Use of aromatic fused ring compounds as trek-1 activators, pharmaceutical compositions comprising the same, analgesics

Abstract

The present application provides the following compound (I) or pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, metabolite thereof, and a pharmaceutical composition containing the compound of the present application, also provides the use of the compound of the present application as a TREK-1 potassium ion channel activator, and application in relieving and / or eliminating pain, and also provides the use of the compound of the present application in the preparation of an analgesic drug. The present application also provides a treatment method for diseases related to TREK-1 potassium ion channel.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and more particularly, to the use of aromatic fused ring compounds as TREK-1 activators, pharmaceutical compositions comprising the same, and analgesics. BACKGROUND

[0002] Pain causes patients to suffer long-term torment, and even malignant emotional reactions such as anxiety and depression. The current clinical drugs for treating pain mainly include opioid analgesics, non-steroidal anti-inflammatory drugs, and anticonvulsant and antidepressant drugs. Opioid drugs have good analgesic effect, but such drugs have toxic side effects such as addiction and respiratory depression, which cause great harm. Non-steroidal anti-inflammatory drugs have weak efficacy and strong side effects on the gastrointestinal tract and cardiovascular system. Pregabalin is a drug for treating neuropathic pain and shingles, but the therapeutic effect is not ideal, and only half of the patients get partial relief. Therefore, developing new drugs with new mechanisms is an urgent need for the treatment of pain.

[0003] TREK-1 potassium ion channel belongs to the family of two-pore potassium ion channels, mediates background potassium current, and participates in the regulation of neural excitability. After knocking out the TREK-1 corresponding gene, the pain sensitivity of rodents to thermal pain and mechanical pain is increased (Alloui et al. EMBO J. 2006, 25:2368-2376). TREK-1 plays an important role in the morphine analgesic pathway, and is not related to the addiction, respiratory depression and constipation of morphine (Devilliers et al. Nat Commun. 2013, 4:2941). Therefore, activating the TREK-1 channel is a new therapeutic strategy for treating neuropathic pain and inflammatory pain, and finding agonists of the TREK-1 channel is a new direction for developing new analgesic (reducing and / or eliminating pain) drugs. SUMMARY

[0004] In order to develop new analgesic drugs, the inventors have conducted in-depth research, and found that the aromatic fused ring derivative compounds as shown in the following formula (I) have TREK-1 potassium ion channel activation activity, which means analgesic use. Specifically, the present application provides the following technical solutions:

[0005] The present application provides the use of aromatic fused ring compounds as shown in formula (I) or pharmaceutically acceptable salts, esters, optical isomers, stereoisomers, metabolites thereof as potassium ion channel TREK-1 agonists,

[0006]

[0007] In formula (I),

[0008] wherein: L 1 , L 2 , L3 , L 4 and L 5 are each independently selected from N or CR 4 ,

[0009] L 6 is selected from the group consisting of -O-, -CO-, -C(=O)O-, -CONH-, -NHCO-, -NHCONH-, -NH-, -NR 8 -, -C(R 8 )2-, -S-, sulfinyl, sulfonyl, sulfinyloxy, sulfonyloxy, -aminosulfonylamino-, alkynylene, alkenylene, cycloalkylene, or any combination thereof, preferably O, S or NH; L 7 is selected from O or CH2;

[0010] L 8 is selected from the group consisting of a bond, saturated or partially unsaturated Ci-6alkylene, saturated or partially unsaturated Ci-6alkylene-O-, saturated or partially unsaturated Ci-6alkylene-NH-, saturated or partially unsaturated C3-10cycloalkylene, saturated or partially unsaturated C3-10cycloalkylene-O-, saturated or partially unsaturated C3-10cycloalkylene-NH-, substituted saturated or partially unsaturated Ci-6alkylene, substituted saturated or partially unsaturated C3-10cycloalkylene, -CO-, -C(=O)O-, -CONH-, -NHCO-, -NHCONH-, sulfinyl, sulfonyl, preferably Ci-6alkylene, further preferably methylene, ethylene, methylethylene, dimethylethylene, propylene; "substituted" herein means optionally substituted with 1-3 halogen, Ci-C3alkyl, Ci-C6cycloalkyl, Ci-C3alkoxy or Ci-C3haloalkyl;

[0011] L 9 is selected from the group consisting of a bond, saturated or partially unsaturated Ci-6alkylene, saturated or partially unsaturated C3-10cycloalkylene, preferably Ci-6alkylene, further preferably methylene, ethylene, methylethylene, dimethylethylene, propylene;

[0012] L 7 is selected from the group consisting of a bond, S, O or CH2;

[0013] Ar is selected from H, halogen, NH2, OH, SH, amino, substituted amino, amido, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, substituted or unsubstituted saturated or partially unsaturated 3-10 membered heterocyclyl, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted 5-14 membered heteroaryl; "substituted" in "substituted or unsubstituted" means optionally substituted with 1-3 halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C6 cycloalkyl, C1-C6 cycloalkoxy, or C1-C3 haloalkyl; cyano, nitro, hydroxyl, amino, phosphinyl, sulfonyl, sulfonamido;

[0014] R 1 is selected from H, -C(O)CH3, or -S(O)2CH3;

[0015] R 2 is selected from H, halogen, cyano, nitro, hydroxymethyl, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;

[0016] R 3 is selected from H or -OH;

[0017] R 4 is selected from H, halogen, or -NH2.

[0018] In a preferred embodiment of the present application, the compound has the structure of the following formula (II),

[0019]

[0020] In formula II, Ar, R 1 , R 2 , L 3 , L 4 , L 6 , L 8 , and L 9 have the same meanings as described above.

[0021] In a preferred embodiment of the present application, the compound has the structure of the following formula (III),

[0022]

[0023] In formula (III), Ar, R 2 , L 3 , L 4 , L 6 , L 8 , and L 9 have the same meanings as described above.

[0024] In preferred embodiments of the application, Ar is selected from the group consisting of

[0025]

[0026]

[0027]

[0028]

[0029] represents the position of attachment, and the expression of the ring structure with a dash through it indicates that the point of attachment can be at any bondable position on the ring structure.

[0030] In preferred embodiments of the application, L 8 and L 9 are each independently one of the following bivalent radicals,

[0031]

[0032] represents the position of attachment, and the expression of the ring structure with a dash through it indicates that the point of attachment can be at any bondable position on the ring structure.

[0033] In preferred embodiments of the application, wherein L 3 is N, and L 4 is CR 4 , or L 3 , L 4 are each CR 4 , or L 3 , L 4 are each N.

[0034] The application also provides the use of an aromatic fused ring compound of formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, metabolite thereof for reducing and / or eliminating pain,

[0035]

[0036] In formula (I),

[0037] wherein: L 1 , L 2 , L 3 , L 4 and L 5 are each independently selected from N or CR 4 ,

[0038] L 6 is selected from -O-, -CO-, -C(=O)O-, -CONH-, -NHCO-, -NHCONH-, -NH-, -NR8 -、-C(R 8 )2-, -S-, sulfinyl, sulfonyl, sulfinyloxy, sulfonyloxy, -aminosulfonylamino-, ynyl, alkenyl, cycloalkyl, Or any combination thereof, with divalent groups, preferably O, S or NH; L 7 Selected from O or CH2;

[0039] L 8 The components are selected from chemical bonds, saturated or partially unsaturated C1-6 alkylene groups, saturated or partially unsaturated C1-6 alkylene groups -O-, saturated or partially unsaturated C1-6 alkylene groups -NH-, saturated or partially unsaturated C3-10 cyclic hydrocarbon groups, saturated or partially unsaturated C3-10 cyclic hydrocarbon groups -O-, saturated or partially unsaturated C3-10 cyclic hydrocarbon groups -NH-, substituted saturated or partially unsaturated C1-6 alkylene groups, and substituted saturated or partially unsaturated... The C3-10 cyclic hydrocarbon group, -CO-, -C(=O)O-, -CONH-, -NHCO-, -NHCONH-, sulfinyl group, sulfonyl group, preferably C1-6 alkylene group, more preferably methylene, ethylene, methyl ethylene, dimethyl ethylene, propylene group; here "substitution" means optionally substituted with 1-3 halogens, C1-C3 alkyl, C1-C6 cycloalkyl, C1-C3 alkoxy or C1-C3 haloalkyl groups;

[0040] L 9 Selected from chemical bonds, saturated or partially unsaturated C1-6 alkylene groups, saturated or partially unsaturated C3-10 cyclic hydrocarbon groups, preferably C1-6 alkylene groups, and more preferably methylene, ethylene, methyl ethylene, dimethyl ethylene, or propylene;

[0041] L 7 Selected from chemical bonds, S, O, or CH2;

[0042] Ar is selected from H, halogen, NH2, OH, SH, amino, substituted amino, amide, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, substituted or unsubstituted saturated or partially unsaturated 3-10 heterocyclic groups, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted 5-14 heteroaryl; here, “substituted or unsubstituted” means optionally substituted by 1-3 halogens, C1-C3 alkyl, C1-C3 alkoxy, C1-C6 cycloalkyl, C1-C6 cycloalkoxy or C1-C3 haloalkyl, cyano, nitro, hydroxyl, amino, phosphono, sulfonyl, sulfonamide;

[0043] R 1 Selected from H, -C(O)CH3 or -S(O)2CH3;

[0044] R 2 selected from H, halogen, cyano, nitro, hydroxymethyl, hydroxy, amino, Ci-C6alkyl, Ci-C6alkoxy;

[0045] R 3 selected from H or -OH;

[0046] R 4 selected from H, halogen or -NH2.

[0047] In a preferred embodiment of the application, the compound has the structure of formula (II),

[0048]

[0049] In formula II, Ar, R 1 , R 2 , L 3 , L 4 , L 6 , L 8 and L 9 have the same meaning as described above. In a preferred embodiment of the application, the compound has the structure of formula (III),

[0050]

[0051] In formula (III), Ar, R 2 , L 3 , L 4 , L 6 , L 8 and L 9 have the same meaning as described above. In a preferred embodiment of the application, Ar is selected from the group consisting of,

[0052]

[0053]

[0054]

[0055] s

[0056] denotes the position of attachment.

[0057] In a preferred embodiment of the application, L 8 and L 9 are each independently one of the following bivalent radicals,

[0058]

[0059] Indicates the position of the connection, both ends of the connection direction can be connected.

[0060] In the preferred embodiment of the present application, wherein L 3 is N, and L 4 is CR 4 , or L 3 , L 4 are both CR 4 , or L 3 , L 4 are both N.

[0061] The analgesic effect of the compound of the present application is not limited to the realization of the agonism of potassium ion channel TREK-1. The preferred embodiment of the use of the compound of the present application for relieving and / or eliminating pain is the same as the preferred embodiment described above.

[0062] In the present application, the pain includes chronic pain, acute pain, cancer pain; wherein the chronic pain includes muscle and soft tissue pain, bone and joint pain, headache, visceral pain, pathological neuralgia.

[0063] The muscle and soft tissue pain includes one or more of myofascial pain, tendon sheath inflammation, periarthritis of shoulder, muscle strain pain, fibromyalgia, cold pain, burn pain, toothache; and / or the bone and joint pain is one or more of knee joint pain, ankle joint pain, wrist joint pain, elbow joint pain, shoulder joint pain, patellar joint pain, hip joint pain, femoral joint pain, ankylosing spondylitis, sacroiliitis, rheumatoid arthritis, rheumatoid arthritis, gouty arthritis, disc herniation, cervical pain, lumbar pain.

[0064] The headache includes one or more of primary headache, secondary headache, cranial neuralgia, central and primary facial pain and other headache; the primary headache includes one or more of migraine without aura, migraine with aura, hemiplegic migraine, chronic migraine, migraine complications, episodic syndromes associated with migraine, tension-type headache, trigeminal autonomic cephalalgia and other primary headaches; the secondary headache includes one or more of headache due to trauma to the head and / or neck, headache due to non-vascular intracranial disease, headache due to substance or substance withdrawal, headache due to vascular disorders of the head and / or neck, headache due to disorders of the internal environment, headache due to psychiatric illness, headache due to disorders of the head, neck, eye, ear, nose, sinuses, teeth, mouth, or other structures of the head and / or face; the cranial neuralgia, central and primary facial pain and other headache includes one or more of trigeminal neuralgia, glossopharyngeal neuralgia, intermediate neuralgia, occipital neuralgia, optic neuritis.

[0065] The visceral pain includes pain from organs of the viscera including the respiratory tract, the gastrointestinal tract, the pancreas, the urinary tract, the kidneys, the gall bladder, the urinary bladder, and the reproductive organs; and / or, the neuropathic pain includes one or more of post-herpetic neuralgia, diabetic neuropathy, painful HIV-related sensory neuropathy, causalgia, post-amputation pain, phantom pain, painful neuromas, traumatic neuromas, entrapment injuries, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug therapy-induced neuropathic pain, cancer chemotherapy-induced neuropathic pain, post-spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy, and trigeminal autonomic cephalalgia.

[0066] The acute pain includes one or more of acute traumatic pain, post-surgical pain, labor pain, visceral pain, pyresis, and post-surgical pain.

[0067] The cancer in the cancer pain includes one or more of adenocarcinoma in glandular tissue, blastoma in embryonic tissue of organs, carcinoma in epithelial tissue, leukemia in blood cell-forming tissue, lymphoma in lymphatic tissue, myeloma in bone marrow, sarcoma in connective or supportive tissue, adrenal cancer, AIDS-related lymphoma, bladder cancer, bone cancer, brain cancer, breast cancer, carcinoid tumor, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head cancer, neck cancer, hepatobiliary cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, Hodgkin's disease, non-Hodgkin's disease, nervous system tumor, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, urethral cancer, myeloid cancer, multiple myeloma, tumor metastasized to bone, tumor infiltrating nerves and hollow viscera, and tumor near neural structures.

[0068] The compound of the present application is used for analgesic purposes, the administration dose of the compound of formula (I) is 0.1-50 mg / kg.

