TW201249841A - Novel salt forms of 3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane - Google Patents

Abstract

The present invention relates to 3-cyclopropylcarbonyl-3, 6-diazabicyclo[3.1.1]heptane, its salt forms, and novel polymorphic forms of these salts.

Description

201249841 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to 3-cyclopropylcarbonyl-3,6-diazabicyclo[3.丨^heptane, its salt form, and novelties of such salts Polymorphic. The invention also includes pharmaceutical compositions in such salt forms and methods for treating a variety of conditions and disorders. [Prior Art] Compound 3-cyclopropyl-based-3,6-dioxabicyclo[3.1.1]heptane (Compound A) is a neuronal nicotinic receptor (NNR) agonist for α4β2* (containing α4β2) and α6β2* (containing α6β2) NNR is selective. In a preclinical rodent model of levodopa-induced dyskinesia (LID), Compound A has been shown to be particularly effective in preventing the complete onset of abnormal involuntary movement (AIm) and attenuating existing AIMs. Has efficacy. Compound A attenuates LID in non-human primates (cynomolgus) and does not interfere with general activity or the effect of L-dopa on motor deficits. Compound a exhibits resistance to rat dopamine neurons. The neuroprotective effect of MPP+ toxicity in primary cultures. 3-Cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane has the following structural formula: γ such as 3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]g The commercial development of drug candidates such as alkanes involves a number of steps, including the development of a versatile synthetic method suitable for large-scale processes 162775.doc 201249841. Commercial research and development also involves research on the salt form of a drug substance that exhibits appropriate purity, chemical stability, medical properties, and properties that facilitate handling and handling. In addition, compositions containing drug substances should have sufficient shelf life. That is, it should not exhibit significant changes in physicochemical properties (such as, but not limited to, chemical composition, water content 'density, water absorption, and solubility) for a relatively long period of time. In addition, a reproducible and constant plasma concentration profile of the drug when administered to a patient is also an important factor. For oral formulations, the solid salt form is generally preferred due to the tendency to exhibit such properties in a preferential manner; and in, for example, 3_cyclopropylcarbonyl-3,6-azabicyclo[3·Μ]heptane In the case of an alkaline drug, the acid addition salt is often in a preferred salt form. However, the ability of the salt form to impart such properties varies significantly and does not accurately predict such properties. For example, some salts are solid at ambient temperatures, while others are liquids, viscous oils or gums at ambient temperatures. In addition, some salt forms are stable to heat and light under extreme conditions and other salt forms are readily decomposed under much milder conditions. Therefore, the development of suitable acid addition salt forms for basic drugs in pharmaceutical compositions is a highly unpredictable process. A synthesis of the compound oxime is disclosed in the pCT application No. PCT/US2 〇 1〇 / 058836 (WO 201 1/071758), the disclosure of which is incorporated herein by reference. However, it is expected that the synthesis of 3-cyclopropylcarbonyl-3,6-diazabicyclo[3.^^heptane can be scaled up to mass production. In addition, salt forms that exhibit improved properties including purity, stability, solubility, and bioavailability are required. The preferred characteristics of these new forms of salt include their ability to increase the manufacture of active ingredients and the ease or efficiency with which they are formulated into commercial products. Finally, there is a need to increase the manufacture of active ingredients and their stable polymorphic forms of such salts formulated to the ease or efficiency of commercially viable products. SUMMARY OF THE INVENTION One aspect of the present invention is an acid addition salt of 3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane. In certain embodiments, the acid is selected from the group consisting of hydrogen acid, p-toluic acid, L-aspartic acid, maleic acid, l- faceted acid, 1-cyano-2-naphthoic acid (ie, hydroxy Naphthoate), fumaric acid, galactosidic acid, hippuric acid, L-mandelic acid, succinic acid, adipic acid or (+)-camphoric acid. In a preferred embodiment, the 'acid addition salt is a p-toluenesulfonate, a maleate, a galactate, a benzoate, a horse urate, a hydroxynaphthoate or a (+) 樟 camphor Acid salt. In still other preferred embodiments, the salt is a galactose salt, a benzoate, a hippurate or a hydroxynaphthoate. Another aspect of the invention includes 3-cyclopropylcarbonyl-3-3,6-diazabicyclo[3.1.1] heptanosemi-galactosidate (11611^£&1&(^&^ 16) Monohydrates Another aspect of the present invention includes 3-acid cyclopropyl- 3,6-diazabicyclo[3.1.1] heptane acid addition salt, wherein the salt is crystallized. One aspect of the invention is a method, use, compound, or use for the manufacture of a medicament for treating or preventing one or more diseases or conditions, for use in treating or preventing one or more diseases or conditions. In one embodiment, The disease or condition is Parkinsonism, Parkinson's disease (Parkins〇n, s

Disease, one or more of abnormal involuntary movements, dyskinesias, and levodopa-induced dyskinesias. In one embodiment, a patient in need is undergoing an existing therapy including a levodopa administration regimen. In yet another embodiment 162775.doc 201249841, the administration of Compound A has a synergistic effect such that the patient is able to reduce the dosage, or change the time course, or otherwise modify the existing administration regimen of levodopa therapy. Thus, one aspect of the invention includes the treatment of levodopa-induced dyskinesia without inhibiting the anti-Parkinsonian activity of levodopa. Another aspect includes retarding the progression of Parkinson's disease to provide a lower dose of levodopa or a later dosing time course, thereby delaying the onset of levodopa-induced dyskinesia. Compound A attenuates abnormal involuntary movements and levodopa-induced dyskinesia. These constitute another aspect of the invention. Yet another aspect of the invention includes alleviating levodopa-induced dyskinesia without hindering the effect of levodopa on motor deficits. Compound A has a neuroprotective effect. One aspect of the invention includes a novel synthetic method for the manufacture of Compound A. Additionally, the invention includes one or more novel intermediates for use in the method of synthesis. Other aspects and embodiments of the invention are set forth herein. The mouthpiece of the present invention includes combinations of aspects, examples, and preferences. [Embodiment] Definitions The following definitions are intended to be clear (but not limited to) defined terms. If a specific term used herein is not explicitly defined, the term should not be construed as inaccurate. Instead, the surgery is used within its accepted meaning. Depending on the naming convention used, 3_cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane may also be referred to as 3,6-diazabicyclo[311]heptane-3-yl (cyclic group). Ketone, or may be referred to as some chemical name. The choice of naming convention = 162775.doc 201249841 should not affect the scope of the invention. As described herein, the structure of the compound is:

And for ease of reference, it may also be referred to herein as a compound hydrazine. The phrase "compound of the present invention" as used herein means 3-cyclopropylcarbonyl-3,6-dioxabicyclo[3.1.1]heptane or an acid addition salt thereof. The acid is selected from the group consisting of hydrochloric acid, p-dosyl sulfonic acid, L-aspartic acid, maleic acid, L-glutamic acid, 丨_hydroxy_2_naphthoic acid (ie, naphthoic acidate), Fuma Acid, galactosedioic acid, hippuric acid, L-mandelic acid, succinic acid, adipic acid or (+)-camphoric acid. In a preferred embodiment, the 'acid addition salt is a p-toluenesulfonate, a maleate, a galactate, a benzoate, a hippurate, a hydroxynaphthoate or a (+) 樟 camphor Acid salt. In still other preferred embodiments, the salt is a galactose salt, a benzoate salt, a hippurate salt or a hydroxynaphthoate salt. The phrase "compound of the invention" includes hydrated or solvated salt forms. In addition, depending on the context, it will be easy to understand, and the term "combination" is used herein.

Form or salt form.

There is now a certain degree of stability to make it suitable for manufacturing and commercial purposes. The terms "effective amount", "therapeutic amount" or "effective amount" as used herein mean an amount of the active ingredient which is sufficient to elicit the desired pharmacological or therapeutic effect, thereby effectively preventing or treating the condition. Prevention of a condition can be manifested by delaying or preventing the progression of the condition, as well as delaying or preventing the onset of symptoms associated with the condition. Treatment of a condition can be manifested as any reduction or elimination of symptoms, inhibition or reversal of the progression of the condition, and any other factor that contributes to the patient's well-being. The effective dose may depend on factors such as the condition of the patient, the severity of the symptoms of the condition, and the manner in which the pharmaceutical composition is administered. In general, the compound to be administered in an effective dose needs to be administered in an amount of less than 5 mg/kg of the patient's body weight. These compounds can often be less than about i mg/kg of patient body weight to less than about 100 Pg/kg of patient body weight, and occasionally Administration is carried out in an amount between about 10 pg/kg to less than about 1 Kg/kg of patient body weight. The above effective doses generally represent amounts administered in a single dose or in one or more doses administered over a 24 hour period. For human patients, an effective dose of the compound may be required to be at least about 1 mg/24 hr/patient, but no more than about 1000 mg/24 hr/patient, and often no more than about 5 〇〇μ hr/patient. Investment. Things. Potential doses can range from 500 Hg to 2 mg in the form of the free base equivalent. As used herein, the phrase "substantially crystallized" includes greater than 2%, preferably greater than 30%. More preferably, it is more than 40% (for example, greater than 5%, 6%, 7%, 8%, or 9%). The term "stability" as defined herein includes chemical stability and solid state stability. _ Gan_. rl·* L1 -» Five "^ δ 〇 chemical stability" is included in isolated form, or in combination with 162775.doc 201249841 (four) Mixing the carrier, diluent, excipient or adjuvant to provide an oral dosage form, such as a tablet, capsule or the like, for storing the salt of the invention under private storage conditions and without: significant potential, and The phrase "solid state stability" includes = mixed with medically acceptable carriers, diluents, excipients or adjuvants. Providing a solid formulation form (for example, in an oral dosage form such as a troche, capsule or the like) for storage of a salt of the invention under standard storage conditions and solids transformation (eg, crystallization, recrystallization, solid phase transformation, hydration, dehydration, solvation or Desolvation) The potential for an insignificant degree. Examples of "standard storage conditions" include - or more of the following: temperatures between -80C and 50. (between, preferably between 〇t: and Fu and better ring i, such as 15C to 30 ° C; pressure between oi and 2 bar, preferably atmospheric pressure; relative humidity between Between 5% and 95%, preferably 1% to 60 〇/〇; and an extended period of exposure in uv 1 / uv or less visible light, for example greater than or equal to 6 months. Under these conditions, It is found that the salt of the present invention (if appropriate) is less than 5%, more preferably less than 2% and especially less than 1% chemically degraded or decomposed or solid state converted. Those skilled in the art should be aware of the above upper limits of temperature, pressure and relative humidity and The lower limit represents the extreme of standard storage conditions and will not undergo some combination of such extremes during standard storage (eg, a temperature of 50 ° C and a pressure of 1 bar). Compounds One embodiment of the invention includes a 3-ring Propylcarbonyl-3,6-diazabicyclo[3.1.1]heptane (Formula I) or a pharmaceutically acceptable salt thereof. 162775.doc 201249841 Η

Formula ι Compound A One embodiment includes the use of 3-cyclopropylcarbonyl-3,6-diazabicyclo[3丄^^, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament. One embodiment of the invention includes a method for treating or preventing a plurality of conditions and dysfunction comprising administering to a mammal in need of such treatment a therapeutically effective amount of 3-cyclopropylcarbonyl-3,6-diazabicyclo [3丄丨]heptane or a pharmaceutically acceptable salt thereof. More specifically, the condition or dysfunction may be selected from a group of Cns disorders (including AIMS and LID), or other disorders as further detailed herein. Another embodiment of the invention encompasses use as a diagnostic reagent and for a compound in a receptor binding assay as described herein. An embodiment of the invention comprises a therapeutically effective amount of 3-cyclopropyl-based-3,6-diazabicyclo[3·1.1]heptane or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable salts A pharmaceutical composition that accepts a carrier. Another embodiment of the invention encompasses the use of a pharmaceutical composition of the invention for the manufacture of a medicament for the treatment of disorders and dysfunctions of the central nervous system. According to any one of the examples, another embodiment of the present invention includes 3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane or a pharmaceutically acceptable salt thereof. Another embodiment of the present invention includes 3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane or a pharmaceutically acceptable salt thereof, which is used as an active therapeutic substance. Another example of the present invention is 162775.doc •10·201249841 Examples include 3-cyclopropylcarbonyl-3,6-diazabicyclo[3丨uheptane or a pharmaceutically acceptable salt thereof, which is used for Adjust the NNR of the individual in need. Further examples of this month include 3-cyclopropylcarbonyl-3-3,6-diazabicyclo[3.1.1]heptane or a pharmaceutically acceptable salt thereof for use in the treatment or prevention by one or more NNR's condition or condition. Another embodiment of the invention includes the use of 3- _cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane or a pharmaceutically acceptable salt thereof, which is suitable for use in conditioning for conditioning One or more of the individual's agents. Further embodiments of the invention include the use of 3-cyclopropylcarbonyl-3,6-dioxabicyclo[3.1.1]heptane or a pharmaceutically acceptable salt thereof for the treatment or prevention of Agents of a condition or disorder mediated by _ or multiple cissicles. Another embodiment of the invention comprises administering 3·cyclopropylheptyl-3,6-diazabicyclo[3.M]heptane or A pharmaceutically acceptable salt modulates one or more of the individuals in need. Unless otherwise indicated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotope collection atoms. For example: 'A compound having the structure of the present invention, replacing hydrogen atoms by helium or gas, or replacing a carbon atom by 13C or 14C, or replacing a nitrogen atom with 15N, or replacing an oxidant with 17〇 or 18〇 Within the scope of the invention. Such isotopically labeled compounds can be used as research or diagnostic tools. As described herein, the invention includes specific representative compounds, which are specifically identified herein. The compounds of the present invention can be prepared by a variety of methods, including standard well-known methods. The specific synthetic compounds of the present invention are prepared in the working examples by way of illustration. In all of the following examples, if necessary, according to the general principles of synthetic chemistry 162775.doc •11·201249841 Protective groups are employed for sensitive or reactive groups. The protecting group is manipulated according to the method of organic synthesis (T. W. Green and P. G. M. Wuts, ecting Groups in Organic Synthesis > ^ 3 M ' John

