Phenoxyethanolamine compound and application thereof as CaV2.2 inhibitor

Abstract

The invention relates to the technical field of medicines, and particularly discloses a phenoxyethanol amine compound and application of the phenoxyethanol amine compound as a CaV2.2 inhibitor. The phenoxyethanol amine compound has a structure as shown in a formula (I), and the compound or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutical composition containing the compound can be used as an N-type calcium channel (CaV2.2) inhibitor, and can also effectively relieve and / or eliminate pain. The phenoxyethanol amine compound provided by the invention has a good application prospect in the field of analgesic drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a phenoxyethanolamine compound and use thereof as a CaV2.2 inhibitor. BACKGROUND

[0002] Pain is a multifaceted, debilitating disease that significantly reduces quality of life and plagues millions of people worldwide. In the United States, pain management relies primarily on non-steroidal anti-inflammatory drugs, traditional opioid drugs, and adjunctive drugs such as antidepressants and anticonvulsants. However, given the substantial side effects often produced by these treatments, achieving comprehensive pain relief has proven to be difficult. To address this ongoing challenge, researchers have explored a wide range of molecular targets, among which the voltage-gated CaV2.2 (N-type) calcium channel is a clinically successful target for pain relief.

[0003] CaV2.2 channels are key in the pain signaling pathway, which are mainly expressed in primary afferent neurons and spinal cord terminals, playing a central role in mediating the transmission of pain signals from the periphery to the central nervous system. Overexpression and overactivity of these channels can lead to hyperexcitability and increased release of excitatory neurotransmitters, conversely, blocking CaV2.2 can lead to reduced neurotransmitter release and pain signals. Multiple lines of evidence support the role of CaV2.2 in nociceptive pathways, studies in CaV2.2 knockout mouse models have shown that CaV2.2-deficient mice exhibit reduced pain-like behaviors, while genetic silencing and pharmacological blockade of these channels have alleviated pain symptoms.

[0004] Ziconotide is a synthetic peptide derived from the conotoxin omega-conotoxin MVIIA, which functions as a selective CaV2.2 inhibitor. It was discovered over 40 years ago and is considered the first non-opioid intrathecal analgesic approved by the U.S. Food and Drug Administration (FDA) for the treatment of intractable chronic pain. Its effectiveness is hindered by its limited ability to cross the blood-brain barrier, requiring intrathecal administration. Systemic administration of ziconotide causes dizziness and sedation, while systemic administration has profound hemodynamic effects. While pore blockers have shown promise in pain management, recent research efforts have focused on identifying state- and use-dependent CaV2.2 inhibitors. TROX-1 is an oral, state- and use-dependent inhibitor of CaV2.2 channels that has the potential to reverse pain-like behaviors. However, its further development has been challenged due to potential impairment of motor and cardiovascular function. While TROX-1 has shown efficacy in reducing pain, these side effects have raised serious concerns that could lead to obstacles in its development and clinical use. Therefore, there remains a need to develop new CaV2.2-specific inhibitors to reduce the side effects of this class of drugs. SUMMARY

[0005] The present application aims at providing a phenoxyethanolamine compound having voltage-gated calcium channel CaV2.2 inhibitory activity, which can be used for developing new analgesic drugs.

[0006] To achieve the above object, the present application adopts the following technical scheme:

[0007] The first aspect of the present application is a compound of formula (I)

[0008]

[0009] or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt thereof, wherein:

[0010] W is selected from the group consisting of a bond, C3-C 20 cycloalkylene, 4-20 membered heterocyclylene;

[0011] R 1 selected from the group consisting of hydrogen, deuterium, halogen, cyano, -(CH2) m R 8 , -(CH2) m (CH=CH)R 8 , -(CH2) m (C≡C)R 8 , -(CH2) m O(CH2) p R 8 , -(CH2) m SR 8 , -(CH2) m COR 8 , -(CH2) m C(O)OR 8 , -(CH2) m S(O) q R 8 , -(CH2) m NR 8 R 9 , -(CH2) m C(O)NR 8 R 9 , -(CH2) m NR 8 C(O)R 9 , -(CH2) m NR 8 C(O)NR 9 R 10 , -(CH2)m S(O) q NR 8 R 9 、

[0012] -(CH2)mNR 8 S(O) q R 9 、-(CH2) m NR 8 S(O) q NR 9 R 10 wherein H in CH2may optionally be substituted; R 8 , R 9 , R 10 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6alkyl, C3-C6cycloalkyl, or 4-20 membered heterocyclyl; or in -(CH2) 18 NR 20 R m , -(CH2) 8 C(O)NR 9 R m , -(CH2) 8 S(O) 9 NR m R q wherein R 8 and R 9 , together with the N atom to which they are attached, form a substituted or unsubstituted 4-8 membered heterocyclyl; or in -(CH2) 8 NR 9 C(O)R m , -(CH2) 8 NR 9 C(O)NR m R 8 、

[0013] -(CH2) 9 NR 10 S(O) m R 8 , -(CH2) q NR 9 S(O)qNR m R 8 wherein R 9 and R 10 , together with the N atom to which they are attached, form a substituted or unsubstituted 4-8 membered heterocyclyl, or R 8 and R 9 , together with the atoms to which they are attached, form a substituted or unsubstituted 4-8 membered heterocyclyl; 9 10 ​​

[0014] R 2 selected from OR 21 , C1-C 18 alkylene, deuterated C1-C 18 alkylene or halogenated C1-C 18 alkylene; R 21 is independently selected from the group consisting of hydrogen, deuterium, C1-C6alkyl or C3-C6cycloalkyl;

[0015] R 3 is selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl or 4-6 membered heterocyclyl, which are substituted or unsubstituted;

[0016] R 4 , R 5 , R 6 , R 7 may be the same or different, each independently selected from the group consisting of cyano, halo, nitro, C1-C6alkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, C1-C4alkoxy,

[0017] wherein the above substitution means being substituted with one or more groups selected from hydrogen, deuterium, C1-C 18 alkyl, deuterated C1-C 18 alkyl, halogenated C1-C 18 alkyl, halogenated C1-C 18 alkylhydroxy, C3-C 20 cycloalkyl, C1-C 18 alkoxy, deuterated C1-C 18 alkoxy, halogenated C1-C 18 alkoxy, C6-C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea;

[0018] m, n are each independently 0, 1, 2, 3, 4 or 5;

[0019] p is 0, 1, 2, 3, 4 or 5;

[0020] q is 1 or 2.

[0021] In a preferred embodiment of the present application, the compound has a structure represented by the general formula (II):

[0022]

[0023] wherein R 1 , R 2 , R 3 , R 4、R 5 、R 7 , W is defined as described in claim 1.

[0024] In a preferred embodiment of the present invention, the compound has a structure represented by general formula (III):

[0025]

[0026] Among them, R 1 、R 2 、R 4 、R 5 、R 7 , W is defined as described in claim 1.

[0027] In a preferred embodiment of the present invention, the compound has a structure represented by general formula (IV):

[0028]

[0029] Among them, R 1 、R 4 、R 5 、R 7 , W is defined as described in claim 1.

[0030] In a preferred embodiment of the present invention, the compound has a structure shown in general formula (V):

[0031] where R 4 、R 5 、R 7 , W are defined as in claim 1. In a preferred embodiment of the present invention, the compound is selected from the following specific compounds (as shown in Table 1):

[0032] Table 1. Compound table.

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047] As specific examples of the most preferred compounds of the present application, the following compounds can be mentioned, although the scope of the present application is not limited to the following specific compounds (see Preferred Compounds of the Invention below).

[0048] The second aspect of the present application is to provide a pharmaceutical composition comprising the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt; and a pharmaceutically acceptable excipient. The pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.

[0049] In the preferred embodiment of the present application, the pharmaceutical composition further contains other active ingredients for treating chronic pain.

[0050] In the preferred embodiment of the present application, the pharmaceutical composition is in the form of an oral dosage form or an injection, and the oral dosage form includes tablets, capsules, films, granules.

[0051] In the present application, "pharmaceutically acceptable carrier" means a diluent, adjuvant, excipient or vehicle for administration of a therapeutic agent, and is suitable for contact with human and / or other animal tissues within the scope of sound medical judgment without undue toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0052] Pharmaceutically acceptable carriers that can be employed in the pharmaceutical compositions of the application include, but are not limited to, sterile aqueous, nonaqueous, and mixed media. Among the acceptable carriers that can be employed are water, isotonic saline, pyrogen-free saline, and phosphate buffered saline. In addition, the pharmaceutical compositions can contain suitable antioxidants, buffers, and bulking agents. Suitable excipients for oral formulations include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The compositions of the application can additionally contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The pharmaceutical compositions can be formulated to be immediate or modified release. The pharmaceutical compositions can be formulated for systemic or local administration. The pharmaceutical compositions can be formulated for oral, buccal, sublingual, nasal, transdermal, transmucosal, topical, or ocular administration.

[0053] The pharmaceutical compositions of the application can act systemically and / or locally. To this end, they can be administered by any 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.

[0054] For these routes of administration, the pharmaceutical compositions of the application can be administered in a suitable dosage form.

[0055] 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.

[0056] 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.

[0057] The pharmaceutical compositions described herein contain a safe and effective amount of the compounds 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 formulations should be matched to the mode of administration.

[0058] 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. The 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.

[0059] 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; and 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.

[0060] The pharmaceutical compositions of the present application can be administered to a subject (e.g., 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.

[0061] When the pharmaceutical compositions are used, 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 not 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 be determined by the route of administration, the health of the patient, and like factors, all within the skill of the artisan.

[0062] 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 refers to the amount of a compound that is sufficient to downregulate or inhibit a CaV2.2 voltage-gated calcium ion channel. An "effective amount" of a compound as used herein refers to the amount of a compound that is sufficient to ameliorate or in some way reduce symptoms, halt or reverse progression of the disease, or downregulate or inhibit a CaV2.2 voltage-gated calcium ion channel. Such an amount can be administered in a single dose, or according to a regimen as effective.

[0063] The dosage regimen will be adjusted to provide the optimum desired response (e.g., a single dose, several divided doses (administered at appropriate intervals throughout the day), or continuously via a delivery device such as a transdermal patch). It will be understood, however, that the specific dose level and frequency of dosage can be varied so as to fall within the scope of the desired therapeutic effect. It will be further understood that the specific dose level and frequency of dosage for any particular patient can depend upon a variety of factors including the type and severity of the disease states being treated, overall health status of the patient, and like factors known in the medical arts.

[0064] As used herein, "treatment" refers to improving or otherwise altering in any manner the symptoms or pathology of a patient's condition, disorder, or disease. As described herein, "improving the symptoms of a particular disease by use of a particular compound or pharmaceutical composition" refers to any decrease, whether permanent or temporary, lasting or transient, attributable to or associated with the use of the composition.

[0065] As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include a human individual (referred to as a patient) having a disease (e.g., 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, domestic animals, and / or laboratory models (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0066] In some embodiments, the pharmaceutical composition of the present application can further comprise one or more additional therapeutic or prophylactic agents.

[0067] A third aspect of the present application is to provide use of the above-mentioned compound or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the manufacture of a voltage-gated calcium ion channel inhibitor.

[0068] Further, the voltage-gated calcium ion channel is CaV2.2.

[0069] A fourth aspect of the present application is to provide use of the above-mentioned compound or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the manufacture of a medicament for alleviating and / or eliminating pain.

[0070] Alleviating and / or eliminating pain means analgesia in general, and the analgesic effect of the compound of the present application is not limited to that achieved by inhibition of the voltage-gated calcium ion channel CaV2.2. The preferred embodiments in the use of the compound of the present application for alleviating and / or eliminating pain are the same as those described above.

[0071] In the present application, the pain includes any one or more of chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, and idiopathic pain.

[0072] Among them, the chronic pain includes muscle and soft tissue pain, bone and joint pain, headache, visceral pain, and pathological neuropathic pain.

[0073] The muscle and soft tissue pain includes one or more of myofascitis, tenosynovitis, periarthritis, muscle strain pain, fibromyalgia, cold pain, burn pain, and toothache; and / or, the bone and joint pain includes 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, herniated disc, cervical pain, lumbar pain.

[0074] 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 headache; 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 withdrawal from substance, headache due to vascular disorder of the brain, headache due to disorder of the internal environment, headache due to psychiatric disease, and headache due to disease of the head, neck, eye, ear, nose, sinuses, teeth, mouth, or other structures of the 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, and optic neuritis.

[0075] The visceral pain includes pain from organs of the respiratory tract, gastrointestinal tract, pancreas, urethra, kidney, gallbladder, bladder, and 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 neuroma, traumatic neuroma, entrapment injury, 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.

[0076] The acute pain includes one or more of acute traumatic pain, postoperative pain, labor pain, visceral pain, pyretic pain, and post-surgical pain.

[0077] The cancer in the cancer pain includes one or several of adenocarcinoma in glandular tissue, blastoma in organ embryonic tissue, carcinoma in epithelial tissue, leukemia in blood cell forming tissue, lymphoma in lymphatic tissue, myeloma in bone marrow, sarcoma in connective or supporting tissue, adrenal cancer, AIDS-related lymphoma, bladder cancer, bone cancer, brain cancer, breast cancer, carcinoid, 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 nerve and hollow viscera, and tumor near nerve structure.

[0078] The present application is a method for alleviating and / or eliminating pain, comprising administering to a human in need of such treatment an effective amount of a compound of the present application, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, or a pharmaceutical composition of the present application.

[0079] The compound of the present application is structurally novel. The compound (I) of the present application can be used in the preparation of a drug for treating a disease related to voltage-gated calcium channel CaV2.2, and can be used in the preparation of an analgesic drug.

[0080] The elements of the present application are described in more detail below.

[0081] Definitions

[0082] Unless otherwise defined herein, 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. References herein to technical terms used herein are intended to refer to technical terms as commonly understood by those in the art, including variations or replacements of those technical terms that are apparent to those skilled 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 better explain the present application.

[0083] The terms "comprising", "containing", "having" "including" or "involving" and other variants thereof are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0084] 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.

[0085] As used herein, the term "alkyl" defines a linear or branched saturated aliphatic hydrocarbon. In some embodiments, an alkyl group has 1 to 12, for example 1 to 6, carbon atoms. For example, as used herein, the term "Ci-6 alkyl" 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, CCI3, C2F5, C2CI5, CH2CF3, CH2CI, or -CH2CH2CF3, etc.). The term "Ci-4 alkyl" 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).

[0086] 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 alkenyl"). 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 a compound of the application contains an alkenyl group, the compound can exist as pure E (entgegen) form, pure Z (zusammen) form, or as any mixture thereof.

[0087] 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, for example ethynyl or propynyl.

[0088] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring including a spiro, fused, or bridged system (such as bicyclo[l. l. l]pentyl, bicyclo[2.2. l]heptyl, bicyclo[3.2. l]octyl, or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.)), 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 "C 3-6 cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, for example a methyl-substituted cyclopropyl group.

[0089] As used herein, the terms "cycloalkylene", "cycloalkyl", and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double 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)hexenyl, and the like.

[0090] As used herein, the terms "heterocyclyl", "heterocyclylene", and "heterocycle" refer to a cyclic group that is saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) having, for example, 3-10 (suitably 3-8, more suitably 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" is a saturated or partially unsaturated (hetero)cycloalkyl 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 and (hetero)cycloalkyl groups include, but are not limited to, (hetero)cyclooxanyl, (hetero)cycloaziridinyl, (hetero)cycloazetidinyl, (hetero)cyclooxetanyl, (hetero)cyclotetrahydrofuranyl, (hetero)cyclooxolanyl, (hetero)cyclopyrrolidinyl, (hetero)cyclopyrrolonyl, (hetero)cycloimidazolidinyl, (hetero)cyclopyrazolidinyl, (hetero)cyclopyrrolinyl, (hetero)cyclotetrahydropyranyl, (hetero)cyclopipecolinyl, (hetero)cyclomorpholinyl, (hetero)cyclo-dithianyl, (hetero)cyclothiomorpholinyl, (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). The heterocyclyl and (hetero)cycloalkyl groups can be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0091] As used herein, the terms "(hetero)aryl" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term "C 6-10 (hetero)aryl" and "C 6-10The term "aromatic ring" means an aromatic group containing 6 to 10 carbon atoms, such as (ene)phenyl (phenyl ring) or (ene)naphthyl (naphthalene ring). The (ene)aryl group and the aromatic ring are optionally substituted by one or more (such as one to three) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0092] As used herein, the terms "heteroaryl(ene)" and "heteroaromatic ring" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being for example oxygen, nitrogen or sulfur) and, in each case, may additionally be benzo-fused. In particular, “heteroaryl” or “heteroaromatic ring” is selected from thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof.

[0093] As used herein, the term "aralkyl" preferably refers to an alkyl group substituted with an aryl or heteroaryl 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.

[0094] As a more specific terminology explanation is as follows:

[0095] "Alkyl" refers to a saturated aliphatic hydrocarbon radical including 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or 1 to 2 carbon atoms, saturated straight-chained or branched, where the alkyl group can be independently optionally substituted with one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, s-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group can be optionally substituted or unsubstituted.

[0096] "Alkenyl" refers to a straight-chained or branched hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, where at least one C-C is sp 2 double bond, where the alkenyl group can be independently optionally substituted with one or more substituents described herein, where specific examples include, but are not limited to, ethenyl, allyl, and crotyl, and the like. The alkenyl group can be optionally substituted or unsubstituted.

[0097] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring including 3 to 20 carbon atoms, preferably including 3 to 12 carbon atoms, more preferably including 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 spirocyclic, fused, and bridged cycloalkyl groups. The cycloalkyl group can be optionally substituted or unsubstituted.

[0098] "Spirocycloalkyl" refers to a polycyclic group of 5 to 18 members, two or more cyclic structures, and a single carbon atom (referred to as a spiro atom) shared between the rings. The rings contain one or more double bonds, but none of the rings has a fully conjugated system of π electrons. Preferably, 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl groups are classified as mono-, bi-, or polycyclic, preferably mono- and bicyclic, preferably 4 / 5, 4 / 6, 5 / 5, or 5 / 6. Non-limiting examples of "spirocycloalkyl" groups include, but are not limited to:

[0099]

[0100] "Fused ring alkyl" refers to a fully carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures sharing a pair of carbon atoms with one another, one or more rings can contain one or more double bonds, but no ring has a fully conjugated system of π electrons, preferably 6 to 12 members, more preferably 7 to 10 members. It can be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl depending on the number of rings comprising the ring system, preferably bicyclic or tricyclic, more preferably 5 / 5 or 5 / 6 bicyclic alkyl. Non-limiting examples of "fused ring alkyl" include, but are not limited to:

[0101]

[0102] "Bridged ring alkyl" refers to a fully carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures sharing two non-adjacent carbon atoms with one another, one or more rings can contain one or more double bonds, but no ring has a fully conjugated system of π electrons, preferably 6 to 12 members, more preferably 7 to 10 members. It can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged ring alkyl depending on the number of rings comprising the ring system, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged ring alkyl" include, but are not limited to:

[0103]

[0104] The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, where the ring that is attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl and the like.

[0105] "Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, at least one of which is a heteroatom such as oxygen, nitrogen, sulfur and the like. Preferably, it is a 5 to 7 membered monocyclic or 7 to 10 membered bicyclic or tricyclic ring which can contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heterocyclyl" 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, where the ring that is attached to the parent structure is a heterocyclyl. The heterocyclyl can be optionally substituted or unsubstituted.

[0106] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) m The heteroatom of m=1 or 2, the remaining ring atoms are carbon, and m=1 or 2. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a bispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a bispiro heterocyclic group. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiro heterocyclic group. Non-limiting examples of "spiro heterocyclic group" include, but are not limited to:

[0107]

[0108] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) m The heteroatom of the ring is 1, the remaining ring atoms are carbon, and m = 1 or 2. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclic group" include but are not limited to:

[0109]

[0110] "Bridged heterocyclic group" refers to a polycyclic group of 5 to 18 members, containing two or more ring structures, sharing two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) m The heteroatom of the cyclic ring is 1 or 2, and the remaining ring atoms are carbon atoms, and m = 1 or 2. It is preferably 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, and more preferably a bicyclic or tricyclic group. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to:

[0111]

[0112] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl. Preferably, aryl is C6-C10 Aryl, more preferably aryl 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 ring, where the ring that is attached to the parent structure is the aryl ring, non-limiting examples include, but are not limited to:

[0113]

[0114] "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, where the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples include, but are not limited to:

[0115]

[0116] "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-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, and the like.

[0117] "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.

[0118] "Hydroxy" means the -OH group.

[0119] "Halo" means fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, and bromo.

[0120] "Amino" means -NH2.

[0121] "Cyano" means -CN.

[0122] "Nitro" means -NO2.

[0123] "Benzyl" means -CH2-phenyl.

[0124] "Carboxy" means -C(O)OH.

[0125] "Acetyl" means -C(O)CH3or Ac.

[0126] "Carboxylate" means -C(O)O(alkyl) or (cycloalkyl), where alkyl, cycloalkyl are as defined above.

[0127] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0128] As used herein, the term "nitrogen-containing heterocycle" means a saturated or unsaturated monocyclic or bicyclic radical 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 the group consisting of N, O, C=O, S, S=O, and S(=O)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.

[0129] 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 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.

[0130] 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 that 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 that there are any hydrogens present) can each be replaced with an independently selected optional substituent.

[0131] 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).

[0132] 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.

[0133] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0134] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0135] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e., 14C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0136] "Substituted" means that one or more hydrogen atoms, preferably up to five, more preferably one to three, of a group are independently of each other replaced with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can be determined (experimentally or theoretically) by a person skilled in the art without undue effort, as possible or impossible. For example, an amino or hydroxyl group with a free hydrogen can be unstable when bound to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0137] "Substituted" or "substitution" as used herein, unless otherwise indicated, means that a group can be substituted with one or more groups selected from the following.

[0138] As used herein, an "effective amount" of a compound means an amount sufficient to downregulate or inhibit a CaV2.2 voltage-gated calcium ion channel.

[0139] As used herein, a "therapeutically effective amount" of a compound means an amount sufficient to ameliorate or in some way reduce symptoms, halt or reverse the progression of a condition, or downregulate or inhibit a CaV2.2 voltage-gated calcium ion channel. Such an amount can be used as a single dose or can be administered according to a regimen effective.

