Method for preparing SSTR4 agonists and salts thereof

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 does not require a separate epimerization step. Novel intermediates useful in the preparation of SSTR4 agonist compounds. The present invention relates to novel salts of certain SSTR4 agonists, such as salts of (1R, 5S, 6r)-N-(2-(1-methyl-1H-indazol-3-yl) propan-2-yl)-3-azabicyclo [3.1. 0] hexane-6-carboxamide succinate and salts of (1R, 5S, 6r)-N-(2-(1-methyl-1H-indazol-3-yl) propan-2-yl)-3-azabicyclo [3.1. 0] hexane-6-carboxamide adipate. Methods of treating pain, such as osteoarthritis pain, neuropathic pain, and lower back pain, by administering certain SSTR4 agonists and pharmaceutically acceptable salts thereof.

Description

TECHNICAL FIELD

[0001] The present invention relates to a process for preparing SSTR4 agonists, such as 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives. The present invention also relates to a process for preparing salts of SSTR4 agonists. The present invention also relates to novel hydrates and novel salts of certain SSTR4 agonists. BACKGROUND

[0003] Somatostatin, or growth hormone release-inhibiting factor (SRIF), is a cyclic peptide found in humans. 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 comprising SSTR2, SSTR3, and SSTR5, and the second subfamily comprising SSTR1 and SSTR4.

[0004] 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.

[0005] 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.

[0006] 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-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide and pharmaceutically acceptable salts, solvates, and / or hydrates thereof.

[0007] Diabetic neuropathy is a common complication of diabetic microvascular disease. About 40% of diabetic patients have diabetic microvascular disease, and about 80% of patients with diabetic neuropathy have peripheral polyneuropathy.

[0008] Symptoms of diabetic peripheral neuropathy include hyperalgesia, paresthesia, and a deep, aching pain. Diabetic peripheral neuropathy (DPNP) symptoms are accompanied by poor sleep, mobility, depression, and quality of life.

[0009] Unfortunately, treatment options for DPNP are limited. 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 effects. Tapentadol is an opioid μ receptor agonist with the same pharmacological limitations and adverse effects as other opioid analgesics. Other classes of drugs are used off-label in the clinic, including gabapentinoids, selective serotonin norepinephrine uptake inhibitors, tricyclic antidepressants, and anticonvulsants. Dose-limiting toxicities of all of these drugs make it impossible for patients to tolerate therapeutic doses, resulting in clinically used doses that are lower than therapeutic doses, further reducing the efficacy of these drugs. Moreover, only 50% of patients continue treatment after 3 months.

[0010] Due to the suboptimal dosing and poor tolerability of non-opioid analgesics for managing DPNP, opioid drugs are used as a last resort. While opioid drugs are effective for acute pain, there is evidence that they have little clinical efficacy for chronic pain, much less the potential for reduced efficacy due to tolerance.

[0011] Furthermore, while opioid compounds are known to relieve symptoms of pain, 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 a dependence on opioid compounds. In fact, US President Donald Trump has declared opioid addiction a national public health emergency on October 26, 2017. Therefore, there is a long-felt but unmet need to develop non-opioid compounds, as well as dosing regimens of opioid compounds, to relieve symptoms of pain without the potential for developing addiction and / or dependence.

[0012] Accordingly, the present invention relates to new processes for the synthesis of SSTR4 agonists and new hydrates and / or salts of SSTR4 agonists, which have potential use in the treatment of pain, e.g. neuropathic pain and / or diabetic neuropathy and / or mixed neuropathy. BRIEF DESCRIPTION OF DRAWINGS

[0014] Figure 1An XRPD spectrum of (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide monohydrate is shown.

[0015] Figure 2 An XRPD spectrum of (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide succinate is shown.

[0016] Figure 3 An XRPD spectrum of (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide adipate is shown. SUMMARY

[0018] Disclosed herein are compounds of the formula:

[0019] or hydrates thereof, wherein M is absent or C1 to C6 alkyl.

[0020] Also disclosed herein are compounds of the formula:

[0021] or hydrates thereof.

[0022] Also disclosed herein are compounds of the formula:

[0023] or hydrates thereof.

[0024] Also disclosed herein are compounds of the formula:

[0025]

[0026] 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-(1-methyl-1H- indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide.

[0027] Also disclosed herein are methods of making compounds of the formula:

[0028] or pharmaceutically acceptable salts thereof,

[0029] wherein Y is a covalent bond, O, S, C1 to C6 ether, or C1 to C6 thioether, and Z is absent, a covalent bond, CH2, or CH2CH2, 8- to 10-membered heteroaryl having 1 to 4 heteroatoms in the heteroaryl group or C6 to C10 aryl, 10 aryl, substituted, and R n substituted, and R n each independently is OH, F, Cl, Br, I, NH2, CF3, C1 to C6 alkyl, C3 to C7 cycloalkyl, C1 to C7 ether, or C1 to C7 thioether,

[0030] The method comprises:

[0031] mixing a compound of the formula: wherein R is C1 to C6 alkyl,

[0032] with a sulfonium salt of the formula: wherein X is halogen and A is an anion,

[0033] to obtain an intermediate compound of the formula:

[0034] from removing the tosyl functional group to obtain the compound.

