Methods of making SSTR4 agonists and salts thereof and dosing regimens using same

Abstract

The invention relates to a method for preparing SSTR4 agonist compounds. A process for the preparation of SSTR4 agonist compounds via a diastereoisomer selective cyclization reaction, without the need for a separate epimerization step. Novel intermediates useful in the preparation of SSTR4 agonist compounds. Dosing regimens for the treatment of pain and / or neuropathic pain, such as diabetic peripheral neuropathy, central neuropathy or mixed neuropathy.

Description

TECHNICAL FIELD

[0001] The present invention relates to a process for preparing SSTR4 agonists. The present invention also relates to a process for preparing salts of SSTR4 agonists.

[0002] The present invention also relates to a dosage regimen for the treatment of chronic lower back pain, osteoarthritic pain, and / or neuropathic pain (e.g., diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy) using SSTR4 agonists and pharmaceutically acceptable salts and / or hydrates thereof. BACKGROUND

[0004] Somatostatin, or growth hormone release inhibiting factor (SRIF), is a cyclic peptide found in the human body. It is produced widely in the human body and acts systemically and locally to inhibit the secretion of various hormones, growth factors, and neurotransmitters. The actions of somatostatin are mediated by a family of G protein-coupled receptors, of which five subtypes are known. These subtypes are divided into two subfamilies, the first subfamily including SSTR2, SSTR3, and SSTR5, and the second subfamily including SSTR1 and SSTR4.

[0005] Somatostatin is involved in the regulation of processes such as cell proliferation, glucose homeostasis, inflammation, and pain. In this regard, somatostatin or other members of the somatostatin peptide family are believed to inhibit nociceptive and inflammatory processes through the SSTR4 pathway.

[0006] WO 2014 / 184275 discloses certain 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives that are SSTR4 agonists and are useful for preventing or treating medical conditions associated with SSTR4. However, the synthesis of 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives with sufficient enantiomeric and diastereomeric purity is challenging. Laboratory scale synthetic routes are known, but the multiple steps used in previous synthetic routes are impractical and / or cost prohibitive for use on a commercial scale.

[0007] Accordingly, alternative routes are needed to prepare certain SSTR4 agonists on a commercial scale and with sufficient purity. Accordingly, the present invention relates to a process for preparing certain SSTR4 compounds, such as (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide and pharmaceutically acceptable salts, solvates, and / or hydrates thereof.

[0008] Diabetic neuropathy is a common complication of diabetic microvascular disease. About 40% of diabetic patients have diabetic microvascular disease, and about 80% of diabetic neuropathy patients have peripheral polyneuropathy.

[0009] Symptoms of diabetic peripheral neuropathy include hyperalgesia, paresthesia, and deep pain sensation. Diabetic peripheral neuropathy (DPNP) symptoms are accompanied by poor sleep, mobility, depression, and poor quality of life.

[0010] Unfortunately, there are limited treatment options for DPNP. The US FDA has only approved three drugs for this indication: pregabalin, duloxetine, and tapentadol. While both pregabalin and duloxetine have shown efficacy in multiple placebo-controlled clinical trials, both drugs require dose titration to minimize adverse reactions. Tapentadol is an opioid μ receptor agonist with the same pharmacological limitations and adverse reactions as other opioid analgesics. Other types of drugs are used off-label in the clinic, including gabapentin, selective serotonin norepinephrine uptake inhibitors, tricyclic antidepressants, and anticonvulsants. However, dose-limiting toxicities of all these drugs make it impossible for patients to tolerate therapeutic doses, resulting in clinically used doses lower than therapeutic doses, further reducing the efficacy of these drugs. In addition, only 50% of patients continue treatment after 3 months.

[0011] Due to the poor dosing and poor tolerability of non-opioid analgesics for managing DPNP, opioid drugs are used as a last resort. Although opioid drugs are effective for acute pain, there is evidence that they have little clinical efficacy for chronic pain, not to mention the possibility of reduced efficacy due to tolerance.

[0012] In addition, while opioid compounds are known to relieve pain symptoms, opioid compounds are also accompanied by a variety of unwanted side effects, including hallucinations, nausea, dizziness, sedation, constipation, urinary retention, drug dependence, and addiction. As many as 25% of patients receiving opioid pain treatment, even for short-term treatment, develop dependence on opioid compounds. In fact, U.S. President Donald Trump has declared opioid addiction a national public health emergency on October 26, 2017. Therefore, the development of non-opioid compounds and dosing regimens for opioid compounds to relieve pain symptoms, while not developing the possibility of addiction and / or dependence, is a long-standing but unmet need.

[0013] Accordingly, the present invention relates to a dosing regimen for the treatment of pain, such as neuropathic pain and / or diabetic neuropathy and / or mixed neuropathy, using non-opioid compounds.

[0014] While methods of making certain SSTR4 compounds are disclosed in WO 2014 / 184275, WO 2021 / 233427, and WO 2022 / 012534, these compounds were produced at laboratory scale, which can include synthetic steps that are impractical at commercial scale. In these previous preparations, the synthetic routes used: (1) expensive catalysts, including palladium and / or rhodium and / or reduction steps using lithium aluminum hydride, and (2) resulted in mixtures of diastereomers that required epimerization after the heterocyclic ring was formed. Both (1) and (2) can increase the overall cost of manufacture and add additional purification steps to remove trace amounts of Pd, Rh, Li, Al, and / or unwanted diastereomers with lower activity.

[0015] Disclosed herein are new routes to obtain certain SSTR4 compounds, e.g., (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide, and salts thereof, that can be performed at commercial scale without the use of transition metal catalysts such as Pd, Pt, Mo, Rh, Fe, Ni, Cr, W, or any combination thereof and / or aluminum hydride salts, e.g., lithium aluminum hydride. In addition, the disclosed methods include a cyclization step with treatment of a (2-haloethyl)diphenylsulfonium salt, which results in the formation of a single diastereomeric intermediate that does not require a subsequent epimerization step. Finally, the disclosed methods have fewer total steps than previously disclosed routes, e.g., fewer than 8 total steps or 4 to 7 total steps.

[0016] Also disclosed herein are methods of treating pain in a patient in need thereof by administering (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1 0]hexane-6-carboxamide and pharmaceutically acceptable salts thereof and / or hydrates thereof, e.g., (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1 0]hexane-6-carboxamide L-tartrate sesquihydrate. Also disclosed herein are methods of treating chronic lower back pain, osteoarthritic pain, and / or neuropathic pain, e.g., diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy, in a patient in need thereof by administering (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1 0]hexane-6-carboxamide and pharmaceutically acceptable salts thereof and / or hydrates thereof, e.g., (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1 0]hexane-6-carboxamide L-tartrate sesquihydrate.

[0017] The non-opioid compound (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1 0]hexane-6-carboxamide is an SSTR4 agonist compound. (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1 0]hexane-6-carboxamide and pharmaceutically acceptable salts thereof and / or hydrates thereof, e.g., (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1 0]hexane-6-carboxamide L-tartrate sesquihydrate are a potential first line treatment for certain pain conditions, e.g., chronic lower back pain, osteoarthritic pain, and / or neuropathic pain, e.g., diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy. Thus, disclosed herein are clinically proven effective dosing regimens for treating certain pain conditions, e.g., chronic lower back pain, osteoarthritic pain, and / or neuropathic pain, e.g., diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 The average change in average pain intensity is shown in a Phase II study of (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartaric acid sesquihydrate in the treatment of diabetic peripheral neuropathy.

[0020] SUMMARY

[0021] Disclosed herein are dosing regimens for the treatment of chronic lower back pain, osteoarthritic pain, and / or neuropathic pain, e.g., diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy, using SSTR4 agonist compounds and pharmaceutically acceptable salts and / or hydrates thereof.

[0022] Also disclosed herein are capsule compositions comprising certain SSTR4 agonist compounds and pharmaceutically acceptable salts and / or hydrates thereof, e.g., (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartaric acid sesquihydrate.

[0023] Also disclosed herein are methods of making certain SSTR4 agonist compounds and pharmaceutically acceptable salts and / or hydrates thereof, e.g., (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide.

[0024] Also disclosed herein are dosing regimens for the treatment of neuropathic pain, e.g., diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy, using (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartaric acid sesquihydrate.

[0025] Also disclosed herein are methods of treating pain in a patient in need of such treatment comprising administering to said patient a dose of about 25 mg to about 1400 mg of a compound of the formula:

[0026] or a pharmaceutically acceptable salt thereof and / or a hydrate thereof.

[0027] Also disclosed herein is a method of treating pain in a patient in need of such treatment comprising administering to said patient a dose of about 25 mg to about 1400 mg of a compound of the formula:

[0028]

[0029] Also disclosed herein is a method of treating neuropathic pain in a patient in need of such treatment comprising administering to said patient a dose of about 50 mg to about 600 mg of a compound of the formula:

[0030]

[0031] Also disclosed herein is a method of treating pain in a patient in need of such treatment comprising administering to said patient a dose of about 25 mg to about 1400 mg of a compound of the formula:

[0032]

[0033] Also disclosed herein is a method of treating neuropathic pain in a patient in need of such treatment comprising administering to said patient a dose of about 50 mg to about 600 mg of a compound of the formula:

[0034]

[0035] Also disclosed herein is a novel method of preparing SSTR4 agonist compounds and pharmaceutically acceptable salts and / or hydrates thereof on a commercial scale.

[0036] Also disclosed herein is a capsule composition comprising a compound of the formula: or a hydrate thereof.

[0037] Also disclosed herein is a method of preparing a compound of the formula

[0038] or a pharmaceutically acceptable salt thereof; and the method comprises:

[0039] mixing a compound of the formula: wherein R is Ci to C6 alkyl,

[0040] with a sulfonium salt of the formula: wherein X is halogen and A is an anion,

[0041] to obtain an intermediate compound of the formula:

[0042] mixing the intermediate compound with to obtain and from removing the tosyl functional group to provide the compound.

[0043] Also disclosed herein are products comprising a compound such as (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate, prepared by the methods disclosed herein. DETAILED DESCRIPTION

[0045] SSTR4 agonists

[0046] The disclosed methods can be used to prepare a compound of Formula I. The disclosed methods can also be used to prepare a salt, solvate, hydrate, and / or combination thereof of Formula I.

[0047]

[0048] Formula I. SSTR4 agonist, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0049] The disclosed methods can be used to prepare a compound of Formula II. The disclosed methods can also be used to prepare a solvate, hydrate, and / or combination thereof of Formula II.

[0050]

[0051] Formula II. Tartrate salt of SSTR4 agonist, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide tartrate salt

[0052] The disclosed methods can be used to prepare a compound of Formula III. The disclosed methods can also be used to prepare a solvate, hydrate, and / or combination thereof of Formula III.

[0053]

[0054] Formula III. L-tartrate salt of SSTR4 agonist, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate salt

[0055] The disclosed methods can be used to prepare a compound of Formula IV.

[0056]

[0057] Formula IV. (1R, 5S, 6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate sesquihydrate

[0058] Method

[0059] Disclosed herein are methods of making SSTR4 agonist compounds. The methods of making SSTR4 agonist compounds can be used for commercial scale production of SSTR4 agonist compounds, pharmaceutically acceptable salts, and / or solvates / hydrates thereof, as discussed further below. In the disclosed methods, preferably, the reactions are carried out in a batch process. In one embodiment, the batch is produced at process scale. In one embodiment, the batch is produced at least 1 kilogram. In one embodiment, the batch is produced at least 10 kilograms. In one embodiment, the batch is produced at least 100 kilograms.