Wiley & Sons, New York (1999)). These libraries are removed at a convenient stage of compound synthesis using methods apparent to those skilled in the art. The method and the choice of reaction conditions and their order of execution should be consistent with the preparation of the compounds of the invention. The present invention also provides a method of synthesizing a compound useful as an intermediate. General Synthetic Methods The manner in which Compound A can be synthesized can vary. In one method, Compound A can be prepared by protecting 3,6-diazabicyclo[3.1.1]heptane with a suitable cyclopropylcarbonyl derivative protected at the 6-position nitrogen atom (preventing reaction with a oximation agent). Coupling (e.g., cyclopropylmethylhydrazine), followed by removal of the protecting group (usually with an acid). Cyclopropylguanidinium chloride can be prepared by treating cyclopropyl decanoic acid, in particular, with a reagent such as sulfoxide or oxalate. Synthesis of a suitably protected 3,6-diazabicyclo[3.1.1]heptane, 6·(t-butoxymethyl)-3,6-azabicyclo[3.1.1]heptane is disclosed in Presented to WO 2005/108402 by pjnna. (About this synthetic teaching is incorporated by reference). Those skilled in the art of organic synthesis should be aware that other suitable 3,6-diazabicyclo[3.1.1] heptane can also be used to prepare compound a (see 'T' W. Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New

York (1999)). Another way of preparing Compound A is by coupling a suitable 6-protected 3,6-diazepine 162775.doc 201249841 bicyclo[3.1.1]heptane with cyclopropylcarboxylic acid, followed by removal of the protecting group. This method usually requires the use of a suitable activator such as N,N'-dicyclohexylcarbodiimide (DCC), hexafluorophosphate (benzotriazol-1-yloxy)indole (didecylamino) hydrazine. (BOP), hexafluorophosphate (benzotriazol-1-yloxy)triazolidine-based scale (PyBOP), hexafluorophosphate 0 (benzotriazol-1-yl)-oxime, oxime, Ν' , Ν1-bis(tetradecyl)urea rust salt (HBPyU), hexafluorophosphate 0-(benzotriazol-1-yl)-team: ^',;^-tetramethylurea rust salt (1 ^丁1;), tetrafluoroboric acid 0-(benzotriazol-1-yl)-indole, hydrazine, hydrazine, Ν'-tetramethylurea rust salt (TBTU) or (1-ethyl-3- (3-Dimethylaminopropyl)carbodiimide) (EDCI) and 1-hydroxybenzotriazole (HOBt) Other activators are well known to those skilled in the art, for example, see Kiso And Yajima, Peptides, pp. 39-91, Academic Press, San Diego, CA (1995) 0 Reaction circle 1: Synthesis of compound A cioCs^/N^coa 1

Bra

BnOH ether Na day H4 thf/ch3oh

Bn〇2〇

BnMH2, dmf

Bn-N- i-C〇2Bn ^C〇2Bn 4

Msa TEA, DCM 10% Ρύ/C, HC02NH4 C2H5OH yV Br Bf CO^Bn 3

Compound A

NaH, NMP Bn,

Bn=benzyl; Ms=methanesulfonyl; DMF=dimercaptocaramine; THF=tetrahydrofuran; TEA=triethylamine; DCM=di-methane; NMP=N-mercapto-2-pyrrolidone . Alternatively, and advantageously, Compound A can be prepared using a reaction sequence similar to that shown in Reaction Scheme 1. This method involves a ring closure process in which the anion of cyclopropylguanamine reacts with a bis-162775.doc-13-201249841 electrophile (e.g., intermediate 6) to reduce the synthesis (e.g., 'WO 2011/071758) The overall length of the synthesis. Specific examples of this method of synthesizing Compound A are given in the Examples section and are summarized in Reaction Scheme 1. However, the reagents used to accomplish the conversion of this method may vary. For example, a plurality of alcohols can be used in the esterification reaction to provide a plurality of diester products (examples are diesters 3). The physical properties of a particular diester can provide advantages in purification or handling. Similarly, a wide variety of amines and solvents can be used for ring closure of a 4-membered (azetidine) ring, and specific amine/solvent mixtures provide advantages in reactivity or product purity, including stereochemical purity. The monoalkyl azepanyl-2,4-dicarboxylate (for example, intermediate 4) can be completed by a plurality of reagents (for example, borohydride and aluminum hydride reagent) present in a plurality of solvents. Reduction of a diol such as diol 5. Importantly, a reducing reagent that preserves the cis relative stereochemistry around the azetidin ring is selected. The conversion of the diol to a suitable bis-electrophile can be accomplished by a variety of reagents known to those skilled in the art. The conversion of alcohols to the corresponding dentates (e.g., vapors, bromides, iodides), and their conversion of alcohols to sulfonates, phosphates, and the like are well known in the chemical literature. The closure of a 6-member (hexahydrogen-to-bite) ring with cyclopropylcarbamamine can also be accomplished using a variety of reagents, including a variety of reagents for the generation of anions and a variety of solvents. Finally, the deprotection of the heterocyclic butyl nitrogen can be reduced under a variety of conditions depending on the nature of the protective ring. Those skilled in the art of organic synthesis should be aware that there are a number of compound continuations that produce one or more atoms that are radiolabeled and suitable for a variety of uses. For example, using the granules listed above, the labeled cyclopropyl formic acid and 6-(the:r-butyl chloride, V-butyl emulsifiable carbonyl)-3,6•2 Azabicyclohexene 162775.doc 14 201249841 [3.1.1] Heptane coupling will give 3_uc·labeled _cyclopropylcarbonylt-butoxycarbonyldiazabicyclo[3.1.1]heptane. Subsequent removal of the first butoxywei group protecting group will result in a compound suitable for use in positron emission tomography, as described above. Similarly, the coupling of 3H_4Mc_labeled cyclopropyl formic acid with 6-(t-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane as described above, followed by removal of the protecting group will result in isotopic modification Compound A, which is suitable for receptor binding and mechanistic studies or as an alternative therapeutic compound. As mentioned above, for oral formulations, the solid salt form is generally preferred due to the tendency to exhibit such properties in a preferential manner; and in, for example, 3_cyclopropylcarbonyl-3,6-diazabicyclo[ In the case of an alkaline drug such as heptane, the acid addition salt is often in a preferred salt form. The ability of different salt forms to impart such properties varies significantly' and these properties are not accurately predictable. For example, some salts are solid at ambient temperatures, while others are liquid, viscous or glue at ambient temperatures. In addition, some salt forms are stable to heat and light under extreme conditions and other salt forms are easily decomposed under far f mild conditions. H is used in pharmaceutical compositions for the determination of suitable acid additions in the form of a suitable acid. Unpredictable process. Salt forms that exhibit improved properties including purity, stability, solubility, and bioavailability are required. The preferred characteristics of these novel salt forms include those which increase the manufacture of the active ingredient and the ease or efficiency of its formulation into a commercial product. Finally, there is a need for stable polymorphs of such salts which increase the manufacture of the active ingredients and their ease of formulation or efficiency into commercial products. σ is determined by the technique of '’·, I itb using X-ray powder diffraction (XRPD). 162775.doc •15· 201249841 Crystal degree (%). Other techniques such as solid state NMR, FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC), and microcalorimetry can also be used. For the compounds of the present invention, it has been found that P field in the form of a substantially crystalline form can be produced. Several of these crystalline salts are confirmed to be sufficient to establish their stability in the production of pharmaceutical preparations. This stability can be confirmed in a variety of ways. The tendency to obtain and release atmospheric moisture can be analyzed by dynamic vapor adsorption (DVS). The solid salt can be used at 40 ° C / 75. /. The storage was carried out under RH for up to 8 days, and then the stability against high temperature and humidity was studied by weight, microscopic appearance and XRPD respective retest. Polymorphs The compounds of the invention may be crystallized in more than one form, i.e., characterized by polymorphisms, and such polymorphic forms ("polymorphs") are within the scope of the invention. Polymorphism can usually occur as a response to temperature, pressure, or both. Polymorphism can also result from changes in the crystallization process. Polymorphs can differ in a variety of physical properties known in the art (e.g., 'XRPD patterns (diffraction patterns), solubility in different solvents, and melting point). The present invention includes different polymorphic forms (including salt hydrates and solvates) of the salt form of 3·cyclopropylcarbonyl-3-3,6-diazabicyclo[3丄丨]heptane. These polymorphs are characterized by their X-ray powder diffraction (XRPD) pattern (diffraction pattern). As noted above, the salt form of 3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane can be present in solvated (e.g., hydrated) as well as unsolvated forms. The present invention covers all such forms. The invention also includes isotopically labeled compounds wherein - or more atoms I62775.doc 201249841 are substituted by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes including hydrogen, carbon, nitrogen and oxygen, such as 2H '4, im丨% and "〇. These isotopically labeled compounds are useful as research or diagnostic tools. While the compounds of the invention may be administered in the form of a physically active chemical, it is preferred to administer the compound in the form of a pharmaceutical composition or formulation. Thus, aspects of the invention include the inclusion of a compound of the invention and/or a plurality of pharmaceutically acceptable A pharmaceutical composition for receiving a carrier, diluent or excipient. Another aspect of the invention provides a method of preparing a pharmaceutical composition comprising mixing a mouthfeel of the invention with - or a plurality of pharmaceutically acceptable carriers , diluent or excipient. The manner of administration of the compound of the present invention may vary. Preferably, the compound of the present invention is orally administered. Preferred pharmaceutical compositions for oral administration include lozenges, sacs, and films. Ingredients ', solutions and stock solutions. The pharmaceutical compositions of the present invention may be provided by modified release dosage forms such as extended release (tetra) and gum (tetra) formulations. : Bi ^ ".. ▲ Grange shot, i.e. intravenous, intramuscular, subcutaneous, intraperitoneal, intraarterial, intraventricular, and Rene administered. Intravenous administration is a preferred method of primary injection. Carriers suitable for injectable use are well known to those skilled in the art and include 5% dextrose, bismuth, excipient, sucrose/liquid, saline and phosphate buffered saline. Formulations may also be administered in other ways. Intestine-administered formulations (e.g., suppositories) have been administered to them, e.g., rectal. For those skilled in the art, 162,775.doc 201249841 can also be obtained by inhaling 'for example, in the form of an aerosol; for example, in the form of a lotion; transdermal, for example, using a transdermal patch. (for example, by using techniques available from N〇Vartis and Xian); by powder injection; or by buccal, sublingual or intranasal absorption. Pharmaceutical compositions can be formulated in unit dosage form or in multiple or subunit dosages. Administration of the pharmaceutical compositions described herein can be administered intermittently, or at a gradual, continuous, ambiguous or controlled rate. The pharmaceutical composition can be administered to a warm-blooded animal, such as a mammal, such as a mouse, rat, juvenile, rabbit, dog, pig, cow or wolf; but is advantageously administered to a human. In addition, the daily time and number of times the pharmaceutical composition is administered per day may vary. The compounds of the invention are useful in the treatment of a variety of conditions and conditions, and thus can be used in combination with a variety of other therapeutic agents suitable for the treatment or prevention of such conditions or conditions. Accordingly, one embodiment of the invention encompasses the combined administration of a compound of the invention with other therapeutic compounds. For example, the compounds of the invention can be used in combination with other NNR ligands (eg, varenicline), antioxidants (eg, free radical scavengers), antibacterial agents (eg, penicillin antibiotics), Antiviral agents (such as nucleoside analogs such as zidovudine and acyclovir), anticoagulants (such as warfarin), anti-inflammatory agents (such as NSAIDs), Antipyretics, analgesics, anesthetics (for example for surgery), acetylcholinesterase inhibitors (such as d〇nepezii and galantamine), antipsychotics (eg Haloperidol (hal〇perid〇1), clozapine 'Olan Ziping (〇ianzapjne), and quetiapine), immunosuppressants (eg, cyclocytosine (cyci〇sp〇) Rine) and amine 162775.doc •18· 201249841 methotrexate, neuroprotective agents (eg A2a inhibitors and caffeine), blood-brain barrier penetration enhancers, steroids (eg steroids), adrenal glands Corticosteroids (eg, cloches) Dexamethasone, predisone and hydrocortisone, vitamins, minerals, nutraceuticals, stimulants (eg imipramine, sulphonic; fluoxetine, paro) Paroxetine, escitalopram, sertraline, venlafaxine, and duloxetine, sleeping pills (eg alprazolam) ) and snail ring _ (buspirone), anti-caries agents (such as phenytoin and gabapentin), vasodilators (such as 0 bottom, prazosin and sildenafil), mood stabilizers (eg valproate and aripiprazole), anticancer drugs (eg antiproliferative agents), antihypertensive agents (eg atenolol, clonidine) ), amlopidine, verapamil, and olmesartan, light fullness, stool softener, diuretic (such as furosemide), antispasmodic (for example) Dicyclomine) Anti-dystonia and anti-ulcer agents (e.g., esomeprazole). A preferred use of the compounds of the invention is in the treatment and prevention of Parkinson's disease, AIM and LID, and thus, the compounds of the invention may be used It is used in combination with medical agents for treating Parkinson's disease, AIM and LID. Such agents include NNR agonists (α4β2, α7, etc.), dopamine precursors (eg, levodopa-carbidopa, levodopa-benserazide, and compound levodopa (duodopa) ), dopamine agonists (eg bromocriptine, cabergoline 162775.doc 19 201249841 (cabergoline), lisuride, perg〇iide, pramipexole ), ropinirole (popinirole), taliexole, rotigotine, and apomorphine, apomorphine, dopa carboxylase inhibitor, MAO-B inhibitor ( For example, selegiline, rasag〇iine, and safinamide, COMT inhibitors (such as entacap〇ne and tolcapone) , anti-facial acid agents (such as amantadine), anticholinergic agents (such as trihexyphenidyl, benztropine, and biperiden) Anti-dementia agents (such as rivastigmine, doneipzi (donepezi) l), galantamine, and memantine), antipsychotic agents (eg, qUetiapine, clozapine, and resperidone) anti-epileptic agents (eg, azoles) Zonisamide, norepinephrine precursor (eg droxidopa), mGluR4 agonist, mGluR5 inhibitor, 5HT1A/1B agonist, 5HT2A #antibody/inverse agonist, class Tablet substance antagonist (μ, δ, κ) ' and AMPA receptor blockers. The combination of pharmaceutically active agents can be administered separately or separately, and when administered separately, sputum is administered simultaneously or sequentially, or in any order. The amount and relative time of administration of the compound or agent should be selected, Achieve the desired therapeutic effect. The combination of a compound of the present invention and other therapeutic agents can be combined by simultaneous administration in the following forms: (1) the whole pharmaceutical composition '丨 includes two compounds; or (7) a single pharmaceutical composition 'each of which includes one of the compounds . Alternatively, the combination can be administered separately in a sequential manner, wherein a therapeutic agent is administered first, followed by another 162775.doc •20·201249841 with another second therapeutic agent. The sequential administration can be administered at a time point close to or after a period of time. Therapeutic Method 3-Cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same can be used for prevention or treatment, has been proposed or displayed other Types of nicotine compounds useful as therapeutic agents for various conditions or conditions, such as CNS disorders (including neurodegenerative diseases), inflammation, inflammatory responses associated with bacterial and/or viral infections, pain, diabetes, metabolic syndrome, autoimmunity Sexual condition, skin condition, addiction, obesity or other conditions as further detailed herein. This compound can also be used as a diagnostic agent in receptor binding studies (in vitro and in vivo). Such treatments and other teachings are set forth, for example, in the references previously cited herein, including wiUiams et al, Drwg iVews corpus eripec 7(4): 205 (1994), Arneric et al, CiVS Drwg 1(1): 1-26 (1995), Arneric et al., χρ· /πναί· DrMgj 5(1): 79-100 (1996), Yang et al., dcia P/zarmiico/· 57«. 30(6): 740- 751 (2009), Bencherif et al., 丄 Pharmacol. Exp. Ther. 279: 1413 (1996), Lippiello^ A > J. · Ελτ?· 77zer. 279: 1422 (1996), Damac et al., /. P/zizrmaco/. 77ier. 291: 390 (1999) ; Chiari et al.

