Method for preparing SSTR4 agonists and their salts

Abstract

A method for preparing SSTR4 agonist compounds. A method for preparing SSTR4 agonist compounds by a diastereomer-selective cyclization reaction that does not require a separate epimerization step. Novel intermediates for preparing SSTR4 agonist compounds. Novel salts of specific SSTR4 agonists such as (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide xiccinate and (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide adipate. A method for treating pain such as osteoarthritis pain, neuropathic pain, and lower back pain by administering specific SSTR4 agonists and their pharmaceutically acceptable salts.

Description

[Technical Field]

[0001] The present invention relates to a method for preparing SSTR4 agonists such as 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives. The present invention also relates to the preparation of salts of SSTR4 agonists. The present invention also relates to novel hydrates and novel salts of specific SSTR4 agonists. [Background technology]

[0002] Somatostatin, or somatotropin-release inhibitory factor (SRIF), is a cyclic peptide found in humans. It is widely produced in the human body and acts systemically and locally to inhibit the secretion of various hormones, growth factors, and neurotransmitters. The effects 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 includes SSTR2, SSTR3, and SSTR5, and the second subfamily includes SSTR1 and SSTR4.

[0003] Somatostatins are involved in the regulation of processes such as cell proliferation, glucose homeostasis, inflammation, and pain. In this context, somatostatins or other members of the somatostatin peptide family are thought to inhibit nociceptive and inflammatory processes via the SSTR4 pathway.

[0004] International Publication 2014 / 184275 discloses certain 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives that are SSTR4 agonists and useful for preventing or treating SSTR4-related medical disorders. However, synthesizing 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives with sufficient enantiomer and diastereomer purity can be challenging. While laboratory-scale synthetic routes are known, many steps used in previous synthetic routes are impractical and / or too costly for commercial use.

[0005] Therefore, there is a need for alternative methods to prepare certain SSTR4 agonists with sufficient purity on a commercial scale. Accordingly, the present invention relates to certain SSTR4 compounds, such as (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide, and methods for preparing pharmaceutically acceptable salts, solvates, and / or hydrates thereof.

[0006] Diabetic neuropathy is a common complication of diabetic microvascular disease. Approximately 40% of patients with diabetes mellitus experience diabetic microvascular disease, and approximately 80% of patients with diabetic neuropathy present with peripheral polyneuropathy.

[0007] Symptoms of diabetic peripheral neuropathy (DPNP) include hyperalgesia, paresthesia, and deep, throbbing pain. Diabetic peripheral neuropathy (DPNP) symptoms are associated with shallow sleep, reduced energy levels, depression, and poor quality of life.

[0008] Unfortunately, treatment options for DPNP are limited. Only three drugs—pregabalin, duloxetine, and tapentadol—are approved by the USFDA for this indication. While pregabalin and duloxetine have demonstrated efficacy in multiple placebo-controlled clinical trials, both drugs require titration to minimize adverse reactions. Tapentadol is an opioid mu receptor agonist and shares the same pharmacological limits and adverse reaction profiles as other opioid analgesics. Other classes of drugs, including gabapentin, selective serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and anticonvulsants, are used clinically off-label. The dose-limiting toxicity of all these drugs prevents patients from tolerating therapeutic doses, leading to the use of sub-therapeutic doses in clinics and further reducing the effectiveness of these drugs. In addition, only 50% of patients continue therapy after 3 months.

[0009] Opioids are used as a last resort because non-opioid analgesics are used for the management of DPNP due to suboptimal dosage and an inadequate tolerability profile. While opioids are effective for acute pain, there is evidence suggesting they offer little clinical benefit in chronic pain, not to mention the potential for decreased efficacy due to tolerance.

[0010] Additionally, while opioid compounds are known to provide relief from pain symptoms, they also come with numerous undesirable side effects, including hallucinations, nausea, dizziness, sedation, constipation, urinary retention, addiction, and intoxication. As many as 25% of patients receiving opioid pain treatment may develop addiction to opioid compounds, even in the short term. In fact, opioid addiction was declared a National Public Health Emergency by U.S. President Donald Trump on October 26, 2017. As such, there is a long-standing but unmet need for the development of non-opioid compounds and drug regimens for non-opioid compounds that provide relief from pain symptoms without the potential for addiction and / or dependence.

[0011] Thus, the present invention relates to SSTR4 agonists having potential use in the treatment of pain such as neuropathic pain and / or diabetic neuropathy and / or mixed neuropathy, and novel methods for synthesizing novel hydrates and / or salts of SSTR4 agonists. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] [Figure 1] (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide monohydrate XRPD pattern is shown. [Figure 2] (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide succinate XRPD pattern is shown. [Figure 3] (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide adipate XRPD pattern is shown. SUMMARY OF THE INVENTION

[0013] This specification discloses a compound of the formula: [Chemical formula] or a hydrate thereof, wherein M is absent or is C1-C6 alkyl.

[0014] This specification also discloses a compound of the formula: [Chemical formula] or a hydrate thereof.

[0015] This specification further discloses a compound of the formula:

化

[0016] Furthermore, this specification includes the formula: [ka] The following compounds are disclosed.

[0017] Furthermore, this specification discloses methods for preparing certain SSTR4 agonist compounds, such as (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide, and pharmaceutically acceptable salts and / or hydrates thereof.

[0018] Furthermore, this specification includes the formula: [ka] A method for preparing the compound or a pharmaceutically acceptable salt thereof is disclosed. In the formula, Y is a covalent bond, O, S, C1-C6 ether, or C1-C6 thioether, and Z is absent, a covalent bond, CH2, or CH2CH2. [ka] However, 8- to 10-membered heteroaryls or C6-C2 heteroaryls have 1 to 4 heteroatoms in the heteroaryl. 10 It is Ariel, [ka] However, one or more R n It is replaced by each R n However, independently, they are OH, F, Cl, Br, I, NH2, CF3, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C7 ether, or C1-C7 thioether. This delicious, formula [ka] Compounds (wherein R is a C1-C6 alkyl group) formula: [ka] When mixed with a sulfonium salt (wherein X is a halogen and A is an anion), the formula is: [ka] To obtain an intermediate compound, [ka] The tosyl functional group is removed from to obtain the compound, Includes.

[0019] Furthermore, this specification includes the formula: [ka] A method for preparing a compound or a pharmaceutically acceptable salt thereof is disclosed, and this method is formula [ka] Compounds (wherein R is a C1-C6 alkyl group) formula: [ka] When mixed with a sulfonium salt (wherein X is a halogen and A is an anion), the formula is: [ka] To obtain an intermediate compound, The intermediate compound [ka] Mix with, [ka] To obtain, [ka] The tosyl functional group is removed from to obtain the compound, Includes.

[0020] Furthermore, this specification discloses products comprising compounds such as (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide, or pharmaceutically acceptable salts and / or hydrates thereof, prepared by the methods described herein. [Modes for carrying out the invention]

[0021] Methods for the preparation of certain SSTR4 compounds are disclosed in International Publications 2014 / 184275, 2021 / 233427, and 2022 / 012534, but these compounds have been produced on a laboratory scale and may involve synthetic steps that are impractical on a commercial scale. In these earlier preparations, the synthetic routes (1) used expensive catalysts including palladium and / or rhodium, and / or lithium aluminum hydride used to carry out the reduction step, and (2) resulted in a mixture of diastereomers requiring epimerization after heterocyclic cyclization. Both (1) and (2) may increase the overall cost of the preparation and may require additional purification steps to remove trace amounts of Pd, Rh, Li, Al, and / or undesirable diastereomers with lower activity.

