CN105906564B - Compound, preparation method and its usage - Google Patents

Compound, preparation method and its usage Download PDF

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Publication number
CN105906564B
CN105906564B CN201610298736.0A CN201610298736A CN105906564B CN 105906564 B CN105906564 B CN 105906564B CN 201610298736 A CN201610298736 A CN 201610298736A CN 105906564 B CN105906564 B CN 105906564B
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compound
base
isoquinolin
preparation
urea
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CN105906564A (en
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周星
孙伟
侯世封
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Hainan Pharmaceutical Research Institute Co., Ltd
Shenyang Pharmaceutical University
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HAINAN PHARMACEUTICAL INST
Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to field of medicinal chemistry, in particular to compound, preparation method and its usage.The present invention relates to compound shown in general formula I and its salt, this kind of compound is TRPV1 antagonist, there is preferable analgesic activity, the application the invention further relates to the preparation method of such compound and containing their pharmaceutical preparation and such compound and its Pharmaceutical composition in treatment pain.

Description

Compound, preparation method and its usage
Technical field
The present invention relates to field of medicinal chemistry, in particular to compound, preparation method and its usage.
Background technique
Pain is a kind of complicated Physiological Psychology activity, is clinically one of most common symptom.Due to pathomechanism Complexity, pain have become one of unsatisfied major medical demand.Currently used for clinical analgesic, there are two main classes： Opioid drug and non-steroidal anti-inflammatory drug (NSAIDs).
Opioid analgesic generates pain effect by conjunction with opiate receptor, activating opiate receptor.Such drug It usually works rapidly, and pain can significantly be mitigated or eliminated.But the maximum side effect of such drug is：Continuously apply repeatedly, Can generate drug resistance and cause it is additive, once being discontinued i.e. there is withrawal symptom, it is very harmful, it is only in extreme circumstances, clinical The upper limited use of.
The mechanism of action of NSAIDs, which mainly passes through, inhibits arachidonic acid cyclooxygenase (COX) to inhibit prostaglandin (PG) biosynthesis.The clinical efficacy of nonsteroidal anti-inflammatory drug is preferable, and be not likely to produce tolerance and it is additive, due to its effect Position cannot substitute the effect of morphines analgesics object mainly in periphery；In addition, the adverse reaction of such drug is still made us Raw fear, mainly gastrointestinal reaction, gastric ulcer, gastrorrhagia and allergy etc..
Vanilloid receptor (VR1 or TRPV1), belong to cationic channel Transient Receptor Channel family (TRP family) without choosing The cationic channel of selecting property ligand control, in many tissues that are covered with to innervate, including skin, bladder, air flue and stomach and intestine It is highly expressed the periphery end of the minor diameter sensory neuron in road.1997, the successful clone of this receptor mentioned for pain therapy New action target spot is supplied.Natural products capsaicine is the TRPV1 receptor stimulating agent found earliest, has high application study Value.But some side effects can be generated using capsaicine, as local use capsaicine has burning heat sensation, after a couple of days to several weeks It will lead to analgesia and reaction lost to various noxious stimulations.Relative to TRPV1 agonist, TRPV1 antagonist can Inhibit the heat in nociception and thermalgesia enhanced sensitivity, especially decrease acute heat nociception inflammatory model different with reduction Hyperalgesia, and can be avoided the side effect of TRPV1 agonist.In recent years, to the research of TRPV1 antagonist gradually by Pay attention to.Therefore it provides TRPV1 antagonist has important practical significance.
Summary of the invention
In view of this, the present invention provides a kind of compound, preparation method and its usage.The compound is TRPV1 antagonist, There is preferable analgesic activity, the invention further relates to the preparation method of such compound and containing their pharmaceutical preparation, and should The application of class compound and its Pharmaceutical composition in treatment pain.
In order to achieve the above-mentioned object of the invention, the present invention provides following technical scheme：
The present invention provides a kind of compound or pharmaceutically acceptable salt thereof, the general formula of the compound is as shown in formula I：
Wherein, X is selected from N or CH；
Y is selected from N or CH；
Z is selected from oxygen or sulphur；
N=1-3；
R1Selected from trifluoromethyl, tert-butyl；R2Selected from H, C1~C10Sulfenyl, halogen, aryloxy group, hydroxyl or azacyclo- take For C2~C5Sulfenyl.
In some specific embodiments of the invention, the compound or pharmaceutically acceptable salt thereof R2It is selected from CH3CH2CH2CH2S-、CH3CH2CH2CH2CH2S-、CH3CH2CH2CH2CH2CH2S-、 (CH3)2CHCH2CH2S-、CF3CH2S-、BrCH2CH2CH2S-、HOCH2CH2CH2S-、 (CH3)2NCH2CH2CH2S-、
In some specific embodiments of the invention, the compound is selected from：
1- (2- butylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (isoquinolin -5- base) -3- (2- penta sulfenyl -4- trifluoromethyl benzyl) urea；
1- (the own sulfenyl -4- trifluoromethyl benzyl of 2-) -3- (isoquinolin -5- base) urea；
1- (2- ring penta sulfenyl -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (2- cyclohexylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (isoquinolin -5- base) -3- (2- (2- methyl cyclohexane sulfenyl) -4- trifluoromethyl benzyl) urea；
1- (isoquinolin -5- base) -3- (2- (4- methyl cyclohexane sulfenyl) -4- trifluoromethyl benzyl) urea；
1- (2- (4- cyclohexyl sulfenyl) -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (2- (4- t-butylcyclohexyl sulfenyl) -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (2- isopentylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (isoquinolin -5- base) -3- (2- (2,2,2- trifluoro ethylmercapto group) -4- trifluoromethyl benzyl) urea；
1- (2- (3- bromine rosickyite base) -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (isoquinolin -5- base) -3- (2- (2- benzene oxygen ethylmercapto group) -4- trifluoromethyl benzyl) urea；
1- (2- (3- hydroxyl rosickyite base) -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (2- (3- dimethylamino rosickyite base) -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (isoquinolin -5- base) -3- (2- (3- (pyrrolidin-1-yl) rosickyite base) -4- trifluoromethyl benzyl) urea；
1- (isoquinolin -5- base) -3- (2- (3- (piperidin-1-yl) rosickyite base) -4- trifluoromethyl benzyl) urea；
1- (isoquinolin -5- base) -3- (2- (3- (4- methyl piperidine -1- base) rosickyite base) -4- trifluoromethyl benzyl) urea；
1- (4- tert-butyl -2- butylthio benzyl) -3- (isoquinolin -5- base) urea；
1- (4- tert-butyl -2- isopentylthio benzyl) -3- (isoquinolin -5- base) urea；
1- (4- tert-butyl -2- cyclohexylthio benzyl) -3- (isoquinolin -5- base) urea；
1- (4- tert-butyl -2- (4- methyl cyclohexane sulfenyl) benzyl) -3- (isoquinolin -5- base) urea；
1- (2- butylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) thiocarbamide；
1- (2- isopentylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) thiocarbamide；
1- (2- cyclohexylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) thiocarbamide；
1- (isoquinolin -5- base) -3- (2- (4- methyl cyclohexane sulfenyl) -4- trifluoromethyl benzyl) thiocarbamide；
1- (4- tert-butyl -2- butylthio benzyl) -3- (isoquinolin -5- base) thiocarbamide；
1- (4- tert-butyl -2- isopentylthio benzyl) -3- (isoquinolin -5- base) thiocarbamide；
1- (4- tert-butyl -2- cyclohexylthio benzyl) -3- (isoquinolin -5- base) thiocarbamide；
1- (4- tert-butyl -2- (4- methyl cyclohexane sulfenyl) benzyl) -3- (isoquinolin -5- base) thiocarbamide.
In some specific embodiments of the invention, compound is selected from：
In some specific embodiments of the invention, the pharmaceutical salts include the addition salts formed with following acid：Hydrochloric acid, Hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, maleic acid, benzene sulfonic acid, succinic acid Or known acceptable acid is at salt.
The present invention also provides the preparation methods of the compound, and using 5- nitroisoquinoline as starting material, methanol is molten Liquid obtains 5- aminoisoquinoline through Pd/C catalytic hydrogenation, then reacts to obtain compound 4 with phenyl chloroformate in acetonitrile --- and it is different Quinoline -5- base-phenyl carbamate；The chloro- 4- trifluoromethylbenzonitrile of 2- or the chloro- 4- tert-butyl benzene formonitrile HCN of 2- and mercaptan are in 18- 6 ether of crown-, the N of potassium carbonate, reaction generates corresponding compound 7 or compound 10 in N '-dimethyl acetamide solution；Describedization The tetrahydrofuran solution for closing object 7 or compound 10 obtains corresponding benzylamine through borane reduction --- compound 8 or compound 11； The compound 8 or the compound 11 react to obtain target compound with the compound 4.Specific reaction step such as Fig. 1 institute Show.
The present invention also provides the preparation methods of the compound, and using 5- nitroisoquinoline as starting material, methanol is molten Liquid obtains 5- aminoisoquinoline through Pd/C catalytic hydrogenation, then reacts to obtain compound 12 with carbon disulfide --- 5- isothiocyano Isoquinolin；The chloro- 4- trifluoromethylbenzonitrile of 2- or the chloro- 4- tert-butyl benzene formonitrile HCN of 2- and mercaptan are in 6 ether of 18- crown-, the N of potassium carbonate, Reaction generates corresponding compound 7 or compound 10 in N '-dimethylacetamide solution；The compound 7 or the compound 10 tetrahydrofuran solution obtains corresponding benzylamine through borane reduction --- compound 8 or compound 11；The compound 8 or The compound 11 reacts to obtain target compound with the compound 12.Specific reaction step is as shown in Figure 2.
The present invention also provides compounds made from the preparation method.
