Substituted 1H-pyrazole-4-carboxamides as SARM1 inhibitors

Abstract

The present invention relates to novel substituted 1H-pyrazole-4-carboxamide compounds as SARM1 inhibitors, pharmaceutical compositions containing said compounds, and methods of using said compounds and compositions for treating and preventing conditions involving axonal degeneration.

Description

[Technical Field]

[0001] The present invention relates to novel SARM1 inhibitors, pharmaceutical compositions containing said compounds, and methods of using said compounds and compositions to treat and prevent conditions involving axonal degeneration.

[0002] Axonal degeneration is a key feature of conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, hereditary neuropathies, traumatic brain injury, and glaucoma. These conditions affect millions of patients and represent a significant economic burden worldwide. [Background technology]

[0003] Sterile Alpha and Toll / Interleukin receptor-1 (TIR) ​​motif-containing 1 (SARM1) has been identified as a central executioner in the injury-induced axonal death pathway known as Wallerian degeneration (O'Neill, LA & Bowie, AG, Nat. Rev. Immunol., 2007, 7, 353-364; Osterloh, JM, et al., Science, 2012, 337, 481-484; Gerdts, J., et al., J. Neurosci. 33, 2013, 13569-13580). Mechanistic studies have revealed that axonal injury-mediated activation of SARM1 or forced dimerization of the SARM1-TIR domain promotes rapid nicotinamide adenine dinucleotide (NAD+) consumption and leads to axonal degeneration (Gerdts, J., et al., Science, 2015, 348, 453-457). Genetic knockout of SARM1 allows axonal preservation more than 14 days after nerve transection (Osterloh, JM, et al., Science, 2012, 337, 481-484; Gerdts, J., et al. J. Neurosci., 2013, 33, 13569-13580) and improves functional outcomes in mice after traumatic brain injury (Henninger, N. et al., Brain 139, 2016, 1094-1105). In addition to the role of SARM1 in direct axonal injury, SARM1 is also required for axonal degeneration seen in pathologies such as chemotherapy-induced peripheral neuropathy. Loss of SARM1 prevents chemotherapy-induced peripheral neuropathy and inhibits both axonal degeneration and the hyperalgesia that develops after vincristine chemotherapy treatment (Geisler et al, Brain, 2016, 139, 3092-3108).

[0004] WO2021 / 142006A1 discloses several compounds and methods that inhibit SARM1 and / or are useful for treating and / or preventing axonal degeneration.

[0005] Currently, there are no approved drugs for treating and / or preventing axonal degeneration. There is an unmet need for potent SARM1 inhibitors with improved metabolic profiles to treat and prevent conditions involving axonal degeneration.

[0006] The present invention provides novel SARM1 inhibitors for use in the treatment and prevention of conditions involving axonal degeneration. Additionally, the present invention provides novel SARM1 inhibitors that have enhanced efficacy and are prone to reduced metabolic clearance. Summary of the Invention

[0007] Thus, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is selected from CH and N; R 1 , R 2 , R 3 and R 4 are each independently H and C 1~4 alkyl, where R 1 and R 2 may optionally form a 6-membered heterocyclic ring together with the atoms to which they are attached, where R 2 and R 3 may optionally form a 6- to 7-membered heterocycle together with the atoms to which they are attached, and wherein R 3 and R 4 may optionally form, together with the atoms to which they are attached, a 5- to 6-membered heterocycle; n is 0, 1 or 2; R 5 is 1 to 3 R m and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R m5-6 membered heteroaryl, optionally substituted with R m is halogen, cyano, C 1~4 Alkyl, trihalomethyl and -OC 1~4 alkyl].

[0008] In some embodiments, R 1 , R 2 , R 3 and R 4 are each independently H and C 1~4 alkyl.

[0009] In certain embodiments, the compound is a compound of formula II: [ka] is.

[0010] In other embodiments, the compound is a compound of formula III: [ka] is.

[0011] In a further embodiment, the compound is a compound of formula IV: [ka] is.

[0012] In some embodiments of the invention, X is CH. In other embodiments, X is N.

[0013] In one embodiment of the invention, R 1 , R 2 , R 3 and R 4 are each independently selected from H, methyl, ethyl, n-propyl, and iso-propyl.

[0014] In some embodiments of the invention, n is 0 or 1. In other embodiments, n is 1.

[0015] In one embodiment of the invention, p is 1.

[0016] In some embodiments of the invention, q is 0. In other embodiments, q is 1.

[0017] In one embodiment of the invention, R 5 is phenyl. In other embodiments, R 5 is 1 to 3 R m In a further embodiment, R 5 is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur. 5 contains 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and 1 to 3 R m In another embodiment, R 5 is a 5-6 membered heteroaryl containing 1-3 nitrogen atoms. 5 contains 1 to 3 nitrogen atoms and 1 to 3 R m In a further embodiment, R is a 5-6 membered heteroaryl substituted with 5 is pyridine. In other embodiments, R 5 is 1 to 3 R m is a pyridine substituted with

[0018] In one embodiment of the invention, R m are each independently selected from F, Cl, Br, I, cyano, and trifluoromethyl.

[0019] In one embodiment of the invention, R 5 has the following structure: [ka] is selected from the group consisting of:

[0020] In one embodiment, the present invention provides a compound selected from: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0021] The present invention provides pharmaceutical compositions comprising a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0022] The present invention provides a method for treating or preventing a disease associated with axonal degeneration in a patient, the method comprising administering to a patient in need of such treatment an effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, according to any of the above embodiments.