[0060] A method of making a SSTR4 agonist compound of the following formula can comprise the following steps:

[0061] or a pharmaceutically acceptable salt, solvate, or hydrate (a) mixing tert-butyl 4-((4-methylphenyl)sulfonyl)aminobut-2-enoate with the appropriate C1-C6 alkyl 4-halo but-2-enoate Step (c) mixing (E)-4-((4-methylphenyl)sulfonylaminobut-2-enoate with the appropriate C1-C6 alkyl 4-halo but-2-enoate

[0062] Step (a) of the method of making a SSTR4 agonist compound can comprise mixing tert- butyl tosylaminoformate with a suitable C1-C6 alkyl ester of 4-halobut-2-enoic acid compound in a polar aprotic solvent, as shown in Formula V, wherein X is a halogen leaving group, such as CI, Br, or I.

[0063]

[0064] Formula V. Step (a) of the method of making a SSTR4 agonist compound

[0065] The components of step (a) can be combined in a polar aprotic solvent at a temperature of about 10 °C to about 25 °C, about 15 °C to 25 °C, or 20 °C to 25 °C. The temperature of the mixture of components in step (a) can be raised to about 25 °C to about 50 °C, about 25 °C to about 40 °C, or about 30 °C. The product mixture of step (a) can be filtered and the collected residue washed with a polar aprotic solvent to yield the product in solution.

[0066] Suitable polar aprotic solvents are known to those of ordinary skill in the art of organic synthesis design. Suitable polar aprotic solvents can include acetonitrile, acetone, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, and the like.

[0067] In another embodiment, the method can include mixing tert-butyl tosylaminoformate with (E) 4-bromobut-2-enoic acid methyl ester compound in acetonitrile to yield (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoic acid methyl ester, as shown in Formula VI.

[0068]

[0069] Formula VI. Step (a) of a method of making SSTR4 agonist compounds

[0070] In another embodiment, step (a) can include mixing with to yield

[0071] The additional components of step (a) can include a base, such as potassium carbonate, and / or a salt, such as potassium iodide.

[0072]

[0073] Step (b) of a method of making SSTR4 agonist compounds can include mixing the product produced in step (a), (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoic acid C1-C6 alkyl ester, with a suitable acid in a polar aprotic solvent, as shown in Formula VII.

[0074]

[0075] Formula VII. Step (b) of a method of making SSTR4 agonist compounds

[0076] The components of step (b) can be combined in a polar aprotic solvent at a temperature of about 10 °C to about 25 °C, about 15 °C to 25 °C, or 20 °C to 25 °C. The temperature of the mixture of components in step (b) can be raised to about 40 °C to about 75 °C, about 40 °C to about 60 °C, or about 55 °C to about 60 °C. The reaction solution can be maintained at the elevated temperature for at least 4 hours, at least 10 hours, or at least 12 hours.

[0077] Following the mixing of step (b), the components can be heated to an elevated temperature and the solution can be concentrated and the remaining polar aprotic solvent exchanged with toluene and / or ethyl acetate.

[0078] The polar aprotic solvent can be the same solvent as in step (a) so that the product can remain in solution without any additional purification steps beyond filtration of the byproduct, or the solvent can be a different polar aprotic solvent.

[0079] Suitable acids in step (b) can be any acid that can be used to remove the tert-butyl ester from the tertiary amine to form the secondary amine. Suitable acids include trifluoroacetic acid, hydrochloric acid, sulfuric acid, hydrofluoric acid, and other acids.

[0080] In another embodiment, step (b) can include mixing (E)-4-((N-(tert-butoxycarbonyl)-4- methylphenyl)sulfonamido)but-2-enoic acid methyl ester with trifluoroacetic acid in acetonitrile to yield (E)-4-((4-methylphenyl)sulfonamido)but-2-enoic acid methyl ester, as shown in Formula VIII.

[0081]

[0082] Formula VIII. Step (b) of a method of making an SSTR4 agonist

[0083] In another embodiment, step (b) can include mixing with trifluoroacetic acid to yield Step (c) mixing (E)-4-((4-methylphenyl)sulfonylaminobut-2-enoate with the appropriate C1-C6 alkyl 4-halo but-2-enoate Step (c) mixing (E)-4-((4-methylphenyl)sulfonylaminobut-2-enoate with the appropriate C1-C6 alkyl 4-halo but-2-enoate

[0084] Step (c) of a method of making an SSTR4 agonist compound can include mixing the product produced in step (b), (E)-4-((4-methylphenyl)sulfonamido)but-2-enoic acid C1-C6 alkyl ester, with a sulfonium salt in a suitable heterocyclic solvent, as shown in Formula IX, to yield the intermediate compound (1R,5S)-3-(p-tolylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid.

[0085]

[0086] Formula IX. Step (c) of a method of making an SSTR4 agonist

[0087] The components of step (c) can be combined at -10 °C to 10 °C or about 0 °C. In addition to the sulfonium salt and (E)-4-((4-methylphenyl)sulfonamido)but-2-enoic acid C1-C6 alkyl ester, potassium fluoride and / or potassium hydroxide can be added. The temperature of the solution can be gradually or stepwise increased to 30 °C over a period of about 10 hours to about 30 hours.

[0088] Suitable heterocyclic solvents include tetrahydrofuran, furan, 2-methyl-tetrahydrofuran, and the like.

[0089] After the temperature of the solution has been increased, a base, such as lithium hydroxide, can be added at the increased temperature, and the reaction can be allowed to proceed for an additional period of time. The additional period of time can be from about 8 hours to about 24 hours, from about 12 hours to about 18 hours, or about 16 hours.

[0090] The intermediate compound (1R,5S)-3-(p-tolylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid can be isolated from solution using conventional synthetic organic chemistry isolation techniques well known to those of ordinary skill in the art.

[0091] The sulfonium salt used in step (c) can be represented by formula X, wherein X is a halogen leaving group, such as CI, Br, or I, and A is any suitable anion, which is well known to those of ordinary skill in the art.

[0092]

[0093] Formula X. Sulfonium salt of step (c)

[0094] The sulfonium salt used in step (c) can also be represented by formula XI.

[0095]

[0096] Formula XI. Sulfonium salt of formula X. step (c)

[0097] In another embodiment, step (c) can comprise mixing (E)-4-((4-methylphenyl)sulfonylamido)but-2-enoic acid methyl ester with 2-(bromoethyl)diphenylsulfonium triflate to yield the intermediate compound (1R,5S)-3-(p-tolylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid, as shown in formula XII.

[0098]

[0099] Formula XII. Step (c) of the method of making SSTR4 agonist

[0100] In another embodiment, step (c) can comprise mixing with to yield the intermediate compound or a salt or solvate thereof.

[0101] Step (d) of the method of making SSTR4 agonist compounds can comprise mixing the intermediate compound (1R,5S)-3-(p-tolylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid produced in step (c) with 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine, as shown in formula XIII. Step (c) mixing (E)-4-((4-methylphenyl)sulfonylaminobut-2-enoate with the appropriate C1-C6 alkyl 4-halo but-2-enoate

[0102] Step (d) of the method of making SSTR4 agonist compounds can comprise mixing the intermediate compound (1R,5S)-3-(p-tolylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid produced in step (c) with 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine, as shown in formula XIII.

[0103]

[0104] Step (d) of the method of preparing SSTR4 agonists of Formula XIII.

[0105] Prior to the addition of 2-methyl-l-((3-methylpyridin-2-yl)oxy)propan-2-amine, the intermediate compound can be reacted with a suitable reagent, such as oxalyl chloride or thionyl chloride, to replace the -OH functionality with -CI in situ under synthetic conditions well known to those of ordinary skill in the art.

[0106] The resulting acyl chloride can be combined with 2-methyl-l-((3-methylpyridin-2- yl)oxy)propan-2-amine at a temperature of about -10 °C to about 10 °C or about 0 °C to about 10 °C.

[0107] After about 2 to about 4 hours, the temperature of the solution can be increased to about 15 °C to about 25 °C.

[0108] In another embodiment, step (d) can comprise combining the intermediate compound with to yield

[0109] Step (c) mixing (E)-4-((4-methylphenyl)sulfonylaminobut-2-enoate with the appropriate C1-C6 alkyl 4-halo but-2-enoate Preparation 1

[0110] Step (e) of the method of preparing SSTR4 agonist compounds can comprise combining the product produced in step (d), ((lR,5S,6r)-N-(2-methyl-l-((3-methylpyridin-2- yl)oxy)propan-2-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane-6-carboxamide, with potassium diphenylphosphide, as shown in Formula XIV.

[0111]

[0112] Step (e) of the method of preparing SSTR4 agonists of Formula XIV.

[0113] ((lR,5S,6r)-N-(2-methyl-l-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-tosyl-3- azabicyclo[3.1.0]hexane-6-carboxamide can be dissolved in a suitable solvent, such as methyl tert-butyl ether. The temperature can be reduced to about -100 °C to about -50 °C, about -80 °C to about -55 °C, or about -70 °C to about -60 °C. Potassium diphenylphosphide can be added dropwise while maintaining the reduced temperature.

[0114] The solution can be maintained at a reduced temperature for at least 4 hours, at least 6 hours, or at least 8 hours after all of the potassium diphenylphosphine has been added. The solution can be allowed to warm to about 15 °C to about 25 °C, and the SSTR agonist compound (1S,5R)-N-[1,1-dimethyl-2-[(3-methyl-2-pyridinyl)oxy]ethyl]-3- azabicyclo[3.1.0]hexane-6-carboxamide can be isolated from the solution using typical methods well known to those of ordinary skill in the art.

[0115] In another embodiment, step (e) can comprise mixing with potassium diphenylphosphine to obtain the SSTR4 agonist compound. In another embodiment, step (e) can comprise mixing with potassium diphenylphosphine to obtain the SSTR4 agonist compound.

[0116] Salts of the SSTR4 agonist compound

[0117] Also disclosed herein are methods of making a pharmaceutically acceptable salt of the SSTR4 agonist compound. The methods of making a pharmaceutically acceptable salt of the SSTR4 agonist compound can comprise: (1) the disclosed methods of making the SSTR4 agonist compound and (2) producing a pharmaceutically acceptable salt of the SSTR4 agonist from (i) reaction with an acid, (ii) a salt metathesis reaction, and / or (iii) other reactions that can form a pharmaceutically acceptable salt of the SSTR4 agonist compound.

[0118] Suitable pharmaceutically acceptable salts of the SSTR4 agonist compound can comprise adipate, bromide, chloride, besylate, ethanesulfonate, methanesulfonate, tosylate, phosphate, succinate, sulfate, citrate, tartrate, L-tartrate, malate, and / or L-malate anions. Other suitable salts can include (1S,5R,6r)-N-[1,1-dimethyl-2-[(3-methyl-2-pyridinyl)oxy]ethyl]-3- azabicyclo[3.1.0]hexane-6-carboxamide tartrate, (1S,5R,6r)-N-[1,1-dimethyl-2-[(3-methyl-2- pyridinyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate, and / or (1R,5S,6r)-N-(2- methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide L- tartrate sesquihydrate. Other suitable salts are shown in Formulae II-IV. The L-tartrate salt can also be referred to as the (2R,3R)-2,3-dihydroxysuccinate salt.