[0022] This specification discloses novel routes to certain SSTR4 compounds, such as (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide and their pharmaceutically acceptable salts, hydrates, or solvates, which can be implemented on a commercial scale without the use of transition metal catalysts such as Pd, Pt, Mo, Rh, Fe, Ni, Cr, W, or combinations thereof, and / or aluminum hydride salts such as lithium aluminum hydride. Additionally, the disclosed methods include a cyclization step involving a reaction with a (2-haloethyl)diphenylsulfonium salt, which yields a single diastereomer intermediate without requiring a subsequent epimerization step. Finally, the disclosed methods have fewer total steps than previously disclosed routes, such as fewer than 8 or 4 to 7 total steps.

[0023] The present invention also relates to novel hydrates of specific SSTR4 agonists, such as (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide monohydrate. The present invention also relates to novel salts of specific SSTR4 agonists, such as (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide succinate and (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide adipate.

[0024] SSTR4 Agonist The disclosed method can be used to prepare compounds of formula I or formula IA, where Z may be absent, covalent, CH2, or CH2CH2, and Y may be covalent, O, S, C1-C6 ether, or C1-C6 thioether. [ka] This refers to an 8- to 10-membered heteroaryl or C6-C heteroaryl having 1 to 4 heteroatoms in the heteroaryl. 10 It is Ariel, [ka] is one or more R n It can be replaced by each R n These can independently be OH, F, Cl, Br, I, NH2, CF3, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C7 ether, C1-C7 thioether, or a combination thereof.

[0025] The disclosed method can also be used to prepare salts, solvates, hydrates, and / or combinations thereof of formula I or formula IA.

[0026] [ka]

[0027] [ka]

[0028] [ka] As described herein, C6~C 10 It may be an aryl or a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms selected from O, N, or S. In some embodiments, [ka] It can be an 8- to 10-membered heteroaryl having 1 to 4 heteroatoms selected from O, N, or S. In some embodiments, [ka] It can be a monocyclic, bicyclic, or polycyclic system. [ka] When it is a monocyclic system,

Chemical Formula

Chemical Formula

[0031] In some embodiments, Z may be absent, a covalent bond, CH2, or CH2CH2. If Z is absent, there is no bond between the two methyl substituents at the α-carbon. If Z is a covalent bond, the α-carbon forms a cyclopropyl functional group. If Z is CH2, the α-carbon forms a cyclobutyl functional group. If Z is CH2CH2, the α-carbon forms a cyclopentyl functional group.

[0032] In some embodiments, the C1-C7 thioethers may be thioethers selected from formula II.

[0033] [ka]

[0034] The disclosed method can be used to prepare compounds of formula III. The disclosed method can also be used to prepare solvates, hydrates, and / or combinations thereof of formula III and / or formula III-A.

[0035] [ka]

[0036] [ka]

[0037] The disclosed method can be used to prepare compounds of formula IV. The disclosed method can also be used to prepare solvates, hydrates, and / or combinations thereof of formula IV.

[0038] [ka]

[0039] method A method for preparing SSTR4 agonist compounds is disclosed herein. The method for preparing SSTR4 agonist compounds can be used in the commercial-scale production of SSTR4 agonist compounds, their pharmaceutically acceptable salts, and / or their solvates / hydrates, as will be further discussed herein. In the disclosed method, the reaction is preferably carried out using a batch processing methodology. In one embodiment, the batch is produced on a method scale. In one embodiment, the batch is produced in at least 1 kilogram. In one embodiment, the batch is produced in at least 10 kilograms. In one embodiment, the batch is produced in at least 100 kilograms.

[0040] formula: [ka] A method for preparing an SSTR4 agonist compound, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, may include the following steps:

[0041] (a) tert-butyl tosylcarbamate is preferred C 1 ~C 6 Steps to mix with alkyl 4-halobuta-2-enoate Step (a) of the method for preparing an SSTR4 agonist compound may include mixing a tert-butyl tosylcarbamate with a suitable C1-C6 alkyl 4-halobuta-2-enoate compound in a polar aprotic solvent, as shown in formula V, where X is a halogen leaving group such as Cl, Br, or I.

[0042] [ka]

[0043] The components of step (a) can be combined in a polar aprotic solvent at temperatures of approximately 10°C to 25°C, 15°C to 25°C, or 20°C to 25°C. The temperature of the component mixture in step (a) can be raised to approximately 25°C to 50°C, 25°C to 40°C, or 30°C. The product mixture of step (a) can be filtered, and the recovered residue can be washed with a polar aprotic solvent to obtain the product in solution.

[0044] Suitable polar aprotic solvents are well known to those skilled in the art of organic synthesis design. Particularly suitable polar aprotic solvents include acetonitrile, acetone, dimethyl sulfoxide, N,N-dimethylformamide, and tetrahydrofuran.

[0045] In another embodiment, the method may include mixing tert-butyltosylcarbamate in MeCN with a (E)methyl 4-bromobuta-2-enoate compound, as shown in formula VI, to obtain methyl(E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamide)buta-2-enoate.

[0046] [ka]

[0047] In another embodiment, step (a) is: [ka] of [ka] Mix with, [ka] It may include obtaining

[0048] Further components for step (a) may include bases such as potassium carbonate and / or salts such as potassium iodide.

[0049] (b)C 1 ~C 6 Steps to mix alkyl(E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamide)buta-2-enoate with acid. Step (b) of the method for preparing the SSTR4 agonist compound may include mixing the product produced in step (a), C1-C6 alkyl(E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamide)buta-2-enoate, with a suitable acid in a polar aprotic solvent, as shown in formula VII.

[0050] [ka]

[0051] The components of step (b) can be combined in a polar aprotic solvent at temperatures 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 a high temperature for at least 4 hours, at least 10 hours, or at least 12 hours.

[0052] After heating the mixture of components in step (b) to a high temperature, the solution can be concentrated and the remaining polar aprotic solvent can be replaced with toluene and / or ethyl acetate.

[0053] The polar aprotic solvent may be the same solvent as in step (a) or it may be a different polar aprotic solvent, such that the product may remain in solution without any further purification steps other than filtering of by-products.

[0054] The preferred acid in step (b) may be any acid that can be used to remove the tert-butyl ester from the tertiary amine to form a secondary amine. Other preferred acids include TFA, hydrochloric acid, sulfuric acid, and hydrofluoric acid.

[0055] In another embodiment, step (b) may include mixing methyl(E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamide)buta-2-enoate with TFA in MeCN as shown in formula VIII to obtain methyl(E)-4-((4-methylphenyl)sulfonamide)buta-2-enoate.

[0056] [ka]

[0057] In another embodiment, step (b) is: [ka] Mix it with TFA, [ka] It may include obtaining

[0058] Process (c)C 1 ~C 6 Steps to mix alkyl(E)-4-((4-methylphenyl)sulfonamide)buta-2-enoate with a sulfonium salt. Step (c) of the method for preparing an SSTR4 agonist compound may include mixing the product produced in step (b), C1-C6 alkyl(E)-4-((4-methylphenyl)sulfonamide)buta-2-enoate, with a sulfonium salt in a suitable heterocyclic solvent, as shown in formula IX, to obtain an intermediate compound, (1R,5S)-3-(p-tolylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid.