[0023] The present invention also provides a method for treating or preventing a disease associated with SARM1 activation in a patient, said method comprising administering to a patient in need of such treatment an effective amount of a compound described in any of the above embodiments or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0024] The present invention also provides a method for treating or preventing a disease selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy and chemotherapy-induced peripheral neuropathy in a patient, said method comprising administering to a patient in need of such treatment an effective amount of a compound according to any of the above embodiments or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0025] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, according to any one of the above embodiments for use in therapy.

[0026] Furthermore, the present invention provides a compound according to any one of the above embodiments, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease associated with axonal degeneration.

[0027] Furthermore, the present invention provides a compound according to any one of the above embodiments or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy and chemotherapy-induced peripheral neuropathy.

[0028] The present invention provides the use of a compound according to any one of the above embodiments, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a disease associated with axonal degeneration.

[0029] Furthermore, the present invention provides the use of a compound or a pharmaceutically acceptable salt according to any one of the above embodiments for the manufacture of a medicament for treating or preventing a disease selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy and chemotherapy-induced peripheral neuropathy. DETAILED DESCRIPTION OF THE INVENTION

[0030] As used herein, the term "alkyl," used alone or as part of a larger moiety, refers to a straight or branched chain saturated hydrocarbon group containing one or more carbon atoms.

[0031] As used herein, the term "heteroaryl" refers to a cyclic aromatic group containing one or more heteroatoms.

[0032] As used herein, the term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0033] As used herein, the term "heterocyclic" refers to a saturated ring group containing carbon atoms and one or more heteroatoms.

[0034] As used herein, the term "patient" refers to a human.

[0035] As used herein, the term "prophylaxis" refers to preventing the onset of a disease or avoiding complications that arise after its onset.

[0036] As used herein, the term "treatment" includes slowing, halting, or reversing the progression or severity of an existing condition or disorder.

[0037] As used herein, the term "effective amount" refers to the amount or dosage of a compound of the present invention, or a pharmaceutically acceptable salt thereof, that provides the desired effect in a patient during diagnosis or treatment, either in a single dose or multiple doses to a patient.

[0038] The compound of the present invention is preferably formulated as pharmaceutical composition, and is administered by any route that makes compound bioavailable (including oral and transdermal route).Most preferably, this composition is for oral administration.This pharmaceutical composition and the process for its preparation are well known in the art (for example, see Remington: The Science and Practice of Pharmacy, A.Adejare, Editor, 23rd edition, Elsevier Academic Press, 2020).

[0039] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be prepared according to the following preparations and examples by methods well known and understood in the art. Suitable reaction conditions for the steps of these preparations and examples are well known in the art, and appropriate substitutions of solvents and co-reagents are within the skill of those in the art. Similarly, those skilled in the art will understand that synthetic intermediates may be isolated and / or purified by various well-known techniques, as necessary or desired, and that often various intermediates will be able to be used directly in subsequent synthetic steps with little or no purification. Illustratively, the compounds of the preparations and examples may be isolated, for example, by silica gel purification, directly by filtration, or by crystallization. Furthermore, those skilled in the art will understand that, in some conditions, the order in which moieties are introduced is not critical. The particular order of steps required to produce the compounds of the present invention will depend on the particular compound being synthesized, the starting compound, and the relative liabilities of the moieties being substituted, and is well understood by chemists skilled in the art. All substituents, unless otherwise indicated, are as previously defined and all reagents are well known and understood in the art.

[0040] Some abbreviations are defined as follows: "AcONa" refers to sodium acetate; "Ar" refers to heteroaryl or aryl; "DCM" refers to dichloromethane; "DIPEA" refers to N,N-diisopropylethylamine; "DMA" refers to dimethylacetamide; "DMF" refers to dimethylformamide; "DIPEA" refers to N,N-diisopropylethylamine; "Et3N" refers to triethylamine; "EtOAc" refers to ethyl acetate; "EtOH" represents ethyl alcohol; "EtONa" refers to sodium ethoxide; HATU refers to (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); "HPLC" refers to high performance liquid chromatography. "hr." or "hrs." refers to hours; "LDA" refers to lithium diisopropylamide; "LiHMDS" refers to lithium bis(trimethylsilyl)amide; "MeCN" refers to acetonitrile; "MeOH" refers to methanol; "min" refers to minutes; "NBS" refers to N-bromosuccinimide; "PdCl2.dppf" refers to 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II); "Prep-HPLC" refers to preparative HPLC; "SEM-Cl" refers to 2-(trimethylsilyl)ethoxymethyl chloride; "TFA" refers to trifluoroacetic acid; "TfOH" refers to trifluoromethanesulfonic acid; "THF" refers to tetrahydrofuran; "T3P" refers to propanephosphonic anhydride.

[0041] [ka] Scheme 1. Step A illustrates the formation of a Weinreb amide from compound (1) using N,O-dimethylhydroxylamine hydrochloride in a solvent such as THF containing a base such as LiHMDS to give compound (2). Step B illustrates the addition of EtOAc to compound (2) in a solvent such as THF using a base such as LDA to give compound (3). Step C illustrates the addition of trichloroacetonitrile to compound (3) using a base such as sodium acetate trihydrate in a solvent such as EtOH to give compound (4). Step D illustrates the cyclization of compound (4) with (4-methoxybenzyl)hydrazine hydrochloride in a solvent such as EtOH using a base such as TEA to give compound (5). 6 When R is ethyl, basic hydrolysis of compound (5) with NaOH in a solvent system such as THF, EtOH, and water is shown in Step E to give compound (6). 6 When t-butyl is used, Step E illustrates the acid deprotection of compound (5) using an acid such as TFA in a solvent such as DCM to give compound (6). Step F illustrates the amide coupling of compound (6) with either ammonium chloride or methylamine hydrochloride using a coupling agent such as HATU and a base such as DIPEA in a solvent such as DMF to give compound (7). Those skilled in the art will appreciate that many other amide coupling agents, bases, and solvents can be used to carry out this coupling. Step G illustrates the amide coupling of compound (7) with an arylpropanoic acid using a coupling agent such as HATU and a base such as DIPEA in a solvent such as DMA to give compound (8). Those skilled in the art will appreciate that many other amide coupling agents, bases, and solvents can be used to carry out this coupling. Step H illustrates the acid deprotection of compound (8) using an acid such as TFA in a solvent such as DCM to give compound (9).