[0119] Intermediate compounds

[0120] Also disclosed herein are novel intermediate compounds produced during the disclosed methods of making SSTR4 agonist compounds, or pharmaceutically acceptable salts thereof, hydrates thereof, and / or solvates thereof. Suitable intermediates can be produced at any time during the disclosed methods. Suitable intermediates can be isolated as neat compounds or produced only in solution.

[0121] Suitable intermediates for making SSTR4 agonist compounds, or pharmaceutically acceptable salts thereof, hydrates thereof, and / or solvates thereof, can include an intermediate of Formula XV, or a pharmaceutically acceptable salt thereof, a hydrate thereof, and / or a solvate thereof, wherein Y is H, OH, NH2 Cl, Br, I, Ci to C6 alkyl, Ci to C6 ether, or any combination thereof, R1and R2are independently H, OH, NH2 Cl, Br, I, Ci to C6 alkyl, Ci to C6 ether, or any combination thereof, and the phenyl functional group is substituted with one or more R', and wherein each R' group is independently H, OH, NH2 Cl, Br, I, Ci to C6 alkyl, Ci to C6 ether, or any combination thereof. In one embodiment, Y can be OH, Cl, Br, I, or NH2, R1and R2may be H, and R' can be CH3in the para position.

[0122]

[0123] Intermediate compound of Formula XV

[0124] In one embodiment, the intermediate compound can also be represented as Formula XVI, or a pharmaceutically acceptable salt thereof, a hydrate thereof, and / or a solvate thereof, wherein Y can be H, OH, NH2 Cl, Br, I, Ci to C6 alkyl, Ci to C6 ether, or any combination thereof, R1and R2may be independently H, OH, NH2 Cl, Br, I, Ci to C6 alkyl, Ci to C6 ether, or any combination thereof; and the phenyl functional group is substituted with one or more R', and wherein each R' group is independently H, OH, NH2 Cl, Br, I, Ci to C6 alkyl, Ci to C6 ether, or any combination thereof. In one embodiment, Y can be OH, Cl, Br, I, or NH2, R1and R2may be H, and R' can be CH3in the para position.

[0125]

[0126] Intermediate compound of Formula XVI

[0127] In one embodiment, the intermediate compound can also be represented as Formula XVII or a pharmaceutically acceptable salt thereof, a hydrate thereof, and / or a solvate thereof, Y can be H, OH, NH2Cl, Br, I, Ci to C6alkyl, Ci to C6ether, or any combination thereof. In one embodiment, Y can be OH, NH2Cl, Br, or I.

[0128]

[0129] Formula XVI. Intermediate compound

[0130] In one embodiment, the intermediate compound can also be represented as Formula XVIII or a pharmaceutically acceptable salt thereof, a hydrate thereof, and / or a solvate thereof.

[0131]

[0132] Formula XVIII. Intermediate compound

[0133] The intermediate compounds as described herein can be used to prepare SSTR4 agonist compounds or a pharmaceutically acceptable salt thereof, a hydrate thereof, and / or a solvate thereof. The intermediate compounds provide a stable scaffold to produce a variety of SSTR4 agonist compounds through amide-carboxylic acid coupling reactions, for example, in step (d) of the method of making SSTR4 agonist compounds as described herein and as illustrated in Formula VIII.

[0134] Compositions

[0135] Also disclosed herein are pharmaceutical compositions comprising a compound of Formula I-IV or a pharmaceutically acceptable salt or hydrate thereof and one or more pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the composition further comprises one or more therapeutic agents.

[0136] In some embodiments, the pharmaceutical composition is a tablet composition. Suitable inactive ingredients for tablet compositions include microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and the like.

[0137] The tablet composition can include from about 25 mg to about 1400 mg, from about 50 mg to about 600 mg, or from about 50 mg to about 200 mg of the SSTR4 agonist or a hydrate or pharmaceutically acceptable salt thereof.

[0138] In some embodiments, the pharmaceutical composition is a capsule composition. In some embodiments, the capsule composition can include the SSTR4 agonist compound, or hydrate or pharmaceutically acceptable salt thereof, without any inactive ingredients. In some embodiments, the capsule composition can include one or more pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the capsule composition can include microcrystalline cellulose, silicon dioxide, colloidal silicon dioxide, and the like suitable inactive ingredients.

[0139] The capsule composition can include from about 25 mg to about 1400 mg, from about 50 mg to about 600 mg, or from about 50 mg to about 200 mg of the SSTR4 agonist, or hydrate or pharmaceutically acceptable salt thereof. The capsule composition can include a suitable capsule, such as a gelatin capsule. The capsule size can be 000, 00, 0, 1, or 2, depending on the total amount of substance added.

[0140] In some embodiments, the pharmaceutical composition is an aqueous composition.

[0141] Methods of treatment

[0142] Also disclosed herein are methods of treating pain in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0143] Also disclosed herein are methods of treating pain in a patient comprising administering to a patient in need thereof from about 25 mg to about 1400 mg of a compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate salt, or a compound of Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate, and one or more pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the methods of treating pain in a patient can comprise administering to a patient in need thereof a first amount of a SSTR4 agonist, the first amount being about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 600 mg of a compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate salt, or a compound of Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate. Additional amounts of a compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate salt, or a compound of Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate, can be administered on the same day. In some embodiments, the first amount can be repeated or a different amount can be administered. For example, the first amount can be 400 mg and the second amount can be 400 mg or 600 mg.

[0144] In some embodiments, the methods of treating pain can comprise administering to a patient in need thereof from about 50 mg to about 600 mg of a compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate salt, or a compound of Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate, twice a day.

[0145] In some embodiments, the method of treating pain can comprise administering to a patient in need of such treatment from about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg of a compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate or Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate, twice a day.

[0146] Also disclosed herein are methods of treating chronic back pain, including chronic lower back pain, in a patient comprising administering to a patient in need of such treatment an effective amount of a compound of Formulas I-IV, or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0147] Also disclosed herein are methods of treating chronic back pain, including chronic lower back pain, in a patient, comprising administering to a patient in need of such treatment from about 25 mg to about 1400 mg of a compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate, or a compound of Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate, and one or more pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the methods of treating chronic back pain, including chronic lower back pain, in a patient can comprise administering to a patient in need of such treatment a first amount of a SSTR4 agonist, the first amount being about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg of a compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate, or a compound of Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate. In some embodiments, a further amount of a compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate, or a compound of Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate, can be administered on the same day. In some embodiments, the first amount can be repeated or a different amount can be administered. For example, the first amount can be 400 mg and the second amount can be 400 mg or 600 mg.

[0148] In some embodiments, the method of treating chronic back pain, including chronic lower back pain, can comprise administering to a patient in need of such treatment from about 50 mg to about 600 mg of the compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1 0]hexane-6-carboxamide L-tartrate, or the compound of Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1 0]hexane-6- carboxamide L-tartrate sesquihydrate, twice a day.

[0149] In some embodiments, the method of treating chronic back pain, including chronic lower back pain, can comprise administering to a patient in need of such treatment from about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg of the compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1 0]hexane-6-carboxamide L-tartrate, or the compound of Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1 0]hexane-6- carboxamide L-tartrate sesquihydrate, twice a day.

[0150] Also disclosed herein are methods of treating neuropathic pain in a patient comprising administering to a patient in need of such treatment an effective amount of a compound of Formulas I-IV, or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. In some embodiments, the neuropathic pain is diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy.

[0151] Also disclosed herein are methods of treating neuropathic pain, including diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy in a patient, comprising administering to a patient in need of such treatment from about 25 mg to about 1400 mg of a compound of Formula III, i.e., (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate or a compound of Formula IV, i.e., (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate, and one or more pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the methods of treating neuropathic pain, including diabetic neuropathy, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, diabetic peripheral neuropathic pain, central neuropathy, and / or mixed neuropathy in a patient can comprise administering to a patient in need of such treatment a first amount of a SSTR4 agonist, the first amount being about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg of a compound of Formula III, i.e., (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate or a compound of Formula IV, i.e., (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate. In some embodiments, a further amount of a compound of Formula III, i.e., (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate or a compound of Formula IV, i.e., (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate can be administered on the same day. In some embodiments, the first amount can be repeated or a different amount can be administered. For example, the first amount can be 400 mg and the second amount can be 400 mg or 600 mg.

[0152] In some embodiments, the method of treating neuropathic pain, including diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy, can comprise administering to a patient in need of such treatment from about 50 mg to about 600 mg of the compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate or the compound of Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate, twice a day.

[0153] In some embodiments, the method of treating neuropathic pain, including diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy, can comprise administering to a patient in need of such treatment from about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg of the compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate or the compound of Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate, twice a day.

[0154] Also disclosed herein are methods of treating pain associated with osteoarthritis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound of Formulas I-IV, or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0155] Also disclosed herein are methods of treating osteoarthritic pain in a patient, comprising administering to a patient in need of such treatment from about 25 mg to about 1400 mg of a compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate, or a compound of Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate, and one or more pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the methods of treating osteoarthritic pain in a patient can comprise administering to a patient in need of such treatment a first amount of a SSTR4 agonist, the first amount being about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 600 mg of a compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate, or a compound of Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate. In some embodiments, a further amount of a compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate, or a compound of Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate, can be administered on the same day. In some embodiments, the first amount can be repeated or a different amount can be administered. For example, the first amount can be 400 mg and the second amount can be 400 mg or 600 mg.

[0156] In some embodiments, the method of treating osteoarthritic pain can comprise administering to a patient in need of such treatment from about 50 mg to about 600 mg of the compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate or the compound of Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate, twice a day.

[0157] In some embodiments, the method of treating osteoarthritic pain can comprise administering to a patient in need of such treatment from about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg of the compound of Formula III, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate or the compound of Formula IV, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide L-tartrate sesquihydrate, twice a day.

[0158] Also disclosed herein are the compounds of Formulas I-IV or a pharmaceutically acceptable salt or hydrate thereof for use in therapy. Additionally, disclosed herein are the compounds of Formulas I-IV or a pharmaceutically acceptable salt or hydrate thereof for use in the treatment of pain. Also disclosed herein are the compounds of Formulas I-IV or a pharmaceutically acceptable salt or hydrate thereof for use in the treatment of chronic back pain, including chronic lower back pain. Also disclosed herein are the compounds of Formulas I-IV or a pharmaceutically acceptable salt or hydrate thereof for use in the treatment of neuropathic pain. In some embodiments, the neuropathic pain is diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy. Also disclosed herein are the compounds of Formulas I-IV or a pharmaceutically acceptable salt or hydrate thereof for use in the treatment of pain associated with osteoarthritis.

[0159] Also disclosed herein is the use of about 25 mg to about 1400 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of pain. Also disclosed herein is the use of about 25 mg to about 1400 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of chronic back pain, including chronic lower back pain. Also disclosed herein is the use of about 25 mg to about 1400 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of neuropathic pain. In some embodiments, the neuropathic pain is diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy. Also disclosed herein is the use of about 25 mg to about 1400 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of pain associated with osteoarthritis.

[0160] Also disclosed herein is the use of about 50 mg to about 600 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of pain. Also disclosed herein is the use of about 50 mg to about 600 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of chronic back pain, including chronic lower back pain. Also disclosed herein is the use of about 50 mg to about 600 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of neuropathic pain. In some embodiments, the neuropathic pain is diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy. Also disclosed herein is the use of about 50 mg to about 600 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of pain associated with osteoarthritis.