[0069] The present application also provides an aromatic fused ring compound represented by formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, metabolite, prodrug, solvate, polymorph, tautomer, isotopologue, or combination thereof,

[0070]

[0071] In formula (I),

[0072] wherein: L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from N or CR 4 ,

[0073] L6 a divalent group selected from -0-, -CO-, -C(=0)0-, -CONH-, -NHCO-, -NHCONH-, -NH-, -NR 8 -, -C(R 8 )2-, -S-, sulfinyl, sulfonyl, sulfinyloxy, sulfonyloxy, -aminosulfonylamino-, alkynylene, alkenylene, cycloalkylene, or any combination thereof, preferably O, S or NH; L 7 is selected from O or CH2;

[0074] L 8 is selected from a bond, saturated or partially unsaturated Ci-6alkylene, saturated or partially unsaturated Ci-6alkylene-O-, saturated or partially unsaturated Ci-6alkylene-NH-, saturated or partially unsaturated C3-10cycloalkylene, saturated or partially unsaturated C3-10cycloalkylene-O-, saturated or partially unsaturated C3-10cycloalkylene-NH-, substituted saturated or partially unsaturated Ci-6alkylene, substituted saturated or partially unsaturated C3-10cycloalkylene, -CO-, -C(=0)0-, -CONH-, -NHCO-, -NHCONH-, sulfinyl, sulfonyl, preferably Ci-6alkylene, further preferably methylene, ethylene, methylethylene, dimethylethylene, propylene; "substituted" herein means optionally substituted with 1-3 halogen, Ci-C3alkyl, Ci-C6cycloalkyl, Ci-C3alkoxy, or Ci-C3haloalkyl;

[0075] L 9 is selected from a bond, saturated or partially unsaturated Ci-6alkylene, saturated or partially unsaturated C3-10cycloalkylene, preferably Ci-6alkylene, further preferably methylene, ethylene, methylethylene, dimethylethylene, propylene;

[0076] L 7 is selected from a bond, S, O or CH2;

[0077] Ar is selected from H, halogen, NH2, OH, SH, amino, substituted amino, amido, Ci-C6alkyl, Ci-C6cycloalkyl, Ci-C6haloalkyl, Ci-C6alkoxy, substituted or unsubstituted saturated or partially unsaturated 3-10 membered heterocyclyl, substituted or unsubstituted C6-10aryl, or substituted or unsubstituted 5-14 membered heteroaryl; "substituted" in "substituted or unsubstituted" herein means optionally substituted with 1-3 halogen, Ci-C3alkyl, Ci-C3alkoxy, Ci-C6cycloalkyl, Ci-C6cycloalkoxy, or Ci-C3haloalkyl; cyano, nitro, hydroxy, amino, phosphinyl, sulfonyl, sulfonamido.

[0078] R 1 is selected from H, -C(O)CH3, or -S(O)2CH3;

[0079] R 2 is selected from H, halogen, cyano, nitro, hydroxymethyl, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;

[0080] R 3 is selected from H or -OH; R 4 is selected from H, halogen, or -NH2.

[0081] In a preferred embodiment of the present application, the compound has the structure of the following formula (II),

[0082]

[0083] In formula II, Ar, R 1 , R 2 , L 3 , L 4 , L 6 , L 8 , and L 9 have the same meaning as described above.

[0084] In a preferred embodiment of the present application, the compound has the structure of the following formula (III),

[0085]

[0086] In formula (III), Ar, R 2 , L 3 , L 4 , L 6 , L 8 , and L 9 have the same meaning as described above.

[0087] In a preferred embodiment of the present application, Ar is selected from the following groups,

[0088]

[0089]

[0090]

[0091] The expression of the ring structure with a dash through it indicates that the connection site is at any bondable position on the ring structure.

[0092] In a preferred embodiment of the present application, L 8and L 9 each independently is one of the following bivalent groups,

[0093]

[0094] indicates the position of attachment, and both ends can be attached in either direction.

[0095] In a preferred embodiment of the present application, wherein L 3 is N, and L 4 is CR 4 , or L 3 , L 4 are both CR 4 , or L 3 , L 4 are both N.

[0096] As specific examples of the most preferred compounds of the present application, the following compounds can be mentioned, however, the scope of the present application is not limited to the following specific compounds.

[0097] The present application also provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the above-mentioned compound of the present application or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, metabolite thereof, and a pharmaceutically acceptable carrier, which is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.

[0098] In a preferred embodiment of the present application, the pharmaceutical composition further comprises other active ingredients for treating chronic pain.

[0099] In a preferred embodiment of the present application, the dosage form of the pharmaceutical composition is an oral dosage form or an injection, and the oral dosage form includes tablets, capsules, films, granules.

[0100] The present application provides a method for alleviating and / or eliminating pain, which comprises administering to a person in need of such treatment an effective amount of the compound of the present application or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, metabolite thereof, or the above-mentioned pharmaceutical composition of the present application.

[0101] The compound of the present application is structurally novel. The compound (I) of the present application can be used in the preparation of a medicament for diseases associated with potassium ion channel TREK-1, and can be used in the preparation of an analgesic medicament.

[0102] The elements of the present application are described in more detail below.

[0103] Definitions

[0104] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Reference herein to techniques used in the present application is intended to refer to techniques generally understood in the art, including variations or substitutions of techniques that would be apparent to one of ordinary skill in the art. Although the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate a better understanding of the present application.

[0105] The terms "comprising," "containing," "having," "including," or "involving," and any variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0106] As used herein, the term "alkylene" denotes a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, such as methylene, ethylene, propylene, or butylene.

[0107] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6, carbon atoms. For example, as used herein, the term "C1-6alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, or n-hexyl), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents such as halogen (when the group is referred to as "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C1-4alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl).

[0108] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon group which contains one double bond and has 2-6 carbon atoms ("C 2-6 The alkenyl group is, for example, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the application contain an alkenyl group, the compounds can exist in pure E (entgegen) form, pure Z (zusammen) form, or in any mixture thereof.

[0109] As used herein, the term "alkynyl" denotes a monovalent hydrocarbon group containing one or more triple bonds, which preferably has 2, 3, 4, 5, or 6 carbon atoms, such as ethynyl or propynyl.

[0110] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused, or bridged systems (such as bicyclo[l. l. l]pentyl, bicyclo[2.2. l]heptyl, bicyclo[3.2. l]octyl, or bicyclo[5.2.0]nonyl, decahydronaphthyl, and the like)), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C3-C8cycloalkyl" (or simply "C3-C8 cycloalkyl") refers to a cycloalkyl group having 3 to 8 carbon atoms. The term "C3-C6cycloalkyl" (or simply "C3-C6 cycloalkyl") refers to a cycloalkyl group having 3 to 6 carbon atoms. The term "C3-C4cycloalkyl" (or simply "C3-C4 cycloalkyl") refers to a cycloalkyl group having 3 to 4 carbon atoms. The term "C4-C6cycloalkyl" (or simply "C4-C6 cycloalkyl") refers to a cycloalkyl group having 4 to 6 carbon atoms. The term "C5-C6cycloalkyl" (or simply "C5-C6 cycloalkyl") refers to a cycloalkyl group having 5 to 6 carbon atoms. The term "C6-C8cycloalkyl" (or simply "C6-C8 cycloalkyl") refers to a cycloalkyl group having 6 to 8 carbon atoms. The term "C3-C4cycloalkyl" (or simply "C3-C4 cycloalkyl") refers to a cycloalkyl group having 3 to 4 carbon atoms. The term "C4-C6cycloalkyl" (or simply "C4-C6 cycloalkyl") refers to a cycloalkyl group having 4 to 6 carbon atoms. The term "C5-C6cycloalkyl" (or simply "C5-C6 cycloalkyl") refers to a cycloalkyl group having 5 to 6 carbon atoms. The term "C6-C8cycloalkyl" (or simply "C6-C8 cycloalkyl") refers to a cycloalkyl group having 6 to 8 carbon atoms. 3-6 As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused, or bridged systems (such as bicyclo[l. l. l]pentyl, bicyclo[2.2. l]heptyl, bicyclo[3.2. l]octyl, or bicyclo[5.2.0]nonyl, decahydronaphthyl, and the like)), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C3-C8cycloalkyl" (or simply "C3-C8 cycloalkyl") refers to a cycloalkyl group having 3 to 8 carbon atoms. The term "C3-C6cycloalkyl" (or simply "C3-C6 cycloalkyl") refers to a cycloalkyl group having 3 to 6 carbon atoms. The term "C3-C4cycloalkyl" (or simply "C3-C4 cycloalkyl") refers to a cycloalkyl group having 3 to 4 carbon atoms. The term "C4-C6cycloalkyl" (or simply "C4-C6 cycloalkyl") refers to a cycloalkyl group having 4 to 6 carbon atoms. The term "C5-C6cycloalkyl" (or simply "C5-C6 cycloalkyl") refers to a cycloalkyl group having 5 to 6 carbon atoms. The term "C6-C8cycloalkyl" (or simply "C6-C8 cycloalkyl") refers to a cycloalkyl group having 6 to 8 carbon atoms. The term "C3-C4cycloalkyl" (or simply "C3-C4 cycloalkyl") refers to a cycloalkyl group having 3 to 4 carbon atoms. The term "C4-C6cycloalkyl" (or simply "C4-C6 cycloalkyl") refers to a cycloalkyl group having 4 to 6 carbon atoms. The term "C5-C6cycloalkyl" (or simply "C5-C6 cycloalkyl") refers to a cycloalkyl group having 5 to 6 carbon atoms. The term "C6-C8cycloalkyl" (or simply "C6-C8 cycloalkyl") refers to a cycloalkyl group having 6 to 8 carbon atoms.

[0111] As used herein, the terms "cycloalkyl" and "cycloalkenyl" refer to saturated (i.e., "cycloalkyl") or unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including but not limited to (cyclo)propyl, (cyclo)butyl, (cyclo)pentyl, (cyclo)hexyl, (cyclo)heptyl, (cyclo)octyl, (cyclo)nonyl, (cyclo)decyl, (cyclo)undecyl, (cyclo)dodecyl, (cyclo)tridecyl, (cyclo)tetrade

[0112] As used herein, the terms "heterocyclyl," "heterocyclyl ene," and "heterocycle" refer to saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) cyclic groups having, for example, 3-10 (suitably having 3-8, more suitably having 3-6) ring atoms, at least one of which is a heteroatom selected from N, O, and S, and the remainder of which are C. For example, a "3-10 membered (hetero)cycloalkyl ene" is a saturated or partially unsaturated (hetero)alkylene having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. Examples of heterocyclyl ene and heterocycle include, but are not limited to, (hetero)cyclooxanyl, (hetero)cycloaziridinyl, (hetero)cycloazetidinyl, (hetero)cyclooxetanyl, (hetero)cyclo tetrahydrofuranyl, (hetero)cyclo dioxolinyl, (hetero)cyclopyrrolidinyl, (hetero)cyclopyrrolidonyl, (hetero)cycloimidazolidinyl, (hetero)cyclopyrazolidinyl, (hetero)cyclopyrrolinyl, (hetero)cyclo tetrahydropyranyl, (hetero)cyclo piperidinyl, (hetero)cyclo morpholinyl, (hetero)cyclo dithianyl, (hetero)cyclo thiomorpholinyl, (hetero)cyclo piperazinyl, or (hetero)cyclo trithianyl. The groups also encompass bicyclic systems, including spiro, fused, or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, and the like). Heterocyclyl ene and heterocycle can be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0113] As used herein, the terms "(hetero)aryl" and "aromatic ring" refer to all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated pi-electron system. For example, as used herein, the terms "C 6-10 (hetero)aryl" and "C 6-10 aromatic ring" mean aromatic groups containing 6 to 10 carbon atoms, such as (hetero)phenyl (benzene ring) or (hetero)naphthyl (naphthalene ring). (Hetero)aryl and aromatic ring are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, and the like).

[0114] As used herein, the terms “(sub)heteroaryl” and “heteroary ring” refer to monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom that may be the same or different (the heteroatom being, for example, oxygen, nitrogen, or sulfur), and additionally, in each case, may be benzofused. Specifically, "(hybrid)aryl" or "heteroary ring" is selected from (hybrid)thienyl, (hybrid)furanyl, (hybrid)pyrroleyl, (hybrid)oxazolyl, (hybrid)thiazolyl, (hybrid)imidazolyl, (hybrid)pyrazolyl, (hybrid)isooxazolyl, (hybrid)isothiazolyl, (hybrid)oxadiazolyl, (hybrid)triazolyl, (hybrid)thiadiazolyl, etc., and their benzo[derivatives]; or (hybrid)pyridinyl, (hybrid)pyridinyl, (hybrid)pyrazinyl, (hybrid)triazinyl, etc., and their benzo[derivatives].

[0115] As used herein, the term "aralkyl" preferably refers to an aryl or heteroaryl-substituted alkyl group, wherein the aryl, heteroaryl, and alkyl groups are as defined herein. Typically, the aryl group may have 6-14 carbon atoms, the heteroaryl group may have 5-14 ring atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0116] A more specific explanation of the terminology is as follows:

[0117] "alkyl" refers to a saturated aliphatic hydrocarbon group comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms of a saturated straight-chain or branched monovalent hydrocarbon group, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in this invention. Further examples of alkyl groups include, but are not limited to, 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, etc. The alkyl group may be optionally substituted or unsubstituted.

[0118] "Alkenyl" refers to a monovalent hydrocarbon group with 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, in which at least one C or C is sp. 2double bond, wherein the group of alkenyl can be independently optionally substituted with 1 or more substituents described herein, wherein specific examples include, but are not limited to, ethenyl, allyl, and crotyl, and the like. Alkenyl can be optionally substituted or unsubstituted.

[0119] "Cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms, more preferably comprising 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. Cycloalkyl groups can be optionally substituted or unsubstituted.