[0042] [ka] Scheme 2. Step A shows the addition of EtOAc to compound 10 using a base such as LDA in a solvent such as THF to give compound 11. Steps B and C are essentially similar to those found in Scheme 1, and Steps C and D show the conversion of compound 11 to compound 12 and then to compound 13. Step D shows the coupling of compound 13 and diphenylmethanimine using a catalyst-ligand system such as Pd(dba) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) in a solvent such as DMF with a base such as cesium carbonate to give compound 14. Step E shows the acid deprotection of compound 14 using an acid such as TFA in a solvent such as DCM to give compound 15. Step F illustrates the intramolecular cyclization of compound 15 to compound 16 using a base such as sodium ethoxide in a solvent such as EtOH. Step G illustrates the amide coupling of compound 16 with an arylpropanoic acid to give compound 17 using a coupling agent such as T3P and a base such as DIPEA in a solvent such as DMA. Those skilled in the art will appreciate that many other amide coupling agents, bases, and solvents can be used to carry out this coupling. Step H illustrates a two-step deprotection of compound 17. The first step removes the amide from the central nitrogen in the interior using a base such as potassium carbonate in a solvent such as MeOH with heating. This is followed by treatment with an acid such as TFA in a solvent such as DCM to give compound 18.

[0043] [ka] Scheme 3. Step A illustrates the bromination of compound 19 using NBS in a solvent such as DMF to give compound 20. Step B illustrates the reaction of compound 20 with SEM-Cl in a solvent such as DMF using a base such as NaH to give compound 21. Step C illustrates the Suzuki coupling of compound 21 with 4-pyridylboronic acid in a solvent system such as dioxane and water using a catalyst such as PdCl.dppf and a base such as potassium carbonate to give compound 22. Those skilled in the art will appreciate that there are many combinations of catalysts, ligands, bases, and solvents that may be utilized to perform this type of coupling. Step D illustrates the conversion of the nitrile of compound 22 to a primary amide by treatment with a base such as KOH in a solvent system such as EtOH and water to give compound 23. Step E illustrates the cyclization of compound 23 with formaldehyde in a solvent such as toluene to give compound 24. Step F shows the reduction of compound (24) with a suitable reducing agent such as NaBH4 in a solvent such as EtOH to give compound (25). The conversion of compound (25) to compound (26) in Step G is essentially the same as in Step G of Scheme 2. The conversion of compound (26) to compound (27) in Step H is essentially the same as in Step H of Scheme 1.

[0044] [ka] Scheme 4, Step A illustrates the amide coupling of compound (28) and (2,4-dimethoxyphenyl)methanamine using a coupling agent such as HATU and a base such as DIPEA in a solvent such as DMF to give compound (29). Those skilled in the art will appreciate that many other amide coupling agents, bases, and solvents can be used to carry out this coupling. The conversion of compound (29) to compound (30) in Step G is essentially the same as in Scheme 2, Step G. Step C illustrates the global deprotection of compound (30) using a system of TFA and an appropriate acid such as TfOH in a solvent such as DCM to give compound (31).

[0045] Preparation 1 N-Methoxy-N,5-dimethylpyridazine-4-carboxamide [ka] A mixture of ethyl 5-methylpyridazine-4-carboxylate (1.2 g, 7.23 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.42 g, 14.46 mmol) in THF (20 mL) was stirred at -70 °C for 5 min. LiHMDS (1.0 M / THF, 50.6 mL, 50.6 mmol) was slowly added and stirred at -70 °C for 2.0 h. The reaction mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with DCM (50 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (eluted with 3% petroleum ether / EtOAc) to give the title compound (0.94 g, 71.2%) as a yellow oil. ES / MS m / z = 182 (M+H).

[0046] Preparation 2 Ethyl 3-(5-methylpyridazin-4-yl)-3-oxo-propanoate [ka] To a mixture of 1.37 g (15.6 mmol) of EtOAc in 20 mL of THF was slowly added LDA (1 M in THF, 15.6 mL) at −70° C., followed by stirring for 1.5 hours. A solution of 0.94 g (5.2 mmol) of N-methoxy-N,5-dimethylpyridazine-4-carboxamide in 8 mL of THF was slowly added, followed by stirring for 2 hours at −70° C. The reaction mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with DCM (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (eluted with 50% petroleum ether / EtOAc) to give the title compound (0.53 g, 49.1%) as a yellow oil. ES / MS m / z = 209 (M+H).

[0047] The compounds set forth in Table 1 were prepared by methods essentially similar to those found in Preparation 2. [Table 1]

[0048] Preparation 4 Ethyl 3-(3-bromopyridin-4-yl)-3-oxopropanoate [ka] A solution of LDA (1M / THF, 32 mL) was slowly added to a mixture of 4.2 g (48 mmol) of EtOAc in 80 mL of THF at −60° C. over 1 h. A solution of 7.0 g (32 mmol) of methyl 3-bromoisonicotinate in 20 mL of THF was slowly added, and the mixture was stirred at −60° C. for 2 h. Saturated aqueous NH4Cl (30 mL) was added to the reaction mixture, which was then extracted with 2 portions of 150 mL of EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash chromatography (eluted with 20:1 petroleum ether:EtOAc) to give the title compound (10 g, 63%) as a yellow oil. ES / MS m / z = 274 (M+H).