Anesthesiology 91: 1447 (1999), Lavand’homme and

Eisenbach, 91: 1455 (1999), Holladay et al., /. Mei Chw. 40(28): 4169-94 (1997), Bannon et al, Science 279: 77 (1998), PCT WO 94/08992, PCT No. 5,583,140 to Dull et al. 5,604,231 and 5'852,041 to Cosford et al. CNS Disorders The compounds and pharmaceutical compositions thereof are useful in the treatment or prevention of a variety of Cns conditions including neurodegenerative disorders, neuropsychiatric disorders, neurological disorders, and addictions. The compounds and pharmaceutical compositions thereof are useful for treating or preventing age-related and other cognitive deficits and dysfunctions, attention disorders, and dementia (including those caused by infections or metabolic disorders); providing neuroprotection, treating convulsions And multiple cerebral infarction; treatment of mood disorders, obsessive-compulsive behaviors and addictive behaviors; provision of analgesia; control of inflammation, such as inflammation mediated by cytokines and nuclear factor kappa B; treatment of inflammatory conditions; provision of pain relief; An anti-infective agent for the treatment of bacterial, fungal and viral infections to treat infections. Conditions, diseases, and conditions that can be treated or prevented using the compounds of the invention and pharmaceutical compositions: age-related memory impairment (AAMI), mild cognitive impairment (MCI), age-related cognitive decline (ARCD), Alzheimer's disease, Early onset of Alzheimer's disease, Alzheimer's disease, Dementia 〇f the Alzheimer's type, Alzheimer's disease, Dementia-free cognitive impairment (CIND), Lewy b〇dy dementia, HIV dementia, AiDS dementia complex, vascular dementia, Down syndrome, head trauma, traumatic brain injury (tbi), boxer dementia 'Kaya II Creutzfeld_Jac〇b Disease and prion diseases, stroke, central ischemia, peripheral ischemia 162775.doc •22· 201249841 Stress deficit disorder, attention deficit dyskinesia, dyslexia, schizophrenia Symptoms, schizophrenia-like mental disorders, schizoaffective disorders, schizophrenia or cognitive dysfunction, cognitive deficits in schizophrenia, Parkinson's disease (including Parkinson's disease, Parkinson's disease after encephalitis, Guam Parkinson's disease _ dementia (parkinsonism-dementia of Gaum) 'Parkinson's type of osteogenic dementia (FTDP)), Pick's disease, Niemann Niemann-Pick's disease, Huntington's Disease, Huntington's chorea, abnormal involuntary movement, dyskinesia, levodopa-induced dyskinesia, late onset Sexual dyskinesia, spastic dystonia, hyperkinesia, progressive supranuclear palsy, progressive supranuclear palsy, restless leg syndrome, Creutzfeld-Jakob disease, multiple Sclerosing, amyotrophic lateral sclerosis (ALS), motor neuron disease (Mnd), multiple system atrophy (MSA), cortical basal degeneration, and Gua Bain Syndrome (GuiUain· BaW Syndr〇me) GBS), and chronic inflammatory demyelinating neurosis (CIDP), epilepsy, autosomal dominant nocturnal frontal lobe epilepsy, mania, anxiety, depression, premenstrual anxiety, panic disorder, bulimia, loss of appetite , narcolepsy Excessive sleep during the day, bipolar disorder, generalized anxiety disorder, obsessive-compulsive disorder, rage 〇utbursts, behavioral disorders, oppositional defiant disorder, Tourette's syndrome, autism, drug and alcohol addiction , tobacco addiction, obsessive overeating and sexual dysfunction. Cognitive impairment or dysfunction can be related to a psychiatric condition or condition, such as schizophrenia and other mental disorders (including but not limited to mental disorders, schizophrenia-like mental disorders, schizoaffective disorders, delusions, short 162775.doc • 23· 201249841 Mental disorders 'common mental disorders, and mental disorders due to general medical conditions), dementia and other cognitive disorders (including but not limited to mild cognitive impairment, Alzheimer's disease, Alzheimer's disease, old age Dementia, Alzheimer's type dementia, age-related memory impairment, Lewy body dementia, vascular dementia, AIDS dementia complex, dyslexia, Parkinson's disease (including Parkinson's disease), dyskinesia, levodopa Induced dyskinesia, abnormal involuntary movement (AIM), cognitive impairment and Parkinson's disease type dementia, cognitive impairment of multiple sclerosis, cognitive impairment caused by traumatic brain injury, dementia due to other general medical conditions, Anxiety disorders (including but not limited to panic disorder in fear of unfamiliar environment, panic disorder in fear of unfamiliar environment, Unfamiliar environmental fears of panic disorder history, specific phobias, social phobias, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder and generalized anxiety disorder due to general medical conditions), mood disorders (including But not limited to major depression, mood disorder, bipolar depression, bipolar mania, bipolar I type affective disorder, depression associated with mania, depression or mixed seizures, bipolar type II affective disorder, cyclical emotions Disorders, and mood disorders due to general medical conditions), sleep dis〇rder (including but limited to sleep disorders (dyss〇mnia dis〇rder), primary insomnia, primary narcolepsy, narcolepsy Hypersomnia, nightmares, night terrors and sleepwalking), mental retardation, learning disabilities, motor skills disorders, communication disorders, systemic developmental delay, attention deficits and destructive behavioral disorders, attention deficit disorder, attention Defective dyskinesia, feeding and eating disorders in infants, children or adults, tic disorder, excretory disorders, substance-related Symptoms (including but not limited to substance dependence, substance abuse, 162775.doc • 24·201249841 substance poisoning, substance withdrawal, alcohol-related disorders, amphetamine or amphetamine-related disorders, caffeine-related disorders, cannabis-related Sexual disorders, cocaine-related disorders, hallucinogen-related disorders, inhalation-related disorders, nicotine-related disorders, opioid-related disorders, phencyclidine or phencyclidine-like Related disorders), and sedative-, hypnotic- or anti-anxiety-related disorders, personality disorders (including but not limited to obsessive-compulsive disorder and impulsive disorder). Cognitive performance can be analyzed using a recognition cognitive scale (e.g., the Alzheimer's Disease Assessment Scale's Cognitive Subscale (ADAS_c〇g)). A measure of the compound of the invention that improves the efficiency of § tolerance can include measuring the degree of change in the patient based on the scale. With regard to compulsive behavior and addictive behavior, the compounds of the invention are useful as therapeutic agents for nicotine addiction and other brain-sustainable conditions, such as substance abuse (including alcohol addiction, illegal and prescription drug addiction), eating disorders ( Other obesity behaviors including obesity, behavioral addiction (eg gambling) or addiction. The above conditions and conditions are discussed in further detail in, for example, the Amedcan Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, Washington, DC, American Psychiatric Association, 2000. This handbook also refers in more detail to the symptoms and diagnostic features associated with substance use, abuse and dependence. This manual is updated and revised from time to time and is intended to be consistent with the revision of this document. Preferably, it can treat or prevent diseases, conditions and conditions without significant disadvantages. 162775.doc -25 - 201249841 Side effects including, for example, significant increase in blood pressure and heart rate, significant side effects on the gastrointestinal tract, and significant effects on skeletal muscle . It is believed that the compounds of the invention may modulate the activity of the * and/or _2* when used in an effective amount, but have no significant interaction with the (4) subtype characterizing the human ganglia, such as by the absence of adrenal pheochromic tissue or bone. The ability of the final base function in the road muscle was confirmed to be further confirmed by the ability to induce nicotine function in a cell preparation exhibiting muscle type nicotinic receptor. Accordingly, it is believed that such compounds are capable of treating or preventing diseases, conditions, and conditions without causing significant side-effect-related activity at the ganglion and neuromuscular sites, and therefore, administration of the compound is believed to provide a therapeutic window, wherein Provide treatment for certain diseases, conditions and conditions, and avoid certain side effects. That is, it is believed that an effective dose of the compound may be sufficient to provide the desired effect on the disease, condition or condition, but it is believed that it is insufficient (i.e., not to a sufficiently high degree) to provide undesirable side effects. Accordingly, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in a therapy (e.g., as described above). In still another aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a CNS disorder, such as a condition, disease or condition as described above. Inflammation The nervous system, primarily known to cross the vagus nerve, regulates the strength of the innate immune response by inhibiting the release of macrophage tumor necrosis factor (TNF). This physiological mechanism is called "choline-induced anti-inflammatory pathway" (see, for example, "The Inflammatory Reflex", 420: 853-9 (2002)). Inflammation and over-synthesis of tumor necrosis factor can cause morbidity and even death in various diseases. 162775.doc •26·201249841 Such diseases include, but are not limited to, endotoxemia, rheumatoid arthritis, osteoarthritis, psoriasis, asthma, atherosclerosis, idiopathic pulmonary fibrosis, and inflammatory bowel disease. Inflammatory conditions which may be treated or prevented by administration of a compound described herein include, but are not limited to, chronic and acute inflammation, psoriasis, endotoxemia, gout, acute pseudogout, acute gouty arthritis, arthritis, rheumatoid Arthritis, osteoarthritis, allograft rejection, chronic graft rejection 'asthma, atherosclerosis, mononuclear phagocyte-dependent lung injury, idiopathic pulmonary fibrosis, atopic dermatitis, chronic obstructive Pulmonary disease, adult respiratory distress syndrome, acute thoracic syndrome in sickle cell disease, inflammatory bowel disease, stimulating bowel syndrome, Crohn's disease, ulcer, ulcerative colitis, acute cholangitis , aphthous stomatitis, cachexia, ileal pouchitis, glomerulonephritis, lupus nephritis, thrombosis and graft versus host response. Inflammatory Responses Associated with Bacterial and/or Viral Infections Many bacterial and/or viral infections are associated with side effects caused by the formation of toxins and the natural reaction of the body to bacteria or viruses and/or toxins. As discussed above, the body's response to infection often involves the production of large amounts of TNF&amp;/other cytokines. Excessive performance of these cytokines can cause significant damage, such as septic shock (when bacteria are sepsis bacteria), endotoxin shock, urinary sepsis, viral pneumonia, and toxic shock syndrome. Cytokine expression is mediated by NNR and can be inhibited by administration of agonists or partial agonists of such receptors. Thus, the compounds described herein as agonists or partial agonists of such receptors can be used to minimize inflammatory responses associated with bacterial 162775.doc -27-201249841 infection and viral and fungal infections. Examples of such bacterial infections include anthrax, botulism, and sepsis. Some of these compounds may also have antimicrobial properties. These compounds can also be used as adjuvant therapies in combination with existing therapies to control bacterial, viral and fungal infections such as antibiotics, antivirals and antifungals. The antitoxin can also be used to bind to the toxin produced by the infectious agent and allow the bound toxin to pass through the body without producing an inflammatory response. An example of an anti-toxin agent is disclosed in, for example, U.S. Patent No. 6,310,043 issued to Bundle et al. Other agents effective against bacteria and other toxins are also effective and can be combined to achieve a complementary therapeutic effect by co-administering with the compounds described herein. Pain can be administered to treat and/or prevent pain, including acute, neurological, inflammatory, neuropathic, and chronic pain. These compounds can be combined with anesthetics to add to the anesthetic. Minimization of the likelihood of disease (eg, 'morpholine protection therapy) ❶ can continue to inflammatory pain and neuropathic pain patterns confirm the analgesic activity of the compounds described herein, as in US Published Patent Application No. 20010056084 A1 (Allgeier et al) It is described (for example, mechanical hyperalgesia in a partial sciatic nerve ligation model of a mouse model of mechanical hyperalgesia and neuropathic pain in a complete Freund's septic rat model). Analgesic effects are suitable for the treatment of various causes or pathogenic pains, in particular for the treatment of inflammatory pain and associated hyperalgesia, neuropathic pain and related hyperalgesia, chronic pain (eg, severe chronic pain, post-operative pain 162775.doc) -28- 201249841 and pain, angina pectoris, kidney or biliary colic, menstrual pain, migraine and gout associated with various conditions including cancer. Inflammatory pain can have different causes, including arthritis and rheumatoid diseases, tenosynovitis, and vasculitis. Neuropathic pain includes trigeminal neuralgia or herpetic neuralgia, neuropathy (such as diabetic neuropathic pain), burning neuralgia, lower back pain, and de-inflammation (such as brachial plexus avulsion). Other Conditions In addition to treating CNS disorders, inflammation, and vascular proliferation and pain, the compounds of the invention may also be used to prevent or treat certain other conditions, diseases, and conditions in which NNRs function. Examples include autoimmune disorders (such as lupus), disorders associated with cytokine release, infection with secondary echinococcosis (eg, such as AIDS, AIDS-related complexes, and neoplasia), obesity, days Pemphigus, urinary incontinence, overactive bladder, diarrhea, constipation, retinopathy, infectious disease, muscle weakness, Eat〇n_Lamben syndrome, hypertension, pre-eclampsia, osteoporosis, vasoconstriction, vasodilation, arrhythmia Qi, sputum type diabetes, „type diabetes, bulimia, loss of appetite and sexual dysfunction, and their indications as disclosed in the published pCT application WO 98/25619. Compounds of the invention may also be administered to treat convulsions ( For example, those with epilepsy symptoms and treatment of conditions such as syphilis and Creutzfeldt-Jakob disease. Finally, the compounds of the present invention are useful for treating a variety of skin conditions including, but not limited to, psoriasis, dermatitis, acne pustule disease, leukoplakia and Such as diagnostic uses, such compounds can be used in diagnostic compositions (eg, probes), especially when they are 162775.doc • 29· 201249841 When 4 is included to include the appropriate label, the probe can be used, for example, to determine the relative amount and/or function of a specific receptor, particularly α4β2* and/or a receptor subtype containing α6. Most preferably, the radioisotope moiety &amp; (e.g., π 〇 labeled with the compound of the invention can be labeled with electron emission tomography (PET). The specific activity is expected to visualize the receptor subtype at an unsaturated concentration. The dosage is usually below the toxicity range and provides a high contrast image. The desired compound can be administered in a non-toxic manner. The dosage is determined in a manner known to those skilled in the art of radiolabel imaging. See, for example, L〇nd〇n et al. U.S. Patent No. 5,969,144, the disclosure of which is incorporated herein by reference to U.S. Pat. Compounds of the type of ingredients of the diagnostic composition are formulated to be administered as a compound. The compounds used in accordance with the practice of the invention are preferably employed in high purity form. U.S. Patent No. 5,853,696 to Elrnalch et al.. After administration of a compound to an individual (e.g., a human subject), the compound present in the individual can be imaged and quantified by appropriate techniques to indicate the selected NNR subtype. The presence, amount and function. In addition to humans, compounds can also be administered to animals such as mice, rats, dogs and monkeys. PET imaging can be performed using any suitable technique and equipment. See Villemagne et al., In: Arneric Neuronal Nicotinic Receptors: Pharmacology and Therapeutic Opportunities, 235-250 (1998) and U.S. Patent No. 5,853,696 to Elmalch et al., the disclosure of which is incorporated herein by reference. in. 162775.doc • 30· 201249841 Radiolabeled compounds bind with high affinity to selective nNR subtypes (eg, α4β2* and/or α6) and preferably to other nicotinic choline-exciting receptor subtypes (eg, These receptor subtypes associated with muscle and ganglia exhibit negligible non-specific binding. Thus, such compounds can be used as medicaments for non-invasive imaging of nicotinic choline stimulating receptor subtypes in individuals, particularly in the brain, for use in the diagnosis of a variety of CNS diseases and conditions. In one aspect, the diagnostic composition can be used in a method of diagnosing a disease in an individual, such as a human patient. The method comprises administering to the patient a compound that is detectably labeled as described herein, and detecting binding of the compound to a selected nnr subtype (e.g., α4β2* and/or a receptor subtype containing α6). Those skilled in the art using diagnostic tools (e.g., sputum) can use the radiolabeled compounds described herein to diagnose a variety of conditions and conditions, including those associated with mesenteric and autonomic nervous system dysfunction. Such conditions include a variety of CNS diseases and conditions, including Alzheimer's disease, Parkinson's disease, and schizophrenia. </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; In another aspect, the diagnostic composition can be used to monitor a selective nicotinic receptor subtype of an individual (e.g., a human patient). The method comprises administering to the patient a compound that is detectably labeled as described herein, and detecting binding of the compound to a selected nicotinic receptor subtype (i.e., a4[beta]2* and/or a [alpha]6 containing receptor subtype). Receptor Binding The compounds of the invention can be used as reference ligands in binding assays for compounds that bind to NNR isoforms, particularly and/or α4β2* and/or receptor subtypes containing α6. 162775.doc • 31- 201249841 For this purpose, the compounds of the invention are preferably labeled with a radioisotope moiety (e.g., !4C). EXAMPLES The following examples are provided to illustrate the invention and are not to be construed as limiting thereof. In the examples, all parts and percentages are by weight unless otherwise indicated. Example 1. Instrument and experimental scheme for characterizing the salt form of 3-cyclopropylcarbonyl-3,6-diazabicyclo[311] heptane. X-ray powder diffraction (XRPD) using CuKa radiation (40 kV, The X-ray powder diffraction pattern is collected on a Bruker AXS C2 GADDS diffractometer with a 40 mA), automatic χγ 标 table, a laser video microscope for automatic sampling and positioning, and a HiStar 2D area detector. The X-ray optics consist of a single G5be丨 multilayer mirror coupled to a 0.3 mm pinhole collimator. The beam divergence (i.e., the effective size of the x-ray beam on the sample) is about 4 mm. A θ·θ continuous scan mode was used with a sample-detector distance of 2 〇 cm, which produced 3.2. To 29.7. Effective 2Θ range. The sample is typically exposed to an X-ray beam for 120 seconds. A sample run under ambient conditions was prepared as a flat sample using a powder that was not ground as received. Approximately 1-2 mg of the sample was gently pressed onto a glass slide to obtain a flat surface. A sample run under non-environmental conditions is mounted on a crucible wafer with a thermally conductive compound. "Data is then collected after the sample is heated to a suitable temperature at about 1 Torr &lt; t /min and then isothermally maintained for about 5 minutes." . The peak position is reported as °2Θ ’ accuracy of ±〇1. . Single crystal XRD (SXD) is equipped with Oxford Cryosystems Cryostream cooling unit 162775.doc 32· 201249841