The present invention also provides compound or pharmaceutically acceptable salt thereofs described made from the preparation method or of the present invention Compound or pharmaceutically acceptable salt thereof is preparing the application in TRPV1 antagonist or TRPV1 agonist drug.
The present invention also provides compound or pharmaceutically acceptable salt thereofs described made from the preparation method or of the present invention Compound or pharmaceutically acceptable salt thereof is preparing the application in analgesic.
The present invention also provides a kind of TRPV1 agonist drug, including compound described made from the preparation method or Its pharmaceutical salts or compound or pharmaceutically acceptable salt thereof of the present invention and pharmaceutically acceptable auxiliary material.
In some specific embodiments of the invention, the pharmaceutically acceptable auxiliary material refers to pharmaceutical field routine Pharmaceutical carrier refers to one or more of inert, atoxic solids or liquid filler material, diluent, auxiliary agent etc., they are not inverse It has an effect to reactive compound or patient.
In some specific embodiments of the invention, the dosage form of the TRPV1 agonist drug be tablet, capsule, pill, Common dosage form in the pharmacies such as suppository, soft capsule, oral solution, suspension, injection.Tablet and capsule for oral use contain tradition Excipient such as filler, diluent, lubricant, dispersing agent and adhesive.The various dosage forms of pharmaceutical composition of the present invention can To be prepared according to method well known in pharmaceutical field.Depending on the dosage of the above activating agent will be because of formula.It is provided by the invention The method that compound is prepared into the TRPV1 agonist drug can be prepared according to the ordinary skill in the art, the present invention couple In drug preparation method and addition auxiliary material without limitation, it is any type of replacement it is within the scope of the present invention.
The present invention relates to compound shown in general formula I and its salt, this kind of compound is TRPV1 antagonist, there is preferable analgesia Effect, the invention further relates to the preparation method of such compound and contains their pharmaceutical preparation and such compound and its Application of the Pharmaceutical composition in treatment pain.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below There is attached drawing needed in technical description to be briefly described.
Fig. 1 shows the preparation method flow chart of the present invention I A01-, I A22 compound；
Fig. 2 shows the preparation method flow chart of the present invention I B01-, I B08 compound.
Specific embodiment
The invention discloses a kind of compound, preparation method and its usage, those skilled in the art can be used for reference in this paper Hold, is suitably modified realization of process parameters.In particular, it should be pointed out that all similar substitutions and modifications are to those skilled in the art For be it will be apparent that they are considered as being included in the present invention.Method and application of the invention, which has passed through, preferably to be implemented Example is described, related personnel obviously can not depart from the content of present invention, in spirit and scope to method described herein and Using being modified or appropriate changes and combinations, carry out implementation and application the technology of the present invention.
Raw materials used and reagent can be purchased by market in a kind of compound provided by the invention, preparation method and its usage ?.
Below with reference to embodiment, the present invention is further explained：
The preparation of 1 5- aminoisoquinoline (2) of embodiment
In 100ml round-bottomed flask, into the 50mL methanol solution of 5- nitroquinoline 1.31g (7.52mmol), it is added 10% Palladium carbon 262mg.By the air extraction in round-bottomed flask, hydrogen is poured, repeatedly for three times.Stirring reduction 1 hour at room temperature, will react Liquid is filtered out palladium carbon therein by a bit of diatomite, and vacuum distillation obtains pale solid, i.e. 5- aminoisoquinoline (2) 1.08g. yield：>99%.
The preparation of 2 isoquinolin -5- base of embodiment-phenyl carbamate (4)
In the round-bottomed flask of 100ml, 5- aminoisoquinoline 200mg (1.39mmol) is dissolved in 50mL acetonitrile, room temperature Under the conditions of be added pyridine 0.14mL (1.67mmol)；After finishing, benzene oxygen formyl chloride 0.18mL (1.46mmol) is slowly added dropwise.Room temperature Under, it stirs 1 hour, evaporating solvent under reduced pressure, liquid separation, ethyl acetate extracts (100mL × 3), merges organic phase, with anhydrous sodium sulfate Powder is dry, and vacuum distillation, residue is isolated and purified with silica gel column chromatograph, obtains white solid, i.e. isoquinolin -5- base - Phenyl carbamate (4) 355mg, yield：97%.
3 2- butylthio -4- trifluoromethylbenzonitrile (7A of embodiment01) preparation
Under room temperature, in the round-bottomed flask of 250ml, the chloro- 4- trifluoromethylbenzonitrile 1g (4.86mmol) of 2-, potassium carbonate 2.01g (14.58mmol), 18- crown- 6- ether 20mg are dissolved in N, and in N '-dimethyl acetamide, n-butyl mercaptan is slowly added dropwise 0.63ml(5.83mmol).After being added dropwise, it is heated to reflux 12 hours.Restore to reaction solution to room temperature, water 50ml, acetic acid is added Ethyl ester liquid separation extracts (200ml × 3), merges organic phase, dry with anhydrous sodium sulfate powder, evaporating solvent under reduced pressure, residue with Silica gel column chromatograph isolates and purifies, and obtains yellow solid, i.e. 2- butylthio -4- trifluoromethylbenzonitrile (7A01) 1.26g, it produces Rate：>99%.
4 2- penta sulfenyl -4- trifluoromethylbenzonitrile (7A of embodiment02) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, n-amyl mercaptan 0.72ml (5.83mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. 2- penta sulfenyl- 4- trifluoromethylbenzonitrile (7A02) 1.33g, yield：>99%.
Own sulfenyl -4- trifluoromethylbenzonitrile (the 7A of 5 2- of embodiment03) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, positive hexyl mercaptan 0.82ml (5.83mmol), remaining operates same 7A01Preparation, obtain yellow solid, the i.e. own sulfenyl-of 2- 4- trifluoromethylbenzonitrile (7A03) 1.40g, yield：>99%.
6 2- ring penta sulfenyl -4- trifluoromethylbenzonitrile (7A of embodiment04) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, cyclopentanethiol 0.62ml (5.83mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. penta sulphur of 2- ring Base -4- trifluoromethylbenzonitrile (7A04) 1.32g, yield：>99%.
7 2- cyclohexylthio -4- trifluoromethylbenzonitrile (7A of embodiment05) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, cyclohexylmercaptan 0.71ml (5.83mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. 2- hexamethylene sulphur Base -4- trifluoromethylbenzonitrile (7A05) 1.39g, yield：>99%.
8 2- of embodiment (2- methyl cyclohexane sulfenyl) -4- trifluoromethylbenzonitrile (7A06) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, 2- methyl cyclohexane mercaptan 0.76g (5.83mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. 2- (2- Methyl cyclohexane sulfenyl) -4- trifluoromethylbenzonitrile (7A06) 1.45g, yield：>99%.
9 2- of embodiment (4- methyl cyclohexane sulfenyl) -4- trifluoromethylbenzonitrile (7A07) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, 4- methyl cyclohexane mercaptan 0.76g (5.83mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. 2- (4- Methyl cyclohexane sulfenyl) -4- trifluoromethylbenzonitrile (7A07) 1.45g, yield：>99%.
10 2- of embodiment (4- cyclohexyl sulfenyl) -4- trifluoromethylbenzonitrile (7A08) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, 4- cyclohexyl mercaptan 0.84g (5.83mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. 2- (4- Cyclohexyl sulfenyl) -4- trifluoromethylbenzonitrile (7A08) 1.52g, yield：>99%.
11 2- of embodiment (4- t-butylcyclohexyl sulfenyl) -4- trifluoromethylbenzonitrile (7A09) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, 4- t-butylcyclohexyl mercaptan 1.0g (5.83mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. 2- (4- t-butylcyclohexyl sulfenyl) -4- trifluoromethylbenzonitrile (7A09) 1.66g, yield：>99%.
12 2- isopentylthio -4- trifluoromethylbenzonitrile (7A of embodiment10) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, isoamyl mercaptan 0.61g (5.83mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. 2- isoamyl sulphur Base -4- trifluoromethylbenzonitrile (7A10) 1.33g, yield：>99%.
13 2- of embodiment (2,2,2- trifluoro ethylmercapto group) -4- trifluoromethylbenzonitrile (7A11) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, 2,2,2- trifluoro ethyl mercaptan 0.68g (5.83mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. 2- (2,2,2- trifluoro ethylmercapto group) -4- trifluoromethylbenzonitrile (7A11) 1.39g, yield：>99%.
14 2- of embodiment (3- bromine rosickyite base) -4- trifluoromethylbenzonitrile (7A12) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, 2- bromine propanethiol 0.90g (5.83mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. 2- (3- bromine Rosickyite base) -4- trifluoromethylbenzonitrile (7A12) 1.58g, yield：>99%.
15 2- of embodiment (2- benzene oxygen ethylmercapto group) -4- trifluoromethylbenzonitrile (7A13) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, 2- benzene oxygen ethyl mercaptan 0.90g (5.83mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. 2- (2- Benzene oxygen ethylmercapto group) -4- trifluoromethylbenzonitrile (7A13) 1.57g, yield：>99%.
16 2- of embodiment (3- hydroxyl rosickyite base) -4- trifluoromethylbenzonitrile (7A14) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, 3- sulfydryl -1- propyl alcohol 0.54g (5.83mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. 2- (3- Hydroxyl rosickyite base) -4- trifluoromethylbenzonitrile (7A14) 1.27g, yield：>99%.
17 2- of embodiment (3- dimethylamino rosickyite base) -4- trifluoromethylbenzonitrile (7A15) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, 3- dimethylamino propanethiol 0.70g (5.83mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. 2- (3- dimethylamino rosickyite base) -4- trifluoromethylbenzonitrile (7A15) 1.40g, yield：>99%.
18 2- of embodiment (3- (pyrrolidin-1-yl) rosickyite base) -4- trifluoromethylbenzonitrile (7A16) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, 3- (pyrrolidin-1-yl) propyl -1- mercaptan 0.85g (5.83mmol), remaining operates same 7A01Preparation, obtain yellow Solid, i.e. 2- (3- (pyrrolidin-1-yl) rosickyite base) -4- trifluoromethylbenzonitrile (7A16) 1.53g, yield：>99%.