[0049] Preparation 5 Ethyl (Z)-3-amino-4,4,4-trichloro-2-(5-methylpyridazine-4-carbonyl)but-2-enoate [ka] To a mixture of ethyl 3-(5-methylpyridazin-4-yl)-3-oxopropanoate (530 mg, 2.55 mmol) in EtOH (10 mL) was added trichloroacetonitrile (404 mg, 2.81 mmol) and sodium acetate trihydrate (251 mg, 3.06 mmol). The mixture was stirred at ambient temperature for 2.0 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (1.08 g, crude) as a yellow oil. ES / MS m / z = 352 (M+H).

[0050] The compounds listed in Table 2 were prepared by methods essentially similar to those found in Preparation 5. [Table 2]

[0051] Preparation 8 tert-Butyl (Z)-3-amino-4,4,4-trichloro-2-isonicotinoylbut-2-enoate [ka] To a mixture of tert-butyl 3-oxo-3-(pyridin-4-yl)propanoate (prepared as described in Bioorg. Med. Chem. Lett., 2015, 25, 3810) (29.0 g, 0.13 mol) in EtOH (150 mL) was added trichloroacetonitrile (20.0 g, 0.14 mmol) and sodium acetate trihydrate (11.5 g, 0.14 mmol). The reaction was stirred at ambient temperature for 2 hours. The reaction mixture was used directly without further workup. ES / MS m / z = 367 (M+H).

[0052] Preparation 9 Ethyl 3-amino-1-(4-methoxybenzyl)-5-(5-methylpyridazin-4-yl)-1H-pyrazole-4-carboxylate [ka] To a mixture of ethyl (Z)-3-amino-4,4,4-trichloro-2-(5-methylpyridazine-4-carbonyl)but-2-enoate (1.08 g, crude product) in EtOH (10 mL) was added TEA (0.77 g, 7.6 mmol) and (4-methoxybenzyl)hydrazine hydrochloride (0.58 g, 3.05 mmol). The mixture was stirred at 65 °C for 2 hours and then concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (eluted with 3% petroleum ether / EtOAc) to give the title compound (0.54 g, 58.1%) as a yellow-brown oil. ES / MS m / z = 368 (M+H).

[0053] The compounds listed in Table 3, as found in Preparation 9, were prepared by essentially the same method. [Table 3]

[0054] Preparation 12 tert-Butyl 3-amino-1-(4-methoxybenzyl)-5-(pyridin-4-yl)-1H-pyrazole-4-carboxylate [ka] To a mixture of tert-butyl (Z)-3-amino-4,4,4-trichloro-2-isonicotinoylbut-2-enoate was added (4-methoxybenzyl)hydrazine hydrochloride (30.0 g, 0.16 mol) and TEA (23.4 g, 0.39 mmol). The mixture was stirred at ambient temperature for 2 hours. The mixture was then filtered, and the resulting solid was dried under reduced pressure to give the title compound (30.0 g, 60%) as a white solid. ES / MS m / z = 381 (M+H)

[0055] Preparation 13 3-Amino-1-(4-methoxybenzyl)-5-(5-methylpyridazin-4-yl)-1H-pyrazole-4-carboxylic acid [ka] To a mixture of ethyl 3-amino-1-(4-methoxybenzyl)-5-(5-methylpyridazin-4-yl)-1H-pyrazole-4-carboxylate (540 mg, 1.47 mmol) in THF (4 mL), EtOH (4 mL), and water (2 mL) was added NaOH (118 mg, 2.94 mmol). The mixture was stirred at 75 °C for 4 hours. The mixture was then concentrated under reduced pressure. The pH of the mixture was adjusted to 3-4 with 1 M HCl. The resulting slurry was filtered, and the filter cake was washed with 20 mL of ice water. The title compound (350 mg, 70.1%) was obtained as a yellow solid. ES / MS m / z = 340 (M+H).

[0056] The compounds listed in Table 4 were prepared by methods essentially similar to those found in Preparation 13. [Table 4]

[0057] Preparation 15 3-Amino-1-(4-methoxybenzyl)-5-(pyridin-4-yl)-1H-pyrazole-4-carboxylic acid [ka] To a mixture of tert-butyl 3-amino-1-(4-methoxybenzyl)-5-(pyridin-4-yl)-1H-pyrazole-4-carboxylate (27.0 g, 0.08 mmol) in DCM (100 mL) was added TFA (100 mL). The mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, followed by the addition of water (50 mL) and saturated NaHCO3 (150 mL). The resulting precipitate was filtered and dried under reduced pressure to give the title compound (12 g, 52%) as a white solid. ES / MS m / z = 325 (M+H).

[0058] Preparation 16 3-Amino-1-(4-methoxybenzyl)-5-(5-methylpyridazin-4-yl)-1H-pyrazole-4-carboxamide [ka] A mixture of 3-amino-1-(4-methoxybenzyl)-5-(5-methylpyridazin-4-yl)-1H-pyrazole-4-carboxylic acid (350 mg, 1.03 mmol), ammonium chloride (1.09 g, 20.6 mmol), HATU (783 mg, 2.06 mmol), and DIPEA (399 mg, 3.09 mmol) in DMF (5 mL) was stirred at ambient temperature for 4 hours. Water (30 mL) was added to the reaction mixture, which was then extracted with DCM (30 mL × 5). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the title compound (400 mg, crude) as a brown oil. ES / MS m / z = 339 (M+H).

