Pyrimidocyclic compounds and their use in preparing drugs for treating pain and spinal cord injury

Abstract

A compound represented by formula (I), its stereoisomers, tautomers or pharmaceutically acceptable salts, and its use in preparing a medicament for treating pain and spinal cord injury. #imgabs0#

Description

Technical Field

[0001] The present application belongs to the field of chemical medicine, and specifically relates to a pyrimidinyl ring compound and its use in preparing drugs for treating pain and spinal cord injury. Background Art

[0002] Pain is a common form of physical pain and suffering and one of the most common reasons patients report it to their doctors. It can be distinguished by its form (nociceptive or neuropathic), duration (chronic or acute), and degree (mild, moderate, or severe). Typically, nociceptive pain is acute and caused by injury, such as burns, sprains, burns, fractures, or inflammation (inflammatory pain, including osteoarthritis and rheumatoid arthritis). On the other hand, the International Association for the Study of Pain defines neuropathic pain as a type of chronic pain caused by a lesion or dysfunction of the nervous system. Typically, neuropathic pain is caused by diabetic neuropathy, HIV infection, and postherpetic neuralgia. Other conditions associated with neuropathic pain include complex regional pain syndrome, trigeminal neuralgia, low back pain, sciatica, phantom limb pain, impact pain, fibromyalgia, and other conditions that cause chronic pain (see Jensen, European Journal of Pain, 2002).

[0003] K + -Cl - The cotransporter KCC2 is responsible for maintaining low Cl in central nervous system (CNS) neurons. - concentration, which is required for postsynaptic inhibition through GABAA and glycine receptors. Although no central nervous system diseases are associated with KCC2 mutations, loss of this transporter activity has emerged as a key mechanism in several neurological and psychiatric disorders, including epilepsy, motor seizures, stress, anxiety, schizophrenia, morphine-induced hyperalgesia, and chronic pain. Studies have shown that enhanced KCC2 activity may be involved in impaired Cl - It is a favorable therapeutic strategy to restore inhibition and normal function under pathological conditions of transport (Gagnon, Martin. et al. Nature Medicine (2013), 19(11), 1524-1528).

[0004] Existing studies have also shown that KCC2 agonists can restore stepping ability in mice with spinal cord injury by selectively expressing KCC2 in inhibitory interneurons between and around interdigitated spinal cord lesions. Mechanistically, these treatments transform injury-induced spinal cord circuit dysfunction into a functional state, promoting the transmission of brain-derived instructions to the lumbar spinal cord. Therefore, KCC2 agonists have the potential to become a therapeutic approach to promote functional recovery after spinal cord injury (Bo Chen, Yi Li. et al. Cell (2018), 174 (3), 521-535). Summary of the Invention

[0005] The present application discloses a pyrimidocyclic compound, which can be used as a potential KCC2 agonist and is used in the preparation of drugs for treating pain and spinal cord injury.

[0006] In one aspect, the present application provides a compound of formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:

[0007]

[0008] wherein Ring A is a cycloalkyl, heterocyclyl, aryl or heteroaryl group containing 0-4 heteroatoms, 5-14 ring atoms;

[0009] Ring B is a cycloalkyl, heterocyclyl, aryl or heteroaryl group containing 0-2 heteroatoms, 5-7 ring atoms;

[0010] X is C or N;

[0011] R1 is each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, amino, hydroxy, hydroxyalkyl, alkoxy, alkylacyl or sulfonyl;

[0012] R2 is each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, amino, hydroxy, hydroxyalkyl, alkoxy, alkylacyl or sulfonyl;

[0013] m, n, n' are selected from 0, 1, 2 or 3; and

[0014] Represents a single bond or a double bond.

[0015] In certain embodiments, Formula (I) is Formula (Ia):

[0016]

[0017] wherein Ring A is a heterocyclic group or heteroaryl group containing 1-4 heteroatoms or 5-14 ring atoms;

[0018] Ring B is a cycloalkyl, heterocyclyl, aryl or heteroaryl group containing 0-2 heteroatoms, 5-7 ring atoms;

[0019] X is C or N;

[0020] R1 is each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, amino, hydroxy, hydroxyalkyl, alkoxy, alkylacyl or sulfonyl;

[0021] R2 is each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, amino, hydroxy, hydroxyalkyl, alkoxy, alkylacyl or sulfonyl;

[0022] m, n are selected from 0, 1, 2 or 3; and

[0023] Represents a single bond or a double bond.

