CN104016907B - Amide compound, compositions and application thereof - Google Patents

Abstract

Provide the compound of formula 1:Wherein A, B, W, X ', L, R¹、R³、R^4bWith m ' is as defined herein.Providing the compound of disease and the pharmaceutical composition thereof for preventing and treat various mammal (including people), described disease includes (as limiting examples) pain, inflammation, cognitive disorder, anxiety, depression etc..

Description

Amide compound, compositions and application thereof

The application is filing date February 27, Application No. 200980111248.2, invention entitled " amide in 2009 Compound, compositions and application thereof " the divisional application of Chinese invention patent application.

Technical field

There is provided herein biphenyl and pyridinylphenyl amide compound and the pharmaceutical composition comprising this compound.Also carry Prevent and/or treat mammalian diseases for compound provided herein and pharmaceutical composition and promote neuroprotective Method, described disease such as (but not limited to) arthritis, parkinson disease, Alzheimer, asthma, myocardial infarction, pain are combined Simulator sickness (acute and chronic or nerve (neuropathic)), neurodegenerative disease, schizophrenia, cognitive disorder, anxiety, Depression, inflammatory bowel and autoimmune disease.

Background technology

Find and be used for effective control pain and central nervous system disorder or the therapeutic strategy of disease.

The international patent application of Publication No. WO 08/000645 discloses tetrazolium-substituted aryl amides and relevantization Compound, it is believed that they are P2X₂And P2X_2/3Receptor modulators.

The international patent application of Publication No. WO 08/055840 disclose thiazole andThe substituted aryl amides of azoles and Related compound, it is believed that they are P2X₂And P2X_2/3Receptor modulators.

US 2007049609, US 2007049610, US 2007049758 and US 2007049534 describe some and make For P2X₃And P2X_2/3The diaminopyrimidine of regulator.

US 2007037974 describes the P2X for treating pain, Genito-urinary, gastrointestinal tract and respiratory disorder₃Heterocycle presses down Preparation.

WO 06/119504 describe for treat multiple disease as P2X₃And P2X_2/3The fused-heterocycle of regulator Compound.WO04/56774 describes some substituted biphenyl-4-carboxylic acid aryl with the possible application as receptor modulators Amide analogue.

WO 08/119773 describes the amide derivatives as aspartyl protease inhibitor and at treatment A Er Application in Ci Haimo disease.

WO 05/065195 describes some as the phenylamide of beta-secretase inhibitor and pyridyl amide.

WO 02/070469 describes some substituted Sulfonylalkyl carboxylic acid amides as selectivity pde3b inhibitor Class.

WO 04/039753 describe some for treat prostaglandin mediated disease as EP1 receptor antagonist Benzoic acid and related compound.

Additionally, WO03/104230 describes some bicyclic pyrimidine derivatives, the U.S. of Serial No. US20030092908 Published application and WO02/087513 describe annelated heterocycles PDE7 inhibitor.

United States Patent (USP) US3,424,760 and 3,424,761 all describe a series of 3-urea groups pyrrolidines, it is believed that they show Show pain relieving, central nervous system and psychopharmacology activity.These patents be correspondingly disclosed especially compound 1-(1-phenyl- 3-pyrrolidinyl)-3-phenylurea and 1-(1-phenyl-3-pyrrolidinyl)-3-(4-methoxyphenyl) urea.Publication No. WO 01/ The international patent application of 62737 and WO 00/69849 discloses a series of pyrazole derivatives, it is believed that they are for treatment and NPY Obstacle that receptor subtype Y5 is relevant and disease, such as fat.WO 01/62737 particularly discloses compound 5-amino-N-isoquinoline Quinoline-5-base-1-[3-(trifluoromethyl) phenyl]-1H-pyrazole-3-formamide.WO 00/69849 particularly discloses compound 5-first Base-N-quinoline-8-yl-1-[3-(trifluoromethyl) phenyl]-1H-pyrazole-3-formamide, 5-methyl-N-quinoline-7-base-1-[3- Trifluoromethyl) phenyl]-1H-pyrazole-3-formamide, 5-methyl-N-quinoline-3-base-1-[3-(trifluoromethyl) phenyl]-1H-pyrrole Azoles-3-Methanamide, N-isoquinolin-5-base-5-methyl isophthalic acid-[3-(trifluoromethyl) phenyl]-1H-pyrazole-3-formamide, 5-first Base-N-quinoline-5-base-1-[3-(trifluoromethyl) phenyl]-1H-pyrazole-3-formamide, 1-(3-chlorphenyl)-N-isoquinolin-5- Base-5-methyl isophthalic acid H-pyrazole-3-formamide, N-isoquinolin-5-base-1-(3-methoxyphenyl)-5-methyl isophthalic acid H-pyrazoles-3-first Amide, 1-(3-fluorophenyl)-N-isoquinolin-5-base-5-methyl isophthalic acid H-pyrazole-3-formamide, 1-(2-chloro-5-trifluoromethylbenzene Base)-N-isoquinolin-5-base-5-methyl isophthalic acid N-pyrazole-3-formamide, 5-methyl-N-(3-methylisoquinolinium-5-base)-1-[3- (trifluoromethyl) phenyl]-1N-pyrazole-3-formamide, 5-methyl-N-(1,2,3,4-tetrahydroisoquinoline-5-base)-1-[3-(three Methyl fluoride) phenyl]-1H-pyrazole-3-formamide.

The Deutsche Bundespatent of Application No. DE 2502588 describes a series of bridged piperazine derivatives.Particularly disclosing of this application Compound N-[3-[2-(diethylamino) ethyl]-1,2-dihydro-4-methyl-2-oxo-7-quinolyl]-4-phenyl-1-piperazine Methanamide.

Summary of the invention

There is provided herein biphenyl and pyridinylphenyl amide compound and pharmaceutical composition thereof, its have prevention and treatment with The effect of the disease that neurological is relevant with dysfunction with inflammatory conditions and selectivity.

Especially, it is provided that compound, pharmaceutical composition and method be applicable to treatment, prevent or alleviate a range of food in one's mouth Breast animal disease, such as but be not limited to the pain of various origin or the cause of disease, the most acute, chronic, inflammatory and nerve pain Bitterly, have a toothache and have a headache (such as migraine, cluster headache and tension headache).In some embodiments, it is provided that chemical combination Thing, pharmaceutical composition and method are applicable to treat inflammatory pain and associated hyperalgesia and allodynia.Some embodiment party In case, it is provided that compound, pharmaceutical composition and method be applicable to treat neuropathic pain and associated hyperalgesia and abnormity (such as nervi trigeminus or herpes neuralgia, diabetic neuropathy, causalgia, sympathetic nerve maintain pain The pain of (sympathetically maintained) and deafferentation syndromes, such as avulsion of brachial plexus (avulsion)).In some embodiments, it is provided that compound, pharmaceutical composition and method be used as the anti-for the treatment of of arthritis Scorching medicine and treatment parkinson disease, Alzheimer, asthma, myocardial infarction, neurodegenerative disease, inflammatory bowel and autoimmune Disease, nephropathy, obesity, eating disorders, cancer, schizophrenia, epilepsy, sleep disorder, cognitive disorder, depression, anxiety, blood Pressure and the medicine of disorders of lipid metabolism.

Therefore, in an aspect, it is provided that there is the compound of formula 1:

Wherein

Each A, B and W are independently selected from CR⁴；

X ' is selected from CR^4aAnd N；

L is-C (R^2aR^2b)-；

R¹Selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxyl C₁-C₄Alkyl, C₃-C₇Cycloalkanes Base-C₁-C₄Alkyl or 4-7 unit Heterocyclylalkyl-C₁-C₄Alkyl；

R^2aAnd R^2bIt is each independently selected from hydrogen, C₁-C₄Alkyl or hydroxyl C₁-C₄Alkyl；

R³It is substituted or unsubstituted C₁-C₆Alkyl；CH(OH)R^3a、OR^3a、CN、COR^3a、COOR^3a、SOR^3a、SO₂R^3a、 CONR^3aR^3b、SONR^3aR^3bOr SO₂NR^3aR^3b；

R^3aIt is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, Substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl；

R^3bIt is H, substituted or unsubstituted C₁-C₆Alkyl；Or R^3aAnd R^3bForm the cycloheteroalkyl ring of 3-7 atom together；

R⁴It is each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted acyl group, replacement or unsubstituted Acylamino-, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio group, substituted or unsubstituted alkoxy carbonyl group, take Generation or unsubstituted alkyl virtue amino, substituted or unsubstituted amino, substituted or unsubstituted aryl alkyl, sulfo group, substituted Sulfo group, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted amino-sulfonyl, replacement or Unsubstituted alkyl sulphonyl, substituted or unsubstituted aryl sulfonyl, azido, substituted or unsubstituted carbamoyl, Carboxyl, cyano group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted dialkylamino, Halogen, nitro and sulfydryl；

R^4aAnd R^4bIt is each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted acyl group, replacement or not Substituted acylamino-, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio group, substituted or unsubstituted alkoxyl, Substituted or unsubstituted alkoxy carbonyl group, substituted or unsubstituted alkyl virtue amino, substituted or unsubstituted alkoxy aryl, replacement Or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, sulfo group, substituted sulfo group, replacement Sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted amino-sulfonyl, substituted or unsubstituted Alkyl sulphonyl, substituted or unsubstituted aryl sulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyanogen Base, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halogen, miscellaneous Aryloxy group, substituted or unsubstituted heteroaryl, substituted or unsubstituted miscellaneous alkyl, hydroxyl, nitro and sulfydryl；

And subscript m ' selected from 0-4；

Condition is

Work as R³It is CO₂Me、SO₂Ph or OR^3aTime, R¹It it not unsubstituted phenyl；

Work as R³It is SO₂-(4-methylpiperazine-1-yl) or SO₂-(thiomorpholine-1-base), and when X ' is CH, R^4bIt not H；

Work as R³Be Me or replaced by alkoxyl methyl time, R¹It it not substituted phenyl；

Work as R³It is CO₂During H, R^4bIt is Cl, F, Br, Me, Et, OMe or CF₃；

Working as X ' is CR^4a, R³It is CONR^3aR^3b, and R^3aWhen being H, R^3bIt not substituted n-pentyl, substituted pentynyl, replacement Benzyl, substituted phenethyl, substituted thienyl ethyl or substituted thiazolylethyl；With

Work as R¹It is 5-6 unit heterocycloalkylmethyl, and R³It is CO₂During Me or n-Pr, R^4bIt not Cl or 4-F；

Or its pharmaceutically acceptable salt, N-oxide, solvate, prodrug, stereoisomer, tautomeride or coordination Element variant.

In a specific embodiments of formula 1, A, B and W are individually CH.

In a specific embodiments of formula 1, L is selected from-CH₂-、-CHMe-、-CMe₂-、-CH(CH₂OH)-and-CH (CH₂CH₂OH)-。

In a specific embodiments of formula 1, L is selected from-CH₂-and-CHMe-.

In a specific embodiments of formula 1, compound is the chemical combination of formula 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h or 2i Thing:

Wherein

X’、R¹、R^3a、R^3b、R^4a、R^4bWith m ' is as described in formula 1；R^2aIt is H, Me, CH₂OH or CH₂CH₂OH,

Or its pharmaceutically acceptable salt, solvate, N-oxide, prodrug, stereoisomer, tautomeride or coordination Element variant.

In one aspect of the method, it is provided that pharmaceutical composition, it comprises biphenyl provided herein and pyridinylphenyl amide With pharmaceutical carrier, excipient or diluent.This pharmaceutical composition can comprise one or more compounds as herein described.

It will be understood that the compound for pharmaceutical composition and Therapeutic Method disclosed herein provided herein is permissible It is prepared as pharmaceutically acceptable and use.

In one aspect of the method, it is provided that for the method preventing, treat or alleviating those diseases enumerated herein, this Disease particularly may be with such as arthritis, asthma, myocardial infarction, disorders of lipid metabolism, cognitive disorder, anxiety, schizophrenia, Depression, memory dysfunction, such as Alzheimer, inflammatory bowel is relevant with autoimmune disease, and the method includes right This mammal needed is had to give effectively to prevent, treat or alleviate one or more of consumption of described disease provided herein Compound or its pharmaceutical composition.

In one aspect of the method, it is provided that be used for preventing, treat or alleviate cause mammalian pain response or with maintenance The method of unbalance relevant disease in its sensory nerve basis activity.Compound provided herein is used as to treat various origins or disease The analgesic of the pain of cause, such as acute pain, inflammatory pain (such as relevant to osteoarthritis and rheumatoid arthritis pain Bitterly)；Various neuropathic pain syndrome (such as postherpetic neuralgia, trigeminal neuralgia, Reflex sympathetic dystrophy (reflex sympathetic dystrophy), diabetic neuropathy, Guillain-Barr é syndrome, fibromyalgia (fibromyalgia), phantom pain, post mastectomy pain, polyneuropathy (peripheral neuropathy), HIV god Through disease, and the neuropathy of chemotherapy induction and other iatrogenic neuropathys)；Encelialgia is (such as with gastroesophageal reflux disease (gastroesophageal reflex disease), irritable bowel syndrome, inflammatory bowel, pancreatitis and various gynecology and The Encelialgia that urologic complaints is relevant), have a toothache and have a headache (such as migraine, cluster headache and tension headache).

In an aspect, it is provided that for preventing, treat or alleviate the side of mammalian nervous degenerative disease or obstacle Method.Neurodegenerative disease or obstacle are it may be that such as parkinson disease, Alzheimer and multiple sclerosis；By neuroinflamation Mediate or cause disease and the obstacle of neuroinflamation, such as encephalitis；The neuropsychopathy of maincenter mediation and obstacle, such as depressed, Manic, bipolar disorder (bipolar disease), anxiety, schizophrenia, eating disorders, sleep disorder and cognition Obstacle；Epilepsy and epilepsy；Prostate, bladder and intestinal dysfunction, such as urinary incontinence, hesitancy in urination, rectum anaphylaxis, Fecal incontinence, benign prostatauxe and inflammatory bowel；Breathe and airway disorders and obstacle, such as allergic rhinitis, asthma and RAD and chronic obstructive pulmonary disease；By inflammation mediated or cause disease and the obstacle of inflammation, such as rheumatoid Arthritis and osteoarthritis, myocardial infarction, various autoimmune disease and obstacle；Itch (itch)/pruritus, such as psoriasis； Fat；Disorders of lipid metabolism；Cancer；And nephropathy.Typically, described method includes giving effectively to control to the mammal having these needs Treat disease or one or more compounds provided herein of prevention disease consumption or its pharmaceutical composition.

In addition to above-mentioned Therapeutic Method, the present invention also extend to any compound of the present invention prepare medicine maybe can be to this Plant the purposes in the medicine of therapeutic administratp and this compound purposes in treatment that is disclosed and that specify.

In in other respects, it is provided that for the method synthesizing compound as herein described, the most representational synthesis Scheme and approach are as described below.In some embodiments, it is provided that by the enantiomer-pure chemical combination of asymmetric synthesis formula 1 The method of thing.In some embodiments, it is provided that by the method for the enantiopure compound of chiral separation formula 1.

Other objects and advantages is apparent when those skilled in the art consider detailed further below.

Detailed Description Of The Invention

Definition

Following term is specified to have implication provided below and for the description understanding the present invention and the scope specified.

Compound, the pharmaceutical composition comprising this compound can be included when describing and use this compound and combination During the present invention of the method for thing, unless otherwise specified, otherwise following term is if it is present have following implication.Will also be understood that Time described herein, the arbitrary portion being defined below can be replaced by various substituent groups, and specifies corresponding definition to be included in This substituted part in scope as described below.Unless otherwise stated, otherwise term " substituted " is defined below.Also should Understand that term " group " and " base " are identified herein as exchanging use.

Article " a kind of (a) " and " a kind of (an) " be used in this article meaning this article one or more (the most extremely Few one) object of grammatical.As an example, " analog " means a kind of analog or more than one analog.