[0035] Also disclosed herein is a method of making a compound of the formula:

[0036] or a pharmaceutically acceptable salt thereof; and

[0037] The method comprises:

[0038] mixing a compound of the formula: wherein R is C1 to C6 alkyl,

[0039] with a sulfonium salt of the formula: wherein X is halogen and A is an anion,

[0040] to obtain an intermediate compound of the formula:

[0041] mixing the intermediate compound with to obtain and

[0042] from removing the tosyl functional group to obtain the compound.

[0043] Also disclosed herein is a product comprising a compound, e.g., (1R,5S,6r)-N-(2-(1- methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide, or a pharmaceutically acceptable salt and / or hydrate thereof, made by the methods described herein. DETAILED DESCRIPTION

[0045] 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 cyclization. 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.

[0046] Disclosed herein are new routes to obtain certain SSTR4 compounds, e.g., (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide, and pharmaceutically acceptable salts, hydrates, or solvates 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 a (2-haloethyl)diphenylsulfonium salt that 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.

[0047] The present invention also relates to new hydrates of certain SSTR4 agonists, e.g., (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide monohydrate. The present invention also relates to new salts of certain SSTR4 agonists, e.g., (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide succinate and (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide adipate.

[0048] SSTR4 agonists

[0049] The disclosed methods can be used to make compounds of Formula I or Formula I-A, wherein Z can be absent, a covalent bond, CH2, or CH2CH2, Y can be a covalent bond, O, S, C1 to C6 ether, or C1 to C6 thioether, It is an 8- to 10-membered heteroaryl group or a C6 to C6 heteroaryl group having 1 to 4 heteroatoms. 10 Aryl, It can be one or more R n Replacement, and R n It can be independently OH, F, Cl, Br, I, NH2, CF3, C1 to C6 alkyl, C3 to C7 cycloalkyl, C1 to C7 ether, C1 to C7 thioether or any combination thereof.

[0050] The disclosed method can also be used to prepare salts, solvates, hydrates and / or combinations thereof of formula I or formula IA.

[0051]

[0052] Formula I. SSTR4 agonist

[0053]

[0054] Formula IA.SSTR4 agonist

[0055] As described in this article It can be C6 to C 10 The aryl group or a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms selected from O, N, or S. In some embodiments, It can be an 8- to 10-membered heteroaryl group having 1 to 4 heteroatoms selected from O, N, or S. In some embodiments, It can be a single-ring, dual-ring, or multi-ring system. If If it is a single-loop system, then It can be a C5 to C6 aryl group or a 5- to 6-heteroaryl group having one or two heteroatoms selected from O, N, or S. If If it is a bicyclic system, then each of the ring systems may include a C5 to C6 aryl group or a 5- to 6-heteroaryl group having one or two heteroatoms selected from O, N or S.

[0056] In some implementation schemes, It can be one or more R n Replace. R n It can be independently selected from OH, F, Cl, Br, I, NH2, C1 to C6 alkyl, C3 to C7 cycloalkyl, C1 to C7 ether, C1 to C7 sulfide, or any combination thereof. In some embodiments, n can represent The number of substituents on it. For example, R1 could be... The first substituent on R2 can be The second substituent, etc.

[0057] In some embodiments, Y can be a covalent bond, O, S, a Ci to C6 ether, or a Ci to C6 thioether. When Y is absent, a covalent bond to the dimethyl substituted carbon atom immediately adjacent to the amide functional group.

[0058] In some embodiments, Z can be absent, a covalent bond, CH2, or CH2CH2. When Z is absent, there is no linkage between the two methyl substituents at the alpha carbon atom. When Z is a covalent bond, the alpha carbon atom forms a cyclopropyl functional group. When Z is CH2, the alpha carbon atom forms a cyclobutyl functional group. When Z is CH2CH2, the alpha carbon atom forms a cyclopentyl functional group.

[0059] In some embodiments, the Ci to C7 thioether can be a thioether selected from Formula II.

[0060]

[0061] The disclosed methods can be used to make a compound of Formula III. The disclosed methods can also be used to make solvates, hydrates, and / or combinations thereof of Formula III and / or Formula III-A.

[0062]

[0063] Formula III. SSTR4 agonists that can be made by the disclosed methods.

[0064]

[0065] Formula III-A. Additional SSTR4 agonists that can be made by the disclosed methods

[0066] The disclosed methods can be used to make a compound of Formula IV. The disclosed methods can also be used to make solvates, hydrates, and / or combinations thereof of Formula IV.

[0067]

[0068] Formula IV. (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide succinate (top), (1R,5S,6r)-N-(2-(1-methyl-1H- indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide adipate (bottom).

[0069] Method

[0070] 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 using a batch process method. 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.

[0071] The method of making SSTR4 agonist compounds of the following formula can comprise the steps of:

[0072] or a pharmaceutically acceptable salt, solvate, or hydrate thereof

[0073] (a) mixing tert-butyl tosyl carbamate with a suitable C1-C6 alkyl ester of 4- halo but-2-enoic acid

[0074] Step (a) of the method of making SSTR4 agonist compounds 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.

[0075]

[0076] Formula V. Step (a) of the method of making SSTR4 agonist compounds

[0077] 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 component mixture in step (a) can be increased 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.

[0078] 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.

