CN106795149B

CN106795149B - Double cyclosubstituted benzenesulfonamide derivatives, its preparation method and purposes pharmaceutically

Info

Publication number: CN106795149B
Application number: CN201680003154.3A
Authority: CN
Inventors: 兰炯; 周福生; 赵金柱; 许峰; 施霞; 谢婧; 徐慧; 王莉肖
Original assignee: Shanghai Hai Yan Pharmaceutical Technology Co Ltd; Yangtze River Pharmaceutical Group Co Ltd
Current assignee: Shanghai Hai Yan Pharmaceutical Technology Co Ltd; Yangtze River Pharmaceutical Group Co Ltd
Priority date: 2015-05-05
Filing date: 2016-05-05
Publication date: 2019-09-24
Anticipated expiration: 2036-05-05
Also published as: CN106795149A; WO2016177340A1

Abstract

The present invention relates to double cyclosubstituted benzenesulfonamide derivatives, its preparation method and purposes pharmaceutically.Specifically, the invention discloses formula (I) compound or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, and its preparation method and application, the definition of each group is detailed in specification and claims in formula.

Description

Double cyclosubstituted benzenesulfonamide derivatives, its preparation method and purposes pharmaceutically

Technical field

The invention belongs to pharmaceutical technology fields.Specifically, the present invention is more particularly directed to a kind of double cyclosubstituted benzsulfamides to spread out Biology and preparation method thereof and application and drug prepared therefrom as sodium-ion channel (especially Nav1.7) inhibitor Composition and Pharmaceutical composition.

Background technique

Recently, Cox of Britain etc. reports the SCN9A gene in the coded voltage gate channel Nav1.7 for the first time on Nature Mutation leads to the unexpected result of study of hereditary individual indifference to pain.The individual of the genetic mutation is congenital to lose the pain sensation, but body Other functions it is completely normal, furthermore it has recently been demonstrated that expression DRG neuron the valtage-gated channel Nav1.7 participate in The generation of pain signal simultaneously plays the incoming function gate of control pain sensation signal.The research prompts the channel Nav1.7 that may become choosing Selecting property treats pain and drug target without side-effects.

Nav1.7 (PN1, SCN9A) VGSC is sensitive to the blocking of tetraodotoxin, is mainly expressed in tip sympathetic neuron And sensory neuron.SCN9A gene is replicated by a variety of species (including the mankind, rat and rabbit), and shows people and rat base Amino acid because between has about 90% consistency.

More and more physical evidences show Nav1.7 in a variety of pain status (including acute, chronic, inflammatory and/or mind Through property pain) in play the part of important role, in the mankind, Nav1.7 protein accumulation especially causes pain in neuroma Neuroma.The increased mutation (whether heredity or sporadic) of Nav1.7 function has been considered being related to primary erythromelalgia (a kind of feature is the cusalgia of four limbs and the disease of inflammation) and sudden extreme pain disease.Related non-selective sodium channel blocks Agent lidocaine and mexiletine, which can mitigate the symptom of heredity erythromelalgia and carbamazepine, effectively to lower PEPD's The number of invasion and the report result of severity are consistent with above-mentioned observation.Other cards of Nav1.7 role in pain According to the phenotype for the mutation that the function of being found in SCN9A gene is lost.The function of will lead to SCN9A gene has been displayed in subsequent research It loses and many different mutation of CIP phenotype.

Since Nav1.7 is specifically expressed in DRG sensory neuron without other in cardiac muscle cell and central nervous system etc. Tissue expression, therefore its specific blockage agent is researched and developed for treating chronic pain, it is not only possible to curative effect is improved, and side effect also can be significantly It reduces, and the selective depressant of Nav1.7 ion channel may be used with nearly the treatment of various pain.

Due to many patients for suffering from acute or chronic pain disease current Pain treatment is responded it is poor, and usually to Ah Tablet preparation generates resistance and insensitivity.In addition, the effect of sodium channel blockers used at present are for above-mentioned disease condition exists Largely limited by many side effects.These side effects include various CNS disorders, such as eye-blurred, dizziness, nausea And calmness, and the more potentially arrhythmia cordis and heart failure of life-threatening.

Therefore, in view of the limited effect of currently available medicament and unacceptable side effect, there is an urgent need to develop more pacify Complete effective antalgesic, makes it have compared with high effect and less side effect.And Nav1.7 ion channel is exploitation without additive town The important target of pain drug, Nav1.7 ion channel high selectivity inhibitor can be used for extensive pain therapy, therefore develop Novel Nav1.7 ion channel high selectivity inhibitor is very necessary.

Summary of the invention

It applies the object of the present invention is to provide a kind of Nav1.7 ion channel high selectivity inhibitor and its in medicine.

First aspect present invention provides a kind of formula (I) compound represented or its pharmaceutically acceptable salt, solvation Object, stereoisomer or prodrug:

In formula,

R₁、R₂、R₃、R₄It is each independently hydrogen, hydroxyl, CN, NO₂, halogen ,-NR_aR_b、C_1-20Alkyl, C_3-20Naphthenic base, C_3-20Cycloalkyloxy, C_2-20Alkenyl, C_2-20Alkynyl, C_1-20Alkoxy ,-CHO ,-CO- (C_1-20Alkyl) ,-CO- (C_6-20Aryl), C_6-20Aryl ,-CONR_aR_b、-C(O)O-(C_1-20Alkyl) ,-OC (O)-(C_1-20Alkyl) ,-SO₂-(C_1-20Alkyl) or-SO₂- (C_6-20Aryl)；

R₅For 5 or 6 unit monocycle heteroaryls ,-CO- (C_1-20Alkyl) or C_3-20Naphthenic base；

L₁For a key or-(CH₂)_r1-；

L₂For a key or-(CH₂)_r2-；

It is 1,2 or 3 that r1, r2, which are each independently,；

L₁Or L₂In 1,2 or 3-CH₂Optionally and each independently by-C (R^yR^x)-、-NR^yC (O)-, sub- cyclopropyl Base ,-C (O) NR^y-、-N(R^y)SO₂-、-SO₂N(R^y)-、-S-、-S(O)-、-SO₂-、-OC(O)-、-C(O)O-、-O-、-N(R^y)- Or-C (O)-displacement；Wherein, R^y、R^xIt is each independently hydrogen or C_1-20Alkyl；

X is key, a NR^z, O or S；R^zFor hydrogen or C_1-10Alkyl；

L₂With it is bicyclic in any annular atom of any one ring connect；

For singly-bound or double bond；

Z₁For-C (R¹¹R¹²)-、-O-、-C(O)-、-C(R¹³)=or-N=；Wherein R¹¹、R¹²Be each independently hydrogen or C_1-20Alkyl；Or R¹¹、R¹²3 to 7 unit monocycles are collectively formed with the carbon atom being connect；R¹³For hydrogen, C_1-20Alkyl or halogen；

Z₂For-C (O)-,-C (R²¹R²²)-、-N(R²³)-,=N- ,=C (R²⁴)-or-O-；Wherein R²¹、R²²Each independently For hydrogen or C_1-20Alkyl；R²³For hydrogen, C_1-20Alkyl or-CO- (C_1-20Alkyl)；R²⁴For hydrogen, C_1-20Alkyl or halogen；

Work as L₂With Z₂When being connected, Z₂It is not-C (O)-,=N- or-O-；Z₂For-N (R²³)-or=C (R²⁴)-when, R²³Or R²⁴It is not present；

Z₃For-N (R³¹)-、-CH₂Or-C (R³²)=；Wherein R³¹For hydrogen or C_1-20Alkyl；R³²For hydrogen, C_1-20Alkyl or halogen Element；

Work as L₂With Z₃When being connected, Z₃It is not-CH₂-；Z₃For-N (R³¹)-or-C (R³²)=when, R³¹Or R³²It is not present；

Z₄For a key ,-N (R⁴¹)-、-CH₂,=C (R⁴²)-or=N-；Wherein R⁴¹For hydrogen or C_1-20Alkyl；R⁴²For hydrogen, C_1-20Alkyl or halogen；

Work as L₂With Z₄When being connected, Z₄It is not a key ,-CH₂Or=N-；Z₄For-N (R⁴¹)-or=C (R⁴²)-when；R⁴¹Or R⁴²It is not present；

A ring is formula (A-1), formula (A-2), structure shown in formula (A-3) or formula (A-4):

Wherein, W₁、W₂、W₃、W₄It is each independently N or CH；And W₁、W₂、W₃And W₄It is not simultaneously N；U₁、U₂It is respectively independent Ground is N or CH；U₃For CH₂, N, O or S；(R_a’)_mFor any position on 5- or 6-membered ring hydrogen by m R_a' replace, m 0,1, 2,3 or 4, each R_a' identical or different, it is each independently hydrogen, halogen, nitro, hydroxyl, cyano, C_6-20It is aryl, deuterium, deuterated C_1-20Alkyl, C_1-20Alkyl, halogenated C_1-20Alkyl, C_1-20Alkoxy, halogenated C_1-20Alkoxy, C_3-20Naphthenic base, halogenated C_3-20Ring Alkyl, C_3-20Cycloalkyloxy, halogenated C_3-20Cycloalkyloxy, C_2-20Alkenyl, halogenated C_2-20Alkenyl, C_2-20Alkynyl, halogenated C_2-20Alkynyl, C_1-20Alkylthio group, halogenated C_1-20Alkylthio group, C_1-20Alkyl amino, halogenated C_1-20Alkyl amino, mercaptan, 3 yuan to 20 yuan of heterocycle alkane Base, 3 yuan to 20 yuan of Heterocyclylalkyl oxygroup, C_3-20Cycloalkylthio, halogenated C_3-20Cycloalkylthio, 3 yuan to 20 yuan of Heterocyclylalkyl sulphur Base, oxo base, C_1-20Hydroxyalkyl, carboxyl ,-NR_aR_b、-C(O)NR_aR_b、-N(R_a)C(O)-(C_1-20Alkyl) ,-N (R_a)SO₂- (C_1-20Alkyl) ,-SO₂N(R_aR_b)、-C(O)O-(C_1-20Alkyl) ,-CHO ,-OC (O)-(C_1-20Alkyl) ,-SO₂-(C_1-20Alkane Base) ,-SO₂-(C_6-20Aryl) ,-CO- (C_6-20Aryl), 5 or 6 unit monocycle heteroaryl or 8 to 10 membered bicyclic heteroaryls；

R_a、R_bIt is each independently hydrogen, C_1-20Alkyl, C_3-20Naphthenic base or C_6-20Aryl.

In another preferred example, A ring is formula (A-1) structure.

In another preferred example, W₁、W₂、W₃、W₄It is CH.

In another preferred example, W₁、W₂、W₃、W₄It is each independently N or CH；And W₁、W₂、W₃、W₄In one be N.

In another preferred example, W₁、W₃、W₄It is CH；And W₂For N.

In another preferred example, W₁、W₂、W₄It is CH；And W₃For N.

In another preferred example, W₁、W₂、W₃、W₄It is each independently N or CH；And W₁、W₂、W₃、W₄In two be N.

In another preferred example, R₂、R₄For hydrogen.

In another preferred example, R₃For hydrogen, fluorine or chlorine.

In another preferred example, R₁For fluorine.

In another preferred example, R₁For fluorine；R₂、R₄For hydrogen；R₃For hydrogen or chlorine.

In another preferred example, L₂It is connect with any carbon atom on A ring.

In another preferred example, L₂With Z₁、Z₂、Z₃Or Z₄Connection.

In another preferred example, 5 or 6 unit monocycle heteroaryls be formula a, formula b, structure shown in formula c or formula d:

In formula, A₁For S or O；A₂、A₃、A₄It is each independently N or CR_a"；B₂For S or O；B₁、B₃、B₄It is each independently N Or CR_b"；C₃For S or O；C₁、C₂、C₄It is each independently N or CR_c"；D₁、D₂、D₃It is each independently N or CR_d"；Wherein, R_a”、 R_b”、R_c”、R_d" it is each independently hydrogen, fluorine, chlorine, C_1-3Alkyl, C_3-6Naphthenic base.

In another preferred example, 5 or 6 unit monocycle heteroaryls are selected from:

In another preferred example,For structure shown in formula (I-a):

In formula, Z₁For-C (R¹¹R¹²)-、-O-、-C(O)-、-C(R¹³)=or-N=；Z₂For-C (O)-,-C (R²¹R²²)-、-N (R²³)-,=N- or=C (R²⁴)-；Z₃For-N (R³¹)-or-CH₂-；For singly-bound or double bond；R_a’、m、W₁、W₂、W₃、 W₄、R¹¹、R¹²、R¹³、R²¹、R²²、R²³、R²⁴、R³¹As defined above.

In another preferred example, L₂With Z₁、Z₂Or Z₃Connection.

In another preferred example, L₂With W₁、W₂、W₃、W₄In any carbon atom connection.

In another preferred example,For singly-bound；Z₁For-C (R¹¹R¹²)-,-O- or-C (O)-；Z₂For-C (O)-or- C(R²¹R²²)-；Z₃For-N (R³¹)-or-CH₂-。

In another preferred example,For double bond；Z₁For-C (R¹³)=or-N=；Z₂For=N- or=C (R²⁴)-； Z₃For-N (R³¹)-or-CH₂-。

In another preferred example,For singly-bound；Z₁For-C (R¹¹R¹²)-or-C (O)-；Z₂For-N (R²³)-；Z₃For- CH₂-。

In another preferred example, formula (I-a) is structure shown in formula (I-a-1) or formula (I-a-2):

In formula, Z₁₁For-C (R¹¹R¹²)-、-O-、-C(O)-、-C(R¹³)=or-N=；Z₁₂For-C (R¹¹R¹²)-or-C (O)-； Z₂For-C (O)-,-C (R²¹R²²)-,=N- or=C (R²⁴)-；Z₃For-CH₂-；For singly-bound or double bond；R_a’、m、R¹¹、 R¹²、R¹³、R²¹、R²²、R²⁴As defined above；W₁₁、W₂₁、W₃₁、W₄₁、W₁₂、W₂₂、W₃₂、W₄₂It is each independently N or CH；And W₁₁、 W₂₁、W₃₁、W₄₁It is not simultaneously N；W₁₂、W₂₂、W₃₂、W₄₂It is not simultaneously N.

In another preferred example, W₁₁、W₂₁、W₃₁、W₄₁It is CH.

In another preferred example, W₁₁、W₂₁、W₃₁、W₄₁In one be N.

In another preferred example, W₁₁、W₂₁、W₄₁It is CH；And W₃₁For N.

In another preferred example, W₁₁、W₂₁、W₃₁、W₄₁In two be N.

In another preferred example, W₁₂、W₂₂、W₃₂、W₄₂It is CH.

In another preferred example, W₁₂、W₂₂、W₃₂、W₄₂In one be N.

In another preferred example, W₁₂、W₃₂、W₄₂It is CH；And W₂₂For N.

In another preferred example, W₁₂、W₂₂、W₄₂It is CH；And W₃₂For N.

In another preferred example, W₁₂、W₂₂、W₃₂、W₄₂In two be N.

In another preferred example, in formula (I-a-1),For singly-bound；Z₁₁For-C (R¹¹R¹²)-,-O- or-C (O)-； Z₂For-C (O)-；R¹¹、R¹²As defined above.(preferably R¹¹、R¹²It is each independently hydrogen or methyl or R¹¹With R¹²With connect Cyclopropylidene is collectively formed in the carbon atom connect.)

In another preferred example, in formula (I-a-1),For singly-bound；Z₁₁For-C (R¹¹R¹²)-；Z₂For-C (R²¹R²²)-；R¹¹、R¹²、R²¹、R²²As defined above.(preferably R¹¹、R¹²、R²¹、R²²It is each independently hydrogen or methyl or R¹¹ With R¹²、R²¹With R²²Cyclopropylidene optionally is collectively formed with the carbon atom being connect respectively.)

In another preferred example, in formula (I-a-1),For double bond；Z₁₁For-C (R¹³)=or-N=；Z₂For=N- Or=C (R²⁴)-；R¹³、R²⁴As defined above.(preferably R¹³、R²⁴It is each independently hydrogen, methyl, ethyl, propyl, isopropyl Base, fluorine or chlorine)

In another preferred example, in formula (I-a-2), Z₁₂For-C (R¹¹R¹²)-or-C (O)-；Z₃For-CH₂-。

In another preferred example, L₁、L₂For-(CH₂)-；X is NR^z, O or S；And L₁Or L₂In-CH₂Optionally and respectively Independently by-C (R^yR^x)-、-NR^yC (O)-, cyclopropylidene ,-C (O) NR^y-、-N(R^y)SO₂-、-SO₂N(R^y)-、-S-、-S (O)-、-SO₂-、-OC(O)-、-C(O)O-、-O-、-N(R^y)-or-C (O)-displacement；Wherein, R^z、R^y、R^xIt is each independently hydrogen Or C_1-20Alkyl.

In another preferred example, L₁、L₂For-(CH₂)-；X is NR^z, O or S；And L₁Or L₂In-CH₂Optionally and respectively Independently by-C (R^yR^x)-,-O- or-C (O)-displacement；Wherein, R^z、R^y、R^xBe each independently hydrogen, methyl, ethyl, propyl or Isopropyl.

In another preferred example, L₁、L₂For-(CH₂)-；X is NR^z, O or S；And only L₂In-CH₂By-C (R^yR^x)-、- NR^yC (O)-, cyclopropylidene ,-C (O) NR^y-、-N(R^y)SO₂-、-SO₂N(R^y)-、-S-、-S(O)-、-SO₂-、-OC(O)-、-C (O)O-、-O-、-N(R^y)-or-C (O)-displacement；Wherein, R^z、R^y、R^xIt is each independently hydrogen or C_1-20Alkyl.

In another preferred example, L₁、L₂For-(CH₂)-；X is NR^z, O or S；And only L₂In-CH₂By-C (R^yR^x)-、-O- Or-C (O)-displacement；Wherein, R^z、R^y、R^xIt is each independently hydrogen, methyl, ethyl, propyl or isopropyl.

In another preferred example, X, L₁、L₂For a key.

In another preferred example, L₁、L₂For a key；X is NR^z, O or S；Wherein, R^zFor hydrogen or C_1-20Alkyl (preferred R^z For hydrogen, methyl, ethyl, propyl or isopropyl).

In another preferred example, X, L₁For a key；L₂For-(CH₂)-；L₂In-CH₂By-C (R^yR^x)-、-NR^yC (O)-, cyclopropylidene ,-C (O) NR^y-、-N(R^y)SO₂-、-SO₂N(R^y)-、-S-、-S(O)-、-SO₂-、-OC(O)-、-C(O) O-、-O-、-N(R^y)-or-C (O)-displacement；Wherein, R^y、R^xIt is each independently hydrogen or C_1-20Alkyl.

In another preferred example, X, L₁For a key；L₂For-(CH₂)-；L₂In-CH₂By-C (R^yR^x)-,-O- or-C (O)-displacement；Wherein, R^yFor hydrogen, methyl, ethyl, propyl or isopropyl；R^xFor methyl, ethyl, propyl or isopropyl.

In another preferred example, X, L₁For a key；L₂For-(CH₂)-。

In another preferred example, L₁For a key；X is NR^z, O or S；L₂For-(CH₂)-；L₂In-CH₂By-C (R^yR^x)-、-NR^yC (O)-, cyclopropylidene ,-C (O) NR^y-、-N(R^y)SO₂-、-SO₂N(R^y)-、-S-、-S(O)-、-SO₂-、-OC (O)-、-C(O)O-、-O-、-N(R^y)-or-C (O)-displacement；Wherein, R^z、R^y、R^xIt is each independently hydrogen or C_1-20Alkyl.

In another preferred example, L₁For a key；X is NR^z, O or S；L₂For-(CH₂)-；L₂In-CH₂By-C (R^yR^x)- Or-C (O)-displacement；Wherein, R^z、R^y、R^xIt is each independently hydrogen, methyl, ethyl, propyl or isopropyl.

In another preferred example, L₁For a key；X is NR^z, O or S；L₂For-(CH₂)-；L₂In-CH₂By-C (R^yR^x)- Displacement；Wherein, R^z、R^yIt is each independently hydrogen, methyl, ethyl, propyl or isopropyl；R^xFor methyl, ethyl, propyl or isopropyl Base.

In another preferred example, L₁For a key；X is NR^z, O or S；L₂For-(CH₂)-；R^zFor hydrogen, methyl, ethyl, propyl Or isopropyl.

In another preferred example,For knot shown in formula (I-b-1), formula (I-b-2) or formula (I-b-3) Structure:

In formula, Z_1a、Z_1b、Z_1cIt is each independently-O- ,-C (R¹¹R¹²)-；Z_2a、Z_2b、Z_3a、Z_3c、Z_4b、Z_4cIt is respectively independent Ground is-C (R²¹R²²)-；R_a’、m、R¹¹、R¹²、R²¹、R²²As defined above；W_1a、W_2a、W_3a、W_4a、W_1b、W_2b、W_3b、W_4b、W_1c、W_2c、 W_3c、W_4cIt is each independently N or CH；And W_1a、W_2a、W_3a、W_4aIt is not simultaneously N；W_1b、W_2b、W_3b、W_4bIt is not simultaneously N；W_1c、W_2c、 W_3c、W_4cIt is not simultaneously N.

In another preferred example, Z_1a、Z_1b、Z_1cIt is each independently-O- or-CH₂-。

In another preferred example, Z_2a、Z_2b、Z_3a、Z_3c、Z_4b、Z_4cIt is each independently-CH₂-。

In another preferred example, W_1a、W_2a、W_3a、W_4aIt is CH.

In another preferred example, W_1a、W_2a、W_3a、W_4aIn one be N.

In another preferred example, W_1a、W_2a、W_3a、W_4aIn two be N.

In another preferred example, W_1b、W_2b、W_3b、W_4bIt is CH.

In another preferred example, W_1b、W_2b、W_3b、W_4bIn one be N.

In another preferred example, W_1b、W_2b、W_3b、W_4bIn two be N.

In another preferred example, W_1c、W_2c、W_3c、W_4cIt is CH.

In another preferred example, W_1c、W_2c、W_3c、W_4cIn one be N.

In another preferred example, W_1c、W_2c、W_3c、W_4cIn two be N.

In another preferred example,For formula (I-b-4), formula (I-b-5), formula (I-b-6) or formula (I-b- 7) structure shown in:

In formula, Z_1d、Z_1eIt is each independently-C (R¹³)=or-N=；Z_2d、Z_2eIt is each independently=N- or=C (R²⁴)-；Z_1f、Z_1g、Z_2f、Z_2g、Z_3f、Z_3g、Z_4f、Z_4gIt is each independently-O- ,-C (R²¹R²²)-or-N (R²³)-；Z_3d、Z_3eRespectively From independently being-C (R³²)=；Z_4d、Z_4eIt is each independently=C (R⁴²)-or=N-；R_a’、m、R¹³、R²¹、R²²、R²³、R²⁴、 R³²、R⁴²As defined above；W_2d、W_3d、W_4d、W_1e、W_3e、W_4e、W_1f、W_2f、W_3f、W_2g、W_3g、W_4gIt is each independently N or CH.

In another preferred example, Z_1f、Z_3f、Z_4f、Z_1g、Z_3g、Z_4gFor-CH₂-。

In another preferred example, Z_2f、Z_2gFor-O- or-N (R²³)-。

In another preferred example, Z_1d、Z_1e、Z_3d、Z_3eIt is each independently-C (C_1-3Alkyl)=,-CH=,-CF=or- CCl=.

In another preferred example, Z_2d、Z_2eIt is each independently=N- or=CH-.

In another preferred example, Z_1g、Z_3g、Z_4gFor-CH₂-；Z_2gFor-N (R²³)-。

In another preferred example, Z_4d、Z_4eIt is each independently=N- or=CH-.

In another preferred example, Z_1d、Z_2d、Z_3d、Z_4dIt is each independently-CH=；W_2dFor N；W_3d、W_4dIt is CH.

In another preferred example, Z_1d、Z_3d、Z_4dIt is each independently-CH=；Z_2dFor=N-；W_2d、W_3d、W_4dIt is CH.

In another preferred example, Z_1d、Z_2d、Z_3d、Z_4dIt is each independently-CH=；W_2d、W_3d、W_4dIt is CH.

In another preferred example, W_2d、W_3d、W_4dIt is CH.

In another preferred example, W_2d、W_3d、W_4dIn one be N.

In another preferred example, W_2dFor N, W_3d、W_4dFor CH.

In another preferred example, W_2d、W_3d、W_4dIn two be N.

In another preferred example, W_1e、W_3e、W_4eIt is CH.

In another preferred example, W_1e、W_3e、W_4eIn one be N.

In another preferred example, W_1e、W_3e、W_4eIn two be N.

In another preferred example, W_1f、W_2f、W_3fIt is CH.