19 2- of embodiment (3- (piperidin-1-yl) rosickyite base) -4- trifluoromethylbenzonitrile (7A17) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, 3- (piperidin-1-yl) propyl -1- mercaptan 0.93g (5.83mmol), remaining operates same 7A01Preparation, it is solid to obtain yellow Body, i.e. 2- (3- (piperidin-1-yl) rosickyite base) -4- trifluoromethylbenzonitrile (7A17) 1.60g, yield：>99%.
20 2- of embodiment (3- (4- methyl piperidine -1- base) rosickyite base) -4- trifluoromethylbenzonitrile (7A18) preparation
Referring to 7A01Preparation, with 5 1g of compound (4.86mmol), potassium carbonate 2.01g (14.58mmol), 18- crown- 6- Ether 20mg, 3- (4- methyl piperidine -1- base) propyl -1- mercaptan 1.01g (5.83mmol), remaining operates same 7A01Preparation, obtain Yellow solid, i.e. 2- (3- (4- methyl piperidine -1- base) rosickyite base) -4- trifluoromethylbenzonitrile (7A18) 1.66g, yield：> 99%.
21 2- butylthio -4- tert-butyl benzene formonitrile HCN (10A of embodiment19) preparation
Referring to 7A01Preparation, with 9 1g of compound (5.16mmol), potassium carbonate 2.14g (15.49mmol), 18- crown- 6- Ether 20mg, n-butyl mercaptan 0.67ml (6.19mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. 2- butylthio- 4- tert-butyl benzene formonitrile HCN (7A19) 1.28g, yield：>99%.
22 2- isopentylthio -4- tert-butyl benzene formonitrile HCN (10A of embodiment20) preparation
Referring to 7A01Preparation, with 9 1g of compound (5.16mmol), potassium carbonate 2.14g (15.49mmol), 18- crown- 6- Ether 20mg, isoamyl mercaptan 0.65g (6.19mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. 2- isoamyl sulphur Base -4- tert-butyl benzene formonitrile HCN (7A20) 1.35g, yield：>99%.
23 2- cyclohexylthio -4- tert-butyl benzene formonitrile HCN (10A of embodiment21) preparation
Referring to 7A01Preparation, with 9 1g of compound (5.16mmol), potassium carbonate 2.14g (15.49mmol), 18- crown- 6- Ether 20mg, cyclohexylmercaptan 0.72g (6.19mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. 2- hexamethylene sulphur Base -4- tert-butyl benzene formonitrile HCN (7A21) 1.41g, yield：>99%.
24 2- of embodiment (4- methyl cyclohexane sulfenyl) -4- tert-butyl benzene formonitrile HCN (10A22) preparation
Referring to 7A01Preparation, with 9 1g of compound (5.16mmol), potassium carbonate 2.14g (15.49mmol), 18- crown- 6- Ether 20mg, 4- methyl cyclohexane mercaptan 0.81g (6.19mmol), remaining operates same 7A01Preparation, obtain yellow solid, i.e. 2- (4- Methyl cyclohexane sulfenyl) -4- tert-butyl benzene formonitrile HCN (7A22) 1.48g, yield：>99%.
25 2- butylthio -4- tert-butyl benzene methylamine (8A of embodiment01) preparation
Under room temperature, in 500ml three-necked bottle, to compound 7A01The tetrahydrofuran solution of 1g (3.86mmol) In (200ml), the tetrahydrofuran solution 9.7ml (19.3mmol) of 2M borane dimethylsulfide ether complexes is slowly added dropwise.It is added dropwise Afterwards, it is heated to reflux 12 hours.Restore to reaction solution to room temperature, water 100ml, liquid separation, ethyl acetate are slowly added into reaction solution It extracts (200ml × 3), merges organic phase, dry with anhydrous sodium sulfate powder, evaporating solvent under reduced pressure, residue is with silica gel column chromatography Column chromatography separating purification obtains yellow oil, i.e. 2- butylthio -4- tert-butyl benzene methylamine (8A01) 0.60g, yield：59%.
26 2- penta sulfenyl -4- trifluoromethyl-benzyl amine (8A of embodiment02) preparation
Referring to 8A01Preparation, with compound 7A02The tetrahydro furan of 1g (3.66mmol), 2M borane dimethylsulfide ether complexes Mutter solution 9.2ml (18.3mmol), remaining operates same 8A01Preparation, obtain yellow oil, i.e. 2- penta sulfenyl -4- fluoroform Base benzene methanamine (8A02) 0.61g, yield：60%.
Own sulfenyl -4- trifluoromethyl-benzyl amine (the 8A of 27 2- of embodiment03) preparation
Referring to 8A01Preparation, with compound 7A03The tetrahydro furan of 1g (3.48mmol), 2M borane dimethylsulfide ether complexes Mutter solution 8.8ml (17.4mmol), remaining operates same 8A01Preparation, obtain yellow oil, the i.e. own sulfenyl -4- fluoroform of 2- Base benzene methanamine (8A03) 0.56g, yield：55%.
28 2- ring penta sulfenyl -4- trifluoromethyl-benzyl amine (8A of embodiment04) preparation
Referring to 8A01Preparation, with compound 7A04The tetrahydro furan of 1g (3.69mmol), 2M borane dimethylsulfide ether complexes Mutter solution 9.4ml (18.5mmol), remaining operates same 8A01Preparation, obtain yellow oil, i.e. 2- ring penta sulfenyl -4- trifluoro Methyl benzene methanamine (8A04) 0.51g, yield：50%.
29 2- cyclohexylthio -4- trifluoromethyl-benzyl amine (8A of embodiment05) preparation
Referring to 8A01Preparation, with compound 7A05The tetrahydro furan of 1g (3.50mmol), 2M borane dimethylsulfide ether complexes Mutter solution 8.9ml (17.5mmol), remaining operates same 8A01Preparation, obtain yellow oil, i.e. 2- cyclohexylthio -4- trifluoro Methyl benzene methanamine (8A05) 0.64g, yield：63%.
30 2- of embodiment (2- methyl cyclohexane sulfenyl) -4- trifluoromethyl-benzyl amine (8A06) preparation
Referring to 8A01Preparation, with compound 7A06The tetrahydro furan of 1g (3.34mmol), 2M borane dimethylsulfide ether complexes Mutter solution 8.5ml (16.7mmol), remaining operates same 8A01Preparation, obtain yellow oil, i.e. 2- (2- methyl cyclohexane sulfenyl) 4- trifluoromethyl-benzyl amine (8A06) 0.49g, yield：48%.
31 2- of embodiment (4- methyl cyclohexane sulfenyl) -4- trifluoromethyl-benzyl amine (8A07) preparation
Referring to 8A01Preparation, with compound 7A07The tetrahydro furan of 1g (3.34mmol), 2M borane dimethylsulfide ether complexes Mutter solution 8.5ml (16.7mmol), remaining operates same 8A01Preparation, obtain yellow oil, i.e. 2- (4- methyl cyclohexane sulphur Base) -4- trifluoromethyl-benzyl amine (8A07) 0.52g, yield：51%.
32 2- of embodiment (4- cyclohexyl sulfenyl) -4- trifluoromethyl-benzyl amine (8A08) preparation
Referring to 8A01Preparation, with compound 7A08The tetrahydro furan of 1g (3.19mmol), 2M borane dimethylsulfide ether complexes Mutter solution 8.1ml (16.0mmol), remaining operates same 8A01Preparation, obtain yellow oil, i.e. 2- (4- cyclohexyl sulphur Base) -4- trifluoromethyl-benzyl amine (8A08) 0.66g, yield：65%.
33 2- of embodiment (4- t-butylcyclohexyl sulfenyl) -4- trifluoromethyl-benzyl amine (8A09) preparation
Referring to 8A01Preparation, with compound 7A09The tetrahydro furan of 1g (2.93mmol), 2M borane dimethylsulfide ether complexes Mutter solution 7.4ml (14.7mmol), remaining operates same 8A01Preparation, obtain yellow oil, i.e. 2- (4- t-butylcyclohexyl sulphur Base) -4- trifluoromethyl-benzyl amine (8A09) 0.54g, yield：53%.
34 2- isopentylthio -4- trifluoromethyl-benzyl amine (8A of embodiment10) preparation
Referring to 8A01Preparation, with compound 7A10The tetrahydro furan of 1g (3.66mmol), 2M borane dimethylsulfide ether complexes Mutter solution 9.2ml (18.3mmol), remaining operates same 8A01Preparation, obtain yellow oil, i.e. 2- isopentylthio -4- trifluoro Methyl benzene methanamine (8A10) 0.50g, yield：49%.
35 2- of embodiment (2,2,2- trifluoro ethylmercapto group) -4- trifluoromethyl-benzyl amine (8A11) preparation
Referring to 8A01Preparation, with compound 7A11The tetrahydro furan of 1g (3.51mmol), 2M borane dimethylsulfide ether complexes Mutter solution 8.8ml (17.6mmol), remaining operates same 8A01Preparation, obtain yellow oil, i.e. 2- (2,2,2- trifluoro second sulphur Base) -4- trifluoromethyl-benzyl amine (8A11) 0.55g, yield：54%.
36 2- of embodiment (3- bromine rosickyite base) -4- trifluoromethyl-benzyl amine (8A12) preparation
Referring to 8A01Preparation, with compound 7A12The tetrahydro furan of 1g (3.08mmol), 2M borane dimethylsulfide ether complexes Mutter solution 7.7ml (15.4mmol), remaining operates same 8A01Preparation, obtain yellow oil, i.e. 2- (3- bromine rosickyite base) -4- Trifluoromethyl-benzyl amine (8A12) 0.58g, yield：57%.