As herein defined, " acyl group " or " alkanoyl " means group-C (O) R²⁰, wherein R²⁰It is hydrogen, C₁-C₈Alkyl, C₃-C₁₀Cycloalkyl, C₃-C₁₀Methyl cycloalkyl, 4-10 unit Heterocyclylalkyl, aryl, aryl alkyl, 5-10 unit heteroaryl or heteroaryl Alkyl.Representational example includes, but are not limited to formoxyl, acetyl group, cyclohexyl-carbonyl, cyclohexylmethylcarbonyl, benzene first Acyl group and benzyloxycarbonyl group.Typically " acyl group " is C (O) H, C (O)-C₁-C₈Alkyl, C (O)-(CH₂)_t(C₆-C₁₀Aryl), C (O)-(CH₂)_t(5-10 unit heteroaryl), C (O)-(CH₂)_t(C₃-C₁₀Cycloalkyl) and C (O)-(CH₂)_t(4-10 unit heterocycle alkane Base), wherein t is the integer of 0-4.

" substituted acyl group " or " substituted alkanoyl " means group-C (O) R²¹, wherein R²¹Independently:

The C replaced by halogen or hydroxyl₁-C₈Alkyl；Or

·C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aryl alkyl, 5-10 unit heteroaryl or heteroaryl Alkyl, each of which is by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Alkyl halide Base, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.

" acylamino-" means group-NR²²C(O)R²³, wherein R²²It is hydrogen, C₁-C₈Alkyl, C₃-C₁₀Cycloalkyl, 4-10 unit are miscellaneous Cycloalkyl, C₆-C₁₀Aryl, aryl alkyl, 5-10 unit heteroaryl or heteroaryl alkyl, R²³It is hydrogen, C₁-C₈Alkyl, C₃-C₁₀Cycloalkanes Base, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aryl alkyl, 5-10 unit heteroaryl or heteroaryl alkyl, as defined herein.Allusion quotation " acylamino-" of type includes, but are not limited to Formylamino, acetyl-amino, cyclohexylcarbonylamino, cyclohexyl methyl-carbonyl Amino, benzoyl-amido and b enzylcarb onylamino.Concrete typical " acylamino-" is-NR²⁴C(O)-C₁-C₈Alkyl ,-NR²⁴C (O)-(CH₂)_t(C₆-C₁₀Aryl) ,-NR²⁴C(O)-(CH₂)_t(5-10 unit heteroaryl) ,-NR²⁴C(O)-(CH₂)_t(C₃-C₁₀Cycloalkanes Base) and-NR²⁴C(O)-(CH₂)_t(4-10 unit Heterocyclylalkyl), wherein t is the integer of 0-4, R²⁴Represent H or C independently of one another₁- C₈Alkyl.

" substituted acylamino-" means group-NR²⁵C(O)R²⁶, wherein:

R²⁵It is independently

H, the C replaced by halogen or hydroxyl₁-C₈Alkyl；Or

·C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aryl alkyl, 5-10 unit heteroaryl or heteroaryl Alkyl, each of which is by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Alkyl halide Base, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace；With

R²⁶It is independently

H, the C replaced by halogen or hydroxyl₁-C₈Alkyl；Or

·C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aryl alkyl, 5-10 unit heteroaryl or heteroaryl Alkyl, each of which is by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Alkyl halide Base, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace；

Condition is R²⁵And R²⁶In at least one be not H.

" acyloxy " means group-OC (O) R²⁷, wherein R²⁷It is hydrogen, C₁-C₈Alkyl, C₃-C₁₀Cycloalkyl, C₃-C₁₀Cycloalkyl Methyl, 4-10 unit Heterocyclylalkyl, aryl, aryl alkyl, 5-10 unit heteroaryl or heteroaryl alkyl, as defined herein.There is generation The example of table includes, but are not limited to formoxyl, acetyl group, cyclohexyl-carbonyl, cyclohexylmethylcarbonyl, benzoyl and benzyl Carbonyl.Typically " acyl group " group is C (O) H ,-C (O)-C₁-C₈Alkyl ,-C (O)-(CH₂)_t(C₆-C₁₀Aryl) ,-C (O)- (CH₂)_t(5-10 unit heteroaryl) ,-C (O)-(CH₂)_t(C₃-C₁₀Cycloalkyl) and C (O)-(CH₂)_t(4-10 unit Heterocyclylalkyl), its Middle t is the integer of 0-4.

" substituted acyloxy " means group-OC (O) R²⁸, wherein R²⁸It is independently

The C replaced by halogen or hydroxyl₁-C₈Alkyl；Or

C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aryl alkyl, 5-10 unit heteroaryl or heteroaryl alkane Base, each of which is by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, Unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.

" alkoxyl " means group-OR²⁹, wherein R²⁹It is C₁-C₈Alkyl.Concrete alkoxyl is methoxyl group, ethyoxyl, just Propoxyl group, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, positive hexyloxy and 1,2-dimethyl butyrate oxygen Base.Concrete alkoxyl is the lower alkoxy with 1-6 carbon atom.It is former that other concrete alkoxyls have 1-4 carbon Son.

" substituted alkoxyl " means by the substituted alcoxyl of group described in one or more this paper " substituted " definition Base, and be particularly intended to have more than 1 (such as 1-5 substituent group of substituent group, particularly 1-3 substituent group, particularly 1 Individual substituent group) alkoxyl, described substituent group be selected from amino, substituted amino, C₆-C₁₀Aryl, aryloxy group, carboxyl, cyano group, C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, halogen, 5-10 unit heteroaryl, hydroxyl, nitro, thio alkoxy, thio-aryloxy, Sulfydryl, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O)₂-and aryl-S (O)₂-.Typically " substituted alkoxyl " is-O- (CH₂)_t(C₆-C₁₀Aryl) ,-O-(CH₂)_t(5-10 unit heteroaryl) ,-O-(CH₂)_t(C₃-C₁₀Cycloalkyl) and-O-(CH₂)_t(4-10 Unit's Heterocyclylalkyl), wherein t is that arbitrary aryl, heteroaryl, cycloalkyl or the Heterocyclylalkyl of the integer of 0-4 and existence self can With by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.Concrete typical " substituted alkoxyl " is OCF₃、OCH₂CF₃、OCH₂Ph、OCH₂-cyclopropyl, OCH₂CH₂OH and OCH₂CH₂NMe₂。

" alkoxy carbonyl group " means group-C (O)-OR³⁰, wherein R³⁰Represent C₁-C₈Alkyl, C₃-C₁₀Cycloalkyl, C₃-C₁₀Cycloalkanes Base alkyl, 4-10 unit hetercycloalkylalkyl, aralkyl or 5-10 unit heteroaryl alkyl, as defined herein.Typically " alcoxyl carbonyl Base " group is C (O) O-C₁-C₈Alkyl ,-C (O) O-(CH₂)_t(C₆-C₁₀Aryl) ,-C (O) O-(CH₂)_t(5-10 unit heteroaryl) ,- C(O)O-(CH₂)_t(C₃-C₁₀Cycloalkyl) and C (O) O-(CH₂)_t(4-10 unit Heterocyclylalkyl), wherein t is the integer of 1-4.

" substituted alkoxy carbonyl group " means group-C (O)-OR³¹, wherein R³¹Represent:

C₁-C₈Alkyl, C₃-C₁₀Cycloalkyl, C₃-C₁₀Cycloalkyl-alkyl or 4-10 unit hetercycloalkylalkyl, it is each by halogen Amino plain, substituted or unsubstituted or hydroxyl replace；Or

C₆-C₁₀Aralkyl or 5-10 unit heteroaryl alkyl, it is each by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy Or hydroxyl replaces.

" aryloxycarbonyl " means group-C (O)-OR³², wherein R³²Represent C₆-C₁₀Aryl, as defined herein.Typical case " aryloxycarbonyl " be C (O) O-(C₆-C₁₀Aryl).

" substituted aryloxycarbonyl " means group-C (O)-OR³³, wherein R³³Represent

C₆-C₁₀Aryl, it is by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄ Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.

" Heteroaryloxycarbonyl " means group-C (O)-OR³⁴, wherein R³⁴Represent 5-10 unit as herein defined heteroaryl Base.Typically " aryloxycarbonyl " is C (O) O-(5-10 unit heteroaryl).

" substituted Heteroaryloxycarbonyl " means group-C (O)-OR³⁵, wherein R³⁵Represent:

5-10 unit heteroaryl, it is by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁- C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.

" alkoxycarbonyl amido " means group-NR³⁶C(O)OR³⁷, wherein R³⁶It is hydrogen, C₁-C₈Alkyl, C₃-C₁₀Cycloalkyl, C₃-C₁₀Methyl cycloalkyl, 4-10 unit Heterocyclylalkyl, aryl, aryl alkyl, 5-10 unit heteroaryl or heteroaryl as herein defined Base alkyl, R³⁷It is C₁-C₈Alkyl, C₃-C₁₀Cycloalkyl, C₃-C₁₀Methyl cycloalkyl, 4-10 unit Heterocyclylalkyl, aryl, aryl alkane Base, 5-10 unit heteroaryl or heteroaryl alkyl as herein defined.

" alkyl " means the straight or branched aliphatic hydrocarbon with 1-20 carbon atom.Concrete alkyl has 1-12 carbon Atom.More specifically alkyl is the low alkyl group with 1-6 carbon atom.Another kind of concrete alkyl group has 1-4 Carbon atom.Typical straight chain group includes methyl, ethyl, n-pro-pyl and normal-butyl.Side chain means one or more low alkyl group (such as methyl, ethyl, propyl group or butyl are connected with linear alkyl chain, and typical branched group includes isopropyl, iso-butyl, uncle Butyl and isopentyl.

" substituted alkyl " means by the group described in one or more this paper " substituted " definition substituted as above-mentioned Defined alkyl, and it is particularly intended to that there is more than 1 substituent group (such as 1-5 substituent group, particularly 1-3 replacement Base, particularly 1 substituent group) alkyl, described substituent group be selected from acyl group, acylamino-, acyloxy (-O-acyl group or-OC (O) R²⁰), alkoxyl, alkoxy carbonyl group, alkoxycarbonyl amido (-NR "-alkoxy carbonyl group or-NH-C (O)-OR²⁷), amino, substituted ammonia Base, amino carbonyl (carbamoyl or acylamino-or C (O)-NR "₂), amino carbonyl amino (-NR "-C (O)-NR "₂), amino Carbonyl epoxide (-O-C (O)-NR "₂), amino-sulfonyl, sulfuryl amino, aryl, aryloxy group, azido, carboxyl, cyano group, ring Alkyl, halogen, hydroxyl, heteroaryl, nitro, sulfydryl ,-S-alkyl ,-S-aryl ,-S (O)-alkyl ,-S (O)-aryl ,-S (O)₂- Alkyl and-S (O)₂-aryl.In a specific embodiment, " substituted alkyl " mean by halogen, cyano group, nitro, three Methyl fluoride, trifluoromethoxy, azido ,-NR " ' SO₂R”、-SO₂NR”R”’、-C(O)R”、-C(O)OR”、-OC(O)R”、-NR”’ C (O) R " ,-C (O) NR " R " ' ,-NR " R " ' or-(CR " ' R " ")_mOR " ' substituted C₁-C₈Alkyl；Wherein R " select independently of one another From H, C₁-C₈Alkyl ,-(CH₂)_t(C₆-C₁₀Aryl) ,-(CH₂)_t(5-10 unit heteroaryl) ,-(CH₂)_t(C₃-C₁₀Cycloalkyl) and- (CH₂)_t(4-10 unit Heterocyclylalkyl), wherein t is integer and aryl, heteroaryl, cycloalkyl or the heterocycle alkane of arbitrarily existence of 0-4 Base self can be by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, not Substituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.R " ' and R " " represent H independently of one another Or C₁-C₈Alkyl.

What " alkylidene " meant to have 1-11 carbon atom and more specifically 1-6 carbon atom can be straight chain or The saturated alkylidene group of bivalence of side chain.This term is with such as methylene (-CH₂-), ethylidene (-CH₂CH₂-), propylidene isomery Body (such as-CH₂CH₂CH₂-and-CH (CH₃)CH₂-) etc. group be typical case.

" substituted alkylidene " means the group described in " substituted " definition herein, and be particularly intended to have 1 with The alkylidene of upper substituent group (such as 1-5 substituent group, particularly 1-3 substituent group), described substituent group is selected from acyl group, acyl ammonia Base, acyl group base, alkoxyl, substituted alkoxyl, alkoxy carbonyl group, alkoxycarbonyl amido, amino, substituted amino, amino carbonyl, Amino-carbonyl amino, amino carbonyl epoxide, aryl, aryloxy group, azido, carboxyl, cyano group, halogen, hydroxyl, ketone group, nitro, Thio alkoxy, substituted thio alkoxy, thio-aryloxy, thioketo, sulfydryl, alkyl-S (O)-, aryl-S (O)-, alkane Base-S (O)₂-and aryl-S (O)₂-。

" thiazolinyl " means have 2-11 carbon atom, particularly 2-8 carbon atom and more specifically 2-6 carbon The monovalence ethylenically unsaturated hydrocarbons base of atom, its can be straight chain or side chain and there is at least 1 and specifically 1- 2 olefinic unsaturation positions.Concrete thiazolinyl includes vinyl (-CH=CH₂), positive acrylic (-CH₂CH=CH₂), isopropyl alkene Base (-C (CH₃)=CH₂), vinyl and substituted vinyl etc..

" substituted thiazolinyl " means the group described in " substituted " definition herein, and is particularly intended to have more than 1 The thiazolinyl of substituent group (such as 1-5 substituent group, particularly 1-3 substituent group), described substituent group selected from acyl group, acylamino-, Acyloxy, alkoxyl, substituted alkoxyl, alkoxy carbonyl group, alkoxycarbonyl amido, amino, substituted amino, amino carbonyl, Amino carbonyl amino, amino carbonyl epoxide, aryl, aryloxy group, azido, carboxyl, cyano group, cycloalkyl, substituted cycloalkyl, halogen Element, hydroxyl, ketone group, nitro, thio alkoxy, substituted thio alkoxy, thio-aryloxy, thioketo, sulfydryl, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O)₂-and aryl-S (O)₂-。

" alkenylene " means have at most about 11 carbon atoms and the bivalence olefinic of more specifically 2-6 carbon atom Unsaturated alkyl, its can be straight chain or side chain and there is at least 1 and specifically 1-2 olefinic is unsaturated Position.This term is with such as ethenylidene (-CH=CH-), propenylene isomers (such as-CH=CHCH₂-and-C (CH₃)= CH-and-CH=C (CH₃The group of)-) etc. is typical case.

" alkynyl " means acetylene series or acetylenic unsaturated alkyl, particularly has 2-11 carbon atom and more specifically The acetylene series unsaturated alkyl of 2-6 carbon atom, its can be straight chain or side chain and there is at least 1 and specifically It is 1-2 acetylene series unsaturation position.The concrete limiting examples of alkynyl includes acetenyl, acetenyl (-C ≡ CH), propine Base (-CH₂C ≡ CH) etc..