In another preferred example, W_1f、W_2f、W_3fIn one be N.

In another preferred example, W_1f、W_2f、W_3fIn two be N.

In another preferred example, W_2g、W_3g、W_4gIt is CH.

In another preferred example, W_2g、W_3g、W_4gIn one be N.

In another preferred example, W_2g、W_3g、W_4gIn two be N.

In another preferred example, formula (I) compound is formula (II-1) to formula (II-9) compound represented:

In formula, R_a1、R_a2、R_a3、R_a4Definition same R respectively_a'；Z₂For-C (O)-or-C (R²¹R²²)-；Y is-O- ,-C (R²¹R²²)-or-N (R²³)-；R₁、R₃、R₅、X、L₁、L₂、R¹¹、R¹²、R²¹、R²²、R²³It is as defined above to be defined.

In another preferred example,For such as flowering structure:

In formula, R_a1、R_a2、R_a3、R_a4Definition same R respectively_a'；R²³、R¹³、R²⁴、R³²、R⁴²As defined above.

In another preferred example, R_a1、R_a2、R_a3、R_a4Be each independently hydrogen, methyl, fluorine, chlorine, methoxyl group, isopropoxy, Trifluoromethoxy, trifluoromethyl, piperidyl, pyrazolyl, dimethylamino.

In another preferred example, R²³For hydrogen, methyl ,-C (O)-CH₃。

In another preferred example, R¹³、R²⁴、R³²、R⁴²Be each independently hydrogen, methyl, fluorine, chlorine, methoxyl group, isopropoxy, Trifluoromethoxy, trifluoromethyl, piperidyl, pyrazolyl, dimethylamino.

In another preferred example, the compound is compound prepared by the embodiment of the present application:

Second aspect of the present invention provides a kind of pharmaceutical composition, and the composition includes described in first aspect present invention Compound or its pharmaceutically acceptable salt, solvate, stereoisomer or prodrug；And pharmaceutically acceptable carrier.

Third aspect present invention provides compound as described in the first aspect of the invention or its is pharmaceutically acceptable Salt, solvate, stereoisomer or prodrug or second aspect of the present invention described pharmaceutical composition are in preparation treatment disease or disease Application in the drug of disease.

In another preferred example, the disease or illness be selected from pain, depression, cardiovascular disease, respiratory disease, Mental disease or combinations thereof.

In another preferred example, the neuropathy that the disease or illness are selected from pain relevant to HIV, HIV therapy induces Change, trigeminal neuralgia, postherpetic neuralgia, Acute Pain, thermo-responsive, sarcoidosis, irritable bowel syndrome, Crohn disease, Related pain, amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral nerve disease with multiple sclerosis (MS) Change, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenic syndrome, flesh Tetanic, malignant fever, cystic fibrosis, pseudohyperaldosteronism, rhabdomyolysis, hypothyroidism, two-phase suppression Strongly fragrant disease, anxiety disorder, schizophrenia, sodium channel toxin associated disease, familial erythromelalgia, primary erythromelalgia Disease, familial rectal pain, cancer, epilepsy, locally and systemically tonic seizures, restless leg syndrome, arrhythmia cordis, fiber flesh Bitterly, the neuroprotection under the ischemic disease state as caused by apoplexy or neurotrosis, tachyarrhythmia, auricular fibrillation And ventricular fibrillation.

In another preferred example, the pain is selected from neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy Pain, trauma pain, surgical pain, postoperative pain, production pain, labor pains, toothache, chronic ache, persistent pain, The pain of periphery mediation, the pain of maincenter mediation, chronic cephalalgia, migraine, sinus headache, tension headache, phantom limb pain, surrounding Neurotrosis, trigeminal neuralgia, postherpetic neuralgia, Acute Pain, familial erythromelalgia, primary are erythematous Acrodynia, familial rectal pain or fibromyalgia or combinations thereof.

Fourth aspect present invention provides a kind of method for treating mammalian diseases or illness, and the method includes giving to need Want object (such as mammal) application therapeutically effective amount first aspect present invention as described in compound or its can pharmaceutically connect Pharmaceutical composition described in salt, solvate, stereoisomer or the prodrug or second aspect of the present invention received.

The present invention also provides a kind of formula (I) compound represented or its pharmaceutically acceptable salt, solvate, stand Body isomers or prodrug:

In formula, R₁、R₂、R₃、R₄It is each independently hydrogen, hydroxyl, CN, NO₂, halogen, C_1-20Alkyl, C_3-20Naphthenic base, C_3-20 Cycloalkyloxy, C_2-20Alkenyl, C_2-20Alkynyl, C_1-20Alkoxy ,-CHO ,-CO- (C_1-20Alkyl) ,-CO- (C_6-20Aryl), C_6-20Virtue Base ,-C (O) O- (C_1-20Alkyl) ,-OC (O)-(C_1-20Alkyl) ,-SO₂-(C_1-20Alkyl) or-SO₂-(C_6-20Aryl)；

L₁For a key or-(CH₂)_r1-；

L₂For a key or-(CH₂)_r2-；

It is 1,2 or 3 that r1, r2, which are each independently,；

X is key, a NR^z, O or S；R^zFor hydrogen or C_1-10Alkyl；

L₂With it is bicyclic in any annular atom of any one ring connect；

For singly-bound or double bond；

Wherein, W₁、W₂、W₃、W₄It is each independently N or CH；And W₁、W₂、W₃And W₄It is not simultaneously N；U₁、U₂It is respectively independent Ground is N or CH；U₃For CH₂, N, O or S；(R_a)_mFor any position on 5- or 6-membered ring hydrogen by m R_aReplace, m 0,1,2, 3 or 4, each R_aIt is identical or different, it is each independently hydrogen, halogen, nitro, hydroxyl, cyano, C_6-20Aryl, deuterium, deuterated C_1-20 Alkyl, C_1-20Alkyl, halogenated C_1-20Alkyl, C_1-20Alkoxy, halogenated C_1-20Alkoxy, C_3-20Naphthenic base, halogenated C_3-20Naphthenic base, C_3-20Cycloalkyloxy, halogenated C_3-20Cycloalkyloxy, C_2-20Alkenyl, halogenated C_2-20Alkenyl, C_2-20Alkynyl, halogenated C_2-20Alkynyl, C_1-20 Alkylthio group, halogenated C_1-20Alkylthio group, C_1-20Alkyl amino, halogenated C_1-20Alkyl amino, mercaptan, 3 yuan to 20 yuan of Heterocyclylalkyl, 3 The Heterocyclylalkyl oxygroup of member to 20 yuan, C_3-20Cycloalkylthio, halogenated C_3-20Cycloalkylthio, 3 yuan to 20 yuan of Heterocyclylalkyl sulfenyl, Oxo base, C_1-20Hydroxyalkyl, carboxyl ,-C (O) O- (C_1-20Alkyl) ,-CHO ,-OC (O)-(C_1-20Alkyl) ,-SO₂-(C_1-20Alkane Base) ,-SO₂-(C_6-20Aryl) ,-CO- (C_6-20Aryl), 5 or 6 unit monocycle heteroaryl or 8 to 10 membered bicyclic heteroaryls.

In another preferred example,For structure shown in formula (I-a):

In formula, Z₁For-C (R¹¹R¹²)-、-O-、-C(O)-、-C(R¹³)=or-N=；Z₂For-C (O)-,-C (R²¹R²²)-、-N (R²³)-,=N- or=C (R²⁴)-；Z₃For-N (R³¹)-or-CH₂-；For singly-bound or double bond；R_a、m、W₁、W₂、W₃、W₄、 R¹¹、R¹²、R¹³、R²¹、R²²、R²³、R²⁴、R³¹As defined above.

In formula, Z₁₁For-C (R¹¹R¹²)-、-O-、-C(O)-、-C(R¹³)=or-N=；Z₁₂For-C (R¹¹R¹²)-or-C (O)-； Z₂For-C (O)-,-C (R²¹R²²)-,=N- or=C (R²⁴)-；Z₃For-CH₂-；For singly-bound or double bond；R_a、m、R¹¹、 R¹²、R¹³、R²¹、R²²、R²⁴As defined above；W₁₁、W₂₁、W₃₁、W₄₁、W₁₂、W₂₂、W₃₂、W₄₂It is each independently N or CH；And W₁₁、 W₂₁、W₃₁、W₄₁It is not simultaneously N；W₁₂、W₂₂、W₃₂、W₄₂It is not simultaneously N.

In formula, Z_1a、Z_1b、Z_1cIt is each independently-O- ,-C (R¹¹R¹²)-；Z_2a、Z_2b、Z_3a、Z_3c、Z_4b、Z_4cIt is respectively independent Ground is-C (R²¹R²²)-；R_a、m、R¹¹、R¹²、R²¹、R²²As defined above；W_1a、W_2a、W_3a、W_4a、W_1b、W_2b、W_3b、W_4b、W_1c、W_2c、 W_3c、W_4cIt is each independently N or CH；And W_1a、W_2a、W_3a、W_4aIt is not simultaneously N；W_1b、W_2b、W_3b、W_4bIt is not simultaneously N；W_1c、W_2c、 W_3c、W_4cIt is not simultaneously N.

In formula, Z_1d、Z_1eIt is each independently-C (R¹³)=or-N=；Z_2d、Z_2eIt is each independently=N- or=C (R²⁴)-；Z_1f、Z_1g、Z_2f、Z_2g、Z_3f、Z_3g、Z_4f、Z_4gIt is each independently-O- ,-C (R²¹R²²)-or-N (R²³)-；Z_3d、Z_3eRespectively From independently being-C (R³²)=；Z_4d、Z_4eIt is each independently=C (R⁴²)-or=N-；R_a、m、R¹³、R²¹、R²²、R²³、R²⁴、R³²、 R⁴²As defined above；W_2d、W_3d、W_4d、W_1e、W_3e、W_4e、W_1f、W_2f、W_3f、W_2g、W_3g、W_4gIt is each independently N or CH.

In formula, R_a1、R_a2、R_a3、R_a4Definition same R respectively_a；Z₂For-C (O)-or-C (R²¹R²²)-；Y is-O- ,-C (R²¹R²²)-or-N (R²³)-；R₁、R₃、R₅、X、L₁、L₂、R¹¹、R¹²、R²¹、R²²、R²³It is as defined above to be defined.

In another preferred example,For such as flowering structure:

In formula, R_a1、R_a2、R_a3、R_a4Definition same R respectively_a；R²³、R¹³、R²⁴、R³²、R⁴²As defined above.

It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.

Detailed description of the invention

Fig. 1 is that the rat cryalgesia comprising compound Z-47 tests baseline chart.

Fig. 2 is compound Z-47 using the additional Dunnett multiple comparative test result of one-way analysis of variance.

Fig. 3 is that the rat cryalgesia comprising compound Z-49 and Z-56 tests baseline chart.

Fig. 4 is compound Z-49 and Z-56 using the additional Dunnett multiple comparative test of one-way analysis of variance.

Fig. 5 is that the rat cryalgesia comprising compound Z-54 tests baseline chart.

Fig. 6 is compound Z-54 using the additional Dunnett multiple comparative test result of one-way analysis of variance.

Fig. 7 is that the rat cryalgesia comprising compound Z-99 and Z-100 tests baseline chart.

Fig. 8 is compound Z-99 and Z-100 using the additional Dunnett multiple comparative test of one-way analysis of variance.

Specific embodiment

The present inventor is after extensive and in-depth study, it has unexpectedly been found that double cyclosubstituted benzsulfamides of the invention spread out Biology is while obviously weaker to the inhibitory activity of Nav1.5 to Nav1.7 inhibitory activity with higher, has to Nav1.7 bright Aobvious selection inhibitory activity.Apparent analgesic effect, therefore series of the invention are also shown in pain model test simultaneously Compound can be developed into the drug of the treatment for extensive pain.On this basis, inventor completes the present invention.

Term definition

As used herein, " C_1-20Alkyl " refers to the aliphatic hydrocarbyl of the saturation of the straight chain comprising 1 to 20 carbon atom and branch, Such as give a definition similar；More preferably C_1-10Alkyl, unrestricted example include: methyl, ethyl, n-propyl, isopropyl, positive fourth Base, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1, 1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methylpent Base, 3- methyl amyl, 4- methyl amyl, 2,3- dimethylbutyl, n-heptyl, 2- methylhexyl, 3- methylhexyl, 4- methyl oneself Base, 5- methylhexyl, 2,3- dimethyl amyl group, 2,4- dimethyl amyl group, 2,2- dimethyl amyl group, 3,3- dimethyl amyl group, 2- Ethylpentyl, 3- ethylpentyl, n-octyl, 2,3- dimethylhexanyl, 2,4- dimethylhexanyl, 2,5- dimethylhexanyl, 2,2- Dimethylhexanyl, 3,3- dimethylhexanyl, 4,4- dimethylhexanyl, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- Methyl -2- ethylpentyl, 2- methyl -3- ethylpentyl, n-nonyl, 2- methyl -2- ethylhexyl, 2- methyl -3- ethylhexyl, 2,2- diethyl amyl groups, positive decyl, 3,3- diethylhexyl, 2,2- diethylhexyl and its various branched isomers etc.；It is more excellent It is selected as C_1-6Alkyl, most preferably C_1-3Alkyl.

As used herein, " alkenyl " refer at least be made of two carbon atoms and at least one carbon-to-carbon double bond it is as defined above Aliphatic hydrocarbyl, " C_2-20Alkenyl " refers to the alkenyl of the straight chain comprising 2 to 20 carbon atoms and branch, such as gives a definition similar；More Preferably C_2-10Alkenyl；More preferably C_2-6Alkenyl；Most preferably C_2-4Alkenyl, for example, vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- cyclobutenyl etc..

As used herein, " alkynyl " refers to and is at least as above determined by what two carbon atoms and at least one carbon-carbon triple bond formed The aliphatic hydrocarbyl of justice, " C_2-20Alkynyl " refers to the alkynyl of the straight chain comprising 2 to 20 carbon atoms and branch, such as gives a definition similar；More Preferably C_2-10Alkynyl；More preferably C_2-6Alkynyl；More preferably C_2-4Alkynyl；Such as acetenyl, 1- propinyl, 2-propynyl, 1-, 2- or 3- butynyl etc..

As used herein, " naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon group, " C_3-20Naphthenic base " Refer to the cyclic hydrocarbon radical comprising 3 to 20 carbon atoms, such as gives a definition similar；More preferably C_3-10Naphthenic base；More preferably C_3-8Cycloalkanes Base；Most preferably C_3-6Naphthenic base.The non-limiting embodiment of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, ring penta Alkenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc., preferably cyclopropyl, cyclopenta, Cyclohexenyl group.The non-limiting embodiment of polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring.

As used herein, " Heterocyclylalkyl " and " heterocycle " is used interchangeably, and refers to the unsaturated monocycle or more of saturation or part Ring cyclic hydrocarbon group, preferably 3 yuan to 20 yuan of Heterocyclylalkyl (refer to that Heterocyclylalkyl includes 3 to 20 annular atoms, and one of them Or multiple annular atoms are selected from nitrogen, oxygen or S (O)_tThe hetero atom of (wherein t is integer 0 to 2), but do not include-O-O- ,-O-S- or- The loop section of S-S-, remaining annular atom are carbon)；More preferably 3 yuan to 10 yuan of Heterocyclylalkyl, wherein 1~3 annular atom is miscellaneous Atom；More preferably 3 yuan to 6 yuan of Heterocyclylalkyl；More preferably 5 yuan to 6 yuan of Heterocyclylalkyl.Monocyclic heterocycles base it is unrestricted Property embodiment includes pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, high piperazine base, pyranose, tetrahydrofuran Base etc..The non-limiting embodiment of multiring heterocyclic includes the heterocycle of loop coil, condensed ring and bridged ring.

As used herein, " part is unsaturated " refers to containing one or more unsaturated bonds but does not have the π of total conjugated Electronic system.

As used herein, " C_1-20Alkoxy " refers to-O- (C_1-20Alkyl), wherein alkyl is as defined above.It is preferred that C_1-10 Alkoxy, more preferable C_1-6Alkoxy, most preferably C_1-3Alkoxy.Non-limiting embodiment includes methoxyl group, ethyoxyl, the third oxygen Base, isopropoxy, butoxy, tert-butoxy, isobutoxy, amoxy etc..

As used herein, " C_3-20Cycloalkyloxy " refers to-O- (C_3-20Naphthenic base), wherein naphthenic base is as defined above.It is excellent Select C_3-10Cycloalkyloxy, preferably C_3-8Cycloalkyloxy, more preferable C_3-6Cycloalkyloxy.Non-limiting embodiment include cyclopropyl oxygroup, Cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..

As used herein, " C_6-20The full carbon monocycle or fused polycycle that aryl " refers to the pi-electron system with conjugation are (namely The ring of shared adjacent carbon atoms pair) group, refer to the aryl containing 6 to 20 carbon atoms；More preferably C_6-12Aryl, more preferable benzene Base and naphthalene, most preferably phenyl.

As used herein, " key ", which refers to, is covalently keyed by two groups of its connection by one.

As used herein, " halogen " refers to fluorine, chlorine, bromine or iodine.

As used herein, " halogenated " refers to that one or more (such as 1,2,3,4 or 5) hydrogen are replaced halogen in group.

For example, " halogenated C_1-20Alkyl " refers to that alkyl is replaced by one or more (such as 1,2,3,4 or 5) halogens, wherein alkane Base is as defined above.Preferably halogenated C_1-10Alkyl, more preferably halogenated C_1-6Alkyl, most preferably halogenated C_1-3Alkyl. Halogenated C_1-20The example of alkyl includes but is not limited to a chloroethyl, dichloromethyl, 1,2- Dichloroethyl, a bromoethyl, a fluorine Ethyl, a methyl fluoride, difluoromethyl, trifluoromethyl etc..

In another example " halogenated C_1-20Alkoxy " refers to that alkoxy is replaced by one or more (such as 1,2,3,4 or 5) halogens, Wherein alkoxy is as defined above.Preferably halogenated C_1-10Alkoxy, more preferably halogenated C_1-6Alkoxy, most preferably Halogenated C_1-3Alkoxy.Including but not limited to trifluoromethoxy, trifluoro ethoxy, a fluorine methoxyl group, a fluorine ethyoxyl, difluoro Methoxyl group, difluoroethoxy etc..

In another example " halogenated C_3-20Naphthenic base " finger ring alkyl is replaced by one or more (such as 1,2,3,4 or 5) halogens, Wherein naphthenic base is as defined above.Preferably halogenated C_3-10Naphthenic base, more preferably halogenated C_3-8Naphthenic base, most preferably Halogenated C_3-6Naphthenic base.Including but not limited to trifluoro cyclopropyl, a fluorine cyclopropyl, a fluorine cyclohexyl, difluorocyclopropyl, difluoro Cyclohexyl etc..

As used herein, " deuterated C_1-20Alkyl " refers to that alkyl is taken by one or more (such as 1,2,3,4 or 5) D-atoms In generation, wherein alkyl is as defined above.Preferably deuterated C_1-10Alkyl, more preferably deuterated C_1-6Alkyl, it is most preferably deuterated C_1-3Alkyl.Deuterated C_1-20The example of alkyl includes but is not limited to single deuterated methyl, single deuterated ethyl, two deuterated methyl, two deuteriums For ethyl, three deuterated methyl, three deuterated ethyls etc..

As used herein, " C_1-20Hydroxyalkyl " refers to the C being optionally substituted by a hydroxyl group_1-20Alkyl, wherein alkyl is as defined above. Preferably C_1-10Hydroxyalkyl, more preferably C_1-6Hydroxyalkyl, most preferably C_1-3Hydroxyalkyl.

As used herein, " amino " refers to-NH₂, " cyano " refers to-CN, and " nitro " refers to-NO₂, " benzyl " refers to-CH₂Phenyl, " oxygen Dai Ji " refers to=O, and " carboxyl " refers to-C (O) OH, and " mercaptan " refers to-SH, " cyclopropylidene " structure are as follows:

As used herein, " carboxylate " refers to-C (O) O- (C_1-20Alkyl) or (C_3-20Naphthenic base), wherein alkyl, naphthenic base It is as defined above.

As used herein, " C_1-20Alkylthio group " refers to-S- (C_1-20Alkyl), wherein alkyl is as defined above.Preferably C_1-10Alkylthio group, more preferably C_1-6Alkylthio group, most preferably C_1-3Alkylthio group.

As used herein, " C_1-20Alkyl amino " refers to-(C_1-20Alkyl)-NH₂Or-NH₂-(C_1-20Alkyl), wherein alkyl It is as defined above.Preferably C_1-10Alkyl amino, more preferably C_1-6Alkyl amino, most preferably C_1-3Alkyl amino.

As used herein, " C_3-20Cycloalkylthio " refers to-S- (C_3-20Naphthenic base), wherein naphthenic base is as defined above.It is excellent It is selected as C_3-10Cycloalkylthio, more preferably C_3-8Cycloalkylthio, most preferably C_3-6Cycloalkylthio.

As used herein, " 3 yuan to 20 yuan of Heterocyclylalkyl sulfenyls " refer to-S- (3 yuan to 20 yuan of Heterocyclylalkyls), wherein miscellaneous Naphthenic base is as defined above.Preferably 3 yuan to 10 yuan of Heterocyclylalkyl sulfenyl.

As used herein, " 3 yuan to 20 yuan of Heterocyclylalkyl oxygroups " refer to-O- (3 yuan to 20 yuan of Heterocyclylalkyls), wherein miscellaneous Naphthenic base is as defined above.Preferably 3 yuan to 10 yuan of Heterocyclylalkyl oxygroup.

As used herein, " heteroaryl ring " is used interchangeably with " heteroaryl ", is referred to 5 to 10 annular atoms, preferably 5 Or 6 unit monocycle heteroaryl or 8 to 10 membered bicyclic heteroaryls；6,10 or 14 pi-electrons are shared in ring array；And outside carbon atom also With 1 to 5 heteroatomic groups." hetero atom " refers to nitrogen, oxygen or sulphur.

As used herein, " 3 to 7 unit monocycle " refers to the unsaturated full carbon list of saturation or part containing 3 to 7 annular atoms Ring.It is preferred that 5 to 6 yuan.The example of monocycle includes but is not limited to: cyclopropyl rings, cyclobutyl ring, cyclopenta ring, cyclopentene basic ring, Cyclohexyl ring, cyclohexene basic ring, cyclohexadiene basic ring, cycloheptyl basic ring, cycloheptatriene basic ring, cyclooctyl ring etc..

As used herein, " 3 to 7 yuan of single heterocycles " refers to 1,2 or 3 carbon atom in 3 to 7 unit monocycles by selected from nitrogen, oxygen Or replaced the hetero atom of sulphur.It is preferred that 5 to 6 yuan.The example of single heterocycle includes but is not limited to tetrahydrofuran ring, thiophane Ring, pyrrolidines basic ring, piperidine ring, pyrrolin ring, oxazolidine ring, piperazine ring, dioxolanes, morpholine ring, thiomorpholine ring, high piperazine Piperazine ring, pyranoid ring etc..

As used herein, " 8 to 10 membered bicyclic " refers to that the full carbon of the saturation containing 8 to 10 annular atoms is bicyclic or part insatiable hunger The full carbon of sum is bicyclic, and bicyclic example includes but is not limited to:

As used herein, " 8 to 10 yuan of double heterocycles " refers to that 1,2,3,4 or 5 carbon atom in 8 to 10 membered bicyclics is selected from Replaced the hetero atom of nitrogen, oxygen or sulphur.The example of double heterocycles includes but is not limited to tetrahydroquinoline ring, tetrahydroisoquinoline ring, ten Hydrogen quinoline ring etc..

As used herein, " 5 to 6 unit monocycle heteroaryl ring " refers to single heteroaryl ring containing 5 to 6 annular atoms, such as wraps It includes (but being not limited to): thiphene ring, N- alkyl pyrrole ring, furan nucleus, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, three Azoles ring, tetrazole ring, isozole ring, oxadiazoles ring, Thiadiazole, pyridine ring, pyridazine ring, pyrimidine ring, pyridine ring etc..

As used herein, " 8 to 10 membered bicyclic heteroaryl ring " refers to double heteroaryl rings containing 8 to 10 annular atoms, such as Including but not limited to: benzofuran ring, benzothiophene ring, indole ring, iso-indoles ring, quinoline ring, isoquinolin ring, indazole ring, Benzothiazole ring, benzimidazole ring, quinazoline ring, quinoxaline ring, cinnolines ring, phthalazines ring.