37 2- of embodiment (2- benzene oxygen ethylmercapto group) -4- trifluoromethyl-benzyl amine (8A13) preparation
Referring to 8A01Preparation, with compound 7A13The tetrahydro furan of 1g (3.09mmol), 2M borane dimethylsulfide ether complexes Mutter solution 7.8ml (15.5mmol), remaining operates same 8A01Preparation, obtain yellow oil, i.e. 2- (2- benzene oxygen ethylmercapto group)- 4- trifluoromethyl-benzyl amine (8A13) 0.52g, yield：51%.
38 3- of embodiment (2- amine methyl -5- trifluoromethylbenzene ethylmercapto group) propyl -1- alcohol (8A14) preparation
Referring to 8A01Preparation, with compound 7A14The tetrahydro furan of 1g (3.83mmol), 2M borane dimethylsulfide ether complexes Mutter solution 9.7ml (19.2mmol), remaining operates same 8A01Preparation, obtain yellow oil, i.e. 3- (2- amine methyl -5- three Methyl fluoride benzene ethylmercapto group) propyl -1- alcohol (8A14) 0.54g, yield：53%.
39 3- of embodiment (2- amine methyl -5- trifluoromethylphenylthio)-N, N dimethyl propyl -1- amine (8A15) preparation
Referring to 8A01Preparation, with compound 7A15The tetrahydro furan of 1g (3.47mmol), 2M borane dimethylsulfide ether complexes Mutter solution 8.8ml (17.4mmol), remaining operates same 8A01Preparation, obtain yellow oil, i.e. 3- (2- amine methyl -5- three Methyl fluoride thiophenyl)-N, N dimethyl propyl -1- amine (8A15) 0.58g, yield：57%.
40 2- of embodiment (3- (pyrrolidin-1-yl) rosickyite base) -4- trifluoromethyl-benzyl amine (8A16) preparation
Referring to 8A01Preparation, with compound 7A16The tetrahydro furan of 1g (3.18mmol), 2M borane dimethylsulfide ether complexes Mutter solution 8.0ml (15.9mmol), remaining operates same 8A01Preparation, obtain yellow oil, i.e. 2- (3- (pyrrolidin-1-yl) Rosickyite base) -4- trifluoromethyl-benzyl amine (8A16) 0.67g, yield：66%.
41 2- of embodiment (3- (piperidin-1-yl) rosickyite base) -4- trifluoromethyl-benzyl amine (8A17) preparation
Referring to 8A01Preparation, with compound 7A17The tetrahydro furan of 1g (3.05mmol), 2M borane dimethylsulfide ether complexes Mutter solution 7.7ml (15.3mmol), remaining operates same 8A01Preparation, obtain yellow oil, i.e. 2- (3- (piperidines -1- base) Rosickyite base) -4- trifluoromethyl-benzyl amine (8A17) 0.65g, yield：64%.
42 2- of embodiment (3- (4- methyl piperidine -1- base) rosickyite base) 4- trifluoromethyl-benzyl amine (8A18) preparation
Referring to 8A01Preparation, with compound 7A18The tetrahydro furan of 1g (2.92mmol), 2M borane dimethylsulfide ether complexes Mutter solution 7.3ml (14.6mmol), remaining operates same 8A01Preparation, obtain yellow oil, i.e. 2- (3- (4- methyl piperidine- 1- yl) rosickyite base) 4- trifluoromethyl-benzyl amine (8A18) 0.59g, yield：58%.
43 2- butylthio -4- tert-butyl benzene methylamine (11A of embodiment19) preparation
Referring to 8A01Preparation, with compound 10A19The tetrahydro furan of 1g (4.04mmol), 2M borane dimethylsulfide ether complexes Mutter solution 10.1ml (20.2mmol), remaining operates same 8A01Preparation, obtain yellow oil, the i.e. tertiary fourth of 2- butylthio -4- Base benzene methanamine (11A19) 0.48g, yield：47%.
44 2- isopentylthio -4- tert-butyl benzene methylamine (11A of embodiment20) preparation
Referring to 8A01Preparation, with compound 10A20The tetrahydro furan of 1g (3.83mmol), 2M borane dimethylsulfide ether complexes Mutter solution 9.6ml (19.2mmol), remaining operates same 8A01Preparation, obtain yellow oil, the i.e. tertiary fourth of 2- isopentylthio -4- Base benzene methanamine (11A20) 0.69g, yield：68%.
45 2- cyclohexylthio -4- tert-butyl benzene methylamine (11A of embodiment21) preparation
Referring to 8A01Preparation, with compound 10A21The tetrahydro furan of 1g (3.66mmol), 2M borane dimethylsulfide ether complexes Mutter solution 9.2ml (18.3mmol), remaining operates same 8A01Preparation, obtain yellow oil, the i.e. tertiary fourth of 2- cyclohexylthio -4- Base benzene methanamine (11A21) 0.61g, yield：60%.
46 2- of embodiment (4- methyl cyclohexane sulfenyl) -4- tert-butyl benzene methylamine (11A22) preparation
Referring to 8A01Preparation, with compound 10A22The tetrahydro furan of 1g (3.66mmol), 2M borane dimethylsulfide ether complexes Mutter solution 9.2ml (18.3mmol), remaining operates same 8A01Preparation, obtain yellow oil, the i.e. tertiary fourth of 2- cyclohexylthio -4- Base benzene methanamine (11A22) 0.61g, yield：60%.
The preparation of 47 5- isothiocyano isoquinolin (12) of embodiment
2 1.44g of compound (10mmol) is added into the two mouth flask with magnetic agitation of 100ml, sulphur 0.058g (4%wt), sodium carbonate 0.058g (4%wt), tetrabutylammonium bromide 0.058g (4%wt), water 15ml are quickly stirred in 80 DEG C Under the conditions of carbon disulfide 0.84g (10mmol) is slowly added dropwise.Reaction very exothermic simultaneously has hydrogen sulfide gas generation.Continue after finishing It is precipitated to light yellow crystal within stirring 5 hours, filters, wash, dry, re-crystallizing in ethyl acetate obtains white plates crystal, i.e. 5- Isothiocyano isoquinolin (12) 1.77g, yield：95%.
48 1- of embodiment (2- butylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea (I A01) preparation
In 50ml round-bottomed flask, by 4 264mg of compound (1mmol), compound 8A01276mg (1.05mmol) is dissolved in In DMSO 20ml.Under the conditions of being stirred at room temperature, triethylamine 0.28ml (2mmol) is slowly added dropwise.After finishing, continue stirring 12 hours. Water 50ml is added, ethyl acetate liquid separation extracts (100ml × 3), merges organic phase, and dry with anhydrous sodium sulfate powder, decompression is steamed Except solvent, residue is isolated and purified with silica gel column chromatograph, obtains white solid, i.e. 1- (2- butylthio -4- trifluoromethyl Benzyl) -3- (isoquinolin -5- base) urea (I A01) 325mg, yield：75%.1H NMR (300MHz, DMSO-d6) δ 9.23 (s, 1H), 8.86 (s, 1H), 8.45 (d, J=6.0Hz, 1H), 7.67 (s, 1H), 7.55 (t, J=7.8Hz, 1H), 7.49 (d, J= 6.0Hz, 1H), 7.41 (d, J=7.7Hz, 1H), 7.30 (d, J=7.2Hz, 1H), 7.24 (t, J=7.7Hz, 1H), 7.05 (d, J=7.2Hz, 1H), 6.80 (d, J=7.7Hz, 1H), 4.43 (d, J=5.5Hz, 2H), 2.94 (m, 2H), 1.45-1.60 (m, 4H), 0.89 (m, 3H)；MS：434(M+1)+
49 1- of embodiment (isoquinolin -5- base) -3- (2- penta sulfenyl -4- trifluoromethyl benzyl) urea (I A02) preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A02291mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (isoquinolin -5- base) -3- (penta sulphur of 2- Base -4- trifluoromethyl benzyl) urea (I A02) 345mg, yield：77%.1H NMR (300MHz, DMSO-d6) δ 9.25 (s, 1H), 8.82 (s, 1H), 8.40 (d, J=6.2Hz, 1H), 7.63 (s, 1H), 7.45 (d, J=6.1Hz, 1H), 7.39 (d, J= 7.2Hz, 1H), 7.27 (d, J=7.6Hz, 1H), 7.21 (t, J=7.1Hz, 1H), 7.08 (d, J=7.7Hz, 1H), 6.87 (d, J=7.2Hz, 1H), 6.75 (t, 1H), 4.50 (d, J=5.0Hz, 2H), 2.94 (m, 2H), 1.25-1.60 (m, 6H), 0.90 (m, 3H)；MS：448(M+1)+