[0079] In another embodiment, the method can comprise mixing tert-butyl tosylaminoformate with a (E) 4-bromobut-2-enoic acid methyl ester compound in MeCN to yield (E)-4- ((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoic acid methyl ester, as shown in Formula VI.

[0080]

[0081] Step (a) of the method of preparing SSTR4 agonist compounds of Formula VI.

[0082] In another embodiment, step (a) can comprise mixing with to give

[0083] The additional components of step (a) can include a base, such as potassium carbonate and / or a salt, such as potassium iodide.

[0084] (b) mixing the C1-C6 alkyl ester of (E)-4-((N-(tert-butoxycarbonyl)-4- methylphenyl)sulfonamido)but-2-enoic acid with an acid (c) mixing the C1-C6 alkyl ester of (E)-4-((4-methylphenyl)sulfonamido)but-2- enoic acid with a sulfonium salt

[0085] Step (b) of the method of preparing SSTR4 agonist compounds can comprise 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.

[0086]

[0087] Step (b) of the method of preparing SSTR4 agonist compounds of Formula VII.

[0088] 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 a temperature of 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.

[0089] Following the mixing of step (b), the components can be heated to an elevated temperature, the solution can be concentrated, and the remaining polar aprotic solvent can be exchanged with toluene and / or ethyl acetate.

[0090] 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 other than filtration of the byproduct, or the solvent can be a different polar aprotic solvent.

[0091] The suitable acid in step (b) can be any acid that can be used to remove the tert-butyl ester from the tertiary amine to form a secondary amine. Suitable acids include TFA, hydrochloric acid, sulfuric acid, hydrofluoric acid, and other acids.

[0092] In another embodiment, step (b) can comprise mixing (E)-4-((N-(tert- butyloxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoic acid methyl ester with TFA in MeCN to yield (E)-4-((4-methylphenyl)sulfonamido)but-2-enoic acid methyl ester, as shown in Formula VIII.

[0093]

[0094] Formula VIII. Step (b) of a method of making an SSTR4 agonist

[0095] In another embodiment, step (b) can comprise mixing with TFA to yield

[0096] (d) 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-indazol-3-yl)propan-2-amine

[0097] Step (c) of a method of making an SSTR4 agonist compound can comprise 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.

[0098]

[0099] Formula IX. Step (c) of a method of making an SSTR4 agonist

[0100] 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 solution temperature can be gradually or stepwise increased to 30 °C over a period of about 10 hours to about 30 hours.

[0101] Suitable heterocyclic solvents include tetrahydrofuran, furan, 2-methyl- tetrahydrofuran, and the like.

[0102] After the solution temperature has been increased, a base, such as lithium hydroxide, can be added at the elevated 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.

[0103] 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.

[0104] 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.

[0105]

[0106] Formula X. Sulfonium salt of step (c)

[0107] The sulfonium salt used in step (c) can also be represented by formula XI.

[0108]

[0109] Formula XI. Sulfonium salt of step (c) of formula X

[0110] 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.

[0111]

[0112] Formula XII. Step (c) of the method of making SSTR4 agonists

[0113] In another embodiment, step (c) can comprise mixing with to yield the intermediate compound or a salt or solvate thereof.

[0114] (e) removal of the tosyl functional group with potassium diphenylphosphide Figure 2

[0115] 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 a suitable mixture, as shown in formula XIII-A.

[0116]

[0117] Formula XIII-A. Step (d) of the method of making SSTR4 agonists

[0118] Step (d) of the method of preparing SSTR4 agonist compounds can further comprise mixing the intermediate compound produced in step (c), (1R,5S)-3-(p-tolylsulfonyl)-3- azabicyclo[3.1.0]hexane-6-carboxylic acid, with 2-(1-methyl-1H-indazol-3-yl)propan-2- amine, as shown in Formula XIII-B.

[0119]

[0120] Step (d) of the method of preparing SSTR4 agonists of Formula XIII-B

[0121] Prior to the addition of the appropriate amine, the intermediate compound can be reacted with an appropriate reagent, such as oxalyl chloride or thionyl chloride, to replace the -OH functionality with -Cl in situ under synthetic conditions well known to those of ordinary skill in the art.

[0122] The resulting acyl chloride can be combined with the appropriate amine at a temperature of about -10 °C to about 10 °C or about 0 °C to about 10 °C.

[0123] After about 2 to about 4 hours, the temperature of the solution is increased to about 15 °C to about 25 °C.

[0124] Some examples of appropriate amines include 2-methyl-1-((3-methylpyridin-2- yl)oxy)propan-2-amine, 2-(1-methyl-1H-indazol-3-yl)propan-2-amine, and the like. The appropriate amine can be selected to yield the intended SSTR4 agonist compound.

[0125] In another embodiment, step (d) can comprise mixing the intermediate compound with to yield

[0126] In another embodiment, step (d) can comprise mixing the intermediate compound with to yield

[0127] Figure 3

[0128] Step (e) of the method of preparing SSTR4 agonist compounds can comprise mixing the product produced in step (d) with potassium diphenylphosphide, as shown in Formula XIV-B.

[0129]

[0130] Step (e) of the method of preparing SSTR4 agonists of Formula XIV-A

[0131] Step (e) of the method of making the SSTR4 agonist compound can include mixing the product produced in step (d), e.g., (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3- toluenesulfonyl-3-azabicyclo[3.1.0]hexane-6-carboxamide, with potassium diphenylphosphine, as shown in Formula XIV-B.