[0161] Also disclosed herein is the use of about 600 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of pain. Also disclosed herein is the use of about 600 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of chronic back pain, including chronic lower back pain. Also disclosed herein is the use of about 600 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of neuropathic pain. In some embodiments, the neuropathic pain is diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy. Also disclosed herein is the use of about 600 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of pain associated with osteoarthritis.

[0162] Also disclosed herein is the use of about 400 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of pain. Also disclosed herein is the use of about 400 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of chronic back pain, including chronic lower back pain. Also disclosed herein is the use of about 400 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of neuropathic pain. In some embodiments, the neuropathic pain is diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy. Also disclosed herein is the use of about 400 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of pain associated with osteoarthritis.

[0163] Also disclosed herein is the use of about 200 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of pain. Also disclosed herein is the use of about 200 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of chronic back pain, including chronic lower back pain. Also disclosed herein is the use of about 200 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of neuropathic pain. In some embodiments, the neuropathic pain is diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy. Also disclosed herein is the use of about 200 mg of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the treatment of pain associated with osteoarthritis.

[0164] Additionally, disclosed herein is the use of a compound of Formulae I-IV, or a pharmaceutically acceptable salt or hydrate thereof, for the manufacture of a medicament for the treatment of a disease or condition selected from the group consisting of pain, chronic back pain, including chronic lower back pain, neuropathic pain, and pain associated with osteoarthritis. In some embodiments, the neuropathic pain is diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy.

[0165] In some embodiments, the first amount or effective amount of the SSTR4 agonist can be administered at least once a day, one to four times a day, at least twice a day, once a day, twice a day, every 24 hours, every 12 hours, every 8 hours, every 6 hours, or every 4 hours.

[0166] Patients in need of treatment for diabetic neuropathy can include any patient that meets one or more of the following characteristics: a visual analog scale (VAS) pain value of 40 or greater and less than 95 prior to initiation of treatment; a history of daily pain for at least 12 weeks according to participant report or medical history; a pain catastrophizing scale value of 30 or below; a body mass index of less than 40 kg / m2(inclusive); a diagnosis of peripheral neuropathy secondary to diabetes mellitus; a diagnosis of peripheral neuropathy secondary to a condition other than diabetes mellitus; a medical history of diabetes mellitus type 1 or type 2; and / or stable glycemic control prior to initiation of treatment, as indicated by a glycosylated hemoglobin level of 11 or less. 2 (incusive); a diagnosis of peripheral neuropathy secondary to diabetes mellitus; a diagnosis of peripheral neuropathy secondary to a condition other than diabetes mellitus; a medical history of diabetes mellitus type 1 or type 2; and / or stable glycemic control prior to initiation of treatment, as indicated by a glycosylated hemoglobin level of 11 or less.

[0167] Definitions

[0168] As used herein, the terms "a," "an," the entity itself, and like terms as used in the context of the present disclosure, particularly in the context of the claims, should be interpreted to cover both singular and plural of the recited phrase, unless otherwise indicated or clearly contradicted by the context.

[0169] As used herein, the term "hydrate" refers to a solid adduct of a compound or salt thereof that contains water molecules incorporated into the crystal lattice of the compound or salt thereof. As used herein, the term "sesquihydrate" refers to a hydrate of a compound or salt thereof in which the stoichiometric ratio of water to the compound or salt thereof is 1.5: 1.

[0170] As used herein, the term "treatment" includes arresting, slowing, stopping, or reversing the progression or severity of an existing symptom or disease.

[0171] As used herein, the term "patient" refers to a mammal, such as a mouse, guinea pig, rat, dog, or human. It is understood that the preferred patient is a human.

[0172] As used herein, the term "effective amount" refers to the amount or dose of a compound of the present disclosure that, upon single or multiple dosing, provides the intended effect in the diagnosed or treated patient.

[0173] An effective amount can be readily determined by one of ordinary skill in the art by using known techniques. In determining the effective amount, a number of factors are considered, including, but not limited to: the species of the patient; its size, age, and general health condition; the specific disease or disorder involved; the degree or severity of the disease or disorder; the individual patient's response to the particular compound; the specific compound being administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; concomitant administration of medications; and other relevant circumstances.

[0174] The term "treatment" is intended to refer to all methods of managing, preventing, controlling, or terminating an existing disease and / or its symptoms, but does not necessarily indicate a total elimination of all symptoms.

[0175] A "pharmaceutically acceptable carrier, diluent or excipient" is a medium generally accepted for the delivery of a biologically active agent to a mammal, such as a human.

[0176] "Dose" refers to a predetermined amount or unit dose of (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide of Formula I calculated to produce the intended therapeutic effect in patients. "mg" as used herein refers to milligrams. As used herein, the dose ranges and doses provided represent the weight of the active pharmaceutical ingredient (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide of Formula I, regardless of the form in which it is provided, such as free base, salt, co-crystal form, or any other composition or form.

[0177] The term "about" as used herein refers to within a reasonable range of the stated value, such as ±10% of the stated value.

[0178] As used herein, the term "alkyl" means a saturated straight chain or branched chain monovalent hydrocarbon radical containing the number of carbon atoms indicated. For example, "Ci-C 20 "Alkyl" means a group having a linear or branched arrangement of 1-20 carbon atoms.

[0179] As used herein, the term "Ci-C n "Thioether" refers to a straight chain or branched chain saturated hydrocarbon containing 1 to n carbon atoms containing a terminal "S" in the chain, i.e., -S(alkyl), wherein the thioether group can be attached to the intended position at the sulfur atom. The term "Ci-C n "Thioether" also refers to a cyclic alkyl or aryl containing a terminal "S" in the molecule, i.e., -S(aryl), wherein the thioether group can be attached to the intended position at the sulfur atom. The term "Ci-C n "Thioether" can include both a saturated hydrocarbon chain and a cyclic alkyl or aryl, i.e., -S-CH2-(aryl), wherein n indicates the total number of carbon atoms in the substituent.

[0180] As used herein, the term "Ci-C n "Ether" refers to a straight chain or branched chain saturated hydrocarbon containing 1 to n carbon atoms containing a terminal "O" in the chain, i.e., -0(alkyl), wherein the ether group can be attached to the intended position at the oxygen atom. The term Ci-C nEther also refers to a cyclic alkyl or aryl group containing a terminal "O" in the molecule, i.e., -O(aryl), wherein the ether group can be attached to the intended position at the oxygen atom. The term "Ci-Cn-alkyl" can include saturated hydrocarbon chains and cyclic alkyl groups, i.e., -CH2-(aryl), wherein n indicates the total number of carbon atoms in the substituent. n Ether also refers to a cyclic alkyl or aryl group containing a terminal "O" in the molecule, i.e., -O(aryl), wherein the ether group can be attached to the intended position at the oxygen atom. The term "Ci-Cn-alkyl" can include saturated hydrocarbon chains and cyclic alkyl groups, i.e., -CH2-(aryl), wherein n indicates the total number of carbon atoms in the substituent.

[0181] As used herein, the term "cycloalkyl" refers to a group derived from a non-aromatic monocyclic or polycyclic ring containing carbon and hydrogen atoms. Cycloalkyl groups can have one or more carbon-carbon double bonds in the ring, as long as their presence does not result in aromaticity. Cycloalkyl groups can be unsubstituted or substituted with one to three suitable substituents known to one of ordinary skill in the art. Cycloalkyl groups can be indicated by the total number of carbon atoms in the monocyclic or polycyclic ring. For example, C3to C7cycloalkyl includes cycloalkyl groups having 3, 4, 5, 6, or 7 carbon atoms.

[0182] As used herein, the term "heterocycloalkyl" refers to a group derived from a non-aromatic monocyclic or polycyclic ring containing one or more carbon atoms and one or more heteroatoms, such as nitrogen, oxygen, and sulfur. Heterocycloalkyl groups can have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring, as long as their presence does not result in aromaticity. Examples of heterocycloalkyl groups include aziridinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, and pyranyl. Heterocycloalkyl groups can be unsubstituted or substituted with one or two suitable substituents. Heterocycloalkyl groups can be indicated by the total number of atoms in the monocyclic or polycyclic ring. For example, 4- to 7-membered heterocycloalkyl includes 4, 5, 6, or 7 members, including carbon atoms and heteroatoms.

[0183] As used herein, the term "aryl" refers to an aromatic monocyclic or polycyclic ring derived from a monocyclic or polycyclic ring containing only carbon atoms. Aryl groups can be unsubstituted or the aryl group can be substituted with 1 to 5 suitable substituents known to one of ordinary skill in the art. Aryl groups can be indicated by the total number of carbon atoms in the monocyclic or polycyclic ring. For example, C5to C7aryl includes aryl groups having 5, 6, or 7 carbon atoms.

[0184] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring derived from a monocyclic or polycyclic ring containing one or more carbon atoms and one or more heteroatoms. Heteroaryl groups can be unsubstituted or the heteroaryl group can be substituted with 1 to 5 suitable substituents known to one of ordinary skill in the art. Heteroaryl groups can be indicated by the total number of atoms in the monocyclic or polycyclic ring. For example, 4- to 7-membered heteroaryl includes 4, 5, 6, or 7 members, including carbon atoms and heteroatoms. Examples

[0185] Some abbreviations are defined as follows: "DCM" refers to dichloromethane; "DMAP" refers to 4-dimethylaminopyridine; "DMF" refers to dimethylformamide; "EtOAc" refers to ethyl acetate; "EtOH" refers to ethanol; "hr / hrs" refers to hour(s); "MeCN" refers to acetonitrile; "MeOH" refers to methanol; "MTBE" refers to methyl tert-butyl ether; "MeTHF" refers to methyltetrahydrofuran; "OTf" refers to triflate; "Ph2PK" refers to potassium diphenylphosphide; "TEA" refers to triethylamine; "TFA" refers to trifluoroacetic acid; and "THF" refers to tetrahydrofuran.

[0186]

[0187] Scheme 1. Commercial synthesis of SSTR4 agonists

[0188] Scheme 1, step A depicts the coupling of compound (1) with 4-bromobut-2- enoic acid methyl ester using an appropriate base such as potassium carbonate and potassium iodide in a suitable solvent such as MeCN at a suitable temperature (e.g., 30 °C) to give compound (2). Step B shows the deprotection of compound (2) using an acid such as TFA in a solvent such as MeCN to give compound (3). Step C shows the cyclization of compound (3) using (2-haloethyl)diphenylsulfonium, e.g., (2-bromoethyl)diphenylsulfonium triflate in the presence of base KOH, KF, and a suitable solvent such as 2-MeTHF to give compound (4). In step D, compound (4) is converted to compound (5) using water and a base such as LiOH. Step E shows the coupling of compound (5) with 2-methyl-l-((3-methylpyridin-2- yl)oxy)propan-2-amine in the presence of a catalyst such as COCl2and a solvent such as DMF, toluene, and DCM to give compound (6). Step F shows the conversion of compound (6) to compound (7): reacting compound (6) with Ph2PK in a solvent such as MTBE at a suitable temperature (e.g., heating from 60 to 70 °C) to give compound (7).