[0024] In certain embodiments, Formula (I) is Formula (Ib):

[0025]

[0026] wherein Ring A is a heterocyclic group or heteroaryl group containing 1-3 heteroatoms or 5-7 ring atoms;

[0027] Ring B is a cycloalkyl or heterocyclyl group containing 0-2 heteroatoms and 5-7 ring atoms;

[0028] R1 is each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, amino, hydroxy, hydroxyalkyl, alkoxy, alkylacyl or sulfonyl;

[0029] R2 is each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, amino, hydroxy, hydroxyalkyl, alkoxy, alkylacyl or sulfonyl; and m and n are selected from 0, 1, 2 or 3.

[0030] In certain embodiments, Formula (I) is Formula (Ic) or (Id):

[0031]

[0032]

[0033] Wherein, Ring B is a cycloalkyl or heterocyclic group containing 0-2 heteroatoms and 5-7 ring atoms;

[0034] R1 is each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, amino, hydroxy, hydroxyalkyl, alkoxy, alkylacyl or sulfonyl;

[0035] R2 is each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, amino, hydroxy, hydroxyalkyl, alkoxy, alkylacyl or sulfonyl; and

[0036] m and n are selected from 0, 1, 2 or 3.

[0037] In certain embodiments, the compound represented by formula (I) is selected from:

[0038]

[0039] In certain embodiments, the structure is:

[0040]

[0041] In certain embodiments, the structure is:

[0042]

[0043] In certain embodiments, the structure is:

[0044]

[0045] The H at any position in the aforementioned compounds may be deuterium.

[0046] On the other hand, the present application also provides a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound, or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, hydrate or isomer thereof; and a pharmaceutically acceptable carrier or excipient.

[0047] On the other hand, the present application also provides the use of the aforementioned compound, or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, hydrate or isomer thereof, in the preparation of a KCC2 agonist drug.

[0048] On the other hand, the present application also provides the use of the aforementioned compound, or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, hydrate or isomer thereof, in the preparation of a drug for treating spinal cord injury.

[0049] On the other hand, the present application also provides the use of the aforementioned compound, or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, hydrate or isomer thereof, in the preparation of analgesic drugs.

[0050] the term:

[0051] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0052] The term "isomer" includes enantiomeric, diastereomeric, and geometric (or conformational) isomeric forms of a given structure. For example, the present application includes R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers, and enantiomeric, diastereomeric, and geometric (or conformational) isomer mixtures.

[0053] The term "pharmaceutically acceptable salt" refers to, for example, acid addition salts and / or base salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts, such as hydrochlorides / chlorides. Suitable base salts are formed from bases that form non-toxic salts, such as calcium salts and sodium salts. Hemi-salts of acids and bases can also be formed, such as hemisulfate salts and hemicalcium salts.

[0054] The term "therapeutically effective amount" refers to an amount of a compound of the present invention that (i) treats a specific disease, condition, or disorder; (ii) alleviates, relieves, or eliminates one or more symptoms of a specific disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein.

[0055] The term "pharmaceutically acceptable carrier or excipient" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated therewith.

[0056] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples of lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.

[0057] The term "alkenyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond. In some embodiments, the alkenyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms. For example, the term "C2-6 The term "alkenyl" includes straight or branched unsaturated groups of 2 to 6 carbon atoms (having at least one carbon-carbon double bond), including but not limited to ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.

[0058] The term "alkynyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond. In some embodiments, the alkynyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 3 to 6 carbon atoms. For example, "C 2-6 "Alkynyl" includes straight or branched chain unsaturated groups (having at least one carbon-carbon triple bond) of 2 to 6 carbon atoms.

[0059] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

[0060] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring comprises 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms (e.g., 3, 4, 5, or 6 carbon atoms), and most preferably 5 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0061] The term " spiroalkyl " refers to a polycyclic group sharing a carbon atom (claiming spiral atom) between 5 to 20 yuan of monocycles, which can contain one or more double bonds, but each ring does not have a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between ring and ring, spiroalkyl is divided into single spiral alkyl, double spiral alkyl or multiple spiral alkyl, preferably single spiral alkyl and double spiral alkyl, more preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan of single spiral alkyl.