As used herein, " 3 to 7 unit monocycle of benzo or 3 to 7 yuan of benzo single heterocycles " refer to the monocycle containing 3 to 7 annular atoms Or it is single heterocyclic fused in the twin nuclei formed on phenyl ring, preferably 5 to 6 unit monocycle of benzo or 5 to 6 yuan of benzo single heterocycles.Non- limit Property embodiment processed includes:

As used herein, " 5 to 6 unit monocycle heteroaryl rings and 3 to 7 unit monocycles or 5 to 6 unit monocycle heteroaryl rings and 3 to 7 First list heterocycle " refers to that 3 to 7 unit monocycles or 3 to 7 yuan of lists are heterocyclic fused in the tomfool's knot formed on 5 to 6 unit monocycle heteroaryl rings Structure, non-limiting embodiment include:

As used herein, " substituted " refers to one or more hydrogen atoms in group, preferably 1~5 hydrogen atom each other Independently replaced by the substituent group of respective number, more preferably 1~3 hydrogen atom is independently of one another by the substituent group of respective number Replace.Self-evident, substituent group is only in their possible chemical position, and those skilled in the art can not pay excessively Possible or impossible substitution (by experiment or theory) is determined in the case where effort.For example, amino or hydroxyl with free hydrogen It may be unstable when base is in conjunction with the carbon atom with unsaturated (such as olefinic) key.

As used herein, the wave in structural formula, such asIn place of expression is connected with the structure.

As used herein, " L₂With it is bicyclic in any annular atom of any one ring connect " in bicyclic refer to

As used herein, alkyl can be substituted or unsubstituted, and alkenyl can be substituted or non-substituted, alkynyl It can be substituted or non-substituted, naphthenic base can be substituted or unsubstituted, and heterocycle can be substituted or not take Generation, alkoxy can be optionally substituted or unsubstituted, and cycloalkyloxy can be optional substituted or unsubstituted, aryl It can be substituted or unsubstituted, 3 to 7 unit monocycles can be substituted or unsubstituted, and 3 to 7 yuan of single heterocycles can be and take Generation or unsubstituted, 8 to 10 membered bicyclics can be substituted or unsubstituted, 8 to 10 yuan of double heterocycles can be it is substituted or Unsubstituted, 3 to 7 unit monocycle of benzo or 3 to 7 yuan of benzo single heterocycles can be substituted or unsubstituted, and 5 to 6 unit monocycles are miscellaneous Simultaneously 3 to 7 yuan of single heterocycles can be substituted or unsubstituted for aryl rings and 3 to 7 unit monocycles or 5 to 6 unit monocycle heteroaryl rings, on When stating group to replace, substituent group is preferably 1 to 5 or less group, independently selected from C_1-20Alkyl, halogenated C_1-20Alkyl, C_2-20 Alkenyl, C_2-20Alkynyl, C_1-20Alkoxy, C_1-20Alkylthio group, C_1-20Alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, C_3-20 Naphthenic base, 3 yuan to 20 yuan of heterocycle, C_6-20The unit monocycle heteroaryl of aryl, 5 or 6 or 8 to 10 membered bicyclic heteroaryls, C_3-20Cycloalkanes Oxygroup, 3 yuan to 20 yuan of Heterocyclylalkyl oxygroup, C_3-20Cycloalkylthio, 3 yuan to 20 yuan of Heterocyclylalkyl sulfenyl, oxo base, ammonia Base, C_1-20Hydroxyalkyl, carboxyl or carboxylate.

Preparation method

The present invention provides the preparation method of formula (I) compound, the compound in the present invention can be grasped by a variety of synthesis It easily prepares, these operations are that one of ordinary skill in the art skillfully grasp.The illustrative preparation method of these compounds It may include (but being not limited to) process described below.

Formula (I) compound of the present invention is referred to following synthetic routes and is prepared, in specific operation process, Ke Yigen According to needing that the step in method is extended or is merged.

Route 1

Step 1: in the presence of alkali systems, passing through the reaction site of possessed nucleophilic property in formula (I-2) compound Or group (such as NH, OH etc.) and formula (I-1) compound occur substitution reaction (such as nucleophilic substitution reaction etc.) production (I-3) and change Object is closed, suitable alkali systems include the potassium tert-butoxide for being present in DMSO, the sodium hydride being present in DMF, the carbonic acid for being present in DMF Potassium etc., the Lev in formula (I-1) are leaving group, including but not limited to triflate；Chlorine, bromine, iodine；Sulfonate group, such as Methanesulfonates, tosylate, brosylate, p-methyl benzenesulfonic acid ester etc.；Acyloxy, such as acetoxyl group, trifluoroacetyl oxygen Base etc..PG in formula (I-1) is amino protecting group, and amino protecting group includes but is not limited to: tert-butoxycarbonyl (Boc)；Aryl Methoxycarbonyl group, benzyloxycarbonyl group (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc)；Benzyl (Bn), 2,4- dimethoxy-benzyl (DMB), three Benzyl (Tr), 1,1- bis--(4 '-methoxyphenyl) methyl；Trimethyl silyl (TMS) and t-butyl-dimethylsilyl Base (TBS) etc..

Step 2: formula (I-3) compound obtains formula (I) compound under suitable conditions, by deprotection reaction, takes off The method of protection can refer to conventional method in that art.

1 Chinese style of route (I-2) and formula (I-1) compound can be according to the differences of specific structure by commercially available, or pass through ability Method known to field technique personnel is prepared.

Route 2

With formula (I-5) compound substitution reaction production (I-3) compound, subsequent remove-insurance can occur for formula (I-4) compound Probationer nurse is at formula (I) compound, reaction condition and group definition with route 1.

Reaction in above each step is known to the skilled in the art popular response.Unless otherwise specified, it synthesizes Reagent used in route and raw material compound are commercially available to be obtained or those skilled in the art do not assimilate according to designed Object structural reference known method is closed to be prepared.

Compared with prior art, main advantages of the present invention are:

A series of double cyclosubstituted benzenesulfonamide derivatives of structure novels are provided, Nav1.7 is pressed down with high selection System activity, can be used as the drug of extensive pain therapy.

Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.Unless separately Definition, the term as used herein have the same meanings as commonly understood by one of ordinary skill in the art.In addition, any similar to described content Or same method and material all can be applied in the present invention.

As used herein, 2 DMB, 4- dimethoxy-benzyl, THF are tetrahydrofuran, and EA is ethyl acetate, and PE is petroleum Ether, Ac₂O is acetic anhydride, and NBS is N-bromosuccinimide, and DCM is methylene chloride, and AIBN is azodiisobutyronitrile, Pd (dppf)Cl₂It is 1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride, TFA is trifluoroacetic acid, and TBSCl is fert-butyidimethylsilyl Chlorosilane, NCS are N- chlorosuccinimide, and DHP is dihydropyran, LiAlH₄For lithium aluminium hydride reduction, PMB is to methoxybenzyl Base, LiHMDS are two (trimethyl silicon substrate) lithium amides, Pd₂(dba)₃For tris(dibenzylideneacetone) dipalladium, RuPhos is bis- ring of 2- Hexyl phosphorus -2 ', 6 '-diisopropoxy -1,1 '-biphenyl, DMAP is 4-dimethylaminopyridine, and THP is oxinane, and n-BuLi is N-BuLi, TMsOTf are Trimethylsilyl trifluoromethanesulfonate, and TEBAC is triethyl benzyl ammonia chloride, and HATU is 2- (7- azo Benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, DMF is dimethylformamide, and DMSO is dimethyl sulfoxide, DIEA is n,N-diisopropylethylamine, and BINAP is (2R, 3S) -2,2 '-bis- 1,1 '-dinaphthalenes of diphenyl phosphine -.

As used herein, room temperature refers to about 20-25 DEG C.

The preparation method of compound Z-A-1:

Step 1: compound Z-A-1-a (35g, 0.2mol) being dissolved in methanol (500mL), is slowly added into the concentrated sulfuric acid (5mL). Reaction solution is in N₂Protect lower 70 DEG C of stirrings 18h.Most of solvent is spun off, 200mL water is then added, (3 x are extracted with ethyl acetate 250mL), drying is spin-dried for obtaining red oil Z-A-1-b (38g, yield 100%).

Step 2: compound Z-A-1-b (38g, 0.2mol) is dissolved in THF (200mL) and methanol (50mL), it is slow at 0 DEG C Slow that sodium borohydride (15.4g, 0.4mol) is added, 2h is stirred at room temperature in reaction.TLC monitors reaction raw materials and disappears, and reacts liquid cooling But to after 0 DEG C plus 300mL water, (3 x 300mL) is extracted with dichloromethane, organic phase is washed with saturated sodium bicarbonate (500mL), is had Mutually drying is spin-dried for obtaining yellow solid Z-A-1-c (32g, yield 99%) machine.

Step 3: compound Z-A-1-c (32g, 0.2mol) being dissolved in DMF (150mL), is then slowly added into imidazoles (42.9g, 0.64mol) and TBSCl (48.2g, 0.32mol).React 2h at room temperature.500mL water is added, is extracted with ethyl acetate It takes (3 x 300mL), drying is spin-dried for.Column chromatographic purifying (petroleum ether: ethyl acetate=20: 1) obtains yellow oil Z-A-1-d (51g, yield 93%).

Step 4: in there-necked flask, compound Z-A-1-d (27.5g, 0.1mol) being dissolved in anhydrous THF (300mL), is reacted Liquid is cooled to -65 DEG C, in N₂It is slowly added dropwise under protection n-BuLi (2.4M, 50mL, 0.12mol), is then rapidly added after 1h SO₂(54g, 0.5mol).Reaction monitors reaction raw materials and disappears in -65 DEG C of holding 1h.Solvent is spin-dried for obtain yellow solid (35g).Methylene chloride (400mL) is added into this yellow solid, NCS (13.6g, 0.1mol) then is added.Reaction solution is in room Temperature stirring 2h.Insoluble solids filter out, and filter cake is eluted with 200mL, and filtrate is spin-dried for, column chromatographic purifying (petroleum ether: ethyl acetate= 20: 1) obtaining yellow oil Z-A-1-e (29g, yield 77%).

Step 5: compound Z-A-2-d (8g, 0.032mol) being dissolved in THF (250mL), is cooled to 0 DEG C, is then slowly added Enter 60%NaH (1.53g, 0.038mol).Then 50mL compound Z-A-1-e is slowly added dropwise in 0 DEG C of stirring 1h in reaction The THF solution of (14.4g, 0.038mol), reaction solution are slowly warmed to room temperature and 2h are stirred at room temperature.50mL water quenching reaction, It is extracted with ethyl acetate (3 x 200mL), drying is spin-dried for.Column chromatographic purifying (petroleum ether: ethyl acetate=10: 1) obtains yellow Grease Z-A-1-f (11.5g, yield 61%).

Step 6: compound Z-A-1-f (11.5g, 0.02mol) being dissolved in THF (250mL), is cooled to 0 DEG C, then slowly Three hydrations tetrabutyl ammonium fluoride (12.4g, 0.04mol) are added.Then reaction is slowly warmed to room temperature simultaneously in 0 DEG C of stirring half an hour 2h is stirred at room temperature.300mL water is added, is extracted with ethyl acetate (2 x 300mL), drying is spin-dried for.Column chromatographic purifying (petroleum Ether: ethyl acetate=4: 1 to 2: 1) obtaining white solid Z-A-1-g (5.3g, yield 57%).

Step 7: compound Z-A-1-g (2.5g, 5.28mmol) being dissolved in methylene chloride (50mL), is cooled to 0 DEG C, then It is slowly added into DIPEA (2.05g, 15.9mmol) and methane sulfonyl chloride (1.2g, 10.5mmol).It reacts in 0 DEG C of stirring half an hour, LC-MS monitors reaction raw materials and disappears, and the dichloromethane solution of 10mL tetrabutylammonium chloride (4.4g, 15.8mmol) is then added. Then reaction solution is slowly warmed to room temperature and 2h is stirred at room temperature.The sodium bicarbonate solution of 25mL saturation is added, uses methylene chloride It extracts (2 x 50mL), drying is spin-dried for.Column chromatographic purifying (petroleum ether: ethyl acetate=5: 1 to 4: 1) obtains white solid Z-A- 1 (1.9g, yield 73%).

The preparation method of compound Z-A-2:

Step 1: under nitrogen protection, will be dissolved with compound Z-A-2-a (30g, 180.72mmol) and compound Z-A-2-b Dimethylbenzene (500ml) solution of (24g, 237.62mmol) is heated to reflux (140 DEG C) and keeps 6h, is then cooled to reaction solution Room temperature, and be slowly added into petroleum ether (1.5L), yellow solid product Z-A-2-c (40g, 89%) is obtained by filtration.ESI-MS: 250(M+H)⁺。

Step 2: compound Z-A-2-c (40g, 160.64mmol) being dissolved in methanol (1L), at room temperature by boron hydrogen Change sodium (12.2g, 321.29mmol) to be added portionwise in methanol solution, then be stirred overnight.Water (100ml) is added drop-wise to reaction solution In, it stirs 5 minutes or so, by the methanol evaporated under reduced pressure in reaction solution, water phase is extracted with ethyl acetate (100ml X3), is associated with Machine is mutually washed with saturated salt solution (100ml), and anhydrous sodium sulfate dries, filters, and is spin-dried for, and crude product is added 90ml ethyl acetate and beats Slurry, is obtained by filtration Z-A-2-d (22g, 55%).ESI-MS 252(M+H)⁺。

Step 3: in N₂Under protection, in the case where temperature is -63 DEG C, to dissolved with compound Z-A-2-d (10g, 32mmol) THF The ethereal solution of LiHMDS (1M, 70ml, 70mmol) is added dropwise in (160ml) solution, at this temperature, stirs 2h, allows reaction solution It is slowly ramped to room temperature, 1h is stirred, is then cooled to -63 DEG C, sulfonic acid chloride (9.4g, 38mmol) is added drop-wise to above-mentioned reaction solution, It maintains at this temperature, to stir 1h, be warmed to room temperature, then washes stirring 2h.Reaction solution is added drop-wise to saturated aqueous ammonium chloride (150ml) In, it being extracted with methylene chloride (100ml x 3), organic phase is washed with saturated salt solution (100ml), and anhydrous sodium sulfate dries, filters, Be spin-dried for, crude product by column chromatograph (100-200 mesh silica gel, PE: EA=5: 1) purifying obtain white solid product Z-A-2 (5.06g, 37%).ESI-MS 484(M+Na)⁺；¹H NMR (400MHz, DMSO-d6): δ 8.49 (s, 1H), 7.74-7.84 (m, 2H), 7.09 (d, J=8.0Hz, 1H), 6.43 (dd, J=8.0Hz, 2.4Hz；1H), 6.26 (d, J=2.4Hz, 1H), 5.28 (s, 2H), 3.71 (s, 3H), 3.61 (s, 3H).

The preparation method of compound Z-A-3:

Step 1: compound Z-A-2-a (2.2g, 13.25mmol) being dissolved in dimethylbenzene (100mL), compound Z-A- is added 3-b (759mg, 13.32mmol).Reaction solution stirs 2h at 100 DEG C.Reaction solution is cooled to room temperature, and sodium borohydride is then added 16h is stirred at room temperature in (1g, 26.5mmol), reaction.TLC monitors reaction raw materials and disappears, and reaction solution is cooling to add 50mL water, uses second Acetoacetic ester extracts (3 x 50mL), and drying is spin-dried for.Column chromatographic purifying (petroleum ether: ethyl acetate=6: 1) obtains yellow oil Z-A-3-c (2g, yield 71%).

Step 2: compound Z-A-3-c (2g, 9.66mmol) being dissolved in THF (100mL), is cooled to 0 DEG C, is then slowly added Enter 60%NaH (773mg, 19.32mmol).Then 20mL compound Z-A-1-e is slowly added dropwise in 0 DEG C of stirring 1h in reaction The THF solution of (3.05g, 10mmol), reaction solution are slowly warmed to room temperature and 2h are stirred at room temperature.30mL water quenching reaction is used Ethyl acetate extracts (3 x 60mL), and drying is spin-dried for.Column chromatographic purifying (petroleum ether: ethyl acetate=10: 1) obtains yellow oily Object Z-A-3-d (3.3g, yield 63%).

Step 3: compound Z-A-3-d (3.3g, 6.08mmol) being dissolved in THF (80mL), is cooled to 0 DEG C, then slowly Three hydrations tetrabutyl ammonium fluoride (2.48g, 8mmol) are added.Reaction in 0 DEG C of stirring half an hour, be then slowly warmed to room temperature and 2h is stirred at room temperature.50mL water is added, is extracted with ethyl acetate (2 x 60mL), drying is spin-dried for.Column chromatographic purifying (petroleum ether: Ethyl acetate=4: 1 to 2: 1) obtaining white solid Z-A-3-e (1.5g, yield 58%).

Step 4: compound Z-A-3-e (1.5g, 3.5mmol) being dissolved in methylene chloride (100mL), is cooled to 0 DEG C, then It is slowly added into DIPEA (903mg, 7mmol) and methane sulfonyl chloride (456mg, 4mmol).Reaction is in 0 DEG C of stirring half an hour, LC-MS It monitors reaction raw materials to disappear, the dichloromethane solution of 8mL tetrabutylammonium chloride (1.1g, 4mmol) is then added.Reaction solution is then It is slowly warmed to room temperature and 2h is stirred at room temperature.The sodium bicarbonate solution of 25mL saturation is added, (2 x are extracted with dichloromethane 50mL), drying is spin-dried for.(petroleum ether: ethyl acetate=5: 1 to 4: 1) obtaining white solid Z-A-3, (1.4g is received column chromatographic purifying Rate 89%).

The preparation method of compound Z-A-4:

Z-A-1-g (2g, 4.23mmol) is dissolved in methylene chloride (100mL), 0 DEG C is cooled to, is then slowly added into DIPEA (1.29g, 10mmol) and methane sulfonyl chloride (683g, 6mmol).Reaction monitors reaction raw materials in 0 DEG C of stirring half an hour, LC-MS It disappears, the dichloromethane solution of 10mL tetrabutylammonium bromide (2.55g, 8mmol) is then added.Then reaction solution slowly rises to room Simultaneously 2h is stirred at room temperature in temperature.The sodium bicarbonate solution of 25mL saturation is added, is extracted with dichloromethane (2 x 50mL), dry rotation It is dry.Column chromatographic purifying (petroleum ether: ethyl acetate=5: 1 to 4: 1) obtains white solid Z-A-4 (1.8g, yield 80%).

The preparation method of compound Z-A-5:

Step 1: chlorosulfonic acid 15ml, reaction being added into the dichloromethane solution of compound Z-A-5-a (3g, 20.8mmol) Liquid stirs 2h at 90 DEG C.Reaction solution is poured into ice water, and is extracted with EA, organic phase is washed with saturation NaCl solution, anhydrous Sodium sulphate is dry, is concentrated under reduced pressure to give yellow oil Z-A-5-b (3.5g), is directly used in reacts in next step without further purification.

Step 2: ammonium hydroxide (4ml) is added into THF (4ml) solution of compound Z-A-5-b (3.5g, 14.4mmol).Instead Liquid is answered to be stirred overnight at room temperature.EA is added into reaction solution, is washed with saturation NaCl solution, anhydrous sodium sulfate is dry, is concentrated to give Huang Color grease.(petroleum ether: ethyl acetate=3: white solid Z-A-5-c (2.9g) 1) is purified to obtain through column chromatography.ESI-MS 223.0(M-H)-。

Step 3: Ac is added into Isosorbide-5-Nitrae-dioxane solution of compound Z-A-5-c (2.9g, 13mmol)₂O (10ml), Reaction solution stirs 2h at 120 DEG C, and EA is added into reaction mixture, is washed with saturated sodium bicarbonate solution, anhydrous sodium sulfate It is dry, it is concentrated to give yellow oil, (petroleum ether: ethyl acetate=2: 1) purifies to obtain white solid Z-A-5-d through column chromatography (1.2g)。ESI-MS 264.0(M-H)-。

Step 4: NBS being added into the carbon tetrachloride solution (10ml) of compound Z-A-5-d (0.53g, 2mmol) (0.43g, 2.4mmol) and AIBN (110mg).Reaction mixture stirs 4h at 90 DEG C.DCM is added into reaction solution, with full It is washed with sodium bicarbonate solution, anhydrous sodium sulfate is dry, is concentrated to give yellow solid (330mg), ESI-MS 344.0 (M+H)⁺。

The preparation method of compound Z-A-6:

Preparation method and preparing for compound Z-A-2 are essentially identical, the difference is that by step Chloro- 2, the 4- difluorobenzene -1- sulfonic acid chloride of 5- in 3 changes 2,4,5- trifluoro-benzene -1- sulfonic acid chlorides into.

The preparation method of compound Z-A-7:

Step 1: by 2,4- dimethoxy benzaldehyde (35.2g, 0.21mol) and compound Z-A-7-a (20.2g, It 0.20mol) is added in dimethylbenzene (350ml).Under nitrogen protection, 140 DEG C are heated to, and keeps 6h, reaction solution is cooled to Room temperature is concentrated to get yellow solid.Yellow solid is dissolved in 400ml methanol.At room temperature, by sodium borohydride (11.4g, It 0.30mol) is added portionwise in reaction solution, under room temperature, is stirred overnight.The water of 500ml is slowly added drop-wise in reaction solution, dimension It holds in room temperature, stirs 15 minutes or so.The methanol of part is rotated, water phase is extracted with ethyl acetate (3 x 200ml).Merge Organic phase is washed with saturated salt solution (300ml), and sodium sulphate is dry.Suction filtration is spin-dried for, crude product 150ml re-crystallizing in ethyl acetate, Filtering, being dried to obtain compound Z-A-7-b, (28g, yield: 56%), product is yellow solid.ESI-MS(M+H)⁺: 252.1.

Step 2: in N₂Under protection, in the case where temperature is -78 DEG C, to the THF dissolved with Z-A-7-b (10g, 0.039mol) The THF solution of LiHMDS (1M, 48ml, 0.048mol) is added dropwise in (200ml) solution, at this temperature, stirs 0.5h, allows anti- It answers liquid to be slowly ramped to room temperature, stirs 1h, be then cooled to -78 DEG C, it will be dissolved with the THF of sulfonic acid chloride (11.81g, 0.048mol) Solution is added drop-wise to above-mentioned reaction solution, maintains at this temperature, to stir 1h, be warmed to room temperature, then wash stirring 2h.Reaction solution is added drop-wise to saturation It in aqueous ammonium chloride solution (300ml), is extracted with ethyl acetate (400mlx3), merges organic phase with saturated salt solution (100ml) It washes, it is dry, it is spin-dried for, crude product crosses column (100-200 mesh silica gel), and leacheate is petroleum ether: ethyl acetate=(5: 1) obtain chemical combination (6.12g, yield: 28%) being white solid to object Z-A-7.ESI-MS:484.0 (M+Na)⁺。¹H NMR (400MHz, DMSO-d6): δ: 9.34 (s, 1H), 7.95-7.90 (m, 2H), 7.11 (d, J=8.4Hz, 1H), 6.43 (m, 2H), 5.14 (s, 2H), 3.72 (s, 3H), 3.66 (s, 3H).

The preparation method of compound Z-A-8:

Step 1: compound Z-A-8-a (25g, 0.114mol) being dissolved in methanol (250mL), thionyl chloride is slowly added dropwise (50mL).Reaction solution is in 75 DEG C of stirring 6h.Most of solvent is spun off, 100mL water is then added, with the sodium hydrate aqueous solution of 2N PH to 8 is adjusted, is then extracted with ethyl acetate (3 x 220mL), it is dry to be spin-dried for obtaining white solid Z-A-8-b (26.2g, receipts Rate 100%).

Step 2: compound Z-A-8-b (26.2g, 0.112mol) being dissolved in THF (200mL) and methanol (50mL), at 0 DEG C Under be slowly added into sodium borohydride (8.54g, 0.244mol), reaction 3h is stirred at room temperature.TLC monitors reaction raw materials and disappears, instead Add 300mL water after answering liquid to be cooled to 0 DEG C, (3 x 300mL), organic phase saturated sodium bicarbonate is extracted with dichloromethane (500mL) is washed, and organic phase drying is spin-dried for obtaining yellow solid Z-A-8-c (23g, yield 100%).

Step 3: compound Z-A-8-c (18.3g, 0.09mol) being dissolved in DMF (150mL), is then slowly added into imidazoles (18.3g, 0.27mol) and TBSCl (20.1g, 0.134mol).Reaction is stirred at room temperature overnight.500mL water is added, uses second Acetoacetic ester extracts (3 x 200mL), and drying is spin-dried for.Column chromatographic purifying (petroleum ether: ethyl acetate=20: 1) obtains yellow oily Object Z-A-8-d (23.5g, yield 83%).