[0189] Preparation 2

[0190] (E)-4-((4-methylphenyl)sulfonylamino)but-2-enoic acid methyl ester

[0191]

[0192] Methyl 4-bromobut-2-enoate (36.29 g, 202.7 mmol) was dissolved in MeCN (500 mL) at 15-25°C. Tert-butyl tosylcarbamate (50.00 g, 184.3 mmol) was added at 15-25°C. KCO (30.57 g, 221.2 mmol) and KI (3.06 g, 202.7 mmol) were added to the 15-25°C solution and warmed at 30°C under nitrogen for 20 hours. The solution was cooled to 20°C, and the mixture was filtered. The filtered residue was washed with MeCN (100 mL) to yield methyl (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonylamino)but-2-enoate. TFA (101.03 g, 886.06 mmol) was added to a solution of methyl (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoate in MeCN (483.72 g, 143 mmol) and heated to 55-60°C for 16 hours. The reaction solution was concentrated in vacuo to ~50 mL and the solvent was exchanged with toluene (2 x 250 mL). Toluene (500 mL) and then EtOAc (50 mL) were added at 15-25°C. The mixture was heated to 60°C for 1 hour and then cooled to 0°C for 12 hours. The solution was filtered, and the wet cake was rinsed with n-heptane (50 mL). The filter cake was dried in vacuo at 50°C to yield the title compound (37.85 g, 74.4%) as a white solid. 1H NMR (CDCl3) δ7.68 (d, J = 8.0 Hz, 2H) 7.25 (d, J = 8.0 Hz, 2H) 6.71 (dt, J = 15.6, 5.2 Hz, 1H) 5.88 (dt, J = 15.6, 1.6 Hz, 1H) 4.55 (t, J = 6.4 Hz, 1H) 3.71–3.67 (m, 2H) 3.65 (s, 3H) 2.37 (s, 3H); HRMS (ESI+) calculated [C 12 H 15 NO4S + H]+: 270.0795, found: 270.0788 (M+H).

[0193] Preparation 3

[0194] (1R,5S,6r)-3-Tosyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid

[0195]

[0196] (E)-4-((4-methylphenyl)sulfonylamido)but-2-enoic acid methyl ester (51.90 g) was dissolved in 2-MeTHF (600 mL) at 0 °C. (2-Bromoethyl)diphenylsulfonium triflate (36.5 g), KF (6.47 g), KOH (18.75 g) were added to the solution at 0 °C. The solution was warmed to 15 °C for 22 h, then to 30 °C for 3 h. Water (100 mL) and MeOH (100 mL) were added to the solution. LiOH.H2O (4.77 g) was added and stirred at 30 °C for 16 h. Cooled to 15-25 °C, n-heptane (100 mL) was added. Stirred at 15-25 °C for 10 min. The aqueous phase was separated and collected, the aqueous phase was washed with n-heptane / 2-MeTHF (50 mL / 200 mL x 2). The aqueous phase was concentrated to ~50 mL in vacuo, 3M aqueous HC1 was added dropwise to adjust the pH to 1-2. The mixture was stirred at 20-30 °C for 2 h. The solution was filtered, rinsed with EtOH / H2O (15 mL 1:4). The wet cake was dried at 45 °C for 8-10 h to give the title compound as a white solid (20.37 g, 65%) 1 H NMR (CDCI3) δ 7.67 (d, J = 8.2 Hz, 2H) 7.34 (d, J = 8.2 Hz, 2H) 3.63 (d, J = 9.4 Hz, 2H) 3.12 (d, J = 9.4 Hz, 2H) 2.46 - 2.40 (m, 4H) 2.07 - 2.01 (m, 2H); HRMS (ESI + ) calcd for C 13 H 15 NO4S+H] + : 282.0795, found: 282.0795 (M+H).

[0197] Preparation 4

[0198] 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine

[0199]

[0200] Dissolve 2-amino-2-methylpropan-1-ol (50.14 g, 562.5 mmol) in toluene (250 mL) at 15-25 °C. Add potassium tert-butoxide (60.59 g, 534.6 mmol) to the solution and warm to 30-40 °C. Add 2-fluoro-3-methylpyridine (50.00 g, 450.0 mmol) to the solution and warm to 80 °C. Stir the mixture at 80 °C for 18 h. Cool the mixture to 15-25 °C, add water (100 mL) and stir for 30 min. Separate the aqueous layer and wash the organic layer with 10% aqueous NaCl (300 mL x 3). Add toluene (250 mL) to the organic layer and concentrate in vacuo to give the title compound as a liquid (107.50 g, 98%). 1 H NMR (CDCI3) δ 7.92-7.82 (m, 1H) 7.32-7.22 (m, 1H) 6.74-6.66 (m, 1H) 3.97 (s, 3H) 2.14 (s, 3H) 1.15 (s, 6H).

[0201] Example 1

[0202] (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- toluenesulfonyl-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0203]

[0204] Dissolve (1R,5S,6r)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (32.33 g, 88.2% purity) in toluene (320 mL) at 15-25 °C. Add DMF (741.0 mg) and (COCl)2(19.20 g) to the solution and heat to 45-55 °C for 3-4 h. Concentrate the mixture in vacuo and exchange with THF (100 mL x 2). Add THF (320 mL) and cool to 0-10 °C. Add 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine (23.60 g), TEA (30.80 g), DMAP (620.0 mg) at 0-10 °C and then warm to 15-25 °C for 2-4 h. Concentrate the mixture in vacuo and exchange the solvent with EtOH (140 mL x 2). Concentrate in vacuo to 140 mL and heat to 50 °C until the solid dissolves. Add water (210 mL) to the solution dropwise at 40 °C. Cool the solution to 10 °C for 14 h. Filter and rinse with EtOH / H2O (75 mL, 1:1.5). Dry the wet cake at 45 °C for 20 h to give the title compound as a solid (41.87 g, 87.4%).1 H NMR(CDCl3)δ7.94–7.87(m,1H)7.60(d,J=8.0Hz,2H)7.37(d,J=6.6Hz,1H)7.26(d,J=8.0Hz,2H)6.78(dd,J=6.6,5.0Hz,1H)6.4 8(s,1H)4.25(s,2H)3.52(d,J=9.4Hz,2H)2.95(d,J=9.4Hz,2H)2.39–2.33(m,3H)2.17(s,3H)1.84(s,2H)1.39(s,6H); HRMS(ESI) + )Calculate [C 23 H 29 N3O4S+H] + :444.1952, measured:444.2089(M+H).

[0205] Example 2

[0206] (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0207]

[0208] Under argon, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane-6-carboxamide (5.00 g) was dissolved in MTBE (50 mL). The mixture was cooled to -70-60°C, and a 1 M solution of Ph2PK in THF (56 mL, 56 mmol) was added dropwise to the solution. The mixture was stirred at -70-60°C for 6-8 hours. 2M aqueous HCl (50 mL) was added to the solution while allowing the temperature to rise to 15-25°C. The aqueous phase was separated and collected, and washed with 2-MeTHF (50 mL x 3). 2-MeTHF (50 mL) was added, and the pH was adjusted to 8-9 with K2CO3 powder. The aqueous phase was separated and extracted with 2-MeTHF (50 mL). The combined organic layers were concentrated in vacuo to afford the title compound as a yellow-brown solid (3.05 g, 89.4%) 1HNMR (CDCI3) δ 8.01 - 7.92 (m, 1H) 7.45 - 7.36 (m, 1H) 6.81 (dd, J = 7.0, 5.0 Hz, 1H) 6.39 (s, 1H) 4.31 (s, 2H) 3.09 - 2.89 (m, 4H) 2.21 (s, 3H) 1.94 - 1.86 (m, 2H) 1.69 (s, 1H) 1.47 (s, 6H) 1.12 (t, J = 2.8 Hz, 1H); HRMS (ESI + ) calculated for C 16 H 23 N3O2+H] + : 290.1863, found: 290.1917 (M+H).

[0209] Example 3

[0210] (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartaric acid salt

[0211]

[0212] To (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide (5.5 g, 18.4 mmol) was added IPA (68 mL) and water (2 ml). The mixture was heated to 65 °C at which point dissolution occurred. To the solution was then added L-tartaric acid (2.86 g, 19.1 mmol) in IPA (34 mL) and water (1.5 mL). The solution was then allowed to cool to ambient temperature overnight. The resulting white solid was isolated by vacuum filtration, rinsing with ice cold IPA (20 mL) to give the title compound (5.7 g, 70%).

[0213] Example 4

[0214] (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartaric acid salt

[0215]

[0216] (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1 0]hexane-6-carboxamide L-malate

[0217] Example 5

[0218] (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1 0]hexane-6-carboxamide L-malate

[0219]

[0220] (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1 0]hexane-6-carboxamide L-malate

[0221] Example 6

[0222] (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate sesqui-hydrate

[0223]

[0224] (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate sesqui-hydrate (Example 5) is currently in Phase II clinical trials for the treatment of diabetic neuropathy, diabetic peripheral neuropathic pain, and mixed neuropathic pain. Prior data from two Phase I studies (J2P-MC-LXBB (LXBB) and LXBA) provide evidence for the concept of safe use of Example 5 in patients for the treatment and / or relief of certain types of pain, e.g., neuropathic pain, including administration of a dose of about 50 mg to about 600 mg of Example 5 to the patient once a day or twice a day.

[0225] Example 7

[0226] (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate sesqui-hydrate (Example 5) is currently in Phase II clinical trials for the treatment of diabetic neuropathy, diabetic peripheral neuropathic pain, and mixed neuropathic pain. Prior data from two Phase I studies (J2P-MC-LXBB (LXBB) and LXBA) provide evidence for the concept of safe use of Example 5 in patients for the treatment and / or relief of certain types of pain, e.g., neuropathic pain, including administration of a dose of about 50 mg to about 600 mg of Example 5 to the patient once a day or twice a day.

[0227] (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate sesqui-hydrate (Example 5) is currently in Phase II clinical trials for the treatment of diabetic neuropathy, diabetic peripheral neuropathic pain, and mixed neuropathic pain. Prior data from two Phase I studies (J2P-MC-LXBB (LXBB) and LXBA) provide evidence for the concept of safe use of Example 5 in patients for the treatment and / or relief of certain types of pain, e.g., neuropathic pain, including administration of a dose of about 50 mg to about 600 mg of Example 5 to the patient once a day or twice a day.

[0228] Example 5, if approved by the respective regulatory authorities, will be a first-in-class SSTR4 agonist. Currently, there are no biomarkers or pharmacokinetic tests available to predict the correct dose by in vitro testing alone. Therefore, it is believed that only in vivo testing can determine a safe and effective dose for the treatment of pain using SSTR4 agonists.

[0229] In the Phase 1 studies LXBB and LXBA, a total of 116 healthy subjects received at least one dose of Example 5. Table 1 summarizes the completed Phase 1 pharmacology study profiles.

[0230] Single-dose pharmacokinetics (PK) of Example 5 were evaluated over a dose range of 20 to 400 mg. Over this dose range, the median time to peak plasma concentration (t max ) for Example 5 was 2 to 3 hours post-dose, the mean terminal half-life (t 1 / 2 ) was approximately 11 to 13 hours. The apparent total body clearance (CL / F) was approximately 21 to 24 L / h. The renal clearance was approximately 10 L / h, approximately 39% to 45% of the administered oral dose was excreted in the urine as unchanged Example 5, plasma concentrations of Example 5 generally increased proportionally to dose, and the coefficient of variation for inter-individual variability was <25%.