[0140] As used herein, "treat" means to ameliorate or otherwise alter in any way the symptoms or pathology of a condition, disorder, or disease in a patient.

[0141] As used herein, "to ameliorate the symptoms of a particular disease by use of a particular compound or pharmaceutical composition" means any reduction, whether permanent or temporary, lasting or transient, attributable to or associated with the use of the composition.

[0142] The use of the definitions and conventions of stereochemistry in this application are generally in accordance with the following references:

[0143] 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. All stereoisomers of the compounds of the present application, including but not limited to, diastereomeric, enantiomeric, atropisic, and their mixtures, such as racemates, form part of the present application. Diastereomeric mixtures can be separated into individual diastereomers by, for example, chromatography, crystallization, distillation, or sublimation, or a combination thereof. Enantiomeric mixtures can be separated into individual enantiomers by, for example, a chiral resolution process, by the formation of diastereomeric salts or complexes with chiral auxiliary compounds, by the use of chiral solvents, or by the formation of stereoisomeric combinations R. R. Scheffer, T. J. deKruif, and E. vanEijck, Recl. Trav. Chim. Pays-Bas 108, 193 (1989); J. Berova, N. Katsuki, and K. Nakanishi, Synlett 1991, 643; S. David, Tetrahedron 1993, 49, 5209; and S. David, Tetrahedron 1993, 49, 6225. Individual stereoisomers of compounds can be obtained, by using, for example, chiral reagents in the synthesis and by chiral chromatographic resolutions in the purification. The compounds of the present application can exist in different tautomeric forms, and 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, L, or R, 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, (-) or 1 meaning that the compound is levorotatory (i.e., it rotates plane-polarized light to the left) and the prefix (+) or d means that the compound is dextrorotatory (i.e., it rotates plane-polarized light to the right). When a specific stereoisomer is indicated, it will be shown by a subscript or superscript, e.g., (-)- or d-.

[0144] "tautomers" or "tautomerically forms" refer to isomers of different energy structures that can interconvert by a low energy barrier. For example, prototropic tautomers (i.e., tautomers that shift protons) include tautomeric interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Atom valence (valency) tautomers include interconversions that reorganize bonding electrons. Unless otherwise indicated, the structural formulae depicted by the present application are meant to include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric isomeric forms) of the structural formulae: for example, the R, S configurations for asymmetric centers, the (Z), (E) isomers for double bonds, and the (Z), (E) conformers. Thus, individual stereoisomers of compounds of the present application or mixtures of stereoisomers, including mixtures of enantiomers, mixtures of diastereomers, mixtures of geometric isomers, mixtures of rotational isomers, mixtures of conformers, mixtures of atropisomers, and the like, are within the scope of the present application.

[0145] "pharmaceutically acceptable salts" refer to salts of the compounds of the present application which 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 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.

[0146] A solid line A solid wedge or a dashed wedge depicts 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 be a single stereoisomer or mixtures of stereoisomers, including mixtures of enantiomers, mixtures of diastereomers, mixtures of geometric isomers, mixtures of rotational isomers, mixtures of conformers, mixtures of atropisomers, and the like. The compounds of the present application can exhibit more than one type of isomerism, and consist of mixtures (e.g., racemic mixtures and diastereomeric pairs) thereof.

[0147] 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.

[0148] It is also to be understood that certain compounds of the 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 application" is intended to encompass all such derivatives.

[0149] Pharmaceutically acceptable salts of the compounds of the application include acid addition salts and base addition salts, including but not limited to salts containing hydrogen or coordinate bonds.

[0150] 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 / dihydrogen phosphate / hydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate.

[0151] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminium, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc.

[0152] A review of suitable salts is given in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing the pharmaceutically acceptable salts of the compounds of the application are known to those skilled in the art.

[0153] 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 the free acid or alcohol form of the compounds of the present application). The compounds of the present application can also be esters themselves.

[0154] 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 a structural element of the crystal lattice of the compound. The amount of polar solvent, particularly water, can be present in stoichiometric or non-stoichiometric amounts.

[0155] One skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires an available lone pair of electrons to oxidize to an oxide; one skilled in the art will recognize which nitrogen-containing heterocycles are 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 and include oxidation of the heterocycle or tertiary amine 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.

[0156] Also included within the scope of the present application are metabolites of the compounds of the present application, i.e., substances formed in vivo upon administration of the compounds of the present application. Such products can result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, and the like. Accordingly, the present application includes metabolites of compounds of the present application, including those produced by the contact of a compound of the present application with a mammal to be treated.

[0157] The present application further includes within its scope prodrugs of the compounds of the application, which are certain derivatives of the compounds of the application that possess little or no pharmacological activity themselves but, upon administration, are converted in the body by, for example, hydrolytic cleavage to form the active compound. Typically such prodrugs will be functional derivatives of the compounds of the application which are readily converted to the desired therapeutic agent in the body. For additional information on prodrugs, see "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 using known methods, for example by replacing appropriate functionalities with groups known to be hydrolyzed under either acidic or basic conditions, or oxidized, to give the desired compound. These modifications can be made when the appropriate functional group is present in the compound of the application.

[0158] The present application also encompasses compounds of the present application that contain 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 well as to protect the compound of the present application itself, thus forming a chemically protected form of the compound of the present application. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is incorporated herein by reference. The protecting groups can be removed at a suitable subsequent stage using methods known from the art.

[0159] The term "about" means within ±10% of the stated value, preferably within ±5%, more preferably within ±2%.

[0160] Compared with the prior art, the technical scheme provided by the present application has the beneficial effects that:

[0161] The compound provided by the present application is unique in structure and can be applied in the preparation of drugs for voltage-gated calcium channel CaV2.2 related diseases and analgesic drugs. DETAILED DESCRIPTION

[0162] In order to make the objectives, technical solutions and advantages of the present application clearer, the specific embodiments of the present application will be further described in detail below. If the specific test methods, instruments, devices or conditions are not specified in the examples, they are all carried out according to the techniques or conditions described in the literature in the field or according to the product instructions. If the reagents or instruments are not specified by the manufacturer, they are all conventional products that can be obtained by purchase in the market.

[0163] The present application will be further described below in conjunction with specific examples. The process, conditions, reagents, experimental methods, etc. for implementing the present application are all general knowledge and common sense in the field, and the present application does not have special limitations. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. The experimental methods in the following examples are not specified, and are generally carried out according to the conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0164] In the following examples 1 The H NMR spectra were measured by using a Bruker instrument (400 MHz), and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 The representation method of H NMR: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, its unit is Hz.

[0165] The mass spectra were measured by using an LC / MS instrument, and the ionization mode was ESI. The high-performance liquid chromatograph was Agilent 1260 and Thermo U3000; the chromatographic column was Waters xbrige C18 (4.6*150 mm, 3.5 μm); the mobile phase was A: ACN, B: Water (0.1% H3PO4); the flow rate was 1.0 mL / min; the gradient was 5% A for 1 min, increased to 20% A within 4 min, increased to 80% A within 8 min, 80% A for 2 min, back to 5% A within 0.1 min; the wavelength was 220 nm; the column oven temperature was 35°C. The thin layer chromatography silica gel plate was Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specification of the silica gel plate used in the thin layer chromatography was 0.2 mm-0.3 mm. The specification of the silica gel plate used in the thin layer chromatography separation and purification of the product was 0.4 mm-0.5 mm. The column chromatography generally used Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0166] In the following examples, all temperatures are in degrees Celsius, unless otherwise indicated, and all starting materials and reagents are commercially available or synthesized according to known procedures, and used without further purification, unless otherwise indicated. The commercial suppliers include, but not limited to, Sinopharm Chemical, Inc., Bailingwei Technology Co., Ltd., Lixi'ai (Shanghai) Chemical Industry Development Co., Ltd., Shanghai Bide Pharmaceutical Technology Co., Ltd., and Shanghai Mayreal Chemical Technology Co., Ltd., etc. CD3OD: deuterated methanol; CDCl3: deuterated chloroform; DMSO-d6: deuterated dimethyl sulfoxide; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium; XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos: 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl; HATU: 2-(7-oxadiazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBT: 1-hydroxybenzotriazole; BINAP: 1,1'-binaphthalene-2,2'-diphenylphosphine; DIPEA: N,N-diisopropylethylamine; DCM: dichloromethane; PE: petroleum ether; EA: ethyl acetate; MeOH: methanol; DMF: N,N-dimethylformamide; TLC: thin layer chromatography; HPLC: high performance liquid chromatography; purity: purity; R f : ratio of the distance from the origin to the center of the spot to the distance from the origin to the solvent front in thin layer chromatography. Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

[0167] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution. Unless otherwise specified in the examples, the temperature of the reaction is room temperature, which is 20-30°C. The monitoring of the reaction progress in the examples is carried out by thin layer chromatography (TLC), and the system of the developing agent used in the reaction, the eluent used in the column chromatography for purifying the compounds, or the system of the developing agent used in the thin layer chromatography includes: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; wherein the volume ratio of the solvents is different according to the polarity of the compounds, and a small amount of acidic or basic reagent can also be added for adjustment, such as acetic acid or triethylamine, etc. The reagent providing basic conditions is selected from one or more of the following: organic bases or inorganic bases, wherein the organic bases are one or more of the following: triethylamine, N,N-diisopropyl ethylamine, n-butyllithium, diisopropyl aminolithium, bis-trimethylsilyl amide lithium, sodium tert-butoxide, sodium methoxide and potassium tert-butoxide, and the inorganic bases are one or more of the following: sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and lithium hydroxide; the reagent providing acidic conditions is one or more of the following: 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;

[0168] The metal catalyst is one or more of the following: palladium on carbon, Raney nickel, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium (Pd(dppf)Cl2), [1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex, bis-triphenylphosphine dichloropalladium (Pd(PPh3)2Cl2) and tris(dibenzylideneacetone) dipalladium (Pd2(dba)3);

[0169] The ligand is one or more of the following: 2-bicyclohexylphosphine-2,6'-dimethoxy biphenyl (SPhos), 4,5-bis-diphenylphosphine-9,9-dimethyl xanthene (XantPhos), 2-dicyclohexylphosphine-2,4,6-triisopropyl biphenyl (XPhos), 2-dicyclohexylphosphine-2'-(N,N-dimethylamine)-biphenyl (DavePhos), 1,1'-bis(diphenylphosphino) ferrocene (Dppf) and 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (BINAP), preferably 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (BINAP);

[0170] The reducing agent is one or more of the following: sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and lithium tetrahydroaluminate;

[0171] The oxidizing agent is one or more of the following: potassium permanganate, manganese dioxide, potassium dichromate, sodium dichromate and potassium osmium acid;

[0172] The above reaction is preferably carried out in a solvent, and the solvent used is one or more of N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane and acetone.

[0173] Pharmaceutical chemical synthesis

[0174] Example 1

[0175] N-(3-(2-tert-butyl)-6-isopropyl-4-methoxyphenoxy)-2-ethoxypropyl)cyclopentylamine 1

[0176]

[0177] The first step is to synthesize compound 1a

[0178] Compound 22 (1.70 g, 4.67 mmol) was dissolved in tetrahydrofuran / saturated sodium carbonate aqueous solution (5 mL / 5 mL), and di-tert-butyl dicarbonate (1.53 g, 7.01 mmol) was added. After the addition was complete, the reaction solution was reacted at room temperature at 15°C for 1 hour. The reaction was complete when detected by TLC (petroleum ether / ethyl acetate = 10:1, R f =0.5). The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the title compound 1a (1.456 g, yield 67.4%) as a colorless transparent oil.

[0179] LC-MS / m / z=464.3[M+H] +

[0180] Step 2: Synthesis of Compound 1b

[0181] Compound 1a (100 mg, 0.22 mmol) was dissolved in dry DMF (5 mL). The reaction solution was cooled to 0°C and NaH (43 mg, 1.07 mmol, 60%) was added. After the addition was complete, the mixture was stirred at room temperature for 10 minutes. Ethyl iodide (67 mg, 0.43 mmol) was added. After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. TLC showed that the reaction of the raw material was complete (PE:EA=10:1, R f =0.3). The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, washed with saturated brine (20 mL x 2), and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the crude product was purified by silica gel column chromatography (EA:PE = 5%) to obtain the title compound 1b (41 mg, yield 37.9%) as a colorless oil.

[0182] Step 3: Synthesis of Compound 1

[0183] Compound 1b (41 mg, 0.08 mmol) was dissolved in dichloromethane (4 mL), cooled to 0°C, and trifluoroacetic acid (1 mL) was added dropwise. After the addition was complete, the mixture was slowly heated to room temperature and reacted for 2 hours. TLC (PE:EA=3:1, R f =0.1) to detect the complete reaction of the starting material. The reaction solution was cooled to 0°C and saturated aqueous sodium carbonate solution was slowly added dropwise to adjust the pH to 9. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by prep-TLC (DCM:MeOH=10:1) to obtain the title compound 1 (23 mg, yield 70.7%) as an off-white solid.

[0184] LC-MS: m / z=392.3[M+H] + (95.37% purity, 210nm)

[0185] 1 H NMR(400MHz,DMSO-d6)δ6.71(d,J=3.2Hz,1H),6.63(d,J=3.2Hz,1H),4.10-4.00(m,1H),3 .83(dd,J=10.4,3.6Hz,1H),3.79(d,J=5.6Hz,1H),3.76-3.74(m,1H),3.71(s,3H),3.70-3 .65(m,1H),3.53-3.48(m,1H),3.29-3.24(m,1H),3.15-3.03(m,2H),2.01-1.92(m,2H),1. 77-1.65(m,4H),1.58-1.49(m,2H),1.34(s,9H),1.22(d,J=6.8Hz,3H),1.21-1.16(m,7H).

[0186] Example 2

[0187] 1-(2-(tert-butyl)-4-methoxyphenoxy)-3-(cyclopentyl(methyl)amino)propan-2-ol

[0188]

[0189] The first step is to synthesize compound 2b

[0190] 4-Hydroxy-3-tert-butyl-anisole 2a (5.00 g, 27.74 mmol) was dissolved in N,N-dimethylformamide (60 mL). Under nitrogen, the mixture was cooled to 0°C. Sodium hydride (1.33 g, 33.28 mmol) was added in batches. After the addition was complete, the reaction mixture was warmed to room temperature (20°C) and reacted for 20 minutes. Epibromohydrin (4.56 g, 33.28 mmol) was added dropwise. After the addition was complete, the reaction mixture was warmed to 50°C and reacted for 1 hour. TLC showed that the reaction of the raw material was complete (PE / EA = 10 / 1, R f =0.6, the raw material and the reaction solution are at the same position, and the reaction solution can be detected by iodine development). The reaction solution was cooled to room temperature and poured into ice water (50 mL) for quenching. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 30 / 1) to obtain the title compound 2b (6.30 g, yield 96.1%) as a colorless transparent liquid.

[0191] Step 2: Synthesis of compound 2c

[0192] Compound 2b (2.92 g, 12.35 mmol) was dissolved in methanol (30 mL), and cyclopentylamine (2.10 g, 24.71 mmol) was added. After the addition was complete, the reaction solution was heated to 60°C for 6 hours. TLC showed that the reaction of the raw material was complete (DCM / MeOH = 20 / 1, R f =0.4). The reaction solution was directly concentrated to obtain the title compound 2c (4.10 g, crude product) as a light yellow oil, which was used directly in the next reaction.

[0193] Step 3: Synthesis of Compound 2

[0194] Compound 2c (200 mg, 0.62 mmol) was dissolved in methanol (5 mL), and formaldehyde (252 mg, 3.11 mmol, 37%) and formic acid (286 mg, 6.22 mmol) were added. After the addition was complete, the reaction solution was heated to 60°C for 5 hours. TLC showed that the reaction of the raw material was complete (DCM / MeOH = 20 / 1, R f =0.5). The reaction solution was cooled to room temperature, diluted with water (20 mL), and saturated sodium bicarbonate solution (30 mL) was added to adjust the pH to about 10. The mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 15 / 1) to obtain the title compound 2 as a white solid (72 mg, two-step yield 34.6%).

[0195] LC-MS: m / z=336.2[M+H] + (96.65% purity, 220nm)

[0196] 1 H NMR (400 MHz, DMSO-d6) δ 6.87 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 3.2 Hz, 1H), 6.72 (dd, J = 8.8, 3.2 Hz, 1H), 4.31 - 4.25 (m, 1H), 3.98 - 3.90 (m, 2H), 3.67 (s, 3H), 3.66 - 3.57 (m, 1H), 3.38 - 3.12 (m, 2H), 2.79 (s, 3H), 2.06 - 1.92 (m, 2H), 1.81 - 1.62 (m, 4H), 1.60 - 1.51 (m, 2H), 1.32 (s, 9H). (Note: the hydroxyl active hydrogen is not observed)

[0197] Example 3

[0198] 1-((3-aminocyclopentyl)amino)-3-(2-(tert-butyl)-4-methoxyphenoxy)propan-2-ol 3

[0199]

[0200] First step to synthesize compound 3b

[0201] Dissolve 3-(BOC-amino)cyclopentanone 3a (3.00 g, 15.06 mmol) in acetonitrile (30 mL), add hydroxylamine hydrochloride (2.09 g, 30.11 mmol) at room temperature, drop in sodium carbonate (3.99 g, 37.64 mmol) in water (15 mL), after adding, heat the reaction solution to 80 °C for 3.5 hours, TLC detection reaction complete (petroleum ether / ethyl acetate = 2 / 1, Rf= 0.1). The reaction solution is cooled to room temperature, add water (100 mL), extract with ethyl acetate (150 mL), wash the organic phase with saturated brine (150 mL), dry over anhydrous sodium sulfate, concentrate, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1-1 / 1) to obtain the title compound 3b (2.09 g, yield 64.7%) as a white solid. f

[0202] Second step to synthesize compound 3c

[0203] Dissolve compound 3b (2.09 g, 9.75 mmol) in ethanol (60 mL), add platinum dioxide (333 mg, 1.46 mmol) at room temperature, after adding, under hydrogen protection, the reaction solution is reacted at room temperature for 16 hours, TLC detection reaction complete (dichloromethane / methanol = 10 / 1, Rf= 0.3). Concentrate the reaction solution to obtain the title compound 3c (1.99 g, crude) as a light brown oil, which is directly used in the next step reaction. f

[0204] ​​Step 3: Synthesis of compound 3d

[0205] Compound 3c (1.99 g, crude) was dissolved in dichloromethane (40 mL), the reaction solution was cooled to 0 °C under nitrogen protection, N,N-diisopropylethylamine (1.58 g, 12.19 mmol) was added, after addition, benzyl chloroformate (1.83 g, 10.73 mmol) was added dropwise, and the temperature was kept at 0-5 °C. After addition, the reaction solution was raised to room temperature (15 °C) for 16 hours, TLC detection showed that the reaction was complete (petroleum ether / ethyl acetate = 2 / 1, Rf= 0.5). The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (150 mL), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1-1 / 1) to obtain the title compound 3d (1.99 g, two-step yield 61.0%) as a white solid. f

[0206] Step 4: Synthesis of compound 3e

[0207] Compound 3d (1.99 g, 5.95 mmol) was dissolved in 1,4-dioxane (7.5 mL), hydrochloric acid dioxane (15 mL, 4M) was added at room temperature under nitrogen protection, and the reaction solution was reacted at room temperature (15 °C) for 2 hours, TLC detection showed that the reaction was complete (petroleum ether / ethyl acetate = 2 / 1, Rf= 0.2). The reaction solution was concentrated to obtain the title compound 3e (1.56 g, crude) as an orange solid, which was directly used in the next step reaction. f

[0208] LC-MS / m / z = 235.1 [M+H] +

[0209] Step 5: Synthesis of compound 3f

[0210] Compound 2b (150 mg, 0.64 mmol) and compound 3e (390 mg, crude) were dissolved in methanol (3 mL), N,N-diisopropylethylamine (328 mg, 2.54 mmol) was added at room temperature, after addition, the reaction solution was heated to 60 °C for 4 hours, TLC detection showed that the reaction was basically complete (dichloromethane / methanol = 10 / 1, Rf= 0.2). The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by Prep-TLC (dichloromethane / methanol = 10 / 1) to obtain the title compound 3f (210 mg, yield 69.7%) as a light yellow oil. f

[0211] LC-MS / m / z = 471.3 [M+H] +

[0212] Step 6: Synthesis of compound 3 ​​​

[0213] Compound 3f (210 mg, 0.45 mmol) was dissolved in ethanol (5 mL), palladium on carbon (21 mg, 10%) was added at room temperature, after addition, the reaction solution was reacted at room temperature (18 °C) for 16 hours under hydrogen protection, TLC detection showed that the reaction was complete (dichloromethane / methanol = 10 / 1, R f = 0.1). The reaction solution was filtered through celite, the filter cake was washed (20 mL, dichloromethane:methanol = 10:1), the filtrate was concentrated to dryness, and the crude product was purified by Prep-TLC (dichloromethane / methanol = 7.5 / 1) to obtain the title compound 3 (23 mg, yield 15.2%) as a gray-white solid

[0214] LC-MS / m / z = 337.2 [M+H] +

[0215] 1 H NMR (400 MHz, DMSO-d6) δ 6.96 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 2.8 Hz, 1H), 6.82-6.79 (m, 1H), 4.24-4.14 (m, 1H), 4.02-3.94 (m, 2H), 3.77 (s, 3H), 3.59-3.56 (m, 1H), 3.47-3.37 (m, 1H), 3.08-2.94 (m, 1H), 2.89-2.80 (m, 1H), 2.32-2.19 (m, 1H), 2.11-1.94 (m, 2H), 1.91-1.65 (m, 3H), 1.42 (s, 9H). (Note: 4 active hydrogens are not out)

[0216] Example 4

[0217] N-(3-((3-(2-(tert-butyl)-4-methoxyphenoxy)-2-hydroxypropyl)amino)cyclopentyl)acetamide 4

[0218]

[0219] First step to synthesize compound 4a

[0220] Compound 3e (600 mg, 2.22 mmol) was dissolved in dichloromethane (10 mL), N,N-diisopropylethylamine (859 mg, 6.65 mmol) was added at room temperature, after addition, the reaction solution was cooled to 0 °C under nitrogen protection. Acetyl chloride (260 mg, 3.32 mmol) was added, after addition, the reaction solution was reacted at room temperature (15 °C) for 1 hour, TLC detection showed that the reaction was complete (dichloromethane / methanol = 20 / 1, R f=0.3). The reaction solution was concentrated, quenched with water (10 mL), extracted with ethyl acetate (30 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1) to obtain the title compound 4a (487 mg, yield 79.4%) as a yellow transparent oil.