[0120] "Spiroalkyl" refers to a 5- to 18-membered, polycyclic group having two or more cyclic structures sharing a single carbon atom (termed a spiro atom) between the rings, the rings containing 1 or more double bonds, but no ring having a fully conjugated system of π-electrons. Preferably, 6- to 14-membered, more preferably 7- to 10-membered. Spiroalkyl groups are classified as mono-, bi-, or polycyclic, preferably mono- and bi-cyclic, preferably 4 / 5-, 4 / 6-, 5 / 5-, or 5 / 6-membered. Non-limiting examples of "spiroalkyl" groups include, but are not limited to:

[0121]

[0122] "Fused cycloalkyl" refers to a 5- to 18-membered, polycyclic group having two or more cyclic structures sharing a pair of carbon atoms between the rings, one or more rings can contain 1 or more double bonds, but no ring having a fully conjugated system of π-electrons, preferably 6- to 12-membered, more preferably 7- to 10-membered. Fused cycloalkyl groups are classified as bi-, tri-, tetra-, or polycyclic, preferably bi- or tri-cyclic, more preferably 5 / 5- or 5 / 6- bi-cyclic alkyl groups. Non-limiting examples of "fused cycloalkyl" groups include, but are not limited to:

[0123]

[0124] "Bridged cycloalkyl" refers to a 5- to 18-membered, polycyclic group having two or more cyclic structures sharing a pair of non-adjacent carbon atoms between the rings, one or more rings can contain 1 or more double bonds, but no ring having a fully conjugated system of π-electrons, preferably 6- to 12-membered, more preferably 7- to 10-membered. Bridged cycloalkyl groups are classified as bi-, tri-, tetra-, or polycyclic, preferably bi-, tri-, or tetra-cyclic, more preferably bi- or tri-cyclic. Non-limiting examples of "bridged cycloalkyl" groups include, but are not limited to:

[0125]

[0126] The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring that is attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.

[0127] "Heterocyclyl," "heterocycle," or "heterocyclic" are used interchangeably herein, and refer to a saturated or partially unsaturated, monocyclic, bicyclic or tricyclic non-aromatic ring system containing between 3 and 12 ring atoms, wherein at least one ring atom is a heteroatom such as oxygen, nitrogen, sulfur and the like. Preferred are 5- to 7-membered monocyclic rings or 7- to 10-membered bicyclic- or tricyclic rings, which can contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heterocyclyl" groups include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl. The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring that is attached to the parent structure is heterocyclyl. The heterocyclyl group can be optionally substituted or unsubstituted.

[0128] "Spiroheterocyclyl" refers to a polycyclic group of 5 to 18 members, two or more cyclic structures, and single rings sharing one atom with each other, containing 1 or more double bonds within the ring, but no ring has a fully conjugated system of π electrons, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) m , and the remaining ring atoms are carbon, m = 1 or 2. Preferred are 6 to 14 members, more preferred are 7 to 10 members. Spiroheterocyclyl groups are classified as mono-, bi- or polyspiroheterocyclyl groups, preferred are mono- and bi- spiroheterocyclyl groups, depending on the number of spiro atoms shared between the rings. More preferred are 4 / 4-, 4 / 5-, 4 / 6-, 5 / 5- or 5 / 6- monospiroheterocyclyl groups. Non-limiting examples of "spiroheterocyclyl" groups include, but are not limited to:

[0129]

[0130] "Fused heterocyclyl" refers to a all-carbon polycyclic group of two or more cyclic structures sharing a pair of atoms with each other, one or more rings can contain one or more double bonds, but no ring has a fully conjugated system of π electrons, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) mheteroatoms, the remaining ring atoms being carbon, and m = 1 or 2. Preferably, the fused heterocyclyl group is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings comprising the fused heterocyclyl group, it can be a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl group. Non-limiting examples of "fused heterocyclyl groups" include, but are not limited to:

[0131]

[0132] "bridged heterocyclyl" refers to a polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two atoms not directly attached to each other, one or more rings can contain one or more double bonds, but no ring has a fully conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) m heteroatoms, the remaining ring atoms being carbon, and m = 1 or 2. Preferably, the fused heterocyclyl group is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings comprising the fused heterocyclyl group, it can be a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl group. Non-limiting examples of "fused heterocyclyl groups" include, but are not limited to:

[0133]

[0134] "aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings can be connected together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferably, the aryl group is a C6-C 10 aryl, more preferably the aryl group is phenyl and naphthyl, most preferably phenyl. The aryl group can be substituted or unsubstituted. The "aryl" group can be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the aryl ring is attached to the parent structure, non-limiting examples include, but are not limited to:

[0135]

[0136] "Heteroaryl" means an aromatic 5- to 6-membered monocyclic ring or 9- to 10-membered bicyclic ring which can contain 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heteroaryl" groups include, but are not limited to, furanyl, pyridinyl, 2-oxo-l,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzoisothiazolyl, benzoxazolyl, and benzoisoxazolyl. The heteroaryl group can be optionally substituted or unsubstituted. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include, but are not limited to:

[0137]

[0138] "Alkoxy" means a group of the formula (alkyl-O-). Alkyl is as defined herein. C1-C6alkoxy is preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, and the like.

[0139] "Haloalkyl" means an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as defined herein. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.

[0140] "Hydroxy" means the -OH group.

[0141] "Halo" means fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, and bromo.

[0142] "Amino" means -NH2.

[0143] "Cyano" means -CN.

[0144] "Nitro" means -NO2.

[0145] "Benzyl" means -CH2-phenyl.

[0146] "Carboxyl" means -C(O)OH.

[0147] "Amino" means -NH2.

[0148] "Carboxylate" means -C(O)O(alkyl) or (cycloalkyl), wherein alkyl, cycloalkyl are as defined above.

[0149] As used herein, the term "halo" or "halogen" group is defined to include F, CI, Br, or I.

[0150] As used herein, the term "nitrogen-containing heterocycle" means a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in the ring, which can also optionally contain one or more (e.g., one, two, three, or four) ring members selected from N, O, C=0, S, S=0, and S(=0)2, which is attached to the remainder of the molecule through a nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atom, which is optionally benzo-fused, and preferably attached to the remainder of the molecule through a nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring.

[0151] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0152] If a substituent is described as "optionally substituted," then the substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, then one or more hydrogens on the carbon (to the extent there are any hydrogens present) can be replaced with an independently selected optional substituent, alone or in combination. If a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, then one or more hydrogens on the nitrogen (to the extent there are any hydrogens present) can each be replaced with an independently selected optional substituent.

[0153] If a substituent is described as "independently selected from" a group, then each substituent is selected independently of the other(s). Thus, each substituent can be the same or different from the other (other) substituent(s).

[0154] As used herein, the term "one or more" means 1 or more than 1, e.g., 2, 3, 4, 5, or 10, under reasonable conditions.

[0155] Unless indicated, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent.

[0156] When the bond of a substituent is shown to be through a bond connecting two atoms in a ring, then such substituent can be bonded to either atom in the ring that can be substituted.

[0157] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium). 2 H), tritium ( 3 H); carbon isotopes (e.g., H); 11 C 13 C and 14 C); isotopes of chlorine (e.g.) 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g. 35 S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e., 14C) are particularly suitable for this purpose due to their ease of incorporation and detection. Positron emission isotopes (e.g.) 11 C 18 F, 15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0158] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0159] As used herein, and unless otherwise specified, "substituted" or "substitution" means that a group can be substituted with one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =0, -C(O)R b , -OC(O)R b , -NR b R b , -C(O)NR b R b , -NR b C(O)R b , -S(O)NR b R b or -S(O)2NR b R b wherein R b is as defined in Formula (I).

[0160] As used herein, the term "pediatric patient" means a patient who is less than 16 years of age at the time of diagnosis or treatment. The term "pediatric" can also be broken down into the following subcategories: neonate (from birth to the first month of life); infant (1 month to 2 years); child (2 to 12 years); and adolescent (12 to 21 years (up to but not including the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson we. Nelson's Textbook of Pediatrics, 15th Edition. Philadelphia: W. B. Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Edition. New York: McGraw-Hill, 2002; and Avery MD, First LR. Avery's

[0161] As used herein, an "effective amount" of a compound means an amount sufficient to downregulate or agonize a TREK-1 potassium ion channel.

[0162] As used herein, a "therapeutically effective amount" of a compound means an amount sufficient to improve or in some way reduce symptoms, halt or reverse the progression of a condition, or downregulate or agonize a TREK-1 potassium ion channel. Such an amount can be used as a single dose or can be administered according to a regimen effective.

[0163] As used herein, "treatment" means any improvement or other alteration in the symptoms or pathology of a patient's condition, disorder, or disease, in any manner.

[0164] As used herein, "improving symptoms of a particular disease by use of a particular compound or pharmaceutical composition" means any decrease, whether permanent or temporary, lasting or transient, attributable to or associated with use of the composition.

[0165] The definitions and conventions used in the description of the stereochemistry of the present application are in accordance with the following documents:

[0166] S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present application can contain asymmetric or chiral centers, and therefore exist in different stereoisomers or geometric isomers. All stereoisomers and geometric isomers of the compounds of the present application, including but not limited to, diastereomeric, enantiomeric, atropisic isomers and mixtures thereof are intended to be within the scope of the present application. Diastereomeric mixtures can be separated by, for example, chromatographic, crystalline, or other standard techniques, or can be resolved by the formation of diastereomeric salts with an appropriate optically active acid or base, and separation of the resulting diastereomeric mixture by standard techniques. Enantiomeric mixtures can be separated by, for example, the formation of covalent diastereomeric derivatives by reaction with an appropriate chiral reagent, separation of the resulting mixture of diastereomers by standard techniques, and regeneration of the pure enantiomers from the separated diastereomeric derivatives. When the compounds described herein contain olefinic bonds, geometric isomers can be present. The specific geometric isomeric forms can be designated as Z (or syn) or E (or anti). The isomers can be separated by standard techniques, or can be resolved by the formation of diastereomeric salts with an appropriate optically active acid or base, and separation of the resulting mixture of diastereomers by standard techniques. The compounds of the present application can also exist in different tautomeric forms. All such forms are embraced within the scope of the present application. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule. The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound, that is, the (-) or 1 form is levorotatory, and the (+) or d form is dextrorotatory. These stereoisomers are each in itself a mixture of two enantiomeric forms. A 50:50 mixture of these enantiomeric forms is called a racemic mixture or racemic modification, and contains no optical activity. The terms "racemic mixture" and "racemic modification" mean a mixture containing equal concentrations of d and 1 (or (+) and (-)) optical isomers.

[0167] "tautomers" or "tautomerically forms" refer to isomers of different energy that can interconvert by a low energy barrier. For example, prototropic tautomers (i.e., proton-shift tautomers) include interconversions by proton migration, such as keto-enol and imine-enamine isomerizations. Atom-valence (valence) tautomers include interconversions by reorganization of bonding electrons. Unless otherwise specified, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric isomeric) forms of the indicated structure. For example, the R, S configurations of asymmetric centers, the (Z) and (E) isomers of double bonds, and the (Z) and (E) conformational isomers of C=C bonds are specifically embraced within the scope of the present application. Thus, individual stereochemical isomers and mixtures of their enantiomers, diastereomers, or geometric isomers, are within the scope of the present application.

[0168] "pharmaceutically acceptable salts" refer to salts of the compounds of the present application that are safe and effective for use in humans or animals. Salts of the compounds can be obtained by addition of a sufficient amount of a base or acid to a pure solution or a suitable inert solvent of the compound to obtain the corresponding addition salt. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, and the like. Pharmaceutically acceptable acid addition salts include inorganic acid and organic acid salts including salts of hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, acetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, and methanesulfonic acid, and the like (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)).

[0169] A solid line a solid wedge or a dashed wedge depicting a chemical bond of a compound of the present application. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers (e.g., particular enantiomers, racemic mixtures, etc.) are included. The use of a solid or dashed wedge to depict a bond to an asymmetric carbon atom is intended to indicate that the depicted stereoisomer is present. When present in a racemic mixture, the solid and dashed wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise indicated, the compounds of the present application are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present application can exhibit more than one type of isomerism, and exist as mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0170] The present application encompasses all possible crystalline forms or polymorphs of the compounds of the present application, which can be a single polymorph or a mixture of more than one polymorph in any ratio.

[0171] It is also to be understood that certain compounds of the present application can exist in free form for treatment, or where appropriate, in the form of a pharmaceutically acceptable derivative thereof. In the present application, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, chelates, complexes, clathrates or prodrugs, which upon administration to a patient in need thereof are capable of providing, directly or indirectly, a compound of this application or a metabolite or residue thereof. Accordingly, as used herein, reference to a "compound of the present application" is intended to encompass all such derivatives.

[0172] Pharmaceutically acceptable salts of the compounds of the present application include acid addition salts and base addition salts, including but not limited to salts containing hydrogen or coordinate bonds.

[0173] Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, heptanoate, hexanoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / diphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate.

[0174] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, benzathines, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc.

[0175] A review of suitable salts is available in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of the compounds of the present application are known to those skilled in the art.

[0176] As used herein, the term "ester" means an ester derived from the various generic compounds of the present application, which includes physiologically hydrolysable esters (which can be hydrolyzed under physiological conditions to release a free acid or alcohol form of a compound of the present application). The compounds of the present application can also be esters themselves.

[0177] The compounds of the present application can exist in solvate (preferably hydrate) form, wherein the compound of the present application contains a polar solvent, particularly, for example, water, methanol or ethanol, as an integral part of the crystal lattice of said compound. The amount of polar solvent, particularly water, can be present in stoichiometric or non-stoichiometric amounts.

[0178] One skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; one skilled in the art will recognize nitrogen-containing heterocycles capable of forming N-oxides. One skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidation of heterocycles and tertiary amines with peroxy acids such as peroxyacetic acid and meta-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.

[0179] Metabolites of the compounds of the present application, i.e., species formed in vivo upon administration of the compounds of the present application, are also within the scope of the present application. Such products can result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the present application includes metabolites of compounds of the present application, including those produced by the in vivo conversion of a compound of the present application.