[0062] The term "fused cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but each ring does not have a completely conjugated π electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl group, preferably a bicyclic or tricyclic group, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl group.

[0063] The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. It may contain one or more double bonds, but each ring does not have a completely conjugated π-electron system. It is preferably 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic.

[0064] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen, or S(O)m (wherein m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; and most preferably, it contains 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, preferably tetrahydropyranyl, piperidinyl, and pyrrolidinyl. Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls, and bridged heterocyclyls.

[0065] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having one atom (called spiro atom) shared between 5 to 20 rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but each ring does not have a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between rings, spiroheterocyclyl is divided into single spiroheterocyclyl, double spiroheterocyclyl or multiple spiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl, more preferably 4 / 4 members, 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members of single spiroheterocyclyl.

[0066] The term "fused heterocyclic radical" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system sharing a pair of atoms adjacent to other rings in the system, one or more rings may contain one or more double bonds, but each ring does not have a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5 / 5 or 5 / 6 member bicyclic fused heterocyclic groups.

[0067] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, wherein any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but each ring does not have a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.

[0068] The heterocyclic group includes the heterocyclic group as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

[0069]

[0070] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.

[0071] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5- to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- or 6-membered, containing 1 to 2 heteroatoms; examples include imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, and pyridazinyl.

[0072] The heteroaryl group includes a heteroaryl group as described above fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0073]

[0074] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0075] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0076] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0077] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0078] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy is as defined above.

[0079] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0080] The term "cycloalkyloxy" refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined above.

[0081] The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

[0082] The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, wherein aryl and alkyl are as defined above.

[0083] The term "hydroxy" refers to an -OH group.

[0084] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0085] The term "amino" refers to -NH2.

[0086] The term "cyano" refers to -CN.

[0087] The term "nitro" refers to -NO2.

[0088] The term "carboxy" refers to -C(O)OH. BRIEF DESCRIPTION OF THE DRAWINGS

[0089] Figure 1 The graph shows the effect of the compound of Example 5 on mechanical allodynia in the hind paw of the SNI nerve injury model.

[0090] Figure 2 The graph shows the effect of the compound of Example 4 on mechanical allodynia in the hind paw of the SNI nerve injury model.

[0091] Figure 3 The graph shows the effect of the compound of Example 2 on mechanical allodynia in the hind paw of the SNI nerve injury model. DETAILED DESCRIPTION

[0092] Intermediate preparation

[0093] Preparation of Intermediate 1.1: 4-(Bromomethyl)-3,5-dichloropyridine

[0094]

[0095] Step 1: Preparation of (3,5-dichloropyridin-4-yl)methanol. 3,5-Dichloropyridine-4-carboxaldehyde (20.0 g, 113.63 mmol, 1.0 eq.) and sodium borohydride (6.44 g, 170.45 mmol, 1.5 eq.) were added to MeOH (200 mL) and reacted at 25°C for 12 hours. After completion of the reaction, the mixture was spin-dried and extracted with EA (200 mL) and water (200 mL). The organic phase was washed once with saturated sodium chloride, dried over magnesium sulfate, filtered, and sanded. EA:PE = 1:8 column chromatography was performed to obtain the title compound (15.1 g, yield 75.5%). MS (m / z) = 179 [M+H] + .

[0096] Step 2: Preparation of 4-(bromomethyl)-3,5-dichloropyridine. (3,5-Dichloropyridin-4-yl)methanol (5.0 g, 28.08 mmol, 1.0 eq.), triphenylphosphine (11.05 g, 42.13 mmol, 1.5 eq.), and carbon tetrabromide (13.96 g, 42.13 mmol, 1.5 eq.) were added to DCM (200 mL) and reacted at 20°C for 12 hours. After completion of the reaction, the mixture was spin-dried, sanded, and purified by column chromatography using EA:PE = 1:20 to obtain the title compound (5.6 g, 83.58% yield). MS (m / z) = 242 [M+H] + .

