertical saccadic gaze palsy and cognitive deficits or gait disorders, using a quinuclidine compound of formula (I), optionally in combination with an enzyme replacement therapy drug. This includes, for example, supranuclear gaze palsy (Palsy) including horizontal and vertical saccadic gaze palsy and cognitive deficits or gait disorders in patients with Gaucher disease or Niemann-Pick disease type C. [Background technology]

[0003] Lysosomal storage disorders Lysosomal storage diseases (LSDs) are a group of about 50 rare inherited metabolic disorders caused by defects in lysosomal function. Generally, patients with LSDs accumulate harmful levels of substrates (i.e., storage materials) in lysosomes due to a deficiency or defect in an enzyme responsible for the metabolism of the substrate or due to a deficiency in an enzyme activator essential for proper enzyme function. Most LSDs are caused by defects or deficiencies with a single enzyme, usually an enzyme involved in the metabolism of lipids or glycoproteins. Some of the more common LSDs include Gaucher disease, Fabry disease, and Niemann-Pick disease (type C). Gaucher, Fabry, and Niemann-Pick are examples of sphingolipidoses. Each of these diseases is associated with a set of symptoms that are caused directly or indirectly by an underlying genetic defect. As a result, it is often difficult to predict whether the symptoms or disorders associated with them can be effectively treated with different treatment methods. Symptoms common to several LSDs include changes in saccadic eye movements, cognitive impairment, and gait disorders, such as ataxia. These symptoms are especially common in Gaucher disease (eg, type 3) and Niemann-Pick disease (type C).

[0004] Saccadic eye movement deficits in LSD There are several functional classifications of eye movements, including saccades, smooth pursuit, optokinetic nystagmus (OKN), vestibular reflex, and binocular vergence, each controlled by distinct cortical, brainstem, and cerebellar supranuclear networks. Brainstem supranuclear saccadic center failure results in supranuclear gaze palsy, also called saccadic gaze palsy. "Supranuclear" refers to the location of the defect superior to the associated cranial nerve nucleus in the midbrain (oculomotor, trochlear) or pons (abducens) of the brainstem. The oculomotor, trochlear, and abducens nerves are the only cranial nerves that control the small muscles that move the eyes, and lesions to the nerves themselves do not result in conjugate gaze palsy.

[0005] A saccade is a rapid simultaneous movement of both eyes between two or more phases of fixation in the same orientation. Saccades contrast with smooth pursuit movements, which are smooth movements without jumps while tracking an object in the normal visual field. Saccades serve as a mechanism for fast phases of visual fixation, rapid eye movements, and optokinetic nystagmus. Saccades are controlled cortically by the frontal eye field region of the frontal cortex, or subcortically by the superior colliculus (a region of the midbrain). Saccades are especially important during reading and when scanning the immediate surroundings. Because the high-resolution region of the retina, the fovea, is very small (approximately 1-2 degrees visual width), saccadic eye movements are important in resolving small objects in the visual field. Skilled readers move their eyes while reading on average every 250 milliseconds, and during each saccade lasting 20-40 milliseconds, the fixation target moves across an average of 7-9 letters (range 1-20 letters).

[0006] The peak angular speed of the eyes during a saccade can reach 900 degrees per second in humans. Saccades in response to unexpected stimuli usually take only about 200 milliseconds to initiate and last about 20 to 200 milliseconds depending on the amplitude. The amplitude of a saccade is the angular distance the eyes move during the eye movement. Head-fixed saccades can have an amplitude of up to 90 degrees, but under most conditions any shift in gaze of more than 20 degrees is accompanied by head movement. During these gaze saccades, the eyes first undergo a saccade to shift gaze to the target, and the head slowly follows, while the eyes maintain focus on the target. The latter is called the vestibulo-ocular reflex (VOR), which functions to slowly shift the eyes in the opposite direction to the head movement in order to maintain visual focus on the retina. The head is almost always moving slightly, and the VOR is essential for stabilizing vision under almost all circumstances, but especially during reading.

[0007] Saccadic gaze paresis may result in delayed saccades horizontally, vertically, or both, and may be present with or without range restriction. Whether horizontal or vertical saccadic paresis is present depends on the exact brain region involved in the condition.

[0008] Gaucher disease (GD) is a rare autosomal recessive lysosomal storage disorder. Patients with GD have mutations in the GBA1 gene, which encodes glucosylceramidase (GC), also known as beta-glucocerebrosidase. This enzyme is responsible for breaking down glycosphingolipids into their constituent parts, e.g., glucosylceramide (GLC; also known as glucocerebroside) into glucose and ceramide. Monocytes and macrophages have a particularly high content of lysosomes containing GLC, and in GD patients, these cells become enlarged and accumulate toxic concentrations of GLC. These so-called "Gaucher cells" accumulate in several organs, including bone, bone marrow, spleen, liver, lungs, and brain. This leads systemically to splenomegaly, hepatomegaly, anemia, thrombocytopenia, leukopenia, osteopenia, osteonecrosis, and other pathological abnormalities.

[0009] There are three subtypes of Gaucher disease, which differ in terms of age at onset, severity, and the presence of neurological findings. Type 1 Gaucher disease (GD-1), a non-neuronopathic GD, is the most common form, with a median age at diagnosis of 28 years and a slightly shorter life expectancy. In GD-1, the GC enzyme retains some function and there is no neurological involvement. Type 2 GD is an acute neuropathic GD, with diagnosis in infancy, severe neurological involvement, and death usually within the first 2 years of life. The GC enzyme in type 2 patients is significantly impaired in terms of function compared to GD-1. Type 3 GD is a chronic neuropathic GD, with diagnosis in childhood, slow worsening of neurological involvement, and a life expectancy usually within 30 years. Symptoms of GD-3 include splenic and liver abnormalities, fatigue, bleeding, seizures, and supranuclear gaze palsy. Neurological findings in GD-3 patients progress progressively over the course of the disease. One of the more debilitating features is gaze paresis, which is a defect in the neural pathways that control saccadic eye movements. During the early phase of the disease, horizontal saccades are slowed. The disease progresses to complete horizontal saccade paresis and varying degrees of vertical saccade paresis. The VOR may also be impaired in GD-3 patients. These features of the disease may severely affect the quality of life of GD-3 patients and impede their educational and employment prospects.

[0010] Existing treatments for GD-1 and GD-3 are limited to recombinant enzyme replacement therapy (ERT) using imiglucerase, velaglucerase, or taliglucerase, and substrate reduction therapy (SRT) using miglustat or eliglustat. See, for example, Non-Patent Document 1. The main treatment regimen, imiglucerase, is a recombinant version of human GC, made from Chinese hamster ovary cells and administered slowly (typically over 1-2 hours) by intravenous injection every 1-2 weeks. Velaglucerase, available in the United States since 1998, is another recombinant human GC analogue, made from a fibrosarcoma cell line and FDA approved in 2010. Taliglucerase is similar, made using genetically modified carrot plant root cells and approved since 2012. All of these treatments require IV administration in a hospital or other medical institution, and the recombinant enzyme does not cross the blood-brain barrier, and as a result, cannot treat the neurological symptoms of GD. Thus, these ERT regimens have proven effective in treating GD-1 patients, but in GD-3 patients, they are only effective in treating the non-neurological symptoms of the disease.

[0011] Substrate reduction therapy is an alternative approach to treat GD. The goal of this therapy is to reduce the accumulation of GLC by inhibiting the enzyme responsible for GLC synthesis. Glucosylceramide synthase (GCS), also known as UDP-glucoseceramide synthase, is the enzyme that catalyzes the first glycosylation step of ceramide to form glucosylceramide.

[0012] GCS inhibitors have been proposed to treat a variety of diseases, including glycolipid storage diseases and lysosomal storage diseases, including Gaucher disease. See, for example, US Patent No. 5,399,366 (Actelion Pharm. Ltd.). Miglustat (Zavesca) is an imino glucose GCS inhibitor. It is an N-alkylated imino sugar that acts as a reversible competitive inhibitor of GCS, binding to the active site of the enzyme. It has been developed to treat neurotoxic forms of GD, GD-2 and GD-3, but is only FDA approved as a second-line therapy for the treatment of patients with mild to moderate GD-1 (patients should not be able to receive ERT treatment). Miglustat crosses the blood-brain barrier, but in clinical trials, it was not effective in treating the neurological manifestations of GD-3. Eliglustat is also a GCS inhibitor and is an analogue of ceramide. It is FDA approved only to treat systemic symptoms in GD-1 patients.

[0013] Niemann-Pick disease type C (NPC) is also a lysosomal storage disease whose cause is quite different in some respects from Gaucher disease, but the end result is similar. NPC is caused by mutations in either the NPC1 or NPC2 genes. NPC1 is a membrane protein that mediates intracellular trafficking of cholesterol to post-lysosomal destinations. In particular, NPC1 acts in concert with NPC2 to facilitate the export of cholesterol from the endosomal / lysosomal compartment. Unesterified cholesterol released from low-density lipoproteins in the lumen of late endosomes / lysosomes is transferred by NPC2 to the cholesterol-binding pocket of NPC1. Approximately 95% of NPC patients have mutations in NPC1, while the majority of the remainder have mutations in NPC2. One of the consequences of this disrupted cholesterol trafficking is the accumulation of cholesterol and glycosphingolipids (including GLC) in liver, spleen, and brain cells. One of the hallmarks of GD3-like NPC is the gradual onset of supranuclear gaze paresis, including horizontal and vertical saccade paresis.

[0014] Another group of diseases and disorders commonly associated with saccadic gaze paresis is the GM2-gangliosidoses (e.g., Tay-Sachs disease, Sandhoff disease, and AB varian disease). There is also GM2 gangliosidosis.

[0015] GM2 gangliosidosis, like Gaucher's disease, is a lysosomal storage disease characterized by genetic defects in glycosphingolipid metabolism. GM2 gangliosidosis is characterized by defects in the enzyme hexosaminidase A and / or its cofactor GM2 activator protein, which are responsible for the degradation of GM2 to GM3. GM2 and GM3 are related gangliosides and are part of the same metabolic pathway in which glucosylceramide is degraded to ceramide. Thus, GM3 is produced by a stepwise process that begins with the conversion of ceramide to glucosylceramide (by GLC), followed by conversion to galactosyl-glucosylceramide, followed by conversion to GM3 (N-acetyl-a-neuramindyl-galactosyl-glucosylceramide), followed by conversion to GM2 (N-acetyl-galactosyl N-acetyl-a-neuramindyl-galactosyl-glucosylceramide). Thus, the pathological accumulation of GM2 that is characteristic of GM2 gangliosidosis can be reversed by GCS inhibitors that block the initial step in the synthesis of glucosylceramide.

[0016] The quinuclidine compounds described herein have activity as inhibitors of enzyme glucosylceramide synthase (GCS).These compounds are disclosed as being generally useful in treating lysosomal storage diseases, such as Fabry disease, Gaucher disease and Niemann-Pick disease.See, for example, U.S. Patent No. 5,233,633 and U.S. Patent No. 5,233,633. [Prior art documents] [Patent documents]

[0017] [Patent Document 1] WO2005 / 068426 [Patent Document 2] WO2012 / 129084 [Patent Document 3] US2016 / 0361301 [Non-patent literature]

[0018] [Non-Patent Document 1] Lunawati L.Bennett&Chris Fellner,Pharmacotherapy of Gaucher Disease:Current and Future Options,P&T43(5):274-280,309(2018) Summary of the Invention [Problem to be solved by the invention]

[0019] There is a real need in the art to develop treatments that are effective in reducing or managing the neurological symptoms associated with Gaucher disease type 3, particularly saccadic eye movement deficits. [Means for solving the problem]

[0020] The present invention relates to a quinuclidine compound (Compound 1) according to formula (I) or a pharma- ceutically acceptable salt or prodrug thereof. [ka] (In the formula: R 1 is hydrogen, halogen (e.g., fluorine), cyano, nitro, hydroxy, thio, amino, C 1~6 -alkyl (e.g., methyl or ethyl), C 2~6 -Alkenyl, C 2~6 -Alkynyl, C 1~6 -Alkyloxy, C 2~6 -alkenyloxy, and C 2~6-alkynyloxy, where said alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, or alkynyloxy is optionally substituted with one or more (e.g., 1, 2, or 3) groups selected from halogen, cyano, nitro, hydroxy, thio, or amino; R 2 and R 3 is C optionally substituted by one or more (e.g., 1, 2 or 3) halogens; 1~3 -alkyl, or R 2 and R 3 together form a cyclopropyl or cyclobutyl group optionally substituted with one or more (e.g., one or two) halogens; R 4 , R 5 and R 6 is hydrogen, halogen, nitro, hydroxy, thio, amino, C 1~6 -Alkyl, and C 1-6 -alkyloxy, where said alkyl or alkyloxy is halogen, hydroxy, cyano, and C 1~6 - optionally substituted by one or more (e.g., 1, 2 or 3) groups selected from alkyl, aryl, aryloxy ... A is halogen, hydroxy, thio, amino, nitro, C 1~6 Alkoxy or C 1~6 is a 5- or 6-membered aryl or heteroaryl group optionally substituted with 1, 2, or 3 groups independently selected from alkyl.

[0021] In a first aspect, the application provides a method for treating or preventing supranuclear gaze paresis, including horizontal and vertical saccadic gaze paresis, in a subject in need thereof, comprising administering to the subject an effective amount of a quinuclidine compound described herein, e.g., a compound according to Formula I. In other aspects, the application further provides a use of a quinuclidine compound described herein for treating or preventing supranuclear gaze paresis, including horizontal and vertical saccadic gaze paresis, and / or for the manufacture of a medicament for treating or preventing supranuclear gaze paresis, including horizontal and vertical saccadic gaze paresis.

[0022] Additional features and advantages of the compounds, compositions and methods disclosed herein will become apparent from the following detailed description. [Brief description of the drawings]

[0023] [Figure 1] Figure 1 shows horizontal saccadic eye movements measured in five patients described in Example 5 (Figure 1 shows patients 1-3, and Figure 2 shows patients 4-5). Saccadic amplitude and peak velocity are measured when the target moves horizontally 15° (gray dots) or 30° (black dots) left or right from a central position. Eye movements to the right are represented by positive peak velocity and movements to the left are represented by negative peak velocity. The grey shaded area on each plot represents the normal range of peak velocity at any given amplitude. [Diagram 2] Figure 1 shows horizontal saccadic eye movements measured in five patients described in Example 5 (Figure 1 shows patients 1-3, and Figure 2 shows patients 4-5). Saccadic amplitude and peak velocity are measured when the target moves horizontally 15° (gray dots) or 30° (black dots) left or right from a central position. Eye movements to the right are represented by positive peak velocity and movements to the left are represented by negative peak velocity. The grey shaded area on each plot represents the normal range of peak velocity at any given amplitude. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Specific embodiments of the present disclosure will now be described with reference to preparations and schemes; however, such embodiments are illustrative only and represent the application of the principles of the present disclosure. It should be understood that these are but a few of the many possible specific embodiments that may be implemented. Various changes and modifications will become apparent to those skilled in the art given the benefit of this disclosure, and are deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims.

[0025] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs. Although any method and material similar or equivalent to those described herein may be used to carry out or test the present invention, exemplary methods, devices, and materials are described herein. All technical and patent publications cited herein are incorporated herein by reference in their entirety. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention.

[0026] The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of tissue culture, immunology, molecular biology, microbiology, cell biology and recombinant DNA, which are within the skill of the art.

[0027] All numerical indications, including ranges, such as pH, temperature, time, concentration, molecular weight, are approximate values ​​that are varied (+) or (-) by increments of 0.1 or 1.0, as appropriate. It is understood, although not always explicitly stated, that all numerical indications are preceded by the term "about". It is also understood, although not always explicitly stated, that the reagents described herein are merely exemplary, and that equivalents of such are known in the art.

[0028] As used herein, the term "optionally substituted" is meant to be equivalent to the phrase "unsubstituted or substituted with."

[0029] As used herein, the phrase "in a method of treating or preventing" (e.g., the phrase "in a method of treating or preventing supranuclear gaze paresis") is meant to be equivalent to the phrase "in the treatment or prevention of" (e.g., the phrase "in the treatment or prevention of supranuclear gaze paresis").

[0030] As used in the specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a cell" includes a plurality of cells, including mixtures thereof. Unless otherwise stated or obvious from the context, the term "or" is understood to be inclusive when used herein. The term "including" is used herein to mean the phrase "including, but not limited to," and is used interchangeably.

[0031] As used herein, the terms "comprising" or "comprising" are intended to mean that the compositions and methods include the recited elements but do not exclude others. "Consisting essentially of," when defining compositions and methods, is intended to mean excluding other elements of any essential importance to the combination for the described purpose. Thus, a composition consisting essentially of elements as defined herein would not exclude trace contaminants from isolation and purification methods, as well as pharma- ceutically acceptable carriers, e.g., phosphate buffered saline, preservatives, and the like. "Consisting of" refers to the inclusion of not only trace elements of other components, but also substantial method steps for administering the compositions of the invention or method steps for producing the compositions or achieving the intended results. "Comprising" is intended to mean excluding the steps of: "a" or "b"; "b" or "c"; "c" or "d"; "d" or "e"; "e" or "f ...

[0032] "Subject", "individual" or "patient" are used interchangeably herein to refer to vertebrates, such as mammals. Mammals include, but are not limited to, mice, rats, rabbits, monkeys, cows, sheep, pigs, dogs, cats, farm animals, sport animals, pets, horses, primates, and humans. In one embodiment, mammals include horses, dogs, and cats. In some embodiments, the mammal is a human, such as a human suffering from a particular disease or disorder, such as Gaucher disease (e.g., GD-3) or Niemann-Pick disease type C.

[0033] "Administering" is defined herein as a means of providing a drug or a composition containing a drug to a subject in a manner that results in the drug being present inside the subject's body. Such administration may be by any route, including but not limited to oral, transdermal (e.g. vaginal, rectal, oral mucosa), by injection (e.g. subcutaneous, intravenous, parenteral, intraperitoneal, CNS), or by inhalation (e.g. oral or nasal). Pharmaceutical preparations are of course provided in a form suitable for each administration route.

[0034] "Treating" a disease or "treatment" thereof generally includes: (1) inhibiting the disease, i.e., arresting or reducing the onset of the disease or its clinical symptoms; and / or (2) palliating the disease, i.e., causing regression of the disease or its clinical symptoms.

[0035] As used herein, "treating" and "treatment" also refer to either the reversal of supranuclear gaze paresis or the stabilization of supranuclear gaze paresis. This is because the diseases and disorders described herein are progressive disorders - if untreated, supranuclear gaze paresis will progress until complete paresis (i.e., paralysis) occurs. The progressive deterioration of the eye movement will continue to worsen. For example, during the early course of the disease, the patient may suffer from slow or inhibited saccadic eye movements, but as the disease progresses, the patient may develop a complete lack of saccades. Thus, treatment includes both the slowing down (e.g., stabilization) of this progressive deterioration as well as the reversal (e.g., improvement) of this progressive deterioration.

[0036] "Preventing" a disease or "prevention" generally involves preventing the development of clinical symptoms of the disease in a patient who may be susceptible to the disease but who has not yet experienced or exhibited symptoms of the disease.

[0037] As used herein, "preventing" or "preventing" also includes preventing the development of supranuclear gaze paresis in patients suspected of or diagnosed with the diseases or disorders described herein.Diseases and disorders described herein are progressive disorders, so various signs and symptoms may appear gradually as the disease progresses.Thus, for example, a patient may be diagnosed with GD-3 or NPC before supranuclear gaze paresis begins to develop.In such patients, the treatment methods described herein can be effective in preventing the development of supranuclear gaze paresis.

[0038] The term "mild paralysis" is synonymous with "complete paralysis" and includes any degree of loss of motor function of one or more skeletal muscles. Thus, as used herein, the term "mild paralysis" includes complete mild paralysis, i.e., complete and total paralysis, as well as partial mild paralysis. It includes both paralysis and complete paralysis. Complete paralysis means that a muscle or muscle group, for example, extraocular muscles, loses the ability to contract. Thus, the affected eye or eyes cannot move. Partial paralysis may manifest as inhibition, slowness, or other defects in movement. These may include loss of range of motion. When applied to saccades, this may include inhibition of saccade initiation (e.g., in response to a stimulus), changes in saccade frequency, changes in peak velocity of saccades, changes in saccade amplitude, changes in intersaccade latency, and / or loss of ability to hold or shift gaze. As used herein, in some embodiments, paralysis includes ophthalmoparesis and / or ophthalmoparesis. Thus, the term includes both weakness and complete paralysis of extraocular muscles. Extraocular muscles include any one or more of the superior rectus, inferior rectus, medial rectus, lateral rectus, inferior oblique, and superior oblique muscles of the eye. Weakness and / or complete paralysis may involve one or more of horizontal, vertical or rotational movements.

[0039] The term "suffering" in conjunction with the term "treatment" refers to a patient or individual who has been diagnosed with a disease. The term "suffering" in conjunction with the term "prevention" refers to a patient or individual who is susceptible to a disease. A patient may also refer to one who is "at risk for" a disease because of a history of the disease in their family or because of the presence of a genetic mutation associated with the disease. A patient at risk for a disease has not yet developed all or some of the characteristic symptoms of the disease.

[0040] An "effective amount" or a "therapeutically effective amount" is an amount sufficient to produce a beneficial or desired result. An effective amount may be administered in one or more administrations, applications or dosages. Such delivery depends on many variables, including the duration of use of the individual dosage units, the bioavailability of the therapeutic agent, and the route of administration. However, it is understood that the specific dosage level of the therapeutic agent of the present invention for any particular subject will depend on a variety of factors, including, for example, the activity of the specific compound used, the subject's age, weight, general health, sex, and diet, the time of administration, the rate of excretion, the drug combination, and the severity and form of administration of the particular disorder being treated. Treatment dosages may generally be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro and / or in vivo studies can initially provide useful guidance regarding the appropriate dose to administer to a patient. In general, it will be desired to administer an effective amount of the compound to achieve serum levels commensurate with the concentration found to be effective in vitro. Determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures, are well known in the art and are described in standard textbooks.Keeping this definition, as used herein, the term "therapeutically effective amount" refers to an amount sufficient to treat (e.g., ameliorate) one or more symptoms associated with disease or disorder described herein (e.g., in any of Method 1 and onward or Method 4 and onward), ex vivo, in vitro or in vivo.

[0041] As used herein, the term "pharmaceutical acceptable excipient" includes any of the standard pharmaceutical excipients, including carriers, such as phosphate buffered saline solution, water, and emulsions, such as oil / water or water / oil emulsions, and various types of wetting agents. Pharmaceutical compositions also include stabilizers and preservatives. For example, examples of carriers, stabilizers and adjuvants can be found in Remington's Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000).

[0042] As used herein, the term "prodrug" refers to a drug that spontaneously reacts with an organism. Prodrugs refer to pharmacological derivatives of parent drug molecules that require biotransformation or enzymatic biotransformation to release the active drug. For example, prodrugs are variants or derivatives of the quinuclidine compounds described herein that have groups that can be cleaved under certain metabolic conditions, which, when cleaved, become the quinuclidine compounds described herein, such as compounds of formula I. Such prodrugs are then pharmacologic active in vivo when they undergo solvolysis or enzymatic degradation under physiological conditions. Prodrug compounds may be referred to as single, double, triple, etc. herein, depending on the number of biotransformation steps required to release the active drug in the organism and the number of functional groups present in the precursor form. Prodrug forms often offer the advantages of solubility, tissue compatibility, or delayed release in mammalian organisms.

[0043] Prodrugs generally known in the art include well-known acid derivatives such as, for example, esters prepared by reaction of an acid compound with a suitable alcohol, and amides prepared by reaction of an acid compound with an amine, which is a basic group that reacts to form an acylated base derivative. Other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability. Thus, those skilled in the art will understand that, for example, some of the compounds disclosed herein that have free amino or hydroxy groups can be converted into prodrugs. Prodrugs include compounds that have an amino acid residue or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues that are covalently linked to the free amino, hydroxy, or carboxylic acid groups of the compounds disclosed herein via peptide bonds. Amino acid residues include the 20 naturally occurring amino acids, commonly designated by their three letter symbols, and also include 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Prodrugs also include compounds having a carbonate, carbamate, amide, or alkyl ester moiety covalently bonded to any of the above substituents disclosed herein.

[0044] As used herein, the term "pharmaceutically acceptable salts" refers to pharmaceutically acceptable acid addition salts or pharmaceutically acceptable base addition salts of the presently disclosed compounds which may be administered without any substantial undesirable biological effects or any adverse interactions as a result with other components of the pharmaceutical composition in which it may be included.

[0045] As used herein, "C 1~6 The term "-alkyl" refers to a saturated linear or branched free radical consisting essentially of one to six carbon atoms and a corresponding number of hydrogen atoms.1-6 -Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl. Other C 1~6 -alkyl groups will be readily apparent to those of skill in the art given the benefit of this disclosure. 1~3 -alkyl", "C 1~4 The terms "-alkyl" and the like have the same meaning, i.e., a saturated linear or branched free radical consisting essentially of one to three (or four) carbon atoms and the corresponding number of hydrogen atoms.

[0046] As used herein, "C 2~6 The term "-alkenyl" refers to an unsaturated linear or branched free radical consisting essentially of 2 to 6 carbon atoms and a corresponding number of hydrogen atoms, and containing at least one carbon-carbon double bond. 2~6 -alkenyl groups include ethenyl, prop-1-enyl, prop-2-enyl, isopropenyl, but-1-enyl, 2-methyl-prop-1-enyl, and 2-methyl-prop-2-enyl. 2~6 The -alkenyl group is It will be readily apparent to those of ordinary skill in the art given the benefit of the disclosure.

[0047] As used herein, "C 2~6 The term "alkynyl" refers to an unsaturated linear or branched free radical consisting essentially of 2 to 6 carbon atoms and a corresponding number of hydrogen atoms, and containing at least one carbon-carbon triple bond. 2~6 -Alkynyl groups include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, and 3-methyl-but-1-ynyl. 2~6 -alkynyl groups will be readily apparent to those of skill in the art given the benefit of this disclosure.