Data was collected on a Bruker AXS IK SMART CCD diffractometer. Resolve the structure using SHELXS or SHEXLD programs and refine it with the SHELXL program that is part of the Bruker AXS SHELXTL suite. Unless otherwise stated, the hydrogen atom attached to carbon is geometrically placed and refined using a riding isotropic displacement parameter. The hydrogen atoms attached to the heteroatoms are located in different Fourier synthesis and are freely refined with isotropic displacement parameters. Nuclear Magnetic Resonance (NMR) Spectroscopy NMR spectra were collected on a Varian Unity 300 MHz instrument or a Bruker 400 MHz instrument equipped with an autosampler and controlled by a DRX400 controller station. Automation experiments were performed using a standard Bruker loading experiment using ICONNMR V4.0.4 (form 1) running with Topspin v 1.3 (patch level 8). For unconventional spectra, data is obtained only by using Topspin. Melting Point A Fisher-Johns hot stage, melting point apparatus was used at a setting corresponding to a heating rate of about 5 ° C / min. Differential Scanning Calorimetry (DSC) DSC data was collected on a Q Instruments Q1000 or Mettler DSC 823e equipped with a 50-bit autosampler. Calibrate the instrument for energy and temperature calibration using qualified indium. 0.5-1.5 mg of each sample in a pin-hole aluminum pan is usually heated from 25 ° C to 175 ° C to 200 ° C at 10 ° C/min. A nitrogen purge was maintained at 30 mL/min on the sample. Thermogravimetric Analysis (TGA) 162775.doc -33 - 201249841 TGA data was collected on a TA Instruments Q500 TGA equipped with a 16-bit autosampler or a Mettler TGA/SDTA 851e equipped with a 34-position autosampler. ΤΑ Instruments Q5〇〇 : Calibrate the temperature of the instrument with a qualified aluminum-alloy (Alumel). Each sample of 5_1 〇 mg is typically loaded onto a pre-weighed gutta-percha and aluminum DSC pan and heated to 350 C from ambient temperature at i〇°c / min. A gas purge was maintained at 60 mL/min on the sample. Mettler TGA/SDTA 851e: Calibrate the instrument with a qualified indium. Typically 5-10 mg of each sample was loaded onto a pre-weighed aluminum crucible and heated from ambient temperature to 350 °C at 1 Torr &lt; t/min. A nitrogen purge was maintained at 50 mL/min on the sample. Polarized Microscopy (PLM) Samples were studied using a Leica LM/DM polarizing microscope with a digital video camera for capturing images. A small amount of each sample was placed on a glass slide&apos; mounted in immersion oil and covered with a glass slide, with individual particles being separated as much as possible. The sample was observed with appropriate magnification and the light was partially polarized and coupled to the dummy filter. Hot Stage Microsharp (HSM) Hot stage microscopy was performed using a Leica LM/DM polarizing microscope in combination with a Mettler-Toledo MTFP82HT hot stage and a digital video camera for capturing images. A small amount of each sample was placed on a glass slide and individual particles were separated as much as possible. The sample is observed with appropriate magnification and the light is partially polarized, coupled to a lambda false color filter, while typically heating at ambient temperature from 10 〇c / min. Dynamic Vapor Sorption (DVS) Adsorption isotherms were determined using an SMS DVS Intrinsic Moisture Absorption Analyzer controlled by the SMS Analysis Suite software. The sample temperature was maintained at 25 ° C by instrument control. The humidity was controlled by mixing dry and wet nitrogen streams at a total flow rate of 200 mL/min. Relative humidity (dynamic range 1.0-100% RH) was measured by the amount of calibrated R〇tr〇nic probe located near the sample 162775.doc •34- 201249841. The weight change (mass relaxation) of the sample as a function of RH% was continuously monitored by a microbalance (accuracy ± 0.005 mg). A 5-20 mg sample is typically placed on a weighed wire mesh stainless steel basket under ambient conditions. The sample was loaded at 40% RH and 25 ° C (typical environmental conditions) and was not loaded. The water adsorption isotherm is implemented as outlined below (2 scans yield 1 full cycle). Standard isotherms were performed at 25 °C at 10% RH intervals in the range of 0-90% RH. DVS Generic Method Parameter Parameter Value Adsorption - Scan 1 40-90 Desorption / Adsorption - Scan 2 90 - Dry, Dry - 40 Interval (RH%) 10 Number of Scans 2 Flow Rate (mL/min) 200 Temperature (°C) 25 Stable Sex (°C/min) 0.2 Adsorption time (hours) 6 hours pause The sample was recovered after completion of the isotherm and reanalyzed by XRPD. Water Determination by Karl Fischer Method (KF) The water content of each sample was measured using a Mettler Toledo DL39 Coulometer using Hydranal Coulomat AG reagent and argon purge. The weighed solid sample was introduced into a vessel on a platinum TGA pan which was connected to the subaseal to avoid water ingress. Approximately 1 〇 mg sample was used for each titration and assayed in duplicate. 162775.doc -35- 201249841 Thermodynamic Water Solubility by HPLC Water solubility was determined by suspending sufficient compound in water to produce a maximum final concentration of 210 mg/mL parent free form compound. The suspension was equilibrated at 25 ° C for 24 h and then the pH was measured. The suspension was then filtered through a glass fiber C filter into a 96 well plate. The filtrate was then diluted 101 times. Quantification was performed by HPLC with reference to a standard solution of about 0.1 mg/mL in DMSO. Standard, diluted and undiluted solutions of different volumes are injected. Solubility was calculated using the peak area determined by integrating the peaks found at the same retention time as the main peak in the standard injection. If sufficient solids are present in the filter plate, XRPD is collected. HPLC method for thermodynamic water solubility method Parameter method Type: Reversed-phase column with gradient elution: Phenomenex Luna, C18 (2) 5 μηι, 5〇x4.6 mm Column temperature (°c): 25 Standard injection ( μ!〇: 1, 2, 3, 5, 7, 10 Test injection (jiL) · Bu 2, 3, 10, 20, 50 Detection: Wavelength, bandwidth (nm): 260, 80 Flow rate (mL/min): 2 Phase A: 0.1% TFA in water Phase B: 0.085% TFA in acetonitrile Schedule: Time (min) Phase A% Phase B% 0.0 95 5 1.0 80 20 2.3 5 95 3.3 5 95 3.5 95 5 4.4 . 95 5 162775.doc -36· 201249841 The analysis was carried out on an Agilent HP 1100 series system equipped with a diode array detector and using ChemStation software vB.02.01-SR1. The chemical purity by HPLC is equipped with a diode Purity analysis was performed on a body array detector using an Agilent HP 11® series system using ChemStation software vB.02.01-SR1. HPLC method for chemical purity determination Specimen sample preparation 0.5 mg/mL ' stored in acetonitrile: water i:i ( In v/v), tube: Phenomenex Luna C18 (2), 150x4.6 mm, 5 μπι Column temperature (°c): 25 Injection (pL): 5 Detection: Wavelength, Bandwidth: (nm): 255, 90 Flow Rate (mL/min): 1 Phase A: 0.1% TFA in Water Phase B: 0.085% TFA in Acetonitrile Schedule: Time (min) Phase A% phase B% 0 95 5 25 5 95 25.2 95 5 30 95 5 Ion chromatography on Metrohm 761 Advanced Compact 1C (for cations) and Metrohm 861 Advanced Compact 1C (for anions) using IC Net software v2.3 The data was collected. The sample was prepared as a 1000 ppm stock solution in DMSO. The sample was diluted to 100 ppm in DMSO prior to testing. By 162775.doc •37·201249841 Positive ions were analyzed with known concentrations Standard solution comparison is achieved. Anion ion chromatography method method type anion change column: Metrosep A Supp 5 - 250 (4.0x250 mm) Column temperature (°c): Ambient temperature injection (0): 20 Detection: Conductivity Detector flow rate (mL/min): 0.7 Eluent: 3.2 mM sodium carbonate, 1.0 mM sodium bicarbonate, ion chromatography in cations in water Method Type Cation change column: Metrosep C 2 - 250 (4.0x250 mm Column temperature (°C): ambient temperature Shot (HL): 20 Detection: Conductivity detector flow rate (mL/min): 1.0 Eluent: 4.0 mM tartaric acid, 0.75 mM dioxin-like bite acid, stored in water pKa determination and prediction using attached D- PAS's Sirius GlpKa instrument collects data. The titration medium was subjected to ion intensity adjustment (ISA) using a 0.15 M KC1 (aqueous solution) in an aqueous solution by UV and in a methanol water mixture at 25 °C. The values found in the methanol water mixture were corrected to the 〇% cosolvent via Yasuda-Shedlovsky extrapolation. Use the Refinement Pro 162775.doc -38- 201249841 software vl.O refinement data. The pKa value was predicted using the ACD pKa prediction software v9.