Step 4: in there-necked flask, compound Z-A-8-d (10g, 0.031mol) being dissolved in anhydrous THF (100mL), is reacted Liquid is cooled to -65 DEG C, in N₂It is slowly added dropwise under protection n-BuLi (2.4M, 15.7mL, 0.038mol), then adds rapidly after 1h Enter SO₂(10g, 0.155mol).Reaction monitors reaction raw materials and disappears in -65 DEG C of holding 1h.Solvent is spin-dried for obtain yellow solid (9.7g).Methylene chloride (150mL) is added into this yellow solid, NCS (4.2g, 0.031mol) then is added.Reaction solution exists It is stirred overnight at room temperature.Insoluble solids filter out, and filter cake 200mL eluent methylene chloride, filtrate is spin-dried for, column chromatographic purifying (petroleum Ether: ethyl acetate=20: 1) yellow oil Z-A-8-e (8g, yield 75%) is obtained.

Step 5: compound Z-A-8-e (2.5g, 10mmol) being dissolved in THF (25mL), is cooled to 0 DEG C, is then slowly added Enter 60%NaH (0.48g, 12mmol).Reaction in 0 DEG C of stirring 1h, then slowly dropwise addition 10mL compound Z-A-2-d (4.1g, THF solution 12mmol), reaction solution are slowly warmed to room temperature and 2h are stirred at room temperature.50mL water quenching reaction, uses ethyl acetate It extracts (2 x 100mL), drying is spin-dried for.Column chromatographic purifying (petroleum ether: ethyl acetate=5: 1 to 3: 1) obtains yellow oil Z-A-8-f (2.8g, yield 50%).

Step 6: compound Z-A-8-f (2.8g, 5.1mmol) being dissolved in THF (30mL), is cooled to 0 DEG C, is then slowly added Enter three hydration tetrabutyl ammonium fluorides (3.2g, 10.2mmol).Reaction in 0 DEG C of stirring half an hour, be then slowly warmed to room temperature and 2h is stirred at room temperature.50mL water is added, is extracted with ethyl acetate (2 x 300mL), drying is spin-dried for.Column chromatographic purifying (petroleum ether: Ethyl acetate=2: 1) white solid Z-A-8-g (2.8g, yield 68%) is obtained.

Step 7: Z-A-8-g (2.8g, 6.4mmol) being dissolved in methylene chloride (30mL), is cooled to 0 DEG C, is then slowly added Enter DIPEA (2.5g, 19.2mmol) and methane sulfonyl chloride (1.45g, 12.8mmol).Reaction is stirred ten minutes at 0 DEG C, LC-MS It monitors reaction raw materials to disappear, tetrabutylammonium chloride (5.3g, 19.2mmol) then is added, reaction is slowly warmed to room temperature and in room temperature Lower stirring 2h.The sodium bicarbonate solution of 25mL saturation is added, is extracted with dichloromethane (2 x 50mL), drying is spin-dried for.Column chromatography Purifying (petroleum ether: ethyl acetate=5: 1 to 4: 1) obtains white solid Z-A-8 (1.9g, yield 65%).ESI-MS:458.0 (M+H)⁺。

The preparation method of compound Z-A-9:

Preparation method with compound Z-A-1 preparation, unlike the Z-A-1-a in step 1 is changed At 2,5- difluoro-benzoic acid.ESI-MS:476.0 (M+H)⁺。

The preparation method of compound Z-A-10:

Step 1: 6- fluorine pyridine -2- amine (6g, 0.0536mol) being dissolved in 1,2- dichloroethanes (100mL), Z-A- is added 2-a (8.9g, 0.0536mol) and sodium cynoborohydride (4.4g, 0.07mol).Reaction solution stirs 16h at normal temperature.80mL water Extraction is gone out, and is extracted with ethyl acetate (3 x 100mL), and drying is spin-dried for column chromatographic purifying and (petroleum ether: ethyl acetate=4: 1) obtains Huang Color solid Z-A-10-a (5.9g, yield 42%).

Step 2 is to 4: with compound Z-A-10-a (1.4g, 0.0053mol) for raw material, step in reference compound Z-A-1 5 to 7 method preparation, obtains faint yellow solid Z-A-10 (780mg, yield 79%).

The preparation method of compound Z-A-11:

Step 1: by the chloro- 5-FU of compound 2- (5.28g, 0.04mol) and (2,4- Dimethoxyphenyl) ethamine (8.01g, 0.048mol) is added in ethyl alcohol (60ml).Triethylamine (6.36g, 0.06mol) is added in mixture, in nitrogen Under protection, 60 DEG C are heated to, and stir 48h.Reaction solution concentrated by rotary evaporation, residue are pure with silicagel column (100-200 mesh silica gel) Change, leacheate is petroleum ether: ethyl acetate=4: 1, obtaining Z-A-11-a, (5.6g, yield: 53%), product is white solid. ESI-MS:264.2 (M+H)⁺。

Step 2: compound Z-A-11-a (2.63g, 0.010mol) being dissolved in THF (30mL), is cooled to -40 DEG C, then It is slowly added into KHMDS (1M/L, 13mL).Reaction is warming up to room temperature and 1h is stirred at room temperature in -40 DEG C of stirring 1h.Mixture is cold But -40 DEG C are arrived, THF (20mL) solution of compound Z-A-1 (4.84g, 0.013mol) is then slowly added dropwise, reaction solution slowly rises To room temperature and 18h is stirred at room temperature.Reaction is quenched with saturated aqueous ammonium chloride (25mL), is extracted with ethyl acetate (3X50mL) merges organic phase.Organic phase is washed with saturated salt solution (50ml), and dry, 40 DEG C are spin-dried for.Residue silicagel column Chromatographic purifying (petroleum ether: ethyl acetate=5: 1) obtains light yellow solid Z-A-11-b (3.1g, yield: 58.4%).

Step 3: compound Z-A-11-b (3.0g, 0.005mol) being dissolved in THF (30mL), is cooled to 0 DEG C, then slowly Three hydrations tetrabutyl ammonium fluoride (2.61g, 0.01mol) are added.Then reaction is slowly warmed to room temperature simultaneously in 0 DEG C of stirring half an hour 2h is stirred at room temperature.100mL water is added, is extracted with ethyl acetate (2 X 100mL), merges organic phase.Organic phase saturation Saline solution (50ml) washing, dry, 40 DEG C are spin-dried for.Crude product, which is beaten, (petroleum ether: ethyl acetate=5: after 1), to be obtained pale yellow Color solid Z-A-11-c (1.8g, yield: 74%).

Step 4: compound Z-A-11-c (1.7g, 0.0035mol) being dissolved in methylene chloride (20mL), is cooled to 0 DEG C, so After be slowly added into triethylamine (0.54g, 0.0053mol) and methane sulfonyl chloride (0.48g, 0.0042mol).Reaction is stirred at 0 DEG C 1h, LC-MS monitor reaction raw materials and disappear, and reaction solution is directly used in next step.

Step 5: to the dichloromethane solution of above compound Z-A-11-d, be added tetrabutylammonium chloride (3.10g, 0.011mol).3h is stirred at room temperature in reaction solution.30mL water is added, is extracted with dichloromethane (2 X 50mL), merges organic Phase.Organic phase is washed with saturated salt solution (50ml), and dry, 40 DEG C are spin-dried for.Residue silica gel column chromatography purify (petroleum ether: Ethyl acetate=5: 1) white solid Z-A-11 (1.41g, yield: 76%) are obtained.ESI-MS(M+Na)⁺: 525.7.¹H NMR (400MHz, DMSO): δ: 8.72 (s, 2H), 7.94 (d, J=8.4Hz, 1H), 7.82 (d, J=10.4Hz, 1H), 7.02 (d, J =8.4Hz, 1H), 6.58 (d, J=2.0Hz, 1H), 6.47 (dd, J=8.4,2.0Hz, 1H), 5.26 (s, 2H), 4.84 (s, 2H), 3.74 (s, 6H).

The preparation method of compound Z-A-12:

Preparation method obtains white solid Z-A-12, yield 70% with compound Z-A-1.

The preparation method of compound Z-A-13:

Step 1: compound Z-A-1-g (1.89g, 4mmol) being dissolved in methylene chloride (20ml), Dai Si-horse is added Fourth oxidant (2.56g, 6mmol).2h is stirred at room temperature in mixture.After mixture is diluted with methylene chloride (30ml), use respectively Saturated sodium bicarbonate (25ml), saturated salt solution (25ml) washing, sodium sulphate are dry.It filters, filtrate concentrated by rotary evaporation, obtains thick Product light yellow solid Z-A-13-a (1.34g, yield: 71%).ESI-MS:493.9 (M+H)⁺。

Step 2: compound Z-A-13-a (1.40g, 3mmol) is dissolved in acetone (20ml).Potassium permanganate is added Water (15ml) solution of (2.37g, 15mmol).After 2h is stirred at room temperature in mixture, sodium sulfide solution to purple is added and takes off. Filtering, filtrate is with spinning off organic solvent.It is extracted with ethyl acetate (3 x 50ml), merges organic phase, sodium sulphate is dry.It takes out Filter, filtrate concentrated by rotary evaporation obtain crude yellow solid Z-A-13-b (0.7g, yield: 46%).ESI-MS:486 (M-H)^-。

Step 3: compound Z-A-13-b (0.7g, 1.44mmol) being dissolved in methylene chloride (15ml), trifluoro is added Acetic acid (2ml).After 2h is stirred at room temperature in mixture, with concentrated by rotary evaporation, residue obtains light yellow solid after prepared by Prep-HPLC Body Z-A-13 (0.3g, yield: 63%).ESI-MS:337.8 (M+H)⁺.Purity=100% (UV214), 1H NMR (400MHz, DMSO): δ: 14.0 (s, 1H), 8.57 (s, 1H), 7.90 (d, J=6.0Hz, 1H), 7.86 (d, J=9.6Hz, 1H).

The preparation method of compound Z-A-14:

Step 1: compound Z-A-14-a (20.0g, 155mmol) is dissolved in the tert-butyl alcohol (150mL), is cooled to 0 DEG C, Diphenyl phosphate azide (47g, 170mmol) is added under nitrogen protection, triethylamine (17.3g, 170mmol).Mixture reflux is stirred After mixing 18h, it is spin-dried for Rotary Evaporators.Residue is dissolved in methylene chloride (400mL), with water (200mLx2), saline solution (200mL) is washed.Anhydrous sodium sulfate is dry, filters.Filtrate is spin-dried for Rotary Evaporators, and residue chromatographs (PE: EA=3: 1) with column Light yellow solid Z-A-14-b (15.2g, yield: 49%) .ESI-MS:145 (M-55) are obtained after purification⁺,¹H NMR (400MHz, CDCl₃): δ: 8.85 (brs, 1H), 8.61 (d, 1H), 7.32 (s, 1H), 1.55 (s, 9H).

Step 2: in N₂Under protective condition, compound Z-A-14-b (8.0g, 0.04mol) is dissolved in anhydrous THF In (80ml), mixture is cooled to -78 DEG C, and the THF solution of LiHMDS (1M, 48ml, 0.048mol) is added dropwise.After being added dropwise to complete, Mixture stirs 0.5h at -78 DEG C.Reaction solution is slowly ramped to room temperature, 1h is stirred, -78 DEG C is then cooled to, by sulfonic acid chloride THF (50ml) solution of (11.1g, 0.048mol) is added drop-wise to above-mentioned reaction solution.Mixture rises to room after stirring 1h at -78 DEG C Temperature, and 16h is stirred at room temperature.It is added in saturated aqueous ammonium chloride (250ml) into reaction solution, with ethyl acetate (3 x It 100ml) extracts, merges organic phase, washed with saturated salt solution (200ml), dry, 40 DEG C are spin-dried for.Crude product crosses column (100-200 mesh Silica gel), leacheate is petroleum ether: ethyl acetate=(4: 1), and obtaining Z-A-14, (5.1g, yield: 31.8%) being white solid. ESI-MS:434.0 (M+Na)⁺。

The preparation method of compound Z-A-15:

In there-necked flask, Z-A-10-a (1.5g, 0.0057mol) is dissolved in anhydrous THF (60mL), reaction solution is cooled to- 78 DEG C, in N₂It is slowly added dropwise under protection LiHMDS (2.5M, 3.4mL, 0.0086mol), it is chloro- to be slowly added dropwise to 20mL 5- after 1h The THF solution of 2,4- difluorobenzene -1- sulfonic acid chlorides (1.47g, 0.006mol), reaction solution are slowly warmed to room temperature and are stirred at room temperature Overnight.50m water quenching reaction is extracted with ethyl acetate (3 x 80mL), and drying is spin-dried for.Column chromatographic purifying (petroleum ether: acetic acid second Ester=6: 1) pale yellow gum Z-A-15 (700mg, yield 26%) is obtained.

The preparation method of compound Z-A-16:

In N₂Under protective condition, Z-A-11-a (2.46g, 0.01mol) is dissolved in anhydrous THF (25ml), mixture - 40 DEG C are cooled to, the THF solution of LiHMDS (1M, 15ml, 0.015mol) is added dropwise.After being added dropwise to complete, mixture is stirred at -40 DEG C Mix 0.5h.Reaction solution is slowly ramped to room temperature, 1h is stirred, -40 DEG C is then cooled to, by 5- chloro- 2,4- difluoro chloride THF (15ml) solution of (3.95g, 0.015mol) is added drop-wise to above-mentioned reaction solution.Mixture rises to room after stirring 1h at -40 DEG C Temperature, and 18h is stirred at room temperature.It is added in saturated aqueous ammonium chloride (50ml) into reaction solution, with ethyl acetate (3 x It 50ml) extracts, merges organic phase, washed with saturated salt solution (100ml), dry, 40 DEG C are spin-dried for.Residue silicagel column (100- 200 mesh silica gel) purifying, leacheate is petroleum ether: ethyl acetate=4: 1, obtain compound Z-A-16 (1.10g, yield: 23%) For white solid.ESI-MS:495.7 (M+Na)⁺。¹H NMR (400MHz, CDCl₃): δ: 8.31 (s, 2H), 8.13 (t, J= 7.6Hz, 1H), 7.18 (d, J=8.4Hz, 1H), 6.98 (t, J=8.8Hz, 1H), 6.41-6.46 (m, 2H), 5.39 (s, 2H), 3.78 (s, 6H).

The preparation method of compound Z-A-17:

Preparation method obtains compound Z-A-17, yield 75.3% with compound Z-A-1.

Compound Z-A-18, Z-A-20, Z-A-21, Z-A-22

Compound Z-A-18, Z-A-20, Z-A-21, Z-A-22 are using Z-A-1-e as raw material, the side of reference compound Z-A-17 Method preparation, the difference is that changing 5- diuril azoles -2- amine in step 1 into 3- methyl-1,2,4- thiadiazoles -5- amine, isoxazole-respectively 3- amine, pyrimidine -2- amine, 5- fluorine pyridine -2- amine.

Compound Z-A-19

For compound Z-A-19 using Z-A-1-e as raw material, prepared by the method for reference compound Z-A-1, The difference is that changing Z-A-2-d in step 5 into N- (2,4- dimethoxy-benzyl) thiazole -2- amine.

The preparation method of compound Z-B-1:

Step 1: to compound Z-B-1-a's (0.94g, 3.06mmol) and compound Z-B-1-b (0.5g, 2.7mmol) Pd (dppf) Cl is added in Isosorbide-5-Nitrae-dioxane solution₂(0.186g, 0.3mmol), cesium carbonate (1g, 5.4mmol).In N₂Under atmosphere, Reaction mixture stirs 5h at 95 DEG C, is poured into 50ml water after reaction solution is cooled to room temperature, and is extracted with DCM (50ml x 3) It takes, merges organic phase, dry with anhydrous sodium sulfate, concentration obtains 400mg white solid Z- through Combi-flash column chromatographic purifying B-1-c, ESI-MS:301 (M+H)⁺。

Step 2: into the 20ml methanol solution of compound Z-B-1-c (0.38g, 1.27mmol) be added Pd/C (0.136g, 0.13mmol).2h is stirred at room temperature in reaction mixture under a hydrogen atmosphere.Filtering reacting liquid is concentrated to give 300mg compound Z-B-1, no It is purified to be directly used in the next step.ESI-MS:303 (M+H)⁺。

The preparation method of compound Z-B-2:

Into the acetic acid solution of compound Z-B-2-a (0.2g, 1.08mmol) be added sodium cyanoborohydride (0.136g, 2.16mmol), after 6h being stirred at room temperature, EA extraction is added into reaction solution, organic phase is washed with water and saturated sodium bicarbonate solution, Anhydrous sodium sulfate is dry, is concentrated to give 238mg yellow oil Z-B-2, ESI-MS:188.1 (M+H)⁺.It is directly used in anti-in next step It answers.

The preparation method of compound Z-B-3:

Step 1: in there-necked flask, compound Z-B-3-a (10g, 41.67mmol) being dissolved in anhydrous THF (200mL), instead Liquid is answered to be cooled to -78 DEG C, in N₂It is slowly added dropwise under protection LDA (2.5M, 18mL, 45.84mmol), is slowly added dropwise 1,1,2- after 1h Three chloro- 1,2,2- trifluoroethane (8.5g, 45.84mmol).Reaction monitors reaction raw materials and disappears in -78 DEG C of five h of holding.50mL Water quenching reaction is extracted with ethyl acetate (3 x 100mL), and drying is spin-dried for obtaining 10g crude yellow oil Z-B-3-b.

Step 2: compound Z-B-3-b (10g, 36.5mmol) being dissolved in the concentrated sulfuric acid (8mL), is slowly added into nitre at 0 DEG C 2h is stirred at room temperature in sour (3mL), reaction.TLC monitors reaction raw materials and disappears, and 20mL water is added after being cooled to 0 DEG C in reaction solution, uses Ph value is tuned into neutrality by sodium hydrate aqueous solution, and (3 x 100mL), organic phase saturated sodium bicarbonate is extracted with dichloromethane (50mL) and saturated sodium-chloride (50mL) are washed, and organic phase drying is spin-dried for.Column chromatographic purifying (petroleum ether: ethyl acetate=10: 1) To yellow oil Z-B-3-c (8g, two step yields 60%).

Step 3: ammonium chloride (2.65g, 50mmol) being dissolved in water (80mL), is added iron powder (4.2g, 75mmol), system adds Heat reflux 30 minutes, then slowly low plus compound Z-B-3-c (8g, 25mmol).Reaction solution stirs 16h under reflux.System Filtering, filtrate are extracted with ethyl acetate (3 x 80mL), and drying is spin-dried for obtaining black solid Z-B-3-d (5g, yield 69%).

Step 4: compound Z-B-3-d (4g, 12.5mmol) being dissolved in methanol (60mL), is added Pd/C (200mg), is passed through Hydrogen.16h is stirred in reaction at normal temperature, and LC-MS monitors reaction raw materials and disappears, and filtering, filtrate drying is spin-dried for obtaining black solid Z-B-3-e (1.9g, yield 73%).

Step 5: compound Z-B-3-e (1.9g, 9mmol) being dissolved in concentrated hydrochloric acid (11mL), is cooled to 0 DEG C, then slowly The aqueous solution of sodium nitrite (0.76g, 11mmol) is added.Then 3mL stannous chloride is slowly added dropwise in 0 DEG C of stirring 1h in reaction The hydrochloric acid solution of (3.4g, 18mmol), reaction solution stir 1h at 0 DEG C.Reaction solution filtering, solid are washed with water, are dried to obtain white Color solid Z-B-3-f (1g, yield 49%).

Step 6: compound Z-B-3-f (1g, 4.4mmol) being dissolved in methylene chloride (10mL), is then slowly added into different Butyraldehyde (410mg, 5.7mmol) and trifluoracetic acid (2.5g, 22mmol).1h is stirred in reaction under reflux, is then cooled to room temperature And sodium borohydride (502mg, 13.2mmol) is added, it stirs ten minutes under reflux.TLC monitors reaction raw materials and disappears, reaction solution It is cooled to 0 DEG C and Ph value is tuned into 9 with ammonium hydroxide, 30mL water is added, is extracted with dichloromethane (3 x 50mL), organic phase saturation chlorine Change sodium (20mL) to wash, drying is spin-dried for.Column chromatographic purifying (petroleum ether: ethyl acetate=5: 1) obtains yellow liquid Z-B-3 (260mg, yield 26%).ESI-MS:266 (M+H)⁺。

The preparation method of compound Z-B-4:

By compound Z-B-4-a (1g, 5.585mmol), isobutylaldehyde (0.42g, 5.866mmol), TFA (3.18g, 27.89mmol) and the mixture of the DCM of 25ml stirs 1.5h at 45 DEG C, adds sodium borohydride (634mg, 16.76mmol) Stirring 10 minutes.It is cooling under ice bath, ammonium hydroxide is added, adds 50ml water, is extracted with DCM, organic phase merges concentration, through Combi- Flash column chromatographic purifying obtains 608mg yellow oil Z-B-4, yield 60.2%, ESI-MS:182.1 (M+H)⁺。

The preparation method of compound Z-B-5:

Under 1:0 DEG C of step stirring, add into the HCl solution (6M, 50ml) of compound Z-B-5-a (2.0g, 15.49mmol) Enter the aqueous solution 20ml of sodium nitrite (1.12g, 16.27mmol).After being stirred 30 minutes at 0 DEG C of reaction mixture, it is added dropwise at 0 DEG C The HCl solution (6M, 75ml) of one hydration stannous chloride (6.43g, 30.98mmol).Drop finishes, and reaction mixture stirs at 0 DEG C 1h, isolated solid, is washed with EA, is dried in vacuo to obtain 2.2g white solid Z-B-5-b, yield 87%.

Under 2:0 DEG C of step stirring, to compound Z-B-5-b (2.2g, 11.17mmol) and isobutylaldehyde (886mg, TFA (6.37g, 55.83mmol) is added in chloroform (100ml) solution 12.28mmol), was reacted at 55 DEG C of reaction mixture Night.Reactant is cooled to 0 DEG C, sodium borohydride (633mg, 16.75mmol) 0 DEG C of reaction 2h afterwards is added, ammonium hydroxide, which will be added, to react The pH value of mixture is adjusted to 8, is extracted with DCM, and organic phase is washed with brine, dry, crude product is concentrated to give, through Combi-flash Column chromatographic purifying obtains grease Z-B-5 (180mg), yield 80.7%.ESI-MS:200 (M+H)⁺。

The preparation method of compound Z-B-6:

Preparation method with compound Z-B-5 preparation, unlike change the Z-B-5-a in step 1 into 3, 4- difluorobenzylamine.ESI-MS:184.1 (M+H)⁺。

The preparation method of compound Z-B-7:

At 1:0 DEG C of step, borine is added dropwise into the THF solution (10ml) of compound Z-B-7-a (0.5g, 2.16mmol) THF solution (5.4ml, 1M), reaction mixture are warmed to room temperature stirring 1h, are quenched with the cryosel acid solution of 6N, with unsaturated carbonate hydrogen It is 7-8 that sodium solution, which adjusts pH value, is extracted with EA (2 x 30ml).Organic phase 20ml salt water washing, anhydrous sodium sulfate is dry, mistake Filter, concentration, crude product obtain 250mg blue grease Z-B-7-b (yield 57.4%) through Combi-flash column chromatographic purifying, ESI-MS:202.7 (M+H)⁺。

Step 2: cyano hydroboration being added into the acetic acid solution (5ml) of compound Z-B-7-b (220mg, 1.09mmol) Sodium (138mg, 2.19mmol), reaction mixture stir 3h at room temperature, and 10ml water is added, and adjust pH value with 2N potassium hydroxide solution For 7-8, (3 x 20ml) is extracted with EA, combined organic phase is washed with brine, and anhydrous sodium sulfate dries, filters, concentration, thick to produce Product obtain 173mg blue grease Z-B-7 (yield 68.6%), ESI-MS:204.1 (M+H through Combi-flash column chromatographic purifying )⁺。

The preparation method of compound Z-B-8:

Step 1: to compound Z-B-8-a (0.2g, 1.24mmol) aqueous solution (7ml) in be added hydrochloric acid (37%, 0.5ml), 2,2,2- trichloroethanes -1,1- glycol (0.22g, 1.34mmol), hydroxylamine hydrochloride (0.26g, 3.72mmol) and sulfuric acid Sodium (1.4g).Reaction mixture stirs 1h at 110 DEG C, cooling, and filtering, filter cake is washed with water, and obtains 0.3g yellow solid Z-B- 8-b.ESI-MS:233 (M+H)⁺。

Step 2: to concentrated sulfuric acid 1ml is added in compound Z-B-8-b (50mg, 0.22mmol), reaction mixture is at 60 DEG C Lower stirring rises to 80 DEG C after 15 minutes and stirs 15 minutes.Reaction mixture is poured into ice water, is extracted with EA, organic phase saturation Sodium bicarbonate solution washing, anhydrous sodium sulfate is dry, is concentrated to give red solid, obtains 20mg through Combi-flash column chromatographic purifying Red solid Z-B-8-c, ESI-MS:215.0 (M+H)⁺。

Step 3 is to 4: using compound Z-B-8-c as raw material, prepared by the method for reference compound Z-B-7, obtains blue solid Z- B-8, ESI-MS:188.1 (M+H)⁺。

The preparation method of compound Z-B-9:

Step 1: by compound Z-B-9-a (1g, 7.52mmol), 2- N-Propyl Bromide (2.77g, 22.56mmol) and potassium carbonate The DMF solution (10ml) of (3.11g, 22.56mmol) stirs 4h at 60 DEG C, and 20ml water is added, and is extracted with EA (2 x 20ml), Combined organic phase is dried, filtered, is concentrated, through Combi- with water (3 x 20ml), salt water (20ml) washing, anhydrous sodium sulfate Flash column chromatographic purifying obtains 561mg brown oil Z-B-9-b, yield 43%, ESI-MS:176.1 (M+H)⁺。

Step 2: using compound Z-B-9-b as raw material, prepared by the method for reference compound Z-B-2, obtains compound Z-B-9, Yellow oil, ESI-MS:178.1 (M+H)⁺。

The preparation method of compound Z-B-10:

Preparation method with compound Z-A-4 preparation, unlike change the Z-B-4-a in step 1 into 1- (3,4- dichlorophenyl) hydrazine hydrochloride.ESI-MS:216.1 (M+H)⁺。

The preparation method of compound Z-B-11:

Step 1: will be cooling under the mixture ice bath of phosphorus oxychloride (1.55g, 10.11mmol) and 3mlDMF, chemical combination is added dropwise The 10mlDMF solution of object Z-B-7-b (1.01g, 5.02mmol), stirs 1h under ice bath, reaction mixture is poured into ice water, Adjusting pH value with potassium hydroxide solution is 10, and filtering is washed with water, dry 810mg white solid Z-B-11-a.ESI-MS: 230.1(M+H)⁺。

Step 2: will be cooling under the mixture ice bath of compound Z-B-11-a (770mg, 3.36mmol) and 20mlDMF, point It criticizes and LiAlH is added₄(300mg, 7.91mmol) is added to 70 DEG C, stirs 2h, be cooled to room temperature.0.5ml water is added under ice bath, 15% sodium hydroxide solution of 0.5ml, filtering, filtrate water washing, EA extract (2 x 20ml), organic phase anhydrous sodium sulfate It is dry, it is concentrated to give 440mg white solid Z-B-11, yield 60.9%.