[0097] Example 1: 2-(((3,5-dichloropyridin-4-yl)methyl)thio)pyrrolo[2,1-f][1,2,4]triazine-4(3H)-one

[0098]

[0099] Step 1: Preparation of ethyl 1-amino-1H-pyrrole-2-carboxylate. At 0°C, NaH (60%, 3.73 g, 93.41 mmol, 1.3 eq.) was added to DMF (100 mL). 1H-pyrrole-2-carboxylate (10.0 g, 71.86 mmol, 1.0 eq.) and O-(2,4-dinitro-phenyl)-hydroxylamine (21.45 g, 107.79 mmol, 1.5 eq.) were added under nitrogen protection. The reaction was allowed to proceed at 25°C for 12 hours. After the reaction, the mixture was spin-dried and poured into water (200 mL). The mixture was extracted twice with EA:methyl tert-ether = 1:1 (100 mL). The organic phase was washed once with saturated sodium chloride, dried over magnesium sulfate, filtered, sanded, and purified by column chromatography with EA:PE = 1:8 to obtain the title compound (10 g, yield 85.4%). MS (m / z) = 155 [M+H] + .

[0100] Step 2: Preparation of ethyl 1-(3-benzoylthioureido)-1H-pyrrole-2-carboxylate. 1-Amino-1H-pyrrole-2-carboxylate (10.0 g, 64.86 mmol, 1.0 eq.) was added to THF (100 mL), followed by a solution of benzoyl isothiocyanate in THF (100 mL) (10.58 g, 64.86 mmol, 1.0 eq.). The mixture was allowed to react at 25°C for 12 hours. After completion of the reaction, the mixture was spin-dried and slurried with PE:methyl tert-ether (9:1). The mixture was filtered, the filter cake dried, and used directly in the next step. MS (m / z) = 318 [M+H] + .

[0101] Step 3: Preparation of 2-thioxo-2,3-dihydropyrrolo[2,1-f][1,2,4]triazine-4(1H)-one. 1-(3-Benzoylthioureido)-1H-pyrrole-2-carboxylic acid ethyl ester (18.86 g, 59.47 mmol, 1.0 eq.) was added to a 2N sodium hydroxide solution (118 mL, 4.0 eq.), heated to 85°C, and reacted for 1.5 hours. After cooling to room temperature, ethanol (35 mL) was added, the temperature was lowered to 0°C, and acetic acid (14.46 g, 240.85 mmol, 4.05 eq.) was added. The reaction was continued at 25°C for 12 hours. After the reaction, the precipitated solid was filtered and dried and used directly in the next step. MS (m / z) = 168 [M+H] + .

[0102] Step 4: Preparation of 2-(((3,5-dichloropyridin-4-yl)methyl)thio)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one. 2-Thio-2,3-dihydropyrrolo[2,1-f][1,2,4]triazin-4(1H)-one (660.9 mg, 3.95 mmol, 1.0 eq.), 4-(bromomethyl)-3,5-dichloropyridine (1.0 g, 4.15 mmol, 1.05 eq.), and triethylamine (599.5 mg, 5.92 mmol, 1.5 eq.) were added to ethanol (10 mL) and reacted at 25°C for 12 hours. After completion of the reaction, the precipitated solid was filtered, dissolved in THF, sanded, and purified by column chromatography using a THF:PE = 1:1 ratio to obtain the title compound (1.4 g, 100% yield). MS (m / z) = 328 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.21(s,1H),8.66(s,2H),7.55-7.56(m,1H),6.87-6.88(m,1H),6.51-6.52(m,1H),4.63(s,2H).

[0103] Example 2: 2-(3,5-dichloropyridin-4-ylmethylsulfanyl)-3,5,6,7-tetrahydrocyclopentanepyrimidin-4-one

[0104]

[0105] Step 1: Preparation of 2-thioxo-1,2,3,5,6,7-hexahydro-4H-cyclopenta[d]pyrimidin-4-one. Ethyl 2-oxocyclopentane-1-carboxylate (5.0 g, 32.42 mmol, 1.0 eq.), thiourea (3.70 g, 48.63 mmol, 1.5 eq.), and DBU (7.40 g, 48.63 mmol, 1.5 eq.) were added to acetonitrile (50 mL) and reacted at 95°C for 12 hours. After the reaction, the temperature was lowered to 0°C and stirred for 30 minutes. The precipitated solid was filtered and placed in 50 mL of water. The pH was adjusted to 1 with 2N hydrochloric acid, filtered, dried, and used directly in the next step. MS (m / z) = 242 [M+H] + .