[0180] The present application further includes within its scope prodrugs of the compounds of the present application, which are certain derivatives of the compounds of the present application that are themselves inactive or less active than the parent compounds but are converted to the active form in vivo by, for example, solvolysis, cleavage of a precursor group, or metabolic cleavage. In general, such prodrugs will be fairly stable in the physiological environment of a patient, but will be cleaved to the active form by the action of enzymes or solvents such as water, present in the body. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series, T. Higuchi and V. Stella. Prodrugs of the present application can be prepared by replacing appropriate functionalities present in the compounds of the present application with certain moieties known to those skilled in the art as "pro-moieties" (for example, as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0181] The present application also encompasses compounds of the present application containing protecting groups. During any of the processes for preparation of the compounds of the present application, it can be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned, as described in "Protective Groups in Organic Chemistry", J. W. F. McOmie (Ed.), Plenum Press, 1973; "Protective Groups in Organic Synthesis", 2nd edition, P. J. Kocienski, Thieme, 1994, and "Lewiε'π Handbook of Reagents for Organic Synthesis, Owing to their chemical properties, the protecting groups can be removed at appropriate stages during the synthesis sequence. The use and choice of the protecting groups will depend on the particular chemistry involved and can be readily selected by a person skilled in the art.

[0182] The term "about" refers to ± 10% of the indicated value, preferably ± 5%, more preferably ± 2%.

[0183] Preferred compounds of the invention

[0184] The general formula and preferred ranges of the compounds of the present application have been described. Further preferably, specific examples of the compounds of the present application can be selected from any one of the following structures, but are not limited to the following compounds:

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199] Typical compounds of the present application include, but are not limited to, the compounds in the above table, the naming of the compounds in the present application follows systematic naming, or, the naming is performed using ChemDraw software.

[0200] General methods for obtaining compounds of the invention

[0201] The aromatic fused ring compounds of the present application represented by the general formula 1 can be obtained by known methods, for example, by synthesizing by known organic synthesis methods. An exemplary synthesis route is given below, but those skilled in the art can also obtain by other known methods.

[0202] In the present application, the synthesis method of the compound is briefly described, the representative synthesis route of the compound of general formula 1 is as follows, it is necessary to explain here, the synthesis route is briefly introduced by selecting the synthesis method of the compound of the same type as compound 2 in the above table. Only for example, Ar, R 1 , R 2 , L 3 , L 4 , L 6 , L 8 , and L 9The synthesis of other compounds of the parallel technical solutions can be achieved by replacing the corresponding raw materials, L 3 、L 4 The construction method of different fused heterocycles can be achieved by known methods.

[0203] Representative technical route:

[0204]

[0205] 【1】Take a and b as important starting intermediates, in an organic solvent, at 0°C- reflux temperature, incubate for 1-48 hours to obtain intermediate c;

[0206] 【2】Intermediates c, after reduction reaction, then perform ring closing reaction to obtain intermediate compound d, the ring closing reaction is according to L 3 、L 4 Different reaction conditions are adopted;

[0207] 【3】Intermediates compound d reacts with raw material e under alkaline conditions;

[0208] 【4】Remove the isopropylidene protecting group and the like to obtain the compounds of the present application.

[0209] For the above preparation method,

[0210] The reagent under alkaline conditions can be selected from one or more of organic bases or inorganic bases, the organic bases are one or more of triethylamine, N, N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, bis-trimethylsilylaminolithium, sodium tert-butoxide, sodium methoxide and potassium tert-butoxide, and the inorganic bases are one or more of sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and lithium hydroxide;

[0211] The reagent providing acidic conditions can be one or more of hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, methanol solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid and phosphoric acid;

[0212] The metal catalyst is one or more of palladium / carbon, Raney nickel, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1, 1'-bis (diphenylphosphino) ferrocene] dichloride palladium (Pd (dppf) Cl2), [1, 1'-bis (diphenylphosphino) ferrocene] dichloride palladium dichloromethane complex, bis-triphenylphosphine dichloride palladium (Pd (PPh3) Cl2) and tris (dibenzalacetone) dipalladium (Pd2 (dba) 3) ;

[0213] The ligand is 2-bicyclohexylphosphine-2, 6'-dimethoxy biphenyl (SPhos), 4, 5-bis diphenylphosphine-9, 9-dimethyl xanthene

[0214] one or more of XantPhos, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (DavePhos), 1,1'-bis(diphenylphosphino)ferrocene (Dppf), and 1,1'-binaphthalene-2,2'-bisdiphenylphosphine (BINAP), preferably 1,1'-binaphthalene-2,2'-bisdiphenylphosphine (BINAP);

[0215] the reducing agent is one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride;

[0216] the oxidizing agent is one or more of potassium permanganate, manganese dioxide, potassium dichromate, sodium dichromate, and potassium osmate;

[0217] the above reaction is preferably carried out in a solvent, and the solvent used is one or more of N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane, and acetone.

[0218] Pharmaceutical compositions and methods of treatment Definitions Preferred compounds of the invention General methods for obtaining compounds of the invention Pharmaceutical compositions and methods of treatment Definitions Preferred compounds of the invention General methods for obtaining compounds of

[0219] The present application provides a pharmaceutical composition comprising an effective amount of the compound of the present application or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, metabolite thereof, and a pharmaceutically acceptable carrier, and the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation, or a gaseous preparation.

[0220] In the present application, the "pharmaceutically acceptable carrier" means a diluent, adjuvant, excipient, or vehicle for administration of a therapeutic agent together, and it is within the scope of sound medical judgment to be suitable for contacting human and / or other animal tissues without excessive toxicity, irritation, allergic reaction, or other problems or complications corresponding to reasonable benefit / risk ratio.

[0221] Pharmaceutically acceptable carriers that can be employed in the pharmaceutical compositions of the application include, but are not limited to, sterile aqueous, nonaqueous, and mixture of aqueous and nonaqueous solutions, suspensions, and emulsions, including those that are isotonic with the blood of the intended recipient; and sterile powders for reconstitution into sterile injectable solutions and / or suspensions. Examples of non-toxic parenterally-acceptable diluents that can be employed are water, physiological saline, physiological buffers, and the like. In some cases, depending on the particular mode of administration, the pharmaceutical compositions of the application will comprise pharmaceutically-acceptable diluents, fillers, salts, or buffers, in addition to the compound of the application. For example, for oral administration, the pharmaceutical compositions can additionally comprise binders, suspensions, diluents, or lubricants; for injection, the compositions can additionally comprise suspensions, or carriers that are potentially biodegradable; and for transdermal delivery, the compositions can additionally comprise penetrants or absorption enhancers.

[0222] The pharmaceutical compositions of the application can act systemically and / or topically. To this end, they can be administered by a suitable route, such as by injection (e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drip infusion) or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of an ophthalmic preparation, or by inhalation.

[0223] For these routes of administration, the pharmaceutical compositions of the application can be administered in a suitable dosage form.

[0224] The dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups.

[0225] The pharmaceutical compositions described herein can be used for the prevention and / or treatment of pain. When the pharmaceutical formulations of the application are used, other pain treatment agents, such as fluoxetine, opioid analgesics, non-opioid analgesics, etc., can also be used simultaneously.

[0226] The pharmaceutical compositions described herein contain a safe and effective amount of the compound of the application and a pharmaceutically acceptable carrier or excipient. Such carriers include, but are not limited to, one or more of saline, buffers, dextrose, water, glycerol, ethanol, powders, etc. The pharmaceutical formulation should be matched to the mode of administration.

[0227] The pharmaceutical compositions of the present application can be prepared in the form of injectables, such as by conventional methods using, for example, physiologically acceptable salts or aqueous solutions of glucose and other adjuvants. Pharmaceutical compositions, such as tablets and capsules, can be prepared by conventional methods. Pharmaceutical compositions, such as injectables, solutions, tablets and capsules, are preferably manufactured under aseptic conditions. The pharmaceutical compositions of the present application can also be prepared in the form of powders for aerosol inhalation.

[0228] The amount of active ingredient administered will be a therapeutically effective amount, such as from about 1 microgram per kilogram body weight to about 50 milligrams per kilogram body weight per day; preferably, from about 5 micrograms per kilogram body weight to about 10 milligrams per kilogram body weight; further preferably, from about 10 micrograms per kilogram body weight to about 5 milligrams per kilogram body weight. In addition, the compounds of the present application can be used in conjunction with other therapeutic agents.

[0229] The pharmaceutical compositions of the present application can be administered to a subject (such as a human or non-human mammal) in need thereof by conventional means. Representative modes of administration include, but are not limited to, oral, injection, aerosol inhalation, and the like.

[0230] When using the pharmaceutical compositions, a safe and effective amount of the pharmaceutical is administered to a mammal, wherein the safe and effective amount is typically at least about 10 micrograms per kilogram body weight, and in most cases no more than about 50 milligrams per kilogram body weight, and preferably, the amount is from about 10 micrograms per kilogram body weight to about 20 milligrams per kilogram body weight. Of course, the specific dose will also depend on the route of administration, the health of the patient, and like factors, which are within the skill of the skilled clinician.

[0231] The present application is further illustrated by the following examples. The procedures, conditions, reagents, and experimental methods used in the practice of the application are those conventional in the art and are not specifically limited unless otherwise specified. It is to be understood that these examples are merely illustrative of the present application and do not in any way limit the scope of the application. Unless otherwise indicated, the experimental methods in the following examples were carried out under conventional conditions or as recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight.

[0232] The term "effective amount" as used herein refers to the amount of a compound that, when administered, will relieve to some extent one or more of the symptoms of the disorder being treated. In particular, an "effective amount" of a compound as used herein, is an amount that is sufficient to downregulate or agonize a TREK-1 potassium ion channel. A "therapeutically effective amount" of a compound as used herein, is an amount that is sufficient to ameliorate or in some way reduce symptoms, halt or reverse progression of the disease, or downregulate or agonize a TREK-1 potassium ion channel. Such an amount can be administered in a single dose, or according to a regimen, as effective.

[0233] Dosage regimens can be adjusted to provide the optimum desired response. For example, a single bolus can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values can vary as indicated by the type and severity of the condition to be alleviated. It is to be further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the

[0234] As used herein, "treatment" means any improvement or other alteration in the symptoms or pathology of a patient's condition, disorder, or disease, in any manner. As described herein, "improving the symptoms of a particular disease by use of a particular compound or pharmaceutical composition" means any decrease, whether permanent or temporary, lasting or transient, attributable to or associated with the use of that composition.

[0235] As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include a human individual (referred to as a patient) who has a disease, such as a disease described herein, or a normal individual. "Non-human animals" in the present application include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles), and mammals, e.g., non-human primates, farm animals, and / or laboratory animals (e.g., sheep, dog, cat, cow, pig, etc.).

[0236] In some embodiments, the pharmaceutical compositions of the present application can further comprise one or more additional therapeutic or prophylactic agents. DETAILED DESCRIPTION

[0237] The present application is described in detail below by way of Examples, but it is not meant to be limited by any of the Examples. The present application has been described in detail by specific embodiments, and various modifications and improvements that one skilled in the art will readily suggest to the preceding description and detailed description thereof, and it is intended that the application be limited only by the scope of the appended claims.

[0238] EXAMPLE

[0239] These examples are provided not to limit the scope of the present application.

[0240] The methods of the present application are illustrated below by specific examples to make the technical solutions of the present application easier to understand and grasp, but the present application is not limited thereto. In the following examples 1 HNMR spectra were determined using a Bruker instrument (400 MHz) and chemical shifts are expressed in ppm using tetramethylsilane internal standard (0.00 ppm). 1NMR representation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets. If coupling constants are given, the units are Hz.

[0241] Mass spectra were determined using LC / MS instrument, ionization mode was ESI.

[0242] High performance liquid chromatography: Agilent 1260, Thermo U3000; Column: Waters xbrige C18 (4.6*150mm, 3.5μm); Mobile phase: A: ACN, B: Water (0.1% H3PO4); Flow rate: 1.0 mL / min; Gradient: 5% A for 1 min, increase to 20% A within 4 min, increase to 80% A within 8 min, 80% A for 2 min, back to 5% A within 0.1 min; Wavelength: 220 nm; Column oven: 35℃.

[0243] Thin layer chromatography silica gel plate: Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification of silica gel plate used in thin layer chromatography (TLC) was 0.2mm-0.3mm, the specification of silica gel plate used in thin layer chromatography separation and purification of products was 0.4mm-0.5mm.

[0244] Column chromatography generally used Yantai Huanghai silica gel 200-300 mesh silica gel as carrier.

[0245] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius, unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, commercially available starting materials and reagents are used directly without further purification, unless otherwise indicated, the commercial suppliers include but are not limited to Sinopharm Group, Bailingwei Technology Co., Ltd., Lixi'ai (Shanghai) Chemical Industry Development Co., Ltd., Shanghai Bide Pharmaceutical Technology Co., Ltd., and Shanghai Maier Chemical Technology Co., Ltd., etc.

[0246] CD3OD: deuterated methanol

[0247] CDCl3: deuterated chloroform

[0248] DMSO-d6: deuterated dimethyl sulfoxide

[0249] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium

[0250] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium

[0251] XantPhos: 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene

[0252] XPhos: 2-Dicyclohexylphosphine-2,4,6-triisopropylbiphenyl

[0253] HATU: 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate

[0254] TLC: Thin-layer chromatography

[0255] HPLC: High Performance Liquid Chromatography

[0256] purity:

[0257] &:and

[0258] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0259] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0260] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃-30℃.

[0261] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, or the developing solvent system for TLC included: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate. The volume ratio of the solvent varied depending on the polarity of the compound and could also be adjusted by adding a small amount of acidic or basic reagents, such as acetic acid or triethylamine.