50 1- of embodiment (the own sulfenyl -4- trifluoromethyl benzyl of 2-) -3- (isoquinolin -5- base) urea (I A03) preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A03306mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, the i.e. 1- (own sulfenyl -4- trifluoromethyl benzyl of 2- Base) -3- (isoquinolin -5- base) urea (I A03) 332mg, yield：72%.1H NMR (300MHz, DMSO-d6) δ 9.21 (s, 1H), 8.78 (s, 1H), 8.35 (d, J=6.0Hz, 1H), 7.59 (s, 1H), 7.41 (d, J=6.0Hz, 1H), 7.33 (d, J= 7.0Hz, 1H), 7.22 (d, J=7.6Hz, 1H), 7.16 (t, J=7.1Hz, 1H), 7.03 (d, J=7.6Hz, 1H), 6.82 (d, J=7.0Hz, 1H), 6.69 (t, 1H), 4.45 (d, J=4.5Hz, 2H), 2.88 (m, 2H), 1.25-1.60 (m, 8H), 0.88 (m, 3H)；MS：462(M+1)+
51 1- of embodiment (2- ring penta sulfenyl -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea (I A04) preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A04289mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (2- ring penta sulfenyl -4- trifluoromethyl Benzyl) -3- (isoquinolin -5- base) urea (I A04) 312mg, yield：70%.1H NMR (300MHz, DMSO-d6) δ 9.35 (s, 1H), 8.88 (s, 1H), 8.49 (d, J=6.0Hz, 1H), 7.70 (s, 1H), 7.54 (d, J=6.0Hz, 1H), 7.46 (d, J= 7.0Hz, 1H), 7.31 (d, J=7.6Hz, 1H), 7.28 (t, J=7.1Hz, 1H), 7.11 (d, J=7.6Hz, 1H), 6.85 (d, J=7.0Hz, 1H), 6.70 (t, 1H), 4.50 (d, J=4.5Hz, 2H), 2.60 (m, 1H), 1.46-1.94 (m, 8H)； MS：446(M+1)+
52 1- of embodiment (2- cyclohexylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea (I A05) preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A05304mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (2- cyclohexylthio -4- trifluoromethyl Benzyl) -3- (isoquinolin -5- base) urea (I A05) 340mg, yield：74%.1H NMR (300MHz, DMSO-d6) δ 9.40 (s, 1H), 8.84 (s, 1H), 8.43 (d, J=6.0Hz, 1H), 7.64 (s, 1H), 7.49 (d, J=6.0Hz, 1H), 7.41 (d, J= 7.0Hz, 1H), 7.26 (m, overlapped, 2H), 7.06 (d, J=7.6Hz, 1H), 6.80 (d, J=7.0Hz, 1H), 6.50 (t, 1H), 4.4 (d, J=4.5Hz, 2H), 2.48 (m, 1H), 1.43-1.87 (m, 10H)；MS：460(M+1)+
53 1- of embodiment (isoquinolin -5- base) -3- (2- (2- methyl cyclohexane sulfenyl) -4- trifluoromethyl benzyl) urea (I A06) Preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A06319mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (isoquinolin -5- base) -3- (2- (2- Methyl cyclohexane sulfenyl) -4- trifluoromethyl benzyl) urea (I A06) 308mg, yield：65%.1H NMR (300MHz, DMSO-d6) δ 9.20 (s, 1H), 8.80 (s, 1H), 8.37 (d, J=6.0Hz, 1H), 7.61 (s, 1H), 7.43 (d, J=6.0Hz, 1H), 7.35 (d, J=7.0Hz, 1H), 7.25 (d, J=7.6Hz, 1H), 7.18 (t, J=7.1Hz, 1H), 7.03 (d, J=7.6Hz, 1H), 6.84 (d, J=7.0Hz, 1H), 6.70 (t, 1H), 4.50 (d, J=4.5Hz, 2H), 2.49 (m, 1H), 1.27-1.88 (m, 9H), 0.96 (m, 3H)；MS：474 (M+1)+
54 1- of embodiment (isoquinolin -5- base) -3- (2- (4- methyl cyclohexane sulfenyl) -4- trifluoromethyl benzyl) urea (I A07) Preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A07319mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (isoquinolin -5- base) -3- (2- (4- Methyl cyclohexane sulfenyl) -4- trifluoromethyl benzyl) urea (I A07) 322mg, yield：68%.1H NMR (300MHz, DMSO-d6) δ 9.18 (s, 1H), 8.78 (s, 1H), 8.35 (d, J=6.0Hz, 1H), 7.60 (s, 1H), 7.41 (d, J=6.0Hz, 1H), 7.33 (d, J=7.0Hz, 1H), 7.25 (d, J=7.6Hz, 1H), 7.16 (t, J=7.1Hz, 1H), 7.01 (d, J=7.6Hz, 1H), 6.83 (d, J=7.0Hz, 1H), 6.70 (t, 1H), 4.50 (d, J=4.5Hz, 2H), 2.48 (m, 1H), 1.27-1.87 (m, 9H), 0.96 (d, J=7.7Hz, 3H)； MS：474(M+1)+
55 1- of embodiment (2- (4- cyclohexyl sulfenyl) -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea (I A08) Preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A08333mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (2- (4- cyclohexyl sulfenyl) -4- three Methyl fluoride benzyl) -3- (isoquinolin -5- base) urea (I A08) 322mg, yield：66%.1H NMR (300MHz, DMSO-d6) δ 9.21 (s, 1H), 8.80 (s, 1H), 8.39 (d, J=6.0Hz, 1H), 7.60 (s, 1H), 7.45 (d, J=6.0Hz, 1H), 7.36 (d, J=7.0Hz, 1H), 7.25 (m, overlapped, 2H), 7.02 (d, J=7.6Hz, 1H), 6.80 (d, J= 7.0Hz, 1H), 6.45 (t, 1H), 4.45 (d, J=4.5Hz, 2H), 2.45 (m, 1H), 1.27-1.86 (m, 9H), 0.91 (d, J =7.8Hz, 3H)；MS：488(M+1)+
56 1- of embodiment (2- (4- t-butylcyclohexyl sulfenyl) -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea (I A09) preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A09363mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (2- (4- t-butylcyclohexyl sulfenyl) -4- Trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea (I A09) 382mg, yield：74%.1H NMR (300MHz, DMSO-d6) δ 9.44 (s, 1H), 8.86 (s, 1H), 8.45 (d, J=6.0Hz, 1H), 7.66 (s, 1H), 7.50 (d, J=6.0Hz, 1H), 7.42 (d, J=7.0Hz, 1H), 7.27 (m, overlapped, 2H), 7.07 (d, J=7.6Hz, 1H), 6.81 (d, J=7.0Hz, 1H), 6.50 (t, 1H), 4.50 (d, J=4.5Hz, 2H), 2.49 (m, 1H), 1.41-1.88 (m, 10H), 0.95 (d, J= 7.9Hz, 9H)；MS：516(M+1)+
57 1- of embodiment (2- isopentylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea (I A10) preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A10291mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (2- isopentylthio -4- trifluoromethyl Benzyl) -3- (isoquinolin -5- base) urea (I A10) 300mg, yield：67%.1H NMR (300MHz, DMSO-d6) δ 9.15 (s, 1H), 8.87 (s, 1H), 8.46 (d, J=6.0Hz, 1H), 7.67 (s, 1H), 7.51 (d, J=6.0Hz, 1H), 7.46 (d, J= 7.0Hz, 1H), 7.40 (d, J=7.6Hz, 1H), 7.27 (t, J=7.1Hz, 1H), 7.08 (d, J=7.6Hz, 1H), 6.82 (d, J=7.0Hz, 1H), 6.50 (t, 1H), 4.51 (d, J=4.5Hz, 2H), 2.94 (m, 2H), 0.97-1.62 (m, 9H)； MS：448(M+1)+
58 1- of embodiment (isoquinolin -- 5- yl) -3- (2- (2,2,2- trifluoro ethylmercapto group) -4- trifluoromethyl benzyl) urea (I A11) preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A11304mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (isoquinolin -- 5- yl) -3- (2- (2, 2,2- trifluoro ethylmercapto group) -4- trifluoromethyl benzyl) urea (I A11) 349mg, yield：76%.1H NMR (300MHz, DMSO-d6) δ 9.15 (s, 1H), 8.80 (s, 1H), 8.39 (d, J=6.0Hz, 1H), 7.60 (s, 1H), 7.44 (d, J=6.0Hz, 1H), 7.35 (d, J=7.0Hz, 1H), 7.28 (d, J=7.6Hz, 1H), 7.19 (t, J=7.1Hz, 1H), 7.02 (d, J=7.6Hz, 1H), 6.76 (d, J=7.0Hz, 1H), 6.65 (t, 1H), 4.53 (d, J=4.5Hz, 2H), 3.29 (s, 2H)；MS：460(M+ 1)+
59 1- of embodiment (2- (3- bromine rosickyite base) -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea (I A12) system It is standby
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A12345mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (2- (3- bromine rosickyite base) -4- fluoroform Base benzyl) -3- (isoquinolin -5- base) urea (I A12) 352mg, yield：72%.1H NMR (300MHz, DMSO-d6) δ 9.16 (s, 1H), 8.83 (s, 1H), 8.42 (d, J=6.0Hz, 1H), 7.63 (s, 1H), 7.47 (d, J=6.0Hz, 1H), 7.39 (d, J= 7.0Hz, 1H), 7.28 (d, J=7.6Hz, 1H), 7.21 (t, J=7.1Hz, 1H), 7.04 (d, J=7.6Hz, 1H), 6.78 (d, J=7.0Hz, 1H), 6.60 (t, 1H), 4.45 (d, J=4.5Hz, 2H), 2.13-3.49 (m, 6H)；MS：498(M+1)+