" substituted alkynyl " means the group described in " substituted " definition herein, and is particularly intended to have more than 1 The alkynyl of substituent group (such as 1-5 substituent group and particularly 1-3 substituent group), described substituent group selected from acyl group, acylamino-, Acyloxy, alkoxyl, substituted alkoxyl, alkoxy carbonyl group, alkoxycarbonyl amido, amino, substituted amino, amino carbonyl, Amino carbonyl amino, amino carbonyl epoxide, aryl, aryloxy group, azido, carboxyl, cyano group, cycloalkyl, substituted cycloalkyl, halogen Element, hydroxyl, ketone group, nitro, thio alkoxy, substituted thio alkoxy, thio-aryloxy, thioketo, sulfydryl, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O)₂-and aryl-S (O)₂-。

" amino " means group-NH₂。

" substituted amino " mean by the substituted amino of one or more groups described in herein " substituted " definition and It is particularly intended to group-N (R³⁸)₂, wherein R³⁸It is each independently selected from:

Hydrogen, C₁-C₈Alkyl, C₆-C₁₀Aryl, 5-10 unit heteroaryl, 4-10 unit Heterocyclylalkyl or C₃-C₁₀Cycloalkyl；Or

The C replaced by halogen or hydroxyl₁-C₈Alkyl；Or

·-(CH₂)_t(C₆-C₁₀Aryl) ,-(CH₂)_t(5-10 unit heteroaryl) ,-(CH₂)_t(C₃-C₁₀Cycloalkyl) or-(CH₂)_t (4-10 unit Heterocyclylalkyl), wherein t is the integer of 0-8, and it is each by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁- C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or Hydroxyl replaces；Or

Two R³⁸Group together forms alkylidene.

As two R³⁸When group is hydrogen ,-N (R³⁸)₂It is amino.Typically " substituted amino " group is-NR³⁹-C₁-C₈ Alkyl ,-NR³⁹-(CH₂)_t(C₆-C₁₀Aryl) ,-NR³⁹-(CH₂)_t(5-10 unit heteroaryl) ,-NR³⁹-(CH₂)_t(C₃-C₁₀Cycloalkyl) With-NR³⁹-(CH₂)_t(4-10 unit Heterocyclylalkyl), wherein t is the integer of 0-4, R³⁹Represent H or C independently of one another₁-C₈Alkyl； And the alkyl self arbitrarily existed can be replaced by halogen, substituted or unsubstituted amino or hydroxyl；And the aryl of arbitrarily existence, Heteroaryl, cycloalkyl or Heterocyclylalkyl self can be by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, not Substituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.For Query, term " substituted amino " is avoided to include group alkylamino as defined above, substituted alkylamino, alkyl virtue ammonia Base, substituted alkyl virtue amino, virtue amino, substituted virtue amino, dialkylamino and substituted dialkylamino.

" alkylamino " means group-NHR⁴⁰, wherein R⁴⁰It is C₁-C₈Alkyl.

" substituted alkylamino " means group-NHR⁴¹, wherein R⁴¹It is C₁-C₈Alkyl；And alkyl by halogen, replacement or does not takes The amino in generation, hydroxyl, C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, 5-10 unit heteroaryl, aralkyl or heteroaryl Alkyl replaces；And aryl, heteroaryl, cycloalkyl or the Heterocyclylalkyl self arbitrarily existed can be by unsubstituted C₁-C₄Alkyl, Halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.

" alkyl virtue amino " means group-NR⁴²R⁴³, wherein R⁴²It is aryl, R⁴³It is C₁-C₈Alkyl.

" substituted alkyl virtue amino " means group-NR⁴⁴R⁴⁵, wherein R⁴⁴It is aryl, R⁴⁵It is C₁-C₈Alkyl；Alkyl is by halogen Amino plain, substituted or unsubstituted, hydroxyl, C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, 5-10 unit heteroaryl, Aralkyl or heteroarylalkyl replace；And aryl, heteroaryl, cycloalkyl or the Heterocyclylalkyl self arbitrarily existed can be unsubstituted C₁-C₄Alkyl, halogen, cyano group, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxyl Base alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.

" virtue amino " means group-NHR⁴⁶, wherein R⁴⁶Selected from C₆-C₁₀Aryl and 5-10 unit heteroaryl, as determined herein Justice.

" substituted virtue amino " means group-NHR⁴⁷, wherein R⁴⁷Independently selected from C₆-C₁₀Aryl and 5-10 unit heteroaryl； The aryl or the heteroaryl self that arbitrarily exist can be by unsubstituted C₁-C₄Alkyl, halogen, cyano group, unsubstituted C₁-C₄Alcoxyl Base, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl take Generation.

" dialkylamino " means group-NR⁴⁸R⁴⁹, wherein R⁴⁸And R⁴⁹It is each independently selected from C₁-C₈Alkyl.

" substituted dialkylamino " means group-NR⁵⁰R⁵¹, the most each R⁵⁹And R⁵¹Independently selected from C₁-C₈Alkyl；At least One alkyl is independently by halogen, hydroxyl, C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, 5-10 unit heteroaryl, Aralkyl or heteroarylalkyl replace；Aryl, heteroaryl, cycloalkyl or the Heterocyclylalkyl self arbitrarily existed can be unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or Unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.

" diarylamino " means group-NR⁵²R⁵³, wherein R⁵²And R⁵³It is each independently selected from C₆-C₁₀Aryl.

" amino-sulfonyl " or " sulfonamide " means group-S (O₂)NH₂。

" substituted amino-sulfonyl " or " substituted sulfonamide " means group such as-S (O₂)N(R⁵⁴)₂, wherein R⁵⁴Each Independently selected from:

·H、C₁-C₈Alkyl, C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aralkyl, 5-10 unit heteroaryl And heteroarylalkyl；Or

The C replaced by halogen or hydroxyl₁-C₈Alkyl；Or

·C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aralkyl, 5-10 unit heteroaryl or heteroarylalkyl, It is each by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace；

Condition is at least one R⁵⁴It not H.

Typically " substituted amino-sulfonyl " or " substituted sulfonamide " group is-S (O₂)N(R⁵⁵)-C₁-C₈Alkyl ,-S (O₂)N(R⁵⁵)-(CH₂)_t(C₆-C₁₀Aryl) ,-S (O₂)N(R⁵⁵)-(CH₂)_t(5-10 unit heteroaryl) ,-S (O₂)N(R⁵⁵)-(CH₂)_t (C₃-C₁₀Cycloalkyl) and-S (O₂)N(R⁵⁵)-(CH₂)_t(4-10 unit Heterocyclylalkyl), wherein t is the integer of 0-4；R⁵⁵The most solely On the spot represent H or C₁-C₈Alkyl；Aryl, heteroaryl, cycloalkyl or the Heterocyclylalkyl self arbitrarily existed can be unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or Unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.

" aralkyl " or " aryl alkyl " mean by one or more definition obtained as described above aryl replace as above-mentioned Defined alkyl.The alkyl that concrete aralkyl or aryl alkyl are replaced by an aryl.

" substituted aralkyl " or " substituted aryl alkyl " means to be determined as above-mentioned by what one or more aryl replaced The alkyl of justice；At least one aryl self existed can be by unsubstituted C₁-C₄Alkyl, halogen, cyano group, unsubstituted C₁-C₄ Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl Base replaces.

" aryl " means the monovalence virtue derivative by removing a hydrogen atom on the single carbon atom of Parent Aromatic ring system Race's alkyl.Specifically, aryl means aromatic monocyclic or multi-ring ring structure, and it includes 5-12 ring members, more generally 6- 10 ring memberses.When aryl is monocycle system, it preferably comprises 6 carbon atoms.Exemplary of aryl includes, but are not limited to derived from vinegar Anthrene, acenaphthylene, vinegar phenanthrene alkene, anthracene, azulenes, benzene, 5, coronene, fluoranthene, fluorenes, hexacene, hexaphene, oneself take alkene (hexalene), no S-indacene, s-indacene, indane, indenes, naphthalene eight benzene, Xin Fen (octaphene), pungent take alkene (octalene), ovum Benzene, amyl-2,4-diene, Benzo[b, pentalene, dibenzo [b, h] phenanthrene, perylene, that alkene non-, phenanthrene, benzo [a, i] Phenanthrene, seven days of the week alkene, pyrene, pyranthrene, rubicene, the luxuriant and rich with fragrance group with trinaphthylene (trinaphthalene) of benzo (9,10).Concrete virtue Base includes phenyl, naphthyl, indenyl and tetralyl.

" substituted aryl " mean by the substituted aryl of one or more groups described in herein " substituted " definition and Specifically mean aryl, its can optionally by more than 1 substituent group (such as 1-5 substituent group, particularly 1-3 substituent group, Particularly 1 substituent group) replace.Especially, " substituted aryl " means by one or more selected from halogen, C₁-C₈Alkyl, C₁- C₈Haloalkyl, cyano group, hydroxyl, C₁-C₈The substituted aryl of group of alkoxyl and amino.

The example of representational substituted aryl includes the following:

In these formulas, R⁵⁶And R⁵⁷One of can be hydrogen, R⁵⁶And R⁵⁷In at least one is each independently selected from C₁-C₈Alkane Base, C₁-C₈Haloalkyl, 4-10 unit Heterocyclylalkyl, alkanoyl, C₁-C₈Alkoxyl, heteroaryloxy, alkylamino, virtue amino, heteroaryl Amino, NR⁵⁸COR⁵⁹、NR⁵⁸SOR⁵⁹NR⁵⁸SO₂R⁵⁹, COO alkyl, COO aryl, CONR⁵⁸R⁵⁹、CONR⁵⁸OR⁵⁹、NR⁵⁸R⁵⁹、 SO₂NR⁵⁸R⁵⁹, S-alkyl, SO alkyl, SO₂Alkyl, S aryl, SO aryl, SO₂Aryl；Or R⁵⁶And R⁵⁷Formation 5-8 can be connected The ring (saturated or unsaturated) of individual atom, it optionally comprises one or more hetero atom selected from N, O or S.R⁶⁰And R⁶¹Independently It is hydrogen, C₁-C₈Alkyl, C₁-C₄Haloalkyl, C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, substituted aryl, 5-10 unit heteroaryl.

" fused-aryl " means have and second aryl rings or the aryl of two the ring carbon total with aliphatic series ring.

" alkoxy aryl " means-O-alkylaryl, and wherein alkylaryl is as herein defined.

" substituted alkoxy aryl " means-O-alkylaryl, and wherein alkylaryl is as defined herein；Arbitrarily exist Aryl self can be by unsubstituted C₁-C₄Alkyl, halogen, cyano group, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-₄Halo Alkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.

" azido " means group-N₃。

" carbamoyl or acylamino-" means group-C (O) NH₂。

" substituted carbamoyl or substituted acylamino-" means group-C (O) N (R⁶²)₂, the most each R⁶²Independently:

·H、C₁-C₈Alkyl, C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aralkyl, 5-10 unit heteroaryl And heteroarylalkyl；Or

The C replaced by halogen or hydroxyl₁-C₈Alkyl；Or

·C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aralkyl, 5-10 unit heteroaryl or heteroarylalkyl, It is each by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace；

Condition is at least one R⁶²It not H.

Typically " substituted carbamoyl " is C (O) NR⁶⁴-C₁-C₈Alkyl ,-C (O) NR⁶⁴-(CH₂)_t(C₆-C₁₀Virtue Base) ,-C (O) N⁶⁴-(CH₂)_t(5-10 unit heteroaryl), C (O) NR⁶⁴-(CH₂)_t(C₃-C₁₀Cycloalkyl) and C (O) NR⁶⁴-(CH₂)_t (4-10 unit Heterocyclylalkyl), wherein t is the integer of 0-4, R⁶⁴Represent H or C independently of one another₁-C₈Alkyl, the virtue arbitrarily existed Base, heteroaryl, cycloalkyl or Heterocyclylalkyl, described group self can be by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy Or hydroxyl replaces.

" carboxyl " means group-C (O) OH.

" cycloalkyl " means the cyclic non-aromatic alkyl with 3-10 carbon atom.This cycloalkyl includes, such as monocycle Structure, such as cyclopropyl, cyclobutyl, cyclopenta and ring octyl group.

" substituted cycloalkyl " means by the one or more groups described in " substituted " definition herein substituted as above State defined cycloalkyl, and be particularly intended to that there is more than 1 substituent group (such as 1-5 substituent group and particularly 1-3 Substituent group, particularly 1 substituent group) cycloalkyl.

" cyano group " means group-CN.

" halo " or " halogen " means fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).Concrete halogen group is fluorine or chlorine.

" miscellaneous " when for describe compound or be present on compound group time mean in compound or group one Or multiple carbon atom is substituted by nitrogen, oxygen or sulfur heteroatom.Miscellaneous can apply to arbitrary above-mentioned alkyl, such as alkyl, the most miscellaneous Alkyl, cycloalkyl, such as Heterocyclylalkyl, aryl, such as heteroaryl, cycloalkenyl group, the such as miscellaneous thiazolinyl of ring etc., described group has 1-5 and particularly 1-3 hetero atom.

" heteroaryl " means monocycle or multi-ring aromatic ring structure, and it comprises one or more hetero atom and 5-12 ring Member, more generally 5-10 ring members.Heteroaryl can be such as 5 yuan or 6 yuan of monocycles or by condensing 5 and 6 rings or two The twin nuclei that individual fused 6 ring is formed, or be to be condensed, by two, the twin nuclei that 5 rings are formed as another example.Respectively Ring can comprise at most 4 hetero atoms being typically chosen from nitrogen, sulfur and oxygen.Typically, heteroaryl ring comprise at most 4 miscellaneous former Son, more typically at most 3 hetero atoms, the most at most 2 hetero atoms, the most single hetero atom.An embodiment In, heteroaryl ring comprises at least one theheterocyclic nitrogen atom.Nitrogen-atoms on heteroaryl ring can be alkalescence for imidazoles or pyridine , or it is substantially non-alkaline for indole or pyrroles's nitrogen.Generally there are and (include the arbitrary ammonia of ring in heteroaryl Base substituent group) in basic nitrogen atom number less than 5.The example of 5 yuan of bicyclic heteroaryls includes, but are not limited to pyrroles, furan, thiophene Fen, imidazoles, furazan,Azoles,Diazole,Triazole, differentAzoles, thiazole, isothiazole, pyrazoles, triazole and tetrazole radical.6 yuan of lists The example of ring heteroaryl includes, but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.Comprise 5 yuan condensed with another 5 ring The instantiation of the bicyclic heteroaryl of ring includes, but are not limited to Imidazothiazole and imidazo imidazoles.Comprise and condense with 5 rings The instantiation of the bicyclic heteroaryl of 6 rings includes, but are not limited to benzofuran, benzothiophene, benzimidazole, benzoAzoles, Different benzoAzoles, benzisoxaAzoles, benzothiazole, benzisothiazole, isobenzofuran, indole, iso-indoles, isoindolone, Yin Piperazine, indoline, isoindoline, purine (such as adenine, guanine), indazole, pyrazolopyrimidine, triazolo pyrimidine, benzene And dioxole and Pyrazolopyridine group.The instantiation of the bicyclic heteroaryl comprising 2 fused 6 rings includes, But it is not limited to quinoline, isoquinolin, chromane, sulfur for chromane, chromene, heterochromatic alkene, chromane, heterochromatic full, benzo twoAlkane, quinolizine, benzene AndPiperazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnolines, phthalazines, naphthyridines and pteridine group.Concrete heteroaryl Base be those derived from thiophene, pyrroles, benzothiophene, benzofuran, indole, quinoline, imidazoles,Azoles and the group of pyrazine.

The example of representational heteroaryl includes the following:

The most each Y is selected from carbonyl, N, NR⁶⁵, O and S；R⁶⁵It is hydrogen, C independently₁-C₈Alkyl, C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl and 5-10 unit heteroaryl.

There is the example comprising heteroatomic substituted representational aryl include the following:

The most each W is selected from C (R⁶⁶)₂、NR⁶⁶, O and S；Each Y is selected from carbonyl, NR⁶⁶, O and S；R⁶⁶It is hydrogen, C independently₁-C₈Alkane Base, C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl and 5-10 unit heteroaryl.