Log P measurements Data were collected by potentiometric titration on a Sirius GlpKa instrument using three ratios of octanol: ionic strength adjustment (ISA) water to produce L〇g p, Log P ions and Log D values. Refine the data using ReHnement Pro software vl.O. The Log P value is predicted using ACD version 9 and Syracuse KOWWIN version 1.67 software. Example 2. Synthesis of cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane (Compound A) equipped with a mechanical stirrer, two reflux condensers, a condenser, a thermometer, nitrogen The three-necked flask at the inlet and discharge outlets (directed to the aqueous sodium bisulfite/sodium hydroxide water separator) was filled with urethane (35 〇g, 2.07 m〇1), followed by bromine (160 mL, 3.12 mol). ). The resulting mixture was stirred under nitrogen and heated under slow reflux, at which time the initial temperature gradually increased from 58 ° C to 91 ° C over a period of 7 h. During the heating period and when bromine consumption/loss was observed, additional bromine was added twice (first 9 〇mL and later 12 〇mL) and then the reaction mixture was gradually cooled to ambient temperature while stirring under nitrogen. Overnight. Analysis of an aliquot of the reaction mixture in the methanol suspension reaction means incomplete conversion to dimethyl 2,4-dibromoglutarate (based on (5 (:) 8 and LCMS analysis> 98%). This 2,4-dibromopentane ruthenium chloride was used in the next step without further purification. A three-necked flask equipped with a mechanical stirrer, nitrogen inlet, addition funnel and thermometer was filled with anhydrous ether (7) L), followed by loading benzyl alcohol (493 g, 4 56 m〇1). The solution was stirred under nitrogen and cooled in an ice water bath until the internal temperature of 8t 162775.doc •39·201249841 was reached. 1.5 h was added to the stirred solution via an addition funnel (washed with anhydrous ether), during which time a maximum observed exotherm of 12 ° C occurred. After the addition, the reaction mixture was Stir in the cold bath (h (the internal temperature is observed to be 12) The reaction mixture was then stirred under a nitrogen atmosphere while gradually warming to ambient temperature overnight. LCMS-based analysis of an aliquot of the reaction mixture diluted in methanol indicated complete consumption of 2,4-dibromopentadienyl ( That is, 2,4-dibromoglutaric acid dimethyl ester was not observed. The reaction mixture was transferred to a separatory funnel (by riddle washing) and the organic solution was washed twice with water and washed with 1 aqueous sodium hydrogen sulfate solution. Two times, it was washed twice with a saturated aqueous solution of sodium hydrogencarbonate (the second washing was tested to be alkaline with a pH test paper) and finally washed once with a saturated aqueous solution of sodium sulphate. The collected organic phase was dried over anhydrous sodium sulfate and filtered. Concentration to dryness under reduced pressure afforded the title compound 2, 4- &gt; succinic acid dibasic vinegar (1.034 kg, quantitative crude yield) which was used in the next One step. NMR (CDC13, 300 MHz): δ 7.38 (s, 10 Η), 5.23 (s, 4H), 4.59-4.41 (m, 2H), 2.97-2.64 (m, 2H). , three-necked flask with nitrogen inlet, thermometer, addition funnel and reflux condenser A solution of dibenzyl 2,4-dibromoglutarate (intermediate 3) (1.034 kg, 2.199 mol) in dimethylformamide (2.93 L) at nitrogen and ambient temperature (internal temperature) The mixture was stirred for 18. The mixture was added benzylamine (707 g '720 mL, 6.60 mol) (addition time &lt; 5 min) by the addition funnel, during which time 55 〇c to (9) it was observed. The exothermic curve of the maximum temperature. LCMS analysis of the aliquot of the reaction mixture diluted in the decyl alcohol by heating the reaction mixture 162775.doc -40· 201249841 at 93 ° C to 95 ° C for 4.5 h immediately after the completion of the addition. Indicates complete consumption of intermediate 3 and formation of the product (and its trans-peer portion). Heating was stopped and the reaction mixture was gradually cooled to ambient temperature under nitrogen overnight. The reaction solution was then poured into a stirred two-phase mixture of 1:1 ethyl acetate/hexane (8 L) and water (6 L). After agitation, the organic phase and the aqueous phase are separated. The organic phase was collected by continuous washing with water, a saturated aqueous solution of sodium hydrogencarbonate (water was tested with a pH test paper), and a saturated aqueous solution of sodium sulphate. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to dryness under reduced pressure to afford 790 g of dark oil &lt;RTI ID=0.0&gt;&gt; Thereafter, it was eluted with 15 〇 / 〇 ethyl acetate / hexane "concentrating the selected portion under reduced pressure to give 543 g of N-pyrazine azetidine 2,4-dicarboxylic acid dibasic vinegar, It has a cis (82 intermediate) of 82:17: trans stereochemistry ratio and 92% overall chemical purity. Crystallized from diethyl ether and air-dried to provide 31 〇g (3 6% overall yield from pentanedioxane) benzyl benzylazetidine-2,4-dicarboxylate as a white solid. (Intermediate 4) (based on LCMS purity &gt; 96%). H NMR (CDC13, 300 MHz): δ 7.30 (m, 10 Η), 5.07 (dd, 4H) 3.89 (s, 2H), 3.67 (dd, 2H), 2.55 (dd, 1H), 2.36 (dd, 1H) LCMS (m/z): 416 (M+l). A three-necked flask equipped with a mechanical stirrer, a thermometer and a nitrogen inlet was charged with cis-N-benzylazetidin-2,4-dicarboxylic acid dibenzyl g (173 g, 416 mmol), after which Methanol (1.14 L) and tetrahydrofuran (56 〇 mL) were charged. The resulting mixture was stirred at ambient temperature and under nitrogen until a uniform sentence was obtained. @ After cooling the solution in a dry ice/acetone bath until the internal temperature of -4 °C is 162775.doc • 41 · 201249841. Sodium borohydride (79 〇, 2 (10) was added in 1 h to 1.5 h, and a slight exothermic curve of maximum temperature was observed during this time. After the addition, the mixture was mixed under nitrogen while gradually Warming to ambient temperature overnight [Note · During heating, a second exotherm of maximum temperature of up to 27 t was observed and controlled by using an ice bath]. Aliquots were taken from the reaction mixture diluted in methanol The lcms analysis carried out indicated that the starting material had been consumed and formed the product (and benzyl alcohol) (&gt; The reaction mixture was then cooled in an ice water bath (internal temperature was 8. 〇 and water was added dropwise via a dropping funnel (100 mL)) The reaction mixture was concentrated under reduced pressure to remove most of the volatiles. The residue was partitioned between &lt;RTI ID=0.0&gt;&gt; The organic phase (upper layer) and the aqueous phase were collected. The aqueous phase was extracted again with 10% methanol/diqi methane (2 x 5 〇〇 mL; now the organic phase became the lower layer). Analysis of the aliquot of the aqueous phase at this stage showed no Product exists. Water and full The combined organic extracts were continuously washed with a gasified aqueous solution. The analysis of the aqueous phase (water plus saturated aqueous sodium chloride) showed the presence of the product (with benzyl alcohol), so it was burned with 10 〇 / 〇 methanol / chloroform (3 X) Back extraction of the aqueous phase. Combine all the decyl alcohol / dioxane extracts and dry over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, 177 g of a yellow oil was obtained. The residue was concentrated to remove most of the benzyl alcohol. After a constant weight was observed, 100 g of oil remained. This material was dissolved in di- methane and concentrated under reduced pressure to give a semi-solid. Suspension in hexane twice and then concentrated under reduced pressure. The remaining solid was suspended in hexane (260 mL) and the resulting suspension was stirred 162 775.doc • 42· 201249841 overnight. The suspension was then filtered and hexanes (2χ) Washing collected solids β The LCMS of the solid sample dissolved in methanol indicated a product purity of about 90°/〇 (containing benzyl alcohol impurities). The solid was resuspended in hexane (2〇〇mL) and The suspension is stirred at 30 ° C (in The evaporator was transferred to the evaporator for 1 hour. The suspension was filtered, and the collected solid was washed again with hexane (1×). LCMS analysis of the solid sample dissolved in decyl alcohol indicated product purity &gt;96%. The solid was further air dried to Constant weight, giving 81.9 g (95% yield) of cis-N-pyryl-2,4-bis(p-fluorenyl)azetidine (interm. 5) as a white solid. iH NMR (CDC13 , 300 MHz): δ 7.28 (m, 5H), 4.24 (dd, 2H), 3.63 (s, 2H), 3.12 (dd, 4H), 3.05 (m, 2H), 2.00 (dd, 1H), 1.57 ( Dd, 1H); LCMS (m/z): 208 (M+l) » Filled with cis-N-benzyl-2,4 in a three-necked flask equipped with a mechanical stirrer, thermometer, nitrogen inlet and addition funnel - Bis(hydroxyindenyl)azetidine (81·9 g '395 mmol), followed by anhydrous dichloromethane (820 mL). The resulting solution was stirred under nitrogen, and then the whole amount of triethylamine (160 g, 220 mL, 1.58 mol) was added at once. The resulting solution was cooled in a dry ice/acetone bath until the internal temperature of -6 C was reached. An exothermic curve with a maximum observed temperature of up to 4 °C was then added during this time by adding a funnel with a concentration of 4 5 m i η by adding a funnel (109 g, 73.4 mL, 948 mmol). After the addition, the reaction mixture was gradually warmed to ambient temperature while stirring overnight under nitrogen. LCMS analysis of aliquots of the reaction mixture diluted in acetonitrile indicated consumption of starting material and formation of product. Water (250 mL) was added dropwise to the reaction mixture, followed by aqueous saturated sodium hydrogen sulfate (250 mL). 162775.doc -43- 201249841 The resulting biphasic mixture was stirred vigorously for 2 〇 min and transferred to a separatory funnel by means of a two-gas methane rinse. The organic phase and the aqueous phase were separated and then the organic layer was washed with a saturated aqueous solution of sodium sulfate. After phase separation (slow), the organic layer was taken, dried over anhydrous sodium sulfate, filtered and evaporated, then evaporated. It was used in the next step without purification.丨H NMR (CDC13,300 ΜΗζ): δ 7.33 (m, 5Η), 3.97 (ddd, 4H), 3.74 (s, 2H), 3.44 (m, 2H), 2.92 (s, 6H), 2.28 (m, 1H), 1.91 (m, 1H); LCMS (m/z): 364 (M+l) 装 Fill the ring in a three-necked flask equipped with a mechanical stirrer, thermometer, nitrogen inlet and reflux condenser under nitrogen atmosphere Propane methotrexate (36 8 g, 432 mmol). Anhydrous 1·methyl-2-pyrrolidinone (Nmethyl-2-pyrrolidone) (900 mL) was added and the resulting mixture was mechanically stirred under nitrogen while cooling in an ice water bath (internal temperature 5 ° C). Subsequently, sodium hydride (39.4 g of 60% dispersion in mineral oil, 98 〇mm〇1) was added via 3 〇 min. The temperature varied between 5 C and 12 C. The bath was stirred for another 10 mir^ to cool the cold liquid to ambient temperature (after 3 Torr), at which time a slight exotherm (to a maximum temperature of 25 C) and gas evolution were observed. The resulting mixture was stirred for an additional 5 Torr at ambient temperature (no other gas evolution), after which a mixture of bis-deferoxamine (intermediate 6) (143 g 393 mmol) was added to the suspension in one portion. _methyl_2_. Bilo bite (6〇〇 mL) in solution. The flask containing the crude intermediate 6 was rinsed with other anhydrous 1-methyl-2-pyrrolidone (2 x 1 〇〇 mL) and each rinse was added to the reaction suspension. The resulting mixture was then heated at 68 ° C for 3 h. Heating and chilling in wet acetonitrile I62775.doc •44·201249841 The LCMS* analysis of the aliquots taken after 2 h of reaction indicated that &gt;96% of intermediate 6 was consumed and was predominantly the desired product. The reaction mixture was cooled to ambient temperature under nitrogen overnight. The reaction viscous solution was stopped by adding water (about 1 〇 mL) in an ice water bath and diluted with decyl tertiary butyl ether (1 〇〇 mL) and stirred for 1 〇 min. The mixture was then transferred to a separatory funnel containing a 5% aqueous solution of sodium chloride (4 mL) and 25% ethyl acetate / decyl-t-butyl ether (3 〇L). The resulting mixture was agitated. After phase separation, the organic layer and the aqueous layer were taken out. The aqueous phase was extracted with a further 25% ethyl acetate / decyl-tert-butyl ether (2 x 3 〇 L). The combined organic extracts were washed with water (1×3. 〇 L) and saturated aqueous sodium sulfate (1 χ 3.0 L). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporatedEtOAc. Purification of this residue by silica gel chromatography initially eluting with 0 to 40% ethyl acetate / hexanes and finally eluting with 60% to EtOAc / EtOAc / hexane . The selected fractions were concentrated to give &lt;RTI ID=0.0&gt;&gt;&gt;&&&&&&&&&&&&& This was used in the next step without further purification.