[0221] LC-MS / m / z=277.1[M+H] +

[0222] Step 2: Synthesis of compound 4b

[0223] Compound 4a (487 mg, 1.76 mmol) was dissolved in ethanol (5 mL), and palladium carbon (50 mg) was added at room temperature. After the addition was complete, the reaction solution was reacted at room temperature (17°C) for 3 hours under hydrogen protection. The reaction was complete when detected by TLC (dichloromethane / methanol = 10 / 1, R f =0.2). The reaction solution was filtered through a pad of celite, and the filter cake was rinsed (10 mL, dichloromethane:methanol=10:1). The filtrate was concentrated to dryness to obtain the title compound 4b (227 mg, crude product) as a colorless transparent oil, which was used directly in the next reaction.

[0224] Step 3: Synthesis of Compound 4

[0225] Compound 2b (140 mg, 0.59 mmol) and compound 4b (168 mg, crude product) were dissolved in ethanol (3 mL). After addition, the reaction solution was heated to 90°C for 2 hours. The reaction was complete when TLC was performed (dichloromethane / methanol = 10 / 1, R f =0.4). The reaction solution was cooled to room temperature and concentrated. The crude product was purified by Prep-TLC (dichloromethane / methanol = 7 / 1) to obtain the title compound 4 as a white solid (15 mg, yield 6.7%).

[0226] LC-MS / m / z=379.2[M+H] +

[0227] 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 3.2 Hz, 1H), 6.80-6.75 (m, 1H), 5.42-5.18 (m, 1H), 4.24-4.13 (m, 1H), 4.11-4.01 (m, 1H), 4.00-3.90 (m, 2H), 3.75 (s, 3H), 2.99-2.88 (m, 1H), 2.84-2.76 (m, 1H), 2.08-1.96 (m, 2H), 1.82 (s, 3H), 1.81-1.66 (m, 2H), 1.52-1.43 (m, 2H), 1.39 (s, 9H). (Note: two active hydrogens not out)

[0228] Example 5

[0229] N-(3-((3-(2-(tert-butyl)-4-methoxyphenoxy)-2-hydroxypropyl)amino)cyclopentyl)methanesulfonamide 5

[0230]

[0231] The synthesis of reference compound 4 was performed using compound 3e and methanesulfonyl chloride as starting materials to yield the title compound 5 as a white gum (42 mg, yield 24.1%).

[0232] LC-MS / m / z = 415.2 [M+H] +

[0233] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 3.2 Hz, 1H), 6.80-6.75 (m, 1H), 5.42-5.18 (m, 1H), 4.24-4.13 (m, 1H), 4.11-4.01 (m, 1H), 4.00-3.90 (m, 2H), 3.75 (s, 3H), 2.99-2.88 (m, 1H), 2.84-2.76 (m, 1H), 2.08-1.96 (m, 2H), 1.82 (s, 3H), 1.81-1.66 (m, 2H), 1.52-1.43 (m, 2H), 1.39 (s, 9H). (Note: two active hydrogens not out)

[0234] Example 6

[0235] 6-((2-(tert-butyl)-4-methoxyphenoxy)methyl)-4-cyclopentylmorpholine-2-one 6

[0236]

[0237] First step synthesis of compound 6

[0238] 1-(2-(tert-butyl)-4-methoxyphenoxy)-3-(cyclopentylamino)propan-2-ol 6a (200 mg, 0.62 mmol) was dissolved in acetonitrile (3 mL), ethyl bromoacetate (312 mg, 1.87 mmol) and potassium carbonate (172 mg, 1.24 mmol) were added at room temperature, after addition, the reaction was heated to 80 °C for 2 hours, TLC detection of raw materials reaction complete (DCM / MeOH = 30 / 1, Rf= 0.2). The reaction was cooled to room temperature, water (10 mL) was added, ethyl acetate was extracted (10 mL x 2), the combined organic phase was washed with saturated brine (10 mL x 3), dried with anhydrous sodium sulfate, the organic phase was concentrated at 45 °C under reduced pressure, and the crude product was purified by Prep-TLC (EA / PE = 3 / 1) to obtain the title compound 6 (81 mg, yield 36.2%) as a white solid. f

[0239] LC-MS: m / z = 362.2 [M+H] +

[0240] 1 H NMR (400 MHz, CDC13) δ 6.90 (d, J = 3.2 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.68 (dd, J = 8.8, 2.8 Hz, 1H), 4.91 - 4.82 (m, 1H), 4.14 (d, J = 5.2 Hz, 2H), 3.77 (s, 3H), 3.58 (d, J = 17.6 Hz, 1H), 3.20 (d, J = 17.2 Hz, 1H), 3.16 - 3.09 (m, 1H), 2.76 - 2.68 (m, 1H), 2.66 - 2.57 (m, 1H), 1.92 - 1.80 (m, 2H), 1.78 - 1.66 (m, 2H), 1.64 - 1.57 (m, 2H), 1.48 - 1.39 (m, 2H), 1.36 (s, 9H).

[0241] Example 7

[0242] N-(3-(2-tert-butyl)-4-methoxyphenoxy)-2-methoxypropyl)cyclopentylamine 7

[0243]

[0244] First step synthesis of compound 7a​

[0245] Compound 2c (400 mg, 1.24 mmol) was dissolved in tetrahydrofuran (4 mL), and saturated aqueous sodium carbonate solution (4 mL) and Boc anhydride (326 mg, 1.49 mmol) were added in sequence. After the addition was complete, the reaction solution was heated to 40°C for 4 hours and monitored by TLC (PE / EA=10 / 1, R f =0.5) The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 15 / 1) to obtain the title compound 7a (418 mg, 79.9% yield) as a colorless, transparent liquid.

[0246] LC-MS: m / z = 422.3 [M+H] +

[0247] Step 2: Synthesis of compound 7b

[0248] Compound 7a (416 mg, 0.98 mmol) was dissolved in N,N-dimethylformamide (5 mL). Under nitrogen protection, the reaction solution was cooled to 0°C, sodium hydride (47 mg, 1.18 mmol) was added, and stirred for 15 minutes. Methyl iodide (168 mg, 1.18 mmol) was added. After the addition was complete, the reaction solution was returned to room temperature and reacted for 16 hours. TLC detection showed that the reaction of the raw material was complete (PE / EA=10 / 1, R f =0.6). The reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain the title compound 7b (139 mg, yield 32.6%) as a light yellow liquid.

[0249] LC-MS: m / z = 336.2 [M-100+H] +

[0250] Step 3: Synthesis of Compound 7

[0251] Compound 7b (139 mg, 0.32 mmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride solution (1 mL, 4 M) was added at room temperature. After the addition was complete, the reaction solution was reacted at room temperature for 16 hours. TLC showed that the reaction of the raw material was complete (DCM / MeOH = 20 / 1, R f= 0.3). The reaction solution was adjusted to pH = 12 with ammonia water (2 mL), water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Prep-TLC (DCM / MeOH = 15 / 1) to obtain the title compound 7 (28 mg, yield 26.1%) as a white solid.

[0252] LC-MS: m / z = 336.2 [M+H] + (96.96% purity, 220 nm)

[0253] 1 H NMR (400 MHz, DMSO-d6) δ 6.90 (d, J = 8.4 Hz, 1H), 6.78-6.69 (m, 2H), 4.09 (dd, J = 10.8, 4.0 Hz, 1H), 4.01 (dd, J = 10.4, 3.6 Hz, 1H), 3.89-3.83 (m, 1H), 3.67 (s, 3H), 3.52-3.43 (m, 1H), 3.40 (s, 3H), 3.23-3.08 (m, 2H), 2.02-1.93 (m, 2H), 1.73-1.63 (m, 2H), 1.60-1.48 (m, 4H), 1.31 (s, 9H). (Note: active hydrogen of amino group is not shown)

[0254] Example 8

[0255] 1-(Cyclopentylamino)-3-(2,6-di-tert-butyl-4-methoxyphenoxy)propan-2-ol 8

[0256]

[0257] First step synthesis of compound 8b

[0258] 2,6-di-tert-butyl-4-methoxyphenol 8a (200 mg, 0.85 mmol) was dissolved in N,N-dimethylformamide (2 mL) under nitrogen protection. The reaction solution was cooled to 0 °C, and sodium hydride (51 mg, 1.27 mmol) was added. After the addition was completed, the reaction solution was slowly warmed to 15 °C and reacted for 30 minutes. Epibromohydrin (139 mg, 1.02 mmol) was added, and the reaction solution was heated to 60 °C and reacted for 2 hours. TLC detection showed that the raw material was reacted completely (PE / EA = 10 / 1, R f = 0.3). The reaction solution was cooled to room temperature, quenched with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 8b (200 mg, crude) as a light yellow oil, which was directly used in the next step reaction.

[0259] Second step to synthesize compound 8

[0260] Compound 8b (200 mg, crude) and cyclopentylamine (116 mg, 1.37 mmol) were dissolved in ethanol (3 mL), the reaction was heated to 90 °C for 16 hours, TLC detection reaction was complete (dichloromethane / methanol = 10 / 1, R f = 0.4). The reaction was cooled to room temperature, concentrated, the crude product was purified by Prep-TLC (dichloromethane / methanol = 10 / 1) to give the white solid title compound 8 (36 mg, 11.2% yield for two steps).

[0261] LC-MS / m / z = 378.2 [M+H] +

[0262] 1 H NMR (400 MHz, DMSO-d6) δ 6.74 (s, 2H), 4.3-4.2 (m, 1H), 3.70 (s, 3H), 3.67-3.56 (m, 2H), 3.55-3.46 (m, 1H), 3.19-3.09 (m, 1H), 2.95-2.84 (m, 1H), 2.02-1.91 (m, 2H), 1.75-1.65 (m, 2H), 1.63-1.49 (m, 4H), 1.36 (s, 18H). (Note: two active hydrogens are not out)

[0263] Example 9

[0264] 1-(2-(tert-butyl)-4-phenoxyphenoxy)-3-(cyclopentylamino)propan-2-ol 9

[0265]

[0266] First step to synthesize compound 9b

[0267] Tert-butyl hydroquinone 9a (2.00 g, 12.03 mmol) and p-nitrofluorobenzene (1.70 g, 12.03 mmol) were dissolved in DMF (20 mL), under nitrogen protection, room temperature, cesium carbonate (7.84 g, 24.06 mmol) was added, after adding, the reaction was reacted at room temperature (15 °C) for 16 hours, TLC detection of raw materials was complete (petroleum ether / ethyl acetate = 5 / 1, R f = 0.4). The reaction was added with water (150 mL), extracted with ethyl acetate (100 mL x 2), the organic phase was washed with water (100 mL x 3), saturated brine (100 mL), dried, concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 4%-6%) to give the yellow solid title compound 9b (2.03 g, crude), which was directly used in the next step reaction.

[0268] Second step to synthesize compound 9c

[0269] Compound 9b (1.46 g, crude) was dissolved in ethyl acetate (30 mL), palladium on carbon (150 mg, 10%) was added at room temperature, after addition, the reaction solution was reacted at room temperature (15 °C) for 16 hours under hydrogen protection, TLC detection reaction was complete (petroleum ether / ethyl acetate = 2 / 1, Rf=0.3). The reaction solution was filtered through celite, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 16%-24%) to obtain the title compound 9c (880 mg, two-step yield 39.6%) as a white solid. f

[0270] Third step to synthesize compound 9d

[0271] Compound 9c (100 mg, 0.39 mmol) was added to acetonitrile (5 mL), p-toluenesulfonic acid monohydrate (222 mg, 1.17 mmol) was added at room temperature, after addition, the reaction solution was heated to 40 °C for 30 minutes. The reaction solution was cooled to about 0 °C, and sodium nitrite (54 mg, 0.78 mmol) aqueous solution was added dropwise (temperature maintained at 0-5 °C), after addition, the reaction was continued at this temperature for 30 minutes, and potassium iodide (161 mg, 0.97 mmol) aqueous solution was added. After addition, the reaction solution was warmed to room temperature and reacted for 30 minutes, TLC detection reaction was complete (petroleum ether / ethyl acetate = 2 / 1, Rf=0.8). The reaction solution was added with water (50 mL), and extracted with ethyl acetate (100 mL), the organic phase was washed with saturated brine (50 mL), dried, concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 4%-8%) to obtain the title compound 9d (114 mg, yield 79.4%) as a yellow oil. f

[0272] LC-MS / m / z = 367.0 [M-H] -

[0273] Fourth step to synthesize compound 9e

[0274] Compound 9d (194 mg, 0.54 mmol) was dissolved in tetrahydrofuran (6 mL), under nitrogen protection, the reaction solution was cooled to about -60 °C, and n-butyllithium (0.64 mL, 1.60 mmol, 2.5 N) was added dropwise, after dropwise addition, the reaction solution was slowly warmed to 0 °C and reacted for 2 hours, LCMS detection reaction was complete. The reaction solution was quenched with ice water (20 mL), and extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness under reduced pressure at 45 °C, and the crude product was purified by silica gel column chromatography (EA / PE = 9%) to obtain the title compound 9e (84 mg, yield 64.3%) as a brown oil.​​

[0275] LC-MS: m / z = 241.1 [M-H] -

[0276] Step 5: Synthesis of compound 9f

[0277] Compound 9e (84 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (3 mL), under nitrogen protection, the reaction solution was cooled to about 0 °C, sodium hydride (18 mg, 0.43 mmol) was added, after addition, the reaction solution was slowly warmed to 15 °C for 30 minutes. Epibromohydrin (74 mg, 0.54 mmol) was added, after addition, the reaction solution was heated to 50 °C for 1 hour, TLC detection of raw materials reaction (PE / EA = 10 / 1, R f = 0.3). The reaction solution was cooled to room temperature, quenched with water (15 mL), extracted with ethyl acetate (15 mL x 2), the combined organic phase was washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure at 45 °C, the crude product was purified by silica gel column chromatography (EA / PE = 10%) to obtain the title compound 9f (79 mg, yield 73.6%) as a light yellow oil.

[0278] Step 6: Synthesis of compound 9

[0279] Compound 9f (79 mg, 0.26 mmol) was dissolved in methanol (3 mL), cyclopentylamine (45 mg, 0.54 mmol) was added at room temperature, after addition, the reaction solution was heated to 60 °C for 6 hours, TLC detection of raw materials reaction (PE / EA = 10 / 1, R f = 0.3). The reaction solution was cooled to room temperature, concentrated, the crude product was purified by Prep-TLC (DCM / MeOH = 10 / 1) to obtain the title compound 9 (61 mg, yield 61.3%) as a white solid.

[0280] LC-MS: m / z = 384.3 [M+H] +

[0281] 1H NMR (400 MHz, DMSO-d6) δ 8.83 (br, 1H), 7.38-7.32 (m, 2H), 7.11-7.05 (m, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.96-6.89 (m, 3H), 6.85 (dd, J = 8.8, 3.2 Hz, 1H), 5.87 (s, 1H), 4.32-4.23 (m, 1H), 4.08-3.97 (m, 2H), 3.57-3.48 (m, 1H), 3.23-3.15 (m, 1H), 3.08-2.99 (m, 1H), 2.05-1.92 (m, 2H), 1.79-1.48 (m, 6H), 1.35 (s, 9H).

[0282] Example 10

[0283] 3-(tert-Butyl)-2-(3-(cyclopentylamino)-2-hydroxypropoxy)-5- methoxybenzonitrile 10

[0284]

[0285] First step to synthesize compound 10a

[0286] Compound 2a (1.00 g, 5.55 mmol) was dissolved in dichloromethane (20 mL), the reaction solution was cooled to -10 °C, a solution of bromine (842 mg, 5.27 mmol) in dichloromethane (2 mL) was added dropwise, after dropwise addition, the reaction solution was reacted at -10 °C for 1 hour, TLC detection showed that a small amount of raw material was not reacted (PE / EA = 10 / 1, Rf= 0.2). The reaction solution was quenched with water (20 mL), extracted with dichloromethane (10 mL x 2), the organic phase was combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure at 40 °C to dryness. The crude product was purified by silica gel column chromatography (EA / PE = 1%) to obtain the title compound 10a (764 mg, yield 53.2%) as orange oil. f

[0287] LC-MS: m / z = 257.0 [M-H] -

[0288] 1 H NMR (400 MHz, CDCl3) δ 6.87 (d, J = 3.2 Hz, 1H), 6.84 (d, J = 3.2 Hz, 1H), 5.41 (s, 1H), 3.74 (d, J = 1.1 Hz, 3H), 1.38 (d, J = 1.2 Hz, 9H).

[0289] Second step to synthesize compound 10b

[0290] ​Compound 10a (764 mg, 2.94 mmol) was dissolved in N-methylpyrrolidone (20 mL), zinc cyanide (346 mg, 2.94 mmol) and tetraphenylpalladium (340 mg, 0.29 mmol) were added at room temperature, after addition, the reaction solution was heated to 140 °C under nitrogen protection for 2 hours, TLC detection of raw materials reaction (PE / EA = 10 / 1, R f = 0.6). The reaction solution was cooled to room temperature, water (50 mL) and ethyl acetate (50 mL) were added, and the mixture was filtered through celite, the filter cake was washed with ethyl acetate (20 mL), and the filtrate was separated into organic and aqueous phases. The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure at 45 °C to dryness. The crude product was purified by silica gel column chromatography (EA / PE = 10%) to obtain the title compound 10b (483 mg, yield 79.9%) as a light yellow solid.

[0291] LC-MS: m / z = 204.1 [M-H] -

[0292] Synthesis of compound 10c in the third step

[0293] Compound 10b (483 mg, 2.35 mmol) was dissolved in N,N-dimethylformamide (10 mL), and the reaction solution was cooled to about 0 °C under nitrogen protection. Sodium hydride (113 mg, 2.82 mmol) was added, after addition, the reaction solution was slowly warmed to 15 °C for 30 minutes, and then epoxide bromopropane (483 mg, 3.52 mmol) was added. After addition, the reaction solution was heated to 50 °C for 1 hour, and TLC detection of raw materials reaction (PE / EA = 10 / 1, R f = 0.3). The reaction solution was cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure at 45 °C to dryness. The crude product was purified by silica gel column chromatography (EA / PE = 5%) to obtain the title compound 10c (372 mg, yield 60.5%) as a light yellow oil.

[0294] LC-MS: m / z = 279.1 [M+H2O] +

[0295] 1H NMR (400 MHz, CDC13) δ 7.11 (d, J = 3.2 Hz, 1H), 6.88 (d, J = 3.2 Hz, 1H), 4.51 (dd, J = 10.8, 3.2 Hz, 1H), 4.15 - 4.08 (m, 1H), 3.79 (s, 3H), 3.53 - 3.47 (m, 1H), 2.93 (t, J = 4.4 Hz, 1H), 2.41 - 2.77 (m, 1H), 1.38 (s, 9H).

[0296] Fourth step to synthesize compound 10

[0297] Compound 10c (343 mg, 1.31 mmol) was dissolved in methanol (10 mL), and cyclopentylamine (224 mg, 2.62 mmol) was added at room temperature. After the addition was completed, the reaction solution was heated to 60 °C and reacted for 6 hours. TLC detection showed that the starting material was substantially completely reacted (PE / EA = 10 / 1, Rf= 0.3). The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by Prep-TLC (DCM / MeOH = 10 / 1) to obtain the title compound 10 as a white solid (218 mg, yield 48.0%). f

[0298] LC-MS: m / z = 347.2 [M+H] +

[0299] 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (br, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.13 (d, J = 3.2 Hz, 1H), 6.00 (br, 1H), 4.40 - 4.32 (m, 1H), 4.18 - 4.05 (m, 2H), 3.78 (s, 3H), 3.60 - 3.49 (m, 1H), 3.27 - 3.21 (m, 1H), 3.05 - 2.97 (m, 1H), 2.03 - 1.91 (m, 2H), 1.78 - 1.61 (m, 4H), 1.58 - 1.49 (m, 2H), 1.36 (s, 9H).

[0300] Example 11

[0301] (1S,3R)-3-((3-(2-tert-butyl)-4-methoxyphenoxy)-2-hydroxypropyl)amino)cyclopentane-1- carboxylic acid methyl ester 11

[0302]

[0303] First step to synthesize compound 11

[0304] ​Compound 2b (208 mg, 0.88 mmol) was dissolved in ethanol (8 mL), (1S,3R)-3- aminocyclopentanecarboxylic acid methyl ester hydrochloride (250 mg, 1.39 mmol) was added at room temperature, after addition, the reaction solution was heated to 80 °C for 4 hours. TLC detection of the starting material was substantially complete (DCM / MeOH = 10 / 1, R f = 0.3). The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by Prep-TLC to obtain 303 mg of a yellowish viscous oil (LCMS detection of about 10% of the ester exchange into ethyl ester), and 109 mg was purified by Prep-HPLC to obtain the title compound 11 (69 mg, yield 57.5%) as a yellowish viscous oil (already free).

[0305] LC-MS: m / z = 380.2 [M+H] +

[0306] 1 H NMR (400 MHz, DMSO-d6) δ 6.86 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 3.2 Hz, 1H), 6.71 (dd, J = 8.8, 3.2 Hz, 1H), 4.88 (t, J = 4.4 Hz, 1H), 3.94 - 3.78 (m, 3H), 3.68 (s, 3H), 3.58 (s, 3H), 3.07 - 3.01 (m, 1H), 2.84 - 2.68 (m, 2H), 2.62 - 2.57 (m, 1H), 2.11 - 2.02 (m, 1H), 1.88 - 1.67 (m, 4H), 1.59 - 1.47 (m, 1H), 1.45 - 1.36 (m, 1H), 1.33 (s, 9H).