[0059] [ka]

[0060] 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 C1-C6 alkyl(E)-4-((4-methylphenyl)sulfonamide)buta-2-enoate, potassium fluoride and / or potassium hydroxide may be added. The temperature of the solution can be gradually or stepwise raised to 30°C over a period of about 10 hours to about 30 hours.

[0061] Suitable heterocyclic solvents include, in particular, tetrahydrofuran, furan, and 2-methyltetrahydrofuran.

[0062] After raising the temperature of the solution, a base such as lithium hydroxide can be added at the elevated temperature, allowing the reaction to proceed for a further period. The additional period may be approximately 8 to 24 hours, 12 to 18 hours, or 16 hours.

[0063] The intermediate compound, (1R,5S)-3-(p-tolylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid, can be separated from solution using conventional synthetic organic chemical separation techniques well known to those skilled in the art.

[0064] The sulfonium salt used in step (c) can be represented by formula X, where X is a halogen leaving group such as Cl, Br, or I, and A is any suitable anion well known to those skilled in the art.

[0065] [ka]

[0066] The sulfonium salt used in process (c) can also be represented by formula XI.

[0067] [ka]

[0068] In another embodiment, step (c) may include mixing methyl(E)-4-((4-methylphenyl)sulfonamide)buta-2-enoate with 2-(bromoethyl)diphenylsulfonium triflate, as shown in formula XII, to obtain the intermediate compound (1R,5S)-3-(p-tolylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid.

[0069] [ka]

[0070] In another embodiment, step (c) is: [ka] of [ka] When mixed with the intermediate compound [ka] This may include obtaining a salt or solvate thereof.

[0071] Step (d) is a step of mixing (1R,5S)-3-(p-tolylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid with a suitable amine such as 2-(1-methyl-1H-indazole-3-yl)propan-2-amine. Step (d) of the method for preparing an SSTR4 agonist compound may include mixing (1R,5S)-3-(p-tolylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid, an intermediate compound produced in step (c), as shown in formula XIII-A, with a suitable substance.

[0072] [ka]

[0073] Step (d) of the method for preparing the SSTR4 agonist compound may also include mixing (1R,5S)-3-(p-tolylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid, which is an intermediate compound produced in step (c), as shown in formula XIII-B, with 2-(1-methyl-1H-indazole-3-yl)propan-2-amine.

[0074] [ka]

[0075] Before adding a suitable amine, the intermediate compound can be reacted with a suitable reagent such as oxalyl chloride or thionyl chloride to insitu to produce an acid chloride, and the -OH functional group can be replaced with -Cl under synthetic conditions well known to those skilled in the art.

[0076] The resulting acid chloride can be miscible with a suitable amine at a temperature of approximately -10°C to approximately 10°C or approximately 0°C to approximately 10°C.

[0077] The solution temperature can be raised to approximately 15°C to 25°C after about 2 to 4 hours.

[0078] Some examples of suitable amines include, in particular, 2-methyl-1-((3-methylpyridine-2-yl)oxy)propan-2-amine and 2-(1-methyl-1H-indazole-3-yl)propan-2-amine. By selecting a suitable amine, the desired SSTR4 agonist compound can be obtained.

[0079] In another embodiment, step (d) is to prepare the intermediate compound. [ka] Mix with, [ka] It may include obtaining

[0080] In another embodiment, step (d) is to prepare the intermediate compound. [ka] Mix with, [ka] It may include obtaining

[0081] Step (e) Removal of tosyl functional groups with potassium diphenylphosphine Step (e) of the method for preparing an SSTR4 agonist compound may include mixing the product generated in step (d) with potassium diphenylphosphine, as shown in formula XIV-B.

[0082] [ka]

[0083] Step (e) of the method for preparing an SSTR4 agonist compound may include mixing the product produced in step (d), such as ((1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane-6-carboxamide, as shown in formula XIV-B, with potassium diphenylphosphine.

[0084] [ka]

[0085] (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane-6-carboxamide, or another suitable SSTR4 agonist precursor produced in step (d), can be dissolved in a suitable solvent such as methyl tert-butyl ether. The temperature can be lowered to about -100°C to about -50°C, about -80°C to about -55°C, or about -70°C to about -60°C. Potassium diphenylphosphine can be added dropwise while maintaining the lowered temperature.

[0086] After adding the entire amount of potassium diphenylphosphine, the reduced temperature of the solution can be maintained for at least 4 hours, at least 6 hours, or at least 8 hours. The temperature of the solution can then be raised to about 15°C to about 25°C, and the SSTR agonist compound (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide can be isolated from the solution using typical methods well known to those skilled in the art.

[0087] In another embodiment, step (e) is: [ka] This may include mixing it with potassium diphenylphosphine to obtain an SSTR4 agonist compound.

[0088] SSTR4 agonist compound salt Methods for preparing pharmaceutically acceptable salts of SSTR4 agonist compounds are also disclosed herein. Methods for preparing pharmaceutically acceptable salts of SSTR4 agonist compounds may include (1) the disclosed methods for preparing SSTR4 agonist compounds, and (2) producing pharmaceutically acceptable salts of SSTR4 agonists via (i) a reaction with an acid, (ii) a salt metathesis reaction, and / or (iii) other reactions that can result in the formation of a pharmaceutically acceptable salt of the SSTR4 agonist compound.

[0089] Suitable pharmaceutically acceptable salts of SSTR4 agonist compounds may include adipines, bromides, chlorides, besilates, esylates, mesilates, tosilates, phosphates, succinates, sulfates, citrates, tartrates, L-tartrates, malates, and / or L-malate anions. Other suitable salts include (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide succinate, which can be described by the XRPD pattern in Figure 2, and (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide adipate, which can be described by the XRPD pattern in Figure 3. Another suitable salt is shown in formula IV.

[0090] Hydrate of SSTR4 agonist compound Furthermore, hydrates of SSTR4 agonist compounds and salts of SSTR4 agonist compounds are disclosed herein. A preferred hydrate is (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide hydrate, which can be described by the XRPD pattern shown in Figure 1.

[0091] composition Furthermore, this specification discloses pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof, a compound of formula IA, or a pharmaceutically acceptable salt or hydrate thereof, a compound of formula III, or a pharmaceutically acceptable salt or hydrate thereof, or a compound of formula IV, or a hydrate thereof, together with one or more pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the composition further comprises one or more therapeutic agents.

[0092] In some embodiments, the pharmaceutical composition is a tablet composition, a capsule composition, or an aqueous composition. Suitable inert components in the tablet composition include, in particular, microcrystalline cellulose, croscarmellose sodium, and stearyl fumarate sodium.

[0093] In some embodiments, the pharmaceutical composition is a capsule composition. In some embodiments, the capsule composition may contain an SSTR4 agonist compound, or its hydrate or a pharmaceutically acceptable salt, without containing an inert component. In some embodiments, the capsule composition may contain one or more pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the capsule composition may contain microcrystalline cellulose, silicon dioxide, or colloidal silicon dioxide, among other suitable inert components.