Term used herein " Heterocyclylalkyl " means the 4-10 stable heterocyclic non-aromatic ring of unit and/or includes comprising one Or the multiple heteroatomic ring condensed therewith independently selected from N, O and S.Annelated heterocycles system can include carbocyclic ring and only need Including a heterocycle.The example of heterocycle includes, but are not limited to morpholine, piperidines (such as piperidino, 2-piperidyl, 3-piperidyl With 4-piperidyl), pyrrolidine (such as 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), ketopyrrolidine, pyrans (2H-pyrrole Mutter or 4H-pyrans), dihydro-thiophene, dihydropyran, dihydrofuran, thiazoline, oxolane, Tetramethylene sulfide, twoAlkane, four Hydrogen pyrans (such as 4-THP trtrahydropyranyl), imidazoline, imidazolidinone (imidazolidinone),Oxazoline, thiazoline, 2-pyrrole Oxazoline, pyrazolidine, piperazine and N-alkyl piperazine class, such as N methyl piperazine.Other examples include thiomorpholine and S-oxidation thereof Thing and S, S-dioxide (particularly thiomorpholine).Other examples include azetidine, piperidones, piperazinones and N-alkyl Piperidines, such as N-methyl piperidine.The instantiation of Heterocyclylalkyl is as shown in following exemplary example:

The most each W is selected from CR⁶⁷、C(R⁶⁷)₂、NR⁶⁷, O and S；Each Y is selected from NR⁶⁷, O and S；R⁶⁷It is hydrogen, C independently₁-C₈Alkane Base, C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, 5-10 unit heteroaryl.These heterocycloalkyl rings can optional quilt One or more groups replace, and described group is selected from acyl group, acylamino-, acyloxy, alkoxyl, alkoxy carbonyl group, alkoxy carbonyl group Amino, amino, substituted amino, amino carbonyl (carbamoyl or acylamino-), amino carbonyl amino, amino-sulfonyl, sulphur Acyl amino, aryl, aryloxy group, azido, carboxyl, cyano group, cycloalkyl, halogen, hydroxyl, ketone group, nitro, sulfydryl ,-S-alkane Base ,-S-aryl ,-S (O)-alkyl ,-S (O)-aryl ,-S (O)₂-alkyl and-S (O)₂-aryl.Substituted radical includes carbonyl or sulfur For carbonyl, it provides such as lactams and urea derivative.

" hydroxyl " means group-OH.

" nitro " means group-NO₂。

" substituted " means the base that wherein one or more hydrogen atoms are substituted by identical or different substituent group independently of one another Group.Typical substituents can be selected from:

Halogen ,-R⁶⁸、-O^-,=O ,-OR⁶⁸、-SR⁶⁸、-S^-,=S ,-NR⁶⁸R⁶⁹,=NR⁶⁸、-CCl₃、-CF₃、-CN、- OCN、-SCN、-NO、-NO₂,=N₂、-N₃、-S(O)₂O^-、-S(O)₂OH、-S(O)₂R⁶⁸、-OS(O₂)O^-、-OS(O)₂R⁶⁸、-P(O) (O^-)₂、-P(O)(OR⁶⁸)(O^-)、-OP(O)(OR⁶⁸)(OR⁶⁹)、-C(O)R⁶⁸、-C(S)R⁶⁸、-C(O)OR⁶⁸、-C(O)NR⁶⁸R⁶⁹、- C(O)O^-,-C(S)OR⁶⁸、-NR⁷⁰C(O)NR⁶⁸R⁶⁹、-NR⁷⁰C(S)NR⁶⁸R⁶⁹、-NR⁷¹C(NR⁷⁰)NR⁶⁸R⁶⁹With-C (NR⁷⁰) NR⁶⁸R⁶⁹；

Wherein R⁶⁸、R⁶⁹、R⁷⁰And R⁷¹Independently of one another:

Hydrogen, C₁-C₈Alkyl, C₆-C₁₀Aryl, aryl alkyl, C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, 5-10 unit are miscellaneous Aryl, heteroaryl alkyl；Or

The C replaced by halogen or hydroxyl₁-C₈Alkyl；Or

·C₆-C₁₀Aryl, 5-10 unit heteroaryl, C₆-C₁₀Cycloalkyl or 4-10 unit Heterocyclylalkyl, it is the most unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or Unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.

In a specific embodiment, substituted group is by one or more substituent groups, particularly 1-3 replacement Base, particularly 1 substituent group replaces.

In another specific embodiment, substituent group or group are selected from halogen, cyano group, nitro, trifluoromethyl, trifluoro Methoxyl group, azido ,-NR⁷²SO₂R⁷³、-SO₂NR⁷³R⁷²、-C(O)R⁷³、-C(O)OR⁷³、-OC(O)R⁷³、-NR⁷²C(O)R⁷³、-C (O)NR⁷³R⁷²、-NR⁷³R⁷²、-(CR⁷²R⁷²)_mOR⁷², wherein R⁷³It is each independently selected from H, C₁-C₈Alkyl ,-(CH₂)_t(C₆-C₁₀Virtue Base) ,-(CH₂)_t(5-10 unit heteroaryl) ,-(CH₂)_t(C₃-C₁₀Cycloalkyl) and-(CH₂)_t(4-10 unit Heterocyclylalkyl), wherein t is The integer of 0-4；And

The alkyl self arbitrarily existed can be replaced by halogen or hydroxyl；And

Aryl, heteroaryl, cycloalkyl or the Heterocyclylalkyl self arbitrarily existed can be by unsubstituted C₁-C₄Alkyl, halogen C plain, unsubstituted₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁- C₄Halogenated alkoxy or hydroxyl replace.R " represent H or C independently of one another₁-C₆Alkyl.

" substituted sulfanyl " means group-SR⁷⁴, wherein R⁷⁴It is selected from:

·C₁-C₈Alkyl, C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aralkyl, 5-10 unit heteroaryl and Heteroarylalkyl；Or

The C replaced by halogen, substituted or unsubstituted amino or hydroxyl₁-C₈Alkyl；Or

·C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aralkyl, 5-10 unit heteroaryl or heteroarylalkyl, It is each by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.

Typically " substituted sulfanyl " is-S-(C₁-C₈Alkyl) and-S-(C₃-C₁₀Cycloalkyl) ,-S-(CH₂)_t(C₆-C₁₀ Aryl) ,-S-(CH₂)_t(5-10 unit heteroaryl) ,-S-(CH₂)_t(C₃-C₁₀Cycloalkyl) and-S-(CH₂)_t(4-10 unit heterocycle alkane Base), wherein t is the integer of 0-4, and aryl, heteroaryl, cycloalkyl or the Heterocyclylalkyl self arbitrarily existed can be unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl Or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.Term " substituted sulfanyl " includes group as defined below " alkyl alkylthio base " or " alkylthio group ", " substituted alkylthio group " or " substituted alkyl alkylthio base ", " cycloalkyl sulfanyl " or " ring Alkylthio group ", " substituted cycloalkyl sulfanyl " or " substituted cycloalkylthio ", " sulfur alkyl aryl " or " arylthio " and " heteroaryl Base sulfanyl " or " heteroarylthio ".

" alkylthio group " or " alkyl alkylthio base " means group-SR⁷⁵, wherein R⁷⁵It is C₁-C₈Alkyl or as herein defined Group.Representational example includes, but are not limited to methyl mercapto, ethylmercapto group, rosickyite base and butylthio.

" substituted alkylthio group " or " substituted alkyl alkylthio base " means group-SR⁷⁶, wherein R⁷⁶By halogen, replacement or Unsubstituted amino or the substituted C of hydroxyl₁-C₈Alkyl.

" cycloalkylthio " or " cycloalkyl sulfanyl " means group-SR⁷⁷, wherein R⁷⁷It is C₃-C₁₀Cycloalkyl or the most herein institute The group of definition.Representational example includes, but are not limited to ring rosickyite base, cyclohexylthio and ring penta sulfenyl.

" substituted cycloalkylthio " or " substituted cycloalkyl sulfanyl " means group-SR⁷⁸, wherein R⁷⁸By halogen, take Generation or unsubstituted amino or the substituted C of hydroxyl₃-C₁₀Cycloalkyl.

" arylthio " or " sulfur alkyl aryl " means group-SR⁷⁹, wherein R⁷⁹It is C as herein defined₆-C₁₀Aryl.

" heteroarylthio " or " heteroaryl sulfanyl " means group-SR⁸⁰, wherein R⁸⁰It it is 5-10 as herein defined unit Heteroaryl.

" substituted sulfinyl " means group-S (O) R⁸¹, wherein R⁸¹It is selected from:

·C₁-C₈Alkyl, C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aralkyl, 5-10 unit heteroaryl and Heteroarylalkyl；Or

The C replaced by halogen, substituted or unsubstituted amino or hydroxyl₁-C₈Alkyl；Or

·C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aralkyl, 5-10 unit heteroaryl or heteroarylalkyl, It is each by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.

Typically " substituted sulfinyl " group is-S (O)-(C₁-C₈Alkyl) and-S (O)-(C₃-C₁₀Cycloalkyl) ,-S (O)-(CH₂)_t(C₆-C₁₀Aryl) ,-S (O)-(CH₂)_t(5-10 unit heteroaryl) ,-S (O)-(CH₂)_t(C₃-C₁₀Cycloalkyl) and-S (O)-(CH₂)_t(4-10 unit Heterocyclylalkyl), wherein t is the integer of 0-4, and arbitrarily exist aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl self can be by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Halo Alkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.The substituted sulfenyl of term Base include group as herein defined " alkyl sulphinyl ", " substituted alkyl sulphinyl ", " cycloalkylsulfinyl ", " substituted cycloalkylsulfinyl ", " aryl sulfonyl kia " and " heteroarylsulfinyl ".

" alkyl sulphinyl " means group-S (O) R⁸², wherein R⁸²It is C as herein defined₁-C₈Alkyl.There is representative The example of property includes, but are not limited to methylsulfinyl, ethylsulfinyl, propylsulfenyl and butylsulfinyl.

" substituted alkyl sulphinyl " means group-S (O) R⁸³, wherein R⁸³Be as herein defined by halogen, take Generation or unsubstituted amino or the substituted C of hydroxyl₁-C₈Alkyl.

" cycloalkylsulfinyl " means group-S (O) R⁸⁴, wherein R⁸⁴It is C₃-C₁₀Cycloalkyl or as herein defined Group.Representational example includes, but are not limited to cyclopropyl sulfinyl, cyclohexylsulfinyl and cyclopenta sulfenyl Base.Typically " cycloalkylsulfinyl " is S (O)-C₃-C₁₀Cycloalkyl.

" substituted cycloalkylsulfinyl " means group-S (O) R⁸⁵, wherein R⁸⁵By halogen, substituted or unsubstituted Amino or the substituted C of hydroxyl₃-C₁₀Cycloalkyl.

" aryl sulfonyl kia " means group-S (O) R⁸⁶, wherein R⁸⁶It is C as herein defined₆-C₁₀Aryl.

" heteroarylsulfinyl " means group-S (O) R⁸⁷, wherein R⁸⁷It it is 5-10 unit as herein defined heteroaryl.

" substituted sulfonyl " means group-S (O)₂R⁸⁸, wherein R⁸⁸It is selected from:

·C₁-C₈Alkyl, C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aralkyl, 5-10 unit heteroaryl and Heteroarylalkyl；Or

The C replaced by halogen, substituted or unsubstituted amino or hydroxyl₁-C₈Alkyl；Or

·C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aralkyl, 5-10 unit heteroaryl or heteroarylalkyl, It is each by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.

Typically " substituted sulfonyl " group is-S (O)₂-(C₁-C₈Alkyl) and-S (O)₂-(C₃-C₁₀Cycloalkyl) ,-S (O)₂-(CH₂)_t(C₆-C₁₀Aryl) ,-S (O)₂-(CH₂)_t(5-10 unit heteroaryl) ,-S (O)₂-(CH₂)_t(C₃-C₁₀Cycloalkyl) and- S(O)₂-(CH₂)_t(4-10 unit Heterocyclylalkyl), wherein t be the integer of 0-4 and the aryl arbitrarily existed, heteroaryl, cycloalkyl or Heterocyclylalkyl self can be by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Halo Alkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.The substituted sulfonyl of term Including group alkyl sulphonyl, substituted alkyl sulphonyl, naphthene sulfamide base, substituted naphthene sulfamide base, arylsulfonyl Base and heteroarylsulfonyl.

" alkyl sulphonyl " means group-S (O)₂R⁸⁹, wherein R⁸⁹It is C as herein defined₁-C₈Alkyl.Representative Example include, but are not limited to methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base and butyl sulfonyl.

" substituted alkyl sulphonyl " means group-S (O)₂R⁹⁰, wherein R⁹⁰It is as herein defined by halogen, replacement Or unsubstituted amino or the substituted C of hydroxyl₁-C₈Alkyl.

" naphthene sulfamide base " means group-S (O)₂R⁹¹, wherein R⁹¹It is C₃-C₁₀Cycloalkyl or as herein defined base Group.Representational example includes, but are not limited to Cyclopropylsulfonyl, cyclohexylsulfonyl and Cyclopentylsulfonyl.

" substituted naphthene sulfamide base " means group-S (O)₂R⁹², wherein R⁹²By halogen, substituted or unsubstituted ammonia Base or the substituted C of hydroxyl₃-C₁₀Cycloalkyl.

" aryl sulfonyl " means group-S (O)₂R⁹³, wherein R⁹³It is C as herein defined₆-C₁₀Aryl.

" heteroarylsulfonyl " means group-S (O)₂R⁹⁴, wherein R⁹⁴It it is 5-10 unit as herein defined heteroaryl.

" sulfo group " or " sulfonic acid " means group such as-SO₃H。

" substituted sulfo group " or " sulphonic acid ester " mean group-S (O)₂OR⁹⁵, wherein R⁹⁵It is selected from:

·C₁-C₈Alkyl, C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aralkyl, 5-10 unit heteroaryl and Heteroarylalkyl；Or

The C replaced by halogen, substituted or unsubstituted amino or hydroxyl₁-C₈Alkyl；Or

·C₃-C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aralkyl, 5-10 unit heteroaryl or heteroarylalkyl, It is each by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl replace.

Typically " substituted sulfo group " or " sulphonic acid ester " group are-S (O)₂-O-(C₁-C₈Alkyl) and-S (O)₂-O-(C₃- C₁₀Cycloalkyl) ,-S (O)₂-O-(CH₂)_t(C₆-C₁₀Aryl) ,-S (O)₂-O-(CH₂)_t(5-10 unit heteroaryl) ,-S (O)₂-O- (CH₂)_t(C₃-C₁₀Cycloalkyl) and-S (O)₂-O-(CH₂)_t(4-10 unit Heterocyclylalkyl), wherein t is the integer of 0-4, and arbitrarily deposits Aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl self can be by unsubstituted C₁-C₄Alkyl, halogen, unsubstituted C₁-C₄ Alkoxyl, unsubstituted C₁-C₄Haloalkyl, unsubstituted C₁-C₄Hydroxy alkyl or unsubstituted C₁-C₄Halogenated alkoxy or hydroxyl Base replaces.

" sulfydryl " means group-SH.

" amino carbonyl amino " means group-NR⁹⁶C(O)NR⁹⁶R⁹⁶, the most each R⁹⁶It is hydrogen, C independently₁-C₈Alkyl, C₃- C₁₀Cycloalkyl, 4-10 unit Heterocyclylalkyl, C₆-C₁₀Aryl, aralkyl, 5-10 unit heteroaryl and heteroaryl alkane as herein defined Base；Or two of which R⁹⁶Group connects formation alkylidene with same N when being connected.

" bicyclic aryl " means by removing what a hydrogen atom derived on the single carbon atom of parent bicyclic aromatic ring system Monovalent aromatic alkyl.Typical case's bicyclic aryl includes, but are not limited to the group derived from indane, naphthalene, naphthane etc..Specifically, virtue Base comprises 8-11 carbon atom.