[0307] Example 12

[0308] (2-(3-(Cyclopentylamino)-2-hydroxypropoxy)-5-methoxyphenyl)(phenyl)methanone 12

[0309]

[0310] First step synthesis of compound 12b

[0311] Benzaldehyde (1.00 g, 9.42 mmol) was dissolved in toluene (20 mL), p-methoxyphenol 12a (1.52 g, 12.25 mmol), copper chloride (63 mg, 0.47 mmol), triphenylphosphine (185 mg, 0.71 mmol) and potassium phosphate (4.40 g, 20.73 mmol) were added at room temperature, after addition, the reaction solution was heated to 110 °C for 20 hours, TLC detection of the starting material was complete (PE / EA = 10 / 1, R fThe reaction solution was cooled to room temperature, 1 N dilute hydrochloric acid was added to adjust pH = 5, and ethyl acetate (50 mL x 3) was added for extraction. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated at 45°C under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 9%) to obtain the title compound 12b (231 mg, yield 10.7%) as a light yellow solid.

[0312] LC-MS: m / z = 229.1 [M+H] +

[0313] 1 H NMR (400 MHz, CDCl3) δ 11.58 (s, 1H), 7.73-7.68 (m, 2H), 7.62-7.57 (m, 1H), 7.55-7.48 (m, 2H), 7.15 (dd, J = 9.2, 3.2 Hz, 1H), 7.06 (d, J = 3.2 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 3.71 (s, 3H).

[0314] Second step synthesis of compound 12c

[0315] Compound 12b (218 mg, 0.96 mmol) was dissolved in N,N-dimethylformamide (6 mL), and the reaction solution was cooled to 0°C under nitrogen protection. Sodium hydride (50 mg, 1.24 mmol, 60%) was added, and after addition, the reaction solution was slowly warmed to 15°C and reacted for 30 minutes. Epibromohydrin (196 mg, 1.43 mmol) was added, and after addition, the reaction solution was heated to 50°C and reacted for 1 hour. TLC detection showed that the raw material was reacted completely (PE / EA = 10 / 1, R f The reaction solution was cooled to room temperature, 1 N dilute hydrochloric acid was added to adjust pH = 5, and ethyl acetate (50 mL x 3) was added for extraction. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated at 45°C under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 9%) to obtain the title compound 12b (231 mg, yield 10.7%) as a light yellow solid.

[0316] LC-MS: m / z = 229.1 [M+H] +

[0317] 1H NMR (400 MHz, CDC13) δ 7.84 - 7.78 (m, 2H), 7.60 - 7.54 (m, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.04 - 6.93 (m, 3H), 4.04 (dd, J = 11.2, 3.2 Hz, 1H), 3.89 (dd, J = 11.2, 5.2 Hz, 1H), 3.80 (s, 3H), 2.98 - 2.92 (m, 1H), 2.63 (t, J = 4.8 Hz, 1H), 2.39 - 2.34 (m, 1H).

[0318] Third step to synthesize compound 12

[0319] Compound 12c (189 mg, 0.66 mmol) was dissolved in ethanol (6 mL), and cyclopentylamine (113 mg, 1.33 mmol) was added at room temperature. After the addition was completed, the reaction solution was heated to 80 °C for 2 hours. TLC detection showed that the starting material was substantially completely reacted (PE / EA = 3 / 1, Rf= 0.5). The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by Prep-TLC (DCM / MeOH = 10 / 1) to obtain the title compound 12 as a white solid (181 mg, yield 74.2%). f

[0320] LC-MS: m / z = 370.2 [M+H] +

[0321] 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (br, 1H), 7.72 (d, J = 7.2 Hz, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.16 (d, J = 8.8 Hz, 1H), 7.11 (dd, J = 9.2 Hz, J = 3.2 Hz, 1H), 6.92 (d, J = 3.2 Hz, 1H), 5.68 (br, 1H), 3.99 - 3.80 (m, 3H), 3.75 (s, 3H), 3.16 - 3.05 (m, 1H), 2.49 - 2.42 (m, 1H), 2.35 (dd, J = 12.8, 9.2 Hz, 1H), 1.85 - 1.73 (m, 2H), 1.71 - 1.58 (m, 2H), 1.55 - 1.36 (m, 4H).

[0322] Example 13

[0323] (1R,3S)-3-((3-(2-(tert-Butyl)-4-methoxyphenoxy)-2-hydroxypropyl)amino)-N- methylcyclopentane-1-carboxamide 13

[0324] ​

[0325] First step to synthesize compound 13b

[0326] (-)-(1R,3S)-N-Boc-3-aminocyclopentanecarboxylic acid 13a (500 mg, 2.18 mmol) and methylamine hydrochloride (294 mg, 4.36 mmol) were dissolved in N,N-dimethylformamide (5 mL), N,N-diisopropylethylamine (1.13 g, 8.72 mmol) and 4-dimethylaminopyridine (133 mg, 1.09 mmol) were added at room temperature, after the addition, the reaction solution was reacted at room temperature for 10 minutes, EDCI (627 mg, 3.27 mmol) was added in batches, after the addition, the reaction solution was reacted at room temperature (10°C) for 12 hours. TLC detection of raw materials was complete (DCM / MeOH=20 / 1, R f =0.45). The reaction solution was quenched with water (15 mL) and 1N dilute hydrochloric acid (30 mL), extracted with ethyl acetate (50 mL), washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the white solid title compound 13b (361 mg, yield 68.3%).

[0327] Second step to synthesize compound 13c

[0328] Compound 13b (361 mg, 1.49 mmol) was dissolved in dichloromethane (3 mL), hydrogen chloride solution in dioxane (8 mL, 32.00 mmol, 4 mol / L) was added at room temperature, after the addition, the reaction solution was reacted at room temperature (12°C) for 14 hours. TLC detection of raw materials was complete (DCM / MeOH=10 / 1, R f =0.15). The reaction solution was concentrated, and the residue was taken with ethanol twice to obtain the title compound 13c (358 mg, crude) as a viscous oil, which was directly used in the next step reaction.

[0329] Third step to synthesize compound 13

[0330] Compound 2b (175 mg, 0.74 mmol) was dissolved in ethanol (8 mL), and the above crude compound 13c (358 mg, crude) was added at room temperature, after the addition, the reaction solution was heated to 80°C and reacted for 4 hours, TLC detection of raw materials was basically complete (DCM / MeOH=10 / 1, R f =0.3). The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 13 (69 mg, yield 24.6%) as a yellowish viscous oil.

[0331] LC-MS: m / z = 379.2 [M+H] +

[0332] 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (br, 2H), 8.21-8.09 (m, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.80-6.67 (m, 2H), 5.86 (t, J = 5.2 Hz, 1H), 4.27-4.19 (m, 1H), 3.99-3.91 (m, 2H), 3.69 (s, 3H), 3.65-3.59 (m, 1H), 3.23-3.13 (m, 1H), 3.10-2.99 (m, 1H), 2.78-2.69 (m, 1H), 2.58 (d, J = 4.4 Hz, 3H), 2.15-2.08 (m, 1H), 2.04-1.95 (m, 1H), 1.95-1.73 (m, 4H), 1.34 (s, 9H). (One more active hydrogen, probably hydrate, this series of compounds many such cases).

[0333] Example 14

[0334] 1-(Cyclopentylamino)-3-(4-methoxy-2-methylphenoxy)propan-2-ol 14

[0335]

[0336] First step synthesis of compound 14b

[0337] 2-Methyl-4-methoxyphenol 14a (400 mg, 2.90 mmol) was dissolved in DMF (5 mL), under nitrogen protection, cooled to about 0 °C with ice water bath, sodium hydride (139 mg, 3.47 mmol) was added in portions, after addition, the reaction solution was slowly warmed to room temperature for 30 minutes. Again cooled to about 0 °C, dropwise added epichlorohydrin (0.28 mL, 3.47 mmol), after addition, the reaction solution was warmed to 30 °C for 1 hour, TLC detection reaction was complete (petroleum ether / ethyl acetate = 10 / 1, Rf = 0.55). The reaction solution was cooled to 0 °C, quenched with water (20 mL), extracted with ethyl acetate (50 mL), washed with water (50 mL x 2), saturated brine (50 mL), dried, concentrated, the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 4%-6%) to give the title compound 14b (421 mg, yield 74.7%) as a yellow transparent oil. f

[0338] 1 ​H NMR (400 MHz, CDC13-dl) δ 6.76-6.72 (m, 2H), 6.65 (dd, J = 3.2 Hz, J = 8.8 Hz, 1H), 4.16 (dd, J = 3.2 Hz, J = 11.2 Hz, 1H), 3.91 (dd, J = 3.2 Hz, J = 11.2 Hz, 1H), 3.75 (s, 3H), 3.36-3.32 (m, 1H), 2.89 (t, J = 4.4 Hz, 1H), 2.76-2.74 (m, 1H), 2.23 (s, 3H).

[0339] Second step to synthesize compound 14

[0340] Compound 14b (100 mg, 0.52 mmol) and cyclopentylamine (88 mg, 1.03 mmol) were dissolved in methanol (1 mL) and heated to 60 °C for 5.5 hours. TLC test showed the reaction was complete (dichloromethane / methanol = 20 / 1, Rf= 0.15). The reaction was cooled to room temperature and concentrated. The crude product was purified by Prep-TLC (DCM:MeOH = 15:1) to give the title compound 14 (74 mg, yield 50.9%) as a white solid. f

[0341] LC-MS / m / z = 280.2 [M+H] +

[0342] 1 H NMR (400 MHz, DMSO-d6) δ 6.89 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 3.2 Hz, 1H), 6.74 (dd, J = 3.2 Hz, J = 8.8 Hz, 1H), 5.20 (br, 1H), 4.05-3.96 (m, 1H), 3.90 (d, J = 5.2 Hz, 2H), 3.73 (s, 3H), 3.23-3.17 (m, 1H), 2.88 (dd, J = 4.0 Hz, J = 12.0 Hz, 1H), 2.88 (dd, J = 7.2 Hz, J = 12.0 Hz, 1H), 2.20 (s, 3H), 1.92-1.79 (m, 2H), 1.71-1.64 (m, 2H), 1.55-1.51 (m, 2H), 1.48-1.41 (m, 2H).(Note: one active hydrogen was not shown or was wrapped up with water peak)

[0343] Example 15

[0344] 1-(2-(tert-Butyl)phenoxy)-3-(cyclopentylamino)propan-2-ol 15

[0345] ​

[0346] First step to synthesize compound 15b

[0347] Dissolve 2-tert-butylphenol 15a (1.00 g, 6.66 mmol) in N,N-dimethylformamide (10 mL), under nitrogen protection, cool the reaction solution to about 0 °C, add sodium hydride (320 mg, 8.00 mmol, 60%) in batches, about twenty minutes to add, cool the reaction solution to about 0 °C, add epoxide bromopropane (1.37 g, 9.99 mmol), add, cool the reaction solution to about 0 °C, recover to room temperature, react for twenty minutes, heat to 50 °C, react for 1 hour, TLC detection, the raw material is basically reacted completely (PE / EA = 20 / 1, Rf= 0.35). Cool the reaction solution to room temperature, add water (30 mL), extract with ethyl acetate (50 mL), wash with saturated brine (30 mL x 3), dry over anhydrous sodium sulfate, concentrate to get yellow oil of the title compound 15b (1.71 g, crude), which is directly used in the next step reaction. f

[0348] Second step to synthesize compound 15

[0349] Dissolve compound 15b (100 mg, crude) in ethanol (10 mL), add cyclopentylamine (82 mg, 0.96 mmol) at room temperature, add, heat the reaction solution to 80 °C, react for 4 hours. TLC detection, the raw material is basically reacted completely (DCM / MeOH = 10 / 1, Rf= 0.3). Cool the reaction solution to room temperature, concentrate, purify the crude product by Prep-TLC to get white solid of the title compound 15 (102 mg, two-step yield 89.9%). f

[0350] LC-MS: m / z = 292.2 [M+H] +

[0351] 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (br, 1H), 7.24 (dd, J = 7.6, 1.6 Hz, 1H), 7.18 (dt, J = 7.6, 1.6 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H), 5.88 (d, J = 4.8 Hz, 1H), 4.33-4.31 (m, 1H), 4.10-3.96 (m, 2H), 3.57-3.50 (m, 1H), 3.20 (dd, J = 12.8, 2.8 Hz, 1H), 3.04 (dd, J = 12.8, 9.2 Hz, 1H), 2.02-1.94 (m, 2H), 1.78-1.61 (m, 4H), 1.60-1.48 (m, 2H), 1.36 (s, 9H).​​

[0352] Example 16

[0353] 1-(2-(tert-butyl)-4-propoxyphenoxy)-3-(cyclopentylamino)propan-2-ol 16

[0354]

[0355] The first step is to synthesize compound 16a

[0356] Compound 9a (2.00 g, 12.03 mmol) was dissolved in acetonitrile (20 mL), and potassium carbonate (3.32 g, 24.06 mmol) and bromopropane (2.22 g, 18.05 mmol) were added at room temperature. After the addition was complete, the reaction solution was heated to 80°C for 20 hours. TLC showed that the raw material was not completely reacted, and new spots were generated (PE / EA=10 / 1, R f =0.2). The reaction solution was cooled to room temperature and quenched with water (50 mL), extracted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure at 45°C. The crude product was purified by silica gel column chromatography (EA / PE = 3%) to obtain the title compound 16a (1.19 g, yield 47.5%) as a brown oil.

[0357] Step 2: Synthesis of Compound 16b

[0358] Compound 16a (1.19 g, 5.71 mmol) was dissolved in N,N-dimethylformamide (15 mL). The reaction solution was cooled to 0°C and sodium hydride (297 mg, 7.42 mmol) was added. After the addition was complete, the reaction solution was slowly heated to 15°C and reacted for 30 minutes. Epibromohydrin (1.17 g, 8.57 mmol) was added. After the addition was complete, the reaction solution was heated to 50°C and reacted for 1 hour. TLC detected that the reaction of the raw material was complete (PE / EA=10 / 1, R f =0.3). The reaction solution was cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (50 mL x 2), and the organic phases were combined, washed with saturated brine (50 mL x 3), and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness under reduced pressure at 45°C. The crude product was purified by silica gel column chromatography (EA / PE = 5%) to obtain the title compound 16b (1.10 g, yield 72.9%) as a light yellow oil.

[0359] 1H NMR (400 MHz, CDC13) δ 6.89 (d, J = 2.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.66 (dd, J = 8.8, 3.2 Hz, 1H), 4.20 (dd, J = 10.8, 3.2 Hz, 1H), 3.98 - 3.92 (m, 1H), 3.86 (t, J = 6.8 Hz, 2H), 3.14 - 3.36 (m, 1H), 2.91 (t, J = 4.4 Hz, 1H), 2.79 - 2.75 (m, 1H), 1.84 - 1.73 (m, 2H), 1.38 (s, 9H), 1.03 (t, J = 7.2 Hz, 3H).

[0360] Third step to synthesize compound 16

[0361] Compound 16b (300 mg, 1.14 mmol) was dissolved in ethanol (10 mL), and cyclopentylamine (193 mg, 2.27 mmol) was added at room temperature. After the addition was completed, the reaction solution was heated to 80 °C for 3 hours. TLC detection showed that the starting material was substantially completely reacted (DCM / MeOH = 10 / 1, Rf= 0.3). The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by Prep-TLC (DCM / MeOH = 10 / 1) to obtain the title compound 16 as a white solid (182 mg, yield 45.7%). f

[0362] LC-MS: m / z = 350.2 [M+H] +

[0363] 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (br, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.79 - 6.70 (m, 2H), 5.85 (d, J = 4.8 Hz, 1H), 4.30 - 4.21 (m, 1H), 4.01 - 3.91 (m, 2H), 3.84 (t, J = 6.4 Hz, 2H), 3.57 - 3.47 (m, 1H), 3.23 - 3.14 (m, 1H), 3.08 - 2.96 (m, 1H), 2.03 - 1.93 (m, 2H), 1.79 - 1.60 (m, 6H), 1.59 - 1.48 (m, 2H), 1.34 (s, 9H), 0.97 (t, J = 7.2 Hz, 3H).

[0364] Example 17

[0365] 1-(4-Methoxy-2-methylphenoxy)-3-(thiazol-4-ylamino)propan-2-ol 17

[0366] ​

[0367] First step to synthesize compound 17

[0368] Compound 14b (100 mg, 0.52 mmol) and 2-aminothiazole (103 mg, 1.03 mmol) were dissolved in methanol (1 mL) and heated to 65 °C for 3 hours. TLC test showed the reaction was complete (dichloromethane / methanol = 10 / 1, R f = 0.30). The reaction was cooled to room temperature and concentrated. The crude product was purified by Prep-TLC (DCM:MeOH = 8:1) to give the title compound 17 (50 mg, yield 32.7%) as a light yellow solid.

[0369] LC-MS / m / z = 295.1 [M+H] +

[0370] 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (br, 1H), 7.10 (d, J = 4.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 2.8 Hz, 1H), 6.75 (dd, J = 8.0 Hz, J = 14.0 Hz, 1H), 6.54 (d, J = 4.8 Hz, 1H), 4.23 - 4.12 (m, 2H), 3.99 (dd, J = 3.2 Hz, J = 8.8 Hz, 1H), 3.94 (d, J = 5.2 Hz, 2H), 3.74 (s, 3H), 2.23 (s, 3H). (Note: there is one active hydrogen not shown)

[0371] Example 18

[0372] 4-(tert-Butyl)-5-(3-(cyclopentylamino)-2-hydroxypropoxy)-2-methoxybenzonitrile 18

[0373]

[0374] First step to synthesize compound 18a

[0375] Compound 2a (1.00 g, 5.55 mmol) was dissolved in acetonitrile (20 mL) and cooled to about 0 °C under nitrogen protection. A solution of N-bromosuccinimide (1.04 g, 5.82 mmol) in acetonitrile (10 mL) was added dropwise. The reaction was slowly warmed to 15 °C and reacted for 2 hours. TLC test showed the starting material was consumed (PE / EA = 10 / 1, R fThe reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 °C. The crude product was purified by column chromatography on silica gel (EA / PE = 5%) to obtain the title compound 18a (805 mg, yield 56.0%) as a yellow solid.

[0376] LC-MS: m / z = 257.0 [M-H] -

[0377] 1 H NMR (400 MHz, CDC13) δ 6.89 (s, 1H), 6.86 (s, 1H), 4.76 (s, 1H), 3.85 (s, 3H), 1.39 (s, 9H).

[0378] Second step to synthesize compound 18b

[0379] Compound 18a (700 mg, 2.70 mmol) was dissolved in N-methylpyrrolidone (20 mL), and zinc cyanide (317 mg, 2.70 mmol) and tetraphenylpalladium (249 mg, 0.22 mmol) were added at room temperature. After the addition, the reaction solution was heated to 140 °C under nitrogen protection, and the reaction was allowed to proceed for 2 hours. TLC detection showed that the starting material was completely reacted (PE / EA = 10 / 1, R f The reaction solution was cooled to room temperature, and water (50 mL) and ethyl acetate (20 mL) were added. The mixture was filtered through celite, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was separated into layers, and the organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 °C. The crude product was purified by column chromatography on silica gel (EA / PE = 15%) to obtain the title compound 18b (438 mg, yield 79.0%) as a light yellow solid.

[0380] LC-MS: m / z = 204.1 [M-H] -

[0381] Third step to synthesize compound 18c

[0382] Compound 18b (200 mg, 0.97 mmol) was dissolved in N,N-dimethylformamide (6 mL), and sodium hydride (47 mg, 1.17 mmol) was added to the reaction solution under nitrogen protection while cooling to about 0 °C. After the addition, the reaction solution was slowly warmed to 15 °C and allowed to react for 30 minutes. Epibromohydrin (200 mg, 1.46 mmol) was added, and the reaction solution was heated to 60 °C and allowed to react for 6 hours. TLC detection showed that a small amount of starting material was not completely reacted (PE / EA = 10 / 1, R fThe reaction solution was cooled to room temperature, concentrated, and the crude product was purified by Prep-TLC (DCM / MeOH=10 / 1) to give the title compound 18 (154 mg, yield 50.5%) as a white solid.

[0383] Fourth step synthesis of compound 18

[0384] Compound 18c (229 mg, 0.88 mmol) was dissolved in methanol (10 mL), and cyclopentylamine (149 mg, 1.75 mmol) was added at room temperature. After the addition was completed, the reaction solution was heated to 60 °C and reacted for 6 hours. TLC detection showed that the starting material was substantially completely reacted (PE / EA=10 / 1, R f The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by Prep-TLC (DCM / MeOH=10 / 1) to give the title compound 18 (154 mg, yield 50.5%) as a white solid.

[0385] LC-MS: m / z = 347.2 [M+H] +

[0386] 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (br, 1H), 7.32 (s, 1H), 7.02 (s, 1H), 5.87 (s, 1H), 4.26 (s, 1H), 4.04 (d, J = 4.8 Hz, 2H), 3.90 (s, 3H), 3.57-3.46 (m, 1H), 3.21-3.11 (m, 1H), 3.00 (dd, J = 12.8, 9.6 Hz, 1H), 2.03-1.91 (m, 2H), 1.78-1.59 (m, 4H), 1.58-1.48 (m, 2H), 1.39 (s, 9H).

[0387] Example 19

[0388] 1-(Cyclopentylamino)-3-(2,6-di-tert-butyl-4-propoxyphenoxy)propan-2-ol 19

[0389]

[0390] First step synthesis of compound 19a

[0391] 2,6-di-tert-butyl-4-methoxyphenol 8a (5.00 g, 21.16 mmol) was dissolved in acetonitrile (50 mL), and acetic anhydride (3.24 g, 31.73 mmol) and sulfuric acid (104 mg, 1.06 mmol) were added at room temperature. After the addition was completed, the reaction solution was heated to 50 °C and reacted for 1 hour. TLC detection showed that the starting material was completely reacted (PE / EA=20 / 1, starting material Rf = 0.5, product R f The reaction solution was cooled to room temperature, water (200 mL) was added, and solids precipitated. The mixture was stirred at room temperature for 30 minutes, filtered, the filter cake was washed with water (10 mL), and the filter cake was dried to obtain the title compound 19a (5.88 g, yield 99.8%) as a white solid.

[0392] LC-MS: m / z = 296.2 [M + H2O] +

[0393] 1 H NMR (400 MHz, CDC13) δ 6.86 (s, 2H), 3.79 (s, 3H), 2.33 (s, 3H), 1.33 (s, 18H).