[0059] The compounds listed in Table 5 were prepared by methods essentially similar to those found in Preparation 16. [Table 5]

[0060] Preparation 19 3-Amino-1-(4-methoxybenzyl)-N-methyl-5-(pyridazin-4-yl)-1H-pyrazole-4-carboxamide [ka] To a solution of 3-amino-1-(4-methoxybenzyl)-5-(pyridazin-4-yl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.5 mmol), HATU (262 mg, 0.7 mmol) in DMF (3 mL) was added methanamine hydrochloride (46 mg, 0.7 mmol) and DIPEA (178 mg, 1.4 mmol). The reaction mixture was stirred at ambient temperature for 1.5 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated, and the crude product was purified by silica gel flash chromatography (eluting with 0-80% EtOAc / petroleum ether) to give the title compound (130 mg, 83.3%) as a green solid. ES / MS m / z = 339.7 (M+H).

[0061] Preparation 20 Ethyl 3-amino-5-(3-((diphenylmethylene)amino)pyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate [ka] To a mixture of ethyl 3-amino-5-(3-bromopyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (1.5 g, 3.5 mmol) in DMF (10 mL) was added CsCO (3.4 g, 10.5 mmol), diphenylmethanimine (1.9 g, 10.5 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (202 mg, 0.35 mmol), and Pd(dba) (320 mg, 0.35 mmol). The mixture was heated in a microwave oven for 8 hours at 110 °C. Water (50 mL) was then added to the mixture, followed by extraction with EtOAc (100 mL × 2). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with 20:1 petroleum ether:EtOAc) to give the title compound (500 mg, 27%) as a yellow solid. ES / MS m / z = 532 (M+H).

[0062] Preparation 21 Ethyl 3-amino-5-(3-aminopyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate [ka] TFA (1 mL) was added to a mixture of ethyl 3-amino-5-(3-((diphenylmethylene)amino)pyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (500 mg, 0.94 mmol) in DCM (4 mL) and stirred at ambient temperature for 1 h. The reaction mixture was concentrated under reduced pressure. Water (5 mL) and saturated NaHCO3 (20 mL) were added to the residue, and the resulting precipitate was filtered and dried under reduced pressure to give the title compound (200 mg, 58%) as a white solid. ES / MS m / z = 368 (M+H).

[0063] Preparation 22 3-Amino-1-(4-methoxybenzyl)-1,5-dihydro-4H-pyrazolo[4,3-c][1,7]naphthyridin-4-one [ka] EtONa (110 mg, 1.62 mmol) was added to a mixture of ethyl 3-amino-5-(3-aminopyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (200 mg, 0.54 mmol) in EtOH (10 mL) and stirred at 85 °C for 4 hours. Water (50 mL) was added to the reaction mixture, which was then extracted with EtOAc (100 mL × 2). The combined organic layers were dried and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography (eluted with 50% petroleum ether / EtOAc) to give the title compound (140 mg, 80%) as a yellow solid. ES / MS m / z = 322 (M+H).

[0064] Preparation 23 5-Amino-3-bromo-1H-pyrazole-4-carbonitrile [ka] A mixture of 5-amino-1H-pyrazole-4-carbonitrile (6 g, 55.6 mmol) and NBS (11 g, 61.1 mmol) in DMF (50 mL) was stirred at ambient temperature overnight. Water (200 mL) was added to the reaction mixture, which was then extracted with EtOAc (50 mL × 3). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography (eluted with 2:3 petroleum ether:EtOAc) to give the title compound (4.7 g, 45.5%) as a yellow solid. ES / MS m / z = 187 (M+H).

[0065] Preparation 24 5-Amino-3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile [ka] To a mixture of 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (4.7 g, 25.2 mmol) in DMF (40 mL) was added NaH (60% dissolved in mineral oil, 1.1 g, 27.8 mmol) at 0 °C, followed by stirring at 0 °C for 30 min. SEM-Cl (5 g, 30.3 mmol) was added at 0 °C, followed by stirring for 2 h while warming to ambient temperature. Water (200 mL) was added to the reaction mixture, followed by extraction with EtOAc (50 mL × 3). The combined organic layers were dried over Na SO and concentrated under reduced pressure to give the title compound (6.6 g, 83.3%) as a yellow solid. ES / MS m / z = 317 (M+H).

[0066] Preparation 25 5-Amino-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile [ka] A mixture of 5-amino-3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile (6.6 g, 20.9 mmol), 4-pyridylboronic acid (5.1 g, 41.8 mmol), K2CO3 (8.7 g, 62.7 mmol), and PdCl2.dppf (292 mg, 0.4 mmol) in 1,4-dioxane / water (100 mL / 20 mL) was stirred at 100 °C under N2 overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (eluting with 2:3 petroleum ether:EtOAc) to give the title compound (5 g, 76%) as a yellow solid. ES / MS m / z = 316 (M+H).

[0067] Preparation 26 5-Amino-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide [ka] A mixture of 5-amino-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile (4.5 g, 14.3 mmol) and KOH (2.7 g, 71.4 mmol) in EtOH / HO (50 mL / 10 mL) was stirred at 100 °C overnight. The reaction mixture was concentrated under reduced pressure, water was added, and the resulting solid was filtered and dried under reduced pressure to give the title compound (3.2 g, 67%) as a yellow solid. ES / MS m / z = 334 (M+H).