[0231] Multiple-dose PK of Example 5 was evaluated at doses of 200 mg, 400 mg, and 600 mg twice daily. The median time to peak plasma concentration (t max ) was 1 to 3 hours post-dose. The accumulation ratio (R A ) for Example 5 ranged from approximately 1-2, consistent with the t 1 / 2 for Example 5. In addition, steady-state C max and AUC 0-24 inter-subject variability was <25%. Results are summarized in Table 2.

[0232] Safety and tolerability of Example 5 was initially based on two completed Phase 1 studies (LXBB and LXBA) and later confirmed by three completed Phase 2 studies (OA03, BP03, and NP03, disclosed below).

[0233] Table 1. Summary of completed Phase 1 pharmacology studies

[0234]

[0235] Abbreviations: BID = twice daily, MAD = multiple ascending doses, PD = pharmacodynamics, PK = pharmacokinetics, Q12H = every 12 hours, QAM = every morning, QD = once daily, QPM = every night, SAD = single ascending doses

[0236] Table 2. Steady-state plasma PK parameters of Example 5 following repeat administration in healthy subjects

[0237] Abbreviations: AUC 0-24 = Area under the plasma concentration-time curve from 0 to 24 hours; AUC (0-τ) = Area under the plasma concentration-time curve over the dosing interval; BID = every 12 hours; C max = Observed maximum plasma concentration; CV% = coefficient of variation %; PK = pharmacokinetics; QD = once daily; R A = Accumulation ratio based on AUC (0-τ) over the dosing interval, where tau = 12 hours; t max = Time to reach maximum observed plasma concentration.

[0238] a AUC 0-24 = 2 x AUC (0-τ) over the dosing interval, where tau = 12 hours.

[0239] Phase I study LXBB was a first-in-human single ascending dose / multiple ascending dose (SAD / MAD) study in 89 healthy subjects (Table 1). Example 5 was well-tolerated in the completed SAD and MAD studies. All adverse events (AEs) were considered mild or moderate in severity. No deaths or serious adverse events (SAEs) were reported. One subject discontinued due to a non-drug related AE of fever. In the SAD study, 1 subject each reported temporomandibular joint disorder and tension headache. In the food effect study, 1 subject reported dry eye and nausea. In the young cohort 10-day multiple dose exposure study, the most frequently reported AEs were headache (2 subjects), diarrhea (2 subjects), nausea, rhinitis, and orthostatic hypotension (1 subject each). In the elderly cohort 10-day multiple dose exposure study, the most frequently reported AEs were headache (5 subjects), limb pain (1 subject), bruising at vascular puncture site (1 subject), dizziness (1 subject), and orthostatic hypotension (1 subject).

[0240] In subjects receiving a single 400 mg dose (SAD), the mean increase in PR interval from baseline was 13 msec; the maximum change in PR interval from baseline in individual subjects was 45 msec (in MAD, following the 300 mg dose). No clinically significant changes in chemistry, hematology, or coagulation parameters occurred.

[0241] The LXBA study was a completed study consisting of two parts: Part A and Part B (Table 1). Part A of the study had 18 healthy subjects, 3 dosing groups, and Part B had 9 healthy subjects exposed to Example 5. Safety data indicated that Example 5 was generally well tolerated. The majority of AEs were mild in severity. There were no deaths, SAEs, or discontinuations due to AEs. In Part A, all treatment-emergent adverse events (TEAEs) were mild in severity, with the exception of 1 moderate presyncope event. Constipation and insomnia (2 cases each) were the only TEAEs reported in more than 1 subject. In Part B, the TEAEs reported were taste disorder, nausea, and vomiting, all of which were mild in severity.

[0242] In summary, the results demonstrated in the two Phase I studies established the safety of Example 5 in 116 healthy subjects at doses of 20 mg to 1200 mg daily and / or 20 mg to 600 mg per dose.

[0243] Example 8

[0244] Capsule composition

[0245] Table A shows the capsule composition used in the clinical studies.

[0246]

[0247] Figure 1

[0248] Phase 2 clinical study of (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate sesquihydrate (Example 5)

[0249] Example 5 has been evaluated in three randomized, placebo-controlled Phase 2 osteo studies, with the OA03 study for the treatment of knee OA pain, the BP03 study for the treatment of CLBP, and the NP03 study for the treatment of DPNP. An overview of the three Phase 2 studies is shown in Table 3. Table 4 shows the study populations in the three Phase 2 studies.

[0250] Table 3. Randomized, placebo-controlled Phase 2 clinical trials to evaluate Example 5 for certain indications

[0251]

[0252] Table 4. Study populations for the Phase 2 studies

[0253]

[0254] For each of these studies, further analyses were performed to identify TEAEs associated with CV, thyroid, and renal abnormalities. Identification of CV AEs employed pre-specified standardized MedDRA Queries / Preferred Terms (SMQs / PTs) for cardiac arrhythmia, hypotension, major adverse cardiovascular events, and congestive heart failure. Thyroid-related AEs were identified with the SMQ "hypothyroidism," and AEs associated with renal abnormalities were identified with the high-level terms (HLT) renal failure and impairment, and select PTs.

[0255] Safety data from the 3 pooled intervention-specific appendices (ISAs) OA03, BP03, and NP03 were analyzed for the following safety topics of interest.

[0256] Pooled data from studies OA03, BP03, and NP03 showed no clinically meaningful differences between patients treated with Example 5 and placebo-treated patients in thyroid-related TEAEs or thyroid analytes of clinical interest.

[0257] Thus, after treatment of a total of 282 patients with 200 mg to 600 mg of Example 5 in the three Phase 2 studies, sufficient safety was established. While the safety of the three Phase 2 studies is discussed together, efficacy results for each study will be discussed herein.

[0258] HO P-MC-OA03 - Randomized, placebo-controlled Phase 2 clinical trial to evaluate Example 5 for the treatment of osteoarthritic pain

[0259] The objective of this study was to test whether Example 5 is effective in relieving osteoarthritis (OA) pain of the knee joint. Data were also collected to assess the safety and tolerability of Example 5 in the study population, which has been discussed previously. Pharmacokinetic properties and pharmacodynamic effects were also explored. The overall data of this proof-of-concept study assessed the benefit and risk associated with Example 5.

[0260] OA03 was a Phase 2, 8-week, randomized, double-blind, placebo-controlled study comparing Example 5 and placebo in patients with OA of the knee joint.

[0261] The primary clinical question of interest was "What is the treatment difference between Example 5 and placebo, in the mean change from baseline to endpoint (Week 8) in average pain intensity (API), as measured on the Numerical Rating Scale (NRS), in participants with OA of the knee joint, regardless of rescue medication or other allowed concomitant medication use, and assuming they would continue to receive the initial randomization treatment condition?"

[0262] The key secondary clinical question of interest was: "What is the difference in mean change in pain from baseline to endpoint (Week 8) as measured by the Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain Subscale in participants with knee OA treated with Example 5 compared to placebo, regardless of rescue medication or other allowed concomitant medication use, and assuming they would have continued to receive the initial randomization treatment condition?"

[0263] Participants were randomized in a 2: 1 ratio to Example 5 or placebo. Participants could take up to 3 capsules (200 mg each) twice daily (BID), approximately every 12 hours, for a total dose of 600 mg, depending on tolerability.

[0264] The protocol was modified to include a titration to the target dose of 600 mg. The Investigator could reduce the dose from 600 mg to 400 mg after discussion with the participant, if necessary, provided the change occurred before the end of Visit 4 (i.e., Week 2 of the study). The Medical Monitor was to be contacted if needed.

[0265] OA03 ISA enrolled a total of 202 participants, of which 135 participants were randomized to Example 5 and 67 participants were assigned to placebo.

[0266] The demographic, disease history, and baseline characteristics were balanced across treatment groups, with a mean age of 62.8 years, a majority of females (57.4%), and a mean pain NRS rating of 5.6 at baseline.

[0267] Exposure duration (days) was calculated as the date of the last dose of the treatment period minus the date of the first dose plus 1. The mean number of days of exposure was 40.5 days for the Example 5 group and 50.4 days for the placebo group. There were 9 participants (6.7%) in the Example 5 group and 7 participants (10.6%) in the placebo group with an exposure duration of at least 60 days. The protocol allowed for changes in the dose for individual participants. Twenty-six participants (13.0%) received a "2 escalations and 1 de-escalation" regimen: 21 participants (15.7%) took 200 mg, then escalated to 400 mg, then escalated to 600 mg, then de-escalated to 400 mg of Example 5, BID, and 5 participants (7.6%) took 1, then 2, then 3, then de-escalated to 2 placebo capsules, BID.

[0268] The primary objective to assess the efficacy of Example 5 compared to placebo on the mean change from baseline to endpoint (Week 8) in API total as measured by the weekly mean NRS did not meet the pre-specified threshold for osteoarthritis pain. ​

[0269] The key secondary objective of assessing the efficacy of Example 5 compared to placebo on the overall mean change in intensity of pain as measured by the WOMAC Pain Subscale from baseline to endpoint (Week 8) did not meet the pre-specified threshold.

[0270] Similarly, in this study, no statistical evidence of superiority of Example 5 over placebo was observed for the other secondary endpoints.

[0271] In summary, when comparing Example 5 to placebo, there was no statistical evidence that Example 5 was superior to placebo for the primary endpoint, key secondary endpoints, or secondary endpoints in this study for the treatment of osteoarthritic pain (as shown in Table 5).

[0272] Table 5. H0P-MC-OA03 Efficacy Overview

[0273]

[0274] H0P-MC-BP03 - Randomized, Placebo-controlled, Phase 2 Clinical Trial to Evaluate Example 5 for the Treatment of Chronic Low Back Pain (CLBP)

[0275] The objective of this study is to test whether Example 5 is effective in relieving chronic low back pain (CLBP). Data will be collected to assess the safety and tolerability of Example 5 in the study population, which has been discussed previously. Pharmacokinetic (PK) properties and pharmacodynamic (PD) effects are also explored. The overall data from this proof-of-concept study will assess the benefit and risk associated with Example 5.

[0276] BP03 is an 8-week, Phase 2, randomized, double-blind, placebo-controlled study that will compare Example 5 and placebo in patients with CLBP. Participants receive either Example 5 or placebo. Participants take up to 3 capsules (200 mg each) orally, twice daily (BID), approximately every 12 hours, for a total dose of 600 mg, depending on tolerability.

[0277] The primary clinical question of interest is, “What is the treatment difference between Example 5 and placebo in CLBP participants, using the mean change in average pain intensity (API) from baseline to endpoint (Week 8), as measured using the Numeric Rating Scale (NRS), regardless of rescue medication or other allowed concomitant medication use, and assuming they would continue to receive the initial randomization treatment condition?”

[0278] A total of 153 participants were enrolled in the BP03 ISA study, of which 102 participants were randomized to Example 5 and 51 participants were randomized to placebo.

[0279] The demographic, medical history, and baseline characteristics were balanced across treatment groups, with a mean age of 52.5 years, a majority of females (56.9%), and a mean pain NRS rating of 5.7 at baseline.

[0280] Exposure duration (days) was calculated as the date of the last dose of the treatment period minus the date of the first dose plus 1. The mean number of days of exposure was 47.5 days for the Example 5 group and 50.8 days for the placebo group. There were 17 (16.7%) participants in the Example 5 group and 7 (14.0%) participants in the placebo group with exposure times of at least 60 days.