[0262] Synthesis Examples

[0263] Example 1

[0264] (1S,2S,3S,5R)-3-(2-aminoethoxy)-5-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2-diol

[0265]

[0266] Step 1 (1S,2S,3S,5R)-3-(2-bromoethoxy)-5-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2-diol 1b

[0267] Triphenylphosphine (166 mg, 0.63 mmol) was dispersed in dichloromethane (5 mL) and stirred in an ice bath at 0 °C for 20 minutes. Then bromine (101 mg, 0.63 mmol) was dissolved in dichloromethane (2 mL) and added slowly to the reaction solution, controlling the temperature change at about 2 °C. After the drop, continue to stir at 0 °C for 30 minutes. Keep at 0 °C, then tegrelor la (300 mg, 0.57 mmol) was dispersed in dichloromethane (5 mL) and slowly added to the reaction solution (Note: cannot be dissolved, emulsion is directly added, after adding to the reaction solution, slowly dissolved by itself). After adding, warm to room temperature and stir for 16 hours, TLC shows that a new spot is generated, and a small amount of raw material is left. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (15 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1) to obtain the white solid title compound lb (250 mg, crude, containing a small amount of triphenylphosphine oxide), which was directly used in the next step.

[0268] LC-MS: m / z = N / A (no molecular weight)

[0269] Second step (1S,2S,3S,5R)-3-(2-aminoethoxy)-5-(7-(((1R,2S)-2-(3,4- difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3- yl)cyclopentane-1,2-diol 1

[0270] In a sealed tube, compound lb (200 mg, crude) was dissolved in amine methanol solution (7 M, 6 mL) and stirred at 50 °C for 16 hours, TLC (DCM / MeOH = 10 / 1) showed that most of the starting material was consumed. The reaction solution was cooled to room temperature and concentrated to obtain the crude product. The crude product was purified by Prep-TLC (dichloromethane / methanol = 5 / 1) to obtain the white solid title compound 1 (30.7 mg, 10% yield for two steps).

[0271] LC-MS: m / z = 522.2 [M+H] + (99.45% purity by HPLC, 254 nm)

[0272] 1H NMR (400 Hz, CD3OD) δ 7.18 (s, 2H), 7.06 (s, 1H), 5.13 (d, J = 7.6 Hz, 1H), 4.76 (s, 1H), 4.16 (s, 1H), 3.90 (s, 1H), 3.63 (s, 2H), 3.13-3.05 (m, 2H), 2.89 (s, 2H), 2.77 (s, 1H), 2.21-2.12 (m, 2H), 1.74-1.29 (m, 5H), 1.04-0.91 (m, 3H). (Five active hydrogens not out)

[0273] Example 2

[0274] (1S,2S,3R,5S)-3-(5-((cyclopropylmethyl)thio)-7-(((1R,2S)-2-(3,4- difluorophenyl)cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2- hydroxyethoxy)cyclopentane-1,2-diol 2

[0275]

[0276] First step 2-((cyclopropylmethyl)thio)pyrimidine-4,6-diol 2b

[0277] 4,6-Dihydroxy-2-mercaptopyrimidine 2a (5.00 g, 34.69 mmol) was dissolved in methanol (100 mL), triethylamine (3.51 g, 34.69 mmol) and bromomethylcyclopropane (4.92 g, 36.42 mmol) were added, the reaction was heated to reflux with an oil bath at 70 °C for 16 hours, TLC monitoring reaction was complete, the reaction was cooled to room temperature, concentrated, washed with water (100 mL), filtered, washed with water (50 mL), the filter cake was collected and dried to give the title compound 2b (5.10 g, yield 74%) as a white solid.

[0278] LC-MS: m / z = 199.1 [M+H] +

[0279] Second step 2-((cyclopropylmethyl)thio)-5-nitropyrimidine-4,6-diol 2c

[0280] Fuming nitric acid (5.21 g, 82.72 mmol) was slowly added to glacial acetic acid (30 mL) at 10 °C, the reaction was cooled to 0-5 °C, then compound 2b (4.10 g, 20.68 mmol) was added to the reaction in batches, after addition, the temperature was slowly increased to room temperature and stirred for 2 hours, LCMS monitoring showed that the raw material was completely reacted, the reaction was filtered, washed with a small amount of glacial acetic acid (10 mL), and the filter cake was dried to give the title compound 2c (3.90 g, yield 61%) as a red-brown solid.

[0281] LC-MS: m / z = 244.1 [M+H] +

[0282] Third step 4,6-dichloro-2-((cyclopropylmethyl)thio)-5-nitropyrimidine 2d

[0283] Compound 2c (1.00 g, 4.11 mmol) was dissolved in phosphorus oxychloride (2.52 g, 16.44 mmol), the reaction system was warmed to 40 °C, after stirring for 10 minutes, N,N-dimethylaniline (1.00 g, 8.22 mmol) was added to the reaction system, after adding, it was warmed to 60 °C and stirred for 2 hours, TLC monitoring showed that the reaction was complete, the reaction liquid was cooled to room temperature, quenched with water (10 mL), extracted with dichloromethane (10 mL x 3), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1) to obtain the title compound 2d (0.70 g, yield 61%) as a colorless oil.

[0284] 1 H NMR (400 MHz, CDCl3) δ 3.14 (d, J = 7.2 Hz, 2H), 1.22-1.12 (m, 1H), 0.70-0.64 (m, 2H), 0.36 (q, J = 4.8 Hz, 2H).

[0285] Fourth step 2-(((3aR,4S,6R,6aS)-6-((6-chloro-2-((cyclopropylmethyl)thio)-5-nitropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol 2f

[0286] Compound 2d (700 mg, 2.50 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 °C, and 2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol (2R,3R)-2,3-dihydroxybutanedioate 2e (941 mg, 2.50 mmol) and N,N-diisopropylethylamine (970 mg, 7.50 mmol) were added. After adding, it was warmed to room temperature and reacted for 3 hours, TLC detection showed that the starting material was completely reacted. The reaction liquid was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1-3 / 1) to obtain the title compound 2f (0.52 g, yield 45%) as a light yellow foam.

[0287] LC-MS: m / z = 244.1 [M+H] +

[0288] 1 H NMR (400 MHz, CDC13) δ 8.62 (d, J = 8.0 Hz, 1H), 4.73 (s, 1H), 4.65 (dd, J = 5.2, 1.6 Hz, 1H), 4.54-4.50 (m, 1H), 3.97 (d, J = 4.4 Hz, 1H), 3.89-3.73 (m, 3H), 3.65-3.59 (m, 1H), 3.21 (dd, J = 13.6, 7.2 Hz, 1H), 3.04 (dd, J = 13.6, 7.2 Hz, 1H), 2.39-2.25 (m, 2H), 1.93 (d, J = 14.8 Hz, 1H), 1.45 (s, 3H), 1.27 (s, 3H), 1.24-1.16 (m, 1H), 0.65-0.59 (m, 2H), 0.37-0.31 (m, 2H).

[0289] Step 5 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-((cyclopropylmethyl)thio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][l,3]dioxol-4-yl)oxy)ethan-l-ol 2g

[0290] Compound 2f (520 mg, 1.13 mmol) was dissolved in methanol (10 mL), and reduced iron powder (633 mg, 11.30 mmol) and acetic acid (2.03 g, 33.90 mmol) were added at room temperature. After addition, the reaction was allowed to react at room temperature for 2 hours. TLC detection showed that the starting material was completely converted. The reaction solution was filtered through diatomite, the filtrate was added with water (20 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 2g (480 mg, yield 98%) in light brown foaming form.

[0291] LC-MS: m / z = 431.1 [M+H] +

[0292] Step 6 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-((cyclopropylmethyl)thio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][l,3]dioxol-4-yl)oxy)ethan-l-ol 2h

[0293] Compound 2g (480 mg, 1.11 mmol) was dissolved in acetic acid (6 mL) and water (3 mL), cooled to 0 °C, and sodium nitrite (92 mg, 1.33 mmol) was added. After the addition was completed, the reaction was continued at 0 °C for 1 h. TLC detection showed that the starting material was completely converted. The reaction solution was added dropwise to saturated aqueous sodium bicarbonate solution to adjust pH = 7, and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 2h (480 mg, yield 98%) as a brown oil.

[0294] LC-MS: m / z = 442.2 [M+H] +

[0295] Seventh Step 2-(((3aR,4S,6R,6aS)-6-(5-((cyclopropylmethyl)thio)-7-(((1R,2S)-2-(3,4- difluorophenyl)cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2- dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol 2j

[0296] Compound 2h (480 mg, 1.09 mmol) was dissolved in dichloromethane (5 mL), and (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (R)-mandelate 2i (421 mg, 1.31 mmol) and N,N-diisopropylethylamine (423 mg, 3.27 mmol) were added. After the addition was completed, the reaction was continued at room temperature for 3 h, and TLC detection showed that the starting material was completely converted. The reaction solution was diluted with dichloromethane (10 mL), and water (20 mL) was added to separate the layers. The aqueous phase was extracted with dichloromethane (10 mL x 2), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 60 / 1) to give the title compound 2j (420 mg, yield 67%) as a white foam.

[0297] Eighth Step (1S,2S,3R,5S)-3-(5-((cyclopropylmethyl)thio)-7-(((1R,2S)-2-(3,4- difluorophenyl)cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2- hydroxyethoxy)cyclopentane-1,2-diol 2

[0298] Compound 2j (120 mg, 0.21 mmol) was dissolved in methanol (5 mL), added to concentrated hydrochloric acid (1 mL), reacted at room temperature for 3 hours, and TLC detection showed that the reaction was complete. The reaction liquid was adjusted to neutral pH with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by Prep-TLC (dichloromethane / methanol = 10 / 1) to obtain the title compound 2 (80 mg, yield 72%) as a white solid.

[0299] LC-MS: m / z = 535.2 [M+H] + (99.34% purity by HPLC, 220 nm)

[0300] 1 H NMR (400 MHz, DMSO-d6) δ 9.38 (d, J = 4.0 Hz, 0.8H), 8.97 (d, J = 4.8 Hz, 0.2H), 7.38-7.22 (m, 2H), 7.09-7.02 (m, 1H), 5.14-5.05 (m, 2H), 5.00-4.91 (m, 1H), 4.61 (t, J = 4.8 Hz, 1H), 4.58-4.51 (m, 1H), 3.96-3.91 (m, 1H), 3.78-3.72 (m, 1H), 3.55-3.43 (m, 4H), 3.19-3.13 (m, 0.7H), 3.10-3.06 (m, 0.3H), 2.91 (dd, J = 13.6, 7.2 Hz, 1H), 2.76 (dd, J = 13.6, 7.2 Hz, 1H), 2.68-2.59 (m, 1H), 2.14-2.07 (m, 0.7H), 2.05-1.96 (m, 1H), 1.91 (s, 0.3H), 1.60-1.53 (m, 0.8H), 1.50-1.43 (m, 0.2H), 1.42-1.31 (m, 1H), 1.10-0.95 (m, 1H), 0.56-0.49 (m, 0.4H), 0.45-0.35 (m, 1.6H), 0.32-0.28 (m, 0.4H), 0.12-0.04 (m, 1.6H).

[0301] Example 3-11

[0302] Example 3-11 was synthesized according to the synthetic method of Example 2:

[0303]

[0304]

[0305]

[0306] Example 12

[0307] (1S,2S,3R,5S)-3-(5-((2-cyclopentylethyl)thio)-7-(((1R,2S)-2-(3,4- difluorophenyl)cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2- hydroxyethoxy)cyclopentan-1,2-diol 12

[0308]

[0309] First step 2-cyclopentylethyl 4-methylbenzenesulfonate 12b

[0310] 2-cyclopentylethanol 12a (5.00 g, 43.79 mmol) was dissolved in dichloromethane (100 mL), triethylamine (8.86 g, 87.56 mmol) and 4-dimethylaminopyridine (0.27 g, 2.21 mmol) were added at room temperature, after addition, ice water bath was cooled to 0 °C, p-toluenesulfonyl chloride (10.85 g, 56.91 mmol) was added in batches, after addition, it was stirred at room temperature for 16 hours, TLC monitoring showed that the raw material reacted completely, the reaction liquid was cooled to 0 °C in an ice water bath, water (80 mL) was added for quenching, dichloromethane (50 mL x 3) was extracted, the combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1-10 / 1) to give the title compound 12b (11.31 g, yield 96%) as a light yellow oil.

[0311] 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.04 (t, J = 6.4 Hz, 2H), 2.45 (s, 3H), 1.85-1.75 (m, 1H), 1.72-1.63 (m, 4H), 1.59-1.55 (m, 2H), 1.52-1.43 (m, 2H), 1.06-0.97 (m, 2H).

[0312] Second step 2-((2-cyclopentylethyl)thio)pyrimidine-4,6-diol 12c

[0313] Compound 2a (5.00 g, 34.69 mmol) was dispersed in ethanol (100 mL), and triethylamine (5.05 g, 49.91 mmol) was added at room temperature. Compound 12b (11.31 g, 42.14 mmol) and potassium iodide (0.69 g, 4.16 mmol) were added, and the reaction solution was heated to reflux and stirred for 16 h. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, concentrated, and washed with water (100 mL). The filter cake was washed with water (50 mL) and dried to give the title compound 12c (4.01 g, yield 40%) as a white solid.

[0314] LC-MS: m / z = 241.1 [M+H] +

[0315] Third step 2-((2-cyclopentylethyl)thio)-5-nitropyrimidine-4,6-diol 12d

[0316] Fuming nitric acid (1.05 g, 16.64 mmol) was slowly added dropwise to glacial acetic acid (5 mL) at room temperature. After the addition was complete, the reaction solution was cooled to 0 °C, and compound 12c (1.00 g, 4.16 mmol) was added in portions. After the addition was complete, the reaction solution was warmed to room temperature and stirred for 5 h. LCMS showed that the reaction was complete. The reaction solution was filtered, washed with a small amount of glacial acetic acid (2 mL), and the solid was collected and dried to give the title compound 12d (0.60 g, yield 51%) as a light brown solid.

[0317] LC-MS: m / z = 286.1 [M+H] +

[0318] Fourth step 4,6-dichloro-2-((3,3-dimethylbutyl)thio)-5-nitropyrimidine 12e

[0319] Compound 12d (0.60 g, 2.10 mmol) was dispersed in phosphorus oxychloride (2.29 g, 14.94 mmol), and the reaction system was warmed to 40 °C and stirred for 10 min. N,N-dimethylaniline (0.61 g, 5.03 mmol) was added, and the reaction solution was continuously warmed to 60 °C and stirred for 2 h. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, slowly added to water (20 mL) to quench, and extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) to give the title compound 12e (0.63 g, yield 93%) as a light yellow oil.