[0048] As used herein, "C 1~6The term "-alkyloxy" refers to a saturated linear or branched free radical consisting essentially of 1 to 6 carbon atoms (and the corresponding number of hydrogen atoms) and oxygen atoms. 1~6 The -alkyloxy group is bonded via an oxygen atom. 1~6 -Alkyloxy groups include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, and isobutyloxy. 1~6 -alkyloxy groups will be readily apparent to those of skill in the art given the benefit of this disclosure. 1~3 -alkyloxy", "C 1~4 The terms "-alkyloxy" and the like have the equivalent meaning, i.e., a saturated linear or branched free radical consisting essentially of 1 to 3 (or 4) carbon atoms (and the corresponding number of hydrogen atoms) and oxygen atoms, in which the group is bonded via an oxygen atom.

[0049] As used herein, "C 2~6 The term "-alkenyloxy" refers to an unsaturated linear or branched free radical consisting essentially of 2 to 6 carbon atoms (and a corresponding number of hydrogen atoms) and oxygen atoms, and containing at least one carbon-carbon double bond. 2~6 The -alkenyloxy group is bonded via an oxygen atom. 2~6 -alkenyloxy group is ethenyloxy; others will be readily apparent to the skilled artisan given the benefit of this disclosure.

[0050] As used herein, "C 2~6 The term "alkynyloxy" refers to an unsaturated linear or branched free radical consisting essentially of 2 to 6 carbon atoms (and a corresponding number of hydrogen atoms) and oxygen atoms, and containing at least one carbon-carbon triple bond. 2~6 The -alkenyloxy group is bonded via an oxygen atom. 2~6-alkenyloxy group is ethynyloxy; others will be readily apparent to the skilled artisan given the benefit of this disclosure.

[0051] As used herein, the term "heteroaryl" refers to an aromatic free radical having 5 or 6 atoms (i.e., ring atoms) forming a ring, with 1 to 5 ring atoms being carbon, and the remaining 1 to 5 ring atoms (i.e., hetero ring atoms) being independently selected from the group consisting of nitrogen, sulfur, and oxygen. Exemplary 5-membered heteroaryl groups include furyl, thienyl, thiazolyl (e.g., thiazol-2-yl), pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 6-membered heteroaryl groups include pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, and benzimidazolyl. Other heteroaryl groups will be readily apparent to one of ordinary skill in the art given the benefit of this disclosure. In general, heteroaryl groups are typically attached to the main structure via a carbon atom. However, it will be understood by those skilled in the art that certain other atoms, such as heterocyclic atoms, can be attached to the main structure.

[0052] As used herein, the term "aryl" refers to an aromatic free radical having 5 or 6 atoms forming a ring (i.e., ring atoms), all of which are carbon. An exemplary aryl group is a phenyl group.

[0053] As used herein, the term "aliphatic" refers to a non-aromatic compound containing carbon and hydrogen atoms, e.g., 1 to 9 carbon atoms. An aliphatic compound may be linear or branched, may contain one or more ring structures, and may contain one or more carbon-carbon double bonds (provided that the compound does not contain an unsaturated ring structure having aromatic character). Examples of aliphatic compounds include ethane, propylene, cyclobutane, and cyclohexadiene.

[0054] As used herein, the terms "halo" and "halogen" refer to fluorine, chlorine, bromine, or iodine. These terms are used interchangeably and may refer to halogen free radical groups or halogen atoms themselves. Those skilled in the art will be able to easily confirm the identity in light of the context in which the terms are used in this disclosure.

[0055] As used herein, the term "cyano" refers to a free radical having a carbon atom linked to a nitrogen atom through a triple bond. The cyano radical is bonded through that carbon atom.

[0056] As used herein, the term "nitro" refers to the -NO2 radical attached through the nitrogen atom.

[0057] As used herein, the terms "hydroxy" and "hydroxyl" refer to an -OH radical attached through its oxygen atom. The term "thio" refers to an -SH radical attached through its sulfur atom.

[0058] As used herein, the term "amino" refers to a free radical having a nitrogen atom and one or two hydrogen atoms. Thus, the term "amino" generally refers to primary and secondary amines. In that respect, as used herein, tertiary amines are represented by the general formula RR'N-, where R and R' are carbon radicals that may or may not be identical. Nevertheless, the term "amino" may be used generally herein to describe primary, secondary, or tertiary amines, and those skilled in the art will be able to easily confirm the identity in light of the context in which the term is used in this disclosure.

[0059] As used herein, the term "oxo" refers to an oxygen radical linked through a double bond. If the atom bonded to the oxygen is a carbon atom, the bond is a carbon-oxygen double bond, which may be written as -(C=O)- and referred to as a ketone.

[0060] The recitation of a list of chemical groups in any definition of a variable herein includes definitions of the variable as any single group or combination of listed groups. The recitation of an embodiment of a variable or aspect herein includes that embodiment in any single embodiment or in combination with any other embodiment or portion thereof.

[0061] Any composition or method provided herein may be combined with any one or more of the other compositions and methods provided herein.

[0062] The following abbreviations are used herein: br Broad signal CDI Carbonyldiimidazole CNS Central Nervous System d doublet DAPI 4',6-diamidino-2-phenylindole dd Doublet of Doublets DME Dimethoxyethane DMEM Dulbecco's Modified Eagle's Medium DMSO-d6 Dimethylsulfoxide-d6 DMF Dimethylformamide DNA deoxyribonucleic acid DTBZ Carbon-11 dihydrotetrabenazine EDTA Ethylenediaminetetraacetic acid ELISA Enzyme-linked Immunosorbent Assay Et2O Diethyl ether EtMgBr Ethyl magnesium bromide EtOAc Ethyl acetate GL1 Glucosylceramide (GlcCer) GM1 monosialotetrahexosylganglioside GM3 monosialylated dihexosylganglioside GSL Glycosphingolipids H&E Hematoxylin and Eosin Staining HPLC High Pressure / Performance Liquid Chromatography HAS Human serum albumin IPA Isopropyl Alcohol J coupling constant LCMS Liquid Chromatography Mass Spectrometry m multiplet ppm parts per million rHA Recombinant Human Albumin s singlet TBME Tert-Butyl Methyl Ether THF Tetrahydrofuran Tris Tris(hydroxymethyl)aminomethane TWEEN20 Polysorbate 20 TWEEN80 Polysorbate 80 WT wild type UPLCMS Ultra-Performance Liquid Chromatography Mass Spectrometry

[0063] compound The present disclosure relates to quinuclidine compounds for use in therapeutic methods associated with the treatment or prevention of the diseases and disorders discussed herein. In all its various aspects, the present invention relates to a quinuclidine compound (Compound 1) according to formula (I) or a pharma- ceutically acceptable salt or prodrug thereof: [ka] (In the formula: R 1 is hydrogen, halogen (e.g., fluorine), cyano, nitro, hydroxy, thio, amino, C 1~6 -alkyl (e.g., methyl or ethyl), C 2~6 -Alkenyl, C 2~6 -Alkynyl, C 1~6 -Alkyloxy, C 2~6 -alkenyloxy, and C 2~6 -alkynyloxy, where said alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, or alkynyloxy is optionally substituted with one or more (e.g., 1, 2, or 3) groups selected from halogen, cyano, nitro, hydroxy, thio, or amino; R 2 and R 3 is C optionally substituted by one or more (e.g., 1, 2 or 3) halogens; 1~3 -alkyl, or R 2 and R 3 together form a cyclopropyl or cyclobutyl group optionally substituted with one or more (e.g., one or two) halogens; R 4 , R 5 and R 6 is hydrogen, halogen, nitro, hydroxy, thio, amino, C 1~6 -Alkyl, and C 1~6 -alkyloxy, where said alkyl or alkyloxy is halogen, hydroxy, cyano, and C 1~6- optionally substituted by one or more (e.g., 1, 2 or 3) groups selected from alkyl, aryl, aryloxy ... A is halogen, hydroxy, thio, amino, nitro, C 1~6 Alkoxy and C 1~6 and alkyl, aryl, aryl group ...

[0064] In further embodiments of any aspect of the disclosure, the disclosure further relates to compounds such as: 1.1 Compound 1 (wherein R 1 is hydrogen, halogen, cyano, nitro, hydroxy, thio, amino, C 1~6 -Alkyl, C 1~6 -alkyloxy, where said alkyl or alkyloxy is optionally substituted with one or more (e.g., 1, 2 or 3) groups selected from halogen, cyano, nitro, hydroxy, thio or amino; 1.2 Compound 1 (wherein R 1 is hydrogen, halogen, C 1~6 -Alkyl, C 1~6 -alkyloxy, where said alkyl or alkyloxy is optionally substituted with one or more (e.g., 1, 2 or 3) groups selected from halogen, cyano, nitro, hydroxy, thio or amino; 1.3 Compound 1 (wherein R 1 is hydrogen, halogen, C 1~4 -Alkyl, C 1~4 -alkyloxy, where said alkyl or alkyloxy is optionally substituted with one or more (e.g., 1, 2 or 3) groups selected from halogen, cyano, nitro, hydroxy, thio or amino; 1.4 Compound 1 (wherein R 1 is hydrogen, halogen, C 1~4 -Alkyl, C 1~4-alkyloxy, wherein said alkyl or alkyloxy is one or more selected from cyano, nitro, hydroxy, thio or amino (e.g., 1, Optionally substituted with 2 or 3, or 1 or 2) groups; 1.5 Compound 1 (wherein R 1 is hydrogen, halogens, and C 1~4 -alkyl, wherein said alkyl is optionally substituted with one or more (e.g., 1 or 2) groups selected from halogen, hydroxy, thio, or amino; 1.6 Compound 1 (wherein R 1 is selected from hydrogen, fluorine, methyl and ethyl, wherein said methyl or ethyl is optionally substituted with one or two groups selected from halogen, hydroxy, thio or amino; 1.7 Compound 1 (wherein R 1 is selected from hydrogen and methyl, wherein said methyl is optionally substituted with one or two halogens; 1.8 Compound 1 (wherein R 1 is hydrogen); 1.9 Compound 1 or any of 1.1 to 1.8 (wherein R 1 is not attached to the nitrogen atom of the quinuclidine moiety); 1.10 Compound 1 or any of 1.1 to 1.9 (wherein R 2 and R 3 each independently represents a C optionally substituted with one or more (e.g., 1, 2, or 3) halogens; 1~3 - alkyl); 1.11 Compound 1.11 (wherein R 2 and R 3 are each independently methyl or ethyl optionally substituted with 1 or 2 halogens; 1.12 Compound 1.11 (wherein R 2 and R 3are each independently selected from methyl and ethyl optionally substituted with one or more fluorines, e.g., 1, 2 or 4 fluorines; 1.13 Compound 1.11 (wherein R 2 and R 3 are each independently methyl substituted with 0, 1, 2 or 3 fluorines; 1.14 Compound 1.11 (wherein R 2 and R 3 are each methyl or trifluoromethyl); 1.15 Compound 1.11(R 2 and R 3 are each methyl); 1.16 Compound 1 or any of 1.1 to 1.9 (wherein R 2 and R 3 together form a cyclopropyl or cyclobutyl group optionally substituted with one or more (e.g., 1 or 2) halogens; 1.17 Compound 1.16 (wherein R 2 and R 3 together form a cyclopropyl group); 1.18 Compound 1 or any of 1.1 to 1.9 (wherein R 2 and R 3 are each methyl or R 2 and R 3 together form a cyclopropyl group; 1.19 Compound 1, or any of 1.1 to 1.9, where R 4 , R 5 and R 6 is hydrogen, halogen, C 1~6 -Alkyl, and C 1~6 -alkyloxy, where said alkyl or alkyloxy is halogen, hydroxy, cyano, and C 1~6 - optionally substituted by one or more (e.g., 1, 2 or 3) groups selected from alkyloxy; 1.20 Compound 1 or any of 1.1 to 1.9 (wherein R4 , R 5 and R 6 is hydrogen, halogen, C 1~3 -Alkyl, and C 1~3 -alkyloxy, where said alkyl or alkyloxy is halogen, hydroxy, cyano, and C 1~3 - optionally substituted by one or more (e.g., 1, 2 or 3) groups selected from alkyloxy; 1.21 Compound 1.19 (wherein R 4 , R 5 and R 6 is hydrogen, halogen, C 1~3 -Alkyl, and C 1~3 -alkyloxy, where said alkyl or alkyloxy is selected from halogen, cyano, and C 1~3 - optionally substituted by one or more (e.g., 1, 2 or 3) groups selected from alkyloxy; 1.22 Compound 1.19 (wherein R 4 , R 5 and R 6 is hydrogen, halogen, C 1~3 -Alkyl, and C 1~3 -alkyloxy, wherein said alkyl or alkyloxy is selected from halogen and C 1~3 -Alkyloxy optionally substituted with one or more (e.g., 1, 2 or 3) groups selected from 1.23 Compound 1.19 (wherein R 4 , R 5 and R 6 is a halogen, C 1~3 -Alkyl, and C 1~3 -alkyloxy, wherein said alkyl or alkyloxy is selected from halogen and C 1~3 -alkyloxy) 1.24 Compound 1 or any of 1.19 to 1.23 (R 4 is hydrogen, halogen, C 1~3 -Alkyl, and C 1~3 -alkyloxy, wherein said alkyl or alkyloxy is selected from halogen and C 1~3 - optionally substituted by one or more (e.g., 1, 2 or 3) groups selected from alkyloxy; 1.25 Compound 1.24(R 4 is halogen (e.g., fluorine), C 1~3 -alkyl (e.g., methyl), and C 1~3 -alkyloxy (e.g., methoxy or ethoxy), wherein said alkyl or alkyloxy is selected from halogen and C 1~3 - optionally substituted by one or more (e.g. 1, 2 or 3) groups selected from alkyloxy (e.g. methoxy or ethoxy); 1.26 Compound 1.26(R 4 is halogen (e.g., fluorine) and C 1~3 -alkyloxy (e.g., methoxy or ethoxy), wherein said alkyloxy is selected from halogen and C 1~3 - optionally substituted by one or more (e.g. 1, 2 or 3) groups selected from alkyloxy (e.g. methoxy or ethoxy); 1.27 Compound 1.26(R 4 is fluorine or halogen and C 1~3 - C optionally substituted by one or more (e.g., 1, 2 or 3) groups selected from alkyloxy (e.g., methoxy). 1~3 - alkyloxy (e.g., ethoxy); 1.28 Compound 1.26 (wherein R 4 is fluorine or one or more (e.g., 1, 2 or 3) C 1~3 -ethoxy optionally substituted with alkyloxy (e.g. methoxy); 1.29 Compound 1 or any of 1.19 to 1.28 (wherein R 6 is hydrogen); 1.30 Compound 1 or any of 1.19 to 1.28 (wherein R 5 and R 6 are hydrogen); 1.31 Compound 1 or any of 1.19 to 1.28 (R 5 and R 6 are hydrogen, and R 4 is fluorine or halogen and C 1~3 - C optionally substituted by one or more (e.g., 1, 2 or 3) groups selected from alkyloxy (e.g., methoxy). 1~3 - alkyloxy (e.g., ethoxy); 1.32 Compound 1.31 (wherein R 5 and R 6 are hydrogen, and R 4 is fluorine or one or more (e.g., 1, 2 or 3) C 1~3 -ethoxy optionally substituted with alkyloxy (e.g. methoxy); 1.33 Compound 1.32 (wherein R 5 and R 6 are hydrogen, and R 4 is fluorine or ethoxy substituted with methoxy (e.g., 2-methoxyethoxy); 1.34 Compound 1.32, where R 4 is fluorine or 2-methoxyethoxy); 1.35 Compound 1 or any of 1.1 to 1.34, wherein R 4 , R 5 and R 6 at least one of which is not hydrogen); 1.36 Compound 1 or any of 1.1 to 1.35 (wherein R 6 is hydrogen, and R 4 and R 5 are located at the 2-, 4-, or 6-position of the phenyl ring to which they are attached (i.e., ortho or para to the A substituent); 1.37 Compound 1 or any of 1.1 to 1.35 (wherein R 6 is hydrogen, and R 4 and R 5 are independently located (relative to the A substituents) at the 2- and 3-positions (i.e., adjacent ortho and meta), at the 3- and 4-positions (i.e., adjacent meta and para), or at the 3- and 5-positions (i.e., meta) of the phenyl ring to which they are attached; 1.38 Compound 1, or any of 1.1-1.35, where R 6 is hydrogen, and R 4 and R 5 are located at the 3 and 5 positions (i.e., meta) of the phenyl ring to which they are attached (relative to the A substituent); 1.39 Compound 1 or any of 1.1 to 1.35 (wherein R 5 and R 6 is hydrogen, and R 4 is located at the 2-, 3-, or 4-position (e.g., ortho, meta, or para to the A substituent) of the phenyl ring to which it is attached); 1.40 Compound 1 or any of 1.1 to 1.35 (wherein R 5 and R 6 is hydrogen, and R 4 is located at the 2- or 4-position of the phenyl ring to which it is attached (e.g., ortho or para to the A substituent); 1.41 Compound 1 or any of 1.1 to 1.35 (wherein R 5 and R 6 is hydrogen, and R 4 is located at the 4-position of the phenyl ring to which it is attached (e.g., para to the A substituent); 1.42 Compound 1 or any of 1.1 to 1.35 (wherein R 4 , R 5 and R 6 None of R is hydrogen. 4 , R 5 and R 6 are independently located at the 2-, 4-, or 6-position (i.e., ortho or para to the A substituent) of the phenyl ring to which they are attached); 1.43 Compound 1 or any of 1.1 to 1.42 (wherein R 4 is located at the 4-position of the phenyl ring to which it is attached (i.e., para to the A substituent); 1.44 Compound 1, or any of 1.1-1.43, where A is a 6-membered aryl group, a 5-membered heteroaryl group (e.g., containing 1, 2 or 3 heteroatoms in the heteroaryl ring selected from N, O and S), or a 6-membered heteroaryl group (e.g., containing 1, 2 or 3 nitrogen atoms in the heteroaryl ring); 1.45 Compound 1.44, where A is a 6-membered aryl group or a 5-membered heteroaryl group (e.g., containing 1, 2 or 3 heteroatoms in the heteroaryl ring selected from N, O and S), optionally the 5-membered heteroaryl group containing 1 or 2 heteroatoms selected from N and S (e.g., one N and / or one S); 1.46 The compound 1.44 or 1.45, wherein A is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, and thiadiazolyl; 1.47 Compound 1.46, wherein A is selected from the group consisting of phenyl, thienyl, thiazolyl, pyrrolyl, and imidazolyl; 1.48 Compound 1.46, where A is selected from the group consisting of phenyl and thiazolyl, e.g., 2-thiazol-4-yl or 4-thiazol-2-yl; 1.49 Compound 1 or any of 1.1 to 1.48, wherein A is unsubstituted. 1.50 Compound 1 or any of 1.1 to 1.48, wherein A is halogen, hydroxy, thio, amino, nitro, C 1~6 Alkoxy and C 1~6 substituted with one or more (e.g., 1, 2, or 3) groups independently selected from alkyl (e.g., methyl); 1.51 Compound 1.50, where A is one halogen (e.g., fluorine), or C1~6 thiazolyl substituted with alkyl (e.g., methyl); 1.52 Compound 1.50, where A is a halogen (e.g., fluorine) and C 1~6 phenyl substituted with 1, 2, or 3 groups independently selected from alkyl (e.g., methyl); 1.53 Compound 1.52 (wherein A is substituted with one or two fluorines or methyl groups) (phenyl). 1.54 Compound 1 or any of 1.1-1.53 ​​(wherein the two groups bonded to the A substituent (i.e., the phenyl ring (-(CHR 4 R 5 R 6 )) and -C(R 2 R 3 )-groups) are positioned in a 1,2, 1,3 or 1,4 relationship to each other (i.e., ortho, meta, or para); 1.55 Compound 1.54, wherein the two groups attached to the A substituent are positioned in a 1,3 relationship (i.e., meta) to each other; 1.56 Compound 1.54, wherein the two groups attached to the A substituent are positioned in a 1,4 relationship (i.e., para) to each other; 1.57 Any of compounds 1.54 to 1.56, wherein the A substituent is a 5-membered heteroaryl group and the two groups attached to the A substituent (i.e., the phenyl ring (-(CHR 4 R 5 R 6 )) or the-C(R 2 R 3 at least one of the aryl- and aryl-groups) is bonded to a carbon atom of the heteroaryl ring, and optionally both such groups are bonded to a carbon atom of the heteroaryl ring;

[0065] 1.58 Compound 1, or any of 1.1-1.57, wherein the compound of formula I may be represented by any one or more of the following structures: [ka] [ka] [ka]

[0066] 1.59 Compound 1, or any of 1.1 to 1.58, wherein the compound of formula I, or any of formulas II to XII, has the (S) configuration; 1.60 Compound 1, or any of 1.1-1.58, wherein the compound of formula I, or any of formulas II-XII, has the (R) configuration; 1.61 Compound 1, or any of 1.1-1.60, wherein the compound of formula I, or any of formulas II to XII, has an enantiomeric excess (e.g., of the (S) configuration) of at least 90%, e.g., at least 92%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9%; 1.62 Compound 1, or any of 1.1-1.58, wherein the compound of formula I, or any of formulas II to XII, is racemic (i.e., approximately a 50:50 ratio of enantiomers) or is some other ratio (e.g., less than 50:50 or more than 50:50) of a mixture of enantiomers; 1.63 Compound 1, or any of 1.1 to 1.62, wherein the compound of formula I is selected from the group consisting of the following tables:

[0067] [Table 1] [Table 2]

[0068] 1.64 Compound 1, or any of 1.1-1.63, wherein the compound is selected from quinuclidin-3-yl (2-(4'-fluoro-[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate, (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate, and (S)-quinuclidin-3-yl (2-(4'-(2-methoxyethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate; 1.65 Compound 1, or any of 1.1-1.63, wherein the compound is quinuclidin-3-yl (2-(4'-fluoro-[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate; 1.66 Compound 1 or any of 1.1 to 1.63, wherein the compound is quinuclidin-3-yl(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate, e.g. (S)-quinuclidin-3-yl(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate; 1.67 Compound 1 or any of 1.1 to 1.66, wherein the compound of formula I or any of formula II to XII is in the form of the free base; 1.68 Compound 1, or any of 1.1 to 1.66, wherein the compound of formula I, or any of formulas II to XII, is in the form of a pharma- ceutically acceptable salt; 1.69 Compound 1.68, wherein said salt form is an acid addition salt form; 1.70 Compound 1.69, wherein the acid addition salt form is a salt selected from hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, hydroxysuccinate, malate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, and pamoate; 1.71 Compound 1.70, wherein the acid addition salt form is selected from hydrochloride, hydroxysuccinate (e.g., 2-hydroxysuccinate), and malate; 1.72 Compound 1.68, wherein said salt form is a base addition salt form; 1.73 Compound 1, or any of 1.1-1.72, wherein the compound is (S)-quinuclidin-3-yl(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate in the malate form; 1.74 Compound 1, or any of 1.1-1.73, wherein the compound of formula I, or any of II-XII, is in the form of a prodrug as described herein; 1.75 Compound 1, or any of 1.1-1.74, wherein the compound of formula I, or any of II-XII, is in the form of a hydrate, solvate and / or polymorph.

[0069] salt The compounds disclosed herein, e.g., any of compounds 1 or 1.1 to 1.75, are basic in nature and can generally form a variety of different salts with various inorganic and / or organic acids. Such salts are generally pharma- ceutically acceptable for administration to animals and humans, but it is often actually desirable to first isolate the compound from the reaction mixture as a pharma- ceutically unacceptable salt, then simply convert the latter back to a free base compound by treatment with an alkaline reagent, and then convert the free base to a pharma-ceutically acceptable acid addition salt. Acid addition salts of basic compounds may be readily prepared using conventional techniques, e.g., by treating the basic compound with a substantially equivalent amount of a selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent, e.g., methanol or ethanol. When the solvent is carefully evaporated, the desired solid salt is obtained. The compounds disclosed herein are positively charged, and include, e.g., quaternary ammonium, and can also form salts with anionic components of various inorganic and / or organic acids.

[0070] Acids which may be used to prepare pharma- ceutically acceptable salts of the quinuclidine compounds are those capable of forming non-toxic acid addition salts, e.g., salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, malate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

[0071] Compounds disclosed herein that are acidic in nature, e.g., compounds that contain a thiol moiety, can generally form a variety of different salts with various inorganic and / or organic bases. Although such salts are generally pharma-ceutically acceptable for administration to animals and humans, it is often actually desirable to first isolate the compound from the reaction mixture as a pharma-ceutically unacceptable salt, then simply convert the latter back to the free acid compound by treatment with an acidic reagent, and then convert the free acid to a pharma-ceutically acceptable base addition salt. These base addition salts may be readily prepared using conventional techniques, e.g., by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation, and then evaporating the resulting solution to dryness, e.g., under reduced pressure. Alternatively, they may be prepared by mixing lower alkanol solutions of the acidic compound and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as described above. In either case, stoichiometric amounts of reagents may be used to ensure completeness of the reaction and maximize the yield of the desired solid salt product.

[0072] Bases which may be used to prepare pharma- ceutically acceptable base addition salts of the quinuclidine compounds are those capable of forming non-toxic base addition salts, for example, salts containing pharmacologically acceptable cations, such as alkali metal cations (e.g., potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amines, such as N-methylglucamine (meglumine), lower alkanolammonium, and other organic amine bases.

[0073] In one embodiment, the pharmaceutically acceptable salt is a succinate salt. In another embodiment, the pharmaceutically acceptable salt is a 2-hydroxysuccinate salt, such as (S)-2-hydroxysuccinate salt. In another embodiment, the pharmaceutically acceptable salt is a hydrochloride salt (i.e., a salt with HCl). In another embodiment, the pharmaceutically acceptable salt is a malate salt.