The preparation method of compound Z-B-12:

To compound Z-B-12-a (400mg, 2.04mmol), compound Z-B-12-b (567mg, 2.04mmol) and carbonic acid Pd (dppf) Cl is added in the water and dioxane (15ml) mixed solution of caesium (1.33g, 4.08mmol)₂(146.2mg, 0.2mmol), reaction mixture is in N₂Under atmosphere, 90 DEG C of stirring 5h are cooled to room temperature, pour into 50ml water, with EA (3 x 50ml) Extraction, anhydrous sodium sulfate is dry, and concentration obtains 130mg grey grease Z-B-12 through Combi-flash column chromatographic purifying.

The preparation method of compound Z-B-13:

At 1:0 DEG C of step, hydrogenation is added into DMF (10ml) solution of compound Z-B-8-c (500mg, 2.33mmol) After reaction mixture stirs 30 minutes at 0 DEG C, 1- (bromomethyl) -4- methoxybenzene is added in sodium (1.2mg, 4,66mmol) (558mg, 2.79mmol).Reaction mixture stirs 2h at 0 DEG C, pours into ice water, and EA extracts (2 x 50ml), anhydrous slufuric acid Sodium is dry, concentration, obtains 550mg yellow solid Z-B-13-a through Combi-flash column chromatographic purifying, yield 70%, ESI-MS: 336(M+H)⁺。

Step 2: hydroxide being added into the ethylene glycol solution (25ml) of compound Z-B-13-a (530mg, 1.58mmol) Potassium (531mg, 9.49mmol), hydrazine hydrate (13.3g, 265.8mmol), reaction mixture 70 DEG C of stirring 1h under an argon, Entering in water, EA extracts (2 x 50ml), and anhydrous sodium sulfate is dry, concentration, obtain yellow solid Z-B-13-b, yield 98.4%, ESI-MS:322 (M+H)⁺。

At 3:0 DEG C of step, hydrogenation is added into the DMF solution (10ml) of compound Z-B-13-b (200mg, 0.62mmol) Sodium (100mg, 2.49mmol) stirs 30 minutes at 0 DEG C of reaction mixture, is added dropwise potassium iodide (264mg, 1.86mmol), at 0 DEG C Lower stirring 4h, is poured into ice water, and EA extracts (2 x 50ml), and anhydrous sodium sulfate is dry, and concentration is chromatographed through Combi-flash column Purify to obtain 120mg yellow solid Z-B-13-c, yield 55.3%, ESI-MS:350 (M+H)⁺。

Step 4: by the trifluoroacetic acid solution (2.5ml) of compound Z-B-13-c (100mg, 0.29mmol) at 150 DEG C It microwave reaction 30 minutes, being concentrated under reduced pressure, saturated sodium bicarbonate solution is added, EA extracts (2 x 50ml), and anhydrous sodium sulfate is dry, Concentration, obtains 60mg compound Z-B-13, without further purification directly in next step, ESI-MS:228 (M-H)^-。

The preparation method of compound Z-B-14:

At 1:0 DEG C of step, nitrous acid is added into the acetic acid solution (8ml) of compound Z-B-14-a (1g, 8.06mmol) The aqueous solution (1.3ml) of sodium (0.56g, 8.13mmol).Nitric acid (0.67ml) is added after stirring 1h at 0 DEG C in reaction mixture. 16h is stirred at room temperature in reaction mixture, pours the mixture into water, is extracted with EA, and organic phase is washed with saturated sodium bicarbonate solution, Anhydrous sodium sulfate is dry, and concentration obtains 550mg yellow oil Z-B-14-b, ESI-MS through Combi-flash column chromatographic purifying: 221.9(M-H)-。

Step 2: Pd/C (100mg) is added into the methanol solution (10ml) of compound Z-B-14-b (900mg, 4mmol), In H₂Under atmosphere, 4h, reaction mixture filtering is stirred at room temperature, concentration filtrate obtains 600mg yellow solid Z-B-14-c, ESI-MS: 192.0(M-H)-。

Step 3: to compound Z-B-14-c (230mg, 1.19mmol) DMF solution (2ml) in be added urea (215mg, 3.57mmol), 160 DEG C of reaction mixture microwave reaction 15 minutes, is added EA, is washed with saturated sodium chloride solution in reaction mixture It washs, anhydrous sodium sulfate is dry, and concentration obtains 20mg brown solid Z-B-14, ESI-MS through Combi-flash column chromatographic purifying: 218.0(M-H)^-。

The preparation method of compound Z-B-15:

Step 1: by compound Z-B-8-c (1.568g, 7.258mmol), potassium hydroxide (2.439g, 43.551mmol), The mixture of hydrazine hydrate (5ml) and 15ml ethylene glycol stirs 2h at 70 DEG C, is cooled to room temperature, adds water, molten with 10% hydrochloric acid Liquid tune pH value is 7, is extracted with EA, and organic phase is washed with brine, and anhydrous sodium sulfate is dry, and concentration is chromatographed through Combi-flash column Purify to obtain 700mg yellow solid Z-B-15-a, yield 53%, ESI-MS:200.0 (M-H)-.

Step 2: in N₂Under atmosphere, by compound Z-B-15-a (467mg, 2.3mmol), di-tert-butyl dicarbonate (1.28g, 5.865mmol), the mixture of sodium bicarbonate (780mg, 9.285mmol) and THF (20ml) are stirred at room temperature 2 days, concentration, 420mg pink solid Z-B-15-b, yield 56.1%, ESI-MS:202.1 (M-100 are obtained through Combi-flash column chromatographic purifying )⁺。

Step 3: by compound Z-B-15-b (290mg, 0.96mmol), 15mlDMF and sodium hydride (73mg, 60%, Mixture 1.825mmol) stirs 1h at room temperature, and the DMF solution (5ml) of Bromofume (240mg, 1.278mmol), room is added After temperature stirring 1h, it is added sodium hydride (73mg, 60%, 1.825mmol), stirs 2h at 80 DEG C of reaction solution.It is cooled to 0 DEG C, with full It is quenched with ammonium chloride solution, 50ml water is added, extracted with EA (3 x 30ml), combined organic phase is washed with brine, and is concentrated, warp Combi-flash column chromatographic purifying obtains 65mg yellow solid Z-B-15-c, yield 20.6%, ESI-MS:228 (M-100)⁺。

Step 4: by compound Z-B-15-c (65mg, 0.198mmol), 4ml methanol and hydrochloric acid (1ml, 4N, 4mmol) Mixture is stirred overnight at room temperature, and concentration of reaction solution obtains 43mg white solid Z-B-15, yield 95.2%, ESI-MS:228 (M+H )⁺。

The preparation method of compound Z-B-16:

Step 1 is to 2: using compound Z-B-16-a as raw material, the method preparation of step 1 to 2 in reference compound Z-B-8, Obtain compound Z-B-16-c, ESI-MS:232.0 (M+H)⁺。

Step 3: the mixture of compound Z-B-16-c (2g, 8.658mmol) and hydrazine hydrate (20ml) are stirred at 135 DEG C 3h is mixed, is poured into ice water after ice bath is cooling, with the hydrochloric acid solution adjustment pH value of 6mol/L, filters obtained solid, washing, vacuum is done It is dry, obtain compound Z-B-16-d.

Under 4:-78 DEG C of step stirring, it is added into the THF solution of compound Z-B-16-d (200mg, 0.92mmol) After TBEDA (427mg, 3.68mmol), it is added dropwise n-BuLi (236mg, 3.68mmol), reaction mixture stirs 1h at -78 DEG C, It is slowly added to iodomethane (523mg, 3.68mmol), 4h is stirred at room temperature in reaction mixture, and reactant is poured into ice water, is extracted with EA It takes (50ml x2), anhydrous sodium sulfate is dry, and concentration obtains 100mg compound Z-B-16 through Combi-flash column chromatographic purifying, produces Rate 44.24%.ESI-MS:244 (M-H)^-。

The preparation method of compound Z-B-17:

Under being stirred at 1:0 DEG C of step, to compound Z-B-17-a (6g, 31.089mmol), methyl chloroacetate (4.7g, 49.743mmol) and the mixture of THF (40ml) in be added potassium tert-butoxide (6.96g, 62.2mmol) THF solution (40ml), 0 2h is stirred at DEG C, reaction mixture is poured into water, is extracted with EA, and organic phase is dry with anhydrous sodium sulfate, is concentrated to give 3.21gization Close object Z-B-17-b, ESI-MS:265 (M+H)⁺。

Step 2: into the 20ml acetum of compound Z-B-17-b (3.21g, 12.1mmol) be added iron powder (4g, 72.7mmol), 60 DEG C of stirring 3h, filtering, are washed with saturated sodium bicarbonate solution, EA extraction, and organic phase is dry with anhydrous sodium sulfate It is dry, it is concentrated to give 400mg compound Z-B-17-c, yield 16%, ESI-MS:203 (M+H)⁺。

Step 3 is to 5: using compound Z-B-17-c as raw material, the method preparation of step 2 to 4 in reference compound Z-B-15, The difference is that changing the Bromofume in step 3 into iodomethane, white solid Z-B-17, ESI-MS:229 (M-H) are obtained^-。

The preparation method of compound Z-B-18:

Step 1 is to 2: using compound Z-B-18-a as raw material, the method preparation of step 1 to 2 in reference compound Z-B-8, Obtain red solid Z-B-18-c, ESI-MS:164 (M-H)^-。

Step 3 is to 6: using compound Z-B-18-c as raw material, the method preparation of step 1 to 4 in reference compound Z-B-15, Obtain yellow oil Z-B-18, ESI-MS:176 (M-H)^-。

The preparation method of compound Z-B-42:

Using compound 3-chlorin -4- fluoroaniline as raw material, prepared by the step of reference compound Z-B-18, different It is that step 4 reaction condition changes 60 DEG C into and is stirred overnight, step 5 Bromofume changes iodomethane into, and reaction condition, which changes into, to be stirred at room temperature Overnight.ESI-MS:214.1 (M+H)⁺

The preparation method of compound Z-B-19:

Step 1: under nitrogen atmosphere, by compound Z-B-19-a (800mg, 3.6mol), Pd/C (800mg, 10%wt) and second 16h is stirred at room temperature in the mixture of alcohol (10ml), and filtering is concentrated to give 650mg compound Z-B-19-b, yield 94%.

Step 2: by compound Z-B-19-b (0.1g, 0.52mmol) and 2- (ethoxymeyhylene) malononitrile The aqueous isopropanol (2ml) of (1.04mol, 0.12g) stirs 16h at 80 DEG C, and concentration of reaction solution, residue is purified to obtain chemical combination Object Z-B-19, ESI-MS:203 (M+H)⁺。

The preparation method of compound Z-B-20:

Step 1: the mixture of compound Z-B-20-a (1g, 5.88mmol) and thionyl chloride (5ml) is anti-at 80 DEG C 3h is answered, is cooled to room temperature, residue is concentrated to give, is dissolved the residue in THF (10ml), AMMONIA TREATMENT is used at 0 DEG C, is stirred at room temperature Overnight, concentration.Residue suspends in water, filtering, and filter cake is dry after being washed with water, and obtains 0.72g white solid Z-B-20-b, directly It connects for lower step, ESI-MS:170 (M+H)⁺。

Step 2: will be reacted at 70 DEG C of mixture of compound Z-B-20-b (3g, 17.8mmol) and thionyl chloride (10ml) 6h, reaction mixture are cooled to room temperature, and are concentrated under reduced pressure, obtained solid is dissolved in DCM, with saturated sodium bicarbonate, salt water washing, Anhydrous sodium sulfate is dry, is concentrated to give 2.64g yellow solid Z-B-20-c, is directly used in lower step without further purification.

Step 3: the n-butanol of compound Z-B-20-c (2.64g, 17.51mmol) and hydrazine hydrate (3g, 60mmol) is molten Liquid (15ml) back flow reaction 4h, is cooled to room temperature, and 3.15g brown oil Z-B-20-d is concentrated under reduced pressure to obtain, is directly used in lower step, ESI-MS:164 (M+H)⁺。

Step 4: by compound Z-B-20-d (3.15g, 19.32mmol) and isobenzofuran -1,3- diketone (5.99g, Mixture 40.51mmol) reacts 30 minutes at 170 DEG C, and EA is added before reaction mixture is cooled to room temperature, by what is obtained Solid filters to obtain 4.8g yellow solid Z-B-20-e, ESI-MS:294.1 (M+H)⁺。

Step 5: by compound Z-B-20-e (1g, 3.4mmol), iodomethane (0.49g, 3.44mmol), potassium carbonate 60 DEG C of reaction 8h of DMF solution of (0.95g, 6.88mmol) are cooled down in falling back, and filter obtained solid, and it is solid to obtain 0.6g yellow Body Z-B-20-f, yield 57%, ESI-MS:308.1 (M+H)⁺。

At 6:-78 DEG C of step, Boron tribromide is added dropwise into the DCM solution of compound Z-B-20-f (0.54g, 1.76mmol) (9ml.1M, 8.78mmol), it is warmed to room temperature reaction overnight, pours into ice water, DCM extraction, organic phase is washed with water, anhydrous sodium sulfate It is dry, it is concentrated to give 2.5g yellow solid Z-B-20, ESI-MS:294.1 (M+H)⁺。

The preparation method of compound Z-B-41:

Using the fluoro- 4- methyl-benzonitrile of compound 2- as raw material, the step 3 of reference compound Z-B-20 to Step 6 preparation.ESI-MS:294.1 (M+H)⁺。

The preparation method of compound Z-B-21:

At 1:0 DEG C of step, two carbonic acid are added dropwise into the DCM solution (20ml) of compound Z-B-21-a (2g, 9.43mmol) The DCM solution (20ml) of di tert butyl carbonate (2.12g, 9.71mmol) stirs 4h, reaction solution saturated ammonium chloride (2 x at 0 DEG C It 100ml) washs, combined organic phase is dried, filtered with anhydrous sodium sulfate, is concentrated to give 2.99g yellow oil Z-B-21-b, no It is purified to be directly used in lower step.

Step 2: by compound Z-B-21-b (100mg, 0.32mmol), dimethyl amine (0.32ml, 0.64mmol), LiHMDS (0.5ml, 0.5mmol), Pd₂(dba)₃(15mg, 0.016mmol), RuPhos (30mg, 0.064mmol) and THF Under an argon, 20ml water is added in 65 DEG C of reaction 18h to the mixture of (5ml), and EA extracts (2 x 20ml), combined organic phase It is dry with anhydrous sodium sulfate, 50mg yellow oil Z-B-21-c is obtained through Combi-flash column chromatographic purifying, yield 56.8%, ESI-MS:277.2 (M+H)⁺。

At 3:0 DEG C of step, into the 10ml methanol of compound Z-B-21-c (1.95g, 7.06mmol) be added hydrochloric acid (4M, 10ml, 40mmol), it is warmed to room temperature stirring 3h, concentration, residue solution E A is filtered, and concentration filtrate obtains 1.43g white solid Z- B-21, yield 95.3%, ESI-MS:177 (M+H)⁺。

The preparation method of compound Z-B-22-g:

By compound Z-B-22-g1 (200mg, 1.031mmol), 3,4- dihydro -2H- pyrans (170mg, 2.061mmol), 1,2- dichloroethane solution, 40 DEG C of reaction 2h of p-methyl benzenesulfonic acid (20mg, 0.13mmol), are quenched with saturated sodium bicarbonate solution, DCM extraction, anhydrous sodium sulfate is dry, is concentrated to give 313mg colorless oil Z-B-22-g, is directly used in the next step.

The preparation method of compound Z-B-22:

Step 1: being slowly added to borine THF into the THF solution (40ml) of compound Z-B-22-a (5g, 21.23mmol) Solution (42.46ml).Reaction mixture is stirred overnight at room temperature, and with the slow quenching reaction of methanol, concentration of reaction solution, residue is molten In EA, water, 1N hydrochloric acid are successively used, the washing of 1N sodium hydroxide solution is concentrated to give 5g white solid Z-B-22-b.

Under 2:0 DEG C of step stirring, to compound Z-B-22-b (1g, 4.5mmol) and triethylamine (2.28g, 22.6mmol) DCM solution (20ml) in be added mesyl chloride (1.55g, 13.5mmol), 2h is stirred at room temperature in reaction mixture, pours into water In, DCM extraction is concentrated, and gained residue is dissolved in acetonitrile, is added triethylamine (910mg, 9mmol) and 2,2- dimethyl amine (710mg, 6.8mmol).Reaction mixture is stirred overnight at room temperature, and is poured into water, EA extraction, concentration, through Combi-flash column layer Analysis purifies to obtain 780mg brown oil Z-B-22-c, yield 56.4%.

Under 3:0 DEG C of step stirring, three are added into the 20mlDCM solution of compound Z-B-22-c (760mg, 2.46mmol) Ethamine (498mg, 4.93mmol), paratoluensulfonyl chloride (703mg, 3.7mmol) and DMAP (30mg, 0.247mmol), reaction are mixed It closes object to be stirred overnight at room temperature, pour into ice water, EA extraction is concentrated organic phase, obtains 300mg through Combi-flash column chromatographic purifying White solid Z-B-22-d, yield 70%.

Step 4: under argon atmospher, compound Z-B-22-d (800mg) is added into the 20mlDCM of alchlor (1.15g) DCM solution (5ml), reaction mixture is stirred overnight at room temperature, pour the mixture into ice water, DCM extraction, merging is concentrated has Machine phase obtains 250mg faint yellow solid Z-B-22-e, ESI-MS:241.9 (M-H)-through Combi-flash column chromatographic purifying.

Step 5: sodium borohydride being added into the acetic acid solution (2ml) of compound Z-B-22-e (20mg, 0.083mmol) (6mg, 0.166mmol), reaction mixture are stirred at room temperature 30 minutes, are poured into water, and adjust pH value with ammonium hydroxide and extract for 8, EA, dense Contract to obtain 40mg grease Z-B-22-f, yield 56%, ESI-MS:246 (M+H)⁺。

Step 6: under argon atmospher, by compound Z-B-22-f (180mg, 0.73mmol), Z-B-22-g (304mg, 1.1mmol), Pd (dppf) Cl₂The dioxane (5ml) of (16mg, 0.022mmol) and sodium carbonate (155mg, 1.46mmol) and Water (1ml) solution reacts 6h at 80 DEG C, and reaction mixture is poured into water, and DCM extraction, concentration, crude product is through Combi-flash Column chromatographic purifying obtains 150mg brown oil Z-B-22, yield 64.64%, ESI-MS:318.1 (M+H)⁺。

The preparation method of compound Z-B-23:

Step 1: sequentially added into the DMF solution of compound Z-B-23-a (2g, 0.0169mol) iodine (8.57g, 0.0338mmol), potassium hydroxide (3.69g, 0.0659mmol).Reaction mixture react at room temperature 3h after with 10% sodium bisulfate Solution is quenched, EA extraction, and organic phase water and salt water washing, anhydrous sodium sulfate is dry, is concentrated to give compound Z-B-23-b, ESI- MS:244.9 (M+H)⁺。

Step 2: by compound Z-B-23-b (100mg, 0.41mmol), compound Z-B-22-g (114mg, 0.41mmol), the mixture microwave 120 of tetra-triphenylphosphine palladium (47mg, 0.041mmol) and sodium carbonate (43mg, 0.41mmol) DEG C reaction 30 minutes, EA extraction, with water and salt water washing, anhydrous sodium sulfate was dry, concentration, chromatographs through Combi-flash column pure Change to obtain 202mg yellow oil Z-B-23, ESI-MS:185.1 (M-THP)⁺。

The preparation method of compound Z-B-24:

At 1:-78 DEG C of step, into the THF solution of compound Z-B-24-a (1.04g, 5mmol) be added dropwise n-BuLi (4ml, 10mmol), it after reaction mixture stirs 0.5h at -78 DEG C, is added DMF (1.46g, 20mmol), continues -78 DEG C of reaction 1h, It is quenched with water, EA extracts (3 x 20ml).Combined organic phase is washed with brine, and anhydrous sodium sulfate is dry, concentration, crude product warp Combi-flash column chromatographic purifying obtains 360mg yellow solid Z-B-24-b, yield 45.8%, ESI-MS:158 (M+H)⁺。

Step 2: sodium borohydride being added into the methanol solution (10ml) of compound Z-B-24-b (335mg, 2.13mmol) 2h is stirred at room temperature in (41mg, 1.07mmol), reaction mixture, and 5ml saturated ammonium chloride solution and 20ml salt water, EA extraction (3 is added X 20ml), colourless sodium sulphate is dry, and concentration obtains 210mg yellow oil Z-B-24 through Combi-flash column chromatographic purifying, produces Rate 62.1%, ESI-MS:160 (M+H)⁺。

The preparation method of compound Z-B-25:

Step 1: to compound Z-B-25-a (11g, 54.7mmol) and compound Z-B-25-b (10.23g, 82.1mmol) 120ml DCM solution in be added DIEA (10.59g, 82.1mmol), 16h is stirred at room temperature in reaction mixture, with 1N hydrochloric acid solution (50ml), salt water (50ml) washing, anhydrous sodium sulfate is dry, and concentration obtains 11.13g yellow through Combi-flash column chromatographic purifying Grease Z-B-25-c, yield 70.4%.

At 2:0 DEG C of step, into the acetonitrile solution (50ml) of compound Z-B-25-c (2.89g, 10mmol), it is added dropwise TMsOTf (0.56g, 2.5mmol), 16h is stirred at room temperature in reaction mixture, is quenched with saturated sodium bicarbonate solution, concentration, gained Residue is diluted with saturated sodium bicarbonate solution, and EA extracts (3 x 50ml), and combined organic phase is washed with brine, anhydrous slufuric acid Sodium is dry, and concentration obtains 300mg light yellow oil Z-B-25-d through Combi-flash column chromatographic purifying.

Step 3 is to 4: using compound Z-B-25-d as raw material, the method preparation of step 1 to 2 in reference compound Z-B-24, Obtain white solid Z-B-25, ESI-MS:165 (M+H)⁺。

The preparation method of compound Z-B-26:

At 1:0 DEG C of step, to compound Z-B-14-c (500mg, 2.59mmol), TEBAC (590mg, 2.59mmol) and Chloracetyl chloride (351mg, 3.11mmol) is added dropwise in the DCM solution (30ml) of sodium bicarbonate (870mg, 10.36mmol), reaction is mixed It closes after stirring 2h at 0 DEG C of object, in 50 DEG C of reaction 2h, reactant is poured into ice water, DCM extraction, combined organic phase salt water Washing, anhydrous sodium sulfate is dry, and concentration obtains 400mg brown solid Z-B-26-b, yield through Combi-flash column chromatographic purifying 66%, ESI-MS:232 (M-H)-.