[0106] Step 2: Preparation of 2-(3,5-dichloropyridin-4-ylmethylsulfanyl)-3,5,6,7-tetrahydrocyclopentylpyrimidin-4-one. 2-Thioxo-1,2,3,5,6,7-hexahydro-4H-cyclopentyl[d]pyrimidin-4-one (6.31 g, 35.72 mmol, 1.0 eq.), 4-(bromomethyl)-3,5-dichloropyridine (8.6 g, 37.50 mmol, 1.05 eq.), and triethylamine (5.42 g, 53.53 mmol, 1.5 eq.) were added to ethanol (100 mL) and reacted at 25°C for 12 hours. After completion of the reaction, the precipitated solid was filtered, slurried twice with 50 mL of ethanol, and dried to obtain the title compound (7.6 g, 64.95% yield). MS (m / z) = 329 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.69(s,1H),8.66(s,2H),4.67(s,2H),2.77-2.80(m,2H),2.59-2.61(d,2H),1.94-2.01(m,2H).

[0107] Example 3: 2-((3,5-dichloropyridin-4-yl)methyl)thio)-5,7-dihydrofuran[3,4-d]pyrimidin-4(3H)-one

[0108]

[0109] Step 1: Preparation of 2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol. 2,4-Dichloro-5,7-dihydrofuro[3,4-d]pyrimidine (2.0 g, 10.47 mmol, 1.0 eq.) and 3N sodium hydroxide solution (17 mL, 52.35 mmol, 5.0 eq.) were added to THF (20 mL) and reacted at 50°C for 12 hours. The pH was adjusted to 6 with 3N hydrochloric acid, and EA (20 mL) and water (20 mL) were added for extraction. The organic phase was dried, spin-dried, slurried with EA (5 mL), filtered, dried, and used directly in the next step. MS (m / z) = 174 [M+H] + .

[0110] Step 2: Preparation of 2-mercapto-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol. 2-Chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol (0.5 g, 2.89 mmol, 1.0 eq.) and sodium hydrosulfide (0.19 mg, 3.47 mmol, 1.2 eq.) were added to DMAc (5 mL) and reacted at 100°C for 12 hours. After the reaction, the system was poured into water, and the precipitated solid was filtered, dried, and used directly in the next step. MS (m / z) = 171 [M+H] + .

[0111] Step 3: Preparation of 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol. 2-Mercapto-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol (0.213 g, 1.25 mmol, 1.0 eq.), 4-(bromomethyl)-3,5-dichloropyridine (0.361 g, 1.501 mmol, 1.2 eq.), and triethylamine (0.379 g, 3.75 mmol, 3.0 eq.) were added to ethanol (10 mL) and reacted at 25°C for 12 hours. After completion of the reaction, the precipitated solid was filtered, slurried twice with ethanol (10 mL), and dried to obtain the title compound (396 mg, 95% yield). MS (m / z) = 331 [M+H] + . 1 H NMR (400MHz, DMSO) δ13.05(s,1H),8.67(s,2H),4.84-4.86(t,4H),4.68(s,2H).

[0112] Example 4: 2-((Pyrimidin-5-ylmethyl)thio)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one

[0113]

[0114] 2-Thioxo-1,2,3,5,6,7-hexahydro-4H-cyclopenta[d]pyrimidin-4-one (0.194 g, 1.15 mmol, 1.0 eq.), 5-chloromethylpyrimidine (0.2 g, 1.211 mmol, 1.05 eq.), and DIPEA (0.372 g, 2.88 mmol, 2.5 eq.) were added to ethanol (10 mL) and reacted at 80°C for 48 hours. After the reaction, the solid was spin-dried and slurried twice with methanol (5 mL) and dried to obtain the title compound (120 mg, 40% yield). MS (m / z) = 261 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.61 (s, 1H), 9.05 (s, 1H), 8.86 (s, 2H) 4.37 (s, 2H), 2.74-2.77 (m, 2H), 2.56-2.59 (m, 2H), 1.93-1.97 (m, 2H).

[0115] Example 5: 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-3,5,6,7-tetrahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one hydrochloride

[0116]

[0117] Step 1: Preparation of tert-butyl 4-oxo-2-thioxo-1,2,3,4,5,7-hexahydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate. 1-(tert-Butyl)-3-ethyl 2-oxopyrrolidine-1,3-dicarboxylate (20.00 g, 77.74 mmol, 1 eq.) and thiourea (8.88 g, 116.60 mmol, 1.5 eq.) were added to acetonitrile (300 mL) at room temperature. DBU (17.75 g, 116.60 mmol, 1.5 eq.) was added and heated to 80°C for 16 hours. The reaction mixture was evaporated to dryness of the acetonitrile, dissolved in water, and adjusted to pH 4-5 with 2N hydrochloric acid. A large amount of white solid precipitated, which was filtered, and the filter cake was washed with water until neutral and dried to obtain the title compound (17.20 g, 82.16% yield).