[0394] Second step synthesis of compound 19b

[0395] Compound 19a (6.41 g, 23.03 mmol) was dissolved in acetonitrile (30 mL), and sodium iodide (6.90 g, 46.05 mmol) and trimethylsilyl chloride (5.00 g, 46.05 mmol) were added at room temperature. After the addition was completed, the reaction solution was heated to 80°C and reacted for 8 hours. TLC detection showed that the starting material was completely reacted (PE / EA = 10 / 1, product R f = 0.3). The reaction solution was cooled to room temperature, quenched with water (150 mL), and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated aqueous sodium sulfite (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45°C to obtain the title compound 19b (6.08 g, yield 99.9%) as a white solid.

[0396] LC-MS: m / z = 263.2 [M - H] -

[0397] Third step synthesis of compound 19c

[0398] Compound 19b (1.40 g, 5.30 mmol) was dissolved in N,N-dimethylformamide (15 mL), and sodium hydride (275 mg, 6.88 mmol) was added under nitrogen protection while the reaction solution was cooled to 0°C. After the addition was completed, the reaction solution was reacted at 0°C for 30 minutes, and bromopropane (977 mg, 7.94 mmol) was added. After the addition was completed, the reaction solution was reacted at 0°C for 2 hours. TLC detection showed that the starting material was completely reacted (PE / EA = 10 / 1, product R fThe reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 °C. The crude product was purified by silica gel column chromatography (EA / PE = 1%) to obtain the title compound 19c (1.25 g, yield 77.2%) as a light yellow oil.

[0399] LC-MS: m / z = 324.2 [M + H2O] +

[0400] Fourth step of synthesizing compound 19d

[0401] Potassium tert-butoxide (2.17 g, 19.38 mmol) was dispersed in n-heptane (30 mL). A solution of compound 19c (990 mg, 3.25 mmol) in n-heptane (3 mL) was added dropwise at room temperature under nitrogen protection. After the dropwise addition was completed, the reaction solution was heated to 60 °C and reacted for 1 hour. TLC detection showed that the raw material was completely reacted (PE / EA = 30 / 1, product R f The reaction solution was cooled to room temperature, 1N dilute hydrochloric acid was added to adjust pH = 5, and ethyl acetate (30 mL x 2) was added for extraction. The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 °C. The crude product was purified by silica gel column chromatography (EA / PE = 1%) to obtain the title compound 19d (597 mg, yield 69.9%) as a yellow oil.

[0402] LC-MS: m / z = 263.2 [M - H] -

[0403] Fifth step of synthesizing compound 19e

[0404] Compound 19d (597 mg, 2.26 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (117 mg, 2.93 mmol) was added to the reaction solution under nitrogen protection, and the reaction solution was slowly warmed to 20 °C and reacted for 30 minutes. Epibromohydrin (464 mg, 3.39 mmol) was added, and the reaction solution was heated to 50 °C and reacted for 1 hour. TLC detection showed that the raw material was completely reacted (PE / EA = 30 / 1, product R f The reaction solution was cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 °C. The crude product was purified by silica gel column chromatography (EA / PE = 1%) to obtain the title compound 19e (482 mg, yield 66.7%) as a light yellow oil.

[0405] Sixth step of synthesizing compound 19

[0406] Compound 19e (482 mg, 1.50 mmol) was dissolved in ethanol (10 mL), and cyclopentylamine (256 mg, 3.01 mmol) was added at room temperature. After the addition was completed, the reaction solution was heated to 80 °C and reacted for 2 hours. TLC detection showed that the starting material was substantially completely reacted (DCM / MeOH = 10 / 1, product R f = 0.6). The reaction solution was cooled to room temperature, and concentrated under reduced pressure at 45 °C to obtain a crude product (669 mg). The crude product (223 mg) was purified by Prep-TLC (DCM / MeOH = 13 / 1) to obtain a white solid (108 mg). The product was slurried in a mixture of methyl tert-butyl ether / petroleum ether = 1 / 1 (4 mL), filtered, and the filter cake was washed with petroleum ether (1 mL x 3) and dried to obtain a white solid of the title compound 19 (79 mg, yield 77.7%).

[0407] LC-MS: m / z = 406.3 [M+H] +

[0408] 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (br, 1H), 6.75 (s, 2H), 5.91 (d, J = 5.2 Hz, 1H), 4.36-4.27 (m, 1H), 3.87 (t, J = 6.4 Hz, 2H), 3.73-3.66 (m, 1H), 3.65-3.49 (m, 2H), 3.16 (d, J = 12.8 Hz, 1H), 2.94-2.85 (m, 1H), 2.01-1.91 (m, 2H), 1.77-1.48 (m, 8H), 1.38 (s, 18H), 0.98 (t, J = 7.2 Hz, 3H).

[0409] Example 20

[0410] 1-(Cyclopentylamino)-3-(2,6-di-tert-butyl-4-ethoxyphenoxy)propan-2-ol 20

[0411]

[0412] First Step to Synthesize Compound 20a

[0413] Compound 19b (1.00 g, 3.78 mmol) was dissolved in DMF (10 mL), and NaH (196 mg, 4.92 mmol, 60%) was added under nitrogen protection while the reaction solution was cooled to about 0 °C. After the addition was completed, the reaction solution was stirred at room temperature for 30 minutes, and iodoethane (885 mg, 5.67 mmol) was added. After the addition was completed, the reaction solution was reacted at 0 °C for 1 hour. TLC (PE:EA = 10:1, R f=0.4) to detect the complete reaction of the starting material. The reaction solution was quenched with water (30 mL), extracted with ethyl acetate (20 mL x 3), and the organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 20a (1.08 g, crude product) as a light yellow oil, which was used directly in the next reaction.

[0414] Step 2: Synthesis of Compound 20b

[0415] Compound 20a (1.08 g, crude product) was dissolved in n-heptane (10 mL), and a suspension of potassium tert-butoxide (2.83 g, 22.16 mmol) in n-heptane (30 mL) was added at room temperature. After the addition, the reaction solution was heated to 60°C under nitrogen for 2 hours. TLC (PE:EA=30:1, R f = 0.6) to detect the complete reaction of the starting material. The reaction solution was adjusted to pH 5 with 1N dilute hydrochloric acid (20 mL). The organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 3%) to obtain the title compound 20b (785 mg, 82.9% yield over two steps) as a white solid.

[0416] Step 3: Synthesis of Compound 20c

[0417] Compound 20b (780 mg, 3.12 mmol) was dissolved in N,N-dimethylformamide (10 mL). Under nitrogen protection, the reaction solution was cooled to about 0°C and NaH (149 mg, 3.74 mmol, 60%) was added. After the addition was complete, the reaction solution was slowly heated to 15°C and reacted for 30 minutes. Epibromohydrin (640 mg, 4.67 mmol) was added and the reaction solution was heated to 50°C and reacted for 2 hours. TLC detection showed that the reaction of the raw material was complete (PE / EA=30 / 1, R f =0.3). The reaction solution was cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (20 mL x 3), and the combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 5%) to give the title compound 20c (767 mg, yield 80.2%) as a light yellow oil.

[0418] Step 4: Synthesis of Compound 20

[0419] Compound 20c (200 mg, 0.65 mmol) was dissolved in ethanol (7 mL), and cyclopentylamine (111 mg, 1.30 mmol) was added at room temperature. After the addition, the reaction solution was heated to 80°C for 2 hours. TLC showed that the reaction of the raw material was basically complete (PE:EA=10:1, R f= 0.2). The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by Prep-TLC (DCM:MeOH = 10:1) to give the title compound 20 (53 mg, yield 20.8%) as a white solid.

[0420] LC-MS: m / z = 392.4 [M+H] + (96.94% purity, 210 nm)

[0421] 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (br, 1H), 6.74 (s, 2H), 5.80 (br, 1H), 4.38-4.29 (m, 1H), 3.96 (q, J = 7.2 Hz, 2H), 3.70-3.59 (m, 2H), 3.53-3.42 (m, 1H), 3.12-3.08 (m, 1H), 2.84 (dd, J = 12.4, 10.0 Hz, 1H), 1.99-1.85 (m, 2H), 1.82-1.60 (m, 4H), 1.56-1.49 (m, 2H), 1.38 (s, 18H), 1.30 (t, J = 7.2 Hz, 3H).

[0422] Example 21

[0423] 1-(Cyclopentylamino)-3-(2,6-di-tert-butyl-4-isopropoxyphenoxy)propan-2-ol 21

[0424]

[0425] Referring to the synthesis method of compound 20, the title compound 21 (113 mg, yield 54.3%) was synthesized using compound 19b and iodoisopropane as raw materials.

[0426] LC-MS: m / z = 406.3 [M+H] +

[0427] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (br, 1H), 6.71 (s, 2H), 5.86 (s, 1H), 4.56-4.45 (m, 1H), 4.34-4.25 (m, 1H), 3.72-3.65 (m, 1H), 3.64-3.56 (m, 1H), 3.55-3.46 (m, 1H), 3.13 (d, J = 12.4 Hz, 1H), 2.87 (t, J = 11.2 Hz, 1H), 2.01-1.89 (m, 2H), 1.75-1.48 (m, 6H), 1.37 (s, 18H), 1.24 (d, J = 6.0 Hz, 6H).

[0428] Example 22

[0429] 1-(2-(tert-butyl)-6-isopropyl-4-methoxyphenoxy)-3-(cyclopentylamino)propan-2-ol 22

[0430]

[0431] The first step is to synthesize compound 22a

[0432] Compound 10a (1.00 g, 3.85 mmol) was dissolved in a mixed solution of 1,4-dioxane (20 mL) and water (4 mL). Potassium isopropenyl trifluoroborate (1.14 g, 7.71 mmol), sodium carbonate (1.23 g, 11.58 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (158 mg, 0.19 mmol) were added at room temperature. After the addition was completed, the reaction solution was heated to 90°C under nitrogen protection for 16 hours. TLC analysis showed that the reaction of the raw material was complete (PE / EA=30 / 1, R f =0.5). The reaction solution was cooled to room temperature, quenched with water (40 mL), extracted with ethyl acetate (30 mL x 2), and the organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness under reduced pressure at 45°C. The crude product was purified by silica gel column chromatography (EA / PE = 1%) to obtain the title compound 22a (458 mg, yield 54.0%) as a light yellow oil.

[0433] 1 H NMR (400MHz, CDCl3) δ6.80(d,J=3.2Hz,1H),6.52(d,J=3.2Hz,1H),5.66(s,1H),5.44(s,1H),5.14(s,1H),3.76(s,3H),2.10(s,3H),1.40(s,9H).

[0434] Step 2: Synthesis of Compound 22b

[0435] Compound 22a (458 mg, 2.08 mmol) was dissolved in methanol (10 mL), and 10% Pd / C (50 mg) was added at room temperature. After the addition was complete, the reaction solution was reacted at 20°C for 16 hours under hydrogen protection. TLC showed that the reaction of the raw material was complete (PE / EA = 30 / 1, R f =0.4). The reaction mixture was filtered through a pad of celite, the filter cake was washed with methanol (10 mL), and the filtrate was concentrated under reduced pressure at 45°C to give the title compound 22b (420 mg, yield 90.8%) as a light yellow solid.

[0436] LC-MS: m / z = 221.2 [MH]-

[0437] Third step to synthesize compound 22c

[0438] Compound 22b (420 mg, 1.89 mmol) was dissolved in N,N-dimethylformamide (10 mL), under nitrogen protection, the reaction solution was cooled to 0 °C, sodium hydride (98 mg, 2.45 mmol) was added, after addition, the reaction solution was slowly warmed to 15 °C for 30 minutes, epoxide bromopropane (388 mg, 2.83 mmol) was added, after addition, the reaction solution was heated to 50 °C for 1 hour, TLC detection showed that the raw material was completely reacted (PE / EA = 30 / 1, R f = 0.4). The reaction solution was cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure at 45 °C, and the crude product was purified by silica gel column chromatography (EA / PE = 1%) to obtain the title compound 22c (317 mg, yield 60.2%) as a light yellow oil.

[0439] Fourth step to synthesize compound 22

[0440] Compound 22c (317 mg, 1.14 mmol) was dissolved in ethanol (10 mL), cyclopentylamine (224 mg, 2.62 mmol) was added at room temperature, after addition, the reaction solution was heated to 80 °C for 2 hours, TLC detection showed that the raw material was completely reacted (DCM / MeOH = 10 / 1, R f = 0.4). The reaction solution was cooled to room temperature, concentrated under reduced pressure at 45 °C, and the crude product was purified by Prep-TLC (DCM / MeOH = 10 / 1) to obtain the title compound 22 (231 mg, yield 55.7%) as a white solid.

[0441] LC-MS: m / z = 364.3 [M+H] +

[0442] 1 H NMR (400 MHz, DMSO-d6) δ 6.69 (d, J = 3.2 Hz, 1H), 6.62 (d, J = 3.2 Hz, 1H), 5.47 (br, 1H), 4.12-4.03 (m, 1H), 3.73-3.62 (m, 5H), 3.30-3.22 (m, 2H), 2.98-2.90 (m, 1H), 2.78 (dd, J = 12.4, 8.4 Hz, 1H), 1.89-1.78 (m, 2H), 1.72-1.61 (m, 2H), 1.56-1.42 (m, 4H), 1.34 (s, 9H), 1.17 (d, J = 6.4 Hz, 6H).(Note: the active hydrogen of amino does not appear)

[0443] Example 23

[0444] 1-(Cyclopentylamino)-3-(2,6-diisopropyl-4-methoxyphenoxy)propan-2-ol 23

[0445]

[0446] The first step is to synthesize compound 23b

[0447] 2-Bromo-4-methoxyphenol 23a (3.00 g, 14.78 mmol) was dissolved in a mixed solution of 1,4-dioxane (50 mL) and water (10 mL). Potassium isopropenyl trifluoroborate (4.37 g, 29.55 mmol), sodium carbonate (4.70 g, 44.33 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (302 mg, 0.37 mmol) were added at room temperature. After the addition was completed, the reaction solution was heated to 90°C under nitrogen protection for 20 hours. The reaction was completed by TLC detection (PE / EA=10 / 1, raw material R f =0.35, product R f =0.3). The reaction solution was cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (50 mL x 2), and the organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness under reduced pressure at 45°C. The crude product was purified by silica gel column chromatography (EA / PE = 9%) to obtain the title compound 23b (2.03 g, yield 83.5%) as a light yellow oil.

[0448] LC-MS: m / z = 165.1 [M+H] +

[0449] Step 2: Synthesis of Compound 23c

[0450] Compound 23b (2.03 g, 12.36 mmol) was dissolved in methanol (30 mL). Pd / C (200 mg, 10%) was added at room temperature. After addition, the reaction mixture was incubated at 15°C under hydrogen atmosphere for 16 hours. LCMS confirmed the complete reaction. The reaction mixture was filtered through a pad of Celite, and the filter cake was washed with methanol (5 mL). The filtrate was concentrated under reduced pressure at 45°C to afford the title compound 23c (1.88 g, crude) as a brown oil, which was used directly in the next reaction.

[0451] LC-MS: m / z = 165.1 [MH] -

[0452] Step 3: Synthesis of Compound 23d

[0453] Compound 23c (1.88 g, crude) was dissolved in dichloromethane (30 mL), the reaction solution was cooled to 0 °C under nitrogen protection, a solution of bromine (1.63 g, 10.18 mmol) in dichloromethane (10 mL) was added dropwise, and the reaction was continued at 0 °C for 1 h. TLC detection showed that the raw material was completely reacted (PE / EA = 30 / 1, product Rf= 0.6). The reaction solution was quenched with water (30 mL), extracted with dichloromethane (20 mL x 2), the combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure at 45 °C. The crude product was purified by silica gel column chromatography (EA / PE = 1%) to obtain the title compound 23d (1.27 g, two-step yield 41.9%) as a yellow oil. f

[0454] 1 H NMR (400 MHz, DMSO-d6) δ 6.84 (d, J = 2.8 Hz, 1H), 6.74 (d, J = 3.2 Hz, 1H), 5.20 (s, 1H), 3.75 (s, 3H), 3.29 (p, J = 6.8 Hz, 1H), 1.23 (s, 3H), 1.21 (s, 3H).

[0455] Fourth step synthesis of compound 23e

[0456] Compound 23d (650 mg, 2.65 mmol) was dissolved in a mixture of 1,4-dioxane (20 mL) and water (5 mL), and isopropenyl potassium trifluoroborate (785 mg, 5.30 mmol), sodium carbonate (843 mg, 7.95 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (108 mg, 0.13 mmol) were added at room temperature. After addition, the reaction solution was heated to 90 °C under nitrogen protection for 16 h. LCMS detection showed that the raw material was completely reacted. The reaction solution was cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (30 mL x 2), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure at 45 °C. The crude product was purified by silica gel column chromatography (EA / PE = 1%) to obtain the title compound 23e (406 mg, yield 74.2%) as a yellow oil.

[0457] LC-MS: m / z = 207.1 [M+H] +

[0458] Fifth step synthesis of compound 23f

[0459] ​Compound 23e (406 mg, 1.97 mmol) was dissolved in methanol (10 mL), and Pd / C (50 mg, 10%) was added at room temperature. After the addition was complete, the reaction solution was reacted at 15°C for 16 hours under hydrogen protection. TLC showed that the reaction of the raw material was complete (PE / EA = 30 / 1, product R f =0.5). The reaction mixture was filtered through a pad of celite, the filter cake was washed with methanol (5 mL), and the filtrate was concentrated under reduced pressure at 45°C to give the title compound 23f (396 mg, crude product) as a brown oil, which was used directly in the next reaction.

[0460] LC-MS: m / z = 209.1 [M+H] +

[0461] Step 6: Synthesis of compound 23g

[0462] Compound 23f (396 mg, crude product) was dissolved in N,N-dimethylformamide (10 mL). Under nitrogen protection, the reaction solution was cooled to 0°C and sodium hydroxide (99 mg, 2.47 mmol, 60%) was added. After the addition was complete, the reaction solution was slowly heated to 20°C and reacted for 30 minutes. Epibromohydrin (391 mg, 2.85 mmol) was added. After the addition was complete, the reaction solution was heated to 50°C and reacted for 1 hour. TLC detection showed that the reaction of the raw material was complete (PE / EA = 30 / 1, product R f =0.45). The reaction solution was cooled to room temperature, quenched with water (30 mL), extracted with ethyl acetate (30 mL x 2), and the organic phases were combined, washed with saturated brine (30 mL x 3), and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness under reduced pressure at 45°C. The crude product was purified by silica gel column chromatography (EA / PE = 1%) to obtain 23 g (353 mg, two-step yield 67.9%) of the title compound as a light yellow oil.

[0463] LC-MS: m / z = 265.1 [M+H] +

[0464] Step 7: Synthesis of Compound 23

[0465] Compound 23g (353 mg, 1.34 mmol) was dissolved in ethanol (10 mL), and cyclopentylamine (227 mg, 2.67 mmol) was added at room temperature. After the addition was complete, the reaction solution was heated to 80°C for 2 hours. TLC showed that the reaction of the raw material was basically complete (DCM / MeOH = 10 / 1, product R f =0.6). The reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure at 45°C. The crude product was purified by Prep-TLC (DCM / MeOH=13 / 1) to obtain the title compound 23 as a white solid (281 mg, yield 60.2%).

[0466] LC-MS: m / z=350.3[M+H]+

[0467] 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (br, 1H), 6.63 (s, 2H), 5.88 (br, 1H), 4.26-4.17 (m, 1H), 3.72 (s, 3H), 3.65 (d, J = 5.2 Hz, 2H), 3.55-3.46 (m, 1H), 3.31-3.24 (m, 2H), 3.21-3.15 (m, 1H), 2.97 (dd, J = 12.8, 10.0 Hz, 1H), 2.03-1.92 (m, 2H), 1.79-1.61 (m, 4H), 1.59-1.48 (m, 2H), 1.17 (d, J = 6.8 Hz, 12H).

[0468] Example 24

[0469] 1-(2-(tert-butyl)-6-ethyl-4-methoxyphenoxy)-3-(cyclopentylamino)propan-2-ol 24

[0470]

[0471] First step to synthesize compound 24a

[0472] Compound 10a (800 mg, 3.09 mmol) and potassium vinyltrifluoroborate (827 mg, 6.17 mmol) were dissolved in a mixed solution of 1,4-dioxane (16 mL) and water (2 mL), cesium carbonate (3.02 g, 9.26 mmol) and Pd(dppf)Cl2(126 mg, 0.15 mmol) were added, after adding, the reaction solution was heated to 100 °C under nitrogen protection for 16 hours, TLC detection of raw materials reaction was complete (PE:EA = 20:1, Rf=0.6). The reaction solution was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 mL), the organic phase was washed with water (50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1) to give the title compound 24a (331 mg, yield 51.9%) as a yellow transparent oil. f

[0473] LC-MS / m / z = 207.1 [M+H] +

[0474] Second step to synthesize compound 24b

[0475] ​Compound 24a (331 mg, 1.60 mmol) was dissolved in methanol (6 mL), palladium on carbon (33 mg, 10%) was added at room temperature, after addition, the reaction solution was reacted at room temperature (15 °C) for 16 hours under hydrogen protection. The reaction solution was filtered through diatomite, the filter cake was rinsed with dichloromethane (5 mL), and the filtrate was concentrated to obtain the title compound 24b (330 mg, crude) in the form of yellow oil, which was directly used in the next step reaction.