Step 2: borane THF solution being added into the THF solution (5ml) of compound Z-B-26-b (250mg, 1.07mmol) (2.14ml).Reaction mixture return stirring 2h, is quenched with methanol, and concentration obtains 200mg through Combi-flash column chromatographic purifying Brown oil Z-B-26, yield 85%.

The preparation method of compound Z-B-27 to Z-B-29:

The preparation method of compound Z-B-27 to Z-B-29 with compound Z-B-2 preparation, unlike will be in step Z-B-2-a changes the chloro- 1H- indoles of 5,6- bis-, the chloro- 1H- indoles of 6- and 5- (trifluoromethyl) -1H- indoles into respectively.

The preparation method of compound Z-B-30 to Z-B-34:

The preparation method of compound Z-B-35:

The preparation method of compound Z-B-36:

The preparation method of compound Z-B-37:

1,2,3,4- tetrahydroisoquinoline -5- alcohol (1g, 6.7mmol) is dissolved in THF (10mL), sodium hydroxide is then added Water (9mL) solution and (Boc) of (0.35g, 8.7mmol)₂O (2.93g, 13.4mmol).2h is stirred at room temperature in reaction.TLC Tracking reaction, raw material disappear.25mL water is added, is extracted with ethyl acetate (3 x 50mL), drying is spin-dried for.Column chromatographic purifying (stone Oily ether: ethyl acetate=10: 1) white solid Z-B-37 (1.3g, yield 74%) is obtained.ESI-MS:194.1. (M-55)⁺。

The preparation method of compound Z-B-38:

Step 1: by Z-B-38-a (4.6g, 0.022mol), being dissolved in methylene chloride (500mL), be slowly added into triethylamine (5.7mL) and Boc acid anhydrides (5.7g, 0.026mol).2h is stirred at room temperature in reaction solution.50mL water is added, is extracted with dichloromethane (3 x 50mL), organic phase drying are spin-dried for, and crude product column chromatographic purifying (petroleum ether: ethyl acetate=10: 1) obtains colorless oil Object Z-B-38-b (6.8g, yield 92%).LC-MS:256.0 (M-55)⁺, 96.5% purity.

Step 2: compound Z-B-38-b (5g, 16mmol) being dissolved in methanol (50mL), is added Pd (dppf)₂Cl₂(0.6g, 0.8mmol), triethylamine (4.1mL, 32mmol) stirs 18h at 100 DEG C under 0.6MPa carbon monoxide pressure.Filtering rotation Dry, column chromatographic purifying (petroleum ether: ethyl acetate=4: 1) obtains colorless oil Z-B-38-c (2.3g, yield 49%).LC- MS:236.1 (M-55)⁺, 100% purity.

Step 3: compound Z-B-38-c (2.1g, 7.2mmol) being dissolved in methanol (30mL), is then slowly added into hydroboration Sodium (2.7g, 72mol).Reaction reflux 2h, TLC is shown about there are also 30% raw material, adds sodium borohydride (1.3g, 36mol), Continue two h that flow back.Reaction is cooled to room temperature, and 50mL aqueous ammonium chloride solution is added, is extracted with dichloromethane (3 x 50mL), dry It is spin-dried for.Column chromatographic purifying (petroleum ether: ethyl acetate=3: 1) obtains colorless oil Z-B-38 (1.8g, yield 91%).Product It is placed on room temperature, slowly becomes white solid.LC-MS:286.1 (M+Na)⁺, 97.99% purity.

The preparation method of compound Z-B-39 and Z-B-40:

Step 1: compound Z-B-38-a (8.1g, 26mmol) being dissolved in acetonitrile (100mL), is being separately added into vinyl just Butyl ether (13.0g, 130mmol), triethylamine (8.0g, 78mmol), triphenyl phosphorus (0.69g, 2.6mmol).Reaction system nitrogen After gas is replaced 3 times, palladium acetate (0.66g, 2.6mmol).Mixture under nitrogen protection, is heated to 95 DEG C and stirs 18h.It is cooling After filter, filtrate is spin-dried for obtaining brown oil crude product Z-B-39-a (12.6g) with Rotary Evaporators, and crude product is directly used in next Step.ESI-MS:332.1 (M+H)⁺。

Step 2: crude product Z-B-39-a (12.6g) being dissolved in methanol (50mL), is added 4N HCl (25mL).Mixture After 3h is stirred at room temperature, organic solvent is spun off with Rotary Evaporators.Water phase is extracted with ethyl acetate (3 X 50mL), is lost organic Phase.Water phase is spin-dried for Rotary Evaporators, is obtained brown solid Z-B-39-b (5.80g), and crude product is directly used in next step.ESI-MS: 176.0(M+H)⁺。

Step 3: crude product Z-B-39-b (5.80g) being dissolved in DCM (50mL), is added (BOC)₂O (5.5g, 0.025mol), triethylamine (4.3g, 0.042mol).Reaction 18h is stirred at room temperature in mixture.Reaction solution evaporated under reduced pressure, gained are thick Product obtain white solid Z-B-39-c (1.2g, three step yields: 20.6%) by column Chromatographic purification.ESI-MS:219.9 (M-t- Bu)⁺。

Step 4: compound Z-B-39-c (1.05g, 3.8mmol) being dissolved in methanol (20mL), sodium borohydride is added (0.29g, 7.6mmol), 2h is stirred at room temperature in mixture.Reaction solution pours into saturated sodium bicarbonate aqueous solution, with acetic acid second Ester (50mL) extraction.Organic phase is separated to be washed with saline solution (50mL).Anhydrous sodium sulfate is dry, filters.It is revolved with Rotary Evaporators It is dry.Residue column chromatographs (PE: EA=1: 3) give light yellow oil (1.0g) after purification.ESI-MS:276.1 (M-H)^-.Shallowly The chiral HPLC column of yellow oil be prepared into Z-B-39 (0.426g, yield: 43%), and retention time: 3.06 points, ee value: 99.12%.Z-B-40 (0.431g, yield: 43%), retention time: 4.02 points, ee value: 99.23%.¹H NMR (400MHz, CDCl3) δ: 7.42 (d, J=7.6Hz, 1H), 7.23 (t, J=7.6Hz, 1H), 7.06 (d, J=7.6Hz 1H), 5.09 (m, 1H), 4.72 (d, J=16.8Hz, 1H), 4.53 (d, J=16.8Hz, 1H), 3.63 (t, 2H), 2.86 (t, 2H), 1.49 (s, 12H)。

The preparation of compound Z-B-43

Step 1: potassium tert-butoxide is added into THF (7mL) solution that methanol (6.3mg, 0.5mmol) is stirred at room temperature (73.5mg, 0.66mmol) is stirred at room temperature 30 minutes, is cooled to subzero 35 DEG C, rapidly join compound Z-A-6 (150mg, THF (1mL) solution 0.33mmol), subzero 35 DEG C of stirrings 3h.Reaction terminates, and replys room temperature, and reaction solution is poured into water, acetic acid Ethyl ester extraction, separates dry organic phase, and reduced pressure purifies to obtain compound Z-90-a (80mg), ESI-MS:457 (M+H)⁺。

Step 2: using compound Z-90-a as raw material, prepared by step 2 method of reference compound Z-7, obtains compound Z-B- 43, ESI-MS:308 (M+H)⁺。¹H NMR (400MHz, DMSO-d₆): δ 8.46 (s, 1H), 7.63 (dd, J₁=6.4Hz, J₂= 4.0Hz, 1H), 7.37 (dd, J₁=6.8Hz, J₂=4.8Hz, 1H), 3.91 (s, 3H)

Embodiment 1:(Z-1) preparation

Into DMF (4ml) solution of compound Z-1-a (100mg, 0.45mmol) be added compound Z-A-1 (200mg, 0.38mmol), potassium carbonate (100mg, 0.76mmol) and sodium iodide (10mg), reaction mixture stir 2h at 100 DEG C, filtering Reaction solution, concentration, gained crude product obtain 41mg white solid Z-1 through Combi-flash column chromatographic purifying, yield 24.4%, ESI-MS:443.0 (M+H)⁺.1H NMR (400MHz, DMSO-d6): δ 7.92 (s, 1H), 7.74 (d, J=6.0Hz, 1H), 7.33 (d, J=10.4Hz, 1H), 6.96 (dd, J=8.4Hz, 2.4Hz, 1H), 6.81-6.76 (m, 1H), 6.45 (m, 1H), 4.27 (s, 2H), 3.34 (t, J=8.4Hz, 2H), 2.94 (t, J=8.4Hz, 2H)

Embodiment 2 to 5

The preparation method is the same as that of Example 1 by compound Z-2 to Z-4, the difference is that changing compound Z-1-a into 5- chlorine Yin respectively Diindyl quinoline, 5- methoxy-Indole quinoline, 5- methyl indol quinoline.

The preparation method is the same as that of Example 1 by compound Z-5, the difference is that compound Z-1-a and compound Z-A-1 are changed respectively At 5--bromo indole quinoline and compound Z-A-12.

Embodiment 6:(Z-6) preparation

Step 1: being prepared referring to the method for embodiment 1, obtain yellow oil Z-6-a, yield 42.3%, ESI-MS:608 (M +H)⁺。

Step 2: hydrochloric acid/dioxane being added into the 5ml methanol solution of compound Z-6-a (120mg, 0.2mmol) 3h is stirred at room temperature in (2ml), reaction mixture, concentration, purifies to obtain 4.6mg white solid Z-6 through HPLC, yield 4.6%, ESI-MS:508 (M+H)⁺。¹H NMR (400MHz, DMSO-d₆): δ 7.97 (s, 1H), 7.92 (d, J=6.0Hz, 1H), 7.29 (d, J=10.8Hz, 1H), 7.02 (s, 1H), 6.90 (d, J=8.0Hz, 1H), 6.31 (d, J=8.4Hz, 1H), 4.31 (s, 2H), 3.47-3.35 (m, 4H), 3.11-2.99 (m, 4H), 2.77-2.74 (m, 1H), 2.03-1.99 (m, 2H), 1.84-1.80 (m, 2H)

Embodiment 7:(Z-7) preparation

Step 1: by compound Z-B-2 (83mg, 0.44mmol), compound Z-A-1 (219mg, 0.44mmol), potassium carbonate The mixture of (122mg, 0.68mmol), sodium iodide (7mg, 0.044mmol) and acetonitrile (3ml) microwave reaction 15 at 120 DEG C Minute, filtering is washed with DCM, and filtrate is concentrated, obtains 60mg compound Z-7-a, yield through Combi-flash column chromatographic purifying 21.2%.

Step 2: 2h is stirred at room temperature in the mixture of compound Z-7-a (60mg, 0.093mmol) and trifluoroacetic acid (2ml), With being concentrated after 20ml dilution with toluene, 12.5mg yellow solid, yield 27.3%, ESI-MS:493.0 (M+H are purified to obtain through HPLC )⁺。¹H NMR(DMSO-d₆, 400MHz): δ 8.03 (s, 1H), 7.77 (d, J=6.4Hz, 1H), 7.35 (d, J=10.0Hz, 1H), 7.19-7.26 (m, 1H), 6.92 (d, J=8.0Hz, 1H), 6.83 (s, 1H), 4.44 (s, 2H), 3.43 (t, J= 8.4Hz, 2H), 3.04ppm (t, J=8.4Hz, 2H)

Embodiment 8 to 10, embodiment 100, embodiment 106-108, embodiment 112, embodiment 115, embodiment 118 are real Apply a 124-125

The preparation method of compound Z-8 to Z-10 is with embodiment 7, the difference is that changing compound Z-B-2 into chemical combination respectively Object Z-B-27, Z-B-28 and Z-B-29.

The preparation method of compound Z-100 is with embodiment 7, the difference is that changing compound Z-B-2 in step 1 into compound Z-B-15, compound Z-A-1 change compound Z-A-10 into, and reaction condition changes 80 DEG C of stirring 1h into.

The preparation method of compound Z-106 is with embodiment 7, the difference is that changing compound Z-B-2 in step 1 into compound Z-B-17, compound Z-A-1 change compound Z-A-11 into, and reaction condition changes 80 DEG C of stirring 1h into.

The preparation method of compound Z-107 is with embodiment 7, the difference is that changing compound Z-B-2 in step 1 into compound Z-B-17, compound Z-A-1 change compound Z-A-10 into, and reaction condition changes 80 DEG C of stirring 1h into.

The preparation method of compound Z-108 is with embodiment 7, the difference is that changing compound Z-B-2 in step 1 into compound Z-B-13, compound Z-A-1 change compound Z-A-19 into, and reaction condition changes 90 DEG C of stirring 3h into.

The preparation method of compound Z-112 is with embodiment 7, the difference is that changing compound Z-B-2 in step 1 into compound Z-B-17, compound Z-A-1 change compound Z-A-19 into, and reaction condition changes 90 DEG C of stirring 3h into.

The preparation method of compound Z-115 is with embodiment 7, the difference is that changing compound Z-B-2 in step 1 into compound Z-B-13, compound Z-A-1 change compound Z-A-10 into, and reaction condition changes 80 DEG C of stirring 3h into.

The preparation method of compound Z-118 is with embodiment 7, the difference is that changing compound Z-B-2 in step 1 into compound Z-B-15, compound Z-A-1 change compound Z-A-19 into, and reaction condition changes 90 DEG C of stirring 1h into.

The preparation method of compound Z-124 is with embodiment 7, the difference is that changing compound Z-B-2 in step 1 into compound Z-B-16, compound Z-A-1 change compound Z-A-10 into, and reaction condition changes 80 DEG C of stirring 3h into.

The preparation method of compound Z-125 is with embodiment 7, the difference is that changing compound Z-B-2 in step 1 into compound Z-B-36, compound Z-A-1 change compound Z-A-10 into, and reaction condition changes 80 DEG C of stirring 3h into.

Embodiment 11:(Z-11) preparation

Using 4--bromo indole quinoline as raw material, is prepared referring to the method for embodiment 7, obtain yellow solid Z-11, yield 8.93%, ESI-MS:459 (M+H)⁺。¹H NMR (400MHz, DMSO-d₆): δ 8.71 (s, 1H), 8.14 (s, 1H), 7.80 (d, J= 6.4Hz, 1H), 7.37 (d, J=10.0Hz, 1H), 7.00 (t, J=7.6Hz, 1H), 6.64 (d, J=8.2Hz, 1H), 6.44 (d, J=8.2Hz, 1H), 4.37 (s, 2H), 3.47 (t, J=8.2Hz, 2H), 3.00 (t, J=8.2Hz, 2H)

Embodiment 12 to 17

Compound Z-12 to Z-17 can refer to the method preparation of embodiment 11, unlike:

When prepare compound Z-12 and Z-13, by the Z-A-12 in 11 step 1 of embodiment change into respectively compound Z-A-1 and Z-A-3。

When prepare compound Z-14 to Z-17, by the Z-A-12 in 11 step 1 of embodiment change into respectively compound Z-A-1, Z-A-2, Z-A-4 and Z-A-4 change 4--bromo indole quinoline into compound Z-B-3, quinoline -6- alcohol, 6- fluoro- 1,2,3,4- tetra- respectively Hydrogen quinoline and 6- (trifluoromethyl) -1,2,3,4- tetrahydroquinolines.

Embodiment 18:(Z-18) preparation

Step 1: by 5- chlorine isoindoline hydrochloride (66mg, 0.347mmol), compound Z-A-4 (150mg, 0.279mmol), 5h is stirred at room temperature in the mixture of potassium carbonate (120mg, 0.868mmol) and 8ml acetonitrile, filtering, EA washing filter Cake, is concentrated filtrate, and crude product obtains 113mg white solid Z-18-a, ESI-MS:609.1 (M through Combi-flash column chromatographic purifying +H)⁺。

Step 2: using compound Z-18-a as raw material, referring to the method preparation of step 2 in embodiment 7, obtaining white solid Z- 18, ESI-MS:459 (M+H)⁺。¹H NMR (400MHz, DMSO-d₆): δ 8.29 (s, 1H), 7.84 (d, J=6.0Hz, 1H), 7.66 (d, J=10.0Hz, 1H), 7.41 (s, 1H), 7.34 (s, 2H), 4.36 (s, 2H), 4.31 (s, 2H), 4.29 (s, 2H)

Embodiment 19 to 38

It is prepared by the similar approach that compound Z-19 to Z-38 can refer to embodiment 7, unlike:

When prepare compound Z-19, the compound Z-B-2 in 7 step 1 of embodiment is changed into compound Z-B-4, compound Z-A-1 changes compound Z-A-12 into.

When prepare compound Z-22, the compound Z-B-2 in 7 step 1 of embodiment is changed into compound Z-B-30, compound Z-A-1 changes compound Z-A-12 into.

When prepare compound Z-23, the compound Z-B-2 in 7 step 1 of embodiment is changed into compound Z-B-30, compound Z-A-1 changes compound Z-A-8 into.

When prepare compound Z-24, the compound Z-B-2 in 7 step 1 of embodiment is changed into compound Z-B-30, compound Z-A-1 changes compound Z-A-9 into.

When prepare compound Z-29, the compound Z-B-2 in 7 step 1 of embodiment is changed into compound Z-B-10, compound Z-A-1 changes compound Z-A-11 into.

When prepare compound Z-30, the compound Z-B-2 in 7 step 1 of embodiment is changed into compound Z-B-10, compound Z-A-1 changes compound Z-A-10 into.

Prepare compound Z-20, Z-21, Z-25, Z-26, Z-27, Z-28, Z-31, Z-32, Z-33, Z-34, Z-36, Z- 37, when Z-38, the compound Z-B-2 in 7 step 1 of embodiment is changed into compound Z-B-4, Z-B-30, Z-B-31, Z-B- respectively 32、Z-B-33、Z-B-10、Z-B-34、Z-B-5、Z-B-35、Z-B-6、Z-B-7、Z-B-8、Z-B-9。

When prepare compound Z-35, the compound Z-B-2 in 7 step 1 of embodiment is changed into compound Z-B-6, compound Z-A-1 changes compound Z-A-11 into.

Embodiment 39:(Z-39) preparation

Step 1: by compound Z-A-1 (878mg, 1.71mmol), the mixture of 10mlDCM and 0.5ml trifluoroacetic acid exists 3h is stirred under ice bath, is filtered, and DCM washs filter cake, and concentration filtrate obtains 650mg white solid Z-39-a, ESI-MS:340 (M-H)-.

Step 2: by the fluoro- 3- Methyl-1H-indole (49mg, 0.328mmol) of 5-, potassium tert-butoxide (110mg, 0.985mmol), the mixture ice bath stirring of 15mlDMF 15 minutes are added compound Z-39-a (208mg, 0.657mmol), rise To room temperature reaction 3h, addition is quenched, EA extraction, and organic phase concentration prepares through HPLC and purifies to obtain compound Z-39, yield 54%, ESI-MS:455.0 (M+H)⁺,¹H NMR (500MHz, DMSO): δ 8.044 (s, 1H), 7.775 (d, J=6.5Hz, 1H), 7.381 (dd, J=4,8.5Hz, 1H), 7.301 (dd, J=2.5,9.5Hz, 1H), 7.275 (s, 1H), 6.972-6.930 (m, 1H), 6.385 (d, J=10Hz, 1H), 5.450 (s, 2H), 2.237 (s, 3H)

Embodiment 40

Using compound Z-B-11 and compound Z-39-a as raw material, referring to embodiment 39 Prepared by the method for step 2, MS [M+H]⁺: 521.0；¹H NMR (500MHz, DMSO-d₆): δ 8.30 (s, 1H), 7.83 (d, J= 6.0Hz, 1H), 7.52 (s, 1H), 7.49 (d, J=9.0Hz, 1H), 7.34 (s, 1H), 7.08 (d, J=9.0Hz, 1H), 6.52 (d, J=10.5Hz, 1H), 5.51 (s, 2H), 2.27 (s, 3H)

Embodiment 41:(Z-41) preparation

To compound Z-A-13 (75mg, 0.222mmol), add in the 4mlDMF solution of HATU (101mg, 0.266mmol) Enter DIEA (57mg, 0.444mmol), compound Z-B-10 (53mg, 0.244mmol) and DMAP (3mg, 0.0222mmol).Instead It answers mixture to be stirred overnight at room temperature, is poured into water, the organic phase of merging is concentrated, and it is white to be prepared into 64mg through Prep-HPLC in EA extraction Color solid, yield 54%, ESI-MS:534.9 (M+H)⁺。¹H NMR (500MHz, DMSO-d₆): δ 8.36 (s, 1H), 8.15 (d, J =8.5Hz, 1H), 7.93 (d, J=6.0Hz, 1H), 7.83 (d, J=9.5Hz, 1H), 7.60 (d, J=8.5Hz, 1H), 3.61 (s, 2H), 1.41 (s, 6H)

Embodiment 42:(Z-42) preparation

Step 1: it is prepared by the method for raw material reference compound Z-B-2 of the chloro- 1H- indoles of 5-, obtains compound Z-42-a, ESI-MS:154 (M+H)⁺。

Step 2: into the acetonitrile solution of compound Z-A-5 (134mg, 0.87mmol) be added Z-42-a (300mg, 0.87mmol) and filtrate is concentrated, through Prep- in potassium carbonate (240mg, 1.74mmol), 100 DEG C of reaction 1h of reaction mixture, filtering HPLC is prepared into 3.5mg yellow solid Z-42, ESI-MS:417 (M+H)⁺。¹H NMR (500MHz, DMSO-d6): δ 8.15 (s, 1H), 7.73 (d, J=6Hz, 1H), 7.20 (d, J=10Hz, 1H), 7.10 (s, 1H), 7.00 (d, J=8.5Hz, 1H), 6.49 (d, J=8.5Hz, 1H), 4.33 (s, 3H), 3.41 (t, J=8.5Hz, 2H), 3.36 (s, 3H), 2.98 (t, J=8Hz, 2H)

Embodiment 43:(Z-43) preparation

Step 1: using compound Z-B-12 and Z-A-1 as raw material, being prepared referring to the method for embodiment 1, obtain compound Z-43- A, yield 43.4%, ESI-MS:575 (M+H)⁺。

Step 2: hydrochloric acid/dioxane being added into the 5ml methanol solution of compound Z-43-a (120mg, 0.23mmol) (2ml), reaction mixture react at room temperature 3h, and concentration is prepared into 5.6mg white solid Z-43, ESI-MS:491 through Prep-HPLC (M+H)⁺。¹H NMR (400MHz, DMSO-d₆): δ 8.03 (s, 1H), 7.94 (d, J=6.4Hz, 1H), 7.81 (s, 2H), 7.38- 7.35 (d, J=10.8Hz, 2H), 7.25 (d, J=7.6Hz, 1H), 6.42 (d, J=8.0Hz, 1H), 4.36 (s, 2H), 3.47 (t, J=8.0Hz, 2H), 3.08 (t, J=8.2Hz, 2H)

Embodiment 44:(Z-44) preparation

Compound Z-39-a is added into the DMF solution (4ml) of compound Z-B-8-c (100mg, 0.465mmol) (160mg, 0.465mmol) and potassium carbonate (130mg, 0.93mmol), reaction mixture stirs 2h at 75 DEG C, into mixture EA is added, is washed with saturated sodium bicarbonate, anhydrous sodium sulfate is dry, and concentration is prepared into 2.11mg yellow solid through Prep-HPLC Z-44, ESI-MS:521.0 (M+H)⁺,¹H NMR (500MHz, DMSO-d₆): δ 8.48 (s, 1H), 7.87 (d, J=6.5Hz, 1H), 7.81 (d, J=8.5Hz, 1H), 7.71 (d, J=10.5Hz, 1H), 7.00 (d, J=8.5Hz, 1H), 4.96 (s, 2H).

Embodiment 45 to 49, embodiment 99, embodiment 102, embodiment 109-111, embodiment 113-114, embodiment 116-117, embodiment 119-123

Compound Z-45 to Z-49 preparation method with embodiment 44, unlike by the compound Z-B-8-c in step points Do not change the chloro- 3- methyl-1 H- indazole of compound Z-B-10,5-, Z-B-13, Z-B-14, Z-B-15 into.

Compound Z-99 preparation method is with embodiment 44, the difference is that changing the compound Z-B-8-c in step into chemical combination Object Z-B-15, compound Z-39-a change compound Z-A-17 into

Compound Z-102 preparation method is with embodiment 44, the difference is that changing the compound Z-B-8-c in step into chemical combination Object Z-B-42, reaction condition change 90 DEG C of stirring 8h into.