60 1- of embodiment (isoquinolin -5- base) -3- (2- (2- benzene oxygen ethylmercapto group) -4- trifluoromethyl benzyl) urea (I A13) Preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A13344mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (isoquinolin -5- base) -3- (2- (2- Benzene oxygen ethylmercapto group) -4- trifluoromethyl benzyl) urea (I A13) 289mg, yield：58%.1H NMR (300MHz, DMSO-d6) δ 9.10 (s, 1H), 8.88 (s, 1H), 8.47 (d, J=6.0Hz, 1H), 7.69 (s, 1H), 7.53 (d, J=6.0Hz, 1H), 7.45 (d, J=7.0Hz, 1H), 7.32 (m, overlapped, 4H), 7.02 (m, 2H), 6.85 (m, 2H), 6.52 (t, 1H), 4.53 (d, J=4.5Hz, 2H), 4.27 (t, J=7.7Hz, 2H), 3.50 (t, J=7.5Hz, 2H)；MS：498(M+1)+
61 1- of embodiment (2- (3- hydroxyl rosickyite base) -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea (I A14) Preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A14279mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (2- (3- hydroxyl rosickyite base) -4- trifluoro Methylbenzyl) -3- (isoquinolin -5- base) urea (I A14) 196mg, yield：45%.1H NMR (300MHz, DMSO-d6) δ 9.16 (s, 1H), 8.90 (s, 1H), 8.49 (d, J=6.0Hz, 1H), 7.69 (s, 1H), 7.53 (d, J=6.0Hz, 1H), 7.45 (d, J=7.0Hz, 1H), 7.30 (m, overlapped, 2H), 7.11 (d, J=7.6Hz, 1H), 6.84 (d, J=7.0Hz, 1H), 6.53 (t, 1H), 4.54 (d, J=4.5Hz, 2H), 4.05 (t, J=6.8Hz, 1H), 3.52 (m, 2H), 2.94 (m, 2H), 1.86 (m, 2H)；MS：436(M+1)+
62 1- of embodiment (2- (3- dimethylamino rosickyite base) -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea (I A15) preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A15307mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (2- (3- dimethylamino rosickyite base) -4- Trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea (I A15) 222mg, yield：48%.1H NMR (300MHz, DMSO-d6) δ 9.25 (s, 1H), 8.85 (s, 1H), 8.43 (d, J=6.0Hz, 1H), 7.68 (s, 1H), 7.49 (d, J=6.0Hz, 1H), 7.41 (d, J=7.0Hz, 1H), 7.35 (d, J=7.6Hz, 1H), 7.26 (t, J=7.1Hz, 1H), 7.06 (d, J=7.6Hz, 1H), 6.80 (d, J=7.0Hz, 1H), 6.62 (t, 1H), 4.49 (d, J=4.5Hz, 2H), 2.90 (t, J=9.2Hz, 2H), 2.26-2.47 (m, 8H), 1.73 (m, 2H)； MS：463(M+1)+
63 1- of embodiment (isoquinolin -5- base) -3- (2- (3- (pyrrolidin-1-yl) rosickyite base) -4- trifluoromethyl benzyl) Urea (I A16) preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A16334mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (isoquinolin -5- base) -3- (2- (3- (pyrrolidin-1-yl) rosickyite base) -4- trifluoromethyl benzyl) urea (I A16) 259mg, yield：53%.1H NMR (300MHz, DMSO-d6) δ 9.18 (s, 1H), 8.78 (s, 1H), 8.37 (d, J=6.0Hz, 1H), 7.58 (s, 1H), 7.42 (d, J= 6.0Hz, 1H), 7.34 (d, J=7.0Hz, 1H), 7.21 (d, J=7.6Hz, 1H), 7.12 (t, J=7.1Hz, 1H), 6.95 (d, J=7.6Hz, 1H), 6.73 (d, J=7.0Hz, 1H), 6.58 (t, 1H), 4.46 (d, J=4.5Hz, 2H), 2.94 (m, 2H), 1.68-2.51 (m, 12H)；MS：489(M+1)+
64 1- of embodiment (isoquinolin -5- base) -3- (2- (3- (piperidin-1-yl) rosickyite base) -4- trifluoromethyl benzyl) urea (ⅠA17) preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A17349mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (isoquinolin -5- base) -3- (2- (3- (piperidin-1-yl) rosickyite base) -4- trifluoromethyl benzyl) urea (I A17) 292mg, yield：58%.1H NMR (300MHz, DMSO- D6) δ 9.18 (s, 1H), 8.87 (s, 1H), 8.42 (d, J=6.0Hz, 1H), 7.67 (s, 1H), 7.51 (d, J=6.0Hz, 1H), 7.43 (d, J=7.0Hz, 1H), 7.30 (d, J=7.6Hz, 1H), 7.25 (t, J=7.1Hz, 1H), 7.08 (d, J= 7.6Hz, 1H), 6.82 (d, J=7.0Hz, 1H), 6.58 (t, 1H), 4.47 (d, J=5.4Hz, 2H), 2.45-2.94 (m, 8H) 1.53-1.73 (m, 8H)；MS：503(M+1)+
65 1- of embodiment (isoquinolin -5- base) -3- (2- (3- (4- methyl piperidine -1- base) rosickyite base) -4- trifluoromethyl Benzyl) urea (I A18) preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 8A18364mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (isoquinolin -5- base) -3- (2- (3- (4- methyl piperidine -1- base) rosickyite base) -4- trifluoromethyl benzyl) urea (I A18) 320mg, yield：62%. 1H NMR (300MHz, DMSO-d6) δ 9.13 (s, 1H), 8.86 (s, 1H), 8.45 (d, J=6.0Hz, 1H), 7.66 (s, 1H), 7.50 (d, J=6.0Hz, 1H), 7.42 (d, J=7.0Hz, 1H), 7.30 (d, J=7.6Hz, 1H), 7.25 (t, J=7.1Hz, 1H), 7.08 (d, J=7.6Hz, 1H), 6.82 (d, J=7.0Hz, 1H), 6.58 (t, 1H), 4.52 (d, J=6.2Hz, 2H), 2.14- 2.94 (m, 8H), 1.34-1.73 (m, 7H), 0.96 (d, J=6.8Hz, 3H)； MS：517(M+1)+
66 1- of embodiment (4- tert-butyl -2- butylthio benzyl) -3- (isoquinolin -5- base) urea (I A19) preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 11A19264mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (4- tert-butyl -2- butylthio benzyl) - 3- (isoquinolin -5- base) urea (I A19) 287mg, yield：68%.1H NMR (300MHz, DMSO-d6) δ 9.18 (s, 1H), 8.82 (s, 1H), 8.41 (d, J=6.0Hz, 1H), 7.41-7.45 (m, 3H), 7.28 (t, J=7.2Hz, 1H), 7.10 (d, J= 8.0Hz, 1H), 7.05 (d, J=7.9Hz, 1H), 6.85 (d, J=7.0Hz, 1H), 6.62 (t, 1H), 4.52 (d, J= 5.8Hz, 2H), 2.90 (t, J=7.6Hz, 2H), 1.44-1.58 (m, 4H), 1.35 (s, 9H), 0.90 (t, J=7.7Hz, 3H)；MS：422(M+1)+
67 1- of embodiment (4- tert-butyl -2- isopentylthio benzyl) -3- (isoquinolin -5- base) urea (I A20) preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 11A20279mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (4- tert-butyl -2- isopentylthio benzyl Base) -3- (isoquinolin -5- base) urea (I A20) 288mg, yield：66%.1H NMR (300MHz, DMSO-d6) δ 9.21 (s, 1H), 8.85 (s, 1H), 8.46 (d, J=6.3Hz, 1H), 7.49 (m, 2H), 7.41 (d, J=7.0Hz, 1H), 7.25 (t, J= 7.2Hz, 1H), 7.13 (d, J=8.2Hz, 1H), 7.05 (d, J=8.0Hz, 1H), 6.80 (d, J=7.0Hz, 1H), 6.58 (t, 1H), 4.50 (d, J=6.4Hz, 2H), 2.88 (t, J=7.6Hz, 2H), 1.59-1.62 (m, 3H), 1.33 (s, 9H), 0.91 (d, J=7.2Hz, 6H)；MS：436(M+1)+
68 1- of embodiment (4- tert-butyl -2- cyclohexylthio benzyl) -3- (isoquinolin -5- base) urea (I A21) preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 11A21291mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (4- tert-butyl -2- cyclohexylthio benzyl Base) -3- (isoquinolin -5- base) urea (I A21) 260mg, yield：58%.1H NMR (300MHz, DMSO-d6) δ 9.20 (s, 1H), 8.84 (s, 1H), 8.46 (d, J=6.3Hz, 1H), 7.49 (m, 2H), 7.39 (d, J=7.0Hz, 1H), 7.27 (t, J= 7.2Hz, 1H), 7.09 (d, J=7.8Hz, 1H), 7.04 (d, J=8.0Hz, 1H), 6.84 (d, J=7.0Hz, 1H), 6.55 (t, 1H), 4.52 (d, J=6.4Hz, 2H), 2.48 (m, 1H), 1.43-1.62 (m, 10H), 1.36 (s, 9H)；MS：448(M+1 )+
69 1- of embodiment (4- tert-butyl -2- (4- methyl cyclohexane sulfenyl) benzyl) -3- (isoquinolin -5- base) urea (I A22) Preparation
Referring to I A01Preparation, with 4 264mg of compound (1mmol), compound 11A22306mg (1.05mmol), three second Amine 0.28ml (2mmol), remaining is operated with I A01Preparation, obtain white solid, i.e. 1- (4- tert-butyl -2- (4- methyl cyclohexane Sulfenyl) benzyl) -3- (isoquinolin -5- base) urea (I A22) 286mg, yield：62%.1H NMR (300MHz, DMSO-d6) δ 9.25 (s, 1H), 8.87 (s, 1H), 8.43 (d, J=6.3Hz, 1H), 7.47 (m, 2H), 7.43 (d, J=7.1Hz, 1H), 7.28 (t, J=7.2Hz, 1H), 7.12 (d, J=7.8Hz, 1H), 7.08 (d, J=8.0Hz, 1H), 6.82 (d, J=7.0Hz, 1H), 6.52 (t, 1H), 4.48 (d, J=6.4Hz, 2H), 2.51 (m, 1H), 1.61-1.87 (m, 5H), 1.27-1.52 (m, 4H), 1.38 (s, 9H), 0.98 (d, J=7.8Hz, 3H)；MS： 462(M+1)+