[0118] Step 2: Preparation of tert-butyl 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-4-oxo-3,4,5,7-tetrahydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate. tert-Butyl 4-oxo-2-thioxo-1,2,3,4,5,7-hexahydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (9.50 g, 35.27 mmol, 1 eq.) was dissolved in EtOH (100 mL). 4-(Bromomethyl)-3,5-dichloropyridine (12.75 g, 52.91 mmol, 1.5 eq.) and TEA (5.35 g, 52.91 mmol, 1.5 eq.) were added at room temperature. The mixture was reacted at room temperature for 12 hours. The precipitated solid in the reaction solution was directly filtered, and the filter cake was washed with ethanol (20 mL) and dried to obtain the title compound (11.35 g, yield 74.9%).

[0119] Step 3: Preparation of 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-3,5,6,7-tetrahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one hydrochloride. 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-4-oxo-3,4,5,7-tetrahydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (11.35 g, 26.44 mmol, 1 eq.) was dissolved in 1,4-dioxane (100 mL). A solution of HCl in dioxane (9.64 g, 264.37 mmol, 10 eq.) was added at room temperature and the mixture was reacted at room temperature for 8 hours. The precipitated solid in the reaction solution was directly filtered, and the filter cake was washed with dioxane (50 mL) and EA (50 mL). The filter cake was dried to obtain the title compound (7.90 g, yield 90.7%). MS (m / z) = 367 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ = 10.29 (brs, 2H), 8.67 (d, 2H), 4.68 (s, 2H), 4.34 (m, 2H), 4.26 (m, 2H).

[0120] Example 6: 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6-methyl-3,5,6,7-tetrahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one

[0121]

[0122] 2-(((3,5-Dichloropyridin-4-yl)methyl)thio)-3,5,6,7-tetrahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one hydrochloride (100 mg, 0.303 mmol, 1.0 eq.), paraformaldehyde (40 mg, 0.455 mmol, 1.5 eq.), and sodium borohydride (17 mg, 0.455 mmol, 1.5 eq.) were added to methanol (5 mL) and reacted at 70°C for 14 hours. After completion of the reaction, the mixture was spin-dried, added with water (10 mL), and filtered through a slurry. The filter cake was slurried with methanol (5 mL) and filtered, and the solid was dried to obtain the title compound (20 mg, 19.23% yield). MS (m / z) = 344 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.59 (s, 1H), 8.67 (s, 2H), 4.68 (s, 2H), 4.35 (s, 2H), 4.17 (s, 2H), 3.23-3.28 (m, 3H).

[0123] Example 7: 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-3,5,6,7,8,9-hexahydro-4H-pyrimidin[4,5-d]azepan-4-one hydrochloride

[0124]

[0125] The title compound was obtained by referring to the preparation method of Example 5. MS (m / z) = 393 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 9.64 (brs, 2H), 8.66 (s, 2H), 4.68 (s, 2H), 3.23 (t, 2H), 3.14 (m, 4H), 2.94 (t, 2H).

[0126] Example 8: 2-((Pyrimidin-5-ylmethyl)thio)-3,5,6,7,8,9-hexahydro-4H-pyrimidinyl[4,5-d]azepin-4-one hydrochloride

[0127]

[0128] The title compound was obtained by referring to the preparation method of Example 5. MS (m / z) = 326 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 9.64 (brs, 2H), 9.08 (s, 1H), 8.92 (s, 2H), 4.37 (s, 2H), 3.19 (t, 2H), 3.11 (m, 4H), 2.90 (t, 2H).

[0129] Example 9: 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-5,6,7,8-tetrahydroquinazolin-4(3H)-one

[0130]

[0131] The title compound was obtained by referring to the preparation method of Example 2. MS (m / z) = 343 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.64(s,1H),8.65(s,2H),4.67(s,2H),2.55(s,2H),2.30(s,2H),1.64-1.71(m,4H).