[0132]

[0133] Formula XIV-B. Step (e) of the method of making the SSTR4 agonist

[0134] The (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3- toluenesulfonyl-3-azabicyclo[3.1.0]hexane-6-carboxamide produced in step (d) or other suitable SSTR4 agonist precursor can be dissolved in a suitable solvent, e.g., 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. The potassium diphenylphosphine can be added dropwise while maintaining the reduced temperature.

[0135] After all of the potassium diphenylphosphine has been added, the solution can be maintained at the reduced temperature for at least 4 hours, at least 6 hours, or at least 8 hours. The solution can be allowed to warm to about 15 °C to about 25 °C, and the SSTR agonist compound (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-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 of ordinary skill in the art.

[0136] In another embodiment, step (e) can include mixing with potassium diphenylphosphine to yield the SSTR4 agonist compound.

[0137] Salts of the SSTR4 agonist compound

[0138] 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 include: (1) the disclosed methods of making the SSTR4 agonist compound and (2) producing a pharmaceutically acceptable salt of the SSTR4 agonist by (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.

[0139] Suitable pharmaceutically acceptable salts of the SSTR4 agonist compound can include 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 (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide succinate, which can be described by the XRPD pattern of Figure 1 ; and (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide adipate, which can be described by the XRPD pattern of Preparation 1 . Other suitable salts are shown in Formula IV.

[0140] Hydrates of the SSTR4 agonist compound

[0141] Also disclosed herein are hydrates of the SSTR4 agonist compound and hydrates of salts of the SSTR4 agonist compound. Suitable hydrates include (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide hydrate, which can be described by the XRPD pattern shown in Preparation 2 .

[0142] Compositions

[0143] Also disclosed herein are pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the composition further comprises one or more therapeutic agents.

[0144] In some embodiments, the pharmaceutical composition is a tablet composition, a capsule composition, or an aqueous composition. Suitable inactive ingredients in a tablet composition include microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and the like.

[0145] In some embodiments, the pharmaceutical composition is a capsule composition. In some embodiments, the capsule composition can include the SSTR4 agonist compound or a 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.

[0146] Methods of treatment

[0147] 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 Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0148] 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 Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0149] 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 Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof, and 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.

[0150] 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 Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0151] Also disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof, for use in therapy. In addition, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof, for use in the treatment of pain. Also disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof, for use in the treatment of chronic back pain, including chronic lower back pain. Also disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof, for use in the treatment of neuropathic pain. In some embodiments, the neuropathic pain is diabetic peripheral neuropathic pain, central neuropathic pain, and / or mixed neuropathy. Also disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof, for use in the treatment of pain associated with osteoarthritis.

[0152] In addition, disclosed herein are uses of compounds of Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof, in 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 peripheral neuropathic pain, central neuropathic pain, and / or mixed neuropathy.

[0153] Intermediate compounds

[0154] Also disclosed herein are novel intermediate compounds produced during the disclosed methods of making SSTR4 agonist compounds or a pharmaceutically acceptable salt, hydrate, and / or solvate 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.

[0155] Suitable intermediates for preparing SSTR4 agonist compounds or pharmaceutically acceptable salts thereof, hydrates thereof, and / or solvates thereof can include intermediates of Formula XV or pharmaceutically acceptable salts thereof, hydrates thereof, and / or solvates 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.

[0156]

[0157] Intermediate compound of Formula XV

[0158] 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.

[0159]

[0160] Intermediate compound of Formula XVI

[0161] 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, NH2 Cl, Br, I, Ci to C6 alkyl, Ci to C6 ether, or any combination thereof. In one embodiment, Y can be OH, NH2 Cl, Br, or I.

[0162]

[0163] Intermediate compound of Formula XVI

[0164] 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.

[0165]

[0166] Formula XVIII. Intermediate compound

[0167] 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 preparing SSTR4 agonist compounds as described herein and illustrated in Formula VIII.

[0168] Table A shows some possible SSTR4 agonist compounds that can be synthesized via the intermediate compounds using the disclosed methods.

[0169] Table 1. SSTR4 agonist compounds that can be synthesized using amide coupling reactions with the intermediate compounds

[0170]

[0171]

[0172] 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 by the language. As used herein, the term "comprising" or "comprise" is used in the sense of "including" and means that other steps, ingredients, elements or materials are optional in some embodiments and not present in other embodiments.

[0173] As used herein, the term "treatment" includes arresting, slowing, stopping, or reversing the progression or severity of an existing symptom or disease.

[0174] 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.

[0175] As used herein, the term "effective amount" refers to the amount or dose of a compound of the present application that, upon single or multiple dosing, provides the intended effect in the diagnosed or treated patient.

[0176] Those skilled in the art can readily determine an effective amount using known techniques. In determining the effective amount for a patient, a variety of factors are considered, including, but not limited to: the species of 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 administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; concomitant medication; and other relevant circumstances.

[0177] As used herein, the term "alkyl" means a saturated linear or branched monovalent hydrocarbon group 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.

[0178] As used herein, the term "C1-C n "Thioether" means a straight chain or branched 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 "C1-C n "Thioether" also means 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 "C1-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.