[0281] The regimen allowed for changes in individual participants’ doses. Most participants (n = 106; 69.7%) received the “2 escalations” regimen: 61 participants (59.8%) took Example 5 at 200 mg, then escalated to 400 mg, then escalated to 600 mg, BID, and 45 participants (90.0%) took 1 placebo capsule, then 2 placebo capsules, then 3 placebo capsules, BID.

[0282] Thirty-five participants (23.0%) received the “2 escalations and 1 de-escalation” regimen: 32 participants (31.4%) took Example 5 at 200 mg, then escalated to 400 mg, then escalated to 600 mg, then de-escalated to 400 mg, BID, and 3 participants (6.0%) took 1 placebo capsule, then 2 placebo capsules, then 3 placebo capsules, then de-escalated to 2 placebo capsules, BID.

[0283] The primary objective of assessing the efficacy of Example 5 compared to placebo on the mean change from baseline to endpoint (Week 8) in overall average pain (as measured by the NRS weekly average) did not meet the pre-specified threshold. Similarly, in this study, no statistical evidence of superiority of Example 5 over placebo was observed for the secondary endpoints (as shown in Table 6).

[0284] In summary, there was no statistical evidence that Example 5 was superior to placebo for the primary or secondary endpoints in this study for the treatment of chronic lower back pain when comparing Example 5 to placebo (as shown in Table 6).

[0285] Table 6. H0P-MC-BP03 Efficacy Overview

[0286]

[0287] H0P-MC-NP03 - Randomized, placebo-controlled, Phase 2 clinical trial to evaluate Example 5 for the treatment of diabetic peripheral neuropathic pain

[0288] The objective of this study was to test whether Example 5 is effective in relieving diabetic peripheral neuropathic pain (DPNP). Data were collected to assess the safety and tolerability of Example 5 in the study population, which has been discussed previously. Pharmacokinetic properties and pharmacodynamic effects were also explored. Overall data from this proof-of-concept study will assess the benefit and risk associated with Example 5.

[0289] NP03 is an 8-week, Phase 2, randomized, double-blind, placebo-controlled study comparing Example 5 and placebo in patients with DPNP.

[0290] Participants received either Example 5 or placebo. Participants took up to 3 capsules (200 mg each) orally, twice daily, approximately every 12 hours, for a total dose of 600 mg, based on tolerability.

[0291] The primary clinical question of interest was, "What is the treatment difference between Example 5 and placebo in the mean change from baseline to endpoint (Week 8) in average pain intensity (API), as measured by the Numerical Rating Scale (NRS), in participants with diabetic peripheral neuropathic pain (DPNP), regardless of rescue medication or other allowed concomitant medication use, and assuming they would continue to receive the initial randomization treatment condition?" The primary efficacy analysis was conducted using an ANCOVA model with treatment as a fixed effect and baseline NRS score as a covariate.

[0292] Participants were randomized in a 2: 1 ratio to either Example 5 or placebo. Participants took up to 3 capsules (200 mg each) orally, twice daily (BID), approximately every 12 hours, for a total dose of 600 mg BID, based on tolerability.

[0293] The protocol allowed individual participants to change dose levels, but the maximum daily dose should not exceed 600 mg BID. The starting dose level was 200 mg BID. The decision to adjust dose levels was made by the investigator in consultation with the participant based on reported tolerability adverse events (AEs). The medical monitor was consulted as needed. All dose level adjustments must be made by the end of Visit 4 (Week 2 of the study).

[0294] The study enrolled men or women who met the following primary criteria: a Visual Analog Scale (VAS) pain score of 40 or greater and less than 95 at Visits 1 and 2; a history of daily pain for at least 12 weeks according to participant report or medical history; a Pain Catastrophizing Scale score of 30 or less; a body mass index less than 40 kg / m2; and a fasting serum creatinine less than 2.5 mg / dL (220 μmol / L) at Screening. 2(inclusive); daily symmetric foot pain for at least 6 months secondary to peripheral neuropathy, as diagnosed by use of the Michigan Neuropathy Screening Instrument Part B 3 or higher; medical history of diabetes mellitus type 1 or type 2 and current diagnosis; at screening, had stable glycemic control, as indicated by a hemoglobin A1c level of 11 or lower.

[0295] Participants received either Example 5 or placebo. Participants could take up to 3 capsules (200 mg each) orally, BID, approximately every 12 hours, for a total dose of 600 mg, depending on tolerability.

[0296] The study included an 8-week DB treatment period.

[0297] A total of 68 participants were enrolled in the NP03 Intervention Specific Appendices (ISAs), of which 45 participants were randomized to Example 5 and 23 participants were randomized to placebo. Demographics, disease history, and baseline characteristics were balanced across treatment groups, with an overall mean age of 60.2 years in the Example 5 group and 58.3 years in the placebo group, with a majority of females (55.9%) and a mean average pain NRS rating of 6.44 in the Example 5 group and 6.45 in the placebo group at baseline.

[0298] Exposure duration (days) was calculated as the date of the last visit of the treatment period minus the date of the first dose plus 1. The mean number of days of exposure was 38.7 (min = 4, max = 64) in the Example 5 group and 45.7 (min = 7, max = 63) in the placebo group. Exposure was > 60 days in 2 (4.4%) participants in the Example 5 group and 3 (13.0%) participants in the placebo group. Most participants (50, 73.5%) received the “2 escalations” regimen. 11 participants (16.2%) received the “2 escalations and 1 de-escalation” regimen.

[0299] The primary objective of the study was to assess the efficacy of Example 5 on the mean change from baseline to endpoint (Week 8) in API, as measured by weekly average NRS (as shown in Table 7). The change from baseline in API at Week 8 was more improved in the Example 5 group compared to placebo, with a posterior probability reaching the pre-specified threshold. Similar results were observed for the biweekly average of API measured by NRS.

[0300] Secondary objectives assessed pain severity and interference (Brief Pain Inventory-Short Form Modified [BPI-SFM]), overall improvement (Patient Global Impression of Change [PGIC]), worst pain intensity (NRS), pain intensity (VAS), sleep quality (Medical Outcomes Study Sleep Scale), and emotional functioning (European Quality of Life 5 Dimension 5 Level). For most secondary endpoints, greater numerical improvement was observed for Example 5 compared to placebo. Posterior probabilities reached pre-specified thresholds, indicating that Example 5 was superior to placebo for the following endpoints:

[0301] Mean change from baseline to endpoint in BPI-SFM individual severity score:

[0302] “Worst 24 hours” and “average”

[0303] Mean change from baseline to endpoint in BPI-SFM individual average score:

[0304] “Mood” and “walking ability”

[0305] Proportion of participants with at least 50% reduction in BPI-SFM average interference from baseline:

[0306] Proportion of participants with at least 30% reduction in BPI-SFM individual interference score from baseline:

[0307] “Normal work”

[0308] PGIC overall improvement from baseline

[0309] Mean change in worst pain intensity from baseline - weekly average of NRS

[0310] Mean change in worst pain intensity from baseline - biweekly average of NRS

[0311] At least 50% reduction in time to first pain of worst pain

[0312] Mean change in VAS from baseline, and

[0313] Proportion of participants with at least 30% reduction in VAS score (Week 4 only).

[0314] NP03 was an 8-week, multicenter, randomized, DB, placebo-controlled, Phase II proof-of-concept study to evaluate the treatment of DPNP with Example 5. Participants were randomized in a 2: 1 ratio to Example 5 or placebo. A total of 68 participants were enrolled in the NP03 ISA, with 45 participants randomized to Example 5 and 23 participants assigned to placebo. The safety population consisted of the 68 participants who received at least 1 dose of study intervention, including all participants in the enrollment population. Example 5 was administered orally using a titration regimen of up to 3 capsules (200 mg each) for a total dose of 600 mg approximately every 12 hours, with or without food. 50% of participants completed the BD treatment phase.

[0315] The primary objective of this study was to evaluate the efficacy of Example 5 on the overall mean change in API from baseline to endpoint (Week 8) as measured by the weekly mean NRS. The Example 5 group had a greater improvement in API change from baseline at Week 8 compared to placebo, and the posterior probability reached the pre-specified threshold. This demonstrated a high degree of confidence that Example 5 was superior to placebo at Week 8 as compared to the standard of care. Similar results were observed for the biweekly mean NRS.

[0316] Table 7 shows the proof-of-concept data to demonstrate the efficacy of Example 5 in the treatment of DPNP as compared to placebo.

[0317] Figure 1 The proof-of-concept data to demonstrate the efficacy of Example 5 in the treatment of DPNP as compared to placebo at 400 mg BID and 600 mg BID is shown.

[0318] Table 7. Summary of efficacy for HOP-MC-NP03

[0319]

[0320] Table 8. Observed mean for mean pain intensity for the dosing regimen of Example 5 as measured by the weekly mean NRS

[0321]

[0322] Table 9. Mean change for mean pain intensity for the dosing regimen of Example 5 as measured by the weekly mean NRS

[0323]

[0324] Tables 8 and 9 and ​Example 5 by dosing regimen on the overall mean change in API from baseline to endpoint (Week 8) as measured by each mean NRS, using a Bayesian repeated measures analysis with PS method. At Week 8, there was a greater reduction in API as measured by NRS in the 400 mg dosing regimen compared to the 600 mg dosing regimen.

[0325] Surprisingly, while the doses of the studies were similar, clinical efficacy was demonstrated in diabetic peripheral neuropathy, but not in chronic lower back pain and knee osteoarthritis. Moreover, it is believed that this efficacy result addresses the long sought need for a non-opioid pain treatment without serious side effects.

[0326] Example 9

[0327] DPNP Phase II (b) Dose Regimen Study Protocol (Study J2P-MC-LXBD)

[0328] Also disclosed herein is a protocol for conducting a DPNP dose regimen study using one of the dosing regimens of the present application. One skilled in the art is able to apply the teachings of Example 8 and other disclosures provided herein and conduct similar studies using other doses and dosing regimens of the present application.

[0329] The objective of this study is to test whether Example 5 is effective in relieving diabetic peripheral neuropathic pain (DPNP) at additional doses.

[0330] LXBD is a 12-week Phase II randomized, double-blind, placebo-controlled study comparing Example 5 and placebo in participants with DPNP.

[0331] Participants will receive either Example 5 or placebo. Patients are randomized in a 2: 1: 1: 1 placebo group: treatment group 1: treatment group 2: treatment group 3 ratio. Each randomization group has a 4-week period to reach full dose titration in all cohorts.

[0332] Based on tolerability, participants in treatment group 1 will receive up to a maximum of 3 capsules (each capsule comprising 50 mg of Example 5 or placebo) orally, twice a day, approximately every 12 hours, for a total dose of 50 mg.

[0333] Based on tolerability, participants in treatment group 1 will receive up to a maximum of 3 capsules (each capsule comprising 50 mg of Example 5 or placebo) orally, twice a day, approximately every 12 hours, for a total dose of 50 mg. There is no current planned dose escalation regimen for treatment group 1, so participants will receive 50 mg of Example 5 for 12 weeks.

[0334] Based on tolerability, participants in Treatment Group 2 will receive orally up to a maximum of 3 capsules (each capsule comprising 50 mg of Example 5, 200 mg of Example 5, or placebo) twice a day, approximately every 12 hours, for a total dose of 200 mg of Example 5. The current planned dose escalation regimen for Treatment Group 2 will include 50 mg BID for Week 1, 100 mg BID for Week 2, and 200 mg BID for Weeks 3-12, with escalation to higher doses of Example 5 tolerated by the participant.