Compound Z-109 preparation method is with embodiment 44, the difference is that changing the compound Z-B-8-c in step into chemical combination Object Z-B-17, Z-39-a change Z-A-18 into.

Compound Z-110 preparation method is with embodiment 44, the difference is that changing the compound Z-B-8-c in step into chemical combination Object Z-B-17, Z-39-a change Z-A-17 into.

Compound Z-111 preparation method is with embodiment 44, the difference is that changing the compound Z-B-8-c in step into chemical combination Object Z-B-13, Z-39-a change Z-A-17 into.

Compound Z-113 preparation method is with embodiment 44, the difference is that changing the compound Z-B-8-c in step into chemical combination Object Z-B-13, Z-39-a change Z-A-18 into.

Compound Z-114 preparation method is with embodiment 44, the difference is that changing the compound Z-B-8-c in step into chemical combination Object Z-B-17, Z-39-a change Z-A-20 into.

Compound Z-116 preparation method is with embodiment 44, the difference is that changing the compound Z-B-8-c in step into chemical combination Object Z-B-15, Z-39-a change Z-A-18 into.

Compound Z-117 preparation method is with embodiment 44, the difference is that changing the compound Z-B-8-c in step into chemical combination Object Z-B-13, Z-39-a change Z-A-20 into.

Compound Z-119 preparation method is with embodiment 44, the difference is that changing the compound Z-B-8-c in step into chemical combination Object Z-B-15, Z-39-a change Z-A-20 into.

Compound Z-120 preparation method is with embodiment 44, the difference is that changing the compound Z-B-8-c in step into chemical combination Object Z-B-13, Z-39-a change Z-A-21 into.

Compound Z-121 preparation method is with embodiment 44, the difference is that changing the compound Z-B-8-c in step into chemical combination Object Z-B-17, Z-39-a change Z-A-21 into.

Compound Z-123 preparation method is with embodiment 44, the difference is that changing the compound Z-B-8-c in step into chemical combination Object Z-B-15, Z-39-a change Z-A-22 into, and reaction condition changes 60 DEG C of 3h into.

Embodiment 50:(Z-50) preparation

At 0 DEG C, 3- methyl-1,2,4- thiadiazoles-are added into the THF solution (2ml) of sodium hydride (15mg, 0.33mmol) 5- amine (15mg, 0.13mmol), compound of reaction 0 DEG C stir 30 minutes after, be added compound Z-A-14 (50mg, 0.11mmol).It is stirred at room temperature 30 minutes, EA is added into mixture, is washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry Dry, concentration is prepared into 18.37mg yellow solid Z-50, ESI-MS:535.0 (M+H) through Prep-HPLC⁺。¹H NMR (500MHz, DMSO-d₆): δ 7.7.83-7.78 (m, 1H), 7.37-7.31 (m, 1H), 7.27-7.18 (m, 1H), 6.54-6.48 (m, 1H), 4.40 (s, 2H), 3.23 (s, 2H), 2.26 (s, 3H), 1.39 (s, 6H)

Embodiment 51 to 53

Compound Z-51 to Z-53 can refer to the method preparation of embodiment 50, the difference is that by the 3- methyl-1 in step, 2,4- thiadiazoles -5- amine change thiazole -2- amine, chloro- 1,2,4- thiadiazoles -5- amine hydrochlorate of 3-, thiazole -4- amine salt acid into respectively Salt.

Embodiment 54 to 57

Compound Z-54 to Z-57 can refer to the method preparation of embodiment 44, the difference is that by the compound Z-B- in step 8-c changes compound Z-B-16, Z-B-36, Z-B-17, Z-B-18 into respectively.

Embodiment 58

Using compound Z-B-19 and compound Z-A-1 as raw material, is prepared referring to the method for embodiment 7, obtains compound Z-58, ESI-MS:508 (M+H)⁺。

Embodiment 60:(Z-60) preparation

Step 1: by compound Z-B-20 (100mg, 0.34mmol), compound Z-A-7 (471mg, 1.02mmol), carbonic acid 2h is stirred at room temperature in the mixture of potassium (94mg, 0.68mmol), DMSO (10ml), is poured into water, EA extraction, organic phase salt water Washing, anhydrous sodium sulfate is dry, and concentration obtains 128mg yellow solid Z-60-a through Combi-flash column chromatographic purifying.

Step 2: being raw material referring to the method for 7 step 2 of embodiment using compound Z-60-a, obtain white solid Z-60, ESI- MS:455.0 (M+H)⁺。¹H NMR (400MHz, DMSO-d₆): δ 8.74 (s, 1H), 7.77 (d, J=6.4Hz, 1H), 7.61 (d, J =6.4Hz, 1H), 6.98 (d, J=6.4Hz, 1H), 6.92 (d, J=7.6Hz, 1H), 6.86 (d, J=10.4Hz, 1H), 5.59 (s, 2H), 3.71 (s, 3H)

Embodiment 61 to 66, embodiment 71 to 77, embodiment 93

The preparation method of compound Z-61 to Z-66, Z-71 to Z-77 with embodiment 60, unlike:

When prepare compound Z-61, Z-62, the compound Z-B-20 in 60 step 1 of embodiment is changed into compound Z- respectively B-37、Z-B-38。

When prepare compound Z-63, the compound Z-B-20 in 60 step 1 of embodiment is changed into compound Z-B-38, chemical combination Object Z-A-7 changes compound Z-A-14 into.

When prepare compound Z-64, the compound Z-B-20 in 60 step 1 of embodiment is changed into compound Z-B-38, chemical combination Object Z-A-7 changes compound Z-A-2 into.

When prepare compound Z-65, the compound Z-B-20 in 60 step 1 of embodiment is changed into compound Z-B-39, chemical combination Object Z-A-7 changes compound Z-A-2 into.

When prepare compound Z-66, the compound Z-B-20 in 60 step 1 of embodiment is changed into compound Z-B-40, chemical combination Object Z-A-7 changes compound Z-A-2 into.

When prepare compound Z-71, the compound Z-B-20 in 60 step 1 of embodiment is changed into compound Z-B-39, chemical combination Object Z-A-7 changes compound Z-A-6 into.

When prepare compound Z-72, the compound Z-B-20 in 60 step 1 of embodiment is changed into compound Z-B-40, chemical combination Object Z-A-7 changes compound Z-A-6 into.

When prepare compound Z-73, the compound Z-B-20 in 60 step 1 of embodiment is changed into compound Z-B-39, chemical combination Object Z-A-7 changes compound Z-A-14 into.

When prepare compound Z-74, the compound Z-B-20 in 60 step 1 of embodiment is changed into compound Z-B-39, chemical combination Object Z-A-7 changes compound Z-A-16 into.

When prepare compound Z-75, the compound Z-B-20 in 60 step 1 of embodiment is changed into compound Z-B-40, chemical combination Object Z-A-7 changes compound Z-A-16 into.

When prepare compound Z-76, the compound Z-B-20 in 60 step 1 of embodiment is changed into compound Z-B-40, chemical combination Object Z-A-7 changes compound Z-A-15 into.

When prepare compound Z-77, the compound Z-B-20 in 60 step 1 of embodiment is changed into compound Z-B-37, chemical combination Object Z-A-7 changes compound Z-A-2 into.

When prepare compound Z-93, the compound Z-B-20 in 60 step 1 of embodiment is changed into compound Z-B-41, chemical combination Object Z-A-7 changes compound Z-A-2 into, and trifluoroacetic acid changes hydrazine hydrate into step 2, and reaction condition becomes the 5h that flows back.

Embodiment 67:(Z-67) preparation

Step 1: using compound Z-B-21 and Z-A-1 as raw material, being prepared referring to the method for embodiment 44, obtain yellow oil Z-67-a, ESI-MS:632.1 (M+H)⁺。

Step 2: using compound Z-67-a as raw material, is prepared referring to the method for 7 step 2 of embodiment, obtain yellow solid Z-67, ESI-MS:482.0 (M+H)⁺,¹H NMR (400MHz, DMSO-d₆): δ 8.07 (s, 1H), 7.83 (d, J=6.4Hz, 1H), 7.67 (d, J=9.6Hz, 1H), 6.70 (d, J=8.4Hz, 1H), 6.62~6.64 (dd, J₁=8.4Hz, J₂=2.4Hz, 1H), 6.53 (s, 1H), 4.37 (s, 2H), 4.15 (s, 2H), 3.58~3.62 (m, 2H), 2.95~3.02 (m, 2H), 2.87 (s, 6H)

Embodiment 68 and 69

The preparation method of compound Z-68 and Z-69 with embodiment 67, unlike, by the Z-A- in 67 step 1 of embodiment 1 changes Z-A-7 and Z-A-2 into respectively.

Embodiment 70:(Z-70) preparation

Into the 10mlTHF solution of compound Z-B-38 (88mg, 0.336mmol) be added potassium tert-butoxide (100mg, 0.898mmol).After being stirred at room temperature 30 points, it is added compound Z-A-6 (100mg, 0.224mmol).Reaction mixture is stirred at room temperature 30 minutes, water quenching is added to go out, EA extracts (4 x 40ml), merges organic phase, concentration, and crude product purifies to obtain 18mg through prep-HPLC White solid Z-70, ESI-MS:439.0 (M+H)⁺,¹H NMR (400MHz, DMSO-d₆): δ 9.03 (s, 2H), 7.95 (s, 1H), 7.58-7.54 (m, 1H), 7.48-7.43 (m, 2H), 7.39 (t, J=7.2Hz, 1H), 7.33 (d, J=7.2Hz, 1H), 5.30 (s, 2H), 4.37 (s, 2H), 3.46 (m, 2H), 3.09 (m, 2H)

Embodiment 78:(Z-78) preparation

Using compound Z-B-22 and Z-A-1 as raw material, referring to the side of embodiment 67 Method preparation, obtains white solid Z-78.ESI-MS:538.9 (M+H)⁺,¹H NMR (400MHz, DMSO-d6): δ 8.11 (s, 1H), 7.88 (s, 2H), 7.75 (d, J=6.0Hz, 1H), 7.51 (d, J=10.4Hz, 1H), 7.31 (d, J=2.0Hz, 1H), 7.17 (s, 1H), 3.98-3.92 (m, 4H), 2.95-2.90 (m, 4H)

Embodiment 80:(Z-80) preparation

Step 1: by compound Z-B-23 (100mg, 0.373mmol), compound Z-A-7 (345mg, 0.746mmol), hydrogen The mixture for changing sodium (30mg, 0.746mmol) and DMF (10ml) stirs 30h at 60 DEG C, and reaction mixture is poured into water, EA extraction, combined organic phase washed with water and salt water washing, anhydrous sodium sulfate is dry, and concentration is chromatographed through Combi-flash column Purify to obtain 102mg yellow oil Z-80-a, ESI-MS:710.3 (M+H)⁺。

Step 2: by the mixture of compound Z-80-a (165mg, 0.232mmol) and hydrochloric acid methanol (0.5ml, 4M) in room Temperature stirring 2h, is concentrated to give 165mg yellow solid Z-80-b, ESI-MS:626.2 (M+H)⁺。

Step 3: using compound Z-80-b as raw material, is prepared referring to the method for 7 step 2 of embodiment, obtain compound Z-80, ESI-MS:475.9 (M+H)⁺,¹H NMR (400MHz, DMSO-d₆): δ 12.23 (s, 1H), 8.77 (s, 1H), 8.37 (s, 2H), 8.20 (d, J=8.0Hz, 1H), 8.06 (d, J=6.8Hz, 1H), 7.84 (d, J=9.6Hz, 1H), 7.51 (t, J=7.2Hz, 1H), 7.43 (d, J=8.4Hz, 1H), 7.34 (t, J=7.6Hz, 1H)

Embodiment 81:(Z-81) preparation

Step 1: to compound Z-B-24's (20mg, 0.126mmol) and compound Z-A-2 (58mg, 0.126mmol) Potassium tert-butoxide (82mg, 0.252mmol) is added in 2mlTHF solution, 2h is stirred at room temperature in reaction mixture, adds water quenching to go out, EA extraction It takes, combined organic phase is washed with brine, and anhydrous sodium sulfate is dry, and concentration purifies to obtain 30mg yellow oil through prep-HPLC Z-81-a, yield 40%, ESI-MS:601.0 (M+H)⁺。

Step 2: using compound Z-81-a as raw material, is prepared referring to the method for 7 step 2 of embodiment, obtain compound Z-81, ESI-MS:451.0 (M+H)⁺。¹H NMR(DMSO-d₆, 400MHz): δ 9.57 (s, 1H), 8.58 (d, J=5.6Hz, 1H), 8.00 (d, J=8.4Hz, 1H), 7.87-7.93 (m, 2H), 7.77-7.87 (m, 2H), 7.71 (d, J=7.2Hz, 1H), 7.56 (d, J =11.6Hz, 1H), 6.09 (br.s., 1H), 5.85 (s, 2H)

Embodiment 82:(Z-82) preparation

To compound Z-65 (23mg, 0.049mmol), dripped in the mixture of triethylamine (0.0588mmol) and THF (2ml) Add chloroacetic chloride (0.0539mmol), reaction mixture ice bath reacts 3h, and water is added into reaction mixture, and EA is extracted, merging Organic phase is dry with anhydrous sodium sulfate, and concentration purifies to obtain 16mg yellow solid, ESI-MS:511 (M+H) through prep-HPLC⁺。¹H NMR (500MHz, DMSO): δ 7.973 (s, 1H), 7.711-7.676 (m, 1H), 7.305 (d, J=7.5Hz, 1H), 7.248- 7.175 (m, 1H), 7.119-7.089 (m, 1H), 6.988 (s, 1H), 5.870-5.832 (m, 1H), 4.874 (t, J= 16.5Hz, 1H), 4.573 (d, J=17Hz, 1H), 3.700-3.626 (m, 2H), 2.898 (td, J=5,10Hz, 1H), 2.784-2.771 (m, 1H), 2.118 (s, 1H), 2.089 (s, 2H), 1.592-1.572 (m, 3H)

Embodiment 83:(Z-83) preparation

Step 1: preparation method referring to compound Z-39-a preparation method.

Step 2: by compound Z-83-a (102mg, 0.621mmol), compound Z-B-25 (194mg, 0.621mmol), The mixture of potassium tert-butoxide (209mg, 1.863mmol) and DMF (10ml) stir 1h at 70 DEG C, after being cooled to room temperature, pour into In water, EA extraction merges organic phase water and salt water washing, and anhydrous sodium sulfate is dry, and concentration is purified through prep-HPLC 58.6mg white solid Z-83, ESI-MS:456.0 (M+H)⁺。¹H NMR (500MHz, DMSO-d₆): δ 7.89 (s, 1H), 7.69 (d, J=7.0Hz, 1H), 7.35-7.30 (m, 2H), 7.21 (t, 6.0Hz, 1H), 7.15 (d, J=7.5Hz, 1H), 7.09 (s, 3H), 5.17 (s, 2H), 4.78 (s, 2H), 3.86 (t, J=5.5Hz, 2H), 2.82 (t, J=5.0Hz, 2H)

Embodiment 84:(Z-84) preparation

Embodiment 85:(Z-85) preparation

Embodiment 86 to 89

The preparation method of compound Z-86 to Z-89 with embodiment 44, unlike, compound Z-B-8-c is changed into respectively Z-B-26,5- (trifluoromethyl) -1H- indoles, the chloro- 1H- indoles of 5- and Z-B-7-b, change compound Z-39-a into Z-A- respectively 4, Z-A-1, Z-A-1 and Z-A-4.

Embodiment 92:(Z-92) preparation

Z-92 with compound Z-83-a and 4- (trifluoromethyl) -2,3- dihydro -1H- indenes -1- alcohol for raw material, referring to embodiment Prepared by 83 method, reaction condition, which changes into, is stirred at room temperature 2h.

Embodiment 94:(Z-94) preparation

Step 1: using compound 1H- indoles -5- alcohol as raw material, prepared by step 2 method of reference compound Z-B-22, different Be to change mesyl chloride into tertiary butyl chloride, obtain compound Z-94-a, ESI-MS:247 (M-H)^-。

Step 2: using compound Z-94-a as raw material, prepared by step 2 method of reference compound Z-B-15, obtains compound Z- 94-b, ESI-MS:349 (M+H)⁺。

Step 3: fluorination four being added into THF (2ml) solution of the compound Z-94-b (50mg, 0.143mmol) of stirring Normal-butyl ammonium (375.1mg, 1.435mmol), is stirred at room temperature 0.5h.Reaction terminates, and is concentrated under reduced pressure, and adds water, and ethyl acetate extracts, Salt washing separates dry concentration organic phase and obtains compound Z-94-c (40mg), ESI-MS:233 (M-H)^-。

Step 4-5: using compound Z-94-c as raw material, prepared by the step 1-2 method of reference compound Z-7, unlike Changing Z-A-1 in Z-7 step 1 into Z-A-2, reaction condition, which changes into, is stirred at room temperature 4h, it obtains compound Z-94 (120mg), ESI-MS: 424(M-H)^-。¹H NMR (500MHz, DMSO-d₆): δ 13.26 (brs., 1H), 8.55 (s, 1H), 8.09 (s, 1H), 7.96 (d, J=7.0Hz, 1H), 7.65 (d, J=9.0Hz, 1H), 7.59 (d, J=2.0Hz, 1H), 7.23 (dd, J=9.0,2.0Hz, 1H), 6.83 (d, J=11.0Hz, 1H)

Embodiment 95:(Z-95) preparation

Step 1: zero DEG C, to 2- fluorine hexamethylene -1,3- diene of the compound furans -2- carboxylic acid (1g, 8.93mmol) of stirring Alchlor (2.14g, 16.1mmol) is added in (10ml) solution, ice bath stirring 1h.Remove ice bath, 75 DEG C of stirring 16h, reaction Terminate, be cooled to room temperature, pour into hydrochloric acid solution (2N, 50ml), ethyl acetate extraction, sodium bicarbonate solution is washed, and is merged organic Phase, hydrochloric acid tune PH are 3-4, and ethyl acetate extraction separates dry concentration organic phase, toluene is added and stirs 12h, filters to obtain compound Z-95-a (496mg), ESI-MS:189 (M-H)^-。

Step 2: using compound Z-95-a as raw material, prepared by step 1 method of reference compound Z-B-22, obtains compound Z- 95-b。

Step 3-4: using compound Z-95-b as raw material, prepared by the step 1-2 method of reference compound Z-7, unlike Change Z-A-1 in Z-7 step 1 into Z-A-2, reaction condition, which changes into, is stirred at room temperature 1.5h, obtains compound Z-95 (2.2mg), ESI- MS:468 (M+H)⁺。¹H NMR(DMSO-d₆, 500MHz): δ=8.13-8.25 (m, 2H), 7.97 (d, J=8.0Hz, 1H), 7.80 (dd, J=10.5,2.5Hz, 1H), 7.76 (d, J=7.5Hz, 1H), 7.71 (d, J=6.5Hz, 1H), 7.56-7.65 (m, 2H), 7.48-7.55 (m, 1H), 5.72ppm (s, 2H)

Embodiment 96:(Z-96) preparation

Compound Z-96 is prepared referring to embodiment 95 by raw material of Z-95-b, the difference is that by Z-A-2 in step 3 Change Z-A-16 into.

Embodiment 97:(Z-97) preparation

Step 1-3: with compound isoquinolin -1- carboxylic acid (173mg) for raw material, the step side 2-4 of reference compound Z-95 Method preparation, obtains compound Z-97 (4.56mg), ESI-MS:451.1 (M+H)⁺。¹H NMR (500MHz, DMSO-d₆): δ 8.44 (d, J=5.5Hz, 1H), 8.23 (d, J=8.5Hz, 1H), 8.14 (s, 1H), 7.97 (d, J=8.0Hz, 1H), 7.82 (d, J= 6.0Hz, 1H), 7.75 (t, J=7.5Hz, 1H), 7.66 (m, 2H), 7.45 (d, J=11.5Hz, 1H), 5.80 (s, 2H)

Embodiment 98:(Z-98) preparation

Step 1: 8- methylquinoline (313mg, 2.186mmol) is added into 100ml there-necked flask, iodobenzene two in nitrogen protection Acetic acid (700mg, 2.173mmol), palladium acetate (13mg, 0.056mmol), 10ml acetic acid, 100 DEG C are stirred overnight.Reaction terminates, It is cooled to room temperature, concentrates and purifies to obtain compound Z-98-a (350mg), ESI-MS:202.1 (M+H)⁺。

Step 2: Z-98-a (350mg, 1.739mmol) is added into 100ml there-necked flask, sodium hydroxide (220mg, 5.5mmol), 10ml ethyl alcohol, 10ml water, 80 DEG C of stirring 2h.Reaction terminates, and is cooled to room temperature, and is concentrated under reduced pressure, and 20ml water is added, Ethyl acetate extraction, salt washing, dry concentration organic phase obtain compound Z-98-b (240mg), ESI-MS:160.1 (M+H)⁺。

Step 3: with compound Z-98-b (80mg) for raw material, prepared by step 1 method of reference compound Z-81, by chemical combination Object Z-A-2 changes Z-83-a into, obtains compound Z-98 (93.2mg), ESI-MS:451.1 (M+H)⁺。¹H NMR (400MHz, DMSO- d₆): δ 8.95 (s, 1H), 8.42 (d, J=δ .8Hz, 1H), 8.01 (d, J=5.6Hz, 1H), 7.95 (d, J=6.4Hz, 1H), 7.89 (m, 2H), 7.56~7.61 (m, 2H), 7.44 (d, J=9.2Hz, 1H), 5.81 (s, 2H)

Embodiment 101:(Z-101) preparation

Step 1: zero DEG C, Cymag (2.4g, 60mmol) is added in compound diethyl malonate (3.9g, 24mmol) THF (150ml) solution, zero DEG C stir 30 minutes, be added the fluoro- 4- nitrobenzene (3.5g, 20mmol) of 1,2,3- tri-, be stirred at room temperature 4h.Reaction terminates, and pours into ice water, ethyl acetate extraction, salt washing, and drying concentrates and purifies to obtain compound Z-101-a (7.5g), ESI-MS:316.1 (M-H)^-。

Step 2: adding into the dimethyl sulfoxide (150ml) and water (5ml) of compound Z-101-a (7.5g, 23.6mmol) Enter lithium chloride (2.04g, 47.3mmol), 150 DEG C of stirring 8h.Reaction terminates, and is cooled to room temperature, ethyl acetate extraction, saline solution It washes, drying concentrates and purifies to obtain compound Z-101-b (2g), ESI-MS:N/A.

Step 3: using compound Z-101-b as raw material, the method preparation of step 2, obtains brown in reference compound Z-B-17 Solid Z-101-c, ESI-MS:168 (M-H)^-。

Step 4: using compound Z-101-c as raw material, the method preparation of step 3, obtains yellow in reference compound Z-B-15 Solid Z-101-d, ESI-MS:195 (M-H)^-。

Step 5: using compound Z-101-d as raw material, prepared by the method for reference compound Z-44, obtains white solid Z-101, ESI-MS:499 (M-H)^-.1H NMR (500MHz, DMSO-d6): δ 8.07 (s, 1H), 7.78 (d, J=6.2Hz, 1H), 7.28- 7.23 (m, 1H), 7.05 (d, J=10.05Hz, 1H), 6.80 (dd, J=8.65Hz, 3.05Hz, 1H), 5.03 (s, 2H), 1.97-1.95 (m, 2H), 1.67-1.64 (m, 2H)

Embodiment 103:(Z-103) preparation

Step 1: with compound 4- fluoro indole -2,3- diketone for raw material, the method system of reference compound Z-B-15 step 1 It is standby, obtain compound Z-103-a, ESI-MS:150 (M-H)^-。

Step 2: using compound Z-103-a as raw material, prepared by the method for reference compound Z-B-15 step 3, obtains compound Z-103-b, ESI-MS:176 (M-H)^-。

Step 3: zero DEG C, chloro succinyl being added into the sulfuric acid (5ml) of compound Z-103-b (70mg, 0.395mmol) Imines (53mg, 0.395mmol), is stirred overnight at room temperature.Reaction terminates, and pours into ice water, and ethyl acetate extraction concentrates and purifies Compound Z-103-c (35mg), ESI-MS:210 (M-H)^-。

Step 4: using compound Z-103-c as raw material, prepared by the method for reference compound Z-44, obtains compound Z-103, ESI-MS:515 (M-H)^-。¹H NMR (500MHz, DMSO-d₆): δ 8.153 (s, 1H), 7.804 (d, J=6.5Hz, 1H), 7.400 (t, J=9.0Hz, 1H), 7.103 (d, J=5.0Hz, 1H), 6.886 (d, J=8.5Hz, 1H), 5.048 (s, 2H), 1.980~1.957 (m, 2H), 1.654~1.631 (m, 2H)

Embodiment 104:(Z-104) preparation

Step 1 is to 2: using compound 2- chloro-5-nitropyridine as raw material, the side of step 1 to 2 in reference compound Z-B-17 6CD5 preparation, obtains yellow solid Z-104-b, ESI-MS:167 (M-H)^-。

Step 3: using compound Z-104-b as raw material, the method preparation of step 3, reacts item in reference compound Z-B-13 Part changes subzero 78 DEG C into, obtains yellow solid Z-104-c, ESI-MS:197.1 (M+H)⁺。

Step 4: using compound Z-104-c as raw material, prepared by the method for reference compound Z-44, obtains yellow solid Z-104, ESI-MS:500 (M-H)^-。¹H NMR (500MHz, DMSO-d₆): δ 8.04 (d, J=5.0Hz, 2H), 7.77 (d, J=6.0Hz, 1H), 7.72 (s, 1H), 7.13 (d, J=9.5Hz, 1H), 4.98 (s, 2H), 1.38 (s, 6H)

Embodiment 105:(Z-105) preparation

Compound Z-105 is prepared referring to embodiment 101 by raw material of Z-101-c, the difference is that by 1- in step 4 Bromo- 2- chloroethanes changes iodomethane into.