[0179] As used herein, the term "C1-C n "Ether" means a straight chain or branched 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 C1-C n "Ether" also means a cyclic alkyl or aryl containing a terminal "O" in the molecule, i.e., -0(aryl), wherein the ether group can be attached to the intended position at the oxygen atom. The term "C1-C n "Ether" can include both a saturated hydrocarbon chain and a cyclic alkyl or aryl, i.e., -0-CH2-(aryl), wherein n indicates the total number of carbon atoms in the substituent.

[0180] As used herein, the term "cycloalkyl" means 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 groups include cycloalkyl groups having 3, 4, 5, 6, or 7 carbon atoms.

[0181] As used herein, the term "heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic group derived from a ring system comprising one or more carbon atoms and one or more heteroatoms, such as nitrogen, oxygen, and sulfur. The heterocycloalkyl group can have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring, so 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. The heterocycloalkyl group can be unsubstituted or substituted with one or two suitable substituents. The heterocycloalkyl group can be indicated by the total number of atoms in the monocyclic or polycyclic ring. For example, 4- to 7-membered heterocycloalkyl groups include 4, 5, 6, or 7 members (including carbon atoms and heteroatoms).

[0182] As used herein, the term "aryl" refers to an aromatic monocyclic or polycyclic group derived from a ring system comprising only carbon atoms in a monocyclic or polycyclic ring. The aryl group 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. The aryl group can be indicated by the total number of carbon atoms in the monocyclic or polycyclic ring. For example, C5 to C7 aryl groups include aryl groups having 5, 6, or 7 carbon atoms.

[0183] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic group derived from a ring system comprising one or more carbon atoms and one or more heteroatoms in a monocyclic or polycyclic ring. The heteroaryl group 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. The heteroaryl group can be indicated by the total number of atoms in the monocyclic or polycyclic ring. For example, 4- to 7-membered heteroaryl groups include 4, 5, 6, or 7 members (including carbon atoms and heteroatoms). Examples

[0184] 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; "Ph2PK" refers to potassium diphenylphosphide; "TEA" refers to triethylamine; "TFA" refers to trifluoroacetic acid; and "THF" refers to tetrahydrofuran.

[0185]

[0186] Scheme 1. Commercial synthesis of SSTR4 agonists

[0187] Ring A, R nand Y is as previously defined.

[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 to 60 °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 ring closure of compound (3) using (2-haloethyl)diphenylsulfonium, for example, (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 a heteroaryl or aryl compound, for example, 2-(l-methyl-lH-indazol-3-yl)propan-2-amine or 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 or THF at a suitable temperature (e.g., heating from 60 to 70 °C) to give compound (7). Step G shows methods to generate salts, for example, methods using reaction with an acid, salt metathesis reactions, and / or reactions that can form a pharmaceutically acceptable salt (8). Salts can include, for example, citrate, succinate, adipate, tartrate, L-tartrate, malate, and / or L-malate anions.

[0189] Preparation 3

[0190] (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)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 tosylcarbamic acid (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 warmed to 30 °C under nitrogen for 20 h. The solution was cooled to 20 °C and the mixture was filtered. The filtered residue was washed with MeCN (100 mL) to give the title product as a solution which was used directly in the next step without isolation.

[0193] Preparation 4

[0194] (E)-4-((4-methylphenyl)sulfonylamido)but-2-enoic acid methyl ester

[0195]

[0196] 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. K2CO3 (30.57 g, 221.2 mmol) and KI (3.06 g, 202.7 mmol) were added to the 15-25 °C solution and warmed to 30 °C for 20 h under nitrogen. The solution was cooled to 20 °C and the mixture was filtered. The filtered residue was washed with MeCN (100 mL) to give (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonylamido)but-2-enoic acid methyl ester. TFA (101.03 g, 886.06 mmol) was added to a MeCN solution of (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonylamido)but-2-enoic acid methyl ester (483.72 g, 143 mmol) and heated to 55-60 °C for 16 h. The reaction solution was concentrated in vacuo to ~ 50 mL and the solvent was exchanged with toluene (2 x 250 mL). Toluene (500 mL) was added at 15-25 °C and then EtOAc (50 mL) was added and heated to 60 °C for 1 h and then cooled to 0 °C for 12 h. The solution was filtered and the wet cake was rinsed with n-heptane (50 mL). The cake was dried in vacuo at 50 °C to give the title compound (37.85 g, 74.4%) as a white solid.1H NMR (CDCI3) δ 7.68 (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+) calcd for [C 12 H 15 NO4S + H]+: 270.0795, found: 270.0788 (M+H).

[0197] Example 1

[0198] (1R,5S,6r)-3-tosyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid

[0199]

[0200] (E)-4-((4-methylphenyl)sulfonylamino)but-2-enoic acid methyl ester (36.50 g, 111.4 mmol) was dissolved in 2-MeTHF (600 mL) at 0 °C. (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (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 to 15 °C for 22 hours, then to 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 solution was cooled to 15–25 °C, and n-heptane (100 mL) was added. The mixture was stirred at 15–25 °C for 10 min. Separate and collect the aqueous phase, washing it with n-heptane / 2-MeTHF (50 mL / 200 mL × 2). Concentrate the aqueous phase to approximately 50 mL under vacuum, and adjust the pH to 1-2 by adding 3M HCl aqueous solution dropwise. Stir the mixture at 20-30°C for 2 hours. Filter the solution and wash with EtOH / H2O (15 mL 1:4). The wet filter cake was dried at 45 °C for 8–10 hours to obtain the title compound as a gray solid (20.37 g, 65%). ¹H NMR (CDCl₃) 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+) calculation [C 13 H 15 NO4S+H]+: 282.0795, Actual measurement: 282.0795 (M+H).