[0068] Preparation 27 3-(Pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] A mixture of 5-amino-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (2 g, 6 mmol) and formaldehyde (180 mg, 12 mmol) in toluene (20 mL) was stirred at 130° C. overnight. The reaction mixture was concentrated under reduced pressure to give the title compound (2.1 g, 99+%) as an off-white solid. ES / MS m / z = 344 (M+H).

[0069] Preparation 28 3-(Pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] To a mixture of 3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (2.1 g, 6 mmol) in EtOH (20 mL) was added NaBH (1.14 g, 30 mmol) and stirred at ambient temperature for 0.5 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 13% MeOH / DCM) to give the title compound (700 mg, 34%) as an off-white solid. ES / MS m / z = 346 (M+H).

[0070] Preparation 29 3-Amino-1-(4-methoxybenzyl)-N-methyl-5-(pyridin-4-yl)-1H-pyrazole-4-carboxamide [ka] A mixture of 3-amino-1-[(4-methoxyphenyl)methyl]-5-(4-pyridyl)pyrazole-4-carboxylic acid (1.2 g, 3.7 mmol), methylamine hydrochloride (726 mg, 11 mmol), HATU (1.7 g, 4.4 mmol), and DIPEA (1.4 g, 11 mmol) in DMA (10 mL) was stirred at ambient temperature for 6 hours. Water (50 mL) was added to the reaction mixture, which was then extracted with EtOAc (100 mL x 2). The combined organic layers were dried and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (eluted with 10% MeOH / DCM) to give the title compound (250 mg, 20%) as a yellow solid. ES / MS m / z = 338 (M+H).

[0071] Preparation 30 3-(3-(4-chlorophenyl)propanamido)-1-(4-methoxybenzyl)-N-methyl-5-(pyridin-4-yl)-1H-pyrazole-4-carboxamide [ka] A mixture of 3-amino-1-(4-methoxybenzyl)-N-methyl-5-(pyridin-4-yl)-1H-pyrazole-4-carboxamide (250 mg, 0.7 mmol), 3-(4-chlorophenyl)propanoic acid (205 mg, 1.1 mmol), T3P (700 mg, 2.2 mmol), and DIPEA (193 mg, 1.5 mmol) in DMA (6 mL) was stirred at ambient temperature for 3 hours. Water (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (40 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (eluted with 2:1 petroleum ether:EtOAc) to give the title compound (240 mg, 65%) as a white solid. ES / MS m / z = 504 (M+H). [Example]

[0072] Example 1 3-(6-chloropyridin-3-yl)-N-(4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridin-3-yl)propanamide [ka] Step 1: A mixture of 3-amino-1-(4-methoxybenzyl)-1,5-dihydro-4H-pyrazolo[4,3-c][1,7]naphthyridin-4-one (1.6 g, 5.0 mmol), 3-(6-chloropyridin-3-yl)propanoic acid (3.7 g, 20 mmol), T3P (6.4 g, 20 mmol), and DIPEA (2.6 g, 20 mmol) in DMA (20 mL) was stirred at 85° C. for 16 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (100 mL × 2). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 3-(6-chloropyridin-2-yl)-N-(5-(3-(6-chloropyridin-2-yl)propanoyl)-1-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c][1,7]naphthyridin-3-yl)propanamide (1.5 g, 45%) as a yellow solid. ES / MS m / z = 656 (M+H).

[0073] Step 2: A mixture of 3-(6-chloropyridin-2-yl)-N-(5-(3-(6-chloropyridin-2-yl)propanoyl)-1-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c][1,7]naphthyridin-3-yl)propanamide (1.5 g, 2.3 mmol) and KCO (345 mg, 2.5 mmol) in MeOH (20 mL) was stirred at 60° C. for 2 hours. To the reaction mixture was added water (40 mL) and EtOAc (80 mL). The resulting solid was filtered, and the filter cake was dried under reduced pressure to give 3-(6-chloropyridin-2-yl)-N-(1-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c][1,7]naphthyridin-3-yl)propanamide (1.0 g, 91%) as a yellow solid. ES / MS m / z = 489 (M+H).

[0074] Step 3: TFA (10 mL) was added to a mixture of 3-(6-chloropyridin-2-yl)-N-(1-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c][1,7]naphthyridin-3-yl)propanamide (1.0 g, 2.0 mmol) in DCM (10 mL), and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. To the crude product, water (2 mL) and saturated aqueous NaHCO3 (8 mL) were added. The resulting precipitate was filtered and dried under reduced pressure to give the title compound (668 mg, 88%) as a white solid. ES / MS m / z = 369 (M+H).

[0075] The compounds listed in Table 6 were prepared by methods essentially similar to those found in Example 1. [Table 6]

[0076] Example 7 5-(3-(3,4-dichlorophenyl)propanamido)-3-(pyridin-4-yl)-1H-pyrazole-4-carboxamide [ka] Step 1: A mixture of 3-amino-1-(4-methoxybenzyl)-5-(pyridin-4-yl)-1H-pyrazole-4-carboxamide (200 mg, 0.6 mmol), 3-(3,4-dichlorophenyl)propanoic acid (263 mg, 1.2 mmol), HATU (456 mg, 1.2 mmol), and DIPEA (232 mg, 1.8 mmol) in DMA (4 mL) was stirred at 65 °C for 3 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (30 mL × 2). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 3-(3-(3,4-dichlorophenyl)propanamido)-1-(4-methoxybenzyl)-5-(pyridin-4-yl)-1H-pyrazole-4-carboxamide (200 mg, 62%) as a yellow solid. ES / MS m / z = 524 (M+H).