[0074] Prodrug The present disclosure further includes prodrugs of compounds 1 and 1.1 to 1.75. The pharma- ceutically acceptable prodrugs disclosed herein are derivatives of quinuclidine compounds that can be converted in vivo to the quinuclidine compounds described herein.Prodrugs may have some activity themselves, for example, when they undergo solvolysis under physiological conditions or enzymatic degradation, they become pharma- ceutically active in vivo.The method for preparing the prodrugs of the compounds described herein will be clear to those skilled in the art based on this disclosure.

[0075] In one embodiment, the carbamate moiety of the quinuclidine compound is modified.For example, the carbamate moiety of the quinuclidine compound may be modified by adding water and / or one or two aliphatic alcohols.In this case, the carbon-oxygen double bond of the carbamate moiety adopts what may be considered a hemiacetal or acetal functionality.In one embodiment, the carbamate moiety of the quinuclidine compound may be modified by adding an aliphatic diol, for example 1,2-ethanediol.

[0076] In one embodiment, one or more of the hydroxy, thio or amino groups in the quinuclidine compound are modified.For example, one or more of the hydroxy, thio and / or amino groups in the quinuclidine compound may be modified to form an acid derivative, such as an ester, a thioester (or a thiol ester) and / or an amide.The acid derivative may be formed, for example, by reacting the quinuclidine compound containing one or more hydroxy, thio or amino groups with an acetylating agent.Examples of acetylating agents include anhydrides, such as acetic anhydride, acid chlorides, such as benzyl chloride, and bicarbonates, such as di-tert-butyl dicarbonate.

[0077] stereochemistry The present disclosure further encompasses stereoisomers and mixtures of stereoisomers of compounds 1 and 1.1 through 1.75. Stereoisomers (e.g., cis and trans isomers) and all optical isomers (e.g., R- and S-enantiomers) of the compounds disclosed herein, as well as racemic, diastereomeric and other mixtures of such isomers, are within the scope of the present disclosure.

[0078] In one embodiment, the quinuclidine-3-yl group of the quinuclidine compounds defined herein has the R-configuration. Thus, the quinuclidine compounds may be selected from the group consisting of compounds of formulae (Ia) to (XIIa), and pharma-ceutically acceptable salts and prodrugs thereof:

[0079] [ka] [ka] [ka]

[0080] In another embodiment, the quinuclidine-3-yl group of the quinuclidine compounds defined herein has the S-configuration. Thus, the quinuclidine compounds may be selected from the group consisting of compounds of formulae (Ib) to (XIIb), and pharma-ceutically acceptable salts and prodrugs thereof:

[0081] [ka] [ka] [ka]

[0082] In one embodiment, the quinuclidine compound is a compound of formula (Xb) or a pharma- ceutically acceptable salt or prodrug thereof. In another embodiment, the quinuclidine compound is a compound of formula (XIIb) or a pharma- ceutically acceptable salt or prodrug thereof.

[0083] In one embodiment, the quinuclidine-3-yl group of the quinuclidine compound defined herein exists in a mixture of isomers having R- and S-configuration.For example, the quinuclidine compound may be a mixture of compounds selected from the group consisting of the compounds of formula (Ia) and (Ib), (IIa) and (IIb), (IIIa) and (IIIb), (IVa) and (IVb), (Va) and (Vb), (VIa) and (VIb), (VIIa) and (VIIb), (VIIIa) and (VIIIb), (IXa) and (IXb), (Xa) and (Xb), (XIa) and (XIb), and (XIIa) and (XIIb), and pharma-ceutically acceptable salts and prodrugs thereof.In one embodiment, the quinuclidine compound exists as a racemic mixture, for example, the R- and S-isomers of the quinuclidine-3-yl group exist in approximately equal amounts. In another embodiment, the quinuclidine compound exists as a mixture of isomers with R- and S-configuration, and R- and S-isomers exist in different amounts.In one embodiment, the S-isomer exists in an enantiomeric excess of at least about 5%, 10%, 25%, 40%, 70%, 80%, 90%, 95%, 97%, 98% or 99%, for example, about 100%.In another embodiment, the R-isomer exists in an enantiomeric excess of at least about 5%, 10%, 25%, 40%, 70%, 80%, 90%, 95%, 97%, 98% or 99%, for example, about 100%.

[0084] Methods for preparing enantiomerically enriched and / or enantiopure quinuclidine compounds will be apparent to those of skill in the art based on the present disclosure.

[0085] The compounds disclosed herein may exist in several tautomers, including enol and imine forms, and keto and enamine forms, as well as geometric isomers, and mixtures thereof. Tautomers exist as a mixture of tautomer sets in solution. In solid form, one tautomer usually predominates. Although one tautomer may be described, all tautomers are within the scope of this disclosure.

[0086] Atropisomers are also within the scope of this disclosure. Atropisomers refer to compounds that can be decomposed into isomers with restricted rotation.

[0087] Other forms The present disclosure further encompasses hydrates, solvates and polymorphs of compounds 1 and 1.1 to 1.75. Pharmaceutically acceptable hydrates, solvates and polymorphs of the quinuclidine compounds described herein are within the scope of the present disclosure. The compound may be in amorphous form and / or in one or more crystalline forms.

[0088] Isotopically labeled compounds are also within the scope of the present disclosure.As used herein, "isotopically labeled compounds" refers to compounds disclosed herein, including pharmaceutical salts and their prodrugs, each of which is described herein, in which one or more atoms are replaced by atoms with atomic mass or mass number that is different from the atomic mass or mass number that is found in nature.Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, respectively: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 There is Cl.

[0089] Medical Indication The quinuclidine compounds described herein and the pharmaceutical compositions comprising them are useful in therapy, particularly in the therapeutic treatment of neurological deficits, including supranuclear gaze paresis, including horizontal and vertical saccade gaze paresis, dementia and gait disorder in patients with diseases such as Gaucher's disease.The subjects that will be treated according to the method described herein include vertebrates, such as mammals.In certain embodiments, mammals are human patients.

[0090] In a first aspect, the present invention provides a method (Method 1) for treating or preventing supranuclear gaze paresis, including horizontal and vertical saccadic gaze paresis, in a subject in need thereof, comprising administering to the subject an effective amount of a quinuclidine compound as described herein, e.g., a compound according to Formula I or any of II-XII, Ia-XIIa, or Ib-XIIb, or any of Compounds 1 or 1.1-1.75. Also provided is a quinuclidine compound as described herein, e.g., a compound according to Formula I or any of II-XIIIa-XIIa, or Ib-XIIb, or any of Compounds 1 or 1.1-1.62, for use in a method for treating or preventing supranuclear gaze paresis, including horizontal and vertical saccadic gaze paresis, in a subject in need thereof, e.g., for use in Method 1 or 1.1-1.62. Further provided is the use of a quinuclidine compound as described herein, e.g., a compound according to any of Formulas I or II-XII, Ia-XIIa, or Ib-XIIb, or compound 1 or any of 1.1 to 1.75, in the manufacture of a medicament for use in a method of treating or preventing supranuclear gaze palsy, including horizontal and vertical saccadic gaze palsy, in a subject in need thereof, e.g., in the manufacture of a medicament for use in any of Methods 1 or 1.1-1.62.

[0091] In certain further embodiments of Method 1, the present disclosure provides: 1.1 Method 1, comprising administering to a subject an effective amount of a compound according to any of Formulas I or II-XII, Ia-XIIa or Ib-XIIb, or any of Compound 1, or any of 1.1 to 1.75; 1.2 Method 1, comprising administering to a subject an effective amount of Compound 1 or any one or more of Compounds 1.1 to 1.75; 1.3 any of Method 1 or 1.1-1.2 comprising administering to a subject an effective amount of a pharmaceutical composition comprising a compound according to any of Formulas I or II-XII, Ia-XIIa or Ib-XIIb, or any of Compound 1 or any of 1.1-1.75;1.4 any of Method 1 or 1.1-1.2 comprising administering to a subject an effective amount of a pharmaceutical composition comprising Compound 1 or any one or more of Compounds 1.1-1.75; 1.5 Method 1.3 or 1.4, wherein the pharmaceutical composition further comprises at least one pharma- ceutically acceptable excipient as described herein; 1.6 Any of Methods 1 or 1.1-1.5 comprising administering an effective amount of a compound or a pharmaceutical dosage form comprising an effective amount of a pharmaceutical composition; 1.7 Method 1.6, where the dosage form is an oral dosage form (e.g., a pill, capsule, caplet, tablet, dragee, powder, granules, film, lozenge, or liquid);1.8 Method 1.7, where the dosage form is a chewable tablet; 1.9 The dosage form is a parenteral dosage form (e.g., when the pharmaceutical composition is formulated for injection), Method 1.6; 1.10 The injection is intravenous, intramuscular, intrathecal or subcutaneous, optionally a sterile injection, Method 1.9; 1.11 Method 1.6, where the dosage form is a topical or rectal dosage form; 1.12 Method 1.6, wherein the dosage form is an intranasal dosage form (e.g., an aerosol); 1.13 Any of Methods 1 or 1.1 through 1.12, further comprising concurrently administering in a patient in need thereof a second active agent as described herein, e.g., a second compound capable of treating or preventing supranuclear gaze palsy; 1.14 Method 1.13, wherein the second active agent is administered in the same pharmaceutical composition or dosage form as the quinuclidine compound; 1.15 Methods 1.13 or 1.14, wherein the second active agent is a GCS inhibitor (e.g., miglustat or eliglustat); 1.16 Any of methods 1, or 1.1 to 1.15, wherein the subject is a mammal; 1.17 Method 1.16, in which the subject is a primate; 1.18 The subject is a human, method 1.17; 1.19 Supranuclear gaze paresis is conjugate gaze paresis, method 1 or any of 1.1 to 1.18; 1.20 Supranuclear gaze paresis includes horizontal saccade paresis, vertical saccade paresis, impaired vestibulo-ocular reflex, impaired gaze holding, impaired horizontal smooth pursuit, and / or impaired vertical smooth pursuit, either method 1 or 1.1 to 1.19; 1.21 Supranuclear gaze paresis includes horizontal saccadic gaze paresis, either method 1 or 1.1–1.20; 1.22 Supranuclear gaze paresis includes vertical saccadic gaze paresis, either method 1 or 1.1–1.21; 1.23 Supranuclear gaze paresis is a complete paresis (e.g., complete paresis), method 1, or any of 1.1 to 1.22; 1.24 The subject has Gaucher disease type 3, method 1, or any of 1.1 to 1.23; 1.25 The subject has Niemann-Pick disease type C, method 1, or any of 1.1-1.24; 1.26 The subject has GM2-gangliosidosis (e.g., Tay-Sachs disease, Sandhoff disease, or GM2 gangliosidosis AB variant), any of methods 1, or 1.1-1.24; 1.27 The subject has been diagnosed with a mutation in gene GBA1, according to method 1, or any of 1.1 to 1.24; 1.28 The subject has been diagnosed with a mutation in genes NPC1 and / or NPC2, according to any of methods 1, or 1.1-1.24; 1.29 Method 1, or any of 1.1-1.24, wherein the subject has been diagnosed with a mutation in the gene HEXA (encoding hexosaminidase A) and / or a mutation in the gene HEXB (encoding hexosaminidase B) and / or a mutation in the gene GM2A (encoding the GM2 ganglioside activator protein); 1.30 The subject has been diagnosed with Parkinson's disease, either method 1 or 1.1-1.29; 1.31 The subject is undergoing concurrent treatment with an enzyme replacement therapy (ERT), e.g., with glucocerebrosidase (e.g., imiglucerase, velaglucerase, or taliglucerase), optionally each such enzyme being a recombinant enzyme, of Method 1, or any of 1.1-1.30; 1.32 Method 1.31, wherein the subject is undergoing concomitant treatment with one or more of imiglucerase, velaglucerase (e.g., velaglucerase alfa), and taliglucerase (e.g., taliglucerase alfa); 1.33 The subject is undergoing concomitant treatment with imiglucerase, Method 1.32; 1.34 Method 1.33, in which the subject is undergoing concurrent treatment with imiglucerase (one unit of imiglucerase is the amount of enzyme that catalyzes the hydrolysis of 1 micromole of the synthetic substrate p-nitrophenyl-β-D-glucopyranoside per minute at 37° C.) at a dosage of 2.5 units / kg body weight to 80 units / kg body weight every 1 to 3 weeks, e.g., 40 to 60 units / kg body weight every 2 weeks; 1.35 The subject's dosage of imiglucerase in each administration (e.g., every 1 to 3 weeks, e.g., every 2 weeks) is administered as an intravenous (IV) infusion over 1 to 3 hours (e.g., 1 to 2 hours), Method 1.34; 1.36 Any of Methods 1 or 1.1-1.35, wherein the subject has been administered an enzyme replacement therapy agent (e.g., imiglucerase, velaglucerase, and / or taliglucerase) prior to initiating treatment with a compound according to Formula I (or any of II-XII, Ia-XIIa, or Ib-XIIb, or any of Compounds 1 or 1.1-1.75); 1.37 Method 1.36, wherein the subject has been administered an imiglucerase therapeutic agent for at least 6 months, e.g., at least 12 months (1 year), or at least 18 months, or at least 2 years, or at least 3 years, prior to initiating treatment with a compound according to Formula I (or any of II-XII, Ia-XIIa, or Ib-XIIb, or any of Compounds 1 or 1.1 to 1.75). 1.38 Method 1.36 or 1.37, wherein the subject has been administered an imiglucerase therapeutic agent at a stable dose for at least 6 months prior to initiating therapy with a compound according to Formula I (or any of II-XII, Ia-XIIa, or Ib-XIIb, or any of Compounds 1 or 1.1 through 1.75); 1.39 Any of Methods 1 or 1.1-1.38, further comprising the step of transitioning the subject from an ERT therapeutic (e.g., imiglucerase, velaglucerase, or taliglucerase) to treatment with a compound according to Formula I (or any of II-XII, Ia-XIIa, or Ib-XIIb, or any of Compounds 1 or 1.1-1.75); 1.40 Any of methods 1 or 1.1-1.39, wherein the subject's hemoglobin level is at least 11 g / dL for women and at least 12 g / dL for men; 1.41 Method 1, or any of 1.1 through 1.40, in which the subject's platelet count is at least 100,000 per cubic millimeter; 1.42 The subject has a spleen volume less than 10 times normal (10 MN) and / or a liver volume less than 1.5 MN, either method 1, or 1.1-1.41; 1.43 The subject has been diagnosed with oculomotor apraxia, e.g., oculomotor apraxia characterized by horizontal saccade abnormalities, according to any of Methods 1, or 1.1-1.42; 1.44 Method 1, or any of 1.1-1.43, wherein the subject is at least 18 years of age (e.g., 18-30 years of age) at the start of treatment with a compound according to formula I (or any of II-XII, Ia-XIIa, or Ib-XIIb, or compound 1 or any of 1.1-1.75); 1.45 The subject's glucosylceramide (GL1) concentration is between 4.4 and 11.1 ng / mL in cerebrospinal fluid (CSF) and between 4.9 and 8.3 μg / mL in plasma, either Method 1, or 1.1 through 1.44; 1.46 The subject's glucosylsphingosine (lyso-GL1) concentration is between 20.1 and 67.6 pg / mL in CSF and between 8.8 and 159.0 ng / mL in plasma, either Method 1, or 1.1 through 1.45; 1.47 Method 1, or any of 1.1-1.46, wherein the subject is administered a daily dose of about 1 mg to about 150 mg of a compound according to Formula I (or any of II-XII, Ia-XIIa, or Ib-XIIb, or any of Compound 1 or 1.1-1.75), selected from about 1 mg to about 150 mg, e.g., 5 to 50 mg, or 10 to 40 mg, or 10 to 30 mg, or 10 to 20 mg, or 20 to 30 mg, or 30 to 40 mg, or 40 to 50 mg, or 5 to 25 mg, or 20 to 50 mg, or 5 to 15 mg, or 15 to 30 mg, or about 15 mg, or 2, 5, 15, 25, 50, 100, or 150 mg; 1.48 Method 1, or any of 1.1-1.47, wherein the subject is a human adult patient, e.g., between 18 and 80 years of age, e.g., between 18 and 60 years of age, or between 18 and 40 years of age, or between 18 and 30 years of age, or between 18 and 25 years of age; 1.49 Method 1, or any of 1.1-1.47, wherein the subject is a human pediatric patient, e.g., between 0 and 18 years of age, e.g., between 1 and 15 years of age, or between 1 and 5 years of age, or between 5 and 10 years of age, or between 10 and 15 years of age, or between 10 and 18 years of age; 1.50 Method 1, or any of 1.1 to 1.49, that is effective to stabilize the progression of supranuclear gaze mild palsy for at least 6 months, or at least 9 months, or at least 12 months; 1.51 Method 1, or any of 1.1 to 1.49, that is effective to reverse the progression of supranuclear gaze mild palsy for at least 6 months, or at least 9 months, or at least 12 months; 1.52 Method 1, or any of 1.1-1.51, wherein the method results in at least a 30%, e.g., at least a 40%, at least a 50%, at least a 60%, or at least a 70% decrease in glucosylceramide concentration in the CSF and / or in the plasma after 6 months of treatment; 1.53 Method 1, or any of 1.1-1.52, wherein the method results in an increase in glucosylsphingosine concentration in the CSF and / or in plasma of at least 30%, e.g., at least 40%, at least 50%, at least 60% or at least 70% after 6 months of treatment; 1.54 Method 1, or any of 1.1-1.53, in which the method results in a statistically or clinically unchanged modified Severity Scoring Tool (mSST) value for neurological disease after 6 months of treatment; 1.55 Method 1, or any of 1.1 to 1.54, wherein a compound according to Formula I (or any of II-XII, Ia-XIIa or Ib-XIIb, or compound 1 or any of 1.1 to 1.75), or a pharma- ceutically acceptable salt or prodrug thereof, is administered by systemic administration, e.g., via a parenteral or non-parenteral route; 1.56 The route of administration is oral (enteral), Method 1.55; 1.57 The route of administration is parenteral, e.g., by injection, e.g., by intravenous injection, method 1.55; 1.58 Method 1, or any of 1.1 to 1.57, wherein a compound according to Formula I (or any of II-XII, Ia-XIIa or Ib-XIIb, or compound 1 or any of 1.1 to 1.75), or a pharma- ceutically acceptable salt or prodrug thereof, is administered by localized administration, e.g., by topical administration; 1.59 Method 1, or any of 1.1-1.58, wherein the compound is (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate or quinuclidin-3-yl (2-(4'-fluoro-[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate; 1.60 The dosage of the compound is 15 mg / day orally, Method 1.59; 1.61 The dosage of the compound is 15 mg / day in a single oral dose, Method 1.60; 1.62 Method 1, or any of 1.1-1.61, wherein the subject is administered a single daily dose of 5 mg, 10 mg, 15 mg, or 20 mg of a compound, e.g., (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate, optionally in the form of an acid addition salt of the malate.

[0092] Diseases and disorders, such as those that result in supranuclear gaze palsy, are often associated with one or more genetic mutations. In some embodiments of the present disclosure, a subject, i.e., a patient, has been diagnosed with a particular disease or disorder, and has also been diagnosed with a particular genetic mutation, e.g., one that is known to result in the disease or disorder in question, but it is often not possible to prove that a particular patient's disease or disorder is caused by the particular mutation that the person has been diagnosed with. When used in this way, the term "diagnosed with a particular genetic mutation" means that the subject or patient has been tested, e.g., by DNA or RNA sequencing, protein profiling, or other suitable means, and is found to have the mutation in question. However, as further described below, many genetic diseases and disorders may have multiple genetic causes (e.g., mutations), and a patient may have multiple mutations that may be sufficient to each result in a disease or disorder under some circumstances, and it is not intended to confirm that a particular mutation results in a particular disease or disorder in a particular patient.

[0093] Methods according to method 1 and onward may be beneficial for subjects who have been diagnosed with lysosomal storage disease, such as Gaucher type 3 or Niemann-Pick type C, but have not yet experienced ocular symptoms associated with the condition. Methods according to method 1 and onward may also be beneficial for subjects who are at risk of developing lysosomal storage disease, such as Gaucher type 3 or Niemann-Pick type C, for example, due to a mutation in the subject or in the subject's family known to cause such disease. As a result, in some embodiments of the methods described herein, the subject has been diagnosed as at risk of developing said disease or disorder, and the method prevents or delays the onset and / or development of ocular symptoms of the disease or disorder (e.g., supranuclear gaze palsy) in the subject. In some embodiments, the subject has been diagnosed as at risk of developing said disease or disorder because of having a mutation in a gene described herein.

[0094] In a second aspect, the present invention provides a method (Method 4) for treating or preventing cognitive impairment and / or gait abnormalities, including ataxia, associated with a lysosomal storage disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a quinuclidine compound described herein (Method 4), e.g., a compound according to any of Formulas I or II-XII, Ia-XIIa or Ib-XIIb, or Compounds 1 or 1.1-1.75. Also provided is a quinuclidine compound described herein, e.g., a compound according to Formulas I or II-XII, Ia-XIIa or Ib-XIIb, or Compounds 1 or 1.1-4.62, for use in a method for treating or preventing cognitive impairment and / or gait abnormalities, including ataxia, associated with a lysosomal storage disease in a subject in need thereof, e.g., for use in any of Methods 4 or 4.1-4.62. In the manufacture of a medicament for use in a method of treating or preventing cognitive impairment and / or gait abnormalities, including ataxia, associated with a lysosomal storage disease in a subject in need thereof, such as in the manufacture of a medicament for use in any of Methods 4 or 4.1-4.62, a quinuclidine compound as described herein, e.g., a compound according to Formula I or any of II-XII, Ia-XIIa or Ib-XIIb. or the use of any of compounds 1 or 1.1 to 1.75.