The preparation of control compounds 1

Control compounds 1 with compound Z-B-43, unlike, using compound Z-A-6 and benzyl alcohol as raw material, step 1 Reaction condition, which changes into, is stirred at room temperature 4h.

The preparation of compound Z-0

Step 1: compound Z-0-1 (20.0g, 155mmol) being dissolved in the tert-butyl alcohol (150mL), is cooled to 0 DEG C, nitrogen Diphenyl phosphate azide (47g, 170mmol) is added under gas shielded, triethylamine (17.3g, 170mmol).Mixture return stirring After 18h, it is spin-dried for Rotary Evaporators.Residue is dissolved in methylene chloride (400mL), with water (200mL x 2), saline solution (200mL) is washed.Anhydrous sodium sulfate is dry, filters.Filtrate is spin-dried for Rotary Evaporators, and residue chromatographs (PE: EA=3: 1) with column After purification light yellow solid Z-0-2 (15.2g, yield: 49%) .ESI-MS (M-55)+: 145, purity=97% (UV214) 。¹H NMR (400MHz, CDCl₃): δ: 8.85 (brs, 1H), 8.61 (d, 1H), 7.32 (s, 1H), 1.55 (s, 9H).

Step 2: in N₂Under protection, Z-0-2 (8.0g, 0.04mol) is dissolved in anhydrous THF (80ml), mixture is cold But -78 DEG C are arrived, the THF solution of LiHMDS (1M, 48ml, 0.048mol) is added dropwise.After being added dropwise to complete, mixture is at -78 DEG C, stirring 0.5h.Reaction solution is slowly ramped to room temperature, 1h is stirred, -78 DEG C is then cooled to, by 5- chloro- 2,4- difluoro chloride THF (50ml) solution of (11.11g, 0.048mol) is added drop-wise to above-mentioned reaction solution.Mixture rises to room after stirring 1h at -78 DEG C Temperature, and 16h is stirred at room temperature.It is added in saturated aqueous ammonium chloride (250ml) into reaction solution, with ethyl acetate (3 x It 100ml) extracts, merges organic phase, washed with saturated salt solution (200ml), dry, 40 DEG C are spin-dried for.Crude product crosses column (100-200 mesh Silica gel), leacheate is petroleum ether: ethyl acetate=(4: 1), and obtaining Z-0-3, (5.11g, yield: 31.8%) being white solid. ESI-MS (M+Na)+: 434.0, purity: 95.9% (UV214).

Step 3: compound Z-0-4 (50.8g, 254mmol) being dissolved in THF (600mL), 0 is cooled in ice bath DEG C stirring, lithium aluminium hydride (8.4g, 220mmol) is added portionwise.Mixture adds water quenching reaction, adds hydrochloric acid after 0 DEG C of stirring 2h (6N) adjusts PH=3, separates water phase, and organic phase anhydrous sodium sulfate is dry, filters.Filtrate is spin-dried for Rotary Evaporators, is obtained white Solid Z-0-5 (32.0g, yield: 73.5%)¹H NMR (400MHz, CDCl₃): δ 7.22-7.16 (m, 1H), 6.77 (d, J= 8.7Hz, 1H), 4.61 (d, J=3.7Hz, 2H), 3.82 (s, 3H), 2.63 (s, 1H)

Step 4: compound Z-0-5 (32.0g, 190mmol) being dissolved in methylene chloride (400mL), chlorine is then added Change sulfoxide (50mL).Mixture under nitrogen protection, is heated to return stirring 3h.Mixture is down to room temperature, and water (200mL) is added to quench It goes out reaction, separates organic phase, (200 x 2mL) is extracted with dichloromethane in water phase.Merge organic phase brine It, anhydrous sulphur Sour sodium is dry, filters.Filtrate is spin-dried for Rotary Evaporators, obtains red solid Z-0-6 (33.0g, yield: 92.2%).¹H NMR (400MHz, CDCl₃): δ 7.34 (d, J=2.6Hz, 1H), 7.25 (dd, J=8.7,2.7Hz, 1H), 6.81 (d, J=8.8Hz, 1H), 4.59 (s, 2H), 3.86 (s, 3H)

Step 5: compound Z-0-6 (32g, 168mmol) is dissolved in DMSO (200mL), addition Cymag (29g, 606mmol).Mixture under nitrogen protection, is heated to 80 DEG C of stirring 3h.Reaction mixture is cooled to room temperature, and adds water dispersion, is taken out Filter.Filter cake is washed with a small amount.Air-dry to obtain orange red solid Z-0-7 (31g, yield: 98.3%).¹H NMR (400MHz, CDCl₃): δ 7.35 (d, J=2.5Hz, 1H), 7.28 (dd, J=8.5,2.3Hz, 1H), 6.82 (d, J=8.7Hz, 1H), 3.86 (s, 3H), 3.66 (s, 2H)

Step 6: compound Z-0-7 (32g, 177mmol) is dissolved in methyl formate (400mL), addition sodium (8.14g, 354mmol).Mixture under nitrogen protection, is heated to reflux stirring for 24 hours.Reaction mixture is cooled to room temperature, and water quenching is added to go out instead It answers, ethyl acetate extracts (400 x 2mL), merges organic phase washing (200 x 2mL), and anhydrous sodium sulfate is dry, filters.Decompression It is evaporated to obtain yellow solid Z-0-8 (10.5g, yield: 28.4%).¹H NMR (400MHz, DMSO-d6): δ 11.91 (s, 1H), 7.71 (d, J=93.3Hz, 1H), 7.40-7.32 (m, 1H), 7.29 (dd, J=12.2,2.6Hz, 1H), 7.08 (dd, J= 8.7,3.1Hz, 1H), 3.82 (s, 3H).

Step 7: compound Z-0-8 (10.5g, 50.2mmol) being dissolved in ethyl alcohol (150mL), tertiary butyl hydrazine is added (7.5g, 60.3mmol).Mixture under nitrogen protection, is heated to reflux stirring 3.5h.Reaction mixture is cooled to room temperature, decompression It is evaporated to obtain yellow solid (15g), rapid column chromatography obtains yellow solid Z-0-9 (14.0g, yield: 99.9%).

Step 8: compound Z-0-9 (13.5g, 48.4mmol) is dissolved in methylene chloride (300mL), it is cold in ice bath But it to 0 DEG C, is added trifluoroacetic anhydride (30.5g, 145.2mmol), triethylamine (14.7g, 145.2mmol).Mixture is in nitrogen Under protection, it is warmed to room temperature stirring 4h.Sodium carbonate quenching reaction is added to neutrality in reaction mixture, separates water phase, organic phase is used full With brine It (100 x 2mL), anhydrous sodium sulfate is dry, filters.Evaporated under reduced pressure obtains brown solid Z-0-10, and (12.0g is received Rate: 66.1%).ESI-MS (M-H): 376, purity=89.23% (UV254)

Step 9: compound Z-0-10 (11.0g, 29.3mmol) being dissolved in methylene chloride (200mL), in ice bath It is cooled to 0 DEG C, is added Boron tribromide (36.7g, 146.6mmol).Mixture under nitrogen protection, is warmed to room temperature stirring 4h.Instead It answers mixture to be slowly added into ice water (100mL), separates water phase, organic phase saturated common salt water washing (100 x 2mL), anhydrous sulphur Sour sodium is dry, filters.Evaporated under reduced pressure obtains brown solid Z-0-11 (6.3g, yield: 68.9%).ESI-MS (M-H): 362, purity =80.83% (UV254)

Step 10: compound Z-0-11 (25.0g, 69mmol) being dissolved in methanol (100mL), hydrochloric acid dioxane is molten Liquid (4M/L, 100mL).Mixture is in 70 DEG C of stirring 18h.After being cooled to room temperature, it is spin-dried for.Slowly by methanol (50mL) solution of ammonia It is added to residue (100mL), 40 DEG C are spin-dried for.Crude product crosses column (100-200 mesh silica gel), and leacheate is methylene chloride: methanol (10 : 1), obtain gray solid Z-0-12 (8.0g, yield: 38%).ESI-MS (M-H): 210.1, purity=90% (UV214).

Step 11: by compound Z-0-12 (4.18g, 20mmol), Z-0-3 (8.20g, 20mmol), potassium carbonate (8.28g, It 60mmol) is dissolved in DMF (100mL), mixture under nitrogen protection, is heated to 40 DEG C of stirring 18h.Reaction mixture is added Water (500mL), methylene chloride extract (200mL x 3), merge organic phase and (100mL x 2), saturated common salt water washing is washed with water (100 x 2mL), anhydrous sodium sulfate is dry, filters.Evaporated under reduced pressure obtains red solid Z-0-13 (15.1g, yield: > 100%). ESI-MS (M+H)+: 600.1, purity=28% (UV254)

Step 12: compound Z-0-13 (12.0g, 20mmol) being dissolved in methylene chloride (40mL), trifluoro second is added Sour (20mL).Mixture under nitrogen protection, stirs for 24 hours at room temperature.It is yellow solid that evaporated under reduced pressure, which obtains crude product, through HPLC system It is standby to obtain white solid powder Z-0 (3.04mg, yield: 31%).ESI-MS (M+H)+: 499.8, purity=100% (UV254)。¹H NMR (400MHz, DMSO-d6): δ 11.56 (s, 2H), 8.91 (d, J=2.4Hz, 1H), 7.90 (d, J= 6.8Hz, 1H), 7.69 (s, 1H), 7.43 (s, 1H), 7.32 (dd, J=8.8,2.4Hz, 1H), 7.22 (dd, J=8.4Hz, 1H), 7.07 (d, J=2.0Hz, 1H), 6.73 (d, J=10.8Hz, 1H), 4.92 (s, 2H).

Electrophysiology measurement

The manual patch clamp experiments in 1 channel hNav1.7 and hNav1.5 of test case

Diaphragm voltage clamp electrophysiology can directly measure and the current blocking of fixed rate voltage gated sodium channel (various Nav) And time and the voltage dependence of blocking can be measured, it has been interpreted the knot of the tranquillization to sodium channel, opening and inactivated state Difference is closed to reflect inhibition or activation effect (Hille, B., Journal of the General Physiology of compound (1977), 69:497-515).

The representative compound of the present invention is carried out using manual patch clamp experiments, and object of this investigation is using manual diaphragm The effect of test compound to the ion channel current on the stable cell line in transfection specific ion channel of the method for pincers.It makes Stable cell line CHO-hNav1.7 and HEK-hNav1.5 respectively from Genionics company and WuXi Apptec (on Sea) company.

Manual patch clamp experiments scheme is as follows:

(1) hNav1.7 and hNav1.5 electric current the preparation of solution and compound: is recorded using whole-cell patch-clamp recording technique. In experiment, the constituent (mM) of extracellular fluid: HEPES:5, NaCl:40, KCl:3, CaCl₂: 1, MgCl₂: 1, CdCl₂: 0.1, TEA-Cl:20.PH value is adjusted to 7.3 with NaOH, while being adjusted infiltration with sucrose and being depressed into 310-320mOsm, 4 DEG C of guarantors after filtering It deposits.The constituent (mM) of intracellular fluid: HEPES:10, NaCl:10, CsOH:5, CsF:140, EGTA:1.PH is adjusted with CsOH Value adjusts infiltration with sucrose and is depressed into 280-290mOsm to 7.3, -20 DEG C of preservations after filtering.

Positive control drug and untested compound are first dissolved in 100%DMSO, and (Sigma-Aldrich, D2650 are configured to certain The stock solution of concentration (100nM, 1000nM).Above-mentioned stock solution is serially diluted with DMSO before experiment, is then used again Extracellular fluid, which further dilutes, obtains the test solution of required concentration.DMSO ultimate density is no more than 0.30% in extracellular fluid.

(2) manual patch clamp experiments: taking cell suspension to be added in the culture dish of 35mm, is placed in inverted microscope objective table On.After cell is adherent, with extracellular fluid perfusion, flow velocity 1-2mL/min.Glass microelectrode draws two step of instrument by microelectrode and draws System, entering water power resistance value is 2-5M Ω.Pass through Digidata 1440 (Molecular Devices) and pCLAMP software (10.2 Version, Molecular Devices) A/D-D/A digital-to-analogue conversion, carry out stimulation granting and signal acquisition；Patch clamp amplifier (Multiclamp 700B, Molecular Devices) amplified signal, is filtered into 4KHz.

Two different voltage stimulation programs are used in the manual patch clamp experiments of hNav1.7 and hNav1.5.

One is inactivation stimulation programs, the V in corresponding channel is arranged in command potential_1/2, i.e., about 50% channel is in Inactivated state.Then voltage is given to -120mV, continues 50ms.Then depolarising extremely -10mV continues 20ms and draws sodium current, Eventually pass back to command potential.This stimulation programs can also be referred to as the voltage stimulation programs of channel status dependence.

Another kind is non-inactivation stimulation programs, keeps command potential in -120mV, and giving voltage stimulates to -10mV, continues 20ms draws sodium current, eventually passes back to command potential.That is under the conditions of this kind of stimulation programs, all channels all do not have Inactivated state is lived through, but is directly activated from quiescent condition.

The time interval of above two voltage stimulation programs is 10s.The depression effect of compound passes through before and after dosing Curent change is calculated, and IC₅₀Numerical value is fitted gained by Hill equation.If compound is above two different The difference for having certain multiple to channelling effect is shown under voltage stimulation, then the compound is with State-dependence to the channel Property.As a result it is shown in Table 1, table 2 and table 3 respectively.

The representative compound of the present invention of table 1 is under two kinds of concentration to the inhibiting rate of Nav1.7

The representative compound of the present invention of table 2 is under two kinds of concentration to the inhibiting rate of Nav1.5

Compound	1000nM (%)	10000nM (%)
			Z-65	3740	11880
Z-21	64890	85340

IC of the representative compound of the present invention of table 3 to Nav1.7 and Nav1.5₅₀Value

Compound	Nav1.7(IC₅₀/nM)	Nav1.5(IC₅₀/nM)	Nav1.5/Nav 1.7
				Z-65	7.85	> 10000	> 1274
Z-21	5.64	800	142
				Z-28	4.13	5280	1278
Z-47	6.14	3040	495
				Z-49	6.18	2430	393
Z-54	12.49	15712	1258
				Z-56	23.51	17115	728

From table 1, table 2 and table 3 as can be seen that representative compound of the present invention is to Nav1.7 inhibitory activity with higher, It is obviously weaker to the inhibitory activity of Nay1.5, therefore there is apparent selection inhibitory activity to Nav1.7.

2 cold stimulation allodynia method of test case

Experimental animal is male Sprague-Dawley rat, weight 140-150g when experiment starts.Animal for research is equal It purchases in this Leco Corp., carries out food and water supply after purchase by the way of being freely eaten, sub-cage rearing, is adopted by 4/cage Animal marking is carried out with animal trailer label method.

Detection compound and grouping:

Solvent control object (Vehicle): 5% dimethyl acetamide (traditional Chinese medicines science and technology), 5%solutol (Sigma) and 90% Physiological saline

Positive control: compound Z-0；

Drug to be measured: compound Z-47, Z-49, Z-54, Z-56, Z-99, Z-100；

The solvent composition of positive control and drug to be measured is 5% dimethyl acetamide, 5%solutol and 90% physiology Salt water.

Positive control and tester inhibit caused by Rat Spinal Nerve Tissue ligation after taking orally 2h respectively with dosage 100mg/kg Cryalgesia is super quick, as shown in table 4.

4 compound of table efficacy testing in spinal nerve ligated rats is grouped

Group	Model	Administration	Dosage (mg/kg)	Administered volume (mL/kg)	Dosage	Size of animal
							1	Untreated (Naive)	-	-	-	-	10
2	Spinal nerve ligation	Solvent group (Vehicle)	-	5	It is oral	10
							3	Spinal nerve ligation	Compound Z-0	100	5	It is oral	10
4	Spinal nerve ligation	Compound Z-47	100	5	It is oral	10
							5	Spinal nerve ligation	Compound Z-49	100	5	It is oral	10
6	Spinal nerve ligation	Compound Z-54	100	5	It is oral	10
							7	Spinal nerve ligation	Compound Z-56	100	5	It is oral	10
8	Spinal nerve ligation	Compound Z-99	60	5	It is oral	10
							9	Spinal nerve ligation	Compound Z-100	60	5	It is oral	10

Experimental method:

1.1. Spinal Nerve Ligation Model

Surgical procedure executes sterile working.

Surgical instrument (scissors, tweezers, scalpel, cotton of performing the operation, suture, dilator) has sterilized before surgery.

Use that (50mg/kg, intraperitoneal injection) anesthetized animal of amobarbital.Animal toe is squeezed to confirm animal surgery Preceding holonarcosis.Ophthalmic ointment is smeared in animal eye to prevent animal corneal dry.

Animal lower part of the body operative region hair is shaved off, using Iodophor and 70% ethyl alcohol to operation area skin disinfection three Time.Start to perform the operation after having dry skin.

A longitudinal cut is opened at animal waist sacrum rear portion using scalpel, exposure left side paraspinal muscle uses dilator Musculature is separated to expose vertebrae.

Separation left side spinal nerve L5 and L6, are ligatured using 6-0 silk thread.

It sews up a wound.

Sterile surgery instrument is sterilized using hot pearl sterilizer.

Animal is placed on electric blanket after operation, 5mL physiological saline is subcutaneously injected to prevent anti-avulsion water.Equal animals are complete It (can be move freely) after revival and put back to animal in cage.

1.2. the super quick baseline test of cryalgesia and grouping

Administration a few days ago, to rat carries out the super quick baseline test of cryalgesia, and 100 μ l acetone are coated in animal using pipettor Art side back foot part skin.Record animal is patted in one minute, and contracting foot, foot-up licks the time for licking art parapodum portion.Acetone test is altogether It carries out twice, two minor ticks 10 minutes.The sum of time is recorded as the rat cryalgesia hypersensitivity time twice.It is previous according to being administered Animal is grouped by it cryalgesia hypersensitivity test result at random.

1.3. the super quick test of cryalgesia

After 2h is administered, 100 μ l acetone are coated in toe section skin behind animal art side using pipettor.Animal is recorded at one point It is patted in clock, contracting foot, foot-up licks the time for licking impacted foot.Acetone test carries out twice altogether, two minor ticks 10 minutes. The sum of time is recorded as the rat cryalgesia hypersensitivity time twice.

1.4. administration

It is administered orally before cold stimulation pain sensation test 2h.

1.5. data collection and analysis

Data are collected using Excel software.Use Prism software analysis data.

Conclusion:

The super quick test result (Z-47) of 5 rat cryalgesia of table

The super quick test result (Z-49, Z-56) of 6 rat cryalgesia of table

The super quick test result (Z-54) of 7 rat cryalgesia of table

The super quick test result (Z-99, Z-100) of 8 rat cryalgesia of table

Experimental result: compared with Fig. 1,3,5,7, as shown in Fig. 2,4,6,8, after taking orally 2h, example compound Z- of the present invention 47, Z-49, Z-54, Z-56, Z-99 and Z-100 have in spinal nerve ligated rats model inhibits Rat Spinal Nerve Tissue ligation induction The super quick effect of cryalgesia, be statistically significant inhibitory effect in rat nerves within the body pain model.

In Fig. 2, compound Z-47 compound in spinal nerve ligated rats model inhibits cold stimulation allodynia effect Fruit, * * * p < 0.001.Compared with solvent group, Dunnett multiple comparative test is added using one-way analysis of variance.Oralization Inhibit the cryalgesia of Rat Spinal Nerve Tissue ligation induction super quick respectively after closing object Z-47 and positive control 100mg/kg 2h.

In Fig. 4, the drug effect of compound Z-49 and Z-56 in spinal nerve ligated rats, * * * p < 0.001 and solvent group ratio Compared with adding Dunnett multiple comparative test using one-way analysis of variance.Oral Z-49, Z-56 and positive control 100mg/ Inhibit the cryalgesia of Rat Spinal Nerve Tissue ligation induction super quick after kg 2h respectively.

In Fig. 6, compound Z-54 compound in spinal nerve ligated rats model inhibits cold stimulation allodynia effect Fruit, * * * p < 0.001.Compared with solvent group, Dunnett multiple comparative test is added using one-way analysis of variance.Oralization Inhibit the cryalgesia of Rat Spinal Nerve Tissue ligation induction super quick respectively after closing object Z-54 and positive control 100mg/kg 2h.

In Fig. 8, the drug effect of compound Z-99 and Z-100 in spinal nerve ligated rats, * * p < 0.01 and solvent group ratio Compared with adding Dunnett multiple comparative test using one-way analysis of variance.Oral Z-99, Z-100 60mg/kg, take orally the positive Inhibit the cryalgesia of Rat Spinal Nerve Tissue ligation induction super quick after reference material 100mg/kg 2h respectively.

All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims

1. a kind of formula (I) compound represented or its pharmaceutically acceptable salt:

In formula,

R₁、R₃It is each independently hydrogen or halogen；

R₂、R₄For hydrogen；

R₅For 5 or 6 unit monocycle heteroaryls；Described 5 or 6 unit monocycle heteroaryls are selected from:

L₁For a key；

L₂For-(CH₂)_r2-；R2 is 1；

X is a key；

ForFor

Wherein, Z₁₁For-C (R¹¹R¹²)-or-C (R¹³)=；

Z₂For-C (O)-,-C (R²¹R²²)-or=C (R²⁴)-；

W₁₁、W₂₁、W₃₁、W₄₁It is CH；

For singly-bound or double bond；

Wherein R¹¹、R¹²It is each independently hydrogen or C_1-20Alkyl；Or R¹¹、R¹²3 to 7 yuan are collectively formed with the carbon atom being connect Monocycle；

R¹³For hydrogen, C_1-20Alkyl or halogen；

R²¹、R²²It is each independently hydrogen or C_1-20Alkyl；

R²⁴For hydrogen or C_1-20Alkyl；

(R_a’)_mFor any position in 6 member rings hydrogen by m R_a' replace, m 0,1,2 or 3, each R_a' identical or different, respectively From independently being hydrogen, halogen, C_1-20Alkyl, halogenated C_1-20Alkyl, C_1-20Alkoxy, halogenated C_1-20Alkoxy or C_3-20Naphthenic base.

2. compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that Z₁₁For-C (R¹¹R¹²)-；

Z₂For-C (O)-or-C (R²¹R²²)-；

R¹¹、R¹²It is each independently C_1-20Alkyl；Or R¹¹、R¹²3 unit monocycles are collectively formed with the carbon atom being connect.

3. compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that in formula (I-a-1),For singly-bound；Z₁₁For-C (R¹¹R¹²)-；Z₂For-C (O)-.

4. compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that in formula (I-a-1),For singly-bound；Z₁₁For-C (R¹¹R¹²)-；Z₂For-C (R²¹R²²)-。

5. compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that in formula (I-a-1),For double bond；Z₁₁For-C (R¹³)=；Z₂For=C (R²⁴)-。

6. compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that

For such as flowering structure:

In formula, R_a1、R_a2、R_a3、R_a4Definition same R respectively_a’。

7. a kind of compound or its pharmaceutically acceptable salt, which is characterized in that the compound is anyization selected from the group below Close object:

8. a kind of pharmaceutical composition, described pharmaceutical composition include compound described in any one of claims 1 to 7 or its Pharmaceutically acceptable salt；And pharmaceutically acceptable carrier.

9. compound or its pharmaceutically acceptable salt as described in any one of claims 1 to 7 or such as claim 8 institute State application of the pharmaceutical composition in the drug of preparation treatment disease or illness, the disease or illness be selected from pain, depression, Cardiovascular disease, respiratory disease, mental disease or combinations thereof.