[0476] LC-MS / m / z = 207.1 [M-H] -

[0477] Third step synthesis of compound 24c

[0478] Compound 24b (330 mg, crude) was dissolved in DMF (5 mL), and the reaction solution was cooled to 0 °C in an ice bath under nitrogen protection. Sodium hydride (77 mg, 1.92 mmol) was added in portions, after addition, the reaction solution was warmed to room temperature and reacted for 30 minutes. It was cooled to 0-5 °C again, and epoxide bromopropane (0.16 mL, 1.92 mmol) was added dropwise, after addition, the reaction solution was heated to 50 °C and reacted for 30 minutes. TLC detection showed that the reaction was complete (petroleum ether / ethyl acetate = 20 / 1, Rf= 0.7). The reaction solution was cooled to 0 °C, quenched with ice water (10 mL), extracted with ethyl acetate (50 mL), washed with water (30 mL x 2), saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1-80:1) to obtain the title compound 24c (258 mg, two-step yield 61.0%) in the form of yellow transparent oil. f

[0479] Fourth step synthesis of compound 24

[0480] Compound 24c (245 mg, 0.93 mmol) and cyclopentylamine (158 mg, 1.85 mmol) were dissolved in methanol (2.5 mL), and the reaction solution was heated to 70 °C and reacted for 3 hours. TLC detection showed that the starting material was completely reacted (dichloromethane / methanol = 10 / 1, Rf= 0.6). The reaction solution was cooled to room temperature, concentrated, and the residue was purified by Prep-TLC (DCM:MeOH = 10:1) to obtain the title compound 24 (128 mg, yield 39.4%) in the form of waxy solid. f

[0481] LC-MS / m / z = 350.3 [M+H] +

[0482] 1 ​​H NMR (400MHz, DMSO-d6) δ8.64 (s, 2H), 6.66 (dd, J = 2.8Hz, J = 14.0Hz, 2H), 5. 85(s,1H),4.30-4.15(m,1H),3.71-3.70(m,4H),3.53-3.49(m,1H),3.17(d ,J=12.4Hz,1H),2.96(t,J=10.8Hz,1H),2.62(dd,J=7.6Hz,J=15.2Hz,2H) ,2.08-1.85(m,2H),1.76-1.52(m,6H),1.34(s,9H),1.20(t,J=7.6Hz,3H).

[0483] Example 25

[0484] 1-(Cyclopentylamino)-3-(2,6-di-tert-butyl-4-ethylphenoxy)propan-2-ol 25

[0485]

[0486] The first step is to synthesize compound 25b

[0487] 2,6-di-tert-butyl-4-ethylphenol 25a (1.00 g, 4.26 mmol) was dissolved in N,N-dimethylformamide (8 mL). Under nitrogen, the reaction solution was cooled to 0°C and sodium hydride (205 mg, 5.11 mmol, 60%) was added. After the addition was complete, the reaction solution was stirred at 0°C for 20 minutes. Epibromohydrin (701 mg, 5.11 mmol) was added dropwise. After the addition was complete, the reaction solution was heated to 50°C and reacted for 2 hours. A small amount of raw material remained (PE / EA = 20 / 1, R f =0.6). The reaction solution was cooled to room temperature and quenched by adding ice water (20 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 30 / 1) to obtain the title compound 25b (693 mg, yield 55.8%) as a yellow liquid.

[0488] Step 2: Synthesis of Compound 25

[0489] Compound 25b (200 mg, 0.69 mmol) was dissolved in ethanol (4 mL), and cyclopentylamine (117 mg, 1.38 mmol) was added. After the addition was complete, the reaction solution was heated to 80°C for 2 hours. TLC showed that the reaction of the raw material was complete (DCM / MeOH = 20 / 1, R f= 0.3). The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by Prep-TLC (DCM / MeOH = 20 / 1) to give the title compound 25 (110 mg, yield 42.7%) as a white solid.

[0490] LC-MS: m / z = 376.3 [M+H] + (97.60% purity, 210 nm)

[0491] 1 H NMR (400 MHz, CDC13) δ 7.05 (s, 2H), 5.14 (br, 1H), 4.81-4.68 (m, 1H), 3.90-3.76 (m, 2H), 3.56-3.45 (m, 2H), 3.07 (t, J = 11.6 Hz, 1H), 2.57 (q, J = 7.6 Hz, 2H), 2.21-2.09 (m, 2H), 2.07-1.89 (m, 4H), 1.68-1.61 (m, 2H), 1.41 (s, 18H), 1.22 (t, J = 7.6 Hz, 3H). (Note: one active hydrogen is not shown)

[0492] Example 26

[0493] N-(3-(2,6-di-tert-butyl-4-propyloxyphenoxy)-2-methoxypropyl)cyclopentylamine 26

[0494]

[0495] First step to synthesize compound 26a

[0496] Compound 19 (446 mg, crude) was dissolved in a mixture of ethyl acetate (10 mL) and water (10 mL), and sodium carbonate (583 mg, 5.50 mmol) and di-tert-butyl dicarbonate (1.20 g, 5.50 mmol) were added at room temperature. After the addition was completed, the reaction solution was reacted at 20 °C for 2 hours, and TLC detection showed that the starting material was completely reacted (PE / EA = 20 / 1, product R f = 0.5). The reaction solution was separated, the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure at 45 °C. The crude product was purified by silica gel column chromatography (EA / PE = 6%) to give the title compound 26a (367 mg, yield 61.4%) as a light yellow oil.

[0497] 1H NMR (400 MHz, CDC13) δ 6.79 (s, 2H), 4.30-4.17 (m, 2H), 3.87 (t, J = 6.4 Hz, 2H), 3.74 (d, J = 6.4 Hz, 2H), 3.52-3.33 (m, 2H), 1.90-1.74 (m, 4H), 1.73-1.60 (m, 4H), 1.56-1.51 (m, 2H), 1.46 (s, 9H), 1.42 (s, 18H), 1.04 (t, J = 7.2 Hz, 3H). (Active hydrogens not in)

[0498] Synthesis of compound 26b

[0499] Compound 26a (367 mg, 0.73 mmol) was dissolved in tetrahydrofuran (10 mL), and the reaction solution was cooled to 0 °C under nitrogen protection. Sodium hydride (46 mg, 1.09 mmol, 60%) was added, and after the addition was completed, the reaction solution was reacted at 0 °C for 30 min. Methyl iodide (206 mg, 1.45 mmol) was added, and after the addition was completed, the reaction solution was reacted at 20 °C for 16 h. TLC detection showed that the raw material was reacted completely (PE / EA = 20 / 1, product R f = 0.6). The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (10 mL x 2), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 °C. The crude product was purified by silica gel column chromatography (EA / PE = 5%) to obtain the title compound 26b (275 mg, yield 72.9%) as a light yellow oil.

[0500] Synthesis of compound 26

[0501] Compound 26b (275 mg, 0.53 mmol) was dissolved in tetrahydrofuran (2 mL), and hydrochloric acid dioxane (4 mL, 4N) was added at room temperature. After the addition was completed, the reaction solution was reacted at room temperature (20 °C) for 2 h. TLC detection showed that the reaction was complete (dichloromethane / methanol = 15 / 1, product R f = 0.3). The reaction solution was concentrated, and the residue was adjusted to pH = 12 with ammonium methylate (1 mL, 7N). The crude product was purified by Prep-TLC (dichloromethane / methanol = 15 / 1), and the crude product was slurried with ether (2 mL) to obtain the title compound 26 (52 mg, yield 23.4%) as a white solid.

[0502] LC-MS / m / z = 420.4 [M+H] +

[0503] 1H NMR (400MHz, DMSO-d6) δ8.61(s,1H),6.75(s,2H),4.11(s,1H),3.92-3.80(m,3H),3.68-3.60(m,1H),3.56( s,3H),3.52-3.44(m,1H),3.15-3.05(m,1H),2.99-2.88(m,1H),2.03-1.89(m,2H),1.77-1.59(m,6H),1.57 -1.48(m,2H),1.39(s,18H),0.97(t,J=7.6Hz,3H).

[0504] Example 27

[0505] N-(3-(2-tert-butyl)-4-propoxyphenoxy)-2-methoxypropyl)cyclopentylamine 27

[0506]

[0507] The first step is to synthesize compound 27a

[0508] Tert-butylhydroquinone 9a (3.00 g, 18.05 mmol) was dispersed in acetonitrile (40 mL), and bromopropane (3.33 g, 27.07 mmol) and potassium carbonate (4.99 g, 36.40 mmol) were added at room temperature. After the addition was complete, the reaction was heated to 80 ° C for 18 hours. TLC detection showed that the remaining raw material was not completely reacted (PE: EA = 10: 1, R f =0.3). The reaction solution was cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, washed with saturated brine (20 mL x 2), and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the crude product was purified by silica gel column chromatography (EA / PE = 5%) to obtain the title compound 27a (2.79 g, yield 74.2%) as a brown oil.

[0509] Step 2: Synthesis of Compound 27b

[0510] Compound 27a (1.00 g, 4.80 mmol) was dissolved in N,N-dimethylformamide (15 mL). Under nitrogen protection, the reaction solution was cooled to 0°C and NaH (230 mg, 5.76 mmol, 60%) was added. After the addition was complete, the reaction solution was slowly heated to 15°C and reacted for 30 minutes. Epibromohydrin (986 mg, 7.20 mmol) was added. After the addition was complete, the reaction solution was heated to 50°C and reacted for 1 hour. TLC showed that the reaction of the raw material was complete (PE / EA = 10 / 1, R f=0.3). The reaction solution was cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (20 mL x 3), and the combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 5%) to obtain the title compound 27b (815 mg, yield 64.2%) as a light yellow oil.

[0511] Step 3: Synthesis of Compound 27c

[0512] Compound 27b (810 mg, 3.08 mmol) was dissolved in ethanol (10 mL), and cyclopentylamine (523 mg, 6.15 mmol) was added at room temperature. After the addition, the reaction solution was heated to 80°C for 2 hours. TLC showed that the reaction of the raw material was basically complete (PE:EA=10:1, R f =0.1). The reaction solution was cooled to room temperature and concentrated to obtain the title compound 27c (1.07 g, crude) as a white solid, which was used directly in the next reaction.

[0513] Step 4: Synthesis of Compound 27d

[0514] Compound 27c (1.07 g, crude product) was dissolved in tetrahydrofuran (12 mL) and saturated sodium carbonate aqueous solution (12 mL), and di-tert-butyl dicarbonate (805 mg, 3.69 mmol) was added at room temperature. After the addition, the reaction solution was slowly heated to 40°C and reacted for 4 hours. TLC showed that the reaction of the raw material was complete (PE:EA=3:1, R f =0.5). The reaction solution was cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (20 mL x 3), and the combined organic phases were 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 (EA:PE = 5%) to give the title compound 27d (1.34 g, two-step yield 96.8%) as a light yellow oil.

[0515] Step 5: Synthesis of compound 27e

[0516] Compound 27d (300 mg, 0.67 mmol) was dissolved in tetrahydrofuran (5 mL). Under nitrogen protection, the reaction solution was cooled to 0°C and NaH (54 mg, 1.33 mmol, 60%) was added. After the addition was complete, the reaction solution was slowly heated to 15°C and reacted for 10 minutes. Methyl iodide (474 ​​mg, 3.34 mmol) was added. After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. TLC showed that the reaction of the raw material was complete (PE:EA=10:1, R f=0.4). The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, washed with saturated brine (20 mL x 2), and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the crude product was purified by silica gel column chromatography (EA:PE = 5%) to obtain the title compound 27e (232 mg, yield 74.7%) as a light yellow oil.

[0517] Step 6: Synthesis of Compound 27

[0518] Compound 27e (100 mg, 0.22 mmol) was dissolved in dichloromethane (4 mL). Under nitrogen protection, the reaction solution was cooled to 0°C and trifluoroacetic acid (1 mL) was added dropwise. After the addition was complete, the temperature was slowly raised to room temperature and reacted for 2 hours. TLC (PE:EA=1:1, R f =0.1) to detect the complete reaction of the starting material. The reaction solution was cooled to 0°C and slowly added dropwise with saturated aqueous sodium carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by prep-TLC (DCM:MeOH = 10:1) to obtain the title compound 27 (53 mg, 66.3% yield) as an off-white solid.

[0519] LC-MS: m / z=364.3[M+H] + (99.64% purity, 210nm)

[0520] 1 H NMR(400MHz,DMSO-d6)δ8.77(br,1H),6.90(d,J=8.8Hz,1H),6.77-6.72(m,2H),4 .12(dd,J=10.4,3.6Hz,1H),4.05(dd,J=10.8,4.0Hz,1H),4.00-3.94(m,1H),3.8 5(t,J=6.4Hz,2H),3.51-3.46(m,1H),3.43(s,3H),3.23-3.19(m,1H)3.13-3.08( m,1H),2.01-1.92(m,2H),1.74-1.49(m,8H),1.34(s,9H),0.97(t,J=7.2Hz,3H).

[0521] Example 28

[0522] N-(3-(2,6-di-tert-butyl-4-methoxyphenoxy)-2-methoxypropyl)cyclopentylamine 28

[0523]

[0524] The first step is to synthesize compound 28a

[0525] Compound 8 (353 mg, 0.93 mmol) was dissolved in a mixture solvent of tetrahydrofuran (5 mL) and water (1 mL), sodium carbonate (198 mg, 1.87 mmol) and di-tert-butyl dicarbonate (245 mg, 1.12 mmol) were added at room temperature, after addition, the reaction solution was reacted at room temperature (15 °C) for 1 hour, TLC detection reaction was complete (petroleum ether / ethyl acetate = 5 / 1, Rf= 0.6). The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL), 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 = 10 / 1) to obtain the title compound 28a (375 mg, yield 84.0%) as colorless transparent oil. f

[0526] LC-MS / m / z = 378.3 [M-100+H] +

[0527] Second step synthesis of compound 28b

[0528] Compound 28a (125 mg, 0.26 mmol) was dissolved in tetrahydrofuran (3 mL), under nitrogen protection, the reaction solution was cooled to 0 °C, sodium hydride (21 mg, 0.52 mmol, 60%) was added, after addition, the reaction solution was stirred for 10 minutes, iodomethane (74 mg, 0.52 mmol) was added, after addition, the reaction solution was reacted at room temperature (15 °C) for 2 hours, TLC detection reaction was complete (petroleum ether / ethyl acetate = 15 / 1, Rf= 0.5). The reaction solution was quenched with methanol (1 mL), concentrated, and the crude product was purified by Prep-TLC (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound 28b (64 mg, yield 49.7%) as colorless oil. f

[0529] Third step synthesis of compound 28

[0530] Compound 28b (64 mg, 0.13 mmol) was dissolved in tetrahydrofuran (1 mL), hydrochloric acid dioxane (3 mL, 4M) was added at room temperature, after addition, the reaction solution was reacted at room temperature (15 °C) for 4 hours, TLC detection reaction was complete (dichloromethane / methanol = 10 / 1, Rf= 0.6). The reaction solution was concentrated, the residue was added with ammonium methanol (1 mL, 4M), and the crude product was purified by Prep-TLC (dichloromethane / methanol = 10 / 1) to obtain the title compound 28 (32 mg, yield 62.8%) as white solid. f

[0531] LC-MS / m / z = 392.3 [M+H] +

[0532] ​​​1 H NMR (400 MHz, DMSO-d6) δ 6.76 (s, 2H), 3.98-3.90 (m, 1H), 3.84-3.77 (m, 1H), 3.71 (s, 3H), 3.69-3.65 (m, 1H), 3.52 (s, 3H), 3.29-3.25 (m, 1H), 2.95-2.85 (m, 1H), 2.85-2.76 (m, 1H), 1.91-1.77 (m, 2H), 1.71-1.61 (m, 2H), 1.54-1.45 (m, 4H), 1.39 (s, 18H). (Active hydrogens not out)

[0533] Example 29

[0534] 1-(2,6-Di-tert-butyl-4-methoxyphenoxy)-3-(pyrrolidin-1-yl)propan-2-ol 29

[0535]

[0536] First Step to Synthesize Compound 29

[0537] Compound 8b (200 mg, 0.68 mmol) was dissolved in ethanol (6 mL), pyrrolidine (97 mg, 1.37 mmol) was added at room temperature, after addition, the reaction was heated to 80 °C for 2 hours, TLC detection of the raw material was basically complete (DCM / MeOH = 10 / 1, Rf= 0.3). The reaction was cooled to room temperature, concentrated at 45 °C under reduced pressure, and the crude product was purified by Prep-TLC (DCM / MeOH = 13 / 1) to give the title compound 29 (153 mg, yield 61.9%) as a light yellow solid. f

[0538] LC-MS: m / z = 364.3 [M+H] +

[0539] 1 H NMR (400 MHz, DMSO-d6) δ 6.75 (s, 2H), 5.86 (br, 1H), 4.41-4.27 (m, 1H), 3.70 (s, 3H), 3.68-3.58 (m, 2H), 3.29-2.99 (m, 6H), 1.99-1.81 (m, 4H), 1.38 (s, 18H).

[0540] Example 30

[0541] 1-(Cyclohexylamino)-3-(2,6-di-tert-butyl-4-methoxyphenoxy)propan-2-ol 30

[0542] ​

[0543] First step to synthesize compound 30

[0544] Compound 8b (200 mg, 0.68 mmol) was dissolved in ethanol (3 mL), cyclohexylamine (2.10 g, 24.71 mmol) was added at room temperature, after addition, the reaction was heated to 80 °C for 3 hours, TLC detection of raw materials reaction complete (DCM / MeOH = 20 / 1, R f = 0.4). The reaction was cooled to room temperature, concentrated, the crude product was purified by Prep-TLC (DCM / MeOH = 20 / 1) to give the title compound 30 (100 mg, yield 37.6%) as a white solid.

[0545] LC-MS: m / z = 392.3 [M+H] + (99.71% purity, 210 nm)

[0546] 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (br, 1H), 6.76 (s, 2H), 5.88 (s, 1H), 4.41 - 4.22 (m, 1H), 3.70 (s, 3H), 3.69 - 3.65 (m, 1H), 3.60 (dd, J = 10.0, 5.6 Hz, 1H), 3.14 (d, J = 12.8 Hz, 1H), 3.08 - 3.00 (m, 1H), 2.90 (t, J = 11.2 Hz, 1H), 2.10 - 1.97 (m, 2H), 1.81 - 1.72 (m, 2H), 1.65 - 1.57 (m, 1H), 1.39 (s, 18H), 1.37 - 1.18 (m, 4H), 1.16 - 1.05 (m, 1H).

[0547] Example 31

[0548] 1-(((1S,4R)-Bicyclo[2.2.1]heptan-2-yl)amino)-3-(2,6-di-tert-butyl-4- methoxyphenoxy)propan-2-ol 31

[0549]

[0550] First step to synthesize compound 31

[0551] Compound 8b (71 mg, 0.24 mmol) and bicyclo[2.2.1]heptan-2-amine (40 mg, 0.36 mmol) were dissolved in ethanol (1 mL), the reaction was heated to 90 °C for 2 hours, TLC detection of reaction complete (dichloromethane / methanol = 10 / 1, R f= 0.4). The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by Prep-TLC (dichloromethane / methanol = 8 / 1) to give the title compound 31 (56 mg, yield 57.1%) as a white solid.

[0552] LC-MS / m / z = 404.3 [M+H] +

[0553] 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (br, 1H), 6.75 (s, 2H), 5.81 (s, 1H), 4.35-4.24 (m, 1H), 3.70 (s, 3H), 3.69-3.63 (m, 1H), 3.63-3.58 (m, 1H), 3.17-3.03 (m, 2H), 2.88-2.78 (m, 1H), 2.31-2.25 (m, 1H), 1.80 (t, J = 10.0 Hz, 1H), 1.68-1.59 (m, 1H), 1.59-1.43 (m, 3H), 1.38 (s, 18H), 1.22-1.06 (m, 4H).

[0554] Example 32

[0555] 1-(Cyclobutylamino)-3-(2,6-di-tert-butyl-4-methoxyphenoxy)propan-2-ol 32

[0556]

[0557] Referring to the synthesis method of compound 31, the title compound 32 (48 mg, yield 62.9%) was synthesized as a white solid using compound 8b and cyclobutylamine as raw materials.

[0558] LC-MS: m / z = 364.3 [M+H] + (99.12% purity, 210 nm)

[0559] 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (br, 1H), 6.75 (s, 2H), 5.81 (s, 1H), 4.35-4.24 (m, 1H), 3.70 (s, 3H), 3.69-3.63 (m, 1H), 3.63-3.58 (m, 1H), 3.17-3.03 (m, 2H), 2.88-2.78 (m, 1H), 2.31-2.25 (m, 1H), 1.80 (t, J = 10.0 Hz, 1H), 1.68-1.59 (m, 1H), 1.59-1.43 (m, 3H), 1.38 (s, 18H), 1.22-1.06 (m, 4H).

[0560] Example 33

[0561] 1-(cycloheptylamino)-3-(2,6-di-tert-butyl-4-methoxyphenoxy)propan-2-ol 34

[0562]

[0563] The synthesis method of Reference Compound 31 was used with compound 8b and cycloheptylamine as starting materials to synthesize the title compound 34 (52 mg, yield 61%) as a white solid.

[0564] LC-MS: m / z = 406.4 [M+H] + (99.40% purity, 210 nm)

[0565] 1 H NMR (400 MHz, DMSO-d6) δ 6.75 (s, 2H), 5.26 (s, 1H), 4.31 - 4.08 (m, 1H), 3.70 (s, 3H), 3.65 - 3.58 (m, 2H), 2.90 (dd, J = 12.0, 3.6 Hz, 1H), 2.73 (dd, J = 12.0, 8.4 Hz, 1H), 2.37 - 2.26 (m, 1H), 1.38 (s, 18H), 0.53 - 0.37 (m, 4H). (Note: One active hydrogen not out)

[0566] Example 34

[0567] 1-(cycloheptylamino)-3-(2,6-di-tert-butyl-4-methoxyphenoxy)propan-2-ol 34

[0568]

[0569] The synthesis method of Reference Compound 31 was used with compound 8b and cycloheptylamine as starting materials to synthesize the title compound 34 (52 mg, yield 61%) as a white solid.

[0570] LC-MS: m / z = 406.4 [M+H] + (99.40% purity, 210 nm)

[0571] 1 H NMR (400 MHz, DMSO-d6) δ 8.06 (br, 1H), 6.75 (s, 2H), 5.73 (br, 1H), 4.35 - 4.18 (m, 1H), 3.70 (s, 3H), 3.69 - 3.56 (m, 2H), 3.17 - 3.01 (m, 2H), 2.89 - 2.75 (m, 1H), 2.04 - 1.87 (m, 2H), 1.75 - 1.62 (m, 2H), 1.59 - 1.45 (m, 8H), 1.38 (s, 18H).