[0335] Based on tolerability, participants in Treatment Group 3 will receive orally up to a maximum of 3 capsules (each capsule comprising 50 mg of Example 5, 200 mg of Example 5, or placebo) twice a day, approximately every 12 hours, for a total dose of 400 mg of Example 5. The current planned dose escalation regimen for Treatment Group 2 will include 50 mg BID for Week 1, 100 mg BID for Week 2, 200 mg BID for Week 3, 300 mg BID for Week 4, and 400 mg BID for Weeks 5-12, with escalation to higher doses of Example 5 tolerated by the participant.

[0336] Based on tolerability of the intended dose, participants can be allowed to cross over from Treatment Group 3 to Treatment Group, from Treatment Group 2 to Treatment Group 1, or from Treatment Group 3 to Treatment Group 1, to minimize patient withdrawal from the study. LXBD will provide safety information (frequency, severity, duration of TEAE’s, DCAE) for each dose cohort and each dose escalation step.

[0337] In summary, three treatment doses will be evaluated to meet the primary efficacy endpoint: 50 mg, 200 mg, and 400 mg BID (twice a day).

Claims

1. A method of treating pain in a patient in need of such treatment, the method comprising administering to said patient from about 25 mg to about 1400 mg per dose of a formula The dosage of the compound or its pharmaceutically acceptable salt and / or its hydrate.

2. The method of claim 1, wherein the compound has the following formula: or a hydrate thereof.

3. The method of claim 1 or 2, wherein the compound has the following formula:

4. The method of claim 1 or 2, wherein the compound has the following formula:

5. The method of any one of claims 1 to 4, wherein the dose is administered to the patient once per day, twice per day, every 24 hours, every 12 hours, every 8 hours, every 6 hours, or every 4 hours.

6. The method of any one of claims 1 to 5, wherein the dose is administered to the patient twice per day.

7. The method of any one of claims 1 to 6, wherein the dose administered to the patient is about 50 mg to about 600 mg.

8. The method of any one of claims 1 to 7, wherein the dose administered to the patient is about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg.

9. The method of any one of claims 1 to 8, wherein the dose administered to the patient is about 50 mg, and the dose is administered twice per day.

10. The method of any one of claims 1 to 8, wherein the dose administered to the patient is about 100 mg, and the dose is administered twice per day.

11. The method of any one of claims 1 to 8, wherein the dose administered to the patient is about 200 mg, and the dose is administered twice per day.

12. The method of any one of claims 1 to 8, wherein the dose administered to the patient is about 300 mg, and the dose is administered twice per day.

13. The method of any one of claims 1 to 8, wherein the dose administered to the patient is about 400 mg, and the dose is administered twice per day.

14. The method of any one of claims 1 to 8, wherein the dose administered to the patient is about 500 mg, and the dose is administered twice per day.

15. The method of any one of claims 1 to 8, wherein the dose administered to the patient is about 600 mg, and the dose is administered twice per day.

16. The method of any one of claims 1 to 15, wherein the pain comprises osteoarthritic pain, chronic lower back pain, or neuropathic pain.

17. The method of any one of claims 1 to 16, wherein the pain comprises neuropathic pain.

18. The method of claim 17, wherein the neuropathic pain comprises diabetic neuropathy, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, diabetic peripheral neuropathy, or mixed neuropathy.

19. The method of any one of claims 1 to 18, wherein the compound is administered to the patient as a tablet composition, a capsule composition, or an aqueous solution.

20. The method of claim 19, wherein the capsule composition comprises microcrystalline cellulose, silicon dioxide, or a combination thereof.

21. A capsule composition comprising a compound of the following formula: or hydrates thereof.

22. The composition of claim 21, wherein the compound has the following formula:

23. The composition of claim 21 or 22, wherein the capsule composition further comprises microcrystalline cellulose, silicon dioxide, or a combination thereof.

24. The composition of any one of claims 21 to 23, wherein the composition comprises about 50 mg to about 600 mg of the compound.

25. The composition of any one of claims 21 to 24, wherein the composition comprises about 50 mg to about 200 mg of the compound.

26. The composition of any one of claims 21 to 25, wherein the composition comprises about 50 mg of the compound.

27. The composition of any one of claims 21 to 26, wherein the composition comprises about 200 mg of the compound.

28. A method of preparing a compound of formula or a pharmaceutically acceptable salt thereof, the method comprising: mixing a compound of the formula: wherein R is Ci to C6 alkyl, with a sulfonium salt of the formula: wherein X is a halogen and A is an anion, to give an intermediate compound of the formula: The intermediate compound is mixed with Mix to get and from Removal of the tosyl functionality affords the compound.

29. The method of claim 28, wherein the method comprises: mixing a compound of the formula: with a sulfonium salt of the formula: to give an intermediate compound.

30. The method of claim 28 or 29, wherein the method comprises fewer than 8 synthetic steps.

31. The method of any one of claims 28 to 30, wherein the method does not comprise a metal catalyst.

32. The method of any one of claims 28 to 31, wherein the method does not use a hydride salt.

33. The method of any one of claims 28 to 32, wherein the method comprises: (a) mixing with to obtain (b) Mix with trifluoroacetic acid to obtain and (c) and Mix to obtain an intermediate compound.

34. The method of claim 33, wherein the method further comprises: (d) reacting the intermediate compound with Mix to get and (e) will and mixing with potassium diphenylphosphine to obtain the compound or its pharmaceutically acceptable salt and / or hydrate.

35. The method of any one of claims 28 to 35, wherein the method comprises: (a) mixing (E) 4-bromobut-2-enoic acid methyl ester with tert-butyl tosyl carbamate to give (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoic acid methyl ester; (b) mixing (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoic acid methyl ester with trifluoroacetic acid to give (E)-4-((4-methylphenyl)sulfonamido)but-2-enoic acid methyl ester; (c) mixing (E)-4-((4-methylphenyl)sulfonamido)but-2-enoic acid methyl ester with 2-bromoethyl)diphenylsulfonium triflate, to give an intermediate compound; (d) mixing the intermediate compound with 2-methyl-l-((3-methylpyridin-2- yl)oxy)propan-2-amine to give (lR,5S,6r)-N-(2-methyl-l-((3-methylpyridin-2- yl)oxy)propan-2-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane-6-carboxamide; (e) mixing ((lR,5S,6r)-N-(2-methyl-l-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- tosyl-3-azabicyclo[3.1.0]hexane-6-carboxamide with potassium diphenylphosphine to give the compound or a pharmaceutically acceptable salt thereof and / or a hydrate thereof.

36. The method of any one of claims 28 to 35, wherein the compound is selected from or any combination thereof.

37. The method of any one of claims 28 to 36, wherein the method further comprises: (f) mixing the compound with L-tartaric acid, citric acid, L-malic acid, or a combination thereof.

38. A method of making an intermediate compound of the formula: or a pharmaceutically acceptable salt thereof; and The method comprises: mixing a compound of the formula: wherein R is Ci to C6 alkyl, with a sulfonium salt of the formula: wherein X is a halogen and A is an anion, to obtain the intermediate compound.

39. The method of claim 38, wherein the method comprises: mixing a compound of the formula: with a sulfonium salt of the formula: to obtain the intermediate compound or a pharmaceutically acceptable salt.

40. The method of claim 38 or 39, wherein the method comprises fewer than 8 synthetic steps.

41. The method of any one of claims 38 to 40, wherein the method does not comprise a metal catalyst.

42. The method of any one of claims 38 to 41, wherein the method does not use a hydride salt.

43. The method of any one of claims 38 to 42, wherein the method comprises: (a) mixing with to obtain (b) combining with trifluoroacetic acid to obtain and (c) combining with to obtain the intermediate compound or a pharmaceutically acceptable salt thereof.

44. The method of any one of claims 38 to 43, wherein the method comprises: (a) mixing (E) 4-bromobut-2-enoic acid methyl ester with tert-butyl tosyl carbamate to obtain (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoic acid methyl ester; (b) mixing (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoic acid methyl ester with trifluoroacetic acid to obtain (E)-4-((4-methylphenyl)sulfonamido)but-2-enoic acid methyl ester; and (c) mixing (E)-4-((4-methylphenyl)sulfonamido)but-2-enoic acid methyl ester with 2-bromoethyl)diphenylsulfonium triflate to obtain the intermediate compound or a pharmaceutically acceptable salt thereof.

45. A compound of the formula: or pharmaceutically acceptable salts thereof and / or hydrates thereof, wherein the compound is made by the method of any one of claims 28 to 37.

46. The compound of claim 45, wherein the compound is of the formula: or any combination thereof.

47. A compound made by the method of any one of claims 28 to 37, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof and / or a hydrate thereof.

48. The compound of claim 47, wherein the compound is selected from: or any combination thereof.

49. A compound of the formula: or a pharmaceutically acceptable salt thereof and / or a hydrate thereof; for treating pain in a patient in need of such treatment, wherein the compound is administered at a dose of about 25 mg to about 1400 mg per dose.

50. The compound of claim 49, wherein the compound is of the formula: or hydrates thereof.

51. The compound of claim 49 or 50, wherein the compound is of the formula:

52. The compound of claim 49 or 50, wherein the compound is of the formula:

53. The compound of any one of claims 49 to 52, wherein the dose is administered to the patient once per day, twice per day, every 24 hours, every 12 hours, every 8 hours, every 6 hours, or every 4 hours.

54. The compound of any one of claims 49 to 53, wherein the dose is administered to the patient twice a day.

55. The compound of any one of claims 49 to 54, wherein the dose administered to the patient is about 50 mg to about 600 mg.

56. The compound of any one of claims 49 to 55, wherein the dose administered to the patient is about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg.

57. The compound of any one of claims 49 to 56, wherein the dose administered to the patient is about 50 mg, and the dose is administered twice a day.

58. The compound of any one of claims 49 to 56, wherein the dose administered to the patient is about 100 mg, and the dose is administered twice a day.

59. The compound of any one of claims 49 to 56, wherein the dose administered to the patient is about 200 mg, and the dose is administered twice a day.

60. The compound of any one of claims 49 to 56, wherein the dose administered to the patient is about 300 mg, and the dose is administered twice a day.

61. The compound of any one of claims 49 to 56, wherein the dose administered to the patient is about 400 mg, and the dose is administered twice a day.

62. The compound of any one of claims 49 to 56, wherein the dose administered to the patient is about 500 mg, and the dose is administered twice a day.

63. The compound of any one of claims 49 to 56, wherein the dose administered to the patient is about 600 mg, and the dose is administered twice a day.

64. The compound of any one of claims 49 to 63, wherein the pain comprises osteoarthritic pain, chronic lower back pain, or neuropathic pain.

65. The compound of any one of claims 49 to 64, wherein the pain comprises neuropathic pain.

66. The compound of claim 65, wherein the neuropathic pain comprises diabetic neuropathy, polyneuropathy, distal sensory polyneuropathy, central neuropathy, diabetic peripheral neuropathy, or mixed neuropathy.

67. The compound of any one of claims 49 to 66, wherein the compound is administered to the patient as a tablet composition, a capsule composition, or an aqueous solution.

68. The compound of claim 67, wherein the capsule composition comprises microcrystalline cellulose, silicon dioxide, or a combination thereof.

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