70 1- of embodiment (2- butylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) thiocarbamide (I B01) preparation
8A is added in the two neck bottles for having magnetic agitation to 50ml01263mg (1mmol), ethyl acetate 30ml, in room temperature Under the conditions of 12 186mg of compound (1mmol) is slowly added dropwise.After being added dropwise, continue to be heated to reflux 5 hours.Restore to reaction solution To room temperature, vacuum distillation, residue is isolated and purified with silica gel column chromatograph, obtains faint yellow solid, i.e. 1- (2- butylthio- 4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) thiocarbamide (I B01) 360mg, yield：80%.1H NMR (300MHz, DMSO- D6) δ 9.18 (s, 1H), 8.85 (s, 1H), 8.44 (d, J=6.3Hz, 1H), 7.65 (s, 1H), 7.49 (d, J=6.6Hz, 1H), 7.41 (d, J=7.0Hz, 1H), 7.26 (m, 2H), 7.08 (d, J=8.0Hz, 1H), 6.80 (d, J=7.0Hz, 1H), 6.48 (t, 1H), 4.72 (d, J=6.8Hz, 2H), 2.94 (t, J=9.0Hz, 2H), 1.44-1.60 (m, 4H), 0.90 (m, 3H)；MS：450(M+1)+
71 1- of embodiment (2- isopentylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) thiocarbamide (I B02) preparation
Referring to I B01Preparation, with compound 8A10277mg (1mmol), 12 186mg of compound (1mmol), remaining behaviour Make with I B01Preparation, obtain faint yellow solid, i.e. 1- (2- isopentylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) Thiocarbamide (I B02) 362mg, yield：78%.1H NMR (300MHz, DMSO-d6) δ 9.21 (s, 1H), 8.83 (s, 1H), 8.42 (d, J=6.2Hz, 1H), 7.63 (s, 1H), 7.47 (d, J=6.4Hz, 1H), 7.39 (d, J=7.0Hz, 1H), 7.24 (m, 2H), 7.04 (d, J=8.0Hz, 1H), 6.78 (d, J=7.0Hz, 1H), 6.46 (t, 1H), 4.70 (d, J=6.6Hz, 2H), 2.94 (t, J=8.8Hz, 2H), 1.59-1.62 (m, 3H), 0.90 (d, J=7.8Hz, 6H)；MS：464(M+1)+
72 1- of embodiment (2- cyclohexylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) thiocarbamide (I B03) preparation
Referring to I B01Preparation, with compound 8A05289mg (1mmol), 12 186mg of compound (1mmol), remaining behaviour Make with I B01Preparation, obtain faint yellow solid, i.e. 1- (2- cyclohexylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) Thiocarbamide (I B03) 357mg, yield：75%.1H NMR (300MHz, DMSO-d6) δ 9.20 (s, 1H), 8.86 (s, 1H), 8.45 (d, J=6.2Hz, 1H), 7.66 (s, 1H), 7.50 (d, J=6.4Hz, 1H), 7.42 (d, J=7.0Hz, 1H), 7.26 (m, 2H), 7.07 (d, J=8.0Hz, 1H), 6.81 (d, J=7.0Hz, 1H), 6.45 (t, 1H), 4.73 (d, J=6.6Hz, 2H), 2.49 (m, 1H), 1.43-1.87 (m, 10H)；MS： 476(M+1)+
73 1- of embodiment (isoquinolin -5- base) -3- (2- (4- methyl cyclohexane sulfenyl) -4- trifluoromethyl benzyl) thiocarbamide (I B04) preparation
Referring to I B01Preparation, with compound 8A07303mg (1mmol), 12 186mg of compound (1mmol), remaining behaviour Make with I B01Preparation, obtain faint yellow solid, i.e. 1- (isoquinolin -5- base) -3- (2- (4- methyl cyclohexane sulfenyl) -4- trifluoro Methylbenzyl) thiocarbamide (I B04) 353mg, yield：72%.1H NMR (300MHz, DMSO-d6) δ 9.18 (s, 1H), 8.78 (s, 1H), 8.37 (d, J=6.2Hz, 1H), 7.58 (s, 1H), 7.42 (d, J=6.4Hz, 1H), 7.34 (d, J=7.0Hz, 1H), 7.19 (m, 2H), 7.01 (d, J=8.0Hz, 1H), 6.74 (d, J=7.0Hz, 1H), 6.39 (t, 1H), 4.65 (d, J= 6.6Hz, 2H), 2.48 (m, 1H), 1.27-1.87 (m, 9H), 0.96 (d, J=7.8Hz, 3H)；MS：490(M+1)+
74 1- of embodiment (4- tert-butyl -2- butylthio benzyl) -3- (isoquinolin -5- base) thiocarbamide (I B05) preparation
Referring to I B01Preparation, with compound 11A19251mg (1mmol), 12 186mg of compound (1mmol), remaining behaviour Make with I B01Preparation, obtain faint yellow solid, i.e. 1- (4- tert-butyl -2- butylthio benzyl) -3- (isoquinolin -5- base) thiocarbamide (ⅠB05) 328mg, yield：75%.1H NMR (300MHz, DMSO-d6) δ 9.17 (s, 1H), 8.84 (s, 1H), 8.45 (d, J= 6.3Hz, 1H), 7.51 (s, 1H), 7.47 (d, J=6.6Hz, 1H), 7.39 (d, J=7.0Hz, 1H), 7.27 (m, 2H), 7.09 (d, J=8.0Hz, 1H), 6.81 (d, J=7.0Hz, 1H), 6.49 (t, 1H), 4.73 (d, J=6.8Hz, 2H), 2.94 (t, J =9.0Hz, 2H), 1.44-1.60 (m, 4H), 1.35 (s, 9H), 0.90 (m, 3H)；MS：438(M+1)+
75 1- of embodiment (4- tert-butyl -2- isopentylthio benzyl) -3- (isoquinolin -5- base) thiocarbamide (I B06) preparation
Referring to I B01Preparation, with compound 11A20265mg (1mmol), 12 186mg of compound (1mmol), remaining behaviour Make with I B01Preparation, obtain faint yellow solid, i.e. 1- (4- tert-butyl -2- isopentylthio benzyl) -3- (isoquinolin -5- base) sulphur Urea (I B06) 307mg, yield：68%.1H NMR (300MHz, DMSO-d6) δ 9.19 (s, 1H), 8.86 (s, 1H), 8.45 (d, J =6.2Hz, 1H), 7.48 (m, 2H), 7.41 (d, J=7.0Hz, 1H), 7.24 (t, J=6.8Hz, 1H), 7.11 (d, J= 8.0Hz, 1H), 7.05 (d, J=7.8Hz, 1H), 6.81 (d, J=7.0Hz, 1H), 6.44 (t, 1H), 4.68 (d, J= 6.6Hz, 2H), 2.94 (t, J=8.4Hz, 2H), 1.59-1.62 (m, 3H), 1.35 (s, 9H), 0.91 (d, J=7.8Hz, 6H)；MS：452(M+1)+
76 1- of embodiment (4- tert-butyl -2- cyclohexylthio benzyl) -3- (isoquinolin -5- base) thiocarbamide (I B07) preparation
Referring to I B01Preparation, with compound 11A21277mg (1mmol), 12 186mg of compound (1mmol), remaining behaviour Make with I B01Preparation, obtain faint yellow solid, i.e. 1- (4- tert-butyl -2- cyclohexylthio benzyl) -3- (isoquinolin -5- base) sulphur Urea (I B07) 306mg, yield：66%.1H NMR (300MHz, DMSO-d6) δ 9.15 (s, 1H), 8.83 (s, 1H), 8.45 (d, J =6.2Hz, 1H), 7.47 (m, 2H), 7.39 (d, J=6.8Hz, 1H), 7.23 (t, J=7.0Hz, 1H), 7.10 (d, J= 7.2Hz, 1H), 7.03 (d, J=7.4Hz, 1H), 6.78 (d, J=7.0Hz, 1H), 6.52 (t, 1H), 4.68 (d, J= 6.6Hz, 2H), 2.49 (m, 1H), 1.43-1.87 (m, 10H), 1.35 (s, 9H)；MS：464(M+1)+
77 1- of embodiment (4- tert-butyl -2- (4- methyl cyclohexane sulfenyl) benzyl) -3- (isoquinolin -5- base) thiocarbamide (I B08) Preparation
Referring to I B01Preparation, with compound 11A22291mg (1mmol), 12 186mg of compound (1mmol), remaining behaviour Make with I B01Preparation, obtain faint yellow solid, i.e. 1- (4- tert-butyl -2- (4- methyl cyclohexane sulfenyl) benzyl) -3- (isoquinoline Quinoline -5- base) thiocarbamide (I B08) 291mg, yield：61%.1H NMR (300MHz, DMSO-d6) δ 9.17 (s, 1H), 8.82 (s, 1H), 8.41 (d, J=6.2Hz, 1H), 7.46 (m, 2H), 7.38 (d, J=6.8Hz, 1H), 7.22 (t, J=7.0Hz, 1H), 7.07 (d, J=7.0Hz, 1H), 7.03 (d, J=6.9Hz, 1H), 6.77 (d, J=7.0Hz, 1H), 6.48 (t, 1H), 4.67 (d, J=6.6Hz, 2H), 2.46 (m, 1H), 1.27-1.87 (m, 9H), 1.35 (s, 9H), 0.94 (d, J=8.2Hz, 3H)； MS：478(M+1)+
I A containing activating agent of embodiment 7808Tablet：
Supplementary material is mixed according to a conventional method, is pelletized, dry, tabletting.
79 pharmacological experiment data of embodiment：
1. part of compounds of the present invention screens the antagonistic activity of TRPV1 receptor
(i) capsaicin-activated analysis
Compound uses Ca to the activity of the function of TRPV1 receptor2+The fluorescent dye of sensitivity and steadily expression people TRPV1 CHO cell line, with according to Ca2+The Molecular Devices Flexstation II of flow analysis is determined.