A 3-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser and gas inlet was charged with 6-benzyl-3-cyclopropylcarbonyl_3,6-diazabicyclo[3.1.1] under nitrogen. Heptane (56 g, 78%, 220 mmol) was stored in ethanol (200 °, 670 mL). Then 10 〇 / 〇 Pd / C (33.6 g, wet) was added, followed by the addition of ammonium formate (82.6 g ' 1.31 mol). The resulting mixture was vigorously stirred under a nitrogen atmosphere and gradually heated at 6 (TC to 66 ° C for 6 h, after adding additional 20 g of 10% Pd/C and 60 g of formic acid for about 3.5 h. The reaction was then heated ( At 66 ° C 162775.doc •45- 201249841 and 71 C for 6 h) and periodic monitoring by LCMS, while adding more reagents in several times (total additional ammonium formate = 96 g; total additional 1% Analysis of an aliquot of the Pd/C = 21 gp reaction mixture then indicated consumption of the starting material. Heating was stopped and the reaction mixture was gradually cooled to ambient temperature overnight under nitrogen. The reaction mixture was then filtered through a bed of diatomaceous earth. The filter cake was washed with decyl alcohol (4×), and the combined filtrate was concentrated under reduced pressure to give 35 g of pale yellow oil. Purified by chromatography eluting with EtOAc to 60% DCMA. This material. [Note: DCMA80 is a mixture of dioxane methane, methanol and aqueous ammonium hydroxide: 8:18:2]. The selected fractions are combined and concentrated under reduced pressure to give 9 2 g of almost white solid, HPLC purity 97.7%. This material can be titrated by thiol tert-butyl ether. The purity was increased to 98.7 ° / (HPLC). Concentration from the less pure fraction of the chromatography 'produced an additional 11 g of material (HPLC showed a purity of about 85%). 4 NMR (D2Os 300 MHz): δ 4.02 (s, 2H), 3.73 (m, 2H), 3.64 (dd, 2H), 2.66 (m, 1H), 1.92 (m, 1H), 1.52 (d, 1H), 0.88 (m, 4H); LCMS (m/z ): 167 (M+l). Example 3: 3-cyclopropylcarbonyl-3,6-diazabicycloindole 3.1.1]heptane hemi-galactosyl monophosphate monohydrate, 6-dioxa Synthesis of bicyclo [3.1.1]heptan-3-yl (cyclopropyl)methanone hemi-galactosyl dihydrate monohydrate} equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen inlet under nitrogen The three-necked round bottom flask was charged with 3-cyclopropylcarbonyl·3,6-diazabicyclo[3.1_1]heptane (132 g, 0.794 mol, representing multiple cycles of the chemistry shown in Example 2). Add ethanol (200 °, 925 mL) and water 162775.doc -46 · 201249841 mL) to the flask and stir the mixture at ambient temperature until a solution is obtained. Then add galactosuccinic acid (86.0 g, 0.397 mol) and The resulting mixture was heated at 5 ° C under nitrogen for 2 h. Then the heating was stopped. The resulting thick polyethylene was cooled to ambient temperature, and stirred overnight under nitrogen granted. The mixture was then cooled in an ice-water bath and filtered under suction to square arts. The solid was collected by simple air drying and then dissolved in hot water (1000 mL; 60 mM). The hot transition solution was removed to remove a small amount of insoluble material and then concentrated to near dryness. To this residue was added ethanol (200 °, 800 mL) and the mixture was taken to 5 hr. (: Mix for 30 min and then cool to 〇〇c in an ice water bath, which was kept for 45 min. Filter the slurry' and dry the collected solids in vacuo overnight. Dry the solid further to blame under vacuum and 56 C Constant weight (during 4 h) to give 208 g (95% yield) of 3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane hemi-galactose Acid salt monohydrate (HPLC purity: 99%). lH NMR (D2 〇, 400 ΜΗζ): δ 4.39 (m, 2H), 4.20 (dd, 2H), 4.09 (s, 1H), 3.88 (d, 1H) ), 3.79 (s, 1H), 3.74 (d, 1H), 2.93 (m, 1H), 1.77 (m, 2H), 0.80 (m, 4H); LCMS (m/z): 167 (M+l) The Karl-Fisher analysis of the dry material indicated a water content of 6.5% (corresponding to the monohydrate stoichiometry). Example 4: 3_cyclopropylcarbonyl-3,6-diazabicyclo ring using a brewing amine coupling procedure [3.1.1] Synthesis of Glycidate Hydrochloride to 3,6-diazabicyclo[3.Μ]heptane-6-decanoic acid second butyl vinegar (50 mg) in a 25 mL round bottom flask , 0.25 mmol) with cyclopropanecarboxylic acid (26 mg, 24 pL, 0.30 mmol), triethylamine (70 mL, 0.50 162775.doc -47- 201249841 m Mol), dioxane (5 mL) and hexafluoroantimonate-benzotriazol-1-yl-tetradecylurea salt (191 mg, 0.50 mmol). The reaction was stirred at ambient temperature 2 h. Add saturated ammonium hydride (5 mL) and stir the reaction mixture for 30 min. Then pass the mixture through a phase extractor and remove the solvent under vacuum. Dissolve the crude mixture in 3 mL of ethyl acetate and add concentrated HC1 (1 mL) ❶The mixture was stirred for 2 h. The solvent was removed in vacuo and the residue was passed through a oxidant-based cation exchange column followed by 2 mL of methanol and 2 mL of methane/methanol (1: 1) Pre-washing. The residue was taken up in i-dioxethane/methanol and passed through a column of '3 mL of dichloromethane/methanol (1:1) and methanol/ammonia (7M). Eluate, and purified by gradient elution with CMA90 (gas/methanol/ammonium hydroxide aqueous solution 9:9:1). Part and the residue was combined with 1 M hydrogenation in methanol (2 mL). The mixture was filtered through a phase extractor (to remove any fine particles) ), and remove the solvent 1 in a vacuum leaving the oily 3,6-diazabicyclo^ 27〇/〇)〇^ ship (CD lion GHz): s 4 49 (m, 吼4 η _ Qiu 4 .〇1(^«),3,3(^^3,6(111, lH),,94(mj2H);〇9; (m,4H note: although this substance cannot crystallize, it can induce hydrochloric acid The other samples of the salt were crystallized (after titration with acetone). The resulting solid is hygroscopic. Example S: Preparation of other salts based on the measured PKa values, selected to include pharmaceutically acceptable acids: 胄 研 九 九 162 162 162 775. doc • 48· 201249841 Acid Category pKa LogP MW Storage Solution Hydrogen Acid 37 wt % (12 Μ) 1 -6.10 - - - 36.46 1 MTHF Sulfuric acid 98% 1 -3.00 1.92 - -1.03 98.08 1 MTHF p-Toluenesulfonic acid. Η20 2 -1.34 - - 0.93 190.22 1 MEtOH Methanesulfonic acid 2 -1.20 - - -1.89 96.10 1 MTHF Oxalic acid 2 1.27 4.27 - - - 1 MTHF Oxalic acid 2 1.27 4.27 - - 1 MTHF L-aspartic acid 1 1.88 3.65 -0.67 133.11 Solid maleic acid 1 1.92 6.23 -0.01 116.07 1 MTHF Phosphate 1 1.96 7.12 12.32 -2.15 98.00 1 MTHF L-glutamic acid 1 2.19 4.25 - -1.43 147.13 Solid 1-hydroxy-2-naphthoic acid (hydroxynaphthoate) 2 2.70 13.50 - 3.29 188.17 Solid L-tartaric acid 1 3.02 4.36 - -1.43 150.09 1 MTHF Fumaric acid 1 3.03 4.38 - -0.01 116.07 0.5 Μ THF/MeOH (1:1) Galactosedioic acid (mucosic acid) 1 3.08 3.63 - -1.46 210.14 1 MDMSO Citric acid 1 3.13 4.76 6.40 -1.72 192.12 1 MTHF D-glucuronic acid 1 3.18 - - -1.49 194.14 Solid malic acid 1 3.46 5.10 -1.26 134.09 1 MTHF Hippuric acid 1 3.55 - - 0.31 179.17 Solid D-gluconic acid 50%, stored in water 1. 3.76 - - -3.18 196.16 Solid L-mandelic acid 3 3.85 - 1Μ, 85% aqueous solution of L-lactic acid in the solvent used 1 3.86 -0.7 90.08 1 MTHF L-ascorbic acid 1 4.17 11.57 -2.41 176.13 1 Μ水162775.doc •49- 201249841 succinic acid 1 4.21 5.64 -0.59 118.09 1 MTHF acetic acid 1 4.76 - - -0.29 60.05 1 MTHF benzoic acid 2 4.19 - - 1MIPA adipic acid 1 4.44 5.44 - 0.08 146.14 solid propionic acid 2 4.87 - - 0.25 74.07 1 MTHF (+)-camphoric acid 2 4.72 5.83 - 1.47 200.23 solid 4-hydroxybenzoic acid 2 4.57 9.22 - 138.12 1Μ, in To the solution of 30.0 mg (0.165 mmol) of the free base in the selected solvent at 50 ° C, add the corresponding acid (according to the quantity and strength of the acidic part of the acid, 0.5 equivalent or 1.1 equivalents of the mixture at 50 it Stir for 1 h, then slowly cool to 〇〇c overnight (0.1 C / min). If no solids are produced, the corresponding solution is slowly evaporated under ambient conditions. In the case of a clarified solution, glue or oil, the materials are cooled to -20. (:, and slowly evaporate to promote crystallization. Thereafter, if the oil/glue is not crystallizable, an anti-solvent (cosolvent; methyl tert-butyl ether) is added; after that, it is titrated with acetone. Many salts produced precipitation when placed in isopropyl acetate (the results shown in the two tables below).