[0320] Step 5 2-(((3aR,4S,6R,6aS)-6-((6-chloro-2-((2-cyclopentylethyl)thio)-5-nitropyrimidin-4-yl)amino)- 2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1 -ol 12f

[0321] Compound 12e (0.63 g, 1.96 mmol) was dissolved in dichloromethane (10 mL), compound 2e (0.86 g, 2.34 mmol) and N, N-diisopropylethylamine (0.76 g, 5.88 mmol) were added at room temperature. After addition, it was stirred at room temperature for 3 hours, TLC showed that the reaction was complete. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1-3 / 1) to obtain the title compound 12f (0.33 g, yield 34%) as a light yellow oil.

[0322] Step 6 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-((2-cyclopentylethyl)thio)pyrimidin-4-yl)amino)- 2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1 -ol 12g

[0323] Compound 12f (0.33 g, 0.66 mmol) was dissolved in methanol (5 mL), and reduced iron powder (0.37 g, 6.62 mmol) and acetic acid (1.19 g, 19.83 mmol) were added at room temperature. After addition, it was stirred at room temperature for 3 hours, TLC showed that the reaction was complete. The reaction solution was stirred with water (20 mL) and ethyl acetate (20 mL) for 5 minutes, then filtered with diatomite, separated, and the organic phase was extracted with ethyl acetate (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 12g (0.29 g, yield 92%) as a light brown foaming substance.

[0324] LC-MS: m / z = 473.2 [M+H] +

[0325] Step 7 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-((2-cyclopentylethyl)thio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)- 2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1 -ol 12h

[0326] Compound 12g (290 mg, 0.61 mmol) was dissolved in a mixture of acetic acid (4 mL) and water (2 mL), sodium nitrite (50 mg, 0.72 mmol) was added slowly at 0 °C, and the mixture was stirred for 30 min. TLC showed that the reaction was complete. The reaction solution was adjusted to neutral pH with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound 12h (280 mg, yield 95%) as a light brown oil.

[0327] Eighth Step (1S,2S,3R,5S)-3-(5-((2-Cyclopentylethyl)thio)-7-(((1R,2S)-2-(3,4- difluorophenyl)cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2- hydroxyethoxy)cyclopentan-1,2-diol 12i

[0328] Compound 12h (280 mg, 0.58 mmol) was dissolved in dichloromethane (5 mL), and compound 2i (225 mg, 0.70 mmol) and N,N-diisopropylethylamine (225 mg, 1.74 mmol) were added at room temperature. After stirring at room temperature for 16 h, TLC showed that the reaction was complete. The mixture was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give the title compound 12i (210 mg, yield 59%) as a colorless foam.

[0329] Ninth Step (1S,2S,3R,5S)-3-(5-((2-Cyclopentylethyl)thio)-7-(((1R,2S)-2-(3,4- difluorophenyl)cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2- hydroxyethoxy)cyclopentan-1,2-diol 12

[0330] Compound 12i (210 mg, 0.34 mmol) was dissolved in methanol (5 mL), and concentrated hydrochloric acid (1 mL) was added at room temperature. After the addition was completed, the mixture was stirred at room temperature for 3 h. TLC showed that the reaction was complete. The mixture was adjusted to neutral pH with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-TLC (dichloromethane / methanol = 10 / 1) to give the title compound 12 (145 mg, yield 74%) as a white solid.

[0331] LC-MS: m / z = 577.2 [M+H] + (98.92% purity by HPLC, 220 nm)

[0332] 1 H NMR (400 MHz, DMSO-d6) δ 9.37 (d, J = 4.0 Hz, 1H), 7.38 - 7.25 (m, 2H), 7.10 - 7.01 (m, 1H), 5.12 (d, J = 6.4 Hz, 1H), 5.05 (d, J = 4.0 Hz, 1H), 4.96 (q, J = 9.2 Hz, 1H), 4.63 - 4.53 (m, 2H), 3.96 - 3.90 (m, 1H), 3.79 - 3.72 (m, 1H), 3.54 - 3.44 (m, 4H), 3.19 - 3.13 (m, 1H), 3.02 - 2.94 (m, 1H), 2.90 - 2.79 (m, 1H), 2.67 - 2.57 (m, 1H), 2.16 - 2.10 (m, 1H), 2.04 - 1.97 (m, 1H), 1.67 - 1.34 (m, 11H), 1.16 - 0.93 (m, 2H).

[0333] Examples 13-14

[0334] The compounds of Examples 13-14 were synthesized according to the synthetic procedure of Example 12:

[0335]

[0336] Example 15

[0337] (1S,2S,3R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5- (propylamino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane- 1,2-diol 15

[0338]

[0339] First step (3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2- dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-amine 15a

[0340] Compound 2e (10 g, 27.22 mmol) was dissolved in dichloromethane (200 mL), and then tert-butyldimethylsilyl chloride (12.31 g, 81.66 mmol) and imidazole (14.83 g, 217.76 mmol) were added successively. After addition, the reaction was allowed to proceed at room temperature for 16 hours. The reaction was complete as determined by TLC. The reaction solution was diluted with water (200 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the title compound intermediate 15a (6.58 g, yield 73%) as a yellow oil.

[0341] Second step 2-(methylthio)-5-nitropyrimidine-4,6-diol 15c

[0342] Fuming nitric acid (2.39 g, 37.82 mmol) was slowly added to acetic acid (20 mL) at 10°C, and 2-methylthio-4,6-dihydroxypyrimidine 15b (2.00 g, 12.64 mmol) was added to the reaction system at the same temperature. After addition, the reaction was allowed to proceed at room temperature for 16 hours, during which a large amount of solid was precipitated. The reaction was complete as determined by TLC. The solid was directly filtered, and the filter cake was washed with acetic acid (2 mL) and dried to obtain the title compound 15c (1.97 g, yield 77%) as a light yellow solid.

[0343] Third step 4,6-dichloro-2-(methylsulfanyl)-5-nitropyrimidine 15d

[0344] Compound 15c (1.95 g, 9.60 mmol) was dispersed in phosphorus oxychloride (10.61 g, 69.22 mmol) at 0°C, and the reaction system was allowed to warm to 40°C. N,N-dimethylaniline (2.33 g, 19.2 mmol) was added dropwise to the reaction system, and after addition, the reaction was allowed to proceed at 60°C for 16 hours. The reaction was complete as determined by TLC. The reaction solution was cooled to room temperature, and then slowly added to ice water to quench the reaction. A large amount of solid was precipitated, which was filtered and dried to obtain the title compound 15d (1.89 g, crude) as a brown solid, which was directly used in the next step.

[0345] Fourth step N-((3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-chloro-2-(methylthio)-5-nitropyrimidin-4-amine 15e

[0346] Compound 15d (240 mg, 1.0 mmol) was dissolved in dichloromethane (3 mL), cooled to 0 °C, compound 15a (331 mg, 1.0 mmol) and N,N-diisopropylethylamine (258 mg, 2.0 mmol) were added, and the reaction was allowed to proceed at room temperature for 3 h. TLC indicated that the starting material was consumed completely. The reaction was quenched with water (10 mL), and the mixture was extracted with dichloromethane (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-30%) to give the title compound 15e (311 mg, 48% yield over two steps) as a light yellow oil.

[0347] Fifth Step N 4 -((3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)-6-chloro-2-(methylthio)pyrimidine-4,5-diamine 15f

[0348] Compound 15e (311 mg, 0.58 mmol) was dissolved in methanol (2 mL), and iron powder (324 mg, 5.8 mmol) and acetic acid (1.04 g, 17.4 mmol) were added. The reaction was allowed to proceed at room temperature for 16 h. TLC indicated that the reaction was complete. The mixture was filtered, diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound 15f (292 mg, crude) as a light yellow oil, which was used directly in the next step.

[0349] Sixth Step 3-((3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)-7-chloro-5-(methylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine 15g

[0350] Compound 15f (290 mg, 0.57 mmol) was dissolved in a mixture of acetic acid (1.25 mL) and water (0.25 mL), and cooled to 0 °C. Sodium nitrite (47 mg, 0.68 mmol) was added to the above system, and the reaction was allowed to proceed at this temperature for 1 h. TLC indicated that the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution, and the pH was adjusted to 7. The mixture was extracted with ethyl acetate (10 mL x 2), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound 15g (291 mg, crude) as a colorless oil, which was used directly in the next step.

[0351] Step 7 3-((3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2- dimethyltetrahydro-4H-cyclopenta[d][l,3]dioxol-4-yl)-N-((lR,2S)-2-(3,4- difluorophenyl)cyclopropyl)-5-(methylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7- amine 15h

[0352] Compound 15g (291 mg, 0.56 mmol) was dissolved in dichloromethane (3 mL), cooled to 0 °C, and compound 2i (216 mg, 0.67 mmol) and N,N- diisopropylethylamine (145 mg, 1.12 mmol) were added. After the addition was complete, the reaction was allowed to proceed at room temperature for 16 h. The reaction was complete as determined by TLC. The reaction was quenched with water (10 mL) and extracted with dichloromethane (10 mL x 2). The combined organic layers were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give the title compound 15h (286 mg, 76% over three steps) as a white solid.

[0353] Step 8 3-((3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2- dimethyltetrahydro-4H-cyclopenta[d][l,3]dioxol-4-yl)-N-((lR,2S)-2-(3,4- difluorophenyl)cyclopropyl)-5-(methylsulfonyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7- amine 15i

[0354] Compound 15h (230 mg, 0.35 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 °C, and m-chloroperoxybenzoic acid (145 mg, 0.71 mmol, 85%) was added. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 h. The reaction was complete as determined by TLC. The reaction was quenched with water (10 mL) and extracted with dichloromethane (10 mL x 2). The combined organic layers were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the title compound 15i (221 mg, 93% yield) as a white solid.

[0355] Step 9 3-((3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2- dimethyltetrahydro-4H-cyclopenta[d][l,3]dioxol-4-yl)-N-((lR,2S)-2-(3,4- difluorophenyl)cyclopropyl)-5-(methylsulfonyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7- amine 15i 7 -((lR,2S)-2-(3,4-difluorophenyl)cyclopropyl)-N 5Propyl-3H-[l,2,3]triazolo[4,5-d]pyrimidine-5,7-diamine 15j

[0356] Compound 15i (100 mg, 0.15 mmol) was dissolved in dimethyl sulfoxide (1.5 mL), n-propylamine (35 mg, 0.60 mmol) and N,N-diisopropylethylamine (97 mg, 0.75 mmol) were added at room temperature, after the addition was completed, the reaction was carried out at 100 °C for 48 hours. TLC detection showed that the reaction was complete, the reaction solution was quenched with water (10 mL), extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by pre-TLC (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound 15j (41 mg, yield 42%) as a white solid.

[0357] Step 10 (IS, 2S, 3R, 5S)-3-(7-(((IR, 2S)-2-(3, 4-difluorophenyl)cyclopropyl)amino)-5- (propylamino)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane- 1,2-diol 15

[0358] Compound 15j (41 mg, 0.062 mmol) was dissolved in methanol (0.5 mL), cooled to 0 °C, and concentrated hydrochloric acid (0.1 mL) was added, after the addition was completed, the reaction was carried out at room temperature for 2 hours. TLC detection showed that the reaction was complete, the reaction solution was adjusted to neutral pH with saturated sodium bicarbonate solution, extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by pre-TLC (dichloromethane / methanol = 20 / 1) to obtain the title compound 15 (17 mg, yield 54%) as a white solid.

[0359] LC-MS: m / z = 506.2 [M+H] + (96.34% purity by HPLC, 220 nm)

[0360] 1H NMR (400 MHz, DMSO-d6): δ 8.23 (br, 1H), 7.57-7.31 (m, 2H), 7.27-7.15 (m, 1H), 7.06 (t, J = 5.2 Hz, 1H), 4.82-4.66 (m, 2H), 4.56 (t, J = 4.8 Hz, 1H), 4.40 (s, 1H), 4.02 (s, 1H), 3.87 (s, 1H), 3.79 (s, 1H), 3.61 (s, 1H), 3.54-3.38 (m, 4H), 3.24 (d, J = 5.2 Hz, 2H), 2.74 (s, 1H), 2.48-2.28 (m, 1H), 2.13-1.91 (m, 1H), 1.75 (s, 1H), 1.61-1.46 (m, 2H), 1.47-1.31 (m, 1H), 0.87 (t, J = 7.2 Hz, 3H).

[0361] Example 16

[0362] (1S,2S,3R,5S)-3-(4-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-2- (isopentylthio)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(2-hydroxyethoxy)cyclopentane- 1,2-diol 16

[0363]

[0364] First step 2-(isopentylthio)pyrimidine-4,6-diol 16a

[0365] 4,6-Dihydroxy-2-mercaptopyrimidine 2a (10.0 g, 69.38 mmol) was dispersed in methanol (50 mL), 1-bromoiso-pentane (10.48 g, 69.38 mmol) and triethylamine (8.42 g, 83.26 mmol) were added at room temperature and heated to reflux under nitrogen for 16 h. TLC monitoring showed that the reaction was complete. The reaction was cooled to room temperature and concentrated. The crude product was slurried in ethyl acetate (50 mL) and water (50 mL), filtered and the filter cake was dried to give the title compound 16a (3.51 g, yield 23.61%) as a white solid.

[0366] LC-MS: m / z = 215.1 [M+H] +

[0367] Second step 4,6-dichloro-2-(isopentylthio)pyrimidine 16b

[0368] Compound 16a (1.0 g, 4.67 mmol) was dispersed in phosphorus oxychloride (2.86 g, 18.68 mmol) at 0 °C, N,N-dimethylaniline (1.13 g, 9.34 mmol) was added, heated to reflux for 16 h, TLC detection showed the reaction was completed. The reaction was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, concentrated, the crude product was purified by silica gel column chromatography (petroleum ether) to give the title compound 16b (0.54 g, yield 46%) as a colorless liquid.