" bicyclic heteroaryl " means by removing a hydrogen on the parent single carbon atom of Bicyclic heteroaromatic ring system former The monovalence Bicyclic heteroaromatic groups that son is derivative.Typical case's bicyclic heteroaryl includes, but are not limited to derived from benzofuran, benzo miaow Azoles, benzo indazole, benzo twoAlkane, chromene, chromane, cinnolines, phthalazines, indole, indoline, indolizine, isobenzofuran, heterochromatic Alkene, iso-indoles, isoindoline, isoquinolin, benzothiazole, benzoAzoles, naphthyridines, benzoDiazole pteridine, purine, benzo Pyrans, benzopyrazines, Pyridopyrimidine, quinazoline, quinoline, quinolizine, quinoxaline, benzomorphans, tetrahydroisoquinoline, tetrahydrochysene quinoline Quinoline etc..Preferably bicyclic heteroaryl is 9-11 unit bicyclic heteroaryl, wherein particularly preferred 5-10 unit heteroaryl.Concrete dicyclo heteroaryl Base is that those are derived from benzothiophene, benzofuran, benzothiazole, indole, quinoline, isoquinolin, benzimidazole, benzoAzoles and Benzo twoThe group of alkane.

" compound of the present invention " and equivalents mean to include compound as above, the most described herein and/ Or the compound of described any formula, this statement includes that prodrug, pharmaceutically acceptable salt and solvent that context allows close Thing, such as hydrate.Similarly, if context allows, then the intermediate related to, the no matter the most requested guarantor of their own Protect, all mean to include its salt and solvate.

" cycloalkyl-alkyl " means the group that the hydrogen atom of wherein alkyl is substituted by cycloalkyl.Typical cycloalkyl alkyl bag Include, but be not limited to Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, CycloheptylmethyI, ring octyl methyl, Cyclopropylethyl, CYCLOBUTYLETHYL, cyclopentyl ethyl, cyclohexyl-ethyl, cycloheptylethyl and ring octyl group ethyl etc..

" hetercycloalkylalkyl " means the group that the hydrogen atom of wherein alkyl is replaced by Heterocyclylalkyl.Typical case's Heterocyclylalkyl alkane Base includes, but are not limited to pyrrolidinylmethyl, piperidino methyl, piperizinylmethyl, morpholinyl methyl, pyrrolidinyl ethyl, piperazine Piperidinyl ethyl, piperazinyl, morpholinyl ethyl etc..

" cycloalkenyl group " means have 3-10 carbon atom and has monocycle or multiple condensed ring (includes condensing and bridged rings System) cyclic hydrocarbon radical, and there is at least one and particularly 1-2 olefinic unsaturation position.This cycloalkenyl group includes, such as Single ring architecture, such as cyclohexenyl group, cyclopentenyl, cyclopropanyl etc..

" substituted cycloalkenyl group " means those groups described in " substituted " definition herein, and is particularly intended to have 1 The cycloalkenyl group of individual above (such as 1-5 substituent group and particularly 1-3 substituent group), described substituent group be selected from acyl group, acylamino-, Acyloxy, alkoxyl, substituted alkoxyl, alkoxy carbonyl group, alkoxycarbonyl amido, amino, substituted amino, amino carbonyl, Amino carbonyl amino, amino carbonyl epoxide, aryl, aryloxy group, azido, carboxyl, cyano group, cycloalkyl, substituted cycloalkyl, halogen Element, hydroxyl, ketone group, nitro, thio alkoxy, substituted thio alkoxy, thio-aryloxy, thioketo, sulfydryl, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O)₂-and aryl-S (O)₂-。

" fused rings thiazolinyl " means have two ring carbon atoms total with second aliphatic series or aromatic ring and have position In this cycloalkenyl group the cycloalkenyl group of the olefinic degree of unsaturation for its applying armaticity.

" vinyl " mean substituted or unsubstituted (C=C)-.

" ethylidene " mean substituted or unsubstituted (C-C)-.

" acetenyl " mean (C ≡ C)-.

" hydrogen bond donor " group means to comprise the group of O-H or N-H functionality.The example of " hydrogen bond donor " group includes- OH、-NH₂With-NH-R⁹⁷, wherein R⁹⁷It is alkyl, acyl group, cycloalkyl, aryl or heteroaryl.

" dihydroxyphosphoryl " means group PO (OH)₂。

" substituted dihydroxyphosphoryl " means those groups described in " substituted " definition herein, and is particularly intended to The dihydroxyphosphoryl that wherein one or two hydroxyl is replaced.The substituent group being suitable for is as described in detail.

" hydroxy amino phosphoryl " means group PO (OH) NH₂。

" substituted hydroxy amino phosphoryl " means those groups described in " substituted " definition herein, and anticipates especially Refer to the hydroxy amino phosphoryl that wherein amino is replaced by one or two substituent group.The substituent group being suitable for is as described in detail. In some embodiments, hydroxyl can also be replaced.

" nitrogen heterocyclic ring alkyl " means the 4-7 unit non-aromatic cyclic groups comprising at least one nitrogen-atoms, such as, but not It is limited to morpholine, piperidines (such as 2-piperidyl, 3-piperidyl and 4-piperidyl), pyrrolidine (such as 2-pyrrolidinyl and 3-pyrroles Alkyl), azetidine, ketopyrrolidine, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine and N-alkyl piperazine class, Such as N methyl piperazine.Instantiation includes azetidine, piperidones and piperazinones.

" thioketo " means group=S.

It is most miscellaneous former that organic synthesis field those of ordinary skill will understand that on the most practicable stable heterocycle Subnumber, either aromatics is the most non-aromatic, all determines according to ring size, degree of unsaturation and hetero atom quantivalence.General and Speech, heterocycle can have 1-4 hetero atom, and condition is that this heterocycle is the most practical and stable.

" pharmaceutically acceptable " means the national corresponding management department approval through federal or management board of state government or non-united states Or can be by they approvals or American Pharmacopeia or other generally acknowledged pharmacopeia being enumerated for animal and more specifically people.

" pharmaceutically acceptable salt " means pharmaceutically acceptable and has the desired pharmacological activity of parent compound The salt of the compounds of this invention.Especially, this salt is avirulent, can be inorganic or the salt of organic acid addition and alkali addition Salt.Specifically, this salt includes: the acid-addition salts that (1) is formed with mineral acid, described mineral acid such as hydrochloric acid, hydrobromic acid, sulfur Acid, nitric acid, phosphoric acid etc.；Or with organic acid formed acid-addition salts, described organic acids such as acetic acid, propanoic acid, caproic acid, Pentamethylene. third Acid, glycolic, acetone acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzene first Acid, 3-(4-hydroxy benzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, 1,2-second-disulfonic acid, 2-hydroxyl Ethyl sulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-LOMAR PWA EINECS 246-676-2,4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl bicycle [2.2.2]-octyl-2- Alkene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylace tonitric, butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, Hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid etc.；Or (2) when the acid proton being present on parent compound by metal from The salt formed when son substitutes, described metal ion such as alkali metal ion, alkaline-earth metal ions or aluminium ion；Or and organic base The coordination compound that (such as ethanolamine, diethanolamine, triethanolamine, N-METHYL-ALPHA-L-GLUCOSAMINE etc.) is formed.Salt is only used as example and also includes Sodium, potassium, calcium, magnesium, ammonium, tetra-allkylammonium etc.；With when compound comprises basic functionality, the salt of avirulence organic or inorganic acid, Such as hydrochlorate, hydrobromate, tartrate, mesylate, acetate, maleate, oxalates etc.." pharmacy can connect term The cation being subject to " mean the acceptable cation counterbalancing ion of acidic functionality.This cation with sodium, potassium, calcium, magnesium, ammonium, four Alkyl ammonium cations etc. are typical case.

Diluent that " pharmaceutically acceptable vehicle " means to give together with the compounds of this invention, adjuvant, excipient or Carrier.

" prodrug " means compound, including the derivant of the compounds of this invention, they have cleavable moiety and Be there is in vivo the compounds of this invention of pharmaceutically active by solvolysis or become in physiological conditions.This example includes, But it is not limited to cholinester derivant etc., N-alkyl morpholine esters etc..

" solvate " means the compound form being generally combined with solvent by solvolysis reaction.This physical bond Including hydrogen bonding.Common solvent includes water, ethanol, acetic acid etc..The compounds of this invention can be prepared as, such as crystal formation shape Formula, and its solvation or aquation can be made.The solvate being suitable for includes pharmaceutically acceptable solvate, such as hydrate And also include stoichiometric solvate and non-stoichiometric solvate.In some instances, such as when a kind of or When multi-solvents molecule is impregnated in crystalline solid lattice, solvate can separate." solvate " includes solution-phase and can divide From solvate.Representational solvate includes hydrate, alcoholate and methylate.

" experimenter " includes people.Term " people ", " patient " and " experimenter " be used interchangeably herein.

" therapeutically effective amount " means to be enough to treat the compound amount of this disease when giving subject's disease. " therapeutically effective amount " can be according to compound, the disease of treated experimenter and seriousness thereof and the difference of age, body weight etc. Change.

" prevent " or " preventing " mean to reduce obtain or development disease or disease risk (i.e. cause not yet contacting pathogen or There is not at least one Disease Clinical symptom in the experimenter of susceptibility to disease before disease occurs.

Term " prevents " relate to " preventing " and mean non-treatment or the preventive measure of cure diseases or method.Preventive measure Limiting examples can include giving vaccine；The inpatient in thrombosis risk is caused because of such as fixing to being in Give low molecular weight heparin；Malaria is given with accessing before malaria is endemic diseases or the high geographic area of the risk contacting malaria Medicine, such as chloroquine.

In one embodiment, " treat " or " treatment " any disease or obstacle means to improve disease or obstacle (i.e. hinders Stop disease or alleviate the performance of its at least one clinical symptoms, degree or seriousness).In another embodiment, " treat " Or " treatment " means to improve at least one body parameter (physical parameter), it possibly cannot be distinguished by experimenter. In another embodiment, " treat " or " treatment " mean (such as to stablize recognizable symptom) from health, physiologically (example Such as stable body parameter) or these two aspects regulation disease or obstacle.In another embodiment, " treat " or " treatment " relates to Slow down progression of disease.

" compound of the present invention " and equivalents mean to include that the compound of formula described above, this statement include such as going up The prodrug hereafter allowed, pharmaceutically acceptable salt and solvate, such as hydrate.Similarly, the intermediate related to, nothing The opinion the most requested protection of their own, all means to include salt and the solvate that its context so allows.

When present document relates to scope, such as, but not limited to C₁-C₈Alkyl, the scope of citation should be considered each member of this scope Expression.

Other derivants of the compounds of this invention are active under its acid and acid derivative form, but in sensitivity to acid shape Formula is typically provided in dissolubility in mammalian organism, histocompatibility or postpone release advantage (see Bundgard, H.,Design of Prodrugs,pp.7-9,21-24,Elsevier,Amsterdam1985).Prodrug includes this area The well-known acid derivative of technical staff, such as by making parent acid and the alcohol being suitable for react the esters of preparation, or by making Parent acid compound and substituted or unsubstituted amine react the amide-type of preparation, or anhydride or mixed acid anhydride.Derived from the present invention The simple aliphatic series of the acidic-group on compounds in side chain or aromatics esters, amide-type and anhydrides are concrete prodrug.? In certain situation, it is desirable to prepare diester-type prodrug, such as (acyloxy) alkyl esters or ((alkoxy carbonyl group) epoxide) alkane Base esters.The particularly C of the compounds of this invention₁-C₈Alkyl, C₂-C₈Thiazolinyl, aryl, C₇-C₁₂Substituted aryl and C₇-C₁₂Virtue Base alkyl esters.

Term used herein " isotopic variations " means to comprise on the one or more atoms constituting this compound The isotopic compound of unnatural proportions.Such as, " isotopic variations " of compound can comprise one or more non-radioactive Property isotope, such as deuterium (²H or D), carbon-13 (¹³C), nitrogen-15 (¹⁵N) etc..It is to be understood that carrying out this isotope In substituted compound, if it is present following atom can change so that, such as arbitrary hydrogen can be²H/D, arbitrarily Carbon can be¹³C or arbitrary nitrogen can be¹⁵N, and the existence of this atom and configuration can be determined by art technology.With Sample, the present invention can include preparing isotopic variations with radiosiotope, and such as, the compound wherein obtained may be used for medicine Thing and/or substrate tissue distribution research.Radiosiotope tritium is i.e.³H and carbon-14 are i.e.¹⁴C be easily incorporate into because of it and be prone to detection and It is used in particular for this purpose.Furthermore, it is possible to preparation is by Positron emitting isotopes (such as¹¹C、¹⁸F、¹⁵O and¹³N) replace and be suitable for In positron emission tomography (PET) research to check the compound of substrate receptor occupancy.

The all isotopic variations (the most radioactive or inactive) specifying compound provided herein are equal It is included in the scope of the present invention.

Additionally will be understood that there is same molecular formula but character its atomic linkage order or its atomic space The compound that arrangement aspect is different is referred to as " isomer ".Isomers different in terms of its steric arrangement is referred to as " three-dimensional different Structure body ".

It is that the stereoisomer of non-mirror image is referred to as " diastereomer " each other, and is that of non-superimposable mirror image each other It is referred to as " enantiomer " a bit.Such as, when compound has asymmetric center, when it is from four different group bondings, then enantiomer pair It is possible.The feature of enantiomer can be its asymmetric center absolute configuration and by the R-of Cahn and Prelog and S-sequence rule is described, or is described by the way of polarization plane rotation by molecule, and referred to as dextrorotation or a left side Rotation (be i.e. respectively (+) or (-)-isomer).Chipal compounds can exist as single enantiomer or its form of mixtures. The mixture comprising equal proportion enantiomer is referred to as " racemic mixture ".

" tautomeride " means particular compound tautomerization form and the chemical combination substituting because of hydrogen atom and electronics and changing Thing.Therefore, two kinds of structures can be moved by pi-electron and atom (typically H) and are in balance.Such as, enol class and ketone It is tautomeride, because they are because processing and quickly change with acid or alkali.Another example of tautomerism is phenyl nitro The acid of methane and nitro versions, they are equally because being formed with acid or alkali process.

Tautomeric form can be to the optimum chemical obtaining paid close attention to compound be reactive and biological activity is relevant.

Pure enantiomeric compounds used herein is substantially free of other enantiomer of compound or stereoisomer is (the most right Reflect body excess).In other words, the serpentine formula of compound is substantially free of " R " form of compound and is thus " R " form pair Reflect body excess.Term " enantiomer-pure " or " pure enantiomer " represent compound comprise more than 75% weight, more than 80% weight, More than 85% weight, more than 90% weight, more than 91% weight, more than 92% weight, more than 93% weight, more than 94% weight Amount, more than 95% weight, more than 96% weight, more than 97% weight, more than 98% weight, more than 98.5% weight, 99% with Upper weight, more than 99.2% weight, more than 99.5% weight, more than 99.6% weight, more than 99.7% weight, more than 99.8% Weight or the enantiomer of more than 99.9% weight.In some embodiments, weight all enantiomer based on compound or vertical The gross weight of body isomer.

As used herein and unless otherwise directed, otherwise " enantiomer-pure R-compound " means at least about term The R-compound of 80% weight and the compound-s of at most about 20% weight, the R-compound of at least about 90% weight and at most about The compound-s of 10% weight, the R-compound of at least about 95% weight and the compound-s of at most about 5% weight, at least about The R-compound of 99% weight and the compound-s of at most about 1% weight, the R-compound of at least about 99.9% weight or at most The compound-s of about 0.1% weight.In some embodiments, weight is based on compound gross weight.

As used herein and unless otherwise directed, otherwise term " enantiomer-pure compound-s " or " compound-s " Mean compound-s and the R-compound of at most about 20% weight, the S-chemical combination of at least about 90% weight of at least about 80% weight Thing and the R-compound of at most about 10% weight, the compound-s of at least about 95% weight and the R-chemical combination of at most about 5% weight Thing, the compound-s of at least about 99% weight and the R-compound of at most about 1% weight or the S-ization of at least about 99.9% weight Compound and the R-compound of at most about 0.1% weight.In some embodiments, weight is based on compound gross weight.