[0572] Example 35

[0573] 3-((3-(2,6-di-tert-butyl-4-methoxyphenoxy)-2-hydroxypropyl)amino)cyclopentan-1-ol 35

[0574]

[0575] First step to synthesize compound 35

[0576] Compound 8b (114 mg, 0.39 mmol) and 3-aminocyclopentan-1-ol hydrochloride (80 mg, 0.58 mmol) were dissolved in ethanol (1 mL), N,N-diisopropylethylamine (76 mg, 0.58 mmol) was added, after addition, the reaction was heated to 90 °C for 2 hours, TLC detection reaction was complete (dichloromethane / methanol = 8 / 1, Rf= 0.4). The reaction was cooled to room temperature, water (3 mL) was added, extracted with ethyl acetate (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, concentrated, the crude product was purified by Prep-TLC (dichloromethane / methanol = 8 / 1) to give the title compound 35 (11 mg, yield 7.2%) as a white waxy solid. f

[0577] LC-MS / m / z = 394.3 [M+H] +

[0578] 1 H NMR (400 MHz, DMSO-d6) δ 6.75 (s, 2H), 5.54 (br, 1H), 4.58 (s, 1H), 4.19 (s, 2H), 3.70 (s, 3H), 3.68-3.59 (m, 2H), 3.54-3.45 (m, 1H), 3.00-2.91 (m, 1H), 2.79-2.70 (m, 1H), 2.03-1.97 (m, 1H), 1.91-1.80 (m, 2H), 1.63 (s, 1H), 1.52-1.43 (m, 2H), 1.38 (s, 18H). (One active hydrogen not out)

[0579] Example 36

[0580] 1-(2,6-di-tert-butyl-4-methoxyphenoxy)-3-(methylamino)propan-2-ol 36

[0581]

[0582] First step to synthesize compound 36

[0583] ​Compound 8b (60 mg, 0.21 mmol) was dissolved in methanol (3 mL), methylamine hydrochloride (46 mg, 0.41 mmol) and N,N-diisopropylethylamine (53 mg, 0.41 mmol) were added at room temperature, after addition, the reaction was heated to 60 °C for 5 hours, TLC (DCM:MeOH = 10:1, Rf = 0.1) detection reaction was complete. The reaction was cooled to room temperature, quenched with water (30 mL), extracted with ethyl acetate (15 mL x 3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, the crude product was purified by Prep-TLC (DCM:MeOH = 10:1) to give the title compound 36 (12 mg, yield 17.7%) as a pink solid. f LC-MS: m / z = 324.3 [M+H]

[0584] LC-MS: m / z = 324.3 [M+H] + (97.51% purity, 210 nm)

[0585] 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (br, 1H), 6.75 (s, 2H), 5.85 (br, 1H), 4.36-4.20 (m, 1H), 3.70 (s, 3H), 3.68-3.64 (m, 1H), 3.61-3.52 (m, 1H), 3.16-.3.04 (m, 1H), 2.86 (t, J = 10.8 Hz, 1H), 2.57 (s, 3H), 1.38 (s, 18H).

[0586] Example 37

[0587] 1-(2,6-Di-tert-butyl-4-methoxyphenoxy)-3-(phenylamino)propan-2-ol 37

[0588]

[0589] The title compound 37 (9 mg, yield 11.1%) was synthesized by referring to the synthesis method of compound 31 using compound 8b and aniline as raw materials.

[0590] LC-MS: m / z = 324.3 [M+H] + (97.51% purity, 210 nm)

[0591] 1H NMR (400 MHz, DMSO-d6) δ 7.06 (t, J = 7.2 Hz, 2H), 6.73 (s, 2H), 6.67 (d, J = 8.0 Hz, 2H), 6.51 (t, J = 7.2 Hz, 1H), 5.57 (t, J = 5.2 Hz, 1H), 5.17 (d, J = 5.2 Hz, 1H), 4.24 - 4.05 (m, 1H), 3.76 - 3.61 (m, 5H), 3.28 - 3.14 (m, 1H), 3.11 - 2.97 (m, 1H), 1.35 (s, 18H).

[0592] Example 38

[0593] 1 -(4-butoxy-2,6-di-tert-butylphenoxy)-3-(cyclopentylamino)propan-2-ol 38

[0594]

[0595] The synthesis method of Reference Compound 20 was used to react Compound 19b and n-bromobutane as raw materials to synthesize the title compound 38 (58 mg, yield 46.1%) as a white solid.

[0596] LC-MS: m / z = 420.4 [M+H] + (99.58% purity, 210 nm)

[0597] 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (br, 1H), 6.73 (s, 2H), 5.80 (br, 1H), 4.31 - 4.20 (m, 1H), 3.90 (t, J = 6.4 Hz, 2H), 3.68 - 3.59 (m, 2H), 3.45 - 3.36 (m, 1H), 3.05 - 3.01 (m, 1H), 2.82 - 2.76 (m, 1H), 1.93 - 1.84 (m, 2H), 1.70 - 1.62 (m, 4H), 1.59 - 1.47 (m, 4H), 1.46 - 1.41 (m, 2H), 1.37 (s, 18H), 0.93 (t, J = 7.2 Hz, 3H).

[0598] Example 39

[0599] 1 -(cyclopentylamino)-3-(2,5-di-tert-butyl-4-methoxyphenoxy)propan-2-ol 39

[0600]

[0601] First step to synthesize Compound 39b

[0602] 2,5-Di-tert-Butylhydroquinone 39a (3.00 g, 13.49 mmol) was dissolved in N,N-dimethylformamide (20 mL). Under nitrogen protection, the reaction solution was cooled to 0°C, and sodium hydride (594 mg, 14.84 mmol, 60%) was added in batches. After the addition was complete, the mixture was stirred for 10 minutes, and iodomethane (2.10 g, 14.84 mmol) was added. After the addition was complete, the reaction solution was warmed to room temperature (15°C) and reacted for 2 hours. The reaction was complete when TLC was performed (petroleum ether / petroleum ether = 30 / 1, R f =0.4). The reaction solution was quenched with ice water (30 mL), extracted with ethyl acetate (50 mL), washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / petroleum ether = 100 / 1) to obtain the title compound 39b (720 mg, yield 22.6%) as a white solid.

[0603] 1 H NMR (400MHz, DMSO-d6) δ8.65(s,1H),6.71(s,1H),6.68(s,1H),3.72(s,3H),1.32(s,9H),1.27(s,9H).

[0604] Step 2: Synthesis of Compound 39c

[0605] Compound 39b (400 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (10 mL). Under nitrogen protection, the reaction solution was cooled to 0°C, and sodium hydride (135 mg, 3.38 mmol, 60%) was added in batches. After the addition was complete, the mixture was stirred for 10 minutes. Epibromohydrin (464 mg, 3.38 mmol) was added. After the addition was complete, the reaction solution was heated to 85°C for 2 hours. The reaction was complete when detected by TLC (petroleum ether / petroleum ether = 30:1, R f =0.4). The reaction solution was quenched with ice water (30 mL), extracted with ethyl acetate (50 mL), washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / petroleum ether = 80 / 1) to obtain the title compound 39c (274 mg, yield 55.4%) as a colorless transparent oil.

[0606] 1H NMR (400 MHz, DMSO-d6) δ 6.80 (s, 1H), 6.79 (s, 1H), 4.31 (dd, J = 11.2, 2.8 Hz, 1H), 3.83 (dd, J = 11.2, 6.4 Hz, 1H), 3.76 (s, 3H), 3.36-3.33 (m, 1H), 2.87-2.83 (m, 1H), 2.73 (dd, J = 5.2, 2.8 Hz, 1H), 1.34 (s, 9H), 1.31 (s, 9H).

[0607] Third step to synthesize compound 39

[0608] Compound 39c (140 mg, 0.48 mmol) and cyclopentylamine (82 mg, 0.96 mmol) were dissolved in ethanol (1 mL), the reaction was heated to 95 °C for 3 hours, TLC detection reaction was completed (dichloromethane / methanol = 10 / 1, Rf= 0.4). The reaction was cooled to room temperature, concentrated, the crude product was purified by Prep-TLC (dichloromethane / methanol = 15 / 1) and then slurried with ether (2 mL) to give the white solid title compound 39 (97 mg, yield 53.7%). f

[0609] LC-MS / m / z = 378.3 [M+H] +

[0610] 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 6.81 (s, 1H), 6.79 (s, 1H), 5.84 (d, J = 4.8 Hz, 1H), 4.27 (s, 1H), 4.02-3.93 (m, 2H), 3.76 (s, 3H), 3.59-3.48 (m, 1H), 3.22-3.14 (m, 1H), 3.06-2.98 (m, 1H), 2.04-1.92 (m, 2H), 1.78-1.61 (m, 4H), 1.58-1.48 (m, 2H), 1.35 (s, 9H), 1.32 (s, 9H).

[0611] Example 40

[0612] 1-(2,6-Di-tert-butyl-4-methoxyphenoxy)-3-(ethylamino)propan-2-ol 40

[0613]

[0614] Referring to the synthesis method of compound 36, compound 8b and ethylamine hydrochloride were used as raw materials to react to synthesize the title compound 40 (22 mg, yield 31.0%) in the form of a pink solid. ​

[0615] LC-MS: m / z = 338.3 [M+H] + (98.41% purity, 210 nm)

[0616] 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (br, 1H), 6.80 (s, 2H), 5.90 (br, 1H), 4.39-4.24 (m, 1H), 3.69 (s, 3H), 3.68-3.65 (m, 1H), 3.36-3.52 (m, 1H), 3.18-3.06 (m, 1H), 3.02-2.94 (m, 2H), 2.90-2.80 (m, 1H), 1.38 (s, 18H), 1.21 (t, J = 6.8 Hz, 3H).

[0617] Example 41

[0618] 1-(2-(tert-butyl)-4-ethyl-6-isopropylphenoxy)-3-(cyclopentylamino)propan-2-ol 41

[0619]

[0620] First step to synthesize compound 41b

[0621] 2-tert-Butyl-4-ethylphenol 41a (1.00 g, 5.61 mmol) was dissolved in dichloromethane (40 mL), the reaction solution was cooled to 0 °C under nitrogen protection, and a solution of liquid bromine (807 mg, 5.05 mmol) in dichloromethane (10 mL) was slowly added dropwise. It took 1 hour to drop. After addition, the reaction was carried out at 0 °C for 1 hour. TLC (PE, R f = 0.8) showed that the unreacted raw material was not completely reacted. The reaction solution was quenched by adding saturated aqueous sodium thiosulfate solution (20 mL), extracted with dichloromethane (30 mL x 3), washed with water (50 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE) to obtain the title compound 41b (1.03 g, yield 71.4%) as colorless oil.

[0622] 1 H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 2.0 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 5.64 (s, 1H), 2.55 (q, J = 7.6 Hz, 2H), 1.39 (s, 9H), 1.20 (t, J = 7.6 Hz, 3H).

[0623] Second step to synthesize compound 41c

[0624] Compound 41b (500 mg, 1.94 mmol) and isopropenyl potassium trifluoroborate (345 mg, 2.83 mmol) were dissolved in a mixed solvent of 1,4-dioxane (8 mL) and water (2 mL), sodium carbonate (309 mg, 2.91 mmol) and Pd(dppf)Cl2-DCM (158 mg, 0.19 mmol) were added at room temperature, after addition, the reaction solution was heated to 90 °C under nitrogen protection for 18 hours. TLC (PE, R f = 0.6) showed that the starting material was substantially reacted. The reaction solution was cooled to room temperature, quenched with water (30 mL), extracted with ethyl acetate (15 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE) to obtain the title compound 41c (350 mg, yield 82.6%) as a light green oil.

[0625] Third step to synthesize compound 41d

[0626] Compound 41c (150 mg, 0.69 mmol) was dissolved in methanol (2 mL), palladium-carbon (20 mg, 10%) was added at room temperature, after addition, the reaction solution was reacted under hydrogen protection at room temperature (15 °C) for 3 hours, TLC (PE:EA = 50:1, R f = 0.8) showed that the starting material was completely reacted. The reaction solution was filtered through celite, the mother liquor was concentrated, and the crude product was purified by silica gel column chromatography (PE:EA = 100:1-80:1) to obtain the title compound 41d (75 mg, yield 49.3%) as a colorless oil.

[0627] Fourth step to synthesize compound 41e

[0628] Compound 41d (75 mg, 0.49 mmol) was dissolved in N,N-dimethylformamide (2 mL), the reaction solution was cooled to 0 °C under nitrogen protection, sodium hydride (24 mg, 0.59 mmol, 60%) was added, and the reaction was continued for 10 minutes. Epibromohydrin (101 mg, 0.74 mmol) was added, after addition, the temperature was raised to 50 °C and reacted for 5 hours, TLC (PE:EA = 50:1, R f = 0.7) showed that the starting material was completely reacted. The reaction solution was cooled to 0 °C, quenched with water (20 mL) carefully, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC (PE:EA = 100:1-50:1) to obtain the title compound 41e (54 mg, yield 39.9%) as a white solid.

[0629] Fifth step to synthesize compound 41

[0630] Compound 41e (50 mg, 0.18 mmol) was dissolved in ethanol (3 mL), and cyclopentylamine (31 mg, 0.36 mmol) was added at room temperature. After the addition was complete, the temperature was raised to 80°C and the reaction was continued for 6 hours. TLC (DCM:MeOH=10:1, R f =0.3) The reaction mixture was cooled to room temperature and concentrated. The crude product was purified by Prep-TLC (DCM:MeOH=10:1) to give the title compound 41 (42 mg, yield 64.5%) as a white solid.

[0631] LC-MS: m / z=362.3[M+H] + (96.64% purity, 210nm)

[0632] 1 H NMR(400MHz,DMSO-d6)δ8.85(br,1H),7.04(s,1H),6.91(s,1H),5.94(s,1H),4.36-4.20(m,1H),3.79-3.66(m,2H),3.60-3.46(m,1H),3.30- 3.23(m,1H),3.20-3.12(m,1H),3.03-2.90(m,1H),2.59-2.52(m,2H), 2.05-1.88(m,2H),1.84-1.44(m,6H),1.35(s,9H),1.23-1.09(m,9H).

[0633] Example 42

[0634] 1-(2-(tert-butyl)-4,6-dimethylphenoxy)-3-(cyclopentylamino)propan-2-ol 42

[0635]

[0636] The first step is to synthesize compound 42b

[0637] 6-tert-Butyl-2,4-dimethylphenol 42a (500 mg, 2.80 mmol) was dissolved in N,N-dimethylformamide (5 mL). Under nitrogen protection, the reaction solution was cooled to 0°C and sodium hydride (135 mg, 3.37 mmol, 60%) was added. After the addition was complete, the mixture was returned to room temperature and reacted for 10 minutes. Epibromohydrin (576 mg, 4.21 mmol) was added and the reaction solution was heated to 50°C for 3 hours. TLC (PE:EA=10:1, R f=0.7) to confirm the completion of the reaction. The reaction solution was cooled to 0°C and quenched with water (30 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 100:1-80:1) to afford the title compound 42b (356 mg, 54.3% yield) as a yellow solid.

[0638] Step 2: Synthesis of Compound 42

[0639] Compound 42b (60 mg, 0.26 mmol) was dissolved in ethanol (3 mL), and cyclopentylamine (44 mg, 0.51 mmol) was added at room temperature. After the addition was complete, the temperature was raised to 80°C and the reaction was continued for 5 hours. TLC (DCM:MeOH=10:1, R f The reaction mixture was cooled to room temperature and concentrated, and the crude product was purified by Prep-TLC (DCM:MeOH=20:1) to obtain the title compound 42 as a white solid (48 mg, yield 57.8%).

[0640] LC-MS: m / z = 320.3 [M+H] + (99.39% purity, 210nm)

[0641] 1 H NMR (400MHz, DMSO-d6) δ8.82(br,1H),6.92(s,1H),6.86(s,1H),5.87(s,1H),4.36-4.16(m,1H),3.74(d,J=5.6Hz,2H),3.60-3.44 (m,1H),3.26-3.14(m,1H),3.03-2.91(m,1H),2.23(s,3H),2.20(s,3H),2.04-1.90(m,2H),1.80-1.46(m,6H),1.39-1.30(m,9H).

[0642] Example 43

[0643] 1-(Cyclopentylamino)-3-(2,4,6-tri-tert-butylphenoxy)propan-2-ol 43

[0644]

[0645] Referring to the synthesis method of compound 42, 2,4,6-tri-tert-butylphenol was used as the starting material to synthesize the title compound 43 (123 mg, yield 48.5%) as a white solid.

[0646] LC-MS: m / z = 404.4 [M+H] +(99.59% purity, 220 nm)

[0647] 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (br, 1H), 7.22 (s, 2H), 5.85 (s, 1H), 4.36-4.26 (m, 1H), 3.74-3.59 (m, 2H), 3.53-3.44 (m, 1H), 3.11 (d, J = 12.4 Hz, 1H), 2.87 (t, J = 11.2 Hz, 1H), 2.02-1.88 (m, 2H), 1.77-1.67 (m, 2H), 1.65-1.57 (m, 2H), 1.57-1.49 (m, 2H), 1.39 (s, 18H), 1.26 (s, 9H).

[0648] Example 44

[0649] 1 -(Cyclopentylamino)-3-(2,6-di-tert-butylphenoxy)propan-2-ol 45

[0650]

[0651] The synthesis method of reference compound 42 was reacted with 2,4,6-trimethylphenol as a starting material to synthesize the title compound 44 (78 mg, yield 27.0%) as a white solid.

[0652] LC-MS: m / z = 278.2 [M+H] + (99.93% purity, 220 nm)

[0653] 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (br, 1H), 7.22 (s, 2H), 5.85 (s, 1H), 4.36-4.26 (m, 1H), 3.74-3.59 (m, 2H), 3.53-3.44 (m, 1H), 3.11 (d, J = 12.4 Hz, 1H), 2.87 (t, J = 11.2 Hz, 1H), 2.02-1.88 (m, 2H), 1.77-1.67 (m, 2H), 1.65-1.57 (m, 2H), 1.57-1.49 (m, 2H), 1.39 (s, 18H), 1.26 (s, 9H).

[0654] Example 45

[0655] 1 -(Cyclopentylamino)-3-(2,6-di-tert-butylphenoxy)propan-2-ol 45

[0656]

[0657] The synthesis method of Reference Compound 42 was used for reaction with 2,6-di-tert- butylphenol as starting material to synthesize the title compound 45 (53 mg, yield 20.0%) as a white solid.

[0658] LC-MS: m / z = 348.3 [M+H] + (97.28% purity, 220 nm)

[0659] 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (br, 1H), 7.24 (d, J = 8.0 Hz, 2H), 6.97 (t, J = 8.0 Hz, 1H), 5.85 (br, 1H), 4.40 - 4.29 (m, 1H), 3.74 - 3.59 (m, 2H), 3.52 - 3.42 (m, 1H), 3.10 (d, J = 11.6 Hz, 1H), 2.91 - 2.82 (m, 1H), 1.99 - 1.87 (m, 2H), 1.76 - 1.46 (m, 6H), 1.39 (s, 18H).

[0660] Example 46

[0661] 1-(2,6-Di-tert-butyl-4-methoxyphenoxy)-3-(isopropylamino)propan-2-ol 46

[0662]

[0663] The synthesis method of Reference Compound 31 was used for reaction with compound 8b and isopropylamine as starting materials to synthesize the title compound 46 (100 mg, yield 41.6%) as a white solid.

[0664] LC-MS: m / z = 352.3 [M+H] + (99.37% purity, 210 nm)

[0665] 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (br, 1H), 6.76 (s, 2H), 5.96 (s, 1H), 4.37 - 4.27 (m, 1H), 3.70 (s, 3H), 3.68 (d, J = 6.8 Hz, 1H), 3.59 (dd, J = 10.0, 5.6 Hz, 1H), 3.41 - 3.35 (m, 1H), 3.11 (d, J = 12.4 Hz, 1H), 2.88 (t, J = 10.8 Hz, 1H), 1.38 (s, 18H), 1.24 (t, J = 6.8 Hz, 6H).

[0666] Example 47

[0667] 1-(2,6-di-tert-butyl-4-methoxyphenoxy)-3-(pentan-3-ylamino)propan-2-ol 47

[0668]

[0669] The synthesis of reference compound 31 was carried out using compound 8b and 3- aminopentane as starting materials to yield the title compound 47 (37 mg, 28.7% yield) as a white solid.

[0670] LC-MS: m / z = 380.3 [M+H] + (98.68% purity, 210 nm)

[0671] 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (br, 1H), 6.75 (s, 2H), 5.94 (br, 1H), 4.44-4.33 (m, 1H), 3.76-3.66 (m, 4H), 3.63-3.59 (m, 1H), 3.19-3.12 (m, 1H), 3.06-3.01 (m, 1H), 2.90-2.84 (m, 1H), 1.72-1.61 (m, 4H), 1.38 (s, 18H), 0.92 (t, J = 7.2 Hz, 6H).

[0672] Example 48

[0673] 1-(cyclopentylamino)-3-(2,6-di-tert-butyl-4-methylphenoxy)propan-2-ol 48

[0674]

[0675] The synthesis of reference compound 42 was carried out using 2,6-di-tert-butyl-4- methylphenol as starting material to yield the title compound 48 (145 mg, 55.7% yield) as a white solid.

[0676] LC-MS: m / z = 362.3 [M+H] + (99.87% purity, 220 nm)

[0677] 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (br, 1H), 7.03 (s, 2H), 5.89 (s, 1H), 4.38-4.28 (m, 1H),

[0678] 3.72-3.65 (m, 1H), 3.63-3.57 (m, 1H), 3.55-3.47 (m, 1H), 3.14 (d, J = 10.8 Hz, 1H), 2.88 (t, J = 10.8 Hz, 1H), 2.22 (s, 3H), 2.01-1.89 (m, 2H), 1.81-1.68 (m, 2H), 1.67-1.58 (m, 2H), 1.56-1.46 (m, 2H), 1.37 (s, 18H).

[0679] Example 49

[0680] 1-(Cyclopentylamino)-3-(4-methoxy-2,6-dimethylphenoxy)propan-2-ol 49

[0681]

[0682] The synthesis method of Reference Compound 42 was used as a raw material reaction with 4-methoxy-2,6-dimethylphenol to synthesize the title compound 49 (54 mg, yield 63.5%) as a white solid.