[0132] Example 10: 2-(((Tetrahydro-2H-pyran-4-yl)methyl)thio)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one

[0133]

[0134] The title compound was obtained by referring to the preparation method of Example 4. MS (m / z) = 267 [M+H] + . 1 H NMR(400MHz,DMSO)δ12.53(s,1H),3.81-3.85(m,2H),3.22-3.28(m,2H)3.08-3.10(d,2H),2.70-2.74( m, 2H), 2.55-2.59 (m, 2H), 1.90-1.98 (m, 2H), 1.82-1.83 (m, 1H), 1.63-1.66 (d, 2H), 1.19-1.29 (m, 2H).

[0135] Example 11: 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-7-(methylsulfonyl)-3,5,6,7,8,9-hexahydro-4H-pyrimidinyl[4,5-d]azepin-4-one

[0136]

[0137] Step 1: Preparation of 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-3,7-bis(methylsulfonyl)-3,5,6,7,8,9-hexahydro-4H-pyrimidin[4,5-d]azepan-4-one. 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-3,5,6,7,8,9-hexahydro-4H-pyrimidin[4,5-d]azepan-4-one hydrochloride (2.50 g, 7.00 mmol, 1 eq.) was added to DCM (50 mL), and TEA (4.25 g, 41.99 mmol, 6.0 eq.) was added at room temperature. After the raw materials were dissolved, they were cooled to 0-5°C in an ice-water bath, and chloro(methyl)dimethylene-λ was added dropwise. 6 -sulfoxide in dichloromethane (3.21 g, 27.99 mmol, 4.0 eq.) was added and the reaction was continued for 4 hours. The reaction solution was quenched with water (20 mL), separated, and the organic phase was evaporated to dryness to obtain a crude product which was directly used in the next reaction.

[0138] Step 2: Preparation of 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-7-(methylsulfonyl)-3,5,6,7,8,9-hexahydro-4H-pyrimidinyl[4,5-d]azepin-4-one. 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-3,7-bis(methylsulfonyl)-3,5,6,7,8,9-hexahydro-4H-pyrimidinyl[4,5-d]azepin-4-one (3.59 g, 6.99 mmol, 1 eq.) was added to MeOH (35 mL), and K2CO3 (1.93 g, 13.98 mmol, 2.0 eq.) was added at room temperature. The reaction was allowed to proceed for 12 hours. The crude product was separated and purified on a 100-200 mesh silica gel column (eluent: DCM:MeOH = 30:1-10:1) to obtain the title compound (650.0 mg, yield: 21.35%). MS (m / z) = 436.35 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.60 (s, 2H), 4.47 (s, 2H), 3.27 (t, 2H), 3.17 (t, 2H), 2.84 (s, 3H), 2.72 (t, 2H), 2.66 (t, 2H) . .

[0139] Example 12: 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-7-methyl-3,5,6,7,8,9-hexahydro-4H-pyrimidinyl[4,5-d]azepin-4-one

[0140]

[0141] Step 1: Add 2-thioxo-1,2,3,5,6,7,8,9-octahydro-4H-pyrimidin[4,5-d]azepan-4-one (990.0 mg, 5.02 mmol, 1 eq.) to MeOH (15 mL). Add (226.04 mg, 7.53 mmol, 1.5 eq.) aqueous formaldehyde solution at room temperature. After stirring for 1-2 hours, sodium triacetoxyborohydride (STAB) (2.13 g, 10.04 mmol, 2.0 eq.) was added and allowed to react for 2 hours. The reaction mixture was quenched with water (10 mL), and the pH was adjusted to alkaline with solid sodium carbonate. The insoluble solid was filtered, and the filtrate was evaporated to dryness. The product was dissolved in ethanol, filtered to remove inorganic salts, and the filtrate was directly used in the next reaction.

[0142] Step 2: Preparation of 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-7-methyl-3,5,6,7,8,9-hexahydro-4H-pyrimidinyl[4,5-d]azepin-4-one. Refer to Example 2 to obtain the title compound. MS (m / z) = 372.28 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.66 (s, 2H), 4.68 (s, 2H), 2.84 ~ 2.87 (t, 2H), 2.67 ~ 2.70 (t, 2H), 2.53 ~ 2.55 (t, 2H), 2.43 ~ 2.46 (t, 2H), 2.30 (s, 3H).