[0094] Treatment method Furthermore, this specification discloses a method for treating pain in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof, a compound of formula IA, or a pharmaceutically acceptable salt or hydrate thereof, a compound of formula III, or a pharmaceutically acceptable salt or hydrate thereof, or a compound of formula IV, or a hydrate thereof, together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0095] Furthermore, this specification discloses a method for treating chronic back pain, including chronic low back pain, in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof, a compound of formula IA, or a pharmaceutically acceptable salt or hydrate thereof, a compound of formula III, or a pharmaceutically acceptable salt or hydrate thereof, or a compound of formula IV, or a hydrate thereof, together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0096] Furthermore, this specification discloses a method for treating neuropathic pain in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof, a compound of formula IA, or a pharmaceutically acceptable salt or hydrate thereof, a compound of formula III, or a pharmaceutically acceptable salt or hydrate thereof, or a compound of formula IV, or a hydrate thereof, together with one or more pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the neuropathic pain is diabetic peripheral neuropathic pain, central neuropathic pain, and / or mixed neuropathy.

[0097] Furthermore, this specification discloses a method for treating pain associated with osteoarthritis in a patient, comprising administering to a patient in need of such treatment an effective amount of the compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof, the compound of formula IA, or a pharmaceutically acceptable salt or hydrate thereof, the compound of formula III, or a pharmaceutically acceptable salt or hydrate thereof, or the compound of formula IV, or a hydrate thereof, together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0098] Furthermore, this specification discloses compounds of formula I or their pharmaceutically acceptable salts or hydrates, compounds of formula IA or their pharmaceutically acceptable salts or hydrates, compounds of formula III or their pharmaceutically acceptable salts or hydrates, or compounds of formula IV or their hydrates for use in therapy. Furthermore, this specification discloses compounds of formula I or their pharmaceutically acceptable salts or hydrates, compounds of formula III or their pharmaceutically acceptable salts or hydrates, or compounds of formula IV or their hydrates for use in the treatment of pain. Furthermore, this specification discloses compounds of formula I or their pharmaceutically acceptable salts or hydrates, compounds of formula IA or their pharmaceutically acceptable salts or hydrates, compounds of formula III or their pharmaceutically acceptable salts or hydrates, or compounds of formula IV or their hydrates for use in the treatment of chronic back pain, including chronic low back pain. Furthermore, this specification discloses compounds of formula I or pharmaceutically acceptable salts or hydrates thereof, compounds of formula III or pharmaceutically acceptable salts or hydrates thereof, or compounds of formula IV or hydrates thereof for use in the treatment of neuropathic pain. In some embodiments, neuropathic pain is diabetic peripheral neuropathic pain, central neuropathic pain, and / or mixed neuropathy. Furthermore, this specification discloses compounds of formula I or pharmaceutically acceptable salts or hydrates thereof, compounds of formula IA or pharmaceutically acceptable salts or hydrates thereof, compounds of formula III or pharmaceutically acceptable salts or hydrates thereof, or compounds of formula IV or hydrates thereof for use in the treatment of pain associated with osteoarthritis.

[0099] Furthermore, this specification also discloses the use of compounds of formula I, or pharmaceutically acceptable salts or hydrates thereof, compounds of formula IA, or pharmaceutically acceptable salts or hydrates thereof, compounds of formula III, or pharmaceutically acceptable salts or hydrates thereof, or compounds of formula IV, or hydrates thereof, for the manufacture of agents for the treatment of diseases or conditions selected from pain, chronic back pain including chronic low back pain, neuropathic pain, and pain associated with osteoarthritis. In some embodiments, neuropathic pain is diabetic peripheral neuropathic pain, central neuropathic pain, and / or mixed neuropathy.

[0100] intermediate compound Also disclosed herein are novel intermediate compounds generated during the disclosed methods for the preparation of SSTR4 agonist compounds, or pharmaceutically acceptable salts thereof, their hydrates, and / or solvates. Preferred intermediates can be generated at any point during the disclosed methods. Preferred intermediates can be isolated as pure compounds or generated only in solution.

[0101] Suitable intermediates for the preparation of SSTR4 agonist compounds, or pharmaceutically acceptable salts thereof, hydrates thereof, and / or solvates thereof include the intermediate of formula XV, or pharmaceutically acceptable salts thereof, hydrates thereof, and / or solvates thereof, where Y is H, OH, NH2Cl, Br, I, C1-C6 alkyl, C1-C6 ether or a combination thereof, R1 and R2 are independently H, OH, NH2Cl, Br, I, C1-C6 alkyl, C1-C6 ether or a combination thereof, the phenyl functional group is substituted with one or more R' groups, each R' group is independently H, OH, NH2Cl, Br, I, C1-C6 alkyl, C1-C6 ether or a combination thereof. In one embodiment, Y may be OH, Cl, Br, I, or NH2R1, R2 may be H, and R' may be a para CH3.

[0102] [ka]

[0103] In one embodiment, the intermediate compound may also be represented by formula XVI, or a pharmaceutically acceptable salt thereof, a hydrate thereof, and / or a solvate thereof, where Y is H, OH, NH2Cl, Br, I, C1-C6 alkyl, C1-C6 ether, or a combination thereof; R1 and R2 may independently be H, OH, NH2Cl, Br, I, C1-C6 alkyl, C1-C6 ether, or a combination thereof; the phenyl functional group is substituted with one or more R' groups, each R' group may independently be H, OH, NH2Cl, Br, I, C1-C6 alkyl, C1-C6 ether, or a combination thereof. In one embodiment, Y may be OH, Cl, Br, I, or NH2R1, R2 may be H, and R' may be a para CH3.

[0104] [ka]

[0105] In one embodiment, the intermediate compound may also be represented by formula XVII, or a pharmaceutically acceptable salt thereof, its hydrate, and / or its solvate, where Y may be H, OH, NH2Cl, Br, I, C1-C6 alkyl, C1-C6 ether, or a combination thereof. In one embodiment, Y may be OH, NH2Cl, Br, or I.

[0106] [ka]

[0107] In one embodiment, the intermediate compound may also be represented by formula XVIII or a pharmaceutically acceptable salt thereof, its hydrate, and / or its solvate.

[0108] [ka]

[0109] The intermediate compounds described herein can be used in the preparation of SSTR4 agonist compounds, or pharmaceutically acceptable salts thereof, hydrates thereof, and / or solvates thereof. The intermediate compounds provide a stable framework for producing a variety of SSTR4 agonist compounds through an amide-carboxylic acid coupling reaction, such as in step (d) of the method for preparing SSTR4 agonist compounds described herein and illustrated by formula VIII.

[0110] Table A shows several possible SSTR4 agonist compounds that can be synthesized via intermediates using the disclosed method.

[0111] [Table 1]

[0112] When used herein, the terms “a,” “an,” “the,” and similar terms used in the context of this disclosure (particularly in the context of the claims) should be construed to cover both singular and plural forms, unless otherwise specified herein or unless the context clearly contradicts this.

[0113] As used herein, the terms “to treat” or “to treat” include suppressing, delaying, stopping, or reversing the progression or severity of an existing condition or disorder.

[0114] 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 human.

[0115] As used herein, the term “effective dose” means the amount or dosage of the compound of the present invention that, when administered to a patient as a single or multiple doses, provides the desired effect to a patient undergoing diagnosis or treatment.