[0095] In certain further embodiments of Method 4, the present disclosure provides: 4.1. Method 4, comprising administering to a subject an effective amount of a compound according to any of Formulas I or II-XII, Ia-XIIa or Ib-XIIb, or any of Compound 1 or any of 1.1 to 1.75; 4.2. Method 4, comprising administering to a subject an effective amount of Compound 1 or any one or more of Compounds 1.1 to 1.75; 4.3. any of Methods 4 or 4.1-4.2 comprising administering to a subject an effective amount of a pharmaceutical composition comprising a compound according to any of Formulas I or II-XII, Ia-XIIa or Ib-XIIb, or any of Compound 1 or any of 1.1-1.75; 4.4. Any of Methods 4 or 4.1-4.2, comprising administering to a subject an effective amount of a pharmaceutical composition comprising Compound 1, or any one or more of Compounds 1.1-1.75; 4.5. Method 4.3 or 4.4, wherein the pharmaceutical composition further comprises at least one pharma- ceutically acceptable excipient as described herein; 4.6. Any of Methods 4 or 4.1-4.5 comprising administering an effective amount of a compound or a pharmaceutical dosage form comprising an effective amount of a pharmaceutical composition; 4.7. Method 4.6, wherein the dosage form is an oral dosage form (e.g., a pill, capsule, caplet, tablet, dragee, powder, granules, film, lozenge, or liquid); 4.8. Method 4.7, wherein the dosage form is a chewable tablet; 4.9. The dosage form is a parenteral dosage form (e.g., the pharmaceutical composition is formulated for injection), method 4.6; 4.10. Method 4.9, where the injection is intravenous, intramuscular, intrathecal or subcutaneous, and optionally is a sterile injection; 4.11. Method 4.6, wherein the dosage form is a topical or rectal dosage form; 4.12. Method 4.6, wherein the dosage form is an intranasal dosage form (e.g., an aerosol);4.13. Any of Methods 4 or 4.1 through 4.12, further comprising simultaneously administering a second active agent, e.g., a second compound described herein that can treat or prevent cognitive impairment and / or gait abnormalities in a patient in need thereof; 4.14. Method 4.13, wherein the second active agent is administered in the same pharmaceutical composition or dosage form as the quinuclidine compound; 4.15. Methods 4.13 or 4.14, wherein the second active agent is a GCS inhibitor (e.g., miglustat or eliglustat); 4.16. Any of methods 4 or 4.1-4.15, wherein the subject is a mammal; 4.17. Method 4.16, in which the subject is a primate; 4.18. Method 4.17, in which the subject is a human; 4.19. The ataxia is cerebellar ataxia, method 4 or any of 4.1 to 4.18; 4.20. Ataxia is characterized by gait unsteadiness, asthenia, insynergia, slowed reaction time, dyschronometria, dysarthria, dysphagia, hypotonia, dysmetria, hypometria, hypometria, hypocalcemia ... Hypermetria, antagonistic repetitive dysfunction, speech slurring, tremor, ataxic breathing, postural instability, and combinations thereof, e.g., the primary ataxic deficit is gait instability, Method 4.19; 4.21. Subjects will complete the Scale for Assessment and Rating of Ataxia at the start of treatment with the method. Baseline ataxia of at least 0.5 on the Standardized Ataxia Assessment (SARA), e.g. having a baseline SARA score of at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at least 10, or at least 20, Method 4.19 or 4.20; 4.22. The cognitive impairment is dementia, method 4 or any of 4.1-4.21;4.23. Dementia is characterized by signs of deficits in visual search speed, scanning processing speed, mental flexibility and / or executive function, e.g., as evidenced by TMT-A >30, or >45, or >60 seconds and / or TMT-B >70, or >90, or >120, or >150, or >180 seconds, and / or TMT-B minus TMT-A >40, or >60, or >90, or >120 seconds, method 4.22; 4.24. The subject has Gaucher disease type 3, any of methods 4 or 4.4-4.23; 4.25. The subject has Niemann-Pick disease type C, any of methods 4 or 4.1-4.24; 4.26. Any of Methods 4 or 4.1-4.24, wherein the subject has GM2-gangliosidosis (e.g., Tay-Sachs disease, Sandhoff disease, or GM2 gangliosidosis AB variant); 4.27. The subject has been diagnosed with a mutation in gene GBA1, according to any of methods 4 or 4.1-4.24; 4.28. Any of methods 4 or 4.1-4.24, wherein the subject has been diagnosed with a mutation in genes NPC1 and / or NPC2; 4.29. Any of methods 4 or 4.1-4.24, wherein the subject has been diagnosed with a mutation in gene HEXA (encoding hexosaminidase A) and / or a mutation in gene HEXB (encoding hexosaminidase B) and / or a mutation in gene GM2A (encoding GM2 ganglioside activator protein); 4.30. The subject has been diagnosed with Parkinson's disease, according to any of methods 4 or 4.1-4.29; 4.31. Any of Methods 4 or 4.1-4.30, wherein the subject is undergoing concomitant treatment with an enzyme replacement therapy (ERT), e.g., with glucocerebrosidase (e.g., imiglucerase, velaglucerase, or taliglucerase), and optionally each such enzyme is a recombinant enzyme; 4.32. Method 4.31, wherein the subject is undergoing concomitant treatment with one or more of imiglucerase, velaglucerase (e.g., velaglucerase alfa), and taliglucerase (e.g., taliglucerase alfa); 4.33. The subject is receiving concurrent treatment with imiglucerase, Method 4.32; 4.34. The subject is receiving concurrent treatment with imiglucerase (one unit of imiglucerase is the amount of enzyme that catalyzes the hydrolysis of 1 micromole of the synthetic substrate p-nitrophenyl-β-D-glucopyranoside per minute at 37° C.) at a dosage of 2.5 units / kg body weight to 80 units / kg body weight every 1 to 3 weeks, e.g., 40 to 60 units / kg body weight every 2 weeks, Method 4.33; 4.35. Method 4.34, wherein the subject's dosage of imiglucerase in each administration (e.g., every 1 to 3 weeks, e.g., every 2 weeks) is administered as an intravenous (IV) infusion over 1-3 hours (e.g., 1-2 hours); 4.36. Any of Methods 4 or 4.1 to 4.35, wherein the subject has been administered an enzyme replacement therapy agent (e.g., imiglucerase, velaglucerase, and / or taliglucerase) prior to initiating treatment with a compound according to Formula I (or any of II-XII, Ia-XIIa, or Ib-XIIb, or any of Compounds 1 or 1.1 to 1.75); 4.37. The subject is a compound of formula I (or II-XII, Ia-XIIa or Ib-XII b, or compounds 1 or any of 1.1 to 1.75), the imiglucerase treatment has been administered for at least 6 months, e.g., at least 12 months (1 year), or at least 18 months, or at least 2 years, or at least 3 years, prior to initiating treatment with the compound. 4.38. Method 4.36 or 4.37, wherein the subject has been administered an imiglucerase therapeutic agent at a stable dose for at least 6 months prior to initiating therapy with a compound according to Formula I (or any of II-XII, Ia-XIIa, or Ib-XIIb, or any of Compounds 1 or 1.1 to 1.75); 4.39. Any of Methods 4 or 4.1-4.38, further comprising the step of transitioning the subject from an ERT therapeutic (e.g., imiglucerase, velaglucerase, or taliglucerase) to treatment with a compound according to Formula I (or any of II-XII, Ia-XIIa, or Ib-XIIb, or any of Compounds 1 or 1.1-1.75); 4.40. Any of Methods 4 or 4.1-4.39, wherein the subject's hemoglobin level is at least 11 g / dL for females and at least 12 g / dL for males; 4.41. Any of Methods 4 or 4.1 through 4.40, wherein the subject's platelet count is at least 100,000 per cubic millimeter; 4.42. The subject has a spleen volume less than 10 times normal (10 MN) and / or a liver volume less than 1.5 MN; 4.43. Any of methods 4 or 4.1-4.42, wherein the subject has been diagnosed with a co-occurring dementia, e.g., Alzheimer's disease or Parkinson's disease; 4.44. Any of Methods 4 or 4.1-4.43, wherein the subject is at least 18 years of age (e.g., 18-30 years of age) at the start of treatment with a compound according to Formula I (or any of II-XII, Ia-XIIa, or Ib-XIIb, or any of Compounds 1 or 1.1-1.75); 4.45. Any of methods 4 or 4.1-4.44, wherein the subject's glucosylceramide (GL1) concentration is between 4.4 and 11.1 ng / mL in cerebrospinal fluid (CSF) and between 4.9 and 8.3 μg / mL in plasma; 4.46. Any of methods 4 or 4.1-4.45, wherein the subject's glucosylsphingosine (lyso-GL1) concentration is 20.1-67.6 pg / mL in CSF and 8.8-159.0 ng / mL in plasma; 4.47. any of Methods 4 or 4.1-4.46, wherein the subject is administered a daily dose of about 1 mg to about 150 mg, e.g., 5 to 50 mg, or 10 to 40 mg, or 10 to 30 mg, or 10 to 20 mg, or 20 to 30 mg, or 30 to 40 mg, or 40 to 50 mg, or 5 to 25 mg, or 20 to 50 mg, or 5 to 15 mg, or 15 to 30 mg, or about 15 mg, or selected from 2, 5, 15, 25, 50, 100, or 150 mg, of a compound according to Formula I (or any of II-XII, Ia-XIIa, or Ib-XIIb, or any of Compounds 1 or 1.1-1.75); 4.48. Any of Methods 4 or 4.1-4.47, wherein the subject is a human adult patient, e.g., between 18 and 80 years of age, e.g., between 18 and 60 years of age, or between 18 and 40 years of age, or between 18 and 30 years of age, or between 18 and 25 years of age; 4.49. Any of Methods 4 or 4.1-4.47, wherein the subject is a human pediatric patient, e.g., between 0 and 18 years of age, e.g., between 1 and 15 years of age, or between 1 and 5 years of age, or between 5 and 10 years of age, or between 10 and 15 years of age, or between 10 and 18 years of age; 4.50. is effective to reduce the SARA ataxia scale by at least 0.5, e.g., to reduce the SARA score by at least 1, or at least 2, or at least 3, or at least 5, or at least 10; or the method reduces the SARA score by between 0.00 and 3.00, or between 0.00 and 2.00, or between 0.00 and 1.50, or between 0.00 and 1.00, or between 0.00 and 0.50 Either method 4 or 4.1 through 4.49 is effective in reducing 4.51. is effective in improving cognitive performance or reducing a cognitive deficit, e.g., as measured by a reduction in the time it takes to complete the Trail Making Test (TMT), TMT-A and / or TMT-B, a reduction in the difference between TMT-A and TMT-B times (TMT-A-TMT-B), e.g., a reduction of at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50% (e.g., a reduction of 5-20% in TMT-A and / or a reduction of 25-30% in TMT-B and / or a reduction of 25-30% in [TMT-A-TMT-B]), in any of Methods 4 or 4.1-4.50; 4.52. Any of Methods 4 or 4.1-4.51, wherein the method results in at least a 30%, e.g., at least a 40%, at least a 50%, at least a 60%, or at least a 70% decrease in glucosylceramide concentration in the CSF and / or in the plasma after 6 months of treatment; 4.53. Any of Methods 4 or 4.1-4.52, wherein the method results in an increase in glucosylsphingosine concentration in the CSF and / or in the plasma of at least 30%, e.g., at least 40%, at least 50%, at least 60%, or at least 70%, after 6 months of treatment; 4.54. Any of Methods 4 or 4.1-4.53, wherein the method results in a statistically or clinically unchanged modified Severity Scoring Tool (mSST) value for neurological disease after 6 months of treatment; 4.55. Any of Methods 4 or 4.1-4.54, wherein a compound according to Formula I (or any of II-XII, Ia-XIIa or Ib-XIIb, or any of Compounds 1 or 1.1-1.75), or a pharma- ceutically acceptable salt or prodrug thereof, is administered by systemic administration, e.g., via a parenteral or non-parenteral route; 4.56. The route of administration is oral (enteral), Method 4.55; 4.57. Method 4.55, in which the route of administration is parenteral, e.g., by injection, e.g., by intravenous injection; 4.58. Any of Methods 4 or 4.1-4.57, wherein a compound according to Formula I (or any of II-XII, Ia-XIIa or Ib-XIIb, or any of Compounds 1 or 1.1-1.75), or a pharma- ceutically acceptable salt or prodrug thereof, is administered by localized administration, e.g., by topical administration; 4.59. Any of Methods 4 or 4.1 through 4.58, wherein the compound is (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate or quinuclidin-3-yl (2-(4'-fluoro-[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate; 4.60. Method 4.59, wherein the dosage of the compound is 15 mg / day, orally; 4.61. Method 4.60, in which the compound dosage is 15 mg / day in a single oral dose; 4.62. Any of Methods 4 or 4.1-4.61, wherein the subject is administered a single daily dose of 5 mg, 10 mg, 15 mg, or 20 mg of a compound, e.g., (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate, optionally in the form of an acid addition salt of the malate.

[0096] In some embodiments of the present disclosure, a subject, i.e., a patient, has been diagnosed with a particular disease or disorder, and has also been diagnosed with a particular genetic mutation, e.g., one known to result in the disease or disorder in question, although it is often not possible to establish that a particular patient's disease or disorder is caused by the particular mutation that the person has been diagnosed with. As used in this manner, the term "diagnosed with a particular genetic mutation" refers to a subject or patient who has been tested, e.g., by DNA or RNA sequencing, protein profiling, or other suitable means, and has been diagnosed with a particular genetic mutation. It is understood that a patient is known to have a particular mutation, meaning that the patient is recognized to have the mutation in question. However, as explained further below, many genetic diseases and disorders may have multiple genetic causes (e.g., mutations), and a patient may have multiple mutations that may each be sufficient to cause the disease or disorder under some circumstances, and it is not intended to establish that a particular mutation causes a particular disease or disorder in a particular patient.

[0097] Methods according to method 4 and onwards may be beneficial for subjects who have been diagnosed with lysosomal storage disease, such as Gaucher type 3 or Niemann-Pick type C, but have not yet experienced the cognitive and / or ataxic symptoms associated with the condition. Methods according to method 4 and onwards may also be beneficial for subjects who are at risk of developing lysosomal storage disease, such as Gaucher type 3 or Niemann-Pick type C, for example, due to a mutation in the subject or in the subject's family known to cause such disease. As a result, in some embodiments of the methods described herein, the subject has been diagnosed as at risk of developing said disease or disorder, and the method prevents or delays the onset and / or development of cognitive and / or ataxic symptoms of the disease or disorder (e.g., supranuclear gaze palsy) in the subject. In some embodiments, the subject has been diagnosed as at risk of developing said disease or disorder because of having a mutation in a gene described herein.

[0098] Pharmaceutical Compositions The disclosure also provides pharmaceutical compositions comprising at least one quinuclidine compound described herein and at least one pharma- ceutically acceptable excipient, e.g., for use in accordance with the methods disclosed herein. Pharmaceutically acceptable excipients can be found, for example, in the literature, such as those described in Remington's Pharmaceutical Sciences, Mack The excipient may be any excipient known in the art, including those described in U.S. Pat. No. 6,399,341, published by The American Pharmaceutical Association in 1985. Pharmaceutical compositions of the compounds disclosed herein may be prepared by conventional means known in the art, such as by mixing at least one compound disclosed herein with a pharma- ceutically acceptable excipient.

[0099] Thus, in one aspect, the disclosure provides a pharmaceutical dosage form comprising a quinuclidine compound described herein and a pharma- ceutically acceptable excipient, the dosage form being formulated to provide a sufficient amount of the compound when administered (e.g., when administered orally) to treat a disease or disorder described herein (e.g., in any of Methods 1 et seq., or Method 4 et seq.).

[0100] The pharmaceutical compositions or dosage forms of the present invention may contain a drug and another carrier, such as an inactive or active compound or composition, such as a detectable agent, a label, an adjuvant, a diluent, a binder, a stabilizer, a buffer, a salt, a lipophilic solvent, a preservative, an adjuvant, etc. Carriers also include pharmaceutical excipients and additives, such as proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides; derivatized sugars, such as alditols, aldonic acids, esterified sugars, and the like; and polysaccharides or sugar polymers), which may be present alone or in combination, including 1 to 99.99% by weight or volume. Exemplary protein excipients include serum albumins, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Exemplary amino acids / antibody components that can also function in a buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, etc. Carbohydrate excipients are also contemplated within the scope of the present invention, examples of which include, but are not limited to, However, there are monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, etc.; disaccharides such as lactose, sucrose, trehalose, cellobiose, etc.; polysaccharides such as raffinose, melezitose, maltodextrin, dextran, starch, etc.; and alditols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol) and myo-inositol.

[0101] Carriers that may be used include buffers or pH adjusters; typically, buffers are salts prepared from organic acids or bases. Representative buffers include organic acid salts, such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers. Additional carriers include polymer excipients / additives, such as polyvinylpyrrolidone, ficoll (polymeric sugar), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin), polyethylene glycol, flavoring agents, antibacterial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates, such as "TWEEN 20" and "TWEEN 80"), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA).

[0102] The present disclosure also provides pharmaceutical compositions and kits that include at least one quinuclidine compound and at least one additional pharmacoactive agent described herein.These pharmaceutical compositions and kits can be adapted to allow simultaneous, sequential and / or separate administration of quinuclidine compound and additional active agent.For example, quinuclidine compound and additional active agent can be formulated in separate dosage forms, for example, separate tablets, capsules, lyophilized agents or liquids, or in the same dosage form, for example, the same tablets, capsules, lyophilized agents or liquids.When quinuclidine compound and additional active agent are formulated in the same dosage form, quinuclidine compound and additional active agent can be substantially present in additive mixture, for example, in the core of a tablet, or in separate regions of the dosage form, for example, in separate layers of the same tablet. In one embodiment, the pharmaceutical dosage form comprises an additional agent described herein that can treat or prevent, e.g., supranuclear gaze palsy in a patient diagnosed with or susceptible to a lysosomal storage disease, e.g., Gaucher type 3 or Niemann-Pick type C, or pain in a patient diagnosed with or susceptible to a lysosomal storage disease, e.g., Fabry disease.

[0103] In a further aspect, the present disclosure provides a pharmaceutical composition comprising: (i) a quinuclidine compound as described herein; (ii) an additional active agent; and (iii) a pharmaceutical acceptable excipient. In one embodiment, the additional active agent is an agent that can treat or prevent supranuclear gaze paresis, gait disturbance or cognitive impairment (e.g., dementia) in patients diagnosed with or susceptible to lysosomal storage disease, such as Gaucher type 3 or Niemann-Pick type C, as described herein.

[0104] The quinuclidine compounds and pharmaceutical compositions disclosed herein may be used in animals or humans. Thus, the compounds disclosed herein may be formulated as pharmaceutical compositions for oral, buccal, parenteral (e.g., intravenous, intramuscular or subcutaneous), topical, rectal or intranasal administration, or in a form suitable for administration by inhalation or insufflation. In certain embodiments, the quinuclidine compounds or pharmaceutical compositions are formulated for systemic administration, e.g., via a route that is not parenteral. In one embodiment, the quinuclidine compounds or pharmaceutical compositions are formulated for oral administration, e.g., in solid form. Such modes of administration and methods for preparing suitable pharmaceutical compositions are described, for example, in Gibaldi's Drug Delivery Systems in Pharmaceutical Care (1st ed., American Society of Health-System Pharmacists 2007).

[0105] The pharmaceutical composition may be formulated to delay, extend or control the release of the active ingredient therein, for example, by using various ratios of hydroxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres to provide the desired release profile. The pharmaceutical composition may also optionally contain opacifying agents, and may optionally be a composition that releases only or preferentially in a certain part of the gastrointestinal tract in a delayed manner, for example, by using an enteric coating. Examples of embedding compositions include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, where appropriate, with one or more pharma- ceutically acceptable carriers, excipients, or diluents known in the art (see, for example, Remington's). The compounds disclosed herein may be formulated for sustained delivery according to methods known to those skilled in the art. Examples of such formulations can be found in U.S. Patent Nos. 3,119,742; 3,492,397; 3,538,214; 4,060,598; and 4,173,626.

[0106] In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules, and the like), the active ingredient may be combined with one or more pharma- ceutically acceptable carriers, excipients, or diluents, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, microcrystalline cellulose, calcium phosphate, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, pregelatinized maize starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose, sucrose, and / or acacia; (3) humectants, such as glucose, glyceryl stearate, glyceryl stearate, and / or glyceryl stearate; (4) humectants, such as glyceryl stearate, glyceryl stearate, and / or glyceryl stearate; (5) humectants, such as glyceryl stearate, glyceryl stearate, and / or glyceryl stearate; (6) humectants, such as glyceryl stearate, glyceryl stearate, and / or glyceryl stearate; (7) humectants, such as glyceryl stearate, glyceryl stearate, and / or glyceryl stearate; glycerol;(4) disintegrants such as agar-agar, calcium carbonate, sodium starch glycolate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) dissolution retarders such as paraffin;(6) absorption enhancers such as quaternary ammonium compounds;(7) wetting agents such as sodium lauryl sulfate, acetyl alcohol, and glycerol monostearate;(8) absorbents such as kaolin and bentonite clay;(9) lubricants such as talc, silica, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) mixed with coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffering agents. Similar types of solid compositions may also be prepared in soft and hard filled gelatin capsules using fillers and excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0107] Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, and / or dispersants. Molded tablets may be prepared by molding a mixture of powdered active ingredient moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as sugar-coated tablets, capsules, pills, and granules, may be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art.

[0108] In an embodiment, the pharmaceutical composition is administered orally in liquid form. The liquid dosage forms of include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid preparations for oral administration may be present as dry products for constitution with water or other suitable vehicles before use. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluents, liquid pharmaceutical compositions may contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, coloring agents, perfumes and preservatives. In addition to the active ingredient, the suspension may contain a suspending agent, such as, but not limited to, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.Suitable liquid preparations may be prepared by conventional means using pharma-ceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose or hydrogenated edible fat); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and / or preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid).The active ingredient may also be administered as a bolus, electuary, or paste.

[0109] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0110] In embodiments, the pharmaceutical compositions are administered by parenteral means, e.g., topical application, transdermal application, injection, etc. In related embodiments, the pharmaceutical compositions are administered parenterally by injection, infusion, or implantation (e.g., intravenous, intramuscular, intraarterial, subcutaneous, etc.).

[0111] The compounds disclosed herein may be formulated for parenteral administration by injection, including using conventional catheter techniques or infusion. The formulations for injection may be in unit dosage form, for example, in ampoules or in multi-dose containers, with the addition of preservatives. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents recognized by those skilled in the art, such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0112] The pharmaceutical composition may be administered directly to the central nervous system. Thus, in certain embodiments, the composition is administered directly to the central nervous system, thereby avoiding the blood-brain barrier. In some embodiments, the composition may be administered via direct spinal injection. In embodiments, the composition is administered by intrathecal injection. In some embodiments, the composition is administered via intraventricular injection. In embodiments, the composition is administered to the lateral ventricle. In embodiments, the composition is administered to both lateral ventricles. In additional embodiments, the composition is administered via intrahippocampal injection. The composition may be administered in one injection or multiple injections. In other embodiments, the composition is administered to more than one location (e.g., two locations in the central nervous system).

[0113] The pharmaceutical compositions may be in the form of a sterile injectable. Sterilization may be achieved by filtration through a filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in water or some other sterile injectable medium immediately before use. To prepare such a composition, the active ingredient is dissolved or suspended in a parenterally acceptable liquid vehicle. Exemplary vehicles and solvents include, but are not limited to, water, water adjusted to a suitable pH by adding an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution and isotonic sodium chloride solution. The pharmaceutical composition may also contain one or more preservatives, such as methyl, ethyl or n-propyl p-hydroxybenzoate. To improve solubility, a solution enhancer or solubilizer may be added, or the solvent may contain 10-60% w / w propylene glycol or similar.

[0114] The pharmaceutical compositions may comprise one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately prior to use. Such pharmaceutical compositions may also contain antioxidants; buffers; bacteriostatic agents; solutes that render the formulation isotonic with the blood of the intended recipient; suspending agents; thickening agents; preservatives; and the like.

[0115] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. In some embodiments, in order to prolong the effect of the active ingredient, it is desirable to delay the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the active ingredient then depends on its rate of dissolution, which may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered active ingredient is accomplished by dissolving or suspending the compound in an oil vehicle. In addition, sustained absorption of an injectable pharmaceutical form may be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0116] The controlled release parenteral composition may be in the form of an aqueous suspension, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, emulsions, or the active ingredient may be incorporated into a biocompatible carrier, liposomes, nanoparticles, implants, or infusion devices. Materials for use in the preparation of microspheres and / or microcapsules include, but are not limited to, biodegradable / bioerodible polymers, such as polyglactin, poly-(isobutylcyanoacrylate), poly(2-hydroxyethyl-L-glutamine) and poly(lactic acid). Biocompatible carriers that may be used when formulating controlled release parenteral formulations include carbohydrates, such as dextran, proteins, such as albumin, lipoproteins, or antibodies. Materials for use in implants may be non-biodegradable, such as polydimethylsiloxane, or biodegradable, such as poly(caprolactone), poly(lactic acid), poly(glycolic acid), or poly(orthoesters).

[0117] For topical administration, the compounds disclosed herein may be formulated into ointments or creams.The compounds disclosed herein may also be formulated into rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

[0118] For intranasal administration or administration by inhalation, the compounds disclosed herein can be conveniently delivered in the form of a solution or suspension from a pump spray container that is pushed or pumped by the patient, or as an aerosol spray presented from a pressurized container or nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer can contain a solution or suspension of the compounds disclosed herein. Inhalers or insufflators for use in capsules and cartridges (e.g., made from gelatin) can be formulated to contain a powder mix of the compounds disclosed herein and a suitable powder base, such as lactose or starch.

[0119] Generally, the reagent and composition described herein is administered in an effective amount or amount sufficient to treat or prevent supranuclear gaze palsy in the subject in need thereof.Typically, dosage can be adjusted within this range based on, for example, age, physical condition, weight, sex, diet, administration time and other clinical factors.The determination of effective amount is well within the ability of those skilled in the art.

[0120] Having been generally described herein, the following non-limiting examples are provided to further illustrate the invention. EXAMPLES

[0121] General Procedure for Chemical Synthesis General Procedure A: Carbamate Formation with Triphosgene To a suspension of amine hydrochloride (1 equiv.) and triethylamine (3-4 equiv.) in THF (concentration about 0.2 M) at room temperature was added triphosgene (0.35 equiv.). The reaction mixture was stirred for 10 min and a small amount of ether (1-2 mL) was added. The triethylammonium salt was filtered off to give a clear solution of the isocyanate in THF / ether.

[0122] To a solution of the alcohol (1.5 eq.) in THF (concentration about 0.2 M) at room temperature was added NaH [60%, oil] (1.5 eq.). The reaction mixture was stirred for 15 min and the above solution (isocyanate in THF / ether) was added dropwise. For standard workup, the reaction was quenched with brine. The solution was extracted with EtOAc and the organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by Combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to give the corresponding carbamate.

[0123] General Procedure B: Alkylation with Organocerium A suspension of CeCl3 (4 eq.) in THF (concentration about 0.2 M) was stirred at room temperature for 1 h. The suspension was cooled to -78°C and MeLi / ether [1.6 M] (4 eq.) was added dropwise. The organocerium complex was allowed to form for 1 h and a solution of the nitrile (1 eq.) in THF (concentration 2.0 M) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 18 h. The solution was cooled to 0°C and quenched with water (about 1 mL), followed by the addition of 50% aqueous ammonium hydroxide (about 3 mL) until a precipitate formed and sank to the bottom of the flask. The mixture was filtered through a Celite pad and concentrated. The crude material was treated with HCl / dioxane [4.0 M] solution. The intermediate arylpropan-2-amine hydrochloride was triturated in ether and used directly in the next step. Alternatively, the crude free-based amines were purified by Combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to give the corresponding arylpropylamines.

[0124] General Procedure C: Suzuki Coupling To a solution of aryl halide (1 equiv.) in a mixture of DME / water [4:1] (concentration ca. 0.2 M) was added boronic acid (2 equiv.), palladium catalyst (0.1-0.25 equiv.) and sodium carbonate (2 equiv.). The reaction mixture was microwaved at 150 °C for 25 min. After filtration through a plug of Celite and concentration, the crude product was purified by Combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to give the corresponding coupling adduct.

[0125] Alternative method: To a solution of aryl halide (1 equiv.) in a mixture of toluene / water [20:1] (concentration about 0.2 M) was added boronic acid (1.3-2.5 equiv.), palladium catalyst (0.05-0.15 equiv.), tricyclohexylphosphine (0.15-0.45 equiv.) and potassium phosphate (5 equiv.). The reaction mixture was microwaved at 150 °C for 25 min. After filtration through a plug of Celite and concentration, the crude product was purified by Combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to give the corresponding coupling adduct.

[0126] General Procedure D: Cyclopropanation To a mixture of aryl nitrile (1 equiv.) and Ti(Oi-Pr)4 (1.7 equiv.) stirred at -70°C, EtMgBr [3.0 M in ether] (1.1 equiv.) was added dropwise. The reaction mixture was warmed to 25°C and stirred for 1 h. To the above mixture, BF3·Et2O (3 equiv.) was added dropwise at 25°C. After the addition, the mixture was stirred for another 2 h and then quenched with aqueous HCI [2 M]. The resulting solution was then basified by adding aqueous NaOH [2 M]. The organic material was extracted with ethyl ether. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography (eluted with petroleum ether / EtOAc: 10 / 1 to 1 / 1) to give the corresponding 1-aryl-cyclopropanamine.

[0127] General Procedure E: Biaryl Coupling Using Suzuki Conditions To a stirred solution of aryl halide component (1 equiv.) in 5:1 (v / v) dioxane / water (~0.15 M) or 5:1 (v / v) N,N-dimethylformamide (~0.15 M) was added aryl boronate or aryl boronic acid component (1-1.5 equiv.), sodium carbonate (2-3 equiv.) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv.). The mixture was heated (90 °C) overnight and then filtered through a Celite plug. The Celite was rinsed with ethyl acetate and the combined filtrate was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica flash chromatography.