[0143] Experimental Example 1: Detection of the analgesic effect of the test compound using a selective nerve injury model of the sciatic nerve branches in mice

[0144] The adult male C57BL / 6J mice used in the experiment were purchased from Shanghai Lingchang Biotechnology Co., Ltd. (8-week-old mice, weighing approximately 21-23g). The experimental animals were kept in an SPF-level (temperature of 21.0±2°C, humidity of 40-70%, 12 / 12 hours of light and dark alternation, 3-5 mice / cage) barrier environment. They were adapted to the breeding environment for 5-7 days before the experiment and were allowed to eat and drink freely. The relevant operational procedures involved in the execution of animal experiments were carried out in accordance with the guidelines of the International Laboratory Animal Care and Use Committee. The number of animals in each group of the tested compounds and solvent controls was 10. The drug was administered intraperitoneally at a dose of 100 mg / kg. The solvent used was a 20% HPCD solution containing 10% DMSO. All test compounds were prepared into 5 mg / mL stock solutions and stored at 4°C for use.

[0145] Positive control CLP290 construct:

[0146]

[0147] C57BL / 6J mice were intramuscularly injected with Zotai ( 50,20mg / kg), shave the left hind leg and buttocks hair after its complete anesthesia. Use alcohol and iodine tincture to disinfect the skin repeatedly, use scalpel to cut the skin of mouse hind leg, and use hemostatic forceps to bluntly separate subcutaneous tissue and muscle downwards, expose sciatic nerve branch. Under the premise of guaranteeing to keep sural nerve integrity, use 6-0 silk thread ligature peroneal nerve and tibial nerve, and cut about 1mm peroneal nerve and tibial nerve branch along the foot end from ligature. Clean the wound repeatedly with normal saline and cotton swab after finishing, and surgical suture muscle and skin, then the experimental mouse is placed in incubator and treats that it wakes up.

[0148] All behavioral tests conducted in the von Frey filament mechanical allodynia test were performed under double-blind guidelines. The 50% paw withdrawal threshold test and calculation method (Chaplan et al., 1994) was used to measure changes in paw withdrawal thresholds in SNI mice at various time points before and after drug administration using manual von Frey filaments (North Coast Medical Inc., USA) to evaluate the potential analgesic effects of test compounds on mechanical allodynia. Before testing, C57BL / 6J mice were placed in individual transparent Plexiglas containers (65*85*60 mm) on a wire mesh stand until they ceased overt exploratory activity and remained in a prostrate, motionless state (approximately 90-100 minutes). Tactile stimulation of varying intensities, starting with a force of 0.008g, was applied to the plantar surface of the mouse's hind paw through the gaps in the wire mesh. Sufficient force was applied to induce a noticeable flexion of the paw for 2-3 seconds. Each von Frey filament test was repeated three times with a minimum of 5 seconds between each stimulation. If the paw withdrawal positive response (rapid withdrawal of the paw, licking the hind paw, paw withdrawal or escape from the stimulus) is less than 6 times in 10 stimulations, a stronger ciliary force is used. On the contrary, if the paw withdrawal positive response is ≥ 6 times, a weaker ciliary force is used. The measurement is repeated until the reaction pattern can be used to calculate the 50% paw withdrawal threshold.

[0149] The changes in paw withdrawal thresholds at each time point were averaged and categorized. Data were grouped according to the experimental design and plotted and statistically analyzed using GraphPad Prism 8 software. Experimental data are expressed as mean ± standard deviation (SEM). Repeated measures two-way ANOVA followed by Bonferroni multiple comparison test was used. Results were considered statistically significant when P < 0.05.

[0150] Mechanical allodynia was assessed by manual von Frey test of the paw withdrawal threshold (PWT) of the hind paw of mice. The corresponding testing time points were before, 0.5 hour, 1 hour and 2 hours after administration of the test compound. Figure 1 、 Figure 2 and Figure 3 The results showed that compared with the vehicle control group, the compounds of Examples 2, 4 and 5 had a significant reversal effect on the mechanical paw withdrawal threshold at 0.5 hours, 1 hour and 2 hours after administration, and were superior to the positive compound CLP290 at 0.5 hours and 1 hour after administration.

Claims

1. A compound having the structure:

2. A compound having the structure:

3. A compound having the structure:

4. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier or excipient.

5. Use of the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the preparation of analgesics.

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