[0116] The effective dose can be readily determined by those skilled in the art using known techniques. When determining the effective dose for a patient, several factors are considered, but are not limited to: the patient's species, size, age, and overall health; the specific disease or disorder involved; the degree, involvement, or severity of the disease or disorder; the individual patient's response; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered preparation; the dose regimen chosen; the use of concomitant medications; and other relevant circumstances.

[0117] As used herein, the term "alkyl(alkyl)" means a saturated linear or branched monovalent hydrocarbon group containing the indicated number of carbon atoms. For example, "C1~C 20 "Alkyl" refers to a radical having 1 to 20 carbon atoms in a linear or branched chain configuration.

[0118] When used herein, "C1~C n The term "thioether" refers to a straight-chain or branched-chain saturated hydrocarbon containing 1 to n carbon atoms with terminal "S" atoms in the chain, i.e., -S(alkyl), where the thioether group can be bonded to any position of the sulfur atom. n The term "thioether" also refers to a cycloalkyl or aryl group containing a terminal "S" in the molecule, i.e., -S(aryl), where the thioether group can be bonded to any desired position of the sulfur atom. n The term "thioether" can include a saturated hydrocarbon chain and either a cycloalkyl or aryl group, i.e., -S-CH2-(aryl), where n refers to the total number of carbon atoms in the substituent.

[0119] When used herein, "C1~C n The term "ether" refers to a straight-chain or branched-chain saturated hydrocarbon containing 1 to n carbon atoms with terminal "O" atoms in the chain, i.e., -O(alkyl), where the ether group can be bonded to any desired position of the oxygen atom. C1~C nThe term ether also refers to a cycloalkyl or aryl group containing a terminal "O" in the molecule, i.e., -O(aryl), where the ether group can be bonded to any desired position on the oxygen atom. n The term "ether" can also include a saturated hydrocarbon chain and either a cycloalkyl or aryl group, i.e., -O-CH2-(aryl), where n refers to the total number of carbon atoms in the substituent.

[0120] As used herein, the term "cycloalkyl" means a radical derived from a non-aromatic monocyclic or polycyclic ring containing carbon and hydrogen atoms. A cycloalkyl group may have one or more carbon-carbon double bonds in the ring, provided that the ring is not made aromatic by their presence. A cycloalkyl group may be unsubstituted or substituted with one to three suitable substituents well known to those skilled in the art. A cycloalkyl group can be represented by the total number of carbon atoms in the monocyclic or polycyclic ring. For example, C3-C7 cycloalkyl groups include cycloalkyl radical groups having 3, 4, 5, 6, or 7 carbon atoms.

[0121] As used herein, the term “heterocycloalkyl” means a radical 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. A heterocycloalkyl group may have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring, provided that the ring is not made aromatic by their presence. Examples of heterocycloalkyl groups include azilidinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl. A heterocycloalkyl group may be unsubstituted or substituted with one or two preferred substituents. A heterocycloalkyl group can be expressed by the total number of atoms in the monocyclic or polycyclic ring. For example, a 4-membered to 7-membered heterocycloalkyl group may contain 4, 5, 6, or 7 members (including carbon atoms and heteroatoms).

[0122] As used herein, the term "aryl" means a radical derived from an aromatic monocyclic or polycyclic ring containing only carbon atoms in the monocyclic or polycyclic ring. The aryl group may be unsubstituted, or it may be substituted with 1 to 5 suitable substituents well known to those skilled in the art. The aryl group can be expressed by the total number of carbon atoms in the monocyclic or polycyclic ring. For example, C5-C7 aryls include aryl radical groups having 5, 6, or 7 carbon atoms.

[0123] As used herein, the term “heteroaryl” means a radical derived from an aromatic monocyclic or polycyclic ring containing one or more carbon atoms and one or more heteroatoms in the monocyclic or polycyclic ring. Heteroaryl groups may be unsubstituted, or they may be substituted with 1 to 5 suitable substituents known to those skilled in the art. Heteroaryl groups can be expressed by the total number of atoms in the monocyclic or polycyclic ring. For example, 4-membered to 7-membered heteroaryls include 4, 5, 6, or 7 members (including carbon atoms and heteroatoms). [Examples]

[0124] Certain 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 time, "MeCN" refers to acetonitrile, "MeOH" refers to methanol, "MTBE" refers to methyl tert-butyl ether, "MeTHF" refers to methyltetrahydrofuran, "Ph2PK" refers to potassium diphenyl phosphide, "TEA" refers to triethylamine, "TFA" refers to trifluoroacetic acid, and "THF" refers to tetrahydrofuran.

[0125] [ka]

[0126] Scheme 1. Commercial synthesis of SSTR4 agonists Ring A, R n And Y are as defined above.

[0127] Scheme 1, step A shows a coupling to obtain compound (2) by mixing compound (1) with methyl 4-bromobuta-2-enoate using a suitable base such as potassium carbonate and potassium iodide in a suitable solvent such as MeCN at a suitable temperature (e.g., 30-60°C). Step B shows deprotection of compound (2) using an acid such as TFA in a solvent such as MeCN to obtain compound (3). Step C shows cyclization to obtain compound (4) by mixing compound (3) with (2-haloethyl)diphenylsulfonium such as (2-bromoethyl)diphenylsulfonium triflate in the presence of a suitable solvent such as the base KOH, KF, and 2-MeTHF. In step D, compound (4) is converted to compound (5) using water and a base such as LiOH. Step E shows a coupling reaction to obtain compound (6) by mixing compound (5) with a heteroaryl or aryl compound such as 2-(1-methyl-1H-indazole-3-yl)propan-2-amine or 2-methyl-1-((3-methylpyridine-2-yl)oxy)propan-2-amine in the presence of a catalyst such as COCl2 and a solvent such as DMF, toluene, and DCM. Step F shows the conversion of compound (6) to compound (7) by reacting compound (6) with Ph2PK in a solvent such as MTBE or THF at a suitable temperature (e.g., heated to 60-70°C) to obtain compound (7). Step G shows a method for producing the salt by means of a reaction with an acid, a salt metathesis reaction, and / or other reactions that can result in the formation of a pharmaceutically acceptable salt (8). Examples of salts include citrate anion, succinate anion, adipicate anion, tartrate anion, L-tartrate anion, malate anion, and / or L-malate anion.

[0128] Preparation 1 Methyl(E)-4-((N-tert-butoxycarbonyl)-4-methylphenyl)sulfonamide)buta-2-enoate [ka]

[0129] Methyl 4-bromobuta-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), K2CO3 (30.57 g, 221.2 mmol), and KI (3.06 g, 202.7 mmol) were added to the solution at 15-25°C, and the mixture was heated under nitrogen at 30°C 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 obtain the title product in solution, which was used directly in the next step without isolation.