[0683] LC-MS: m / z = 294.2 [M+H] + (98.96% purity, 210 nm)

[0684] 1 H NMR (400 MHz, DMSO-d6) δ 6.56 (s, 2H), 4.95-4.83 (m, 1H), 3.88-3.77 (m, 1H), 3.66 (s, 3H), 3.65-3.62 (m, 1H), 3.58-3.52 (m, 1H), 3.06-2.93 (m, 1H), 2.75-2.62 (m, 1H), 2.62-2.54 (m, 1H), 2.19 (s, 6H), 1.79-1.56 (m, 4H), 1.51-1.42 (m, 2H), 1.36-1.21 (m, 2H). (Note: One active hydrogen not out)

[0685] Example 50

[0686] The following compounds were synthesized according to the synthesis method of the above-mentioned compounds:

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693] Pharmacological experiments

[0694] Verification of activity of test example 1 compound and characterization of calcium channel mechanism of action

[0695] 1. Preparation of compounds and drug configuration

[0696] In the experiment, the compound sample was accurately weighed, and an appropriate amount of dimethyl sulfoxide (DMSO) solvent was added to prepare a 50 mM stock solution. Then, 2 μL of the stock solution was accurately transferred and added to 998 μL of the corresponding electrophysiological external solution to prepare a working solution with a final concentration of 100 μM. On this basis, using the method of continuous multiple dilution, the working solution and the corresponding electrophysiological external solution were mixed in a specific ratio to prepare experimental working solutions with different concentration gradients for subsequent electrophysiological experimental research.

[0697] 2. Whole-cell patch clamp recording

[0698] 2.1 Voltage-gated calcium channel current recording extracellular solution and intracellular solution

[0699] Extracellular solution composition: 138 mM NaCl, 20 mM TEA-Cl, 2.6 mM KCl, 2.6 mM CaCl2, 1.2 mM MgCl2, 5 mM D-glucose, 5 mM HEPES (adjusted to pH 7.4 with NaOH);

[0700] Intracellular solution composition: 120 mM CsMeSO4, 11 mM EGTA, 2 mM Mg-ATP, 10 mM HEPES (adjusted to pH 7.4 with CsOH);

[0701] 2.2 Cell transfection and dish

[0702] The experiment uses a transient transfection method to introduce Ca V 2.2 Introduction of channel eukaryotic expression plasmid into HEK293T cells. Select HEK cells cultured in 3.5 cm culture dishes with a fusion degree of 80%-90% for transfection. First, remove the original DMEM complete culture medium, gently wash the cells once with 1 mL of PBS buffer, and then add 2 mL of Opti-MEM medium to put the cells in a serum-starved state. In the transfection operation, prepare two sterile EP tubes, A and B, to configure the transfection reaction solution. Tube A: accurately add rCa V 2.2 Substrate plasmid 2.5 μg, αβ sub-plasmid 1 μg, β 3-2Substrate plasmid 1 μg, and eGFP fluorescent reporter plasmid 0.5 μg into an EP tube containing 250 μL Opti-MEM medium, gently mixed and stand for 5 min; B tube: take 10 μL Lipofectamine 2000 transfection reagent into another EP tube containing 250 μL Opti-MEM medium, also gently mixed and stand for 5 min. Then slowly transfer the solution in B tube to A tube, gently mixed, stand for 20 min at room temperature to form DNA-liposome complex. Formed 500 μL transfection complex is slowly added to the culture dish, and mixed evenly by cross method.

[0703] Cell dish after 8 h transfection. First remove the culture medium, wash once with 1 mL PBS buffer, and add 250 μL trypsin digestion solution to facilitate cell detachment from the culture dish bottom. Then add 1 mL DMEM complete medium to terminate the digestion reaction, gently resuspend the cells, and transfer the cell suspension to a 3.5 cm culture dish pre-coated with poly-L-lysine (PLL) coated coverslips. After 16-24 h incubation, patch clamp experiment can be performed. For hERG channel transfection, Ca V 2.2 Replace the channel plasmid with 3 μg hERG eukaryotic expression plasmid, and the remaining operation steps remain the same.

[0704] 2.3 Whole-cell recording

[0705] This experiment uses HEKA EPC-10USB electrophysiology platform combined with PatchMaster software to record target ion channel current by whole-cell recording mode. The detailed operation steps are as follows:

[0706] 1) Take out the coverslips attached with transfected cells, place them in a 3.5 cm culture dish, add 1.5 mL extracellular solution, and place the culture dish on the stage of the electrophysiology platform microscope, connect and fix the reference electrode.

[0707] 2) The glass microelectrode capillary used in the experiment is purchased from Hydcell Biotechnology Co., Ltd. (specification: 100 mm long, outer diameter 0.87 mm, inner diameter 1.14 mm). The glass microelectrode is accurately drawn by two-step method using PC-10 electrode puller. By fine adjustment of the heating temperature of the electrode puller, the water entry resistance value of the drawn electrode is controlled to be stable in the range of 2-3 MΩ.

[0708] 3) Start the fluorescent light source, identify and select a single cell expressing green fluorescent protein in the field of view, and position it at the center of the field of view. Install the glass microelectrode pre-filled with internal solution to the electrode probe, ensuring that the probe silver wire is in full contact with the internal solution. Open the pressure valve and apply moderate positive pressure. Operate the micromanipulator to slowly immerse the electrode in water and compensate for the liquid junction potential.

[0709] 4) Under low magnification, precisely position the electrode tip directly above the target cell, then switch to high magnification, control the electrode tip to slowly contact the cell membrane until a slight deformation of the cell surface is observed.

[0710] 5) Open the valve, apply moderate negative pressure, when the seal resistance (R-memb) rises to about 100 MΩ, stop applying negative pressure, balance the pressure in the glass electrode with the external atmospheric pressure, wait for the seal resistance to rise to more than 1 GΩ, indicating that a high-impedance seal has been successfully formed.

[0711] 6) Compensate the fast capacitance (C-fast), switch to the whole-cell recording mode, give a short and continuous negative pressure through the hose connected to the glass electrode, when the characteristic double-peak slow capacitance waveform appears on the oscilloscope screen, it indicates that the cell membrane has been successfully broken and the whole-cell recording configuration has been formed.

[0712] 7) Complete the slow capacitance (C-slow) compensation. Set the clamping voltage parameters, compensate the series resistance to 80%, and compensate the leakage current. In the Pulse Generator File, edit the corresponding stimulation program according to the experimental requirements. For rCaV2.2, Nav1.4, Nav1.5 whole-cell patch clamp recording, set the resting clamping voltage to -80 mV and the depolarization stimulation voltage to +10 mV.

[0713] 8) After the ion channel current recording is stable, first add 50 μL of electrophysiological recording external solution as a control group, at this time the current amplitude should remain relatively stable (I Ctrl ); then add 50 μL of pre-prepared test compound solution, observe its adjustment effect on the channel current in real time, after the current amplitude is stable again, record the residual current size (I res ).

[0714] 9) Normalize the residual current value to the control current value before drug administration, calculate the inhibition rate of the drug on the ion channel current according to the formula: inhibition% = 1-I res / I Ctrl , which is used to evaluate the channel regulation activity of the compound.

[0715] The control compound selected in the study is C2230, the structure of which is shown below:

[0716]

[0717] The results are shown in Table 2.

[0718] Table 2. Activity table of the compound of the present application.

[0719]

[0720]

[0721]

[0722] NT (NOT TEST) means not tested.

[0723] As shown in Table 1, the activity of the compound of the present application is significantly improved compared with the activity of the compound C2230 of the control group, and the result is non-obvious and creative.

[0724] In the case of no conflict, the above-mentioned embodiments and features in the embodiments can be combined with each other.

[0725] The above only describes the preferred embodiments of the present application and is not intended to limit the present application, and any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A compound of formula (I) or its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts, wherein: W is selected from the group consisting of substituted or unsubstituted bonds, C3-C 20 Cycloalkylene, 4-20 membered heterocyclylene; R 1 Selected from the group consisting of hydrogen, deuterium, halogen, cyano, -(CH2) m R 8 、-(CH2) m (CH=CH)R 8 、-(CH2) m (C≡C)R 8 、-(CH2) m O(CH2) p R 8 、-(CH2) m SR 8 、-(CH2) m COR 8 、-(CH2) m C(O)OR 8 、-(CH2) m S(O) q R 8 、-(CH2) m NR 8 R 9 、-(CH2) m C(O)NR 8 R 9 、-(CH2) m NR 8 C(O)R 9 、-(CH2) m NR 8 C(O)NR 9 R 10 、-(CH2) m S(O) q NR 8 R 9 、-(CH2)mNR 8 S(O) q R 9 、-(CH2) m NR 8 S(O) q NR 9 R 10 , wherein the H in CH2 may be optionally substituted; R 8 、R 9 、R 10 Each independently selected from the group consisting of substituted or unsubstituted hydrogen, C1-C 18 Alkyl, C3-C 20 Cycloalkyl or 4-20 membered heterocyclic group; or in -(CH2) m NR 8 R 9 、-(CH2) m C(O)NR 8 R 9 、-(CH2) m S(O) q NR 8 R 9 In, R 8 and R 9 With its adjacent N atom, it forms a substituted or unsubstituted 4-8 membered heterocyclic group; or in -(CH2) m NR 8 C(O)R 9 、-(CH2) m NR 8 C(O)NR 9 R 10 、-(CH2) m NR 8 S(O) q R 9 、-(CH2) m NR 8 S(O)qNR 9 R 10 In, R 8 and R 9 and the adjacent N atom to form a substituted or unsubstituted 4-8 membered heterocyclic group, or R 9 and R 10 It is cyclized with adjacent atoms to form a substituted or unsubstituted 4-8 membered heterocyclic group; R 2 Selected from OR 21 、C1-C 18 Alkylene, deuterated C1-C 18 Alkylene or halogenated C1-C 18 Alkylene; R 21 Independently selected from the group consisting of substituted or unsubstituted hydrogen, deuterium, C1-C6 alkyl, or C3-C6 cycloalkyl; R 3 A substituted or unsubstituted group selected from the following groups: C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl; R 4 、R 5 、R 6 、R 7 may be the same or different and are independently selected from the following groups: substituted or unsubstituted: cyano, halo, nitro, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C4 alkoxy, Wherein, the above substitution refers to substitution by one or more groups selected from the following groups: hydrogen, deuterium, C1-C 18 Alkyl, deuterated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl hydroxyl, C3-C 20 Cycloalkyl, C1-C 18 Alkoxy, deuterated C1-C 18 Alkoxy, halogenated C1-C 18 Alkoxy, C6-C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic group, halogen, oxo, nitro, hydroxy, cyano, ester, amino, amide, sulfonamide or urea; m and n are each independently 0, 1, 2, 3, 4 or 5; p is 0, 1, 2, 3, 4, or 5; q is 1 or 2.

2. The compound according to claim 1 or its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt, wherein: The compound has a structure shown in general formula (II): Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 7 , W is defined as described in claim 1.

3. The compound according to claim 1 or its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt, wherein: The compound has a structure shown in general formula (III): Among them, R 1 、R 2 、R 4 、R 5 、R 7 , W is defined as described in claim 1.

4. The compound according to claim 1 or its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt, wherein: The compound has a structure shown in general formula (IV): Among them, R 1 、R 4 、R 5 、R 7 , W is defined as described in claim 1.

5. The compound according to claim 1 or its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt, wherein: The compound has a structure shown in general formula (V): where R 4 、R 5 、R 7 , W is defined as described in claim 1.

6. The compound according to claim 1 or its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt, wherein: The compound is selected from the following specific compounds: N-(3-(2-tert-butyl)-6-isopropyl-4-methoxyphenoxy)-2-ethoxypropyl)cyclopentylamine; 1-(2-(tert-Butyl)-4-methoxyphenoxy)-3-(cyclopentyl(methyl)amino)propan-2-ol; 1-((3-aminocyclopentyl)amino)-3-(2-(tert-butyl)-4-methoxyphenoxy)propan-2-ol, N-(3-((3-(2-(tert-butyl)-4-methoxyphenoxy)-2-hydroxypropyl)amino)cyclopentyl)acetamide, N-(3-((3-(2-(tert-butyl)-4-methoxyphenoxy)-2-hydroxypropyl)amino)cyclopentyl)methanesulfonamide, 6-((2-(tert-butyl)-4-methoxyphenoxy)methyl)-4-cyclopentylmorpholin-2-one, N-(3-(2-tert-butyl)-4-methoxyphenoxy)-2-methoxypropyl)cyclopentylamine, 1-(cyclopentylamino)-3-(2,6-di-tert-butyl-4-methoxyphenoxy)propan-2-ol, 1-(2-(tert-butyl)-4-phenoxyphenoxy)-3-(cyclopentylamino)propan-2-ol, 3-(tert-butyl)-2-(3-(cyclopentylamino)-2-hydroxypropoxy)-5-methoxybenzonitrile, (1S,3R)-3-((3-(2-tert-butyl)-4-methoxyphenoxy)-2-hydroxypropyl)amino)cyclopentane-1-carboxylic acid methyl ester, (2-(3-(cyclopentylamino)-2-hydroxypropyloxy)-5-methoxyphenyl)(phenyl)methanone, (1R,3S)-3-((3-(2-(tert-butyl)-4-methoxyphenoxy)-2-hydroxypropyl)amino)-N-methylcyclopentane-1-carboxamide, 1-(cyclopentylamino)-3-(4-methoxy-2-methylphenoxy)propan-2-ol, 1-(2-(tert-butyl)phenoxy)-3-(cyclopentylamino)propan-2-ol, 1-(2-(tert-butyl)-4-propoxyphenoxy)-3-(cyclopentylamino)propan-2-ol, 1-(4-methoxy-2-methylphenoxy)-3-(thiazol-4-ylamino)propan-2-ol, 4-(tert-butyl)-5-(3-(cyclopentylamino)-2-hydroxypropoxy)-2-methoxybenzonitrile, 1-(cyclopentylamino)-3-(2,6-di-tert-butyl-4-propoxyphenoxy)propan-2-ol, 1-(cyclopentylamino)-3-(2,6-di-tert-butyl-4-ethoxyphenoxy)propan-2-ol, 1-(cyclopentylamino)-3-(2,6-di-tert-butyl-4-isopropoxyphenoxy)propan-2-ol, 1-(2-(tert-butyl)-6-isopropyl-4-methoxyphenoxy)-3-(cyclopentylamino)propan-2-ol, 1-(cyclopentylamino)-3-(2,6-diisopropyl-4-methoxyphenoxy)propan-2-ol, 1-(2-(tert-butyl)-6-ethyl-4-methoxyphenoxy)-3-(cyclopentylamino)propan-2-ol, 1-(cyclopentylamino)-3-(2,6-di-tert-butyl-4-ethylphenoxy)propan-2-ol, N-(3-(2,6-di-tert-butyl-4-propoxyphenoxy)-2-methoxypropyl)cyclopentylamine, N-(3-(2-tert-butyl)-4-propoxyphenoxy)-2-methoxypropyl)cyclopentylamine, N-(3-(2,6-di-tert-butyl-4-methoxyphenoxy)-2-methoxypropyl)cyclopentylamine, 1-(2,6-di-tert-butyl-4-methoxyphenoxy)-3-(pyrrolidin-1-yl)propan-2-ol, 1-(cyclohexylamino)-3-(2,6-di-tert-butyl-4-methoxyphenoxy)propan-2-ol, 1-(((1S,4R)-bicyclo[2.2.1]hept-2-yl)amino)-3-(2,6-di-tert-butyl-4-methoxyphenoxy)propan-2-ol, 1-(cyclobutylamino)-3-(2,6-di-tert-butyl-4-methoxyphenoxy)propan-2-ol, 1-(cyclopropylamino)-3-(2,6-di-tert-butyl-4-methoxyphenoxy)propan-2-ol, 1-(cycloheptylamino)-3-(2,6-di-tert-butyl-4-methoxyphenoxy)propan-2-ol, 3-((3-(2,6-di-tert-butyl-4-methoxyphenoxy)-2-hydroxypropyl)amino)cyclopentan-1-ol, 1-(2,6-di-tert-butyl-4-methoxyphenoxy)-3-(methylamino)propan-2-ol, 1-(2,6-di-tert-butyl-4-methoxyphenoxy)-3-(phenylamino)propan-2-ol, 1-(4-butoxy-2,6-di-tert-butylphenoxy)-3-(cyclopentylamino)propan-2-ol, 1-(cyclopentylamino)-3-(2,5-di-tert-butyl-4-methoxyphenoxy)propan-2-ol, 1-(2,6-di-tert-butyl-4-methoxyphenoxy)-3-(ethylamino)propan-2-ol, 1-(2-(tert-butyl)-4-ethyl-6-isopropylphenoxy)-3-(cyclopentylamino)propan-2-ol, 1-(2-(tert-butyl)-4,6-dimethylphenoxy)-3-(cyclopentylamino)propan-2-ol, 1-(cyclopentylamino)-3-(2,4,6-tri-tert-butylphenoxy)propan-2-ol, 1-(cyclopentylamino)-3-(mesityloxy)propan-2-ol, 1-(cyclopentylamino)-3-(2,6-di-tert-butylphenoxy)propan-2-ol, 1-(2,6-di-tert-butyl-4-methoxyphenoxy)-3-(isopropylamino)propan-2-ol, 1-(2,6-di-tert-butyl-4-methoxyphenoxy)-3-(pentan-3-ylamino)propan-2-ol, 1-(cyclopentylamino)-3-(2,6-di-tert-butyl-4-methylphenoxy)propan-2-ol, 1-(cyclopentylamino)-3-(4-methoxy-2,6-dimethylphenoxy)propan-2-ol, 1-(3,5-di-tert-butyl-4-(3-(cyclopentylamino)-2-hydroxypropyloxy)phenyl)ethan-1-one, 1-(2,6-di-tert-butyl-4-methoxyphenoxy)-3-((3-methylcyclopentyl)amino)propan-2-ol, 1-(2-(tert-butyl)-6-cyclopropyl-4-methoxyphenoxy)-3-(cyclopentylamino)propan-2-ol, 3-((3-(2-(tert-butyl)-4-methoxyphenoxy)-2-hydroxypropyl)amino)cyclopentyl acetate, 1-(2-(tert-butyl)-4-methoxyphenoxy)-3-(thiazol-4-ylamino)propan-2-ol, 1-(2-(tert-butyl)-4-methoxyphenoxy)-3-(thiazol-5-ylamino)propan-2-ol, 1-(2-(tert-butyl)-6-fluoro-4-methoxyphenoxy)-3-(cyclopentylamino)propan-2-ol, 1-(cyclopentylamino)-3-(2-(1-cyclopropylethyl)-6-isopropyl-4-methoxyphenoxy)propan-2-ol, 1-(2-(tert-butyl)-4,6-dimethoxyphenoxy)-3-(cyclopentylamino)propan-2-ol, 1-(2-(tert-butyl)-6-isopropoxy-4-methoxyphenoxy)-3-(cyclopentylamino)propan-2-ol, 1-(cyclopentylamino)-3-(2,6-dicyclopropyl-4-methoxyphenoxy)propan-2-ol, 1-(2-(tert-butyl)-6-chloro-4-methoxyphenoxy)-3-(cyclopentylamino)propan-2-ol, (R)-1-(cyclopentylamino)-3-(2,6-di-tert-butyl-4-methoxyphenoxy)propan-2-ol, (S)-1-(cyclopentylamino)-3-(2,6-di-tert-butyl-4-methoxyphenoxy)propan-2-ol, (R)-1-(2-(tert-butyl)-6-isopropyl-4-methoxyphenoxy)-3-(cyclopentylamino)propan-2-ol, (S)-1-(2-(tert-butyl)-6-isopropyl-4-methoxyphenoxy)-3-(cyclopentylamino)propan-2-ol, N-(3-(2-tert-butyl)-6-isopropyl-4-methoxyphenoxy)-2-methoxypropyl)cyclopentylamine, 1-(2-(tert-butyl)-6-isopropyl-4-methoxyphenoxy)-3-(cyclopentylamino)propan-2-yl acetate, 1-(2-(tert-butyl)-6-isopropyl-4-methoxyphenoxy)-3-(cyclopentylamino)propan-2-yl propionate, N-(3-(2-tert-butyl)-6-isopropyl-4-methoxyphenoxy)-2-methoxypropyl)-N-methylcyclopentylamine, ethyl (3-(2-(tert-butyl)-6-isopropyl-4-methoxyphenoxy)-2-methoxypropyl) 1-(2-(tert-butyl)-6-isopropyl-4-methoxyphenoxy)-3-(cyclopentyl(ethyl)amino)propan-2-ol, 1-(cyclopentylamino)-3-(2,5-dicyclopropyl-4-methoxyphenoxy)propan-2-ol, Cyclopentyl(3-{[4-methoxy-6-(2-methylpropan-2-yl)-2-(propyl-2-yl)phenyl]oxy}-2-(propyloxy)propyl)amine, Cyclopentyl(3-{[4-methoxy-2-(2-methylpropan-2-yl)-6-(propan-2-yl)phenyl]oxy}-2-(propan-2-yloxy)propyl)amine, Cyclopentyl(3-{[6-(1-cyclopropylethyl)-4-methoxy-2-(propan-2-yl)phenyl]oxy}-2-ethoxypropyl)amine, 3-(cyclopentylamino)-1-{[2-(1-cyclopropylethyl)-4-methyl-6-(propan-2-yl)phenyl]oxy}propan-2-ol, 3-(Cyclopentylamino)-1-{[4-methyl-2,6-di(propan-2-yl)phenyl]oxy}propan-2-ol, Cyclopentyl(3-{[6-(1-cyclopropylethyl)-4-methyl-2-(propan-2-yl)phenyl]oxy}-2-ethoxypropyl)amine, Cyclopentyl(3-{[6-(1-cyclopropylethyl)-4-methyl-2-(propan-2-yl)phenyl]oxy}-2-methoxypropyl)amine, 3-(Cyclopentylamino)-1-{[4-methyl-2-(propan-2-yl)phenyl]oxy}propan-2-ol.

7. A pharmaceutical composition, characterized in that The invention comprises a compound according to any one of claims 1 to 6 or a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

8. Use of the compound according to any one of claims 1 to 6 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or the pharmaceutical composition according to claim 7 in the preparation of a voltage-gated calcium channel inhibitor.

9. The use according to claim 8, characterized in that The voltage-gated calcium ion channel is CaV2.

2.

10. Use of the compound according to any one of claims 1 to 6 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 7 in the preparation of a drug for alleviating and / or eliminating pain.

11. The use according to claim 10, characterized in that The pain includes any one or more of chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

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