[0128] General Procedure F: Carbamate formation using isocyanates generated via the mixed anhydride / Curtius rearrangement route To a stirred solution of the carboxylic acid component (1 eq) in tetrahydrofuran (ca. 0.1 M) was added triethylamine (2 eq). The reaction was cooled (0° C.) and treated with isobutyl chloroformate (1.5 eq). After 1 h at 0° C., a solution of sodium azide (2 eq) in water (ca. 1 M) was added and the reaction was allowed to warm to room temperature. After stirring overnight, the reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with aqueous sodium bicarbonate and brine, dried (Na2SO4), and concentrated. The crude acyl azide was further dried via coevaporation with toluene and then taken up in toluene (ca. 0.1 M). The stirred solution was refluxed for 2-2.5 h, cooled, and treated with the alcohol component (1.25-2 eq). The reaction was heated to reflux overnight and then concentrated. The residue was taken up in either ethyl acetate or chloroform, washed with aqueous sodium carbonate, dried (Na2SO4), and concentrated. The crude product was dissolved in chloroform / methanol (less polar carbamates) or chloroform / methanol / ammonia. The product was purified by flash chromatography on silica using a more polar carbamate solvent gradient. EXAMPLES

[0129] Synthesis of quinuclidine compounds 1-Azabicyclo[2.2.2]oct-3-yl[2-(4'-fluorobiphenyl-3-yl)propan-2-yl]carbamate (Compound 1) Using general procedure C, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromophenyl)propan-2-yl]carbamate (600 mg, 1.63 mmol), 4-fluorophenylboronic acid (457 mg, 3.27 mmol) and palladium(II) acetate afforded the title compound as a white solid (373 mg; 60%). 1 H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.52 (dd, J = 5.4, 8.4 Hz, 2H), 7.42-7.38 (m, 3H), 7.12 (m, 2H), 5.18 (5, 1H), 4.62 (s, 1H), 2.66 (m, 6H), 1.72 (s, 6H), 2.01-0.83 (m, 5H) ppm. 13 C NMR (100 MHz, CDCl3) δ 125.0, 124.0, 123.8, 116.0, 116.0, 71.3, 55.9, 55.5, 47.6, 46.7, 29.6, 25.6, 24.8, 19.8 ppm. Purity: 98.0% UPLCMS (210 nm); retention time 0.95 min; (M+1) 382.9. Anal. Calcd. for C 23 H 27 FN2O2·0.37(CHCl3): C, 65.86; H, 6.47; N, 6.57. Found: C, 65.85; H, 6.69; N, 6.49.

[0130] (S)-Quinuclidin-3-yl 2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-ylcarbamate (Compound 2) To a stirred solution of 4-fluorothiobenzamide (8.94 g, 57.6 mmol) in ethanol (70 mL) was added ethyl 4-chloroacetate (7.8 mL, 58 mmol). The reaction was heated to reflux for 4 h, treated with an aliquot of ethyl 4-chloroacetoacetate (1.0 mL, 7.4 mmol) and refluxed for an additional 3.5 h. The reaction was then concentrated and the residue partitioned between ethyl acetate (200 mL) and aqueous NaHCO3 (200 mL). The organic layer was combined with a back-extraction of the aqueous layer (ethyl acetate, 1 x 75 mL), dried (Na2SO4), and concentrated. The resulting amber oil was purified by flash chromatography using a hexane / ethyl acetate gradient to give ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)acetate as a low melting, nearly colorless solid (13.58 g, 89%).

[0131] To a stirred solution of ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)acetate (6.28 g, 23.7 mmol) in DMF (50 mL) was added sodium hydride [60% dispersion in mineral oil] (2.84 g, 71.0 mmol). The foamy mixture was stirred for 15 min, then cooled in an ice bath and iodomethane (4.4 mL, 71 mmol) was added. The reaction was stirred overnight, allowing the cooling bath to slowly warm to room temperature. The mixture was then concentrated and the residue partitioned between ethyl acetate (80 mL) and water (200 mL). The organic layer was washed with a second portion of water (1×200 mL), dried (Na2SO4) and concentrated. The resulting amber oil was purified by flash chromatography using a hexanes / ethyl acetate gradient to give ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoate as a colorless oil (4.57 g, 66%).

[0132] To a stirred solution of ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoate (4.56 g, 15.5 mmol) in 1:1:1 THF / ethanol / water (45 mL) was added lithium hydroxide monohydrate (2.93 g, 69.8 mmol). The reaction was stirred overnight, concentrated, and redissolved in water (175 mL). The solution was washed with ether (1×100 mL), acidified by the addition of 1.0 N HCl (80 mL), and extracted with ethyl acetate (2×70 mL). The combined extracts were dried (Na2SO4) and concentrated to give 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoic acid as a white solid (4.04 g, 98%). This material was purified. It was used in the next step without purification.

[0133] To a stirred, cooled (0° C.) solution of 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoic acid (4.02 g, 15.2 mmol) in THF (100 mL) was added trimethylamine (4.2 mL, 30 mmol), followed by isobutyl chloroformate (3.0 mL, 23 mmol). The reaction was stirred cold for an additional hour before a solution of sodium azide (1.98 g, 30.5 mmol) in water (20 mL) was added. The reaction was stirred overnight, allowing the cooling bath to slowly warm to room temperature. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (2×60 mL). The combined extracts were washed with aqueous NaHCO3 (1×150 mL) and brine (1×100 mL), dried (Na2SO4), and concentrated. After coevaporation with toluene (2 x 50 mL), the resulting white solid was taken up in toluene (100 mL) and refluxed for 4 h. (S)-3-quinuclidinol (3.87 g, 30.4 mmol) was then added and reflux continued overnight. The reaction was concentrated and the residue was partitioned between ethyl acetate (100 mL) and aqueous NaHCO3 (150 mL). The organic layer was washed with water (1 x 150 mL), dried (Na2SO4) and concentrated. The resulting off-white solid was purified by flash chromatography using a chloroform / methanol / ammonia gradient to give the title compound as a white solid (4.34 g, 73%).1 H NMR (400 MHz, CDCl3) δ 7.96-7.88 (m, 2H), 7.16-7.04 (m, 3H), 5.55 (br s, 1H), 4.69-4.62 (m, 1H), 3.24-3.11 (m, 1H), 3.00-2.50 (m, 5H), 2.01-1.26 (m, 11H) ppm. 13 C NMR (400 MHz, CDCl3) δ 166.4, 165.1, 163.8 (d, J=250.3 Hz), 162.9, 155.0, 130.1 (d, J=3.3 Hz), 128.4 (d, J= 8.5 Hz), 115.9 (d, J= 22.3 (Hz), 112.5, 71.2, 55.7, 54.2, 47.5, 46.5, 28.0, 25.5, 24.7, 19.6 ppm. Purity: 100 % UPLCMS (210 nm & 254 nm); retention time 0.83 min; (M+1) 390.

[0134] (S)-Quinuclidin-3-yl (2-(4'-(2-methoxyethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate (Compound 3) Using general procedure E, the reaction used ethyl 2-(4-bromophenyl)-2-methylpropanoate and 4-(2-methoxyethoxy)phenylboronic acid (input), and ethyl 2-(4'-(2-Methoxyethoxy)-[1,1'-biphenyl]-4-yl)-2-methylpropanoate was prepared as an off-white solid. To a stirred solution of this compound (3.01 g, 8.78 mmol) in 1:1:1 (v / v / v) tetrahydrofuran / ethanol / water (45 mL) was added lithium hydroxide monohydrate (1.47 g, 61.4 mmol). The mixture was heated to reflux overnight and then concentrated. The residue was dissolved in water, treated with 1N hydrochloric acid (65 mL), and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to give 2-(4'-(2-methoxyethoxy)-[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid as a white solid (2.75 g, 100%). This intermediate and (S)-quinuclidin-3-ol were reacted according to general procedure F to yield the title compound as a colorless glassy solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.62-7.29 (m, 7H), 7.01 (d, J = 8.9 Hz, 2H), 4.47-4.37 (m, 1H), 4.17-4.08 (m, 2H), 3.72-3.62 (m, 2H), 3.32 (s, 3H), 3.09-2.25 (m, 6H), 2.05-1.18 (m, 11H) ppm. 13 C NMR (100 MHz, DMSO-d6) δ 157.9, 154.5, 146.7, 137.4, 132.5, 127.5, 125.7, 125.2, 114.8, 70.4, 70.0, 66.9, 58.2, 55.4, 54.2, 46.9, 45.9, 29.4, 25.3, 24.2, 19.2 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; retention time: 0.87 min; (M+H + ) 439.5.

[0135] 1-Azabicyclo[2.2.2]oct-3-yl[2-(biphenyl-3-yl)propan-2-yl]carbamate (compound 4) Using general procedure C, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromophenyl)propan-2-yl]carbamate (600 mg, 1.63 mmol), phenylboronic acid (398 mg, 3.27 mmol) and palladium(II) acetate were prepared. This gave the title compound as a white solid (379 mg, 64%). 1 H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.56 (d, J= 7.4 Hz, 2H), 7.50-7.38 (m, 4H), 7.34 (m, 2H), 5.16 (s, 1H), 4.63 (s, 1H), 3.39-2.09 (m, 6H), 1.72 (s, 6H), 2.02-0.73 (m, 5H) ppm. 13 C NMR (100 MHz, CDCl3) δ 154.8, 147.8, 141.6, 129.0, 129.0, 128.6, 127.5, 125.8, 125.0, 124.0, 71.6, 71.3, 55.9, 55.5, 47.6, 46.8, 31.5, 30.2, 30.0, 29.5, 25.6, 24.8, 19.8 ppm. Purity: 99% UPLCMS (210 nm); retention time 0.84 min; (M+1) 365.0. Anal. Calcd. for C 23 H 28 N2O2·0.29(CHCl3): C, 70.02; H, 7.14; N, 7.01. Found: C, 70.02; H, 7.37; N, 6.84.

[0136] (S)-Quinuclidin-3-yl 2-(biphenyl-4-yl)propan-2-ylcarbamate (Compound 5) Using general procedure B, bromobenzonitrile (2.00 g, 11.0 mmol) was converted to the corresponding 2-(4-bromophenyl)propan-2-amine (1.20 g, 51%) as a brown oil.

[0137] Using general procedure A, 2-(4-bromophenyl)propan-2-amine (1.0 g, 4.7 mmol) and (S)-quinuclidin-3-ol gave (S)-quinuclidin-3-yl 2-(4-bromophenyl)propan-2-ylcarbamate (1.0 g, 58%) as a brown oil.

[0138] Using general procedure C, the above bromide (200 mg, 0.540 mmol), phenylboronic acid (133 mg, 1.10 mmol) and [PdCl2(pddf)]CH2Cl2 afforded the title compound as a white solid (70 mg, 35%). 1 H NMR (500 MHz, CDCl3) δ 7.60-7.53 (m, 4H), 7.47 (d, J = 8.5 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 1H), 5.26 (br s, 1H), 4.64 (m, 1H), 3.33-3.15 (m, 1H), 3.10-2.45 (m, 5H), 2.40-1.80 (m, 2H), 1.78-1.58 (m, 7H), 1.55-1.33 (m, 2H) ppm. 13 C NMR (125 MHz, CDCl3) δ154.5, 146.1, 140.8, 139.5, 128.7, 127.2, 127.1, 127.1, 125.2, 70.9, 55.5, 55.1, 47.4, 46.4, 31.1, 29.5, 25.3, 24.5, 19.5 ppm. Purity: 100 % LCMS (214 nm & 254 nm); retention time 1.56 min; (M+1) 365.

[0139] Quinuclidin-3-yl 1-(biphenyl-4-yl)cyclopropylcarbamate (Compound 6) Using general procedure D, bromobenzonitrile (3.00 g, 16.5 mmol) was converted to the corresponding 1-(4-bromophenyl)cyclopropanamine (1.80 g, 51%) as a yellow solid.

[0140] Using general procedure A, 1-(4-bromophenyl)cyclopropanamine (1.0 g, 4.7 mmol) and quinuclidin-3-ol gave quinuclidin-3-yl 1-(4-bromophenyl)cyclopropyl-carbamate (1.3 g, 75%) as a white semi-solid.

[0141] Using general procedure C, the above carbamate (400 mg, 1.12 mmol), phenylboronic acid (267 mg, 2.22 mmol) and [PdCl2(pddf)]CH2Cl2 afforded the title compound as a viscous oil (100 mg, 25%). 1 H NMR (500 MHz, CDCl3) δ 7.47 (d, J= 7.5 Hz, 2H), 7.43 (d, J= 8.0 Hz, 2H), 7.33 (t, J= 7.5 Hz, 2H), 7.26-7.15 (m, 3H), 5.93 (br s, 0.6H), 5.89 (br s, 0.4H), 4.67 (m, 1H), 3.20-3.06 (m, 1H), 2.88-2.42 (m, 5H), 1.98-1.08 (m, 9H) ppm. 13 C NMR (125 MHz, CDCl3) δ 155.0, 141.0, 139.7, 138.2, 127.7, 126.1, 126.0, 124.8, 124.1, 70.0, 54.5, 46.3, 45.4, 34.1, 24.3, 23.2, 18.3, 17.0 ppm. Purity: 100 % LCMC (214 nm & 254 nm); retention time 1.52 min; (M+1) 363.

[0142] (S)-Quinuclidin-3-yl 1-(4'-fluorobiphenyl-4-yl)cyclopropylcarbamate (Compound 7) Using general procedure C, (S)-quinuclidin-3-yl 1-(4-bromophenyl)cyclopropylcarbamate, 4-F-phenylboronic acid and [PdCl2(pddf)]CH2Cl2 afforded the title compound as a white solid (45%). 1 H NMR (500 MHz, DMSO-d6) δ 8.06-7.83 (d, 1H), 7.69-7.66 (m, 2H), 7.59-7.55 (m, 2H), 7.29-7.22 (m, 4H), 4.56-4.54 (m, 1H), 3.13-2.32 (m, 6H), 1.91-1.19 (m, 9H) ppm. 13 C NMR (125 MHz, DMSO-d6) δ 163.2, 161.2, 156.4, 143.7, 136.9, 128.9, 128.8, 126.8, 125.6, 116.2, 116.0, 70.7, 55.8, 47.4, 46.4, 34.8, 25.7, 24.6, 19.6, 18.7, 18.6 ppm. Purity: > 97 % LCMS (214 nm & 254 nm); retention time 1.96 min; (M+1) 381.2.

[0143] (S)-1-Azabicyclo[2.2.2]oct-3-yl[1-(2',4'-difluorobiphenyl-4-yl)cyclopropyl]carbamate (Compound 8) Using general procedure C, (S)-quinuclidin-3-yl 1-(4-bromophenyl)cyclopropylcarbamate (0.446 g, 1.22 mmol), 2,4-difluorophenylboronic acid (0.386 g, 2.44 mmol) and Pd(OAc)2 (0.015 g, 0.067 mmol) gave the title compound as a tan solid (0.111 g, 23%). 1H NMR (CDCl3) δ 7.43 (dd, J = 8.4, 1.6 Hz, 2H), 7.40-7.33 (m, 1H), 7.31 (d, J = 7.7 Hz, 2H), 6.99-6.81 (m, 2H), 5.54 (d, J = 48.0 Hz, 1H), 4.82-4.65 (m, 1H), 3.30-3.07 (m, 1H), 2.98-2.44 (m, 5H), 1.97 (d, J = 32.7 Hz, 1H), 1.83 (d, J = 10.3 Hz, 1H), 1.64 (s, 1H), 1.52 (s, 1H), 1.39 (s, 1H), 1.31 (d, J = 6.8 Hz, 4H) ppm. 13 C NMR major rotomer (CDCl3) δ 162.2 (dd, J = 12.8, 249.1 Hz), 159.8 (dd, J = 11.8, 251.0 Hz), 156.9, 156.0, 142.6, 133.1, 131.3 (m), 128.9, 125.6, 124.9, 111.5 (dd, J = 3.9, 21.2 Hz) 104.4 (dd, J = 25.2, 29.4 Hz), 72.1, 71.6, 55.7, 47.4, 46.5, 35.7, 35.3, 25.5, 24.6, 24.4, 19.5, 18.1 ppm. Purity: LCMS > 99.3 % (214 nm & 254 nm); retention time 0.90 min; (M+1) 399.0.

[0144] 1-Azabicyclo[2.2.2]oct-3-yl[1-(4'-methoxybiphenyl-4-yl)cyclopropyl]carbamate (Compound 9) Using general procedure C, quinuclidin-3-yl 1-(4-bromophenyl)cyclopropylcarbamate (0.485 g, 1.33 mmol), 4-methoxyphenylboronic acid (0.404 g, 2.66 mmol) and Pd(OAc)2 (0.016 g, 0.071 mmol) gave the title compound as a grey solid (0.337 mg, 65%). 1 H NMR (CDCl3) δ 7.48 (dd, J = 8.6, 5.5 Hz, 4H), 7.29 (d, J = 7.6 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 5.58 (d, J = 48.7 Hz, 1H), 4.83-4.63 (m, 1H), 3.84 (s, 3H), 3.20 (dd, J = 24.0, 15.5 Hz, 1H), 2.97-2.42 (m, 5H), 1.97 (d, J = 30.9 Hz, 1H), 1.81 (s, 1H), 1.75-1.33 (m, 3H), 1.28 (d, J = 6.8 Hz, 4H) ppm. 13 C NMR major rotomer (CDCl3) δ 159.1, 156.0, 141.4, 139.0, 133.4, 128.0, 126.7, 125.9, 114.2, 71.5, 55.7, 55.3, 47.4, 46.5, 35.3, 25.5, 24.6, 19.6, 17.8 ppm. Purity: LCMS >97.1 % (214 nm & 254 nm); retention time 0.88 min; (M+1) 393.4.

[0145] Quinuclidin-3-yl 2-(5-(4-fluorophenyl)thiophen-3-yl)propan-2-ylcarbamate (Compound 10) To a stirred, cooled (0° C.) solution of ethyl 5-bromothiophene-3-carboxylate (13.30 g, 56.57 mmol) in THF (100 mL) was added a solution of methylmagnesium bromide in diethyl ether [3.0 M] (55.0 mL, 165 mmol) dropwise over 20 min. After 2 h, the reaction solution was concentrated. The residue was taken up in aqueous NH4Cl (200 mL) and extracted with ethyl acetate (2×100 mL). The combined extracts were dried and cooled. (Na2SO4) and concentrated. The resulting amber oil was purified by flash chromatography using a hexanes / ethyl acetate gradient to give 2-(5-bromothiophen-3-yl)propan-2-ol as a light amber oil (8.05 g, 64%).

[0146] To a stirred solution of 2-(5-bromothiophen-3-yl)propan-2-ol (8.03 g, 36.3 mmol) in methylene chloride (80 mL) was added sodium azide (7.08 g, 109 mmol) followed by trifluoroacetic acid (8.0 mL; dropwise over 5-6 min). The thick suspension was stirred for 1.5 h, then diluted with water (350 mL) and extracted with ethyl acetate (1×200 mL). The organic layer was washed with aqueous NaHCO3 (1×250 mL), dried (Na2SO4), and concentrated to give the crude azide product. To a stirred solution of this material in THF (160 mL) was added water (11 mL) followed by triphenylphosphine (23.8 g, 90.7 mmol). The reaction was stirred for 2 days and then concentrated. The resulting residue was dissolved in ethyl acetate (250 mL) and extracted with 1 N aqueous HCl (4×75 mL). The combined extracts were basified with concentrated NH4OH and extracted with ethyl acetate (2 x 100 mL). These extracts were dried (Na2SO4) and concentrated. The resulting amber oil was purified by flash chromatography using a methylene chloride / methanol / ammonia gradient to give a mixture of 2-(5-bromothiophen-3-yl)propan-2-amine and triphenylphosphine oxide (approximately 70 / 30 ratio) as a viscous amber oil (1.32 g, 17%).

[0147] To a stirred solution of 3-quinuclidinol (3.00 g, 23.6 mmol) in THF (100 mL) was added 4-nitrophenyl chloroformate (5.94 g, 29.5). After stirring for 4 h, the precipitate was filtered off, rinsed with THF, and air-dried on a frit under house vacuum. The filtrate was dissolved in ethyl acetate (150 mL) and washed with aqueous NaHCO3 (1 x 150 mL), water (2 x 150 mL). The organic layer was dried (Na2SO4) and concentrated to give the crude 4-nitrophenyl quinuclidin-3-yl carbonate product, which was used in the next step without purification.

[0148] To a stirred solution of 2-(5-bromothiophen-3-yl)propan-2-amine (0.366 g, 1.66 mmol) in THF (10 mL) was added 4-nitrophenylquinuclidin-3-yl carbonate (0.571 g, 1.95 mmol) and a small amount of granular 4-(dimethylamino)pyridine. The mixture was refluxed overnight, concentrated, and partitioned between ethyl acetate (50 mL) and aqueous NaHCO3 (50 mL). The organic layer was washed again with aqueous NaHCO3 (1 x 50 mL), dried (Na2SO4), and concentrated. The resulting dull yellow gum was purified by flash chromatography using a chloroform / methanol / ammonia gradient to give quinuclidin-3-yl (1-(5-bromothiophen-3-yl)cyclopropyl)carbamate as an off-white solid (0.305 g, 49%).

[0149] Using general procedure C, quinuclidin-3-yl (1-(5-bromothiophen-3-yl)cyclopropyl)carbamate (0.227 g, 0.742 mmol), 4-fluorophenylboronic acid (0.208 g, 1.49 mmol), tricyclohexylphosphine (0.021 g, 0.075 mmol), potassium phosphate (0.866, 4.08 mmol) and palladium acetate (8.0 mg, 36 μmol) afforded the title compound as a grey solid (0.142 g, 49%). 1H NMR (400 MHz, CDCl3) δ 7.60-7.45 (m, 2H), 7.24-7.19 (m, 1H), 7.10-6.97 (m, 3H), 5.23 (br s, 1H), 4.72-4.61 (m, 1H), 3.30-3.04 (m, 1H), 3.03-2.25 (m, 5H), 2.09-1.02 (m, 11H) ppm. 13 C NMR (400 MHz, CDCl3) δ 162.3 (d, J = 247.1 Hz), 154.5, 149.8, 143.6, 130.7, 127.4 (d, J = 8.1 Hz), 121.8, 118.9, 115.8 (d, J = 21.6 Purity: 95.8 % UPLCMS (210 nm & 254 nm); retention time 0.90 min; (M+1) 389.

[0150] (S)-Quinuclidin-3-yl 2-(3-(4-fluorophenyl)isothiazol-5-yl)propan-2-ylcarbamate (Compound 11) To a stirred solution of 2-(3-(4-fluorophenyl)isothiazol-5-yl)propan-2-amine (1.21 g, 5.12 mmol) in toluene was added a solution of phosgene in toluene [ca. 1.9 M] (10.8 mL, 20.5 mmol). The reaction was heated to reflux for 2 h and then concentrated. The residue was co-evaporated with toluene (2×15 mL) to give the crude isocyanate intermediate as a golden oil. This material was taken up in toluene (10 mL) and treated with (S)-3-quinuclidinol (0.749 g, 5.89 mmol). The reaction was heated to reflux overnight and concentrated. The residue was purified by flash chromatography using a chloroform / methanol / ammonia gradient to give the title compound as a white solid (0.971 g, 49%). 1 H NMR (400 MHz, DMSO-d6) δ 8.09-8.00 (m, 2H), 7.87 (br s, 1H), 7.75 (s, 1H), 7.35-7.25 (m, 2H), 4.54-4.45 (m, 1H), 3.14-2.92 (m, 1H), 2.87-2.17 (m, 5H), 1.98-0.98 (m, 11H) ppm. 13 C NMR (400 MHz, DMSO-d6) δ 180.1, 165.6, 162.6 (d, J = 246.4 Hz), 154.7, 131.2 (d, J = 3.0 Hz), 128.7 (d, J = 8.4 Hz), 118.2, 115.7 (d, J = (M+1) 390.

[0151] (S)-Quinuclidin-3-yl 2-(4-(4-fluorophenyl)thiazol-2-yl)propan-2-ylcarbamate (Compound 12) To a stirred solution of ethyl 3-amino-3-thioxopropanoate (20.00 g, 135.9 mmol) in ethanol (120 mL) was added 2-bromo-4'-fluoroacetophenone (29.49 g, 135.9 mmol). The mixture was refluxed for 1 h, concentrated, and partitioned between ethyl acetate (300 mL) and aqueous NaHCO3 (400 mL). The organic layer was combined with a back-extraction of the aqueous layer (ethyl acetate, 1 x 100 mL), dried (Na2SO4), and concentrated. The resulting light brown solid was purified by flash chromatography using a hexane / ethyl acetate gradient to give ethyl 2-(4-(4-fluorophenyl)thiazol-2-yl)acetate as an off-white solid (29.92 g, 83%).

[0152] A stirred, cooled (-78°C) solution of ethyl 2-(4-(4-fluorophenyl)thiazol-2-yl)acetate (10.00 g, 37.69 mmol) in THF (250 mL) was added dropwise over 15 min to a solution of potassium t-butoxide in THF [1.0 M] (136 mL, 136 mmol) followed by 18-crown-6 (1.6 mL, 7.5 mmol). After a further 30 min at -78°C, iodomethane (8.5 mL) was added dropwise over 5 min. The reaction was stirred cold for a further 2 h before being poured into water (450 mL) and extracted with ethyl acetate (2 x 150 mL). The combined extracts were washed with brine (1 x 200 mL), dried (Na2SO4) and concentrated. The resulting brown oil was purified by flash chromatography using a hexane / ethyl acetate gradient to give ethyl 2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropanoate as a light amber oil (8.64 g, 78%).

[0153] To a stirred solution of ethyl 2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropanoate (0.900 g, 3.07 mmol) in 1:1:1 THF / ethanol / water (15 mL) was added lithium hydroxide monohydrate (0.451 g, 10.7 mmol). After stirring overnight, the reaction was concentrated and redissolved in water (80 mL). The solution was washed with ether (1×50 mL), acidified by the addition of 1N HCl (15 mL), and extracted with ethyl acetate (2×50 mL). The combined extracts were dried (Na2SO4), concentrated, and concentrated. Condensation gave 2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropanoic acid as a pale gold solid (0.808 g, 99%).