[0130] Preparation 2 Methyl(E)-4-((4-methylphenyl)sulfonamide)buta-2-enoate [ka]

[0131] Methyl 4-bromobuta-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. K2CO3 (30.57 g, 221.2 mmol) and KI (3.06 g, 202.7 mmol) were added to the solution at 15-25°C, and the mixture was heated under nitrogen at 30°C 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 obtain methyl(E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamide)buta-2-enoate. In a MeCN solution, methyl(E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamide)buta-2-enoate (483.72 g, 143 mmol) was mixed with TFA (101.03 g, 886.06 mmol) and heated at 55-60°C for 16 hours. The reaction solution was concentrated to approximately 50 mL under vacuum, and the solvent was replaced with toluene (2 × 250 mL). 500 mL of toluene was added at 15-25°C, followed by ELISA (50 mL), and the mixture was heated at 60°C for 1 hour, then cooled to 0°C for 12 hours. The solution was filtered, and the wet cake was rinsed with n-heptane (50 mL). The cake was dried under vacuum at 50°C to obtain the title compound (37.85 g, 74.4%) as a white solid. 1 H NMR(CDCl3)δ7.68(d,J=8.0Hz,2H)7.25(d,J=8.0Hz,2H)6.71(dt,J=15.6,5.2Hz,1H)5.88(dt ,J=15.6,1.6Hz,1H)4.55(t,J=6.4Hz,1H)3.71-3.67(m,2H)3.65(s,3H)2.37(s,3H);HRMS(ESI + )[C 12 H 15 [NO4S+H] + Calculated value for this: 270.0795, measured value: 270.0788 (M+H).

[0132] Preparation 3 (1R,5S,6r)-3-tosyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid [ka]

[0133] Methyl(E)-4-((4-methylphenyl)sulfonamide)buta-2-enoate (36.50 g, 111.4 mmol) was dissolved in 2-MeTHF (600 mL) at 0°C. (2-bromoethyl)diphenylsulfonium triflate (51.90 g, 117.1 mmol), KF (6.47 g, 111.6 mmol), and KOH (18.75 g, 334 mmol) were added to the solution at 0°C. The solution was heated at 15°C for 22 hours, then at 30°C for 3 hours. Water (100 mL) and MeOH (100 mL) were added to the solution. LiOH . H2O (4.77 g, 113 mmol) was added and the mixture was stirred at 30°C for 16 hours. The mixture was cooled to 15-25°C and n-heptane (100 mL) was added. The mixture was stirred at 15-25°C for 10 minutes. The aqueous phase was separated and collected, and washed with n-heptane / 2-MeTHF (50 mL / 200 mL × 2). The aqueous phase was concentrated to approximately 50 mL under vacuum, and 3 M HCl aqueous solution was added dropwise to adjust the pH to 1-2. The mixture was stirred at 20-30°C for 2 hours. The solution was filtered and rinsed with EtOH / H2O (15 mL 1:4). The wet cake was dried at 45°C for 8-10 hours to obtain the title compound as a gray solid (20.37 g, 65%). 1 HNMR(CDCl3)δ7.67(d,J=8.2Hz,2H)7.34(d,J=8.2Hz,2H)3.63(d,J=9.4Hz,2H)3.12(d,J=9.4Hz,2H)2.46-2.40(m,4H)2.07-2.01(m,2H);HRMS(ESI + )[C 13 H 15 [NO4S+H] + Calculated value for this: 282.0795, measured value: 282.0795 (M+H).

[0134] Preparation 4 (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane-6-carboxamide [ka]

[0135] Oxalyl chloride (91.6 g, 721.5 mmol) was added to a mixture of (1R,5S,6r)-3-tosyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (135.2 g, 481 mmol) in toluene (1350 mL), followed by the addition of DMF (3.51 g, 48 mmol). The mixture was heated at 50°C for 30 minutes. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was co-evaporated with THF (2 × 600 mL). THF (1350 mL) was added to the residue, followed by TEA (145.7 g, 1443 mmol), DMAP (2.93 g, 24 mmol), and 2-(1-methyl-1H-indazole-3-yl)propan-2-amine (CAS No. 1539323-37-9, 100 g, 529.1 mmol) at 0°C. The reaction mixture was stirred at 0°C for 15 minutes, then at ambient temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was diluted with DCM (800 mL) and water (800 mL). The two layers were separated, and the aqueous layer was extracted with DCM (3 × 400 mL). The combined organic layer was dehydrated with sodium sulfate, filtered, and concentrated under vacuum. The residue was ground with a 10:1 mixture of MTBE and DCM (1000 mL) for 16 hours. The mixture was filtered to obtain the title product (136.5 g, 63%) as a light brown solid. 1 H-NMR(CDCl3)δ=7.78(dt,J=8.4,0.8Hz,1H),7.69(dt,J=8.4,2Hz,2H),7.42-7.31(m,5H),7.15-7.11(m,1H),4.05(s,3H),3.66(d, J=9.6Hz,2H),3,05(dd,J=8.0,1.2Hz,2H),2.43(s,3H),1.96-1.95(m,2H),1.90(s,6H),1.69(t,J=3.2Hz,1H)ES / MSm / z:453[M+1]. R t =3.4 minutes

[0136] Example 1 (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide [ka]

[0137] Potassium tert-butoxide (27.2 g, 243 mmol) was added at ambient temperature to a solution of diphenylphosphine (45.2 g, 243 mmol) in anhydrous THF (240 mL). The suspension was stirred at ambient temperature for 10 minutes. The resulting potassium diphenylphosphine solution was then transferred at 66°C to a solution of compound (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane-6-carboxamide (110 g, 243 mmol) in anhydrous THF (1500 mL). A freshly prepared potassium diphenylphosphine solution was added every 1.5 hours. The reaction mixture was stirred at 66°C for a further 16 hours. After cooling to ambient temperature, the reaction mixture was adjusted to pH 1 with 3.0 M HCl (650 mL). Volatile substances were removed under reduced pressure. The aqueous solution was washed with dimethylammonium sulfate (600 mL and 5 × 300 mL). The aqueous layer was adjusted to pH 8 with saturated potassium carbonate and extracted with dimethyl chlorine (DCM) (600 mL), then adjusted to pH 12 with saturated potassium carbonate and extracted with dimethyl chlorine (6 × 300 mL). The combined organic layer was dehydrated with sodium sulfate (100 g), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using elution with 10% DCM in MeOH containing 10% ammonium hydroxide to obtain the title product (62.77 g, 87% yield) as an off-white solid. 1H-NMR(CDCl3)δ=7.80(d,J=8.4Hz,1H),7.41-7.35(m,2H),7.20(brs,1H),7.15-7.11(m,1H),4.02(s ,3H),3.09(d,J=11.2Hz,1H),3.0(d,J=11.2Hz,1H),1.96(s,2H),1.93(s,6H),1.37(t,J=3.2Hz,1H). ES / MS m / z:299.2(M+1). Rt=3.1 minutes.

[0138] Example 2 (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide monohydrate [ka]

[0139] A 30 g monohydrate preparation was placed in a reaction vessel with 100 mL of ACN / H2O (20:80). The suspension was mixed at room temperature and isolated after 24 hours of mixing. The solid was isolated by vacuum filtration and dried in a vacuum oven to recover 8.2 g of (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide monohydrate.

[0140] Example 3 (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide succinate [ka]

[0141] 200 mg of (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide was dissolved in 3 mL of IPA at 40°C. 67 mg of succinic acid (1.1 mol) was added to 3 mL of IPA. A suspension was prepared and cooled to room temperature for isolation. In the scale-up procedure, 10 g of (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide was dissolved in 100 mL of IPA:H2O (88:12) and used. 4.5 g of succinic acid was added and the mixture was heated at 55°C for 1 hour. The mixture was cooled to 45°C, and seed crystals were added from the material prepared using the above procedure for crystal growth. After 2 hours at 45°C, the suspension was cooled to room temperature. To increase the yield, an additional 50 mL of IPA was added, and the solid was isolated by vacuum filtration. After drying in a vacuum oven at 45°C, 5.8 g of succinate was recovered.