In compositions provided herein, enantiopure compound or its pharmaceutically acceptable salt, solvate, hydrate Or prodrug can exist together with other active component or non-active ingredient.Such as, enantiomer-pure R-compound is comprised Pharmaceutical composition can comprise e.g., from about 90% excipient and about 10% enantiomer-pure R-compound.In some embodiments, Enantiomer-pure R-compound in such a composition such as can comprise the R-ization accounting for compound gross weight at least about 95% weight Compound and the compound-s of at most about 5% weight.Such as, the pharmaceutical composition comprising enantiomer-pure compound-s such as can wrap Containing e.g., from about 90% excipient and about 10% enantiomer-pure compound-s.In some embodiments, in such a composition Enantiomer-pure compound-s such as can comprise compound-s and at most about 5% weight accounting for compound gross weight at least about 95% weight The R-compound of amount.In some embodiments, excipient or carrier can be used hardly, or without excipient or carrier Preparation active component.

The compound of the present invention can have one or more asymmetric center；This compound thus can be prepared as list Only (R)-or (S)-stereoisomer or its mixture.

Unless otherwise directed, otherwise description or the name appointment of particular compound include list in specification and claims Only enantiomer and mixture thereof, be exactly otherwise its racemate.Measure the stoichiometry of stereoisomer and separate three-dimensional different The method of structure body is well-known in the art.

Compound

In certain aspects, there is provided herein the compound of multiple disease for preventing and/or treat mammal, its In have arthritis, parkinson disease, Alzheimer, apoplexy, uveitis, asthma, a myocardial infarction, treat and prevent pain Syndrome (acute and chronic or nerve), traumatic brain injury, acute spinal cord injury, neurodegenerative disease, bald (alopecia), inflammation Property enteropathy and autoimmune disease or disease.

In an aspect, there is provided herein the compound of formula 1:

Wherein

B and W is each independently selected from CR⁴；

X ' is selected from CR^4aAnd N；

L is-C (R^2aR^2b)-；

R¹Selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxyl C₁-C₄Alkyl, C₃-C₇Cycloalkanes Base-C₁-C₄Alkyl or 4-7 unit Heterocyclylalkyl-C₁-C₄Alkyl；

R^2aAnd R^2bIt is each independently selected from hydrogen, C₁-C₄Alkyl or hydroxyl C₁-C₄Alkyl；

R³It is substituted or unsubstituted C₁-C₆Alkyl；CH(OH)R^3a, OR^3a, CN, COR^3a, COOR^3a, SOR^3a, SO₂R^3a, CONR^3aR^3b, SONR^3aR^3bOr SO₂NR^3aR^3b；

R^3aIt is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, Substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl；

R^3bIt is H, substituted or unsubstituted C₁-C₆Alkyl；Or R^3aAnd R^3bForm the cycloheteroalkyl ring of 3-7 atom together；

R⁴It is each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted acyl group, replacement or unsubstituted Acylamino-, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio group, substituted or unsubstituted alkoxy carbonyl group, take Generation or unsubstituted alkyl virtue amino, substituted or unsubstituted amino, substituted or unsubstituted aryl alkyl, sulfo group, substituted Sulfo group, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted amino-sulfonyl, replacement or Unsubstituted alkyl sulphonyl, substituted or unsubstituted aryl sulfonyl, azido, substituted or unsubstituted carbamoyl, Carboxyl, cyano group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted dialkylamino, Halogen, nitro and sulfydryl；

R^4aAnd R^4bIt is each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted acyl group, replacement or not Substituted acylamino-, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio group, substituted or unsubstituted alkoxyl, Substituted or unsubstituted alkoxy carbonyl group, substituted or unsubstituted alkyl virtue amino, substituted or unsubstituted alkoxy aryl, replacement Or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, sulfo group, substituted sulfo group, replacement Sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted amino-sulfonyl, substituted or unsubstituted Alkyl sulphonyl, substituted or unsubstituted aryl sulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyanogen Base, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halogen, miscellaneous Aryloxy group, substituted or unsubstituted heteroaryl, substituted or unsubstituted miscellaneous alkyl, hydroxyl, nitro and sulfydryl；

And subscript m ' selected from 0-4；

Condition is

Work as R³It is CO₂Me、SO₂Ph or OR^3aTime, R¹It it not unsubstituted phenyl；

Work as R³It is SO₂-(4-methylpiperazine-1-yl) or SO₂-(thiomorpholine-1-base), when X ' is CH, R^4bIt not H；

Work as R³Be Me or replaced by alkoxyl methyl time, R¹It it not substituted phenyl；

Work as R³It is CO₂During H, R^4bIt is Cl, F, Br, Me, Et, OMe or CF₃；

Working as X ' is CR^4a, R³It is CONR^3aR^3b, R^3aWhen being H, R^3bIt it not substituted n-pentyl, substituted pentynyl, substituted Benzyl, substituted phenethyl, substituted thienyl ethyl or substituted thiazolylethyl；With

Work as R¹It is 5-6 unit heterocycloalkylmethyl, R³It is CO₂During Me or n-Pr, R^4bIt not Cl or 4-F；

Or its pharmaceutically acceptable salt, N-oxide, solvate, prodrug, stereoisomer, tautomeride or coordination Element variant.

Provide the pharmaceutical composition of formula 1 compound the most in one aspect of the method:

Wherein A, B, W, X ', L, R¹、R³、R^4bWith m ' is described above；

Condition is

I) R is worked as³It is CO₂Me、SO₂Ph or OR^3aTime, R¹It it not unsubstituted phenyl；

Ii) R is worked as³It is SO₂-(4-methylpiperazine-1-yl) or SO₂-(thiomorpholine-1-base), when X ' is CH, R^4bIt not H；

Iii) R is worked as³Be Me or replaced by alkoxyl methyl time, R¹It it not substituted phenyl；

Iv) R is worked as³It is CO₂During H, R^4bIt is Cl, F, Br, Me, Et, OMe or CF₃；

V) working as X ' is CR^4a, R³It is CONR^3aR^3b, R^3aWhen being H, R^3bIt not substituted n-pentyl, substituted pentynyl, replacement Benzyl, substituted phenethyl, substituted thienyl ethyl or substituted thiazolylethyl；With

Vi) R is worked as¹It is 5-6 unit heterocycloalkylmethyl, R³It is CO₂During Me or n-Pr, R^4bIt not Cl or 4-F；

Or its pharmaceutically acceptable salt, N-oxide, solvate, prodrug, stereoisomer, tautomeride or coordination Element variant.

Provide the pharmaceutical composition of formula 1 compound the most in one aspect of the method；Wherein A, B, W, X ', L, R¹、R^3a、R^4b With m ' is described above；R³It is CO₂Me、SO₂Ph or OR^3a；R¹It it is unsubstituted phenyl.

Provide the pharmaceutical composition of formula 1 compound the most in one aspect of the method；Wherein A, B, W, L, R¹、R^3aAnd m ' as Upper described；R³It is SO₂-(4-methylpiperazine-1-yl) or SO₂-(thiomorpholine-1-base)；X ' is CH；R^4bIt is H.

Provide the pharmaceutical composition of formula 1 compound the most in one aspect of the method；Wherein A, B, W, X ', L, R^3a、R^4bWith M ' is described above；R³It is Me or the methyl replaced by alkoxyl；R¹It it is substituted phenyl.

Provide the pharmaceutical composition of formula 1 compound the most in one aspect of the method；Wherein A, B, W, X ', L, R¹、R^3aWith M ' is described above；R³It is CO₂H；R^4bIt not Cl, F, Br, Me, Et, OMe or CF₃。

Provide the pharmaceutical composition of formula 1 compound the most in one aspect of the method；Wherein A, B, W, L, R¹、R³、R^3a、R^4b With m ' is described above；X ' is CR^4a；R³It is CONR^3aR^3b；R^3aIt is H；And R^3bIt is substituted n-pentyl, substituted pentynyl, replacement Benzyl, substituted phenethyl, substituted thienyl ethyl or substituted thiazolylethyl；

Provide the pharmaceutical composition of formula 1 compound the most in one aspect of the method；Wherein A, B, W, X ', L, R^3aAnd m ' as Upper described；R¹It is 5-6 unit heterocycloalkylmethyl, R³It is CO₂Me or n-Pr and R^4bIt is Cl or 4-F.

In a specific embodiments of formula 1, A, B and W are individually CH.

In a specific embodiments of formula 1, L is selected from-CH₂-、-CHMe-、-CMe₂-、-CH(CH₂OH)-and-CH (CH₂CH₂OH)-。

In a specific embodiments of formula 1, L is selected from-CH₂-and-CHMe-.

In a specific embodiments of formula 1, compound be formula 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, The compound of 2l, 2m or 2n:

Wherein

X’、R¹、R^3a、R^3b、R^4a、R^4bWith m ' is as described in formula 1；R^2aIt is H, Me, CH₂OH or CH₂CH₂OH；Het be replace or not Substituted Heterocyclylalkyl；Or its pharmaceutically acceptable salt, solvate, N-oxide, prodrug, stereoisomer, change Body or isotopic variations.

In a specific embodiments of formula 1-2n, subscript m ' it is 1,2 or 3.

In a specific embodiments of formula 1-2n, subscript m ' it is 1.

In a specific embodiments of formula 1-2n, R^4bIt is H, C independently of one another₁-C₄Alkyl, halo C₁-C₄Alkyl, CN、NO₂Or halogen.

In a specific embodiments of formula 1, compound be formula 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, The compound of 3l or 3m:

Wherein

X’、R¹、R^3a、R^3b、R^4a、R^4bWith m ' is as described in formula 1；R^2aIt is H, Me, CH₂OH or CH₂CH₂OH；Het be replace or not Substituted Heterocyclylalkyl；Or its pharmaceutically acceptable salt, solvate, N-oxide, prodrug, stereoisomer, change Body or isotopic variations.

In a specific embodiments of formula 1, compound is the compound of formula 2b, 2c, 2h, 2i, 3b, 3c, 3h or 3i； R^3aIt is H.

In a specific embodiments of formula 1-3n, R^3aIt it is substituted or unsubstituted alkyl.

In a specific embodiments of formula 1-3n, R^3aIt is Me, Et, i-Pr, n-Pr, i-Bu, t-Bu, CF₃、CH₂CF₃ Or benzyl.

In a specific embodiments of formula 1-3n, R^3aIt it is substituted methyl.

In a specific embodiments of formula 1-3n, R^3aIt is methoxy, methoxy ethyl, dimethylaminomethyl Or dimethyl aminoethyl.

In a specific embodiments of formula 1-3n, R^3aIt is hetervaromatic methyl or heterocycloalkylmethyl.

In a specific embodiments of formula 1-3n, R^3aIt is heteroarylethyl or Heterocyclylalkyl ethyl.

In a specific embodiments of formula 1-3n, R^3aIt it is pyridylmethyl.

In a specific embodiments of formula 1-3n, R^3aBe piperidino methyl, piperizinylmethyl, pyrrolidinylmethyl or Morpholinyl methyl.

In a specific embodiments of formula 1-3n, R^3aIt is pyridyl-ethyl group, piperidinoethyl, piperazinyl, pyrrole Cough up alkyl ethyl or morpholinyl ethyl.

In another specific embodiment of formula 1-3n, compound has formula 3b, R^3aIt is piperidino methyl, piperazinyl Methyl, pyrrolidinylmethyl or morpholinyl methyl.

In a specific embodiments of formula 1-3n, R^3aIt is cyclopropyl, cyclopenta, Cvclopropvlmethvl or cyclopenta first Base.

In a specific embodiments of formula 1-3n, R^3aIt it is substituted or unsubstituted heteroaryl.

In a specific embodiments of formula 1-3n, R^3aIt is substituted or unsubstituted pyridine radicals, pyrazinyl or pyrimidine radicals.

In a specific embodiments of formula 1-3n, R^3aIt it is substituted or unsubstituted phenyl.

In a specific embodiments of formula 1-3n, R^3aBe pyrrole radicals, furyl, thienyl, pyrazolyl, imidazole radicals,Oxazolyl, thiazolyl, triazolyl, thiadiazolyl group, it is unsubstituted or is replaced by alkyl or haloalkyl.

In a specific embodiments of formula 1-3n, R^3aSelected from substituted or unsubstituted quinolyl, isoquinolyl, methylene Methylenedioxyphenyl, imidazopyridyl, benzoOxazolyl, benzothiazolyl and indyl.

In a specific embodiments of formula 1-3n, R^3aIt is

And wherein subscript n 1 is selected from 1-5, R^5aIt is each independently selected from hydrogen, substituted or unsubstituted alkyl, replacement or does not takes The acyl group in generation, substituted or unsubstituted acylamino-, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio group, replacement Or unsubstituted alkoxyl, aryloxy group, alkoxy carbonyl group, substituted alkoxy carbonyl group, substituted or unsubstituted alkyl virtue amino, aryl Alkoxyl, substituted alkoxy aryl, amino, aryl, substituted aryl, aryl alkyl, sulfo group, substituted sulfo group, substituted Sulfinyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted amino-sulfonyl, substituted or unsubstituted alkane Base sulfonyl, substituted or unsubstituted aryl sulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano group, Substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halogen, heteroaryl Epoxide, substituted or unsubstituted heteroaryl, substituted or unsubstituted miscellaneous alkyl, hydroxyl, nitro and sulfydryl.

In a specific embodiments of formula 1-3n, R^3bIt is H or alkyl.

In a specific embodiments of formula 1-3n, R^3bIt is H, Me, Et or i-Pr.

In a specific embodiments of formula 1-3k, R^3bIt is H.

Formula 2j, 2k, 2j, 3k or 3n a specific embodiments in, Het be azetidine-1-base, pyrrolidine- 1-base, piperidin-1-yl, morpholine-1-base, piperazine-1-base and azepines-1-base, it is unsubstituted or by one or more choosings Replace from the group of alkyl, alkoxyl, dialkylamino, halogen, haloalkyl, hydroxyl or hydroxy alkyl.

Formula 2j, 2k, 2j, 3k or 3n a specific embodiments in, Het be azetidine-1-base, pyrrolidine- 1-base, piperidin-1-yl, morpholine-1-base, piperazine-1-base and azepines-1-base, it is unsubstituted or by one or more choosings From Me, Et, i-Pr, OMe, NMe₂, Cl, F, OH or CF₃Group replace.

In a specific embodiments of formula 2l or 3l, R^3aIt is Me, Et, i-Pr, n-Pr, i-Bu, t-Bu, CF₃、 CH₂CF₃Or benzyl.

In a specific embodiments of formula 2l or 3l, R^3aIt is Me.

In a specific embodiments of formula 2m or 3m, R^3aIt is Me, Et or i-Pr.

In a specific embodiments of formula 2m or 3m, R^3bIt is Me, Et or i-Pr.

In a specific embodiments of formula 2m or 3m, R^3aAnd R^3bIt is Me, Et or i-Pr independently of one another.

In a specific embodiments of formula 2m or 3m, R^3aAnd R^3bIt is individually Me.

In another embodiment of formula 1, compound is the compound of formula 4,5,6,7,8 or 9:

Wherein

X’、R¹、R^4bWith m ' is as described in formula 1；R^5cIt is R^5a；Subscript n 3 is 1,2 or 3；R^5aAs mentioned above；

R^2aAnd R^2bIt is each independently selected from hydrogen, C₁-C₄Alkyl or hydroxyl C₁-C₄Alkyl；Q is-O-or-C (OH) H-；

Or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomeride or isotopic variations.

In an embodiment of formula 4-9, subscript m ' it is 1,2 or 3.

In another embodiment of formula 4-9, subscript m ' it is 1.

In another embodiment of formula 1, compound is the compound of formula 10,11,12,13,14 or 15:

Wherein

X’、R¹、R^4aAnd R^4bAs described in formula 1；R^5cIt is R^5a；Subscript n 3 is 1,2 or 3；R^5aAs mentioned above；

R^2aAnd R^2bIt is each independently selected from hydrogen, C₁-C₄Alkyl or hydroxyl C₁-C₄Alkyl；

Or R^2aAnd R^2bForm cycloalkyl or the cycloheteroalkyl ring of 3-7 atom together；Q is-O-or-C (OH) H-；

Or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomeride or isotopic variations.