[0154] To a stirred, cooled (0° C.) solution of 2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropanoic acid (0.784 g, 2.96 mmol) in THF (25 mL) was added triethylamine (0.82 mL, 5.9 mmol), followed by isobutyl chloroformate (0.58 mL, 4.4 mmol). The reaction was stirred cold for an additional hour before a solution of sodium azide (0.385 g, 5.92 mmol) in water (7 mL) was added. The reaction was stirred overnight, allowing the cooling bath to slowly warm to room temperature. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (2×60 mL). The combined extracts were washed with aqueous NaHCO3 (1×150 mL) and brine (1×100 mL), dried (Na2SO4), and concentrated. After coevaporation with toluene (2×30 mL), the resulting off-white solid was taken up in toluene (25 mL) and refluxed for 4 h. (S)-3-quinuclidinol (0.753 g, 5.92 mmol) was then added and reflux continued for 3 h. The reaction was concentrated and the residue was purified by flash chromatography using a chloroform / methanol / ammonia gradient to give the title compound as a white solid (0.793 g, 69%). 1 H NMR (400 MHz, CDCl3) δ 7.90-7.81 (m, 2H), 7.32 (s, 1H), 7.14-7.05 (m, 2H), 5.76 (br s, 1H), 4.72-4.65 (m, 1H), 3.26-3.10 (m, 1H), 3.03-2.37 (m, 5H), 2.05-1.23 (m, 11H) ppm. 13C NMR (400 MHz, CDCl3) δ 177.6, 162.6 (d, J = 248.4 Hz), 154.8, 153.6, 130.8 (d, J = 3.2 Hz), 128.1 (d, J = 8.1 Hz), 115.9 (d, J = 21.7 Hz), 112.2, 71.6, 55.7, 47.4, 46.5, 29.1, 25.4, 24.7, 19.6 ppm. Purity: 100 % UPLCMS (210 nm & 254 nm); retention time 0.82 min; (M+1) 390.

[0155] Quinuclidin-3-yl (2-(4'-(2-methoxyethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate (Compound 13) Using general procedure F, the reaction employed 2-(4'-(2-methoxyethoxy)-[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 3) and quinuclidin-3-ol to produce the title compound as a colorless glassy solid (23%). NMR data was consistent with that of Example 3. Purity: 100%, 99.1% (210 and 254 nm) UPLCMS; Retention time: 0.87 min; (M+H + )439.0.

[0156] (S)-Quinuclidin-3-yl (2-(3'-(2-methoxyethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate (Compound 14) 2-(3'-(2-methoxyethoxy)-[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid was prepared by exchanging 4-(2-methoxyethoxy)phenylboronic acid for 3-(2-methoxyethoxy)phenylboronic acid and using the reaction sequence outlined in Example 3. This intermediate and quinuclidin-3-ol were reacted according to general procedure F to yield the title compound as a glassy colorless solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.63-7.31 (m, 6H), 7.24-7.10 (m, 2H), 6.92 (dd, J = 8.2, 1.9 Hz, 1H), 4.51-4.34 (m, 1H), 4.21-4.08 (m, 2H), 3.72-3.64 (m, 2H), 3.32 (s, 3H), 3.09-2.26 (m, 5H), 2.04-1.22 (m, 9H) ppm. 13 C NMR (100 MHz, DMSO-d6) δ 158.9, 154.6, 147.6, 141.5, 137.6, 129.9, 126.3, 125.2, 118.9, 113.2, 112.5, 70.4, 70.0, 66.9, 58.2, 55.4, 54.2, 46.9, 45.9, 29.4, 25.3, 24.2, 19.2 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; retention time: 0.91 min; 15 (M+H + ) 439.4.

[0157] Quinuclidin-3-yl (2-(4'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate (Compound 15) Ethyl 2-(4-bromophenyl)-2-methylpropanoate to ethyl 2-(3-bromophenyl) 2-(4'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-methylpropanoic acid was prepared by exchanging 4'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl)-2-methylpropanoate and using the reaction sequence outlined in Example 3. This intermediate and quinuclidin-3-ol were reacted according to general procedure F to produce the title compound as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.62-7.20 (m, 7H), 7.03 (d, J = 8.7 Hz, 2H), 4.48-4.35 (m, 2H), 4.18-4.08 (m, 2H), 3.72-3.62 (m, 2H), 3.32 (s, 3H), 3.10-2.19 (m, 6H), 2.10-1.10 (m, 11H) ppm.13 C NMR (100 MHz, DMSO-d6) δ 158.0, 154.6, 148.8, 139.5, 133.1, 128.5, 127.7, 123.8, 123.2, 122.7, 114.8, 70.4, 69.9, 67.0, 58.2, 55.3, 54.5, 47.0, 45.9, 29.4, 25.3, 24.2, 19.2 ppm. Purity: 97.4%, 94.6% (210 & 254 nm) UPLCMS; retention time: 0.88 min; (M+H + ) 439.3.

[0158] Quinuclidin-3-yl (2-(4'-(3-methoxypropoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate (Compound 16) To a stirred solution of 4-iodophenol (10.05 g, 45.68 mmol) in acetonitrile (100 mL) was added potassium carbonate (6.95 g, 50.2 mmol) and 1-chloro-3-methoxypropane (6.4 mL, 57.1 mmol). The mixture was heated to reflux overnight and then concentrated. The residue was taken up in water and extracted with ethyl acetate. The combined extracts were washed with aqueous sodium bicarbonate, dried (Na2SO4) and concentrated. The crude material was purified by flash chromatography on silica using a hexane / ethyl acetate eluent to give 1-iodo-4-(3-methoxypropoxy)benzene as a colorless oil (4.39 g, 33%). This intermediate and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate were reacted according to general procedure E to produce ethyl 2-(4'-(3-methoxypropoxy)-[1,1'-biphenyl]-4-yl)-2-methylpropanoate. To a stirred solution of this compound (0.693 g, 1.94 mmol) in 1:1:1 (v / v / v) tetrahydrofuran / ethanol / water (10 mL) was added lithium hydroxide monohydrate (0.326 g, 7.77 mmol). The mixture was heated to reflux overnight and then concentrated. The residue was dissolved in water, treated with 1N hydrochloric acid (10 mL), and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give 2-(4'-(3-methoxypropoxy)-[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid as a waxy off-white solid (0.630 g, 99%). This intermediate and quinuclidin-3-ol were reacted according to general procedure F to yield the title compound as a glassy colorless solid (62%). 1H NMR (400 MHz, DMSO-d6) δ 7.61-7.29 (m, 7H), 7.00 (d, J= 8.8 Hz, 2H), 4.47-4.36 (m, 1H), 4.05 (t, J= 6.4 Hz, 2H), 3.48 (t, J=6.3 Hz, 2H), 3.26 (s, 3H), 3.10-2.25 (m, 6H), 2.04-1.74 (m, 4H), 1.65-1.23 (m, 9H) ppm. 13 C NMR (100 MHz, DMSO-d6) δ 158.0, 154.5, 146.7, 137.4, 132.4, 127.5, 125.7, 125.2, 114.8, 69.9, 68.5, 64.6, 57.9, 55.4, 54.2, 46.9, 46.0, 29.4, 29.0, 25.2, 24.1, 19.2 ppm. Purity: 97.7%, 98.2% (210 & 254 nm) UPLCMS; retention time: 0.96 min; (M+H + ) 453.5.

[0159] Quinuclidin-3-yl (2-(4'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate (Compound 17) Using general procedure E, ethyl 2-(4'-formyl-[1,1'-biphenyl]-4-yl)-2-methylpropanoate was prepared as a light amber solid using ethyl 2-(4-bromophenyl)-2-methylpropanoate and 4-formylphenylboronic acid in the reaction. This intermediate and quinuclidin-3-ol were reacted according to general procedure F to produce quinuclidin-3-yl (2-(4'-formyl-[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate as a foamy yellow solid. To a stirred solution of this material (0.755 g, 1.92 mmol) in 2:1 (v / v) tetrahydrofuran / ethanol (15 mL) was added sodium borohydride (0.073 g, 1.93 mmHg). ol) was added. After 45 min, the reaction was diluted with water and extracted with chloroform. The combined extracts were dried (Na2SO4) and concentrated onto silica. Flash chromatography on silica using chloroform / methanol / ammonia eluent afforded the title compound as a white solid (0.323 g, 43%). 1 H NMR (400 MHz, DMSO-d6) δ 7.66-7.29 (m, 9H), 5.18 (t, J= 5.7 Hz, 1H), 4.53 (d, J= 5.7 Hz, 2H), 4.46-4.37 (m, 1H), 3.11-2.19 (m, 6H), 2.11-1.10 (m, 11H) ppm. 13 C NMR (100 MHz, DMSO-d6) δ 154.7, 147.3, 141.5, 138.4, 137.7, 127.0, 126.2, 126.1, 125.3, 70.0, 62.6, 55.4, 54.2, 46.9, 45.9, 29.4, 25.3, 24.2, 19.2 ppm. Purity: 97.5%, 99.1 % (210 & 254 nm) UPLCMS; retention time: 0.73 min; (M+H + ) 395.

[0160] Quinuclidin-3-yl (2-(4'-(2-hydroxyethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate (Compound 18) Using general procedure E and employing 1-(2-(benzyloxy)ethyl)-4-bromobenzene and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate in the reaction, ethyl 2-(4'-(2-(benzyloxy)ethyl)-[1,1'-biphenyl]-4-yl)-2-methylpropanoate was prepared as a colorless gum. To a stirred solution of this compound (1.34 g, 3.33 mmol) in 1:1:1 (v / v / v) tetrahydrofuran / ethanol / water (18 mL) was added lithium hydroxide monohydrate (0.698 g, 16.6 mmol). After heating at reflux overnight, the reaction was concentrated and partitioned between water and diethyl ether. The resulting emulsion was repeatedly extracted with 0.2 N aqueous sodium hydroxide solution (5 x 50 mL). The clear part of the aqueous layer was removed each time. The combined aqueous layers were then treated with 1.0 N hydrochloric acid (80 mL) and the resulting suspension of a white solid was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated to give 2-(4'-(2-(benzyloxy)ethyl)-[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid as a white solid (1.20 g, 96%). This compound and quinuclidin-3-ol were reacted according to general procedure F to produce quinuclidin-3-yl (2-(4'-(2-benzyloxyethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate. To a stirred solution of this material (0.435 g, 0.806 mmol) in methanol was added 1.0 N hydrochloric acid (1 mL) and 10% palladium on carbon (50% water; 0.087 g). The mixture was cycled between vacuum and nitrogen purge several times, finally evacuating and refilling with hydrogen. After 1.25 h, the reaction was filtered through Celite and concentrated. The residue was taken up in aqueous sodium carbonate and extracted with 4:1 (v / v) chloroform / isopropanol. The combined extracts were dried (Na2SO4) and concentrated onto silica. Flash chromatography on silica using a chloroform / methanol / ammonia gradient afforded the purified title compound as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 7.85-7.63 (m, 1H), 7.63-7.19 (m, 8H), 4.78-4.62 (m, 2H), 3.71-2.78 (m, 8H), 2.76 (t, J= 6.8 Hz, 2H), 2.26-1.96 (m, 2H), 1.96-1.40 (m, 9H) ppm. 13 C NMR (100 MHz, DMSO-d6) δ 153.8, 146.8, 138.7, 137.9, 137.6, 129.4, 126.3, 126.1, 125.3, 66.2, 62.1, 54.4, 52.8, 45.4, 44.5, 38.6, 29.5, 29.2, 24.0, 19.9, 16.6 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; retention time: 0.75 min; (M+H + ) 409.

[0161] Quinuclidin-3-yl (2-(2-(4-(3-methoxypropoxy)phenyl)thiazol-4-yl)propan-2-yl)carbamate (Compound 19) To a stirred suspension of 4-methoxythiobenzamide (9.99 g, 59.7 mmol) in ethanol (75 mL) was added ethyl 4-chloroacetoacetate (8.1 mL, 60 mmol). The mixture was heated to reflux for 4 h, then cooled and additional ethyl 4-chloroacetoacetate (0.81 mL, 6.0 mmol) was added and returned to reflux. After heating for an additional 4 h, the reaction was concentrated and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was combined with additional ethyl acetate extracts, dried (Na2SO4), and concentrated. Crude product was purified by silica flash chromatography using a hexane / ethyl acetate gradient to give ethyl 2-(2-(4-methoxyphenyl)thiazol-4-yl)acetate as a light amber oil (14.51 g, 87%). To a stirred solution of this compound (14.48 g, 52.2 mmol) in N,N-dimethylformamide (125 mL) was added sodium hydride (60% dispersion in mineral oil; 6.27 g, 157 mmol) in portions over 15 min. The resulting red suspension was cooled (0° C.) and treated dropwise with iodomethane (9.80 mL, 157 mmol) over 10 min. The cooling bath was removed and the reaction was stirred for 4 h before being concentrated and the residue partitioned between ethyl acetate and water. The organic layer was washed twice more with water, dried (Na2SO4) and concentrated. The residue was purified by silica flash chromatography using a hexane / ethyl acetate gradient to give ethyl 2-(2-(4-methoxyphenyl)thiazol-4-yl)-2-methylpropanoate as a light amber oil (14.12 g, 89%). To a stirred solution of this intermediate (14.12 g, 46.24 mmol) in methylene chloride (250 mL) was added boron tribromide (11.0 mL, 116 mmol) dropwise over 5 min. After stirring overnight, the reaction was quenched by slow addition of methanol (ca. 20 mL) and then concentrated. The residue was taken up in methanol (250 mL) and concentrated sulfuric acid (7.0 mL). The stirred solution was heated to reflux for 2 h, concentrated, and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was combined with the second ethyl acetate extract of the aqueous layer, dried (Na2SO4), and concentrated to give methyl 2-(2-(4-hydroxyphenyl)thiazol-4-yl)-2-methylpropanoate as a white solid (12.56 g, 98%). To a stirred solution of 1-bromo-3-methoxypropane (1.66 g, 10.8 mmol) in acetone (30 mL) was added the phenol intermediate (2.00 g, 7.21 mmol) and potassium carbonate (1.25 g, 9.04 mmol). The mixture was heated to reflux overnight, filtered, and concentrated.The residue was purified by silica flash chromatography using a hexane / ethyl acetate gradient to give methyl 2-(2-(4-(3-methoxypropoxy)phenyl)thiazol-4-yl)-2-methylpropanoate as a faint amber gum (2.47 g, 98%). To a stirred solution of this compound (2.45 g, 7.01 mmol) in 1:1:1 (v / v / v) tetrahydrofuran / ethanol / water (45 mL) was added lithium hydroxide monohydrate (1.47 g, 35.0 mmol). After stirring overnight, the reaction was concentrated and partitioned between water and diethyl ether. The aqueous layer was treated with 1.0 N hydrochloric acid (40 mL) and extracted with ethyl acetate. The combined extracts were dried (Na2SO4) and concentrated to give 2-(2-(4-(3-methoxypropoxy)phenyl)thiazol-4-yl)-2-methylpropanoic acid as a white solid (2.19 g, 4093%). This compound and quinuclidin-3-ol were reacted according to general procedure F to yield the title compound as a soft, faint amber solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 8.9 Hz, 2H), 7.36 (br s, 1H), 7.24 (br s, 1H), 7.03 (d, J = 8.9 Hz, 2H), 4.49-4.41 (m, 1H), 4.07 (t, J = 6.4 Hz, 2H), 3.48 (t, J = 6.4 Hz, 2H), 3.26 (s, 3H), 3.09-2.26 (m, 6H), 2.02-1.91 (m, 2H), 1.91-1.03 (m, 11H) ppm. 13 C NMR (100 MHz, DMSO-d6) δ165.8, 162.4, 160.0, 154.6, 127.5, 126.1, 114.9, 112.1, 70.1, 68.4, 64.8, 57.9, 55.4, 53.5, 46.9, 45.9, 28.9, 28.3, 25.2, 24.2, 19.2 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; retention time: 0.87 min; (M+H + ) 460.

[0162] Quinuclidin-3-yl (2-(2-(4-(2-methoxyethoxy)phenyl)thiazol-4-yl)propan-2-yl)carbamate (Compound 20) To a stirred solution of 2-bromoethyl methyl ether (1.88 g, 13.5 mmol) in acetone was added methyl 2-(2-(4-hydroxyphenyl)thiazol-4-yl)-2-methylpropanoate (prepared as described in Example 19, 2.00 g, 7.21 mmol) and potassium carbonate (1.56 g, 11.3 mmol). After heating at reflux overnight, the mixture was treated with additional 2-bromoethyl methyl ether (1.88 g, 13.5 mmol) and potassium carbonate (1.56 g, 11.3 mmol). The reaction was stirred for 2 hours at rt for 30 min. Heated to reflux, filtered and concentrated. The residue was purified by silica flash chromatography using a hexane / ethyl acetate gradient to give methyl 2-(2-(4-(2-methoxyethoxy)phenyl)thiazol-4-yl)-2-methylpropanoate as a white solid (2.71 g, 90%). To a stirred solution of this compound (2.71 g, 8.08 mmol) in 1:1:1 (v / v / v) tetrahydrofuran / ethanol / water (50 mL) was added lithium hydroxide monohydrate (1.70 g, 40.5 mmol). After stirring overnight, the reaction was concentrated and partitioned between water and diethyl ether. The aqueous layer was treated with 1.0 N hydrochloric acid (41 mL) and extracted with ethyl acetate. The combined extracts were dried (Na2SO4) and concentrated to give 2-(2-(4-(2-methoxyethoxy)phenyl)thiazol-4-yl)-2-methylpropanoic acid as a white solid (2.57 g, 99%). This compound and quinuclidin-3-ol were reacted according to general procedure F to produce the title compound as a light amber solid. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 8.8 Hz, 2H), 7.36 (br s, 1H), 7.24 (br s, 1H), 7.04 (d, J = 8.8 Hz, 2H), 4.49-4.41 (m, 1H), 4.19-4.12 (m, 2H), 3.71-3.65 (m, 2H), 3.32 (s, 3H), 3.11-2.87 (m, 1H), 2.86-2.19 (m, 5H), 1.92-1.16 (m, 11H) ppm. 13 C NMR (100 MHz, DMSO-d6) δ 165.7, 162.9, 159.9, 154.6, 127.5, 126.2, 114.9, 112.2, 70.3, 70.1, 67.1, 58.2, 55.4, 53.5, 46.9, 45.9, 28.3, 25.2, 24.3, 19.2 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; retention time: 0.85 min; (M+H + ) 446.

[0163] Quinuclidin-3-yl 2-(5-(4-(2-methoxyethoxy)phenyl)pyridin-2-yl)propan-2-ylcarbamate (Compound 21) 5-(4-(2-Methoxyethoxy)phenyl)picolinonitrile was prepared using general procedure E, using 5-bromopicolinonitrile and 2-(4-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the reaction. Cerium trichloride (8.05 g, 21.6 mmol) was placed in a flask and dried by heating (170° C.) under vacuum for 3 hours. The solid was placed in tetrahydrofuran (20 mL) and stirred vigorously for 30 minutes. The suspension was cooled to −78° C. and treated dropwise with a 3.0 M solution of methyllithium in diethyl ether (7.2 mL, 21.6 mmol). After the addition, the reaction was stirred at −78° C. for 1 hour before adding a solution of the above arylborate (1.83 g, 7.20 mmol) in tetrahydrofuran (20 mL). The mixture was maintained at −78° C. for 2 hours and then warmed to room temperature. At this time, the reaction was quenched by the addition of aqueous ammonium hydroxide (10 mL) and filtered through a Celite plug. The filtrate was extracted with ethyl acetate and the combined extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica using ethyl acetate eluent to give 2-(5-(4-(2-methoxyethoxy)phenyl)pyridin-2-yl)propan-2-amine as a yellow solid (0.800 g, 39%). To a stirred suspension of this intermediate (0.500 g, 1.75 mmol) in water (10 mL) and concentrated hydrochloric acid (0.44 mL) was added toluene (10 mL). The mixture was cooled (0° C.) and simultaneously treated with a solution of triphosgene (0.776 g, 2.62 mmol) in toluene (10 mL) and sodium bicarbonate (2.2 g, 26 mmol) in water (20 mL) for 1 h. After the addition, the reaction was stirred for an additional 30 minutes before removing the top toluene layer and drying (Na2SO4). Concurrently, a stirred solution of quinuclidin-3-ol (0.445 g, 3.64 mmol) in tetrahydrofuran (10 mL) was treated with sodium hydride (60% dispersion in mineral oil; 0.154 g, 3.85 mmol). This mixture was stirred for 5 minutes and then added to the crude isocyanate solution in toluene. The reaction was stirred for 10 minutes, quenched by the addition of brine (5 mL) and extracted with ethyl acetate.The combined extracts were dried (Na2SO4) and concentrated. The residue was purified by reverse-phase silica flash chromatography to give the title compound as a pale yellow solid (0.100 g, 13%). 1 H NMR (500 MHz, CDCl3) δ 8.70-8.70 (d, J = 2.0 Hz, 1H), 7.83-7.81 (m, 1H), 7.49-7.47 (d, J = 9.0 Hz, 2H), 7.45-7.43 (d, J = 8.0 Hz, 1H), 7.03-7.01 ( d, J = 8.5 Hz, 2H), 6.63 (br s, 1H), 4.68-4.66 (m, 1H), 4.16 (t, J = 5.0 Hz, 2H), 3.77 (t, J = 5.0 Hz, 2H), 3.45 (s, 3H), 3.19-2.70 (m, 6H), 2.15-1.89 (m, 2H), 1.76 (s, 6H), 1.73-1.36 (m, 3H) ppm. 13 C NMR (125 MHz, CDCl3) δ 162.7, 158.9, 154.9, 145.9, 134.8, 134.3, 130.1, 128.1, 119.2, 115.2, 71.0, 70.8, 67.4, 59.2, 55.9, 55.7, 47.4, 46.5, 46.4, 27.9, 25.4, 24.6, 19.5 ppm. Purity: >99% (214 & 254 nm) LCMS; retention time: 1.32 min; (M+H + ) 440.2.

[0164] Quinuclidin-3-yl (2-(4'-(3-cyanopropoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate (Compound 22) To a stirred solution of 4-bromophenol (17.1 g, 98.8 mmol) in acetonitrile (150 mL) was added 1-bromobutylnitrile (12.3 mL, 124 mmol) and potassium carbonate (15.0 g, 109 mmol). The mixture was heated to reflux overnight, cooled, and concentrated. The residue was taken up in water and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), concentrated, and the crude material was purified by flash chromatography on silica using a hexane / ethyl acetate eluent to give 4-(4-bromophenoxy)butanenitrile as a white solid (20.8 g, 88%). To a stirred solution of this product in N,N-dimethylformamide (100 mL) was added bis(pinacolato)diboron (4.60 g, 18.1 mmol), potassium acetate (7.41 g, 75.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (0.616 g, 1.04 mmol). The mixture was heated to reflux overnight and then concentrated. The residue was taken up in ethyl acetate and washed with water and brine. The organic layer was dried (Na2SO4), concentrated and the crude product was purified by flash chromatography on silica using a hexane / ethyl acetate eluent to give 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butanenitrile as a white solid (3.43 g, 79%). This product and quinuclidin-3-yl (2-(4-bromophenyl)propan-2-yl)carbamate (prepared by reacting quinuclidin-3-ol and 2-(4-bromophenyl)propan-2-amine using general procedure F) were reacted according to general procedure E to yield the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.67-7.26 (m, 7H), 7.02 (d, J = 8.8 Hz, 2H), 4.50-4.33 (m, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.14-2.18 (m, 8H), 2.04 (quin, J = 6.7 Hz, 2H), 1.94-1.70 (m, 11H) ppm. 13C NMR (100 MHz, DMSO-d6) δ 157.7, 154.5, 146.8, 137.4, 132.7, 127.6, 125.7, 125.2, 120.2, 114.9, 70.0, 65.8, 55.4, 54.2, 46.9, 45.9, 29.4, 25.3, 24.7, 24.2, 19.2, 13.4 ppm. Purity: 100%, 98.9% (210 & 254 nm) UPLCMS; retention time: 0.88 min; (M+H + ) 448.6.