[0142] Example 4 (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide adipate [ka]

[0143] 300 mg of (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide was dissolved in 5 mL of IPA at 30°C. 148 mg of adipic acid (1 mol) was added to the solution. After the addition of acid, a suspension was prepared and cooled to room temperature for isolation. In the scale-up procedure, 15.4 g of (1R,5S,6r)-N-(2-(1-methyl-1H-indazole-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide was dissolved in 225 mL of IPA at 50°C and used. 9.1 g of adipic acid was added, and a small batch of seed crystals was added. The seeds were retained for crystal growth. The suspension was cooled to room temperature. The solid was isolated by vacuum filtration and dried to obtain the adipine salt.

[0144] X-ray powder diffraction (XRPD) method The XRPD pattern of the crystalline solid is obtained on a Bruker D8 Endeavor X-ray powder diffractometer operating at 40 kV and 40 mA with a CuKα (1.5418 Å) source and a Lynxeye™ detector. The sample is scanned from 4 to 42 2θ° with a step size of 0.009 2θ° and a scan speed of 0.5 s / step using a 0.3° primary slit aperture and a 3.9° PSD aperture. The dry powder is filled into a quartz sample holder, and a smooth surface is obtained using a glass slide. The diffraction pattern of the crystalline form is collected at ambient temperature and relative humidity. The crystal peak positions are determined with MDI-Jade after global pattern shifting based on an internal NIST 675 standard having peaks at 8.853 and 26.774 2θ°. In the field of crystallography, it is well known that for any crystalline form, the relative intensity of diffraction peaks may vary due to preferred orientation arising from factors such as crystalline form and crystal habit. When the effect of preferred orientation is present, the peak intensities change, but the characteristic peak positions of the polymorphs remain invariant. See, for example, The United States Pharmacopeia#23, National Formulary#18, pages 1843 - 1844, 1995. Further, in the field of crystallography, it is also well known that for any crystalline form, the angular peak positions may vary slightly. For example, the peak positions may shift due to fluctuations in the temperature at which the sample is analyzed, displacement of the sample, or the presence or absence of an internal standard. In this case, peak position variations of ±0.2 2θ° are estimated to account for these potential variations without preventing the clear identification of the indicated crystalline form. Confirmation of the crystalline form can be made based on any unique combination of characteristic peaks.

[0145] XRPD in Example 2 The prepared sample of Example 2 includes the diffraction peaks (2θ values) described / illustrated in Table 1, Table 2, and FIG. 1. In particular, it is characterized by an XRPD pattern using CuKα radiation that includes a peak at a diffraction angle 2θ of 10.1° and one or more of the peaks at 12.8°, 17.3°, or 21.9°, with an allowable error of 0.2 degrees for the diffraction angle.

[0146] XRPD of Example 3 The prepared sample of Example 3 includes the diffraction peaks (2θ values) described / illustrated in Table 3, Table 4, and FIG. 2. In particular, it is characterized by an XRPD pattern using CuKα radiation that includes a peak at a diffraction angle 2θ of 22.6° and one or more of the peaks at 12.9°, 14.8°, or 18.2°, with an allowable error of 0.2 degrees for the diffraction angle.

[0147] XRPD of Example 4 The prepared sample of Example 4 includes the diffraction peaks (2θ values) described / illustrated in Table 5, Table 6, and FIG. 3. In particular, it is characterized by an XRPD pattern using CuKα radiation that includes a peak at a diffraction angle 2θ of 11.5° and one or more of the peaks at 12.2°, 18.0°, or 22.4°, with an allowable error of 0.2 degrees for the diffraction angle.

[0148] [Table 2] <​​​​​​​​​​​​​​​​​​​​​​​​​ Table 6

[0153] Table 7

Claims

1. formula: 【Chemistry 1】 A compound or hydrate thereof, In the formula, M does not exist, or C １ ~C ６ A compound or hydrate thereof that is alkyl.

2. The aforementioned compound has the formula: 【Chemistry 2】 The compound according to claim 1, which is one of the above, or a combination thereof.

3. The aforementioned compound has the formula: 【Transformation 3】 The compound according to claim 1 or 2, wherein the compound is as described above.

4. The compound according to any one of claims 1 to 3, wherein the compound is crystalline.

5. The compound according to claim 4, characterized in that the compound has an X-ray powder diffraction pattern using CuKα rays, which includes a peak at a diffraction angle 2θ of 22.6°±0.2° and one or more peaks at 12.9°, 14.8°, or 18.2°±0.2°.

6. The compound according to claim 4 or claim 5, characterized in that the compound has an X-ray powder diffraction pattern using CuKα rays that includes peaks at diffraction angles 2θ of 12.9°, 14.1°, 14.8°, 16.1°, 16.4°, 18.2°, 19.7°, 20.3°, 21.3°, 21.7°, 22.6°, 23.1°, and 26.0°.

7. The aforementioned compound has the formula: 【Chemistry 4】 The compound according to claim 1 or 2, wherein the compound is as described above.

8. The compound according to any one of claims 1, 2, or 7, wherein the compound is crystalline.

9. The compound according to claim 8, characterized in that the compound has an X-ray powder diffraction pattern using CuKα rays, the pattern comprising a peak at a diffraction angle 2θ of 11.5° ± 0.2° and one or more peaks at 12.2°, 18.0°, or 22.4° ± 0.2°.

10. The compound according to claim 8 or 9, characterized in that the compound has an X-ray powder diffraction pattern using CuKα rays that includes peaks at diffraction angles 2θ of 5.9°, 10.9°, 11.5°, 12.2°, 13.7°, 15.4°, 15.8°, 18.0°, 18.7°, 20.1°, 22.4°, 23.2°, and 25.3°±0.2°.

11. formula: 【Transformation 5】 A compound of [this].

12. The compound according to claim 11, characterized by being crystalline and having an X-ray powder diffraction pattern using CuKα rays that includes a peak at a diffraction angle 2θ of 10.1°±0.2° and one or more peaks at 12.8°, 17.3°, or 21.9°±0.2°.

13. The compound according to claim 11 or 12, characterized by being crystalline and having an X-ray powder diffraction pattern using CuKα rays that includes peaks at diffraction angles 2θ of 10.1°, 11.4°, 12.8°, 13.7°, 15.0°, 17.3°, 19.9°, 20.6°, 21.0°, 21.9°, 23.7°, 25.6°, and 26.5°±0.2°.

14. (a) A compound according to any one of claims 1 to 13, (b) one or more pharmaceutically acceptable carriers, diluents, or excipients, A pharmaceutical composition containing the following:

15. A method for treating pain in a patient, comprising administering an effective amount of a compound according to any one of claims 1 to 13 to the patient in need of such treatment.

16. A method for treating chronic back pain in a patient, comprising administering an effective amount of any one of claims 1 to 13 to the patient in need of such treatment.

17. A method for treating neuropathic pain in a patient, comprising administering an effective amount of any one of claims 1 to 13 to the patient in need of such treatment.

18. The method according to claim 17, wherein the neuropathic pain is diabetic peripheral neuropathic pain and / or central neuropathic pain.