In an embodiment of formula 4-15, Q is-O-.

In another embodiment of formula 4-15, Q is-C (OH) H-.

In an embodiment of formula 4-15, R^2aIt is H, Me, CH₂OH or CH₂CH₂OH。

In an embodiment of formula 4-15, R^2bIt is H.

In an embodiment of formula 4-15, n3 is 1 or 2.

In an embodiment of formula 4-15, R^5cIndependently selected from H, alkyl, halogen, cyano group, alkoxyl and alkyl halide Base.

In an embodiment of formula 4-15, R^5cIt is H, Cl, F, Me, OMe or CF₃。

In formula 1,2^a-2n, 3a-3n and 4-15 a specific embodiments in, X ' is CR^4a；R^4aIt is H, C₁-C₄Alkyl, Halo C₁-C₄Alkyl, CN, NO₂Or halogen.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, X ' is CR^4a；R^4aIt is H, Me, CF₃、Cl、 F, CN or NO₂。

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, X ' is CR^4a；R^4aIt is CN.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, X ' is N.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R^4bIt is H, C₁-C₄Alkyl, halo C₁-C₄ Alkyl or halogen.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R^4bIt is H, Me, CF₃, Cl, Br or F.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R¹Be substituted or unsubstituted aryl or Heteroaryl.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R¹It it is substituted or unsubstituted dicyclo virtue Base, bicyclic alkyl or bicyclic heteroaryl.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in R¹It it is substituted or unsubstituted phenyl.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R¹Be substituted or unsubstituted pyridine radicals, Pyrazinyl, thiazolyl or pyrimidine radicals.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R¹It it is substituted or unsubstituted pyridine radicals.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R¹It it is substituted or unsubstituted pyrimidine radicals.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, wherein R¹Selected from substituted or unsubstituted Quinolyl, isoquinolyl, methylenedioxyphenyl, imidazopyridyl, benzoOxazolyl, benzothiazolyl and indyl.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R¹It is

And wherein subscript n 2 is selected from 1-5 and each R^5bIndependently selected from hydrogen, substituted or unsubstituted alkyl, replacement or unsubstituted Acyl group, substituted or unsubstituted acylamino-, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio group, replacement or Unsubstituted alkoxyl, aryloxy group, alkoxy carbonyl group, substituted alkoxy carbonyl group, substituted or unsubstituted alkyl virtue amino, aryl alkane Epoxide, substituted alkoxy aryl, amino, aryl, substituted aryl, aryl alkyl, sulfo group, substituted sulfo group, substituted Asia Sulfonyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted amino-sulfonyl, substituted or unsubstituted alkyl Sulfonyl, substituted or unsubstituted aryl sulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano group, take Generation or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halogen, heteroaryl oxygen Base, substituted or unsubstituted heteroaryl, substituted or unsubstituted miscellaneous alkyl, hydroxyl, nitro and sulfydryl.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, subscript n 2 is 1,2 or 3.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, subscript n 2 is 1 or 2.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R¹It is

And wherein R^5bAs mentioned above.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R^5bIt is each independently selected from H, alkyl, halogen Element, cyano group, alkoxyl and haloalkyl.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R^5bBe each independently selected from H, Me, Et, n-Pr、iso-Pr、Ph、Cl、F、Br、CN、OH、OMe、OEt、OPh、COPh、CO₂Me、CH₂-N-morpholino, CH₂-N-(4-Me- Piperidino), NH₂、CONH₂、CF₃、CHF₂、OCF₃、OCHF₂, t-Bu, SMe, CH=CH-CO₂H、SOMe、SO₂Me、SO₂CF₃、 SO₂NH₂,SO₃H、SO₃Me, cyclopropyl, triazolyl, morpholinyl and pyridine radicals.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R^5bBe each independently selected from H, Cl, F, Me, OMe or CF₃。

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R^5bIt is individually Me.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R^5bIt is individually OMe.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R^5bIt is individually CF₃。

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R¹Selected from hydroxyl C₁-C₄Alkyl, C₃-C₇Ring Alkyl-C₁-C₄Alkyl or 4-7 unit Heterocyclylalkyl-C₁-C₄Alkyl.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R¹Selected from hydroxymethyl, 1-hydroxyethyl With 2-hydroxyethyl.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R¹Selected from piperidin-1-yl methyl, piperazine- 1-ylmethyl and morpholine-1-ylmethyl.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R^2aIt is hydrogen.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R^2aIt is methyl, hydroxymethyl or hydroxyl second Base.

Formula 1,2a-2n, 3a-3n and 4-15 a specific embodiments in, R^2aIt it is methyl.

In a specific embodiments of formula 1, compound is the compound of formula 3g；X ' is CH.

In a specific embodiments of formula 1, compound is the compound of formula 3g；X ' is C-CN.

In a specific embodiments of formula 1, compound is the compound of formula 3g；X ' is N.

In a specific embodiments of formula 1, compound is the compound of formula 3g；R^2aIt is methyl, hydroxymethyl or hydroxyl Base ethyl.

In a specific embodiments of formula 1, compound is the compound of formula 3g；R^4bIt it is methyl.

In a specific embodiments of formula 1, compound is the compound of formula 3g；R¹It is

And wherein R^5bIt is Me, CF₃Or OMe.

In a specific embodiments of formula 1, compound is the compound of formula 3g；R¹It is

And wherein R^5bIt is Me, CF₃Or OMe.

In a specific embodiments of formula 1, compound is the compound of formula 3g；R¹It is

And wherein R^5bIt is Me, CF₃Or OMe.

In a specific embodiments of formula 1, compound is the compound of formula 3g；X’、R¹、R^2aAnd R^4bSuch as above-mentioned paragraph Described in, R^3aIt is Me or Et.

In a specific embodiments of formula 1, compound is the compound of formula 3g；X’、R¹、R^2aAnd R^4bSuch as above-mentioned paragraph Described in, R^3aIt is Me.

In another specific embodiments of formula 1, compound is the compound of formula 16,17,18,19,20 or 21:

Wherein

R^2aIt is H, Me, CH₂OH or CH₂CH₂OH；R^4aIt is H or CN；R^4bIt is F, Cl, Br, Me or CF₃；R^5bBe F, Cl, Br, Me, OMe or CF₃；

R³It is i) CH₂R^3c；ii)C(OH)(H)R^3a；iii)C(OH)(Me)R^3a；iv)OR^3a；V) C (=O) R^3a；Vi) C (= O)OR^3a；vii)S(O)₂R^3a；Viii) C (=O) NR^3aR^3b；ix)S(O)₂NR^3aR^3b；X) C (=O)-Het；xi)S(O)₂-Het； xii)CH₂OR^3a；xiii)CH₂NR^3aR^3b；And xiv) C (OH) (H) CH₂-Het；

And R^3a、R^3b、R^3cWith Het to as described in formula 2a-3n；

Or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomeride or isotopic variations.

In an embodiment of formula 16-21, R^5bIt is Me.

In an embodiment of formula 16-21, R^5bIt is CF₃。

In an embodiment of formula 16-21, R^5bIt is OMe.

In another specific embodiments of formula 1, compound is the compound of formula 22 or 23:

Wherein

Cy is substituted or unsubstituted 4-7 unit Heterocyclylalkyl Han N；

R^2aIt is H, Me, CH₂OH or CH₂CH₂OH；R^4aIt is H or CN；R^4bIt is F, Cl, Br, Me or CF₃；

R³It is i) CH₂R^3c；ii)C(OH)(H)R^3a；iii)C(OH)(Me)R^3a；iv)OR^3a；V) C (=O) R^3a；Vi) C (= O)OR^3a；vii)S(O)₂R^3a；Viii) C (=O) NR^3aR^3b；ix)S(O)₂NR^3aR^3b；X) C (=O)-Het；xi)S(O)₂-Het； xii)CH₂OR^3a；xiii)CH₂NR^3aR^3b；Or xiv) C (OH) (H) CH₂-Het；

And R^3a、R^3b、R^3cWith Het to as described in formula 2a-3n；

Or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomeride or isotopic variations.

In an embodiment of formula 22-23, Cy is morpholine-1-base.

In an embodiment of formula 16-23, R^2aIt is H.

In an embodiment of formula 16-23, R^2aIt is Me.

In an embodiment of formula 16-23, R^2aIt is CH₂OH。

Formula 16-18 and 22 an embodiment in, R^4aIt is H.

Formula 16-18 and 22 an embodiment in, R^4aIt is CN.

In an embodiment of formula 16-23, R^4bIt is Me.

In a specific embodiments of formula 16-23, R^3aIt is Me, Et, i-Pr, n-Pr, i-Bu, t-Bu, CF₃、CH₂CF₃ Or benzyl.

In a specific embodiments of formula 16-23, R^3aIt is methoxy, methoxy ethyl, dimethylamino first Base or dimethyl aminoethyl.

In a specific embodiments of formula 16-23, R^3aIt is piperidino methyl, piperizinylmethyl, pyrrolidinylmethyl Or morpholinyl methyl.

In a specific embodiments of formula 16-23, R^3aIt is pyridylmethyl, pyridyl-ethyl group, piperidinoethyl, piperazine Piperazine base ethyl, pyrrolidinyl ethyl or morpholinyl ethyl.

In a specific embodiments of formula 16-23, R^3aIt is cyclopropyl, cyclopenta, Cvclopropvlmethvl or cyclopenta first Base.

In a specific embodiments of formula 16-23, R^3aBe substituted or unsubstituted phenyl, pyridine radicals, pyrazinyl or Pyrimidine radicals.

In a specific embodiments of formula 16-23, R^3aBe pyrrole radicals, furyl, thienyl, pyrazolyl, imidazole radicals,Oxazolyl, thiazolyl, triazolyl, thiadiazolyl group, it is unsubstituted or is replaced by alkyl or haloalkyl.

In a specific embodiments of formula 16-23, R^3aIt is quinolyl, isoquinolyl, methylenedioxyphenyl, imidazoles And pyridine radicals, benzoOxazolyl, benzothiazolyl and indyl.

In a specific embodiments of formula 16-23, R^3bIt is H, Me, Et or i-Pr.

In a specific embodiments of formula 16-23, R^3bIt is H.

In a specific embodiments of formula 16-23, Het be azetidine-1-base, pyrrolidin-1-yl, piperidines- 1-base, morpholine-1-base, piperazine-1-base and azepines-1-base, its unsubstituted or by one or more selected from Me, Et, i-Pr, OMe、NMe₂, Cl, F, OH or CF₃Group replace.

In a specific embodiments of formula 1, the compound that compound is enumerated in table 1.

In a specific embodiments of formula 1, compound is selected from

4'-methyl-5-(propane-1-sulfonyl)-biphenyl-3-carboxylic acid ((S)-2-hydroxyl-1-methyl-ethyl)-amide；

2,4'-dimethyl-5-(pyrrolidine-1-sulfonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-acyl Amine；

2'-cyano group-4'-methyl-5-(pyrrolidine-1-sulfonyl)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5- Base)-ethyl]-amide；

2'-cyano group-4'-methyl-5-(pyrrolidine-1-sulfonyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3-Ji Jia Base)-amide；

4'-methyl-5-(2-methyl-propan-1-sulfonyl)-biphenyl-3-carboxylic acid ((S)-2-hydroxyl-1-methyl-ethyl)- Amide；

5-Pentamethylene. sulfonyl-4'-methyl-biphen-3-carboxylic acid ((S)-2-hydroxyl-1-methyl-ethyl)-amide；

4'-methyl-5-(propane-2-sulfonyl)-biphenyl-3-carboxylic acid ((S)-2-hydroxyl-1-methyl-ethyl)-amide；

3-mesyl-5-(5-methvl-pyridinium-2-base)-N-(2-methyl-pvrimidine-5-ylmethyl)-Benzoylamide；

3-(4-hydroxy-pyrrolidine-3-base epoxide)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(2-methyl-phonetic Pyridine-5-base)-ethyl]-Benzoylamide；

5-(2-dimethylamino-1-hydroxy-ethyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-Ji Jia Base)-amide；

4'-methyl-5-(4-methyl-3-oxo-niperazin-1-carbonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-Ji Jia Base)-amide；

4'-methyl-5-(2-methyl-aziridin-1-carbonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-acyl Amine；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid ((S)-1-methyl-2-morpholine-4-base-ethyl)-acyl Amine；

5-[1-hydroxyl-2-(4-thyl-piperazin-1-base)-ethyl]-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium- 3-ylmethyl)-amide；With

5-{1-hydroxyl-2-[(2-hydroxy-ethyl)-Methyl-amino]-ethyl }-4'-methyl-biphen-3-carboxylic acid (6-first Base-pyridin-3-yl methyl)-amide；

Or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomeride or isotopic variations.

In a specific embodiments of formula 1, compound is selected from

4'-methyl-biphen-3,5-dicarboxylic acids 5-[(6-chloro-pyridin-3-yl methyl)-amide] 3-(isobutyl-methyl-acyl Amine)；

4'-methyl-biphen-3,5-dicarboxylic acids 3-(isobutyl-methyl-amide) 5-[(2-methyl-pvrimidine-5-ylmethyl)- Amide]；

4'-methyl-biphen-3,5-dicarboxylic acids 3-(isobutyl-methyl-amide) 5-{ [(R)-1-(2-methyl-pvrimidine-5- Base)-ethyl]-amide }；

4'-methyl-5-[(2-methyl-pvrimidine-5-ylmethyl)-carbamoyl]-biphenyl-3-carboxylic acid, ethyl ester；

5-(3,3-bis-fluoro-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (2-methyl-pvrimidine-5-Ji Jia Base)-amide；

4'-methyl-5-(piperidines-1-carbonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-amide；

5-(azepan-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [1-(4-chloro-3-Metlianesulfonyl-phenyl)-ethyl]-amide；

5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (2-methyl-pvrimidine-5-Ji Jia Base)-amide；

5-(azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-amide；

5-(3-methoxymethyl-pyrrolidin-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)- Amide；

4'-methyl-5-(2-Trifluoromethyl-pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-Ji Jia Base)-amide；

5-(3,3-difluoro-pyrrolidin-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)- Amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-trifluoromethylpyridin-3-base)-ethyl]-acyl Amine；

5-mesyl-4'-methyl-biphen-3-carboxylic acid 3-mesyl-4-methyl-benzylamide；

2'-cyano group-4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)- Amide；

4'-methyl-5-(propane-1-sulfonyl)-biphenyl-3-carboxylic acid 3-mesyl-4-methyl-benzylamide；

4'-methyl-5-(propane-1-sulfonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (2-methoxy-pyrimidine-5-ylmethyl)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (imidazo [1,2-a] pyridin-7-yl methyl)-acyl Amine；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (5-Methyl-pyrazin-2-ylmethyl)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]- Amide；

4'-methyl-5-(propane-1-sulfonyl)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]- Amide；

4'-methyl-5-(propane-1-sulfonyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-amide；

4'-methyl-5-(propane-1-sulfonyl)-biphenyl-3-carboxylic acid (imidazo [1,2-a] pyridin-7-yl methyl)-acyl Amine；

5-mesyl-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-amide；

2'-cyano group-4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)- Amide；

2'-cyano group-5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium- 3-ylmethyl)-amide；

2'-cyano group-5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-trifluoromethyl- Pyridin-3-yl methyl)-amide；

2'-cyano group-4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (6-chloro-pyridin-3-yl methyl)-acyl Amine；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid 3-mesyl-4-methyl-benzylamide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (1,1-dioxo-2,3-dihydro-1H-1 $ l%6& amp；-benzo [b] thiophene-6-ylmethyl)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (3-chloro-5-trifluoromethylpyridin-2-ylmethyl)- Amide；

5-(azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-trifluoromethylpyridin-3- Base)-ethyl]-amide；