[0369] Third step 2-(4,6-dichloro-2-(isopentylthio)pyrimidin-5-yl)ethan-1-ol 16d

[0370] Compound 16b (0.40 g, 1.59 mmol) was dissolved in tetrahydrofuran (20 mL), under nitrogen protection, n-butyllithium (0.96 mL, 2.39 mmol, 2.5 M) was added dropwise at -78 °C, after stirring for 30 min, 1,3,2-dioxazolothiophene-2,2-dioxide 16c (0.28 g, 2.23 mmol) was added, continue to stir for 2 h. TLC detection showed that the reaction was completed. The reaction was slowly raised to room temperature, diluted hydrochloric acid (5.6 mL, 6N) was added, room temperature reaction for 16 h, TLC detection showed that the reaction was completed. The reaction was adjusted to neutral pH with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, concentrated, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give the title compound 16d (0.33 g, yield 70.19%) as a yellow oily liquid.

[0371] LC-MS: m / z = 295.1 [M+H] +

[0372] Fourth step 2-(4-(((3aR,4S,6R,6aS)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2- dimethyltetrahydro-4H-cyclopenta[d][1,3])dioxolan-4-yl)amino)-6-chloro-2- (isopentylthio)pyrimidin-5-yl)ethan-1-ol 16e

[0373] Compound 16d (0.33 g, 1.18 mmol) was dissolved in 1,4-dioxane (10 mL), compound 15a (0.59 g, 1.77 mmol) and N,N-diisopropylethylamine (0.76 g, 5.9 mmol) were added at room temperature, and the reaction was heated under reflux for 16 hours under nitrogen protection. TLC detection found that the reaction was completed. The reaction was cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (20 mL x 2), the organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the title compound 16e (0.46 g, yield 70%) as a yellow oil.

[0374] Step 5 7-((3aR,4S,6R,6aS)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2- dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-2-(isopentylthio)- 7H-pyrrolo[2,3-d]pyrimidine 16f

[0375] Compound 16e (0.46 g, 0.78 mmol) was dissolved in dichloromethane (15 mL), and Dess-Martin oxidant (0.99 g, 2.34 mmol) was added at 0°C, and the reaction was slowly warmed to room temperature for 1 hour. TLC detection found that the reaction was completed. The reaction was quenched with saturated aqueous sodium thiosulfate solution (5 mL), diluted with water (10 mL), extracted with dichloromethane (10 mL x 2), the organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the title compound 16f (0.33 g, yield 74%) as a yellow oil.

[0376] Step 6 7-((3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2- dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-N-((1R,2S)-2-(3,4- difluorophenyl)cyclopropyl)-2-(isopentylthio)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 16g

[0377] Compound 16f (0.33 g, 0.58 mmol) was dissolved in dimethyl sulfoxide (4 mL), compound 2i (0.37 g, 1.16 mmol) and anhydrous potassium carbonate (0.40 g, 2.9 mmol) were added, after heating to 50 °C for 16 hours, TLC detection showed that a new spot was generated. The reaction was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain the title compound 16g (0.19 g, yield 47%) as a yellow oily liquid.

[0378] Seventh step (1S,2S,3R,5S)-3-(4-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-2- (isopentylthio)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol 16

[0379] Compound 16g (0.09 g, 0.14 mmol) was dissolved in methanol (2 mL), concentrated hydrochloric acid (0.6 mL) was added dropwise at 0 °C, after addition, it was slowly warmed to room temperature for 1 hour, TLC detection showed that the reaction was completed. The reaction was adjusted to neutral pH with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Pre-HPLC to obtain the title compound 16 (8.6 mg, yield 11%) as a white solid.

[0380] LC-MS: m / z = 549.2 [M+H] + (96.05% purity by HPLC, 210 nm)

[0381] 1H NMR (400 MHz, CDC13) δ 11.38 (s, 1H), 7.13 (d, J = 9.2 Hz, 1H), 6.99 (s, 1H), 6.91 - 6.77 (m, 2H), 6.36 (s, 1H), 5.01 (d, J = 7.6 Hz, 1H), 4.42 (s, 1H), 4.20 (s, 1H), 3.96 (s, 1H), 3.80 (s, 2H), 3.69 (s, 2H), 3.18 (t, J = 7.2 Hz, 2H), 3.04 (s, 1H), 2.78 (s, 1H), 2.24 (s, 1H), 1.98 (s, 1H), 1.80 - 1.59 (m, 4H), 1.49 - 1.19 (m, 3H), 0.95 (d, J = 6.0 Hz, 6H). (One active hydrogen not peaked)

[0382] Examples 17-29

[0383] Examples 17-28 were synthesized according to the synthetic procedure of Example 12 and Example 16:

[0384]

[0385]

[0386]

[0387] Example 30

[0388] (1S,2S,3R,5S)-3-(6-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-2- (propylthio)-9H-purin-9-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol 30

[0389]

[0390] First step 2-(((3aR,4S,6R,6aS)-6-((6-chloro-5-nitro-2-(propylthio)pyrimidin-4-yl)amino)- 2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-ethanol 30b

[0391] Compound 30b (710 mg, 1.58 mmol) was dissolved in a mixture of water (1 mL) and ethanol (7 mL), and then reduced iron powder (883 mg, 15.8 mmol) and ammonium chloride (845 mg, 15.8 mmol) were added at room temperature. After the addition was completed, the reaction was heated to 80 °C and refluxed for 16 hours. TLC detection showed that the reaction was complete. The reaction was cooled to room temperature, filtered, and the filtrate was diluted with water (20 mL). The organic phase was extracted with ethyl acetate (20 mL x 2), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound 30c (400 mg, yield 60%) as a yellow solid.

[0392] Second step 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-ethanol 30c

[0393] Compound 30b (710 mg, 1.58 mmol) was dissolved in a mixture of water (1 mL) and ethanol (7 mL), and then reduced iron powder (883 mg, 15.8 mmol) and ammonium chloride (845 mg, 15.8 mmol) were added at room temperature. After the addition was completed, the reaction was heated to 80 °C and refluxed for 16 hours. TLC detection showed that the reaction was complete. The reaction was cooled to room temperature, filtered, and the filtrate was diluted with water (20 mL). The organic phase was extracted with ethyl acetate (20 mL x 2), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound 30c (400 mg, yield 60%) as a yellow solid.

[0394] LC-MS: m / z = 419.2 [M+H] +

[0395] Third step N 4 -((3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-chloro-2-(propylthio)pyrimidine-4,5-diamine 30d

[0396] Compound 30c (250 mg, 0.6 mmol) was dissolved in dichloromethane (3 mL), tert-butyldimethylsilyl chloride (136 mg, 0.9 mmol) and imidazole (82 mg, 1.2 mmol) were added at room temperature, and the reaction was allowed to proceed at room temperature for 2 hours. TLC detection showed that the reaction was complete. The reaction solution was diluted with water (6 mL), extracted with dichloromethane (6 mL x 2), and the combined organic phases were washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by pre-TLC (petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound 30d (300 mg, yield 94%) as a yellow solid.

[0397] Fourth step 9-((3aS,4R,6S,6aR)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-chloro-2-(propylthio)-9H-purine 30e

[0398] Compound 30d (300 mg, 0.56 mmol) was dissolved in acetic acid (1.5 mL), and triethyl orthoformate (1245 mg, 8.4 mmol) was added at room temperature. After the addition was completed, the reaction was heated to 130°C and allowed to proceed for 8 hours. TLC detection showed that the reaction was complete. The reaction solution was adjusted to pH = 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (10 mL x 2), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by pre-TLC (petroleum ether / ethyl acetate = 3 / 2) to obtain the title compound 30e (80 mg, yield 26%) as a white solid.

[0399] Fifth step 2-(((3aR,4S,6R,6aS)-6-(6-chloro-2-(propylthio)-9H-purin-9-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-ethanol 30f

[0400] Compound 30e (80 mg, 0.15 mmol) was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride trihydrate (71 mg, 0.22 mmol) was added at room temperature. The reaction was allowed to proceed at room temperature for 2 hours. TLC detection showed that the reaction was complete. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by pre-TLC (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound 30f (55 mg, yield 87%) as a white solid.

[0401] Step 6 2-(((3aR,4S,6R,6aS)-6-(6-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-2- (propylthio)-9H-purin-9-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4- yl)oxy)-ethanol 30g

[0402] Compound 30f (55 mg, 0.13 mmol), compound 2i (84 mg, 0.26 mmol) and N,N- diisopropylethylamine (67 mg, 0.52 mmol) were added to n-butanol (0.5 mL) at room temperature, heated to 40 °C for 24 hours, TLC test showed the starting material was consumed completely. The reaction was cooled to room temperature, diluted with water (5 mL), extracted with ethyl acetate (5 mL x 2), the organic phase was combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated, the crude product was purified by pre-TLC (dichloromethane / methanol = 15 / 1) to give the title compound 30g (42 mg, yield 58%) as a white solid.

[0403] LC-MS: m / z = 562.3 [M+H] + (98.86% purity, 220 nm)

[0404] Step 7 (1S,2S,3R,5S)-3-(6-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-2- (propylthio)-9H-purin-9-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol 30

[0405] Compound 30g (42 mg, 0.075 mmol) was added to methanol (0.5 mL), concentrated hydrochloric acid (0.1 mL) was added at room temperature, the reaction was stirred at room temperature for 4 hours, TLC test showed the reaction was completed. The reaction was adjusted to pH = 7 with saturated sodium bicarbonate solution, extracted with ethyl acetate (5 mL x 2), the organic phase was combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated, the crude product was purified by pre-TLC (dichloromethane / methanol = 10 / 1) to give the title compound 30 (15 mg, yield 38%) as a white solid.

[0406] LC-MS: m / z = 522.3 [M+H] +

[0407] 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.07 (s, 1H), 7.36-7.25 (m, 2H), 7.04 (m, 1H), 5.01 (d, J = 25.6 Hz, 2H), 4.64-4.57 (m, 2H), 4.44 (s, 1H), 3.89 (d, J = 4.8 Hz, 1H), 3.71 (t, J = 4.8 Hz, 1H), 3.51-3.46 (m, 4H), 3.05-2.81 (m, 3H), 2.06-1.91 (m, 2H), 1.49 (s, 3H), 1.32-1.23 (m, 2H), 0.82 (s, 3H).

[0408] Example 31

[0409] (1S,2S,3R,5S)-3-(7-(((1R)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5- propoxy-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2- diol 31

[0410]

[0411] First step propyl carbamate methanesulfonate 31b

[0412] Monocyanamide 31a (4.2 g, 99.90 mmol) was dissolved in n-propanol (24.02 g, 399.6 mmol) and methanesulfonic acid (9.60 g, 99.90 mmol) was added at room temperature. The reaction was stirred at room temperature for 24 h. TLC indicated the reaction was complete. The reaction was concentrated and the crude product was slurried in methyl tert-butyl ether (50 mL) to give the title compound 31b (15 g, crude) as a white solid which was used directly in the next step.

[0413] LC-MS: m / z = 103.2 [M+H] +

[0414] Second step 2-propoxy pyrimidine-4,6-diol 31c

[0415] Compound 31b (10.0 g, 50.51 mmol) was dissolved in methanol (50 mL). The reaction system was cooled to 0 °C, and sodium methoxide (13.10 g, 242.43 mmol) was added in three portions. After the addition was complete, dimethyl malonate (11.53 g, 87.27 mmol) was added. The reaction solution was brought to room temperature and reacted for 6 hours. The reaction was confirmed to be complete by TLC. The reaction solution was concentrated, and the crude product was diluted with water (30 mL). The pH was adjusted to 4 with dilute hydrochloric acid (1 N), resulting in the precipitation of a large amount of solid. The solid was filtered, the filter cake was collected, and dried to obtain a white solid, title compound 31c (4.5 g, crude product), which was used directly in the next step.

[0416] Step 3: 5-Nitro-2-propoxypyrimidine-4,6-diol 31d

[0417] Fuming nitric acid (5.29 g, 0.084 mol) was slowly added dropwise to acetic acid (15 mL) at 10 °C. After the addition was complete, the reaction mixture was cooled to 0 °C. Then, compound 31c (3.50 g, 0.021 mol) was added to the reaction system in portions. After the addition was complete, the mixture was allowed to react at room temperature for 4 hours. The reaction was confirmed to be complete by TLC. The reaction mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a yellow solid, title compound 31d (3.2 g, crude product), which was used directly in the next step.

[0418] LC-MS: m / z = 216.1 [M+H] +

[0419] Step 4: 4,6-Dichloro-5-nitro-2-propoxypyrimidine 31e

[0420] Compound 31d (700 mg, 3.25 mmol) was slowly added to phosphorus oxychloride (2.5 mL) at 0 °C. After the addition was complete, the mixture was heated to 40 °C, and N,N-diethylaniline (1.2 mL) was added dropwise. After the addition was complete, the mixture was heated to 60 °C and reacted for 3 hours. The reaction was confirmed to be complete by TLC. The reaction mixture was cooled to room temperature, quenched by slow addition of water (20 mL), extracted with dichloromethane (20 mL x 2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a yellow solid, title compound 31e (550 mg, 19% yield in four steps).

[0421] Step 5: 2-(((3aR,4S,6R,6aS)-6-((6-chloro-5-nitro-2-propoxypyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopentadiene[d][1,3]dioxolane-4-yl)oxy)-ethanol-1-ol 31f

[0422] Compound 31e (310 mg, 1.23 mmol) was dissolved in dichloromethane (3 mL), the reaction system was cooled to 0 °C, compound 2e (452 mg, 1.23 mmol) and N, N- diisopropylethylamine (477 mg, 3.69 mmol) were added, the reaction was carried out at room temperature for 1 h, TLC detection showed that the raw material was completely reacted, water (10 mL) was added, dichloromethane (10 mL x 2) was extracted, the combined organic phase was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-1.5) to obtain the title compound 31f (270 mg, yield 51%) as a yellow solid.