[0165] Quinuclidin-3-yl (2-(4'-(cyanomethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate (Compound 23) Using general procedure E, the reaction employed quinuclidin-3-yl (2-(4-bromophenyl)propan-2-yl)carbamate (prepared by reacting quinuclidin-3-ol and 2-(4-bromophenyl)propan-2-amine using general procedure F) and 4-(cyanomethoxy)phenylboronic acid to prepare the title compound as a light amber solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J= 8.2 Hz, 2H), 7.60-7.31 (m, 5H), 7.15 (d, J = 8.9 Hz, 2H), 5.21 (s, 2H), 4.53-4.30 (m, 1H), 3.18-2.19 (m, 6H), 2.05-1.18 (m, 11H) ppm. 13 C NMR (100 MHz, DMSO-d6) δ155.8, 154.6, 147.2, 137.2, 134.4, 127.8, 126.0, 125.3, 116.7, 115.3, 70.0, 55.4, 54.2, 53.5, 46.9, 45.9, 29.4, 25.2, 24.2, 19.2 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; retention time: 0.85 min; (M+H + ) 420.3. EXAMPLES

[0166] (S)-Quinuclidin-3-yl(2-(2-(4-fluorophenyl)thiazole-4 Preparation of (2-yl)propan-2-yl)carbamate free base Step 1: Dimethylation using methyl iodide [ka] A 3N RB flask was equipped with a thermometer, addition funnel and nitrogen inlet. The flask was flushed with nitrogen and potassium tert-butoxide (MW 112.21, 75.4 mmol, 8.46 g, 4.0 equiv., white powder) was weighed and added to the flask via the powder funnel followed by THF (60 mL). A cloudy solution resulted when most of the potassium tert-butoxide had dissolved. This mixture was cooled to 0-2 °C (internal temperature) in an ice-water bath. In a separate flask, the starting ester (MW 265.3, 18.85 mmol, 5.0 g, 1.0 equiv.) was dissolved in THF (18 mL + 2 mL as a rinse) and transferred to the addition funnel. This solution was added dropwise to the cooled mixture over 25-30 min, maintaining the internal temperature below 5 °C during the addition. The reaction mixture was cooled back to 0-2 °C. In a separate flask, a solution of methyl iodide (MW 141.94, 47.13 mmol, 6.7 g, 2.5 equiv.) in THF (6 mL) was prepared and transferred to the addition funnel. The flask containing the methyl iodide solution was then rinsed with THF (1.5 mL) and then transferred to the addition funnel already containing the clear, colorless solution of methyl iodide in THF. This solution was carefully added dropwise to the dark brown reaction mixture over 30-40 min, maintaining the internal temperature below 10 °C throughout the addition. After the addition was complete, the slightly cloudy mixture was stirred for an additional 1 h, during which time the internal temperature dropped to 0-5 °C. After stirring at 0-5 °C for 1 h, the reaction mixture was quenched by the slow dropwise addition of 5.0 M aqueous HCl (8 mL) over 5-7 min. The internal temperature was maintained below 20 °C during this addition. After the addition, water (14 mL) was added and the mixture was stirred for 2-3 min. Stirring was stopped and the two layers were separated. The two layers were then transferred to a 250 mL 1N RB flask and as much THF as possible was evaporated in vacuum to give a biphasic layer of THF / product and water. The two layers were separated. The THF solution of the product from step 1 was used in the next reaction.

[0167] Step 2: Hydrolysis of the ethyl ester using LiOH monohydrate [ka] The crude ester in THF was added to the reaction flask. Separately, LiOH.H2O (MW 41.96, 75.0 mmol, 3.15 grams, 2.2 equiv.) was weighed into a 100 mL beaker to which a stir bar was added. Water (40 mL) was added and the mixture was stirred until all solids were dissolved to give a clear, colorless solution. This aqueous solution was then added to a 250 mL RB flask containing a solution of the ester in tetrahydrofuran (THF). A condenser was attached to the neck of the flask and a nitrogen inlet was attached to the top of the condenser. The mixture was heated to reflux for 16 hours. After 16 hours, heating was discontinued and the mixture was allowed to cool to room temperature. The THF was evaporated in vacuo to give a brown solution. An aliquot of the brown aqueous solution was analyzed by HPLC and LC / MS / MS. Hydrolysis of the ethyl ester was complete as analyzed by MS. Water (15 mL) was added and the aqueous basic solution was extracted with TBME (2×40 mL) to remove the t-butyl ester. The aqueous basic layer was cooled to 0-10° C. in an ice-water bath and acidified with concentrated HCl dropwise with stirring to a pH of about 1. TBME (60 mL) was added to the sticky solid in the aqueous acidic solution and the mixture was shaken and then vigorously stirred to dissolve all the acid in the TBME layer. The two layers were transferred to a separatory funnel and the TBME layer was separated. The pale yellow aqueous acidic solution was re-extracted with TBME (40 mL) and the TBME layer was separated and combined with the aforementioned TBME layer. The aqueous acidic layer was discarded. The combined TBME layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to remove TBME and to give the crude acid as an orange / dark yellow oil which solidified under high vacuum to a dull yellow solid. The crude acid was weighed and crystallized by heating it in heptane / TBME (3:1, 5 mL / g crude) to give the acid as a yellow solid.

[0168] Step 3: Formation of hydroxamic acid using NHOH.HCl [ka] The carboxylic acid (MW 265.3, 18.85 mmol, 5.0 g, 1.0 equiv) was weighed and transferred to a 25 mL 1N RB flask under nitrogen. The acid readily dissolved upon addition of THF (5.0 mL) to give a clear dark yellow to brown solution. The solution was cooled to 0-2 °C (bath temperature) in an ice bath and N,N'-carbonyldiimidazole (CDI; MW 162.15, 20.74 mmol, 3.36 g, 1.1 equiv) was added slowly in small portions over 10-15 min. The ice bath was removed and the solution was stirred at room temperature for 1 h. After stirring for 1 h, the solution was cooled again to 0-2 °C (bath temperature) in an ice-water bath. Hydroxylamine hydrochloride (NH2OH.HCl; MW 69.49, 37.7 mmol, 2.62 g, 2.0 equiv.) was added slowly as a solid in small portions over 3-5 min as this addition was exothermic. After the addition was complete, water (1.0 mL) was added dropwise to the heterogeneous mixture over 2 min and the reaction mixture was stirred in an ice-water bath at 0-10 °C for 5 min. The cooling bath was removed and the reaction mixture was stirred overnight at room temperature under nitrogen for 20-22 h. The solution became clear as all the NH2OH.HCl dissolved. After 20-22 h, an aliquot of the reaction mixture was analyzed by high pressure liquid chromatography (HPLC). The THF was then evaporated in vacuum and the residue was taken up in dichloromethane (120 mL) and water (60 mL). The mixture was transferred to a separatory funnel, which was shaken and allowed to separate into two layers. The aqueous layer was discarded and the dichloromethane layer was washed with 1 N hydrochloride (HCl; 60 mL). The acid layer was discarded. The dichloromethane layer was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo to give the crude hydroxamic acid as a pale yellow solid, which was dried under high vacuum overnight.

[0169] Continuation of step 3: Conversion of hydroxamic acid to cyclic intermediate (no isolation) [ka] The crude hydroxamic acid (MW 280.32, 5.1 g) was transferred to a 250 mL 1N RB flask equipped with a nitrogen inlet. A stir bar was added followed by acetonitrile (50 mL). The solid was insoluble in acetonitrile. The yellow heterogeneous mixture was stirred under nitrogen for 2-3 min and CDI (MW 162.15, 20.74 mmol, 3.36 g, 1.1 equiv) was added in one portion at room temperature. No exotherm was observed. The solid immediately dissolved and the clear yellow solution was stirred at room temperature for 2-2.5 h. After 2-2.5 h, an aliquot was analyzed by HPLC and LC / MS, which indicated conversion of the hydroxamic acid to the desired cyclic intermediate.

[0170] The acetonitrile was then evaporated in vacuo to give the crude cyclic intermediate as a thick reddish oil, which was taken up in toluene (60 mL) and the reddish mixture was heated to reflux for 2 h, during which time the cyclic intermediate released CO2 and rearranged to the isocyanate (see below). [ka]

[0171] Step 3 continued: Conversion of isocyanate to free base [ka] The reaction mixture was cooled to 50-60 °C and (S)-(+)-quinuclidinol (MW 127.18, 28.28 mmol, 3.6 g, 1.5 equiv) was added as a solid to the mixture in one portion. The mixture was again heated to reflux for 18 h. After 18 h, an aliquot was analyzed by HPLC and LC / MS, which showed that conversion of the isocyanate to the desired product was complete. The reaction mixture was transferred to a separatory funnel and toluene (25 mL) was added. The mixture was washed with water (2 × 40 mL) and the aqueous layer was separated. The combined aqueous layers were re-extracted with toluene (30 mL) and the aqueous layer was discarded. The combined toluene layers were washed with 1 N HCl (2 × 6 The toluene layer (containing O-acyl impurities) was discarded. The combined HCl layers were transferred to a 500 mL Erlenmeyer flask equipped with a stir bar. This stirred clear yellow / reddish orange solution was basified to pH 10-12 by dropwise addition of 50% w / w aqueous NaOH. The desired free base precipitated out of solution as a dull yellow sticky solid which could be captured with the stir bar. To this mixture was added isopropyl acetate (100 mL) and the mixture was stirred vigorously for 5 min whereupon the sticky solid transitioned to the isopropyl acetate. Stirring was stopped and the two layers separated. The yellow isopropyl acetate layer was separated and the basic aqueous layer was re-extracted with isopropyl acetate (30 mL). The basic aqueous layer was discarded and the combined isopropyl acetate layers were dried over anhydrous Na2SO4, filtered into a pre-weighed RB flask and the solvent evaporated in vacuo to give the crude free base as a beige to tan solid which was dried under high vacuum overnight.

[0172] Continued from step 3: Recrystallization of the crude free base The beige to tan crude free base was weighed and recrystallized from heptane / isopropyl acetate (3:1, 9.0 mL solvent / 1 g crude free base). The appropriate amount of heptane / isopropyl acetate was added to the crude free base and stir bar and the mixture was heated to reflux for 10 minutes (the free base was initially partially dissolved, but when heated to reflux it dissolved and gave a clear reddish orange solution). When a white precipitate formed, the heat source was removed and the mixture was cooled to room temperature with stirring. After stirring at room temperature for 3-4 hours, the precipitate was filtered off using a Buchner funnel with a vacuum hose, washed with heptane (20 mL) and dried on the Buchner funnel with a vacuum hose overnight. The precipitate was transferred to a crystallizing dish and dried in a vacuum oven at 55°C overnight. 1H NMR (400 MHz, CDCl3) δ 8.04 - 7.83 (m, 2H), 7.20 - 6.99 (m, 3H), 5.53 (s, 1H), 4.73 - 4.55 (m, 1H), 3.18 (dd, J = 14.5, 8.4 Hz, 1H), 3.05 - 2.19 (m, 5H), 2.0 - 1.76 (m, 11H) ppm. 13 C NMR (100 MHz, CDCl3) δ 166.38, 165.02, 162.54, 162.8-155.0 (d, CF), 130.06, 128.43, 128.34, 116.01, 115.79, 112.46, 71.18, 55.70, 54.13, 47.42, 46.52, 27.94, 25.41, 24.67, 19.58 ppm. EXAMPLES

[0173] Preparation of crystalline forms of (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate salt The crystalline salt of (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate may be formed from the free base prepared as described in Example 23.

[0174] For example, the free base of (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate (approximately 50 mmol) is dissolved in IPA (140 ml) at room temperature and filtered. The filtrate is added to a 1 L rb flask equipped with an overhead stirrer and nitrogen inlet / outlet. L-Malic acid (approximately 50 mmol) is dissolved in IPA (100+30 ml) at room temperature and filtered. The filtrate is added to the 1 L flask. The resulting solution is stirred under nitrogen at room temperature for 4 to 24 hours (with or without seeding). Crystals form during this time. The product is collected by filtration and washed with a small amount of IPA (30 ml). The crystalline solid is dried in a vacuum oven at 55° C. for 72 hours to give the desired malate salt.

[0175] Other salt crystalline forms, such as acid addition salts with succinic acid or HCl, may be prepared in a similar manner. EXAMPLES

[0176] In-vitro GCS inhibition (compound 2 and analogues) Inhibition of glucosylceramide synthase activity can be measured using one or more assays. The first assay is a microsomal assay, which directly measures the conversion of ceramide to glucosylceramide by HPLC. Microsomes are the source of glucosylceramide synthase activity in the microsomal assay. The second assay is a cell-based phenotypic assay, which monitors the cell surface expression of the downstream lipid GM3 by antibody-mediated immunofluorescence. A specific protocol is provided below.

[0177] Microsomal assay for glucosylceramide synthase activity: Enzyme assay using microsomes as source of glucosylceramide synthase activity. Fluorescent ceramide substrate is delivered to the membrane-bound enzyme as a complex with albumin. After reaction, ceramide and glucosylceramide are separated and quantified by reversed-phase HPLC with fluorescence detection. Enzyme activity is assessed using a fluorescently labeled substrate and microsomes as source of glucosylceramide synthase. C6-NBD-ceramide is delivered in complex with albumin to microsomes isolated according to the procedure described below. The final concentration of C6-NBD-ceramide in the stock solution is 0.5 mM; the final concentration of BSA is 0.5 mM. Separation and quantification of the substrate and product (glucosylceramide) is achieved by reversed-phase HPLC with fluorescence detection.

[0178] Preparation of microsomes from A375 human melanoma cells; Microsomes are isolated from A375 human melanoma cells. 8 to 10 million cells are harvested by trypsinization and washed with ice-cold PBS. The cells are resuspended in ice-cold lysis buffer containing protease inhibitors. The cell lysate is sonicated on ice using a probe sonicator. After sonication, the cell lysate is separated from debris by centrifugation at 10,000 g for 10 min at 4° C. The supernatant is removed and clarified by additional centrifugation at 100,000 g for 1 h at 4° C. The pellet is then resuspended in lysis buffer, aliquoted, and stored at −80° C. before use.

[0179] Glucosylceramide synthase assay To determine glucosylceramide synthase inhibition, substrates (fluorescent ceramide and UDP-glucose, 3 μM and 4 μM, respectively) at twice their Km are combined 1:1 with microsomes (diluted 1:50) and incubated for 1 h at room temperature on a plate shaker in the dark. The reaction is stopped by adding 150 μL of 100 μM C8-ceramide in 50% aqueous isopropanol; 10 μL of the final mix is ​​analyzed by HPLC (equipped with a fluorescence detector). The mobile phase is 1% formic acid in 81% methanol / 19% water, with a flow rate of 0.5 mL / min. Fluorescence is measured at λ ex = 470 nm and λ em = 530 nm. Under these conditions, the retention time of NBD-C6-GluCer is about 1.7 min, and NBD-C6-Cer elutes from the column after about 2.1 min. Both peaks were separated from each other and from the baseline and were automatically integrated by the HPLC software. The conversion rate of substrate to product is used as the readout for the inhibitor test.

[0180] GM3 Fluorescence Linked Immunosorbent Assay (FLISA): This is a phenotypic assay that measures GM3 expression in B16 mouse melanoma or C32 human melanoma cells following treatment with a test compound. Cell surface GM3 expression is determined by antibody-mediated fluorescence.

[0181] Compounds are diluted in media and plated in DMSO in 384-well plates. B16 and C32 cells are assayed at densities of 20,000 cells / ml and 62,500 cells / ml per well, respectively. Each titration curve contains 10 points, which are assayed in duplicate in each test run. Plates are incubated at 37°C with 5% CO2 for 48 hours and then washed once with TBS. Anti-GM3 antibody is added to each well and the plates are then incubated for an additional hour at room temperature. Plates are then washed twice. After the final incubation, the plate is washed twice and incubated with λ ex= D640 / 20nm and λ em Fluorescence at 657 nm is detected in a fluorescence reader.

[0182] Assay Results The individual assay results for certain exemplified compounds in these assays are shown in the table below. The microsomal assay results were grouped into "GCS IC 50 ", which represents the concentration of compound that results in 50% inhibition of glucosylceramide synthase activity. The results of the cell-based assays are listed as "GM3B16IC 50 " or "GM3C32IC 50 These values ​​represent the concentration of compound that results in 50% inhibition of GM3 expression at the cell surface.

[0183] [Table 3]

[0184] These comparative results demonstrate that the compounds disclosed herein have in vitro activity comparable to that of GCS inhibitors. It is anticipated that these compounds will demonstrate similar in vivo benefits and, as a result, be expected to demonstrate similar in vivo benefits. EXAMPLES

[0185] Clinical Study of Compound 2 in GD-3 Patients We have initiated a 156-week, multi-part, open-label, multinational study of the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of compound 2 in combination with imiglucerase in adult patients with imiglucerase-stabilized Gaucher disease type 3.

[0186] Patients aged 18 years or older with a clinical diagnosis of GD3 and documented acid beta-glucosidase activity deficiency who had been treated with ERT for at least 3 years and imiglucerase (Cerezyme) for at least 6 months at a stable monthly dose prior to enrollment were included in the study. Patients must have achieved the following GD treatment goals: hemoglobin level ≥11.0 g / dL for women and ≥12.0 g / dL for men; platelet count ≥100,000 / mm3; spleen volume <10 times normal (10 MN) or total splenectomy (provided splenectomy occurred ≥3 years prior to randomization); liver volume <1.5 MN; and no bone crisis or bone pain due to symptomatic bone disease, e.g., osteonecrosis and / or pathological fractures within the last year. Patients must have GD3 characterized by oculomotor apraxia (supranuclear gaze paresis) characterized by horizontal saccade abnormalities.

[0187] (A) 26-week interim analysis An interim analysis of five patients was performed upon completion of 26 weeks of concurrent treatment with (1) imiglucerase (Cerezyme Sanofi Genzyme) under each patient's established regimen, and (2) compound 2 administered orally at a single dose of 15 mg / day. During the study, patients were evaluated for safety and tolerability, CSF and plasma biomarkers (glucosylceramide, GL-1; glucosylsphingosine, lyso-GL1), pharmacokinetics, markers of systemic disease (spleen and liver volumes measured by magnetic resonance imaging (MRI), platelet count, hemoglobin levels), signs of interstitial lung disease (high-resolution computed tomography (CT) of the lungs), and horizontal saccadic eye movements.

[0188] At baseline, four patients had mild neurological involvement and one had moderate neurological involvement as measured using the modified Severity Scoring Tool (mSST; Davies, et al., 2011). All patients had evidence of interstitial lung disease based on chest CT. One patient had anemia as evidenced by a plasma hemoglobin level of 10.6 g / dL.

[0189] No patients reported any serious or persistent treatment-emergent adverse events. The most frequently reported events were headache and back pain, which were mild to moderate in intensity and considered to be only transient in duration (possibly related to the lumbar puncture performed for CSF testing).

[0190] Compound 2 was found to effectively cross the blood-brain barrier in all patients, as demonstrated in the table below:

[0191] [Table 4]

[0192] The high variability in CSF concentrations of Compound 2 observed at Week 26 was due to a decrease in exposure in one patient (Patient 5) from Weeks 12 to 26 for unknown reasons. Patient 1 was excluded from CSF evaluation at Week 26 due to an error in sample collection.

[0193] At 26 weeks, significant improvements were observed in plasma and CSF biomarkers for GD-3. At baseline, the mean (±SD) GL-1 concentration in CSF was 7.1±2.8ng / mL (range 4.4-11.1ng / mL) and at the same time the mean (±SD) lyso-GL-1 concentration in CSF was 39.3±22.9pg / mL (range 20.1-67.6pg / mL). For comparison, healthy GL-1 concentrations in CSF are 4.5-5.9ng / mL and healthy levels of lyso-GL-1 in CSF are less than 5.0pg / mL. At 4 and 26 weeks, the individual reductions in CSF biomarkers were as follows (shown as percent reduction from baseline CSF concentrations):

[0194] [Table 5]

[0195] The severity of interstitial lung disease was characterized by the percent lung volume affected by ILD as measured by high-resolution CT in four lung regions (aortic arch, carina, lower zone L3, lower zone L4). Patients were graded as having severe ILD (51-100% of lung volume affected), moderate ILD (26-50% of lung volume affected), mild ILD (1-25% of lung volume affected) or normal (0% of lung volume shows ILD). All patients showed ILD at baseline, and four out of five patients showed regression of ILD after 26 weeks of treatment (five patients showed slight progression of ILD):

[0196] [Table 6]

[0197] No patient showed systemic deterioration. Two patients showed a decrease in spleen volume of 10% or more. There were no clinically important changes in hemoglobin levels. On average, platelet counts increased by 17% from baseline to week 26, with the three patients with the lowest baseline platelet counts individually showing increases of 23-42% at week 26. Individual patient data regarding platelet counts are shown in the table below (10 9 (expressed as platelets / L):

[0198] [Table 7]

[0199] Quantification of horizontal and vertical saccadic eye movements (HSEM and VSEM, respectively) was performed in all five patients. In five patients, the mean peak velocity (PV) of 15° horizontal right saccades was 50.8° / sec (+ / -8.1° / sec) at baseline and 47.5° / min (+ / -12.6° / sec) at 26 weeks; the mean PV of 15° horizontal left saccades was 44.7° / sec (+ / -17.9° / sec) at baseline and 32.3° / sec (+ / -15.9° / sec) at 26 weeks. Slower velocities suggest a more pronounced degree of neurological injury. The mean PV for horizontal right 30° saccades was 77.7° / sec (+ / - 16.4° / sec) at baseline and 68.1° / min (+ / - 24.7° / sec) at 26 weeks; the mean PV for horizontal left 30° saccades was 58.7° / sec (+ / - 21.5° / sec) at baseline and 49.9° / sec (+ / - 8.5° / sec) at 26 weeks. Normal ranges for 15° and 30° horizontal saccades have been previously reported as >200° / sec and >400° / sec (Bremova-Ertl et al, 2018). HSEM measurements in each of the five patients are shown in Figures 1 and 2. In summary, no clinically significant changes in HSEM were observed over the 26-week treatment period. Similar to HSEM, VSEM measurements were stable between baseline and 26 weeks.

[0200] Four exploratory biomarkers were quantified in plasma, serum and / or CSF of GD3 patients at 4 and 26 weeks: chitotriosidase (CHITO; an enzyme known to be elevated in GD patients) was measured in CSF and serum; GM3 (a glycosphingolipid marker known to be elevated in GD patients) was measured in CSF and plasma; and glycoprotein nonmetastatic melanoma protein B (GPNMB; a reported biomarker for neuropathic GD3) was measured in CSF. Results are presented in the following table as percent change from baseline at 4 and 26 weeks for each parameter:

[0201] [Table 8]

[0202] (B) 52-week interim analysis A second interim analysis was performed when the first six patients reached 52 weeks of treatment, as described above in section (A). This analysis included patients 1-5 described in section (A) as well as the six new patients. All six patients had the L444P (1448T / C) homozygous Gaucher phenotype.

[0203] At week 52, all patients remained enrolled in the study.A total of 30 treatment-emergent adverse events were reported among the six patients, all of which were mild or moderate in severity, and none of which were considered related to treatment with Compound 2 or imiglucerase.The events were initially headache and back pain, possibly related to the lumbar puncture.

[0204] Analysis of plasma and CSF concentrations of Compound 2 shows values ​​roughly equivalent to those obtained at 26 weeks. However, patient 5 was noted to have approximately 50% lower concentrations of Compound 2 in plasma and CSF at 26 weeks and undetectable concentrations at 52 weeks. This was likely due to either compliance or dosing error, and as a result, the analysis has been repeated without the 26 and 52 week data for patient 5. The data support the conclusion that steady state concentrations of Compound 2 are reached in plasma and CSF at or before 4 weeks:

[0205] [Table 9]

[0206] [Table 10]

[0207] At 52 weeks, the data further demonstrate sustained and significant improvements in plasma and CSF biomarkers for GD-3. Results are similar to those obtained at week 26. Across all six GD3 patients, plasma and CSF GL-1 and lyso-GL-1 concentrations were as follows:

[0208] [Table 11]

[0209] Thus, at 52 weeks, compared with baseline, the changes in plasma and CSF concentrations were as follows:

[0210] [Table 12]

[0211] In addition, the following exploratory biomarkers were quantified in the CSF of GD3 patients: ceramide (the precursor of GL-1), chitotriosidase (CHITO), GM3, and GPNMB. No significant changes were observed in CSF concentrations of ceramide, CHITO, or GPNMB after 52 weeks of treatment. Four of six patients had measurable concentrations of GM3 in their CSF at baseline, and each of these patients was found to have undetectable GM3 in their CSF at weeks 4, 26, and 52.

[0212] At 52 weeks, quantification of horizontal and vertical saccadic eye movements was performed in all six patients in a similar manner as described in section (A). However, it was determined that the methodology used may have introduced bias into the results due to noise (e.g., caused by eye blinks or head movements). As a result, the noise calculation method was modified and a set of control criteria was developed to evaluate the validity of the data set obtained by the eye movement reader. In reevaluating the 26-week saccadic eye movement data, and in evaluating the 52-week data, it was recognized that the level noise was too high to draw any conclusions from the data.

[0213] Furthermore, at 52 weeks, 5 of 6 patients showed improvement in ataxia. The severity of ataxia at baseline and throughout the study was assessed by the Scale for Assessment and Rating of Ataxia (SARA; Schmitz-Hubsch et al., 2006), which assesses 8 different attributes of cerebellar ataxia on a scale of 0 to 40. The eight attributes were gait, posture, sitting, speech disturbance, finger tracking, nose-to-finger test, rapid alternating hand movements, and heel-to-shin slides. The resulting SARA ataxia scores for all six patients are shown in the chart below:

[0214] [Table 13]

[0215] As shown in the table, five of the six patients had mild ataxia at baseline, with a mean cumulative SARA score of 2.8 (SD=1.2). The most common deficit at baseline was gait disturbance. With the exception of patient 5 due to the low level of exposure to compound 2 in this patient and the patient's baseline ataxia score being essentially normal (only 0.5), four of the five patients showed improvement in ataxia at 52 weeks (mean improvement=-0.9; SD=3.2). Patient 4 showed an increase in ataxia scoring, with a score of 3 at baseline and 7.5 at 52 weeks. It should be noted that this apparent deterioration was almost entirely due to changes in the "posture" scoring parameter (posture score at baseline and 26 weeks=1; score at 52 weeks=5), and the patient complained of pain in the left knee at the time of examination. Additionally, the subject had an injury to his left big toe prior to examination; this injury was considered to have resolved 11 days after examination. Excluding these outlier effects in patient 4, treatment with Compound 2 led to a significant reduction in mean SARA scores by 26 weeks, which further improved slightly by 52 weeks.

[0216] The Trail Making Test (TMT) was used to assess cognitive function in patients. The TMT is one of the most widely used neuropsychological tests and is included in most test series. It is a diagnostic tool for assessing general intelligence and cognitive impairment (Tombaugh et al., 2004; Cavaco et al., 2013). In part A of the TMT, subjects are asked to connect groups of digits in ascending order. This task evaluates the combination of visual search and general visual acuity and motor processing speed. Part B represents a sequence that alternates between numbers and letters. Connecting them in ascending but alternating order requires subjects to actively switch between both categories. Thus, this task is considered to include an executive function component, as subjects must actively switch between categories and connect symbols at the same time (MacPherson et al., 2017).