5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine- 5-yl)-ethyl]-amide；

5-(azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methoxy-pyrimidine-5-base)- Ethyl]-amide；

5-(azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-second Base]-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (3,5-Dichloro-pendin-2-ylmethyl)-amide；

5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-trifluoromethyl-pyrrole Pyridine-3-base)-ethyl]-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [(S)-1-(6-difluoromethyl-pyridin-3-base)-2- Hydroxy-ethyl]-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (benzoAzoles-5-ylmethyl)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (6-chloro-pyridin-3-yl methyl)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [(S)-2-hydroxyl-1-(6-trifluoromethylpyridin- 3-yl)-ethyl]-amide；

5-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-Ji Jia Base)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [(S)-2-hydroxyl-1-(2-methyl-pvrimidine-5- Base)-ethyl]-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid 4-chloro-3-[1,2,4] triazole-4-yl-benzyl acyl Amine；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [1-(6-methvl-pyridinium-3-base)-ethyl]-acyl Amine；

4'-methyl-5-(pyrrolidine-1-sulfonyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-amide；

3-(5-methvl-pyridinium-2-base)-N-(6-methvl-pyridinium-3-ylmethyl)-5-(pyrrolidine-1-sulfonyl)-benzene Methanamide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [(R)-1-(5-chloro-1-methyl isophthalic acid H-pyrazoles-4- Base)-ethyl]-amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]-amide；

3-(5-methvl-pyridinium-2-base)-N-[1-(6-methvl-pyridinium-3-base)-ethyl]-5-(pyrrolidine-1-carbonyl)- Benzoylamide；

3-(5-methvl-pyridinium-2-base)-N-(6-methvl-pyridinium-3-ylmethyl)-5-(pyrrolidine-1-carbonyl)-benzene first Amide；

3-(5-methvl-pyridinium-2-base)-5-(pyrrolidine-1-carbonyl)-N-(6-trifluoromethylpyridin-3-ylmethyl)- Benzoylamide；

5-(hexahydro-pyrrolo-[1,2-a] pyrazine-2-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3- Ylmethyl)-amide；

5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (3-chloro-5-trifluoromethyl-pyrrole Pyridine-2-ylmethyl)-amide；

5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-trifluoromethylpyridin-3-base Methyl)-amide；

5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-chloro-pyridin-3-yl methyl)- Amide；

5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-Ji Jia Base)-amide；

5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (3,5-Dichloro-pendin-2-Ji Jia Base)-amide；

3-(5-methvl-pyridinium-2-base)-5-(pyrrolidine-1-carbonyl)-N-[(R)-1-(6-trifluoromethylpyridin-3- Base)-ethyl]-Benzoylamide；

3-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-5-(5-methvl-pyridinium-2-base)-N-(6-trifluoromethylpyridin- 3-ylmethyl)-Benzoylamide；

3-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-fluoroform Base-pyridin-3-yl)-ethyl]-Benzoylamide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (6-methoxv-pyridine-3-ylmethyl)-amide；

5-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine- 5-yl)-ethyl]-amide；

5-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-trifluoromethyl-pyrrole Pyridine-3-base)-ethyl]-amide；

4'-methyl-biphen-3,5-dicarboxylic acids 3-(methvl-pyridinium-4-cyclohexylmethyl-amide) 5-[(6-methvl-pyridinium-3- Ylmethyl)-amide]；

4'-methyl-biphen-3,5-dicarboxylic acids 5-[(6-methvl-pyridinium-3-ylmethyl)-amide] 3-[methyl-(2,2,2- Trifluoro ethyl)-amide]；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-amide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-5-(pyrrolidine-1-carbonyl Base)-Benzoylamide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]-5-(pyrrolidine-1-carbonyl Base)-Benzoylamide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]- Amide；

3-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-Benzoylamide；

3-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-5-(5-methvl-pyridinium-2-base)-N-(6-methvl-pyridinium-3-base Methyl)-Benzoylamide；

4'-methyl-5-(2-methyl-propan-1-sulfonyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-acyl Amine；

4'-methyl-5-(2-methyl-propan-1-sulfonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-acyl Amine；

5-(2,5-dimethyl-pvrrolidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-Ji Jia Base)-amide；

5-(hexahydro-pyrrolo-[1,2-a] pyrazine-2-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl- Pyrimidine-5-base)-ethyl]-amide；

5-(hexahydro-pyrrolo-[1,2-a] pyrazine-2-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methyl- Pyridin-3-yl)-ethyl]-amide；

5-(7-aza-bicyclo [2.2.1] heptane-7-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3- Ylmethyl)-amide；

4'-methyl-5-(2-methyl-propan-1-sulfonyl)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5- Base)-ethyl]-amide；

5-((2R, 5R)-2,5-dimethyl-pvrrolidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium- 3-ylmethyl)-amide；

4'-methyl-5-(propane-2-sulfonyl)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]- Amide；

4'-methyl-5-(propane-2-sulfonyl)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]- Amide；

4'-methyl-5-(propane-2-sulfonyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-amide；

The bromo-5-of 4'-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-amide；

4'-methyl-5-(propane-2-sulfonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(R)-3-hydroxyl-1-(6-methvl-pyridinium-3-base)-propyl group]- Amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(S)-2-hydroxyl-1-(6-methoxv-pyridine-3-base)-second Base]-amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(S)-1-(6-difluoromethyl-pyridin-3-base)-2-hydroxyl-second Base]-amide；

5-ethylsulfonyl-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-amide；

5-ethylsulfonyl-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]-amide；

5-ethylsulfonyl-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-amide；

5-ethylsulfonyl-4'-methyl-biphen-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-amide；

The bromo-5-of 4'-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]-acyl Amine；

The bromo-5-of 4'-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-acyl Amine；

5-Pentamethylene. sulfonyl-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-acyl Amine；

5-Pentamethylene. sulfonyl-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]-acyl Amine；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(S)-2-hydroxyl-1-(2-methyl-pvrimidine-5-base)-ethyl]- Amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(R)-3-hydroxyl-1-(6-methoxv-pyridine-3-base)-the third Base]-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (6-methyl isophthalic acid-epoxide-pyridin-3-yl methyl)-acyl Amine；

4'-methyl-5-(pyrimidine-2-yloxy)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]- Amide；

4'-methyl-5-(thiazol-2-yl epoxide)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]- Amide；

4'-methyl-5-(thiazol-2-yl epoxide)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]- Amide；

5-(Hydroxy-pyridine-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-acyl Amine；

5-(Hydroxy-pyridine-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)- Ethyl]-amide；

5-(2-Mehtoxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-amide；

5-(2-Mehtoxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-second Base]-amide；

5-(2-Mehtoxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-second Base]-amide；

2'-cyano group-5-(2-Mehtoxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

2'-cyano group-5-(2-Mehtoxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5- Base)-ethyl]-amide；

2'-cyano group-4'-methyl-5-(thiazol-2-yl epoxide)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5- Base)-ethyl]-amide；

2'-cyano group-4'-methyl-5-(thiazol-2-yl epoxide)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid (6-methyl isophthalic acid-epoxide-pyridin-3-yl methyl)-amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(S)-2-hydroxyl-1-(6-methvl-pyridinium-3-base)-ethyl]- Amide；

2'-cyano group-4'-methyl-5-(pyridine-2-base epoxide)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-5-(thiazol-2-yl oxygen Base)-Benzoylamide；

5-(Hydroxy-pyridine-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-acyl Amine；

5-(Hydroxy-pyridine-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)- Ethyl]-amide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]-5-(thiazol-2-yl oxygen Base)-Benzoylamide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]-5-(pyridine-2-base oxygen Base)-Benzoylamide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-5-(pyridine-2-base oxygen Base)-Benzoylamide；

3-(HYDROXY-PHENYL-METHYL)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)- Ethyl]-Benzoylamide；

3-(HYDROXY-PHENYL-METHYL)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(2-methyl-pvrimidine-5-base)- Ethyl]-Benzoylamide；

2'-cyano group-5-(HYDROXY-PHENYL-METHYL)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5- Base)-ethyl]-amide；

2'-cyano group-5-(HYDROXY-PHENYL-METHYL)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

5-(Hydroxy-thiazol-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)- Ethyl]-amide；

5-(Hydroxy-thiazol-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)- Ethyl]-amide；

2'-cyano group-5-(Hydroxy-pyridine-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-amide；

2'-cyano group-5-(Hydroxy-pyridine-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-phonetic Pyridine-5-base)-ethyl]-amide；

3-(Hydroxy-pyridine-2-base-methyl)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(2-methyl-pvrimidine-5- Base)-ethyl]-Benzoylamide；

3-(Hydroxy-pyridine-2-base-methyl)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-Benzoylamide；

5-(1,2-dihydroxy-ethyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-second Base]-amide；

2'-cyano group-5-hydroxymethyl-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-second Base]-amide；

3-(Hydroxy-thiazol-2-base-methyl)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-Benzoylamide；

3-(Hydroxy-thiazol-2-base-methyl)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(2-methyl-pvrimidine-5- Base)-ethyl]-Benzoylamide；

2'-cyano group-5-(Hydroxy-thiazol-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-phonetic Pyridine-5-base)-ethyl]-amide；

2'-cyano group-5-(Hydroxy-thiazol-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-amide；

2'-cyano group-4'-methyl-5-(2,2,2-tri-fluoro-1-hydroxy-ethyl)-biphenyl-3-carboxylic acid [(R)-1-(6-methyl- Pyridin-3-yl)-ethyl]-amide；

2'-cyano group-4'-methyl-5-(2,2,2-tri-fluoro-1-hydroxy-ethyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3- Ylmethyl)-amide；

2'-cyano group-5-(1,2-dihydroxy-ethyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

5-(2-methoxyl group-1-methyl-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

5-(2-methoxyl group-1-methyl-ethoxy)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)- Amide；

5-(2-Hydroxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]- Amide；

2'-cyano group-5-(2-Hydroxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

4'-methyl-5-(tetrahydro-furan-3-base epoxide)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)- Ethyl]-amide；

4'-methyl-5-(tetrahydro-furan-2-ylmethoxy)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

2'-cyano group-5-(1-hydroxy-ethyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)- Ethyl]-amide；

2'-cyano group-4'-methyl-5-(tetrahydro-furan-2-ylmethoxy)-biphenyl-3-carboxylic acid [(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-amide；

2'-cyano group-4'-methyl-5-(tetrahydro-furan-3-ylmethoxy)-biphenyl-3-carboxylic acid [(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-amide；

2'-cyano group-4'-methyl-5-(tetrahydro-furan-3-base epoxide)-biphenyl-3-carboxylic acid [(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-amide；

2'-cyano group-5-(2-methoxyl group-1-methyl-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methyl- Pyridin-3-yl)-ethyl]-amide；

2'-cyano group-5-([1,4] twoAlkane-2-ylmethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methyl- Pyridin-3-yl)-ethyl]-amide；

5-(2,3-dihydroxy-propoxyl group)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-second Base]-amide；

5-(1-hydroxy-ethyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-acyl Amine；

5-(1-hydroxymethyl-2-Mehtoxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-amide；

3-(2-methoxyl group-1-methyl-ethoxy)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-Benzoylamide；

5-[hydroxyl-(3-methyl-3H-imidazol-4 yl)-methyl]-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-first Base-pyridin-3-yl)-ethyl]-amide；

3-(1-hydroxy-ethyl)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)-second Base]-Benzoylamide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-5-(tetrahydro-furan- 3-base epoxide)-Benzoylamide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-5-(tetrahydro-furan- 3-ylmethoxy)-Benzoylamide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-5-(tetrahydro-furan- 2-ylmethoxy)-Benzoylamide；

5-(4-dihydroxy-tetrahydro-furan-3-base epoxide)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium- 3-yl)-ethyl]-amide；

2'-cyano group-5-(4-dihydroxy-tetrahydro-furan-3-base epoxide)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-first Base-pyridin-3-yl)-ethyl]-amide；

3-(2-hydroxyl-1-methyl-ethoxy)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium- 3-yl)-ethyl]-Benzoylamide；

5-(2-hydroxyl-1-methyl-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

3-(2-hydroxyl-1-methoxy methyl-ethoxy)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methyl- Pyridin-3-yl)-ethyl]-Benzoylamide；

2'-cyano group-4'-methyl-5-(2,2,2-tri-fluoro-1-hydroxy-ethyl)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl- Pyrimidine-5-base)-ethyl]-amide；

5-[hydroxyl-(3-methyl-3H-imidazol-4 yl)-methyl]-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-first Base-pyrimidine-5-base)-ethyl]-amide；

2'-cyano group-4'-methyl-5-(tetrahydro-furan-3-base epoxide)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-phonetic Pyridine-5-base)-ethyl]-amide；

4'-methyl-5-(tetrahydro-furan-3-base epoxide)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)- Ethyl]-amide；

5-(4-dihydroxy-tetrahydro-furan-3-base epoxide)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine- 5-yl)-ethyl]-amide；

2'-cyano group-5-(4-dihydroxy-tetrahydro-furan-3-base epoxide)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-first Base-pyrimidine-5-base)-ethyl]-amide；

5-(1-hydroxyl-2-morpholine-4-base-ethyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-Ji Jia Base)-amide；

3-(5-Hydroxymethyl-thiazol-2-base epoxide)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-Benzoylamide；

2'-cyano group-4'-methyl-5-(4-methYl-thiazol-2-base epoxide)-biphenyl-3-carboxylic acid [(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-amide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-5-(4-methyl-thiophene Azoles-2-base epoxide)-Benzoylamide；

3-(benzothiazole-2-base epoxide)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-Benzoylamide；

2'-cyano group-5-(2-hydroxyl-1-methyl-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-amide；

2'-cyano group-5-(1-hydroxymethyl-2-Mehtoxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6- Methvl-pyridinium-3-base)-ethyl]-amide；

5-(1-hydroxyl-propyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-acyl Amine；

5-(1,2-Dimethoxy-ethyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-second Base]-amide；With

3-(4-chloro-thiazol-2-yl epoxide)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-Benzoylamide；

Or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomeride or isotopic variations.

In the range of provided herein is, other embodiments are lifted in other parts and embodiment herein in a non-limiting manner Go out.It should be understood that these embodiments are only for the purposes of illustration, but it is considered restriction effect never in any form.

In certain aspects, there is provided herein prodrug and the derivant of the compound of above-mentioned formula.Prodrug is this The derivant of compound that literary composition provides, it has can be by the cleaved group of metabolic way and by solvolysis or giving birth to Changing into compound provided herein under the conditions of reason, it has pharmaceutically active in vivo.This example includes, but are not limited to Cholinester derivant etc., N-alkyl morpholine ester derivant etc..

Compounds more provided herein are active under its acid and acid derivative form, but in sensitivity to acid form Be typically provided in dissolubility in mammalian organism, histocompatibility or postpone release advantage (see Bundgard, H., Design of Prodrugs,pp.7-9,21-24,Elsevier,Amsterdam1985).Prodrug includes this area skill The well-known acid derivative of art personnel, such as by making parent acid react the esters of preparation with the alcohol being suitable for, or by making mother Body acid compound and substituted or unsubstituted amine react the amide-type of preparation, or anhydride or mixed acid anhydride.Derived from the present invention The simple aliphatic series of the acidic-group on compounds in side chain or aromatics esters, amide-type and anhydrides are preferred prodrug.? In certain situation, it is desirable to prepare diester-type prodrug such as (acyloxy) alkyl esters or ((alkoxy carbonyl group) epoxide) alkyl Esters.The C of compound the most provided herein₁-C₈Alkyl, C₂-C₈Thiazolinyl, aryl, C₇-C₁₂Substituted aryl and C₇-C₁₂Virtue Base alkyl esters.

Pharmaceutical composition

When as medicine, typically give compound provided herein with pharmaceutical compositions.Can lead with pharmacy The well-known mode in territory prepares this compositions and they comprise at least one reactive compound.

It is said that in general, give compound provided herein with therapeutically effective amount.Typically by clinicist according to concerning feeling mutually Condition determines the