19. A method for treating pain associated with osteoarthritis in a patient, comprising administering an effective amount of a compound according to any one of claims 1 to 13 to the patient in need of such treatment.

20. formula: 【Transformation 6】 A method for preparing a compound or a pharmaceutically acceptable salt thereof, During the ceremony, Y is a covalent bond, O, S, C １ ~C ６ Ether, or C １ ~C ６ It is a thioether, Z is non-existent, a covalent bond, CH ２ , or -CH ２ CH ２ and 【Transformation 7】 However, an 8- to 10-membered heteroaryl or C having 1 to 4 heteroatoms in the heteroaryl. ６ ~C １０ It is Ariel, 【Transformation 8】 However, one or more R ｎ It is replaced with and Each R ｎ However, independently, OH, F, Cl, Br, I, NH ２ CF ３ , C １ ~C ６ Alkyl, C ３ ~C ７ Cycloalkyl, C １ ~C ７ Ether, or C １ ~C ７ It is a thioether, The method described above is formula: 【Chemistry 9】 (In the formula, R is C １ ~C ６ Compounds that are alkyl, formula: 【Chemistry 10】 When mixed with a sulfonium salt of (wherein X is a halogen and A is an anion), the formula is: 【Chemistry 11】 To obtain an intermediate compound, The aforementioned intermediate compound 【Chemistry 12】 Mix with, 【Chemistry 13】 To obtain, 【Chemistry 14】 The tosyl functional group is removed from the compound to obtain the compound, Methods that include...

21. Z is absent, and the compound has the formula: 【Chemistry 15】 The method according to claim 20, wherein the product is or a pharmaceutically acceptable salt thereof.

22. Y is a covalent bond, and the compound is given by formula: 【Chemistry 16】 The method according to claim 21, wherein the product is or a pharmaceutically acceptable salt thereof.

23. The method described above is formula: 【Chemistry 17】 The compound is given by the formula: [Chemistry 18] Mix with the sulfonium salt, To obtain the aforementioned intermediate compound, The method according to any one of claims 20 to 22, including the method described in any one of claims 20 to 22.

24. The method according to any one of claims 20 to 23, wherein the method comprises fewer than eight synthesis steps.

25. The method according to any one of claims 20 to 24, wherein the method does not include a metal catalyst.

26. The method according to any one of claims 20 to 25, wherein the method does not utilize a hydride salt.

27. The method described above is (a) 【Chemistry 19】 of 【Chemistry 20】 Mix with, 【Chemistry 21】 The process of obtaining, (b) 【Chemistry 22】 Mix it with trifluoroacetic acid, 【Chemistry 23】 The process of obtaining, (c) 【Chemistry 24】 of 【Chemistry 25】 Mix with, The process of obtaining the aforementioned intermediate compound, The method according to any one of claims 20 to 26, including the method described in any one of claims 20 to 26.

28. The method described above is (d) The intermediate compound 【Chemistry 26】 Mix with, 【Chemistry 27】 The process of obtaining, (e) 【Chemistry 28】 Mix it with potassium diphenylphosphine to form the formula: 【Chemistry 29】 The process of obtaining the compound, The method according to claim 27, further comprising:

29. The method described above is (d) The intermediate compound 【Transformation 30】 Mix with, 【Chemistry 31】 The process of obtaining, (e) 【Chemistry 32】 Mix it with potassium diphenylphosphine to form the formula: 【Transformation 33】 The process of obtaining the compound, The method according to claim 27, further comprising:

30. The method described above is (d) The intermediate compound 【Transformation 34】 Mix with, 【Chemistry 35】 The process of obtaining, (e) 【Transformation 36】 Mix it with potassium diphenylphosphine to form the formula: 【Chemistry 37】 The process of obtaining the compound, The method according to claim 27, further comprising: 【Request Item 31】 【Chemistry 38】 The method according to any one of claims 20 to 30, wherein the compound is a nine-membered heteroaryl having one or two heteroatoms.

32. The aforementioned compound has the formula: 【Chemistry 39】 The method according to any one of claims 20 to 31, wherein the product is one of the above, or a pharmaceutically acceptable salt thereof.

33. The aforementioned compound has the formula: 【Chemistry 40】 The method according to any one of claims 20 to 32, wherein the product is one of the above, or a pharmaceutically acceptable salt thereof.

34. Y does not exist, 【Chemistry 41】 However, R １ A single R ｎ It is replaced with R １ However, C １ ~C ７ The method according to any one of claims 20 to 33, wherein the material is a thioether.

35. Said C １ ~C ７ Thioether, 【Chemistry 42】 The method according to claim 34, selected from the group consisting of the following.

36. The aforementioned compound has the formula: 【Chemistry 43】 The method according to any one of claims 20 to 32, wherein the product is or a pharmaceutically acceptable salt thereof.

37. The method described above is (f) Mixing the compound with an acid or a salt containing a conjugate base of the acid. The method according to any one of claims 27 to 36, further comprising:

38. The method according to claim 37, wherein the acid comprises succinic acid, adipic acid, or a combination thereof.

39. The aforementioned compound has the formula: 【Chemistry 44】 The method according to claim 36 or 38, which is one of the above, or a combination thereof.

40. formula: 【Chemistry 45】 A method for preparing an intermediate compound of or a pharmaceutically acceptable salt thereof, The method described above is formula: 【Chemistry 46】 (In the formula, R is C １ ~C ６ Compounds of alkyl formula: 【Chemistry 47】 The intermediate compound is obtained by mixing it with a sulfonium salt of (wherein X is a halogen and A is an anion) Methods that include...

41. The method described above is formula: 【Chemistry 48】 The compound formula: 【Chemistry 49】 Mix with the sulfonium salt, To obtain the aforementioned intermediate compound or a pharmaceutically acceptable salt thereof, The method according to claim 40, including the method described in claim 40.

42. The method according to claim 40 or 41, wherein the method includes fewer than eight synthesis steps.

43. The method according to any one of claims 40 to 42, wherein the method does not include a metal catalyst.

44. The method according to any one of claims 40 to 43, wherein the method does not utilize a hydride salt.

45. The method described above is (a) [Transformation 50] of 【Chemistry 51】 Mix with, 【Chemistry 52】 The process of obtaining, (b) 【Chemistry 53】 Mix it with trifluoroacetic acid, 【Chemistry 54】 The process of obtaining, (c) 【Transformation 55】 of 【Transformation 56】 Mix with, A step of obtaining the aforementioned intermediate compound or a pharmaceutically acceptable salt thereof, The method according to any one of claims 40 to 44, including the method described in any one of claims 40 to 44.

46. The method described above is (a) A step of mixing methyl(E)4-bromobuta-2-enoate with tert-butyltosylcarbamate to obtain methyl(E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamide)buta-2-enoate, (b) A step of mixing methyl(E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamide)buta-2-enoate with trifluoroacetic acid to obtain methyl(E)-4-((4-methylphenyl)sulfonamide)buta-2-enoate, (c) A step of mixing methyl(E)-4-((4-methylphenyl)sulfonamide)buta-2-enoate with 2-bromoethyl)diphenylsulfonium triflate to obtain the intermediate compound or a pharmaceutically acceptable salt thereof, The method according to any one of claims 40 to 45, including the method described in any one of claims 40 to 45.

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