[0201] Example 2

[0202] (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propane-2-yl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0203]

[0204] 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 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 x 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-indazol-3-yl)propan-2-amine (CAS No. 1539323-37-9, 100 g, 529.1 mmol) at 0 °C. The reaction 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 x 400 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a 10:1 mixture of MTBE and DCM (1000 mL) for 16 hours. The mixture was filtered to give the title product (136.5 g, 63%) as a light brown solid.1H-NMR (CDCI3) δ = 7.78 (dt, J = 8.4, 0.8 Hz, 1H), 7.69 (dt, J = 8.4, 2 Hz, 2H), 7.42 - 7.31 (m, 5H), 7.15 - 7.11 (m, 1H), 4.05 (s, 3H), 3.66 (d, J = 9.6 Hz, 2H), 3,05 (dd, J = 8.0, 1.2 Hz, 2H), 2.43 (s, 3H), 1.96 - 1.95 (m, 2H), 1.90 (s, 6H), 1.69 (t, J = 3.2 Hz, 1H) ES / MS m / z: 453 [M+1]. Rt = 3.4 min

[0205] Example 3

[0206] (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide

[0207]

[0208] Potassium tert-butoxide (27.2 g, 243 mmol) was added to a solution of diphenylphosphine (45.2 g, 243 mmol) in anhydrous THF (240 mL) at ambient temperature. The suspension was stirred at ambient temperature for 10 minutes. The resulting potassium diphenylphosphine solution was then transferred to a solution of compound (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propane-2-yl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-6-carboxamide (110 g, 243 mmol) in anhydrous THF (1500 mL) at 66 °C. Freshly prepared potassium diphenylphosphine solution was added every 1.5 hours. The reaction mixture was stirred at 66 °C for another 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 EtOAc (600 mL and 5 x 300 mL). The aqueous layer was adjusted to pH 8 with saturated potassium carbonate, extracted with DCM (600 mL), then adjusted to pH 12 with saturated potassium carbonate, and extracted with DCM (6 x 300 mL). The combined organic layers were dried over sodium sulfate (100 g), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography by elution with a 10% solution of DCM containing 10% ammonium hydroxide in MeOH to give the title product (62.77 g, 87% yield) as a grayish-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=3.1min.

[0209] Example 4

[0210] (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propane-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide monohydrate

[0211]

[0212] The monohydrate preparation (30 g) was placed in a reaction vessel containing 100 mL ACN / H2O (20:80). The suspension was mixed at room temperature and separated 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-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide monohydrate.

[0213] X-ray powder diffraction (XRPD) method

[0214] (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide succinate

[0215]

[0216] At 40 °C, 200 mg of (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide was dissolved in 3 mL of IPA. 67 mg of succinic acid (1.1 mol) was added to 3 mL of IPA. A suspension resulted and was cooled to room temperature for isolation. The process was scaled up using 10 g of (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide dissolved in 100 mL of IPA:H2O (88:12). 4.5 g of succinic acid was added and heated to 55 °C for 1 hour. The mixture was cooled to 45 °C and seeded with material from the above procedure for crystallization to grow. The suspension was cooled to room temperature after 2 hours at 45 °C. The solid was isolated by vacuum filtration. After drying in a vacuum oven at 45 °C, 5.8 g of the succinate salt was recovered.

[0217] XRPD of Example 2

[0218] (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide adipate

[0219]

[0220] Dissolve 300 mg of (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide in 5 mL of IPA at 30 °C. Add 148 mg of adipic acid (1 mol) to the solution. After the addition of the acid, a suspension is generated, which is cooled to room temperature for isolation. The process is scaled up using 15.4 grams of (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide dissolved in 225 ml of IPA at 50 °C. Add 9.1 g of adipic acid, seeded with the small scale amount. The seed is used for crystallization growth. The suspension is cooled to room temperature. The solid is isolated by vacuum filtration and dried to give the adipic acid salt.

[0221] Figure 1

[0222] XRPD patterns of crystalline solids were obtained on a Bruker D8 Endeavor X-ray powder diffractometer equipped with a Cu Ka source and Lynxeye TM detector operating at 40 kV and 40 mA. The samples were scanned between 4 and 42 2Q° in steps of 0.009 2Q° with a scan rate of 0.5 seconds / step using a 0.3° primary slit opening and a 3.9° PSD opening. Dry powder was loaded onto a quartz sample holder using a glass slide to obtain a smooth surface. Diffraction patterns were collected for the crystalline forms at ambient temperature and relative humidity. Peak positions for the crystalline forms were determined after full pattern shifting based on internal standard NIST 675, which has peaks at 8.853° and 26.774° 2Q, in MDI-Jade. It is well known in the art of crystallography that the relative intensities of diffraction peaks can vary for any given crystalline form due to preferred orientation caused by crystal morphology and habit, among other factors. When the effects of preferred orientation are present, peak intensities will vary, but the characteristic peak positions of a polymorph remain unchanged. See, e.g., The United States Pharmacopeia 23rd Edition, National Formulary #18, pp. 1843-1844, 1995. Furthermore, it is well known in the art of crystallography that the diffraction angle peak positions can vary slightly for any given crystalline form. For example, peak positions can shift due to variations in temperature of the sample being analyzed, sample position, or the presence or absence of an internal standard. In the present case, a peak position variation of ±0.2 2Q° was assumed to account for these possible variations without hindering the unambiguous identification of the indicated crystalline form. A crystalline form can be confirmed based on any unique combination of peaks that distinguish it.