162775.doc -50- 201249841

Methanesulfonic acid 1.1 Solid solid - deliquescent oxalic acid 0.5 solid solid after a few minutes of separation - deliquescent oxalic acid within a few minutes after separation 1.1 solid solids separated within a few minutes after deliquescence L-aspartic acid 0.5 solid solid crystal L-aspartic acid L-aspartic acid 1.1 solid solid crystal L-aspartic acid maleic acid 0.5 solid solid crystals identical to TB-09-10 XRPD maleic acid 1.1 solid solid crystals identical to TB-09-09 XRPD phosphoric acid 1.1 Solid solids - deliquescent L-glutamic acid 0.5 solid solid crystals within a few minutes after separation - L-glutamic acid 1.1 solid solid crystals 1-meryl-2-caeic acid (hydroxynaphthoic acid) 1.1 Solid solid crystal L-tartaric acid 0.5 solid solid - deliquescent L-tartaric acid in a few minutes after separation 1.1 solid solid - deliquescent fumaric acid within a few minutes after separation 0.5 solid solid crystal - fumaric acid 1.1 solid solid crystal with TB-09-17 with extra peak The same XRPD galactosedioic acid (mucosic acid) 0.5 solid solid crystal and semi-galactose diacid salt reference XRPD 162775.doc .51 · 201249841 half Sodium disaccharide (mucoacid) 1.1 Solid solid crystal and semi-galactose diphosphate refer to the same XRPD citric acid 0.5 Solid solid separated after a few minutes of decomposing citric acid 1.1 Solids decomposed D-glucan within a few minutes after separation Acid 1.1 solid solids separated within a few minutes after deliquescence of malic acid 1.1 gel solids separated within a few minutes of deliquescent hippuric acid 1.1 solid solid crystal - D-gluconic acid 50%, stored in water 1.1 oil - L - mandelic acid 1.1 solid solid Crystalline L-Lactic Acid 85% Aqueous Solution 1.1 Glue - - L-Ascorbic Acid 1.1 Clarified Solution Oil - Succinic Acid 0.5 Solid Solid Crystallization - Succinic Acid 1.1 Clear Solution Clear Solution • Acetic Acid 1.1 Clear Solution Clear Solution - Benzoic Acid 1.1 Clear Solution Clear Solution - Adipic acid 0.5 solid solid crystals identical to TB-09-35 XRPD adipic acid 1.1 solid solid crystals identical to TB-09-34 XRPD propionic acid 1.1 clear solution clear solution - - (+)-camphoric acid 1.1 solid solid Crystalline 162775.doc ·52· 201249841 Acid equivalent observed at -20 °c after slow evaporation After maturing in TBME, observe the observation of XRPD hydrochloric acid 37wt% (12 Μ) after titration with acetone 1.1 Glue rubber solid crystal sulfuric acid 1.1 Glue rubber D-gluconic acid 50%, stored in water 1.1 Oil gelatin solid non- Crystal L-Lactic acid 85% Aqueous solution 1.1 Glue gel clear solution - L-aspartic acid 1.1 Clarified lysine gel solid amorphous succinic acid 1.1 Clear solution Glue acetate acetic acid 1.1 Clear solution Glue phthalic acid 1.1 Solid - Crystalline Propionic Acid 1.1 Clarified Solution Glue Clarification Solution Initially, salt screening was performed using isopropyl acetate, however, for the experiments in which they produced inseparable salts, isopropanol and 2-butanone (mercaptoethyl) were used. Ketone) Perform further salt sieving (see the two tables below). The acid equivalent was slowly evaporated at 50 ° C under o ° c. After observation, the XRPD sulfuric acid was observed after titration with propyl acetate. 1.1 Clarified solution solid - deliquescent L-aspartic acid 0.5 clear solution clear solution gel L-aspartate Acid 1.1 Clear solution Clear solution Glue L-glutamic acid 0.5 Clear solution After 1 month, it is a solid such as free crystals + Extra peak L-glutamic acid 1.1 Clear solution Clear solution 1 month after solid - Crystallization 162775.doc •53· 201249841 D-glucuronic acid 1.1 oil-oil gel solid amorphous L·lactic acid 1.1 clear solution clear solution gel clear solution _ propionic acid 1.1 clear solution clear solution gel clear solution 4-hydroxybenzoic acid 1.1 clear solution Solid - crystallization acid equivalent slowly evaporating at -20 ° C at 50 ° C after observation of anti-solvent addition / maturation after observation of XRPD sulfuric acid 1.1 oil gum glue - L-aspartic acid 0.5 clarification Solution clear solution clear solution glue L-aspartic acid 1.1 clear solution clear solution clear solution gel - L-glutamic acid 0.5 clear solution Clear solution clear solution gel solid same as TB-776-24-05 crystal L-glutamic acid 1.1 clear solution oil oil gel solid the same crystal as TB-776-24-05 D-glucuronic acid 1.1 clear solution oil Oil Glue Solid Amorphous L-Lactic Acid 85% Aqueous Solution 1.1 Clarified Solution Glue Rubber Glue - Propionic Acid 1.1 Clarified Solution Clarified Solution Clear Solution Glue - 4-Hydroxybenzoic Acid 1.1 Solid Glue Solid Crystals Filter all solids and use XRPD analysis. 162775.doc -54- 201249841 Figure 1 depicts the crystal structure of the semi-galactose dihydrate monohydrate of Compound A. Figure 2 illustrates the crystal structure in numerical order. Figure 3 depicts the TGA/DSC of the semi-galactosate monohydrate of Compound A. Figure 4 depicts the GVS of the semi-galactosate monohydrate of Compound A. Figure 5 depicts the XRPD pattern of the semi-galactosuccinate monohydrate of Compound A before and after storage at 40 °C / 75% RH and after GVS. Figure 6 depicts the XRPD of the hydroxynaphthoate salt of Compound A. Figure 7 depicts the TGA/DSC of the hydroxynaphthoate salt of Compound A. Figure 8 depicts the GVS of the hydroxynaphthoate salt of Compound A. Figure 9 depicts the XRPD of the benzoate salt of Compound A. Figure 10 depicts the TGA/DSC of the benzoate salt of Compound A. Figure 11 depicts the GVS of the benzoate salt of Compound A. Figure 12 depicts the high resolution VT-XRPD of the benzoate salt of Compound A. Figure 13 depicts the XRPD of the hippurate salt of Compound A. Figure 14 depicts the TGA/DSC of the hippurate of Compound A. Figure 15 depicts the GVS of the hippurate of Compound A. Figure 16 depicts the high resolution VT-XRPD of the hippurate of Compound A. Figure 17 depicts XRPD of the semi-galactosidate of Compound A for polymorphic analysis. Figure 18 depicts the XRPD of the benzoate salt of Compound A for polymorphic analysis. Figure 19 depicts 162775.doc -55 - 201249841 XRPD of the hippurate of Compound A for polymorphic analysis. Figure 20 depicts XRPD of the hydroxynaphthoate salt of Compound A for polymorphic analysis. Figure 21 depicts the XRPD of Compound A (+)-camphorate. Figure 22 depicts TGA/DSC of compound A (+)-camphorate. Figure 23 depicts the XRPD of the tosylate salt of Compound A. Figure 24 depicts the TGA/DSC of the tosylate salt of Compound A. Figure 25 depicts XRPD of the maleate salt of Compound A using 0.5 equivalents of acid. The sample was deliquescent, so TGA and DSC were not measured. Figure 26 depicts XRPD of the maleate salt of Compound A using 1 equivalent of acid. Figure 27 depicts TGA/DSC of the maleate salt of Compound A using 1 equivalent of acid. Figure 28 depicts the XRPD of L-mandelate of Compound A. Figure 29 depicts the TGA/DSC of L-mandelate of Compound A. Salts having acceptable physical properties for drug discovery include hydrochloride, p-toluenesulfonate, L-aspartate, maleate, L-glutamate, 1-hydroxy-2-naphthoquinone An acid salt (hydroxynaphthoate), a fumarate, a galactose salt, a hippurate, an L-mandelate, a succinate, an adipate, or a (+)-camphorate. Preferred salts include p-toluenesulfonate, maleate, galactate, benzoate, hippurate, hydroxynaphthoate, or (+)-camphorate. The NMR spectrum and melting point of several salts are given below. These data were obtained from preliminary salt screening. p-Toluenesulfonate of Compound A: 4 NMR (d6-DMS 〇, 400 162775.doc • 56·201249841 MHz): δ 7.48 (d, 2H), 7.12 (d, 2H), 4.37 (m, 2H), 4.13 (dd, 2H), 3.79 (d, 1H), 3.70 (d, 1H), 2.81 (m, 1H), 2.29 (s, 3H), 1_87 (m, 1H), 1·75 (d, 1H) , 0.81 (m, 4H); mp: 172〇C. Maleate of Compound A: NMR (d6-DMSO, 400 MHz): δ 6.08 (s, 2H), 4.42 (m, 2H), 4.20 (dd, 2H), 3.84 (d, 1H), 3.78 (d , 1H), 2.88 (m, 1H), 1.94 (m, 1H), 1.82 (d, 1H), 0.85 (m, 4H); mp: 163 °C. Hydroxynaphthoate of Compound A: 1111 &lt;[1411((16-01^80,4001^1^): δ 8.24 (m, 1Η), 7.75 (m, 2H), 7.51 (dd, 1H), 7.41 (dd, 1H), 7.06 (d, 1H), 4.42 (m, 2H), 4.19 (m, 2H), 3.82 (dd, 2H), 2.91 (m, 1H), 1.93 (m, 1H), 1.79 ( d,1H), 0.84 (m, 4H). L-mandelic acid salt of compound A: NMR (d6-DMSO, 400 MHz): δ 7.41 (d, 2H), 7.31 (m5 2H), 7.23 (m, 1H) ), 4.72 (s, 1H), 4.10 (m, 4H), 3.69 (dd, 2H), 2.72 (m, 1H), 1.91 (m, 1H), 1.62 (d, 1H), 0.82 (m, 4H) ; mp: 143 ° C. Horse urate of Compound A: NMR (d6-DMSO, 400 MHz): δ 7.92 (d, 2H), 7.57 (m, 3H), 4.01 (s, 2H), 3.88 (m, 4H), 3.60 (dd, 2H), 2.62 (m, 1H), 1.94 (m, 1H), 1-52 (d, 1H), 0.82 (m, 4H). Benzoate of Compound A·· iH NMR (d6-DMSO, 400 MHz): δ 7.92 (d, 2H), 7.54 (t, 1H), 7.44 (m, 2H), 3.95 (m, 2H), 3.84 (m, 2H), 3.56 (dd, 2H), 2.63 (m, 1H), 1.87 (m, 1H), 1.49 (d, 1H), 0.77 (m, 4H). (+)-camphorate of compound A: lH NMR (d6-DMSO, 400 162775.doc -57- 201249841 MHz): δ 3.94 (m, 2H), 3.70 (m, 2H), 3.56 (dd, 2H), 2.78 (t, 1 H), 2.55 (m, 1H), 2.40 (m, 1H), 2.04 (m, 1H), 1.91 (m, 1H), 1.75 (η, 1H), 1.44 (m, 2H), 1.23 (s, 3H) ), 1.16 (s, 3H), 0.82 (m, 7H); mp: 170d. The synthesis of certain salts identified in salt screening is preferentially amplified. Their procedures, melting points and solubility data are reported here. Naphthoic acid salt of compound A: 3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1] heptane (500 mg, 3.01 mmol) dissolved in isopropyl acetate at 7 °C Base vinegar (5 mL). Nafanoic acid (xinaf〇ic acid) (626 mg, 3.31 mmol) was suspended in 98:2 isopropyl acetate/water (6.1 mL) at 60 C and added to a solution of the free base. The resulting mixture was slowly cooled to dryness, and the suspension solid was collected by suction filtration and dried under vacuum and ambient temperature for 5 h» to obtain an off-white powder (l.oi g, 95% yield). The sample exhibited a dazzling point of m〇c and a water solubility of 2.6 mg/mL. The benzoate salt of Compound A: at 7 Torr. (: 3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1] heptane (500 mg, 3.01 mmol) was dissolved in isopropyl acetate (5 mL) at 60. : Benzoic acid (405 mg, 3.31 mmol) was dissolved in 98.2 acetic acid isopropyl vinegar / water (3.1 mL) and added to the free solution. The resulting mixture was slowly cooled to 〇 ° C, and by pumping The suspended solid was collected by suction filtration and dried under vacuum and ambient temperature for 5 h to give a white powder (833 mg, 95% yield). The sample exhibited 136. (: melting point and &gt; 15 mg/mL water solubility. Horse salt of Compound A: 3-cyclopropylcarbonyl-3,6-diazabicyclo[3.M]heptane (500 mg, 3.01 mmol) was dissolved in isopropyl acetate at 7 〇eC. -58- 201249841 Base S (5 mL). Capric acid (596 mg, 3.31 mmol) was suspended in 98:2 isopropyl acetate/water (6.1 mL) at 60 ° C and added to the free base The solution was slowly cooled to 0 ° C, and the suspended solid was collected by suction filtration and dried under vacuum and ambient temperature for 5 h to give an off-white powder (884 mg, 85% yield). 157 ° C Melting point and water solubility of &gt; 15 mg/mL. Example 6: Characterization of interaction at the nicotinic acetylcholine receptor. Cell line SH-EP1/human α4β2 (Eaton et al., 2003), SH-EP1 /Human α4β4 (Gentry et al., 2003), 3Η-ΕΡ1/α6β3β4α5 (Grinevich et al., 2005), SH-EP1_ human (obtained from Paul Whiteaker, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona) , TE671/RD and SH-SY5Y cell lines (obtained from Dr. Ron Lukas, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona) in Dulbecco's modified Eagle's medium (Gibco) /BRL) maintained in the proliferative growth phase with 10% horse serum (Gibco BRL), 5% fetal bovine serum (HyClone, Logan UT), 1 mM sodium pyruvate, 4 mM L-glutamine. In order to maintain stable transfectants, α4β2 and α4β4 cell culture media were supplemented with 0.25 mg/mL 26〇(^11 and 〇.13 11^/1111^ hygromycin 8. For the maintenance of 〇160304〇15 cells, 0.25 mg/ was used. mL zeocin, 0.13 mg/mL hygromycin B, 0.4 mg/mL geneticin and 0.2 mg/mL glucosinolate. For the maintenance of α6/α3β2β3 cells, use 0.3 mg/mL zeocin and 0.3 162775.doc -59 - 201249841 mg/mL hygromycin B and 0.6 mg/mL G418 sulfate. HEK/human a7/RIC3 cells (obtained from J. Lindstrom, U. Pennsylvania, Philadelphia, Pennsylvania) in Dubec's modified Eagle The medium (Gibco/BRL) is maintained in the proliferative growth phase with 1 〇〇/〇 fetal bovine serum (HyClone, Logan UT), 1 mM sodium pyruvate, 4 mM L-glutamine, 0.4 Mg/mL geneticin, 0_2 mg/ml hygromycin B. Receptor binding assay preparation from rat tissue membrane: from Analytical Biological

The rat cortex was obtained from Services, Incorporated (ABS, Wilmington, Delaware). Tissues were dissected from female Sprague-Dawley rats, frozen and transported on dry ice. Tissues were stored at -20 °C until film preparation was required. The cortex of 10 rats was pooled and ice-cold preparative buffer (KC1 » 11 mM; KH2P〇4 * 6 mM; NaCl 137 mM; Na2HP04 8 mM) by Polytron (Kinematica GmbH, Switzerland) in 10 volumes (by weight: volume). HEPES (free acid) '20 mM; mothylamine, 5 mM; 〇 八 八, 1.5 1111^; 0.1111^1?]^?卩117.4) homogenization. The resulting homogenate was centrifuged at 40,000 g for 20 minutes at 4 ° C and the resulting precipitate was resuspended in 20 volumes of ice-cold water. After incubation for 60 minutes at 4 t, the new sink was collected by centrifugation at 40,000 g for 20 minutes at 4 C. The final sediment was resuspended in preparative buffer and stored at -20 °C. On the day of analysis, the tissue was thawed 'centrifuged at 40,000 g for 2 min and then resuspended in PBS (Dulbecker Sulfate Buffered Saline, Life Technologies, pH 7.4) to a final concentration of 2-3 mg protein/ml. . Use the Pierce BCA Protein Analysis Kit (Pierce Bi〇techn〇1〇gy, 162775.doc -60- 201249841