Preparation tests compound as stock solution and tests the activity of several log units in DMSO.It is used in analysis Further diluted compounds are it needs to be determined that IC in assay buffer50。
Under the control of CMV promoter, 24 hours before analysis, by CHO-K1 cell, the recombined human steadily expressed In the 96 hole plate analysis plates (BD Biosciences) of TRPV1, inoculation (20000 cells/wells) and black clear bottom.Cell quilt Maintain 37 DEG C/5%CO2In normal growth medium (Dulbecco ' s Modified Eagles medium).Before analysis, carefully With analysis buffer, (100 μ l, HBSS- buffered saline pH7.4 supplement 10mM glucose, 2mM CaCl to born of the same parents2,1mM MgCl2With 0.5mM Probenicid) it washed once.Then it is used in the Fluo-4AM of the 100 μ l prepared in analysis buffer in the dark In 37 DEG C/5%CO2Incubated cell 1 hour.With the test compound of suitable concentration or independent buffer preincubation (10 minutes, RT before), cell is washed more than twice to remove excessive dyestuff with excessive buffer, cell is then placed on FLIPR equipment Reader chamber in.50 μ l compound solutions are added into cell at the 10th second of experiment operation.Then it was lagged at 3 minutes, In the 190th second 50 μ l capsaicines of addition to attack TRPV1 receptor.The time span of experiment operation is 240 seconds.It was run in experiment Fluorescence reading was carried out with 1 to 5 second interval in journey.It calculates from 190 seconds until the Relative fluorescence units that experiment terminates (subtract basis Value) peak value increment, be expressed as to 0.05 μM of capsaicine (control) response percentage.Use GraphPad Prism Four parameter logistic Hill's equations in (GraphPad Software, Inc., San Diego, Calif) carry out the curve of data Fitting calculates IC50It is worth (result shown in table 1).
The compound tested in above-mentioned analysis has the IC of about 4nM to about 250nM50.For example, chemical combination described herein Object shows about 4nM to about 230nM, or about 4nM to about 100nM.
(iii) rat telemetering regulation：
Male, Sprague Dawley rat, is anaesthetized with sevoflurane by 225-250 grams.Rat is placed on heating cushion simultaneously And it is covered with aseptic operation list.Do midline abdominal abdominal incision and using sterile cot ton tip applicator gently move interior tissue and Make abdominal aorta exposure to transplant telemetering conduit (Data Sciences International；TL11M2-C50-PXT).With Diffenbach pincers prevent the blood flow (5-7 minutes) to lower limb temporarily to allow for be inserted into abdominal aorta telemetering conduit.One Denier insertion, asepsis cellulose patch is placed on conduit/aorta and is fixed using a small amount of tissue adhesive.One Denier conduit, which is placed, to be completed, and is removed and is clamped and make restoration of blood flow to lower limb.Transmitter is placed in intraperitoneal cavity.Transmitter sutures rib quilt It is in place to be fixed to sew up abdomen suture.It is taken by skin closure and from sevoflurane using aseptic wound folder Animal out.Give Buprenex (0.01mg/ml s.c.；Phoenix) so as to Postoperative Analgesia After.Animal is maintained on heating cushion It until walking about, then individually accommodates, freely absorbs food and water.After the transfer after 7-10 days, surgical closure device is removed.Make Rat has 2 week recovery time after surgery, then with test compound processing.It is administered orally in time zero, wherein rat receives The compound for being dissolved in excipient of the excipient of single dose or 100 μm of ol/kg dosage.During entire research (24 hours), often 15 minutes record measured temperatures.
Table 1 shows the compound relative to excipient, tested for big after administration (100 μm of ol/kg) 1 hour Mouse core temperature as a result, and hTRPV1 (capsaicine) IC50Value.
Table 1
Comparative example
According to the test method of embodiment 79, above-mentioned test is carried out to the compound of control group (shown in formula II).
The activity data of control group compound is：IC50(nM) 1281, Δ temperature (DEG C) 2.2, with chemical combination provided by the invention The effect of object is compared, and compound provided by the invention extremely significant (P < 0.01) is better than control group.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered It is considered as protection scope of the present invention.

Claims (8)

1. a kind of compound or pharmaceutically acceptable salt thereof, which is characterized in that the general formula of the compound is as shown in formula I：
Wherein, X is selected from N or CH；
Y is selected from N or CH；
Z is selected from oxygen or sulphur；
N=1-3；
R1Selected from trifluoromethyl, tert-butyl；
R2Selected from CH3CH2CH2CH2S-、CH3CH2CH2CH2CH2S-、CH3CH2CH2CH2CH2CH2S-、 (CH3)2CHCH2CH2S-、CF3CH2S-、BrCH2CH2CH2S-、 HOCH2CH2CH2S-、(CH3)2NCH2CH2CH2S-、
The compound is selected from：
1- (2- butylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (isoquinolin -5- base) -3- (2- penta sulfenyl -4- trifluoromethyl benzyl) urea；
1- (the own sulfenyl -4- trifluoromethyl benzyl of 2-) -3- (isoquinolin -5- base) urea；
1- (2- ring penta sulfenyl -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (2- cyclohexylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (isoquinolin -5- base) -3- (2- (2- methyl cyclohexane sulfenyl) -4- trifluoromethyl benzyl) urea；
1- (isoquinolin -5- base) -3- (2- (4- methyl cyclohexane sulfenyl) -4- trifluoromethyl benzyl) urea；
1- (2- (4- cyclohexyl sulfenyl) -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (2- (4- t-butylcyclohexyl sulfenyl) -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (2- isopentylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (isoquinolin -- 5- yl) -3- (2- (2,2,2- trifluoro ethylmercapto group) -4- trifluoromethyl benzyl) urea；
1- (2- (3- bromine rosickyite base) -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (isoquinolin -5- base) -3- (2- (2- benzene oxygen ethylmercapto group) -4- trifluoromethyl benzyl) urea；
1- (2- (3- hydroxyl rosickyite base) -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (2- (3- dimethylamino rosickyite base) -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) urea；
1- (isoquinolin -5- base) -3- (2- (3- (pyrrolidin-1-yl) rosickyite base) -4- trifluoromethyl benzyl) urea；
1- (isoquinolin -5- base) -3- (2- (3- (piperidin-1-yl) rosickyite base) -4- trifluoromethyl benzyl) urea；
1- (isoquinolin -5- base) -3- (2- (3- (4- methyl piperidine -1- base) rosickyite base) -4- trifluoromethyl benzyl) urea；
1- (4- tert-butyl -2- butylthio benzyl) -3- (isoquinolin -5- base) urea；
1- (4- tert-butyl -2- isopentylthio benzyl) -3- (isoquinolin -5- base) urea；
1- (4- tert-butyl -2- cyclohexylthio benzyl) -3- (isoquinolin -5- base) urea；
1- (4- tert-butyl -2- (4- methyl cyclohexane sulfenyl) benzyl) -3- (isoquinolin -5- base) urea；
1- (2- butylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) thiocarbamide；
1- (2- isopentylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) thiocarbamide；
1- (2- cyclohexylthio -4- trifluoromethyl benzyl) -3- (isoquinolin -5- base) thiocarbamide；
1- (isoquinolin -5- base) -3- (2- (4- methyl cyclohexane sulfenyl) -4- trifluoromethyl benzyl) thiocarbamide；
1- (4- tert-butyl -2- butylthio benzyl) -3- (isoquinolin -5- base) thiocarbamide；
1- (4- tert-butyl -2- isopentylthio benzyl) -3- (isoquinolin -5- base) thiocarbamide；
1- (4- tert-butyl -2- cyclohexylthio benzyl) -3- (isoquinolin -5- base) thiocarbamide；
1- (4- tert-butyl -2- (4- methyl cyclohexane sulfenyl) benzyl) -3- (isoquinolin -5- base) thiocarbamide.
2. compound or pharmaceutically acceptable salt thereof according to claim 1, which is characterized in that the pharmaceutical salts include and following sour shape At addition salts：Hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, Malaysia Acid, benzene sulfonic acid, succinic acid or its corresponding salt.
3. the preparation method of compound according to claim 1 or 2, which is characterized in that with 5- nitroisoquinoline be starting Raw material, methanol solution obtains 5- aminoisoquinoline through Pd/C catalytic hydrogenation, then reacts to obtain with phenyl chloroformate in acetonitrile Compound 4 --- isoquinolin-5- base-phenyl carbamate；The chloro- 4- trifluoromethylbenzonitrile of 2- or the chloro- 4- tert-butyl benzene first of 2- Nitrile and mercaptan are in 6 ether of 18- crown-, the N of potassium carbonate, and reaction generates corresponding compound 7 or changes in N '-dimethyl acetamide solution Close object 10；The tetrahydrofuran solution of the compound 7 or compound 10 obtains corresponding benzylamine through borane reduction --- compound 8 Or compound 11；The compound 8 or the compound 11 react to obtain target compound with the compound 4.
4. the preparation method of compound according to claim 1 or 2, which is characterized in that with 5- nitroisoquinoline be starting Raw material, methanol solution obtain 5- aminoisoquinoline through Pd/C catalytic hydrogenation, then react to obtain compound with carbon disulfide 12 --- 5- isothiocyano isoquinolin；The chloro- 4- trifluoromethylbenzonitrile of 2- or the chloro- 4- tert-butyl benzene formonitrile HCN of 2- and mercaptan are in 18- 6 ether of crown-, the N of potassium carbonate, reaction generates corresponding compound 7 or compound 10 in N '-dimethyl acetamide solution；Describedization The tetrahydrofuran solution for closing object 7 or the compound 10 obtains corresponding benzylamine through borane reduction --- compound 8 or compound 11；The compound 8 or the compound 11 react to obtain target compound with the compound 12.
5. compound made from preparation method according to claim 3 or 4.
6. compound or pharmaceutically acceptable salt thereof according to claim 1 or 2 or compound according to claim 5 or its medicine The application in TRPV1 antagonist or TRPV1 agonist drug is being prepared with salt.
7. compound or pharmaceutically acceptable salt thereof according to claim 1 or 2 or compound according to claim 5 or its medicine The application in analgesic is being prepared with salt.
8. a kind of TRPV1 agonist drug, which is characterized in that including compound or pharmaceutically acceptable salt thereof of any of claims 1 or 2 or root According to the compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary material described in claim 5.
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