[0077] Step 2: To a mixture of 3-(3-(3,4-dichlorophenyl)propanamido)-1-(4-methoxybenzyl)-5-(pyridin-4-yl)-1H-pyrazole-4-carboxamide (200 mg, 0.38 mmol) in DCM (3 mL) was added TFA (3 mL) and the reaction was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added water (2 mL) and saturated aqueous NaHCO3 (10 mL). The resulting precipitate was filtered and dried under reduced pressure to give the title compound (137 mg, 88%) as a white solid. ES / MS m / z = 404 (M+H).

[0078] The compounds listed in Table 7 were prepared by methods essentially similar to those found in Example 7. [Table 7] [Table 8] [Table 9]

[0079] Example 22 5-(3-(6-fluoropyridin-3-yl)propanamido)-3-(pyridin-4-yl)-1H-pyrazole-4-carboxamide [ka] Step 1: A mixture of 3-amino-1-(4-methoxybenzyl)-5-(pyridin-4-yl)-1H-pyrazole-4-carboxylic acid (4.0 g, 12.3 mmol), (2,4-dimethoxyphenyl)methanamine (3.4 g, 18.5 mmol), HATU (5.6 g, 14.8 mmol), and DIPEA (3.2 g, 24.6 mmol) in DMF (50 mL) was stirred at ambient temperature for 3 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (100 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with 10% MeOH / DCM) to give 3-amino-N-(2,4-dimethoxybenzyl)-1-(4-methoxybenzyl)-5-(pyridin-4-yl)-1H-pyrazole-4-carboxamide (2.0 g, 35%) as a yellow solid. ES / MS m / z = 474 (M+H).

[0080] Step 2: A mixture of 3-amino-N-(2,4-dimethoxybenzyl)-1-(4-methoxybenzyl)-5-(pyridin-4-yl)-1H-pyrazole-4-carboxamide (100 mg, 0.2 mmol), 3-(6-fluoropyridin-3-yl)propanoic acid (68 mg, 0.4 mmol), T3P (382 mg, 0.6 mmol), and DIPEA (52 mg, 0.4 mmol) in DMA (3 mL) was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography (eluting with 5% MeOH / DCM) to give N-(2,4-dimethoxybenzyl)-3-(3-(6-fluoropyridin-2-yl)propanamido)-1-(4-methoxybenzyl)-5-(pyridin-4-yl)-1H-pyrazole-4-carboxamide (100 mg, 76%) as a white solid. ES / MS m / z = 625 (M+H).

[0081] Step 3: To a mixture of N-(2,4-dimethoxybenzyl)-3-(3-(6-fluoropyridin-2-yl)propanamido)-1-(4-methoxybenzyl)-5-(pyridin-4-yl)-1H-pyrazole-4-carboxamide (100 mg, 0.15 mmol) in DCM (2 mL) was added TFA (1 mL) and TfOH (0.2 mL). The mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. To the residue, water (10 mL) and saturated aqueous NaHCO solution (50 mL) were added, and the mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (water:MeCN = 2:3) to give the title compound (11 mg, 19%) as a white solid. ES / MS m / z = 355 (M+H).

[0082] The compounds listed in Table 8 were prepared by methods essentially similar to those found in Example 22. [Table 10]

[0083] Example 24 3-(3-(4-chlorophenyl)propanamido)-N-methyl-5-(pyridin-4-yl)-1H-pyrazole-4-carboxamide [ka] To a mixture of 3-(3-(4-chlorophenyl)propanamido)-1-(4-methoxybenzyl)-N-methyl-5-(pyridin-4-yl)-1H-pyrazole-4-carboxamide (240 mg, 0.5 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. To the resulting residue, water (4 mL) and saturated aqueous NaHCO3 (16 mL) were added and extracted with EtOAc (40 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 5:1 DCM:MeOH) to give the title compound (80 mg, 44%) as a white solid. ES / MS m / z = 384 (M+H).

[0084] Example 25 7-(3-(4-chlorophenyl)propanoyl)-3-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Step 1: A mixture of 3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (150 mg, 0.4 mmol), 3-(4-chlorophenyl)propanoic acid (93 mg, 0.5 mmol), T3P (226 mg, 0.7 mmol), and DIPEA (0.2 mL) in DMA (5 mL) was stirred at 100 °C overnight. Saturated aqueous NaHCO3 solution (30 mL) was added to the mixture, which was then extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with 3% MeOH / DCM) to give 7-(3-(4-chlorophenyl)propanoyl)-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (140 mg, 63%) as a yellow solid. ES / MS m / z = 512 (M+H).

[0085] Step 2: A mixture of 7-(3-(4-chlorophenyl)propanoyl)-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (140 mg, 0.27 mmol), TFA (1 mL), and DCM (5 mL) was stirred at ambient temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, MeCN / 10 mMol NH4HCO3; 22-52% (9 min), retention time = 10.8 min) to afford the title compound (4.4 mg, 4.2%) as a white solid. ES / MS m / z = 382 (M+H).

[0086] The examples listed in Table 9 were prepared essentially as described for Example 25 using the appropriate starting materials and reagents. [Table 11]

[0087] ARM-SAM-TIR SARM1 IC 50 Assay This section describes an assay for ARM-SAM-TIR NADase activity and its use to measure the efficacy of compounds of the invention in blocking SARM1-mediated NAD+ cleavage. The assay was optimized to characterize the efficacy of compounds of the invention in inhibiting SARM1 activity, and the IC of each compound was calculated. 50 Values ​​were calculated. This assay utilized full-length SARM1, encompassing the ARM, SAM, and TIR domains. As shown herein, expression of this fragment, lacking the autoinhibitory N-terminal domain, generates a constitutively active NAD+-cleaving enzyme.