[0223] XRPD of Example 3

[0224] The prepared sample of Example 2 was characterized by XRPD spectrum using Cu Ka radiation, which included peaks at 2-theta values as set forth in Table 1, Table 2 and Figure 2 the indicated diffraction peaks (2-theta values), particularly including a peak at 22.6° 2- theta diffraction angle and one or more peaks at 12.9°, 14.8° or 18.2°; the tolerance for diffraction angles is 0.2 degrees.

[0225] XRPD of Example 4

[0226] The prepared sample of Example 3 was characterized by XRPD spectrum using Cu Ka radiation, which included peaks at 2-theta values as set forth in Table 3, Table 4 and Figure 3 the indicated diffraction peaks (2-theta values), particularly including a peak at 22.6° 2- theta diffraction angle and one or more peaks at 12.9°, 14.8° or 18.2°; the tolerance for diffraction angles is 0.2 degrees.

[0227] X-ray powder diffraction (XRPD) method

[0228] The prepared sample of Example 4 was characterized by XRPD spectrum using Cu Ka radiation, which included peaks at 2-theta values as set forth in Table 5, Table 6 and XRPD of Example 2 Figure 1 XRPD of Example 3 Figure 2 XRPD of Example 4 Figure 3 X-ray powder diffraction (XRPD) method XRPD of Example 2 Figure 1 XRPD of Example 3 Figure 2 XRPD of Example 4 Figure 3 X-ray powder diffraction (XRPD) method XRPD of Example 2 Figure 1 XRPD of Example 3 Figure 2 XRPD of Example 4 Figure 3 X-ray powder diffraction (XRPD) method XRPD of Example 2 Figure 1 XRPD of Example 3 Figure 2 XRPD of Example 4 Figure 3 X-ray powder diffraction (XRPD) method XRPD of Example 2 Figure 1 XRPD of Example 3 Figure 2 XRPD of Example 4 Figure 3 X-ray powder diffraction (XRPD) method XRPD of Example 2 Figure 1 XRPD of Example 3 Figure 2 XRPD of Example 4 Figure 3 X-ray powder diffraction (XRPD) method XRPD of Example 2 Figure 1 XRPD of Example 3 Figure 2 XRPD of Example 4 Figure 3 X-ray powder diffraction (XRPD) method XRPD of Example 2 Figure 1 XRPD of Example 3 Figure 2 XRPD of Example 4 Figure 3 X-ray powder diffraction (XRPD) method XRPD of Example the indicated diffraction peaks (2-theta values), particularly including a peak at 22.6° 2- theta diffraction angle and one or more peaks at 12.9°, 14.8° or 18.2°; the tolerance for diffraction angles is 0.2 degrees.

[0229] Table 1. X-ray powder diffraction peaks of Example 2 arranged by angle

[0230]

[0231] Table 2. X-ray powder diffraction peaks of Example 2 arranged by relative intensity

[0232]

[0233]

[0234] Table 3. X-ray powder diffraction peaks of Example 3 arranged by angle

[0235]

[0236] Table 4. X-ray powder diffraction peaks of Example 3 arranged by relative intensity

[0237]

[0238] Table 5. X-ray powder diffraction peaks of Example 4 arranged by angle

[0239]

[0240] Table 6. X-ray powder diffraction peaks of Example 4 arranged by relative intensity

[0241]

Claims

1. The following compound: or its hydrate, Where M is absent or a C1 to C6 alkyl group.

2. The compound of claim 1, wherein the compound has the following formula: Or any combination thereof.

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

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

5. The compound of claim 4, wherein the compound is characterized by X-ray powder diffraction using Cu Kα emission, the spectrum comprising a peak at a diffraction angle of 22.6° ± 0.2° 2θ and one or more peaks at 12.9°, 14.8° or 18.2° ± 0.2°.

6. The compound of claim 4 or claim 5, wherein the compound is characterized by X-ray powder diffraction using Cu Kα emission, the spectrum comprising peaks at the following 2θ diffraction angles: 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 compound of claim 1 or 2, wherein the compound has the following formula:

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

9. The compound of claim 8, wherein the compound is characterized by X-ray powder diffraction using Cu Kα emission, the spectrum comprising a peak at a diffraction angle of 11.5° ± 0.2° 2θ and one or more peaks at 12.2°, 18.0° or 22.4° ± 0.2°.

10. The compound of claim 8 or 9, wherein the compound is characterized by X-ray powder diffraction using Cu Kα emission, the spectrum comprising peaks at the following 2θ diffraction angles: 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. The following compounds:

12. The compound of claim 11, which is crystalline and characterized by X-ray powder diffraction using Cu Kα emission, the spectrum comprising a peak at a diffraction angle of 10.1° ± 0.2° 2θ and one or more peaks at 12.8°, 17.3° or 21.9° ± 0.2°.