Rockford, IL) determined protein concentration using bovine serum albumin as a standard. Preparation of membranes from pure cell lines: Cells were harvested in ice-cold PBS (pH 7.4) and subsequently homogenized with a polytron (Brinkmann Instruments, Westbury, NY). The homogenate was centrifuged at 40,000 g for 20 minutes (4 ° C). The precipitate was resuspended in PBS and protein concentration was determined using a Pierce BCA protein assay kit (Pierce Biotechnology, Rockford, IL). Competitive binding to receptors in membrane preparation. Binding to nicotinic receptors was analyzed on membranes using standard methods adapted from published procedures (Lippiello and Fernandes, 1986; Davies et al., 1999). Briefly, reconstituted membranes from frozen stock (approximately 0.2 mg protein) and incubated on ice for 2 h in 150 ml assay buffer (PBS) in the presence of competitor compounds (0.001 nM to 100 mM) and radioligand . Human α4β2 binding studies were performed using [3H]-nicotine (L-(-)-[N-mercapto-3H]-nicotine, 69.5 Ci/mmol, Perkin-Elmer Life Sciences). Binding studies at other receptor subtypes were performed using [3Η]-G. serrata (52 Ci/mmol, Perkin-Elmer Life Sciences). Reducing non-specific binding by rapid filtration using a GF/B filter pre-soaked in 0.33% polyethyleneimine (w/v) on a multi-manifold tissue harvester (Brandel, Gaithersburg, MD) The filter was washed 3 times and the retained radioactivity was determined by liquid scintillation counting. Combine data analysis. Binding data is expressed as the percentage of total control binding. The average of the replicates for each point is taken and plotted against the logarithm of the drug concentration. IC5Q (concentration of compound producing 50% binding inhibition 162775.doc -61 - 201249841 degrees) was determined by least square linear regression using GraphPad Prism software (GraphPAD, San Diego, CA). Calculated using the Cheng-Prusoff equation (Cheng and Prusoff, 1973)

Ki. Table 1 Structure CO. &lt;s GO. n ca 賧&lt; ¥ i 140 20 3.0 2.3 620 Example 7: Pharmacological overview In vitro pharmacology: Compound A has a high affinity for α6β2* and α4β2* NNR , and confirmed to have a lower affinity for ct7 NNR. The compound lanthanide is a full agonist of all three subtypes and exhibits sufficient functional separation from muscle and gangliotype nicotinic receptors as well as non-dry standard receptors. In the &60; dry standard Novascreen group, Compound A did not interact with any non-NNR receptors. Compound A also exhibits robust desensitization of the three α4β2* NNR subtypes known to be present in the striatum. Specifically, the compound is ((α4)2(β2)3-“high sensitivity”, (α4)3(β2)2-“low sensitivity”, and α5(α4)2(β2)2 receptor, respectively DC5〇 with 24 nm, 68 nm, and 42 nm was completely inhibited in each case (&gt;98% Imax before administration of 10 μιη 醯 醯 30 30 min). Desensitization is potentially related to the efficacy of the therapeutic LID (see Bordia et al., &quot;1^1'111. £\卩· Ther. 327(1): 239-247 (2008)). I62775.doc •62- 201249841 As reported initially in WO 2011/071758, Compound A produces an extremely potent neuroprotective effect against MPP+ toxicity in primary cultures of rat dopamine neurons. Pre-incubation 24 or 48 prior to MPP+ exposure. Compound A is protective over a wide dose range (1 pM to i μΜ) at hours. The minimum effective dose is 1 〇 ρ 在 when used for 24 hours of pre-incubation, making Compound a effective' and more effective than the final test in this analysis. The greater receptor selectivity and greater neuroprotective efficacy of Compound A may result in better long-term administration tolerance in disease modification with Parkinson's disease compared to the final assay. In vivo pharmacology: Rat study: The ability of Compound A to attenuate AIM was determined in 6-OHDA-induced (semi-) Parkinson's disease rats repeatedly administered with levodopa. Compound A was tested in both Parkinson's disease rats that had not been treated with levodopa (molar prevention or delayed LID episodes) and levodopa pretreatment (modeled treatment of existing LID). In the first phase of the reunion, the compound was administered to the subcutaneous mini-pump at 0.75 mg/kg/day for two weeks prior to the administration of levodopa, followed by an additional 3 weeks with levodopa. Compound A prevented complete onset of LID (34% reduction in AIM, see Figure 30A) at 0.75 mg/kg/day in levodopa-untreated rats and maintained at dose reduction (K3 mg/kg/day for additional weeks) Effect. The drug was then cross-administered to expose animals that had received vehicle combination with levodopa levodopa (levodopa pretreatment) to Compound A. Compound A was administered at 0.3 mg/kg/day via a micro pump. A small but significant reduction (13%) in established LID after 2 weeks. Increased to 21% at doses increased to 0.7 mg/kg/day for an additional 2 162775.doc 63·201249841 weeks (see Figure 30B) Compound A reduced the established AIM of moderately injured animals by 36% when analyzing data based on the severity of the injury. Since AIM-relieving drugs can worsen Parkinson's disease, limb asymmetry test or cylinder test is also used ( It is a sensitive measure of the degree of unilateral dopamine loss). It is a test for the motor function test compound A in Parkinson's disease rats. The results show that Compound A does not deteriorate the baseline motor function (without taking levodopa) and does not make use of it. Levodopa treatment Enhance the deterioration of limb use (see Figure 30C). It is important that Compound A does not produce detectable side effects during the efficacy test (ie, for body weight, body temperature, finishing, urination, defecation, secretion). Primate studies: To further analyze the ability of Compound A to ameliorate lid without reducing the anti-Parkinson's effect of levodopa, the MPTP-infected cynomolgus monkey model of Parkinson's disease was used. In this study, the use of each animal was used. A variable dose of levodopa (20-35 mg/kg/day, orally, once a day) that reverses the symptoms of Parkinson's disease but induces significant to severe dyskinesia is treated for MPTP-injured cynomolgus monkeys for two weeks. Six-week animals continued to receive levodopa, but also received (by oral gavage) vehicle (once a day) or Compound A (2 times a day, 8 hours apart, morning treatment in parallel with levodopa treatment). There were 7 animals in the group (therapeutic and vehicle-treated animals received an increased dose of Compound A: two weeks for 〇.〇3 mg/kg, followed by 0.10 mg/kg for the next two weeks; and 0.30 mg/kg for the next two weeks;曰On each of the 7th '13, 21, 28, 35, 42, 49, and 59 days, the animals were rated as "poor quality" on-time (significant to severe dyskinesia) and 162,775. Doc -64- 201249841 "Good quality" start-up period (no dyskinesia, mild or moderate dyskinesia). This assessment period begins in the morning and lasts for 6 hours. β is between the end of the first hour and the end of the third hour. During the hourly period, both the severity of dyskinesia and the disability of Parkinson's disease were assessed. As shown in Figure 31a, the compound Α significantly reduced 1 „). This effect is particularly strong at doses of 〇1〇 mg/kg. As shown in Figures 31b and 31c, Compound a did not significantly alter the total initiation period (the total time when levodopa was resistant to Parkinson's disease) or Parkinson's disease disability (efficiency of levodopa treatment). As shown in Figure 32, Compound A significantly reduced the percentage of poor quality initiation period (time characterized by annoying dyskinesia) from 50-55% to approximately 30% and correspondingly a good quality initiation period (no order) The percentage of time when people are troubled with movement disorders is from 45-50°/. Increase to about 70%. Total dyskinesia, as well as chorea and dystonia endpoints were significantly reduced. Compound A was well tolerated in this study and did not negatively affect the general motor activity of the animal and did not offset the effect of levodopa on Parkinson's disease. The specific pharmaceutical response observed can be based on the particular active compound selected or the presence or absence of a pharmaceutical carrier, and the type of formulation employed, and the manner in which it is administered, and in accordance with the practice of the present invention, such differences or differences in expected results are also It is encompassed by the present invention. Although specific embodiments of the invention have been described and illustrated in detail herein, the invention is not limited thereto. The above detailed description is provided as an example of the invention and should not be construed as limiting the invention. Those skilled in the art will appreciate that modifications may be made without departing from the spirit of the invention, and are intended to be included within the scope of the appended claims. 162775.doc •65· 201249841 [Simple description of the diagram] Fig. 1 depicts the crystal structure of the semi-galactose dihydrate monohydrate of the compound A. Figure 2 illustrates the crystal structure in numerical order. Figure 3 depicts the TGA/DSC of the semi-galactosate monohydrate of Compound A. Figure 4 depicts the GVS of the semi-galactosate monohydrate of Compound A. Figure 5 depicts the xrpd pattern of the semi-galactosuccinate monohydrate of Compound A before and after storage at 40 °C / 75% RH and after GVS. Figure 6 depicts the xrpd of naphthoate salt of Compound A. Figure 7 depicts the tgA/DSC of the hydroxynaphthoate salt of Compound A. Figure 8 depicts the GVS of the naphthoate salt of Compound A. Figure 9 depicts the xrpd of the benzoate salt of Compound A. Figure 10 depicts the tga/DSC of the abbreviated acid salt of Compound A. Figure 11 depicts the gvs of the stearate of Compound A. Figure 12 depicts the high resolution ντ-XRPD of the abbreviated acid salt of Compound A. Figure 13 depicts the xrpd of the hippurate of Compound A. Figure 14 depicts the tga/dsc of the hippurate salt of Compound A. Figure 15 depicts the GVS of the hippurate of Compound A. Figure 16 is a graph showing the high resolution ντ-XRPD of the hippurate of Compound A. Figure 17 is a graph showing the XRPD of the semi-galactose diphosphate of Compound a for polymorph analysis. Figure 18 is a graph showing XRPD of the benzoate of Compound a. 162775.doc • 66 - 201249841 Figure 19 depicts XRPD of the hippurate of Compound A for polymorphic analysis. Figure 20 depicts XRPD of the hydroxynaphthoate salt of Compound A for polymorphic analysis. Figure 21 depicts the XRPD of Compound A (+)-camphorate. Figure 22 depicts TGA/DSC of compound A (+)-camphorate. Figure 23 depicts the XRPD of the tosylate salt of Compound A. Figure 24 depicts the TGA/DSC of the tosylate salt of Compound A. Figure 25 depicts XRPD of the maleate salt of Compound A using 0.5 equivalents of acid. The sample was deliquescent, so TGA and DSC were not measured. Figure 26 depicts XRPD of the maleate salt of Compound A using 1 equivalent of acid. Figure 27 depicts TGA/DSC of the maleate salt of Compound A using 1 equivalent of acid. Figure 28 depicts the XRPD of L-mandelate of Compound A. Figure 29 depicts the TGA/DSC of L-mandelate of Compound A. Figure 30 depicts Compound A's ability to reduce AIM in Parkinson's disease rats. Figure 31 depicts the ability of Compound A to reduce LID in non-human primates. Figure 32 depicts the ability of Compound A to increase the good quality initiation period during levodopa treatment. 162775.doc 67-

Claims (1)

201249841 VII. Patent application scope: 1. An acid addition of 3-cyclopropylcarbonyl-3,6-diazabicyclo[3. M]heptane. 2. An acid addition salt of 3-cyclopropylcarbonyl-3,6-diazabicyclo[3丨丨]heptane, wherein the acid is selected from the group consisting of hydrogen acid, p-toluenesulfonic acid, and L_aspartate Aminic acid, maleic acid, L- faceted acid, 1-carbo-2-carotic acid, fumaric acid, galactosuccinic acid, hippuric acid, L-mandelic acid, succinic acid, adipic acid or (+ )_ camphoric acid. 3. The acid addition salt of claim 2 wherein the salt is p-toluene, maleate, galactate, benzoate, hippurate, xinafoate Or (+)·camphorate. 4. The acid addition salt of claim 3 wherein the salt is a galactose salt, a benzoate, a hippurate or a hydroxynaphthoate. 5. A 3_cyclopropylcarbonyl-3,6-diazabicyclo[3丨丨]heptane hemi-galactose dihydrate (hemigalactarate) monohydrate. 6. The acid addition salt of any one of claims 1 to 6, wherein the salt is crystalline. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and one or more pharmaceutically acceptable carriers, diluents or excipients. 8. A method of treating or preventing a disease or condition mediated by a neuronal nicotinic receptor, comprising administering a compound according to any one of claims 6 to 6. 9. Use of a compound according to any one of claims 1 to 3 for the preparation of a medicament for the treatment or prevention of a disease or condition mediated by a neuronal nicotinic receptor. 10. A compound according to claims 1 to 6 for use as an active therapeutic substance. 162775.doc 201249841 11. A compound according to claims 1 to 6, which is a receptor-mediated disease or condition which is used for the treatment or prevention of a tobacco by a neuron smoke 12. For example, a method, use or compound* Alkaline is affected by the system α4β2* subtype. And 13. The method, use or compound of the claim, wherein the elemental nicotinic acid is affected by the system α6β2* subtype. By the method of claim, the method, the use, or the compound, wherein the metabasin is affected by both the system α4β2* and the α6β2* subtype. 15. The method, use or compound of claim, wherein the condition is a CNS disorder. Or 16. The method, use or compound of claim 8 to ^ wherein the condition is abnormally involuntary. The method, use or compound of claim 8 to U, wherein the disease or condition is levodopa-induced dyskinesia. 18. The method, use or compound of claim 8 to 11, wherein the disease condition is dyskinesia. 19. The method, use or compound of claim 8 to 11, wherein the disease or condition is Parkinson&apos;s Disease. 20. The method, use or compound of claim 19, wherein the administration does not interfere with the effects of any existing therapies on motor deficits. 21. The method, use or compound of claim 8 to 11, wherein the disease or condition is Parkinsonism. 22. The method, use or compound of claim 8 to 11, wherein the method, use or compound further comprises levodopa being administered. I62775.doc 201249841 23. The method of claim 22, provided during the course of an existing treatment period. Use or compound, wherein the levodopa is administered at a lower dose or at a lower dose. 24. A method of protecting nerves, which comprises administering 3-cyclopropylcarbonyl-3,6-diaza Heterobicyclo[3.1.1] heptane or a pharmaceutically acceptable salt thereof. 25. The medical group of claim 7 you +χ, A, see 〇物' wherein the composition is formulated for transdermal, intranasal, buccal or sublingual administration. 26. A method for synthesizing 3-cyclopropylcarbonyl·36-diazabicyclo[3丨^heptane or a pharmaceutically acceptable salt thereof, which comprises reacting a cyclopropylguanamine nucleophile with nitrogen Hetero%: butyl bis-electrophile reacts to form hexahydrogen. Than the bite ring. 27. A compound Bn-N^^OMs OMs 28. The compound of claim 27 which is in the form of the corresponding halide. 162775.doc