[0088] Preparation of ARM-SAM-TIR lysate (STL) NRK1-HEK293T cells were cultured at 150 cm 2 20 × 10 cells per plate were seeded onto plates. The next day, the cells were transfected with 15 μg of ARM-SAM-TIR expression plasmid (SEQ ID NO: 1 (disclosed in WO2019 / 236879, pages 77-81, paragraph

[0310] )).

[0089] At the time of transfection, 1 mM NR was added to the medium to minimize toxicity due to overexpression of ARM-SAM-TIR. Forty-eight hours after transfection, cells were harvested, pelleted by centrifugation at 1,000 rpm (Sorvall ST 16R centrifuge, Thermo Fisher Scientific), and washed once with ice-cold PBS (0.01 M phosphate-buffered saline, NaCl 0.138 M; KCl 0.0027 M; pH 7.4). Protease inhibitors (Complete TMCells were resuspended in PBS containing a protease inhibitor cocktail (Roche product number 11873580001), and cell lysates were prepared by sonication (Branson Sonifer 450, power = 3, 20 strokes). The lysates were centrifuged (12,000 × g, 10 min, 4°C) to remove cell debris, and the supernatant (containing ARM-SAM-TIR protein) was stored at -80°C for later use in an in vitro ARM-SAM-TIR NADase assay (see below). Protein concentrations were determined by the bicinchoninic acid (BCA) method and used to normalize lysate concentrations.

[0090] ARM-SAM-TIR IC of compounds of formula I 50 Assay Enzyme assays were performed in 384-well polypropylene plates containing 20 μL of Dulbecco's PBS buffer. ARM-SAM-TIR lysate (5 μg / mL final concentration) was preincubated with each compound (1% DMSO final assay concentration) for 2 hours at room temperature. The reaction was initiated by adding NAD+ as substrate (5 μM final assay concentration). After 2 hours of incubation at ambient temperature, the reaction was stopped with 40 μL of stop solution (7.5% trichloroacetic acid / acetonitrile). NAD+ and ADPR concentrations were analyzed using a RapidFire high-throughput mass spectrometry system (Agilent Technologies, Santa Clara, CA) on an API4000 triple quadrupole mass spectrometer (AB Sciex, Framingham, MA).

[0091] The results are shown in Table 10 below. Compounds with an activity designated "A" have an IC of less than 50 nM 50 compounds with activity designated "B" have an IC of 51-100 nM 50 compounds having an activity designated "C" have an IC of 101 to 500 nM 50 compounds having an activity designated "D" have an IC of 501-1000 nM50 compounds having an activity designated "E" have an IC of greater than 1000 nM 50 was provided. [Table 12] The results shown in Table 10 above demonstrate that the compounds of the present invention have hSARM1 inhibitory activity.

Claims

1. A compound of the formula: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof [In the formula, X is selected from CH and N; R １ , R ２ , R ３ and R ４ are each independently H and C １～４ alkyl, where R １ and R ２ may optionally form a 6-membered heterocycle together with the atoms to which they are attached, where R ２ and R ３ may optionally form a 6- to 7-membered heterocycle together with the atoms to which they are attached, where R ３ and R ４ may optionally, together with the atoms to which they are attached, form a 5- to 6-membered heterocycle; n is 0, 1 or 2; R ５ is 1 to 3 R ｍ and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R ｍ 5-6 membered heteroaryl, optionally substituted with R ｍ is halogen, cyano, C １～４ Alkyl, trihalomethyl and —OC １～４ alkyl].

2. R １ , R ２ , R ３ and R ４ are each independently H and C １～４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

3. R １ , R ２ , R ３ and R ４ 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein each is independently selected from H, methyl, ethyl, n-propyl, and isopropyl.

4. The following formula: 【Chemistry 2】 2. The compound of claim 1, wherein:

5. R ３ and R ４ 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein each is independently selected from H, methyl, ethyl, n-propyl, and isopropyl.

6. The following formula: 【Transformation 3】 2. The compound of claim 1, wherein: [wherein p is 1 or 2].

7. R １ and R ４ 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein each is independently selected from H, methyl, ethyl, n-propyl, and isopropyl.

8. The following formula: 【Chemistry 4】 2. The compound of claim 1, wherein: [wherein q is 0 or 1].

9. R １ and R ２ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein each is independently selected from H, methyl, ethyl, n-propyl, and isopropyl.

10. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is CH.

11. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N.

12. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1.

13. 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein p is 1.

14. 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein q is 0.

15. R ５ But 1 to 3 R ｍ 2. The compound of claim 1, wherein R is phenyl optionally substituted with R, or a pharmaceutically acceptable salt thereof.

16. R ５ contains 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R ｍ 2. The compound of claim 1, wherein R is a 5- to 6-membered heteroaryl optionally substituted by R , or a pharmaceutically acceptable salt thereof.

17. R ｍ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each is independently selected from F, Cl, Br, I, cyano, and trifluoromethyl.

18. R ５ but has the following structure: 【Transformation 5】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

19. 10. The compound of claim 1 selected from the following formulas, or a pharmaceutically acceptable salt thereof: 【Transformation 6】 【Transformation 7】 【Transformation 8】

20. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

21. 21. The pharmaceutical composition of claim 20 for treating or preventing a disease associated with axonal degeneration in a patient.

22. 21. The pharmaceutical composition of claim 20 for treating or preventing a disease associated with SARM1 activation in a patient.

23. 21. The pharmaceutical composition of claim 20 for treating or preventing a disease selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy and chemotherapy-induced peripheral neuropathy in a patient.