[0423] LC-MS: m / z = 433.2 [M+H] +

[0424] Sixth step 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-propoxy-pyrimidin-4-yl)amino)- 2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-ethan-1-ol 31g

[0425] Compound 31f (270 mg, 0.62 mmol) was dissolved in methanol (3 mL), iron powder (346 mg, 6.2 mmol) and acetic acid (1.1 g, 18.6 mmol) were added at room temperature, and the reaction was carried out at room temperature for 16 h. TLC detection showed that the reaction was complete, filtered, the filtrate was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 31g (245 mg, crude) as a yellow solid, which was directly used in the next step.

[0426] LC-MS: m / z = 403.2 [M+H] +

[0427] Seventh step 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-propoxy-3H-[1,2,3]triazolo[4,5-d]pyrimidin- 3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-ethan-1-ol 31h

[0428] Compound 31g (245 mg, 0.61 mmol) was dissolved in a mixture of acetic acid (2.5 mL) and water (1.25 mL), and cooled to 0 °C. Sodium nitrite (51 mg, 0.73 mmol) was added portionwise. After the addition was completed, the reaction was continued at 0 °C for 0.5 h. TLC detection showed that the reaction was complete. The reaction solution was adjusted to pH = 7 with saturated sodium bicarbonate solution, extracted with ethyl acetate (10 mL x 2), washed with water (10 mL), saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound 31h (250 mg, crude) as a white solid, which was used directly in the next step. LC-MS: m / z = 414.2 [M+H] +

[0429] Eighth Step 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5- propoxy-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)oxy)-ethan-1-ol 31i

[0430] Compound 31h (100 mg, 0.24 mmol) was dissolved in dichloromethane (1 mL), and the reaction system was cooled to 0 °C. Compound 2i (93 mg, 0.29 mmol) and N,N-diisopropyl ethylamine (93 mg, 0.72 mmol) were added. After the addition was completed, the reaction was continued at room temperature for 4 h. TLC detection showed that the starting material was completely consumed. The reaction solution was added with water (10 mL), extracted with dichloromethane (10 mL x 2), and the combined organic phases were washed with water (10 mL), saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0-0.1) to give the title compound 31i (130 mg, 96% for three steps) as a white solid.

[0431] LC-MS: m / z = 547.3 [M+H] +

[0432] Ninth Step (1S,2S,3R,5S)-3-(7-(((1R)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5- propoxy-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2- diol 31

[0433] Compound 31i (130 mg, 0.075 mmol) was added to methanol (1.5 mL), and concentrated hydrochloric acid (0.5 mL) was added. The reaction was stirred at room temperature for 4 h, and TLC detection showed that the reaction was complete. The reaction solution was adjusted to pH = 7 with saturated sodium bicarbonate solution, extracted with ethyl acetate (5 mL x 2), the combined organic phase was washed with water (5 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by pre-TLC (dichloromethane / methanol = 10 / 1) to give the title compound 31 (100 mg, yield 82%) as a white solid.

[0434] LC-MS: m / z = 507.2 [M+H] + (99.46% purity by HPLC, 210 nm)

[0435] 1 H NMR (400 MHz, DMSO-d6) δ 9.27-8.81 (m, 1H), 7.35-7.28 (m, 2H), 7.07-7.00 (m, 1H), 5.09 (d, J = 6.4 Hz, 1H), 5.04 (d, J = 4.0 Hz, 1H), 4.91 (q, J = 8.8 Hz, 1H), 4.60 (t, J = 4.4 Hz, 1H), 4.56-4.51 (m, 1H), 4.21, 4.08 (t, J = 6.8 Hz, 2H), 3.94 (s, 1H), 3.74 (t, J = 4.8 Hz, 1H), 3.53-3.42 (m, 4H), 3.16-3.09 (m, 1H), 2.65-2.57 (m, 1H), 2.24-2.09 (m, 1H), 2.00-1.97 (m, 1H), 1.71-1.56 (m, 2H), 1.54-1.45 (m, 1H), 1.38-1.33 (m, 1H), 0.95, 0.83 (t, J = 7.6 Hz, 3H).

[0436] Pharmacological experiments

[0437] Whole-cell electrophysiological test

[0438] The cDNA of human TREK-1 was subcloned into the pEGFP-N1 expression vector. The constructed plasmid was transfected into CHO-K1 cells using Lipofectamine 3000. The cell culture medium used in the experiment was DMEM / F12, containing 10% FBS and 1% penicillin-streptomycin. The culture conditions were 37°C constant temperature and 5% CO2 gas environment.

[0439] Cells were cultured for 16-36 hours after transfection and used for electrophysiological experiments. The Whole-Cell Recording patch clamp recording mode was used for detection. The experiment used HEKA EPC10 amplifier, Sutter Instrument MP-225 micro-operation system, Nikon fluorescence microscope, and Bio-Logic RSC-200 drug delivery system. The glass electrode was drawn by Sutter Instrument P-97 electrode puller, and the liquid entry resistance was 3-7 MΩ. The composition of the TREK-1 intracellular solution includes: 140 mM KCl, 2 mM MgCl2, 10 mM EGTA, 1 mM CaCl2, 10 mM HEPES, and the pH is adjusted to 7.3 with KOH; the composition of the extracellular solution includes: 150 mM NaCl, 5 mM KCl, 0.5 mM CaCl2, 1.2 mM MgCl2, 10 mM HEPES, and the pH is adjusted to 7.3 with NaOH. The I-V curve of TREK-1 was detected by using a ramp from -100 mV to +100 mV with a duration of 1 s, and the clamping voltage was -80 mV. The current signal detected was filtered by using a low-frequency filter with a frequency of 2 kHz, and the sampling frequency was 10 kHz.

[0440] The test concentration of the compound is 1 μM, 5 μM or 10 μM, and the specific test concentration is indicated in the brackets. The activation multiple greater than 1 indicates that the compound has TREK-1 agonistic activity, and the greater the value, the better the agonistic activity.

[0441] Table 1: List of TREK-1 agonistic activity of compounds

[0442]

[0443] Conclusion: The compound of the embodiment of the application has significant activation capacity on the TREK-1 channel, and is an agonist of TREK-1.

[0444] Test Example 2: Determination of the inhibitory activity of the compound on P2Y12 receptor by HTRF cAMP method

[0445] The detection concentration of the positive control Ticagrelor is 10 μM initially, 5-fold dilution, 10 concentrations, and 2 repeats. The control is 0.2% DMSO.

[0446] Cell culture: A CHO cell line stably expressing P2Y12 receptor (constructed by Beijing Aisipu Biotechnology Co., Ltd., expressing human P2Y12 gene) was used. The P2Y12 stably expressed CHO cell line was cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B, and the culture temperature was 37°C and the carbon dioxide concentration was 5%.

[0447] Cell passage: Remove the old culture medium and wash once with PBS, then add 1 mL of TrypLE™ Express solution and incubate at 37°C for approximately 2 minutes. When the cells detach from the bottom of the dish, add approximately 5 mL of preheated (37°C) complete culture medium. Gently pipette the cell suspension to separate any aggregated cells. Transfer the cell suspension to a sterile centrifuge tube, centrifuge at 1000 rpm for 5 minutes to collect the cells for experimental or passage culture purposes.

[0448] To maintain the physiological activity of the cells, the degree of cell fusion in the experiment was controlled at around 80%.

[0449] Cell passage, resuscitation, and cryopreservation were all performed according to standard procedures. All operations followed the standard operating procedures for cell culture of Beijing Aisiyipu Biotechnology Co., Ltd.

[0450] Determination of the inhibitory activity of the compound against P2Y12:

[0451] (1) Prepare 1×Stimulation Buffer according to the kit instructions;

[0452] (2) The compound was serially diluted 10 times, and then diluted to 10× with 1× Stimulation Buffer;

[0453] (3) Culture the stable cell line to 80% confluence; collect cells by trypsin digestion, count them and seed 5 μL / well into 384-well plates;

[0454] (4) Take 1 μL of the diluted compound from step 2 and add it to the corresponding experimental well. After centrifugation, place it at 37°C for 15 min.

[0455] (5) Then add 4 μL of 2.5 μM Forskolin & 4 nM 2-MeSADP solution, centrifuge and incubate at 37 °C for 30 min to induce cAMP production;

[0456] (6) Dilute Eu-cAMP to working concentration with detection buffer and add 5 μL to the experimental well;

[0457] (7) ULight TM Anti-cAMP was diluted to the working concentration with detection buffer, and 5 μL was added to each well. After centrifugation, the mixture was incubated at room temperature for 1 h.

[0458] (8) After the incubation is completed, the wavelength 330 nm excitation under 665 nm and 620 nm reading values are detected by using an enzyme label instrument. The ratio (665 / 620) and the compound concentration are plotted.

[0459] Data analysis:

[0460] 1) Z' factor = 1 - 3 * (SD Max + SD Min ) / (AVG Max - AVG Min );

[0461] 2) CV Max = (SD Max / AVG Max ) * 100%;

[0462] 3) CV Min = (SD Min / AVG Min ) * 100%;

[0463] 4) S / B = Signal / Background;

[0464] 5) The IC 50 of the compound is calculated by using a non-linear fitting formula of GraphPad Prism:

[0465] Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X) * HillSlope))

[0466] The results are shown in Table 2:

[0467] Table 2: P2Y12 inhibitory activity list of compounds

[0468]

[0469] Conclusion: From the above table, it can be seen that, through structural optimization, the activity of a large number of compounds of the application on P2Y12 has been greatly reduced compared with ticagrelor, and the compounds can be used as high-selectivity TREK-1 agonists for further research, so as to promote the development of the field.

[0470] The present application is not limited to the above-described embodiments, and does not mean that the present application must depend on the above-described embodiments to be implemented. It should be understood by those skilled in the art that any improvement of the present application, equivalent replacement of each raw material of the product of the present application, addition of auxiliary ingredients, selection of specific modes, etc. all fall within the protection scope and disclosure scope of the present application.

[0471] The preferred embodiments of the present application are described in detail above, but the present application is not limited to the specific details in the above-described embodiments, and various simple modifications can be made to the technical solutions of the present application within the technical concept of the present application, and these simple modifications all belong to the protection scope of the present application.

[0472] In addition, it should be noted that each specific technical feature described in the above-described specific embodiments can be combined in any appropriate manner without contradiction, and in order to avoid unnecessary repetition, the present application will not further describe various possible combination manners.

Claims

1. Use of a compound, which is: ###0001### or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament having the effect of an agonist of the potassium ion channel TREK-1.

2. Use according to claim 1, wherein, The medicament is for the reduction and / or elimination of pain.

3. Use according to claim 2, wherein the pain is selected from the group consisting of chronic pain, acute pain, the chronic pain is selected from the group consisting of muscle and soft tissue pain, bone and joint pain, headache, visceral pain, pathological neuralgia. The pain is cancer pain, the cancer is selected from the group consisting of sarcoma, adrenal gland cancer, bladder cancer, bone cancer, brain cancer, breast cancer, carcinoid, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, head cancer, neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, nervous system tumor, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, urethral cancer, myeloid cancer.

4. The use according to claim 2, wherein, The pain is selected from the group consisting of one or more of muscle strain pain, cold pain, burn pain, postoperative pain, dental pain.

5. The use according to claim 2, wherein, The pain is selected from the group consisting of myofascial pain, tendon sheath pain, frozen shoulder pain, fibromyalgia pain.

6. The use according to claim 2, wherein, 7. Use according to claim 2, wherein the pain is selected from the group consisting of one or more of knee joint pain, ankle joint pain, wrist joint pain, elbow joint pain, shoulder joint pain, hip joint pain, femur joint pain, ankylosing spondylitis, herniated disc, primary headache, secondary headache, cranial neuralgia, central and primary facial pain and other headaches. The pain is rheumatoid arthritis pain, rheumatoid arthritis pain, gouty arthritis pain. The pain is patellar joint pain, sacroiliitis pain, cervical spine pain, lumbar spine pain.

8. The use according to claim 2, wherein, The pain is selected from the group consisting of one or more of migraine without aura, migraine with aura, hemiplegic migraine, chronic migraine, migraine complications, episodic syndromes associated with migraine, tension-type headache, trigeminal autonomic cephalalgias, and other primary headaches; headache due to trauma to the head and / or neck, headache due to non-vascular intracranial disorders, headache due to substances or substance withdrawal, headache due to vascular disorders of the head and / or neck, headache due to disorders of homeostasis, headache due to psychiatric diseases, head and / or facial pain due to diseases of the head and / or facial structures; one or more of trigeminal neuralgia, glossopharyngeal neuralgia, intermediate neuralgia, occipital neuralgia, optic neuritis; pain from internal organs selected from the group consisting of respiratory tract, gastrointestinal tract, pancreas, urethra, kidney, gallbladder, bladder and reproductive organs; post-herpetic neuralgia, diabetic neuropathic pain, painful HIV-related sensory neuropathy, causalgia, post-amputation pain, traumatic neuromas, entrapment injuries, spinal stenosis, radicular pain, sciatica, nerve avulsion injury, complex regional pain syndrome, medication-induced neuropathic pain, post-spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy; acute traumatic pain, labor pain, visceral pain, pyretic pain, itch.

9. The use according to claim 2, wherein, The pain is pain resulting from a disease selected from the group consisting of AIDS-related lymphoma, Hodgkin's disease, non-Hodgkin's disease.

10. The use according to claim 2, wherein, ​ 11. The use according to claim 2, wherein, ​ 12. The use according to claim 2, wherein, The pain is pain caused by a disease selected from the group consisting of phantom pain, pain neuroma, carpal tunnel syndrome, brachial plexus avulsion injury.

13. The use of claim 2, wherein, The pain is cancer chemotherapy-induced neuropathic pain.

14. A compound of the following formula: The compound is: 。 15. A pharmaceutical composition for alleviating and / or eliminating pain, characterized in that, A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of claim 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition according to claim 15, which is a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.

17. The pharmaceutical composition according to claim 15, which is in a dosage form selected from the group consisting of a tablet, a capsule, a film, a granule, an oral dosage form or an injection.

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