13. The compound of claim 11 or 12, which is crystalline and characterized by X-ray powder diffraction using Cu Kα emission, the spectrum comprising peaks at the following 2θ diffraction angles: 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 pharmaceutical composition comprising: (a) the compound according to any one of claims 1 to 13, and (b) One or more pharmaceutically acceptable carriers, diluents or excipients.

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

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

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

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

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

20. Methods for preparing compounds of the following formula: Or its pharmaceutically acceptable salt. in Y is a covalent bond, O, S, C1 to C6 ether, or C1 to C6 thioether. Z represents non-existence, covalent bond, CH2 or CH2CH2. It is an 8- to 10-membered heteroaryl group or a C6 to C6 heteroaryl group having 1 to 4 heteroatoms. 10 Aryl, by one or more R n Replace, and R n Each of these elements independently is OH, F, Cl, Br, I, NH2, CF3, C1 to C6 alkyl, C3 to C7 cycloalkyl, C1 to C7 ether, or C1 to C7 thioether. The method includes: The following compound: Where R is a C1 to C6 alkyl group. Mix with the following sulfite salt, Where X is a halogen and A is an anion, the intermediate compound is obtained as follows: The intermediate compound and Mix, to obtain and from The compound was obtained by removing the toluenesulfonyl functional group.

21. The method of claim 20, wherein Z is absent, and the compound has the following formula: Or its pharmaceutically acceptable salt.

22. The method of claim 21, wherein Y is a covalent bond and the compound has the following formula: Or its pharmaceutically acceptable salt.

23. The method of any one of claims 20 to 22, wherein the method comprises: The following compound: Mix with the following sulfite: An intermediate compound was obtained.

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

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

26. The method of any one of claims 20 to 25, wherein the method does not use hydride salts.

27. The method of any one of claims 20 to 26, wherein the method comprises the step of: (a) taking and Mix, to obtain (b) will When mixed with trifluoroacetic acid, we obtain and (c) will and Mix to obtain an intermediate compound.

28. The method of claim 27, wherein the method further comprises the following steps: (d) The intermediate compound and Mix, to obtain (e) will When mixed with potassium diphenylphosphine, the following compound is obtained:

29. The method of claim 27, wherein the method further comprises the following steps: (d) The intermediate compound and Mix, to obtain (e) will When mixed with potassium diphenylphosphine, the following compound is obtained:

30. The method of claim 27, wherein the method further comprises the following steps: (d) The intermediate compound and Mix, to obtain (e) will When mixed with potassium diphenylphosphine, the following compound is obtained.

31. The method according to any one of claims 20 to 30, wherein It is a 9-membered heteroaryl group with 1 or 2 heteroatoms.

32. The method of any one of claims 20 to 31, wherein the compound has the following formula: Or its pharmaceutically acceptable salt.

33. The method of any one of claims 20 to 32, wherein the compound has the following formula: Or its pharmaceutically acceptable salt.

34. The method of any one of claims 20 to 33, wherein Y is absent. by a single R n Replace, R n It is called R1, and R1 is a C1 to C7 sulfide.

35. The method of claim 34, wherein the C1 to C7 sulfides are selected from:

36. The method of any one of claims 20 to 32, wherein the compound has the following formula: Or its pharmaceutically acceptable salt.

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

38. The method of claim 37, wherein the acid comprises succinic acid, adipic acid, or any combination thereof.

39. The method of claim 36 or 38, wherein the compound has the following formula: Or any combination thereof.

40. A method for preparing intermediate compounds of the following formula: Or a pharmaceutically acceptable salt thereof; and the method includes The following compound: Where R is a C1 to C6 alkyl group. Mix with the following sulfite: Where X is a halogen and A is an anion, an intermediate compound is obtained.

41. The method of claim 40, wherein the method comprises: The following compound: Mix with the following sulfite: To obtain an intermediate compound or its pharmaceutically acceptable salt.

42. The method of claim 40 or 41, wherein the method comprises fewer than eight synthesis steps.

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

44. The method of any one of claims 40 to 43, wherein the method does not use hydride salts.

45. The method of any one of claims 40 to 44, wherein the method comprises the following steps: (a) will and Mix, to obtain (b) will When mixed with trifluoroacetic acid, we obtain and (c) will and Mix to obtain an intermediate compound or a pharmaceutically acceptable salt.

46. ​​The method of any one of claims 40 to 45, wherein the method comprises the following steps: (a) Mixing (E)4-bromobut-2-enoic acid methyl ester with toluenesulfonylcarbamate tert-butyl ester yields (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonylamino)but-2-enoic acid methyl ester; (b) Mixing (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonylamino)but-2-enoic acid methyl ester with trifluoroacetic acid yields (E)-4-((4-methylphenyl)sulfonylamino)but-2-enoic acid methyl ester; and (c) Mixing (E)-4-((4-methylphenyl)sulfonylamino)but-2-enoic acid methyl ester with 2-bromoethyl)diphenylsulfonate trifluoromethanesulfonate yields an intermediate compound or a pharmaceutically acceptable salt.

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