[0217] TMT-A primarily assesses perceptual and psychomotor speed; TMT-B more specifically assesses mental flexibility and shifting ability. TMT-B minus TMT-A score is used to remove variance attributable to graphomotor and vision scanning components of TMT-A. This introduced score reflects the unique task requirements of TMT-B.

[0218] In a study of exemplar data on TMT A and TMT B in community-dwelling individuals aged 18-89 years (n=911), the mean (SD) values ​​in the 18-24 year age group (n=155) were 22.9 seconds (6.9) for TMT A and 49 seconds (12.7) for TMT B (Tombauch et al., 2004). In contrast, the mean time taken to complete trails A and B for the patients in the study was 67.8 seconds (SD=60.3 seconds) and 193.8 seconds (SD=197.0), respectively. At baseline, the mean difference in time taken to complete trail B minus trail A was 126.0 seconds (SD=142.9 seconds). This indicates that some degree of cognitive impairment at baseline was demonstrated by the GD-3 patients in this study.

[0219] At 52 weeks, the mean time to complete Trail A was 56.5 seconds (SD=55.2 seconds) and Trail B was 122.7 seconds (SD=91.8 seconds). Four of six patients showed a decrease in the time it took to complete Trail A and six of six patients showed a decrease in the time it took to complete Trail B. Excluding patient 5 due to the low level of exposure to Compound 2 in this patient, four of five patients showed a decrease in TMT-A and five of five patients showed a decrease in TMT-B.

[0220] At week 52, 5 of 6 patients showed a decrease in (TMT B-TMT A) time. Individual results are shown in the table below.

[0221] [Table 14]

[0222] At 52 weeks, the mean difference in time to complete Trail B minus Trail A was 66.2 seconds (SD=54.3). Excluding patient 5, 4 of 5 patients showed improvement in Trail B minus Trail A, with a mean improvement of -71.4 seconds (-31.6%) (SD 99.3 seconds (37.6%)) at 52 weeks.

[0223] Neurological function was further assessed using functional magnetic resonance imaging (fMRI). Patient 2 was excluded because he did not collect fMRI data at the 52-week session. Resting-state fMRI screening sessions were conducted at the baseline screening, 26-week, and 52-week visits. Connectivity assessments from four subjects (patients 1, 3, 4, and 5) were entered into the second level of analysis as the "adherent" group. Patient 5 was isolated due to possible non-compliance with study medication, as described above. Analyses were performed as described elsewhere (Smith et al., 2009).

[0224] Adherent subjects demonstrated enhanced connectivity between a more widely distributed set of brain regions than non-adherent subjects, most notably with increased strength between posterior and anterior regions. At the anatomical level, adherent subjects demonstrated widespread and robust strengthening of connections between occipital-parietal structures and frontal, temporal and limbic targets. Connectivity changes in patient 5 were more subtle and restricted to spatially proximal structures. At the functional level, all subjects except patient 5 showed enhanced connectivity between the default mode and medial frontal networks. This suggests that signals within these different networks become more coherent, and as a result brain activity can communicate more effectively between cognitive reserve (posterior) and higher executive functions (anterior). A consistent reverse spatial mapping from resting-state networks (RSNs) 2 and 3 (cognitive-linguistic-orthographic and cognitive-spatial) to RSNs 8 and 9 (executive and left frontoparietal) is also evident. The spatial distribution of connectivity changes was even more focused for patient 5, with overlap between medial-frontal and frontoparietal networks. Both perspectives suggest that patients who fully adhered to the treatment protocol developed greater coherence between the posterior and anterior brain regions, making the entire brain more susceptible to efficient information transfer. In a clear case, the connectivity changes for patient 5 appeared within a narrower set of anterior brain regions, representing less overall evidence of therapeutic benefit.

[0225] The results are summarized in the table below. A spatial analysis of the connectivity between different anatomical regions of the brain was performed to define correlation coefficients on the regressed voxel-wise mean intensities. The results showed that the connectivity between the default mode (resting) network and the executive function network was increased in patients 1, 3, 4 and 6, but decreased in patient 5.

[0226] [Table 15]

[0227] Two patients experienced a decrease in spleen volume at 52 weeks, and mean platelet concentration increased by a mean of 9.3% (range -8.2% to +45.3%), with all patients reaching the therapeutic goal of 120 × 10 9 It was further noted that platelet counts remained above 10 / L. The increase in mean platelet concentration was primarily driven by increases in 3 of 6 patients. There were no clinically significant changes in hemoglobin levels. EXAMPLES

[0228] Pharmacokinetics of Compound 2 in Healthy Human Volunteers A two-part Phase 1 clinical study was conducted to evaluate the pharmacokinetics, pharmacodynamics, safety and tolerability of Compound 2, also known as benglustat, in healthy human volunteers in the presence and absence of food.

[0229] Research 1 Study 1 was a two-part, single-center trial in healthy adult male volunteers. Part 1 was a double-blind, randomized, placebo-controlled, ascending single-dose study of Compound 2 for safety, tolerability, and PK. Part 2 was an open-label, single-cohort, randomized, two-sequence, two-period, two-treatment crossover study of Compound 2 for PK with and without a high-fat meal.

[0230] Fifty-five healthy men (placebo, n=14; 2, 5, 15, 25, 50, and 100 mg doses, n=6 each; 150 mg dose, n=5) were enrolled and randomized in part 1 of the study. Eight healthy men participated in part 2.

[0231] In part 1, subjects were randomized to receive 2, 5, 15, 25, 50, 100, or 150 mg of Compound 2 (L-malate form) or a matching placebo on the first morning after at least 10 hours of fasting. In part 2, subjects were randomized to receive a single oral dose of 5 mg of Compound 2 given either on an empty stomach (at least 10 hours before and 4 hours after dosing) or 30 minutes after a standardized high-fat breakfast (approximately 815 kcal). After a 7-day washout period, participants were cross-linked to the other condition. It was over.

[0232] In Study 1, Part 1, blood was sampled for plasma concentrations of Compound 2 at the time of study drug administration (0 hours) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours after dosing. Urine samples were collected and analyzed for Compound 2 concentrations beginning 2 hours before and continuing through 48 hours after study drug administration.

[0233] In Study 1, Part 2, blood was sampled for plasma concentrations of Compound 2 at 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, and 48 hours after dosing.

[0234] From Part 1, the maximum plasma concentrations (C max ) occurred at a median time of 3 to 5.5 hours before the plasma concentration began to decline exponentially, and the geometric mean t 1 / 2 The exposure increased approximately dose-proportionally over the entire dose range: a 75-fold dose increase resulted in a geometric mean C max , AUC last , and AUC inf The PK results were shown in the table below (AUC = area under the time concentration curve where a measurable concentration persists or is extrapolated to infinity; t 1 / 2 = terminal half-life; CL / F = apparent total clearance from plasma; CV = coefficient of variation; SD = standard deviation; tmax =C max time to saturation; Vss / F = apparent volume of distribution at steady state):

[0235] [Table 16]

[0236] Part 2 showed that a 5 mg dose administered with a high-fat meal had no effect on exposure to Compound 2 compared to fasting conditions. Median t max was 6.00 h whether fed or fasted. The geometric mean ratio of fed / fasted was C max and AUC last and 0.92 and 0.91, respectively. Within-subject variability (i.e., fed vs. fasted) accounted for less than half of the total subject variability.

[0237] Research 2 Study 2 was a single-center, double-blind, randomized, placebo-controlled, ascending-dose study of the safety, tolerability, PK, and pharmacodynamics of Compound 2 in healthy adult male and female volunteers.

[0238] The study enrolled and randomized 36 healthy adults (19 men and 17 women) (n=9 per group) to receive Compound 2 at 5, 10, or 20 mg (provided in the form of a 5-mg capsule of the L-malate salt) or placebo, administered once daily after at least a 10-hour fast, for 14 days.

[0239] Blood was sampled for plasma concentrations of Compound 2 as follows: Day 1, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 16 hours post-dose; Days 2-5, 8, 11, and 13, 0 hours; Day 14, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 15-17, 24, 48, and 72 hours post-dose on Day 14, respectively. Urine samples were collected and analyzed for Compound 2 concentrations 0-24 hours post-dose on Day 1 (0 hours post-dose) and consecutively on Day 14. Pharmacodynamic endpoints (plasma GL-1, GL-3, and GM3 concentrations) were assessed 0 hours post-dose on Days 1-5, 8, 11, 13, and 14; and 24 hours post-dose on Day 15.

[0240] In subjects receiving 5, 10, or 20 mg of Compound 2 once daily for 14 days, plasma C max were observed to occur at a median time of 2 to 5 hours after dosing on days 1 and 14. trough Compound 2 exposure increased approximately dose-proportionally over the dose range of 5 to 20 mg: this four-fold dose increase resulted in a geometric mean C max and AUC 0-24 There was a 3.76- and 3.69-fold increase in values, respectively. The PK results from Study 2 are summarized in the following table:

[0241] [Table 17]

[0242] After 14 days of once-daily administration of Compound 2, the 24-hour urinary excretion rate of unchanged compound (mean fe 0-24 ) ranged between 26.3% and 33.1%, without any clear dose-related association. R(0-24) ranged between 1.49 L / h and 2.07 L / h, approximately 3.18-3.86-fold lower than the observed plasma CL / F.

[0243] Plasma GL-1, GL-3, and GM3 in placebo recipients remained similar across baseline, while across the three Compound 2 dose groups, plasma GL-1 and GM3 levels decreased from baseline in a time- and dose-dependent manner as shown in the following table (point estimates of treatment ratios for glucosylceramide (GL-1), globotriaosylceramide (GL-3), and GM3 ganglioside (GM3) at day 15 of the repeated ascending dose study):

[0244] [Table 18]

[0245] The maximum sustained effect for GL-1 occurred on Day 11 in the 5 and 10 mg groups and by Day 8 in the 20 mg group. The mean calculated GL-1 reduction from baseline on Day 15 was 41.9%, 69.6%, and 74.6% in the 5, 10, and 20 mg groups, respectively. GL-1 values ​​were below the lower limit of quantification (LLOQ) at baseline in one 5 mg Compound 2 recipient and on Day 15 in three, five, and nine subjects in the 5, 10, and 20 mg groups, respectively.

[0246] The greatest sustained GM3 reduction occurred across all dose groups of Compound 2, beginning on day 13. Mean plasma GM3 levels on day 15 were 42.7%, 49.4%, and 57.8% of baseline for the 5, 10, and 20 mg dose groups, respectively. GM3 was below the LLOQ on day 15 in one and two subjects, respectively, in the 10 and 20 mg dose groups.

[0247] Plasma GL-3 also decreased over time in all Compound 2 dose groups, but baseline GL-3 values ​​were variable and low compared to the LLOQ, limiting the calculated mean decrease in GL-3. In the placebo, 5, 10, and 20 mg dose groups, GL-3 values ​​were below the LLOQ in 1, 3, 1, and 6 subjects, respectively, at baseline and in 4, 9, 7, and 9 subjects, respectively, at day 15.

[0248] C of Compound 2 in the 5, 10, and 20 mg dose groups trough The mean estimated plasma GL-1 reductions from baseline attributable to the treatment (19.0, 47.5, and 69.9 ng / mL, respectively) (90% CI) were 67.0% (54.4-79.7%), 74.4% (63.7-85.2%), and 76.3% (64.8-87.8%), respectively. Ta.

[0249] conclusion In these studies, exposure to compound 2 (C max and AUC) were approximately dose proportional when administered over a range of 2 to 150 mg as a single dose or 5 to 20 mg as repeated daily doses for 14 days. A high-fat meal had no effect on exposure in subjects receiving a single 5 mg dose compared with fasting. At repeated daily doses of 5 to 20 mg, steady state was reached within 5 days; neither age nor sex influenced accumulation. Pharmacodynamically, repeated daily doses of compound 2 reduced plasma concentrations of GL-1 and GM3 in a time- and dose-dependent manner, consistent with compound 2-mediated GCS inhibition, although baseline levels of GL-3 were too low to be useful as a pharmacodynamic biomarker. The dose-dependent reduction in GL-1 supported the intended mechanism of action of compound 2: inhibition of GL-1 formation from ceramide by GCS.

[0250] In all studies, the safety profile, including serious adverse events [SAEs], ECG monitoring, clinical laboratory values, and physical examinations, was assessed by treatment-emergent adverse event (TEAE) monitoring for 10 days after the last dose of study medication. There were no deaths, SAEs, severe TEAEs, or TEAEs leading to study discontinuation in any study.

[0251] No clinically relevant blood or biochemical abnormalities were reported in any study. Vital signs showed no relevant changes from baseline in any study. ECG parameters showed no relevant changes in ascending single dose and food effect studies; in multiple ascending dose studies, ECG parameters did not change statistically significantly from mean baseline vs. placebo in Compound 2 recipients at any dose. While the present invention has been described in conjunction with the above embodiments, it should be understood that the foregoing descriptions and examples are intended to be illustrative and not limiting of the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the present invention pertains. EXAMPLES

[0252] Clinical Study of Compound 2 in Patients with Fabry Disease method A 3-year open-label study of Compound 2 in young patients with classic Fabry disease was conducted to evaluate the long-term safety, pharmacodynamics, and exploratory efficacy of Compound 2 in adult male Fabry patients. Eleven subjects were enrolled in the study, with seven subjects completing all aspects of the study. All subjects were men with a diagnosis of classic Fabry disease confirmed by genotype and residual alpha-galactosidase activity below the level of detection (9 of the 11 had a nonsense mutation in the GLA gene). All subjects had plasma lyso-GL3 levels of at least 65 ng / mL and had no history of Fabry-specific treatments. The median age of subjects was 24 years (range 19-37 years).

[0253] Patients were administered a daily oral dose of 15 mg of compound 2. Skin clearance of GL-3 deposits was monitored by performing biopsies at weeks 12, 26, 52, and 156, which were semiquantitatively assessed by light microscopy (focusing on dermal capillary endothelial cells). Each sample was independently scored by three pathologists for the presence of GL-3 inclusions on a 4-point scale and graded as 0 (none / slight), 1 (mild), 2 (moderate), or 3 (severe) according to Eng et al., N. Engl. J. Med. 345:9-16 (2001). A single score per patient per time point was derived by taking the scores graded by the majority of the three pathologists. When a majority score could not be derived, the median score was used (several fractional scores were obtained). Plasma samples were also collected at baseline and at weeks 12, 26, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, Analysis was performed for GL-3, lyso-GL-3, GL-1, and GM3 at weeks 52 and 156. Pain scores and abdominal symptoms were analyzed at baseline and weeks 12, 26, 52, 104, and 156 using the SF-36 scoring protocol.

[0254] Patients were assessed at multiple visits from baseline to week 156 using the Short Form-36 (SF-36) questionnaire. This is a 36-item questionnaire used to measure eight different aspects of health (vitality, physical functioning, bodily pain, general well-being, physical role functioning, mental role functioning, social role functioning, and emotional health). Scores for each of the eight aspects range from 0 (maximum disability) to 100 (no disability), with higher scores indicating better health status. In addition, gastrointestinal symptoms, including abdominal pain, abdominal distension, and bowel movements, were assessed using a modified version of the Inflammatory Bowel Severity Scoring System. Specific questions asked as part of these assessments included: (1) whether the patient had abdominal pain within the past 10 days, (2) using a scale of 0 (no pain) to 100 (very severe pain), how severe was the abdominal pain suffered in the past 10 days, and (3) how many days within the past 10 days the patient had abdominal pain.

[0255] result By 156 weeks, five patients showed a 1 point reduction in skin GL-3 scores, two patients had complete clearance of GL-3 inclusions, one patient had no change, and one patient had no samples. Over the course of the 156 week study, mean plasma GL-1 levels decreased by 69%, mean plasma GM3 levels decreased by 60%, mean plasma GL-3 levels decreased by 77%, and mean plasma lyso-GL3 levels decreased by 52%. Plasma GL-1 and GM3 showed extremely rapid declines within the first 2-4 weeks of treatment. All four measures showed sustained maintenance of reduced plasma burden, which nearly stabilized by 52 weeks.

[0256] Plasma and urine data are summarized in the following table:

[0257] [Table 19]

[0258] These results demonstrate that Compound 2, administered at 15 mg / day, consistently reduced body levels of GL-1, lyso-GL-1 and GM3 in a generally progressive manner.

[0259] Additionally, data from a previously completed placebo-controlled Phase 3 trial of agalsidase beta (Fabrazyme) were analyzed and compared (see Eng et al., N. Eng. J. Med., 345:9 (2001)). For the comparison with agalsidase beta, the historical control group was patients treated with agalsidase beta in a Phase 3 trial, and changes in plasma GL-3 were compared at multiple time points up to 3 years. Inclusion criteria and baseline characteristics were similar between the two studies. To strengthen the comparison, patients receiving Compound 2 were randomly assigned to receive either Compound 2 or Compound 2, based on age, plasma GL-3, sex, UPCR (<500 mg / g vs. 500-1000 mg / g vs. >1000 mg / g), and eGFR (80 mL / min / 1.73 m 2 Less than 80mL / min / 1.73m2 Patients were matched to Phase 3 study patients based on a propensity score using baseline variables including: ≥ 100 mg / g (≥ 100 mg / g) and ≥ 100 mL / min / 1.73 m2 (≥ 100 mg / g). Eleven Compound 2-receiving patients were matched to 19 patients for the placebo comparison and 28 patients for the agalsidase beta comparison. In all three groups, all patients were male and had elevated plasma GL-3, UPCR < 500 mg / g, and ≥ 80 mL / min / 1.73 m2. 2 A greater eGFR was demonstrated. Mean age was similar across the three groups. Comparisons show that treatment with Compound 2 for 26 weeks resulted in a significant reduction in plasma GL-3 compared to placebo, -3.62 μg / mL vs. -1.06 μg / mL (P<0.0001). Treatment with Compound 2 resulted in a similar reduction in plasma GL-3 at 52 weeks compared to agalsidase beta, but at 104 and 156 weeks, the reduction in plasma GL-3 from compound treatment was significantly greater (p=0.0351 at 104 weeks; p=0.0081 at 156 weeks). After 156 weeks, plasma GL-3 levels were 1.90 μg / mL for patients treated with Compound 2 and 4.44 μg / mL for patients treated with agalsidase beta.

[0260] Detailed results for skin GL-3 inclusion scores are shown in the table below (a score of 0 indicates no GL-3 inclusions):

[0261] [Table 20]

[0262] [Table 21]

[0263] [Table 22]

[0264] [Table 23]

[0265] In addition to scoring GL-3 skin inclusions by light microscopy, the percentage of endothelial cell cytoplasmic volume occupied by GL-3 inclusions was assessed using point counting of electron microscopy images by a masked reader. Images from at least 50 superficial endothelial cell capillaries were obtained at 7500x magnification using an electron microscope. A two-tailed t-test was used to assess differences between baseline and post-treatment values ​​at each time point. The results are shown in the table below:

[0266] [Table 24]

[0267] These results demonstrate that Compound 2 administered at 15 mg / day consistently reduced the levels of GL-3 inclusions in skin in a generally progressive manner. The results were generally more pronounced for superficial vascular endothelial cells compared to deep vascular endothelial cells and other skin tissues.

[0268] Seven of nine patients had improvement in overall bodily pain scores (SF-36) at 26 weeks, while three of six patients had improvement in overall bodily pain scores (SF- 36) improved. Among patients with gastrointestinal pain at baseline, pain severity (abdominal pain) decreased in 4 of 5 patients at 26 weeks and in 4 of 4 patients at 156 weeks. The number of days with gastrointestinal pain decreased in 5 of 5 patients at 26 weeks and in 3 of 4 patients at 156 weeks.

[0269] Detailed results regarding abdominal pain measurements are shown in the table below.

[0270] [Table 25]

[0271] These results demonstrate that Compound 2, administered at 15 mg / day, consistently reduced physical abdominal pain and discomfort in a generally progressive manner.

[0272] Furthermore, when features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also described with respect to any individual members or subgroups of members of the Markush group.

[0273] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each was individually incorporated by reference. In the case of conflict, the present specification, including definitions, will control.

Claims

1. A method for treating or preventing supranuclear gaze palsy (e.g., associated with a lysosomal storage disease) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmacologic acceptable salt or prodrug thereof. 【Chemistry 1】 (In the formula: R １ is hydrogen, halogen (e.g., fluorine), cyano, nitro, hydroxy, thio, amino, C １～６ - alkyl (e.g. methyl or ethyl), C ２～６ -Alkenyl, C ２～６ -Alkynyl, C １～６ -Alkyloxy, C ２～６ -alkenyloxy, and C ２～６ -alkynyloxy, where said alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, or alkynyloxy is optionally substituted with one or more (e.g., 1, 2, or 3) groups selected from halogen, cyano, nitro, hydroxy, thio, or amino; R ２ and R ３ is C optionally substituted with one or more (e.g., 1, 2 or 3) halogens; １～３ -alkyl or R ２ and R ３ together form a cyclopropyl or cyclobutyl group optionally substituted with one or more (e.g., one or two) halogens; R ４ , R ５ and R ６ is hydrogen, halogen, nitro, hydroxy, thio, amino, C １～６ -Alkyl, and C １～６ -alkyloxy, where said alkyl or alkyloxy is selected from halogen, hydroxy, cyano, and C １～６ -alkyloxy; A is halogen, hydroxy, thio, amino, nitro, C １～６ Alkoxy and C １～６ and alkyl, aryl or heteroaryl groups (eg, phenyl or thiazolyl) optionally substituted with 1, 2, or 3 groups independently selected from aryl, aryl, heteroaryl, aryl and heteroaryl groups (eg, phenyl or thiazolyl).

2. R １ 2. The method of claim 1, wherein is selected from hydrogen, fluorine, methyl and ethyl, said methyl or ethyl being optionally substituted with one or two groups selected from halogen, hydroxy, thio or amino.

3. R ２ and R ３ 3. The method of claim 1 or 2, wherein each is independently selected from methyl and ethyl groups optionally substituted with one or more fluorines.

4. R ４ is a halogen (e.g., fluorine), C １～３ - alkyl (e.g. methyl) and C １～３ - alkyloxy (e.g. methoxy or ethoxy), wherein said alkyl or alkyloxy is selected from halogen and C １～３ A method according to any one of claims 1 to 3, optionally substituted by one or more (eg 1, 2 or 3) groups selected from - alkyloxy (eg methoxy or ethoxy).

5. R ５ and R ６ The method of any one of claims 1 to 4, wherein each is hydrogen.

6. R ４ is fluorine or 2-methoxyethoxy, R ５ and R ６ The method of any one of claims 1 to 5, wherein is hydrogen.

7. R ４ The method of any one of claims 1 to 6, wherein is located at the 4-position of the phenyl ring to which it is attached (i.e., para to the A substituent).

8. A is halogen, hydroxy, thio, amino, nitro, C １～６ Alkoxy and C １～６ The method of any one of claims 1 to 7, wherein the aryl group is phenyl optionally substituted with 1, 2 or 3 groups independently selected from alkyl (eg methyl).

9. 9. The method of claim 8, wherein the two groups attached to the A substituent are positioned in a 1,3 or 1,4 relationship to each other (i.e., meta or para).

10. The method of any one of claims 1 to 7, wherein A is a 5-membered heteroaryl group containing 1 or 2 heteroatoms selected from N and S.

11. 11. The method of claim 10, wherein the two groups attached to the A substituent are positioned in a 1,3 relationship (i.e., meta) to each other.

12. The method of any one of claims 1 to 11, wherein the compound is a compound of formula (II), (III) or (IV) or a pharma- ceutically acceptable salt or prodrug thereof. 【Chemistry 2】

13. The method of any one of claims 1 to 11, wherein the compound is a compound of formula (V) or a pharma- ceutically acceptable salt or prodrug thereof: 【Chemistry 3】

14. The method of any one of claims 1 to 11, wherein the compound is a compound of formula (VI), (VII) or (VIII) or a pharma- ceutically acceptable salt or prodrug thereof: 【Chemistry 4】

15. The method of any one of claims 1 to 11, wherein the compound is a compound of formula (IX) or (XI) or a pharma- ceutically acceptable salt or prodrug thereof: 【Chemistry 5】

16. R ４ The method of claim 15 , wherein is fluorine.

17. 2. The method of claim 1, wherein the compound is selected from quinuclidin-3-yl (2-(4'-fluoro-[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate; (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate; (S)-quinuclidin-3-yl (2-(4'-(2-methoxyethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate; and pharma- ceutically acceptable salts and prodrugs thereof.

18. The method of claim 1, wherein the compound is quinuclidin-3-yl (2-(4'-fluoro-[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate.

19. The method of claim 1, wherein the compound is (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate.

20. The method of any one of claims 1 to 19, wherein the subject has Gaucher disease type 3 or Niemann-Pick disease type C.

21. The method according to any one of claims 1 to 20, wherein the supranuclear gaze paresis is conjugate gaze paresis.

22. The method of any one of claims 1 to 21, wherein the subject is a mammal, such as a human.

23. The compound, or a pharma- ceutically acceptable salt or prodrug thereof, is administered systemically.

23. The method of any one of claims 1 to 22, wherein the compound is administered via a route other than parenteral, for example.

24. 24. The method of claim 23, wherein the compound, or a pharma- ceutically acceptable salt or prodrug thereof, is administered orally.

25. The method of any one of claims 1 to 24, wherein the subject is undergoing concomitant treatment with an enzyme replacement therapy (ERT), e.g., with glucocerebrosidase (e.g., imiglucerase, velaglucerase, or taliglucerase).

26. 26. The method of any one of claims 1 to 25, wherein the subject is administered a daily dose of about 1 mg to about 50 mg of the compound, for example, 5 to 50 mg, or 10 to 40 mg, or 10 to 30 mg, or 10 to 20 mg, or 20 to 30 mg, or 30 to 40 mg, or 40 to 50 mg, or 5 to 25 mg, or 20 to 50 mg, or 5 to 15 mg, or 15 to 30 mg, or about 15 mg of the compound.

27. 20. A compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt or prodrug thereof, for use in a method of treating or preventing supranuclear gaze palsy (e.g., associated with a lysosomal storage disease) in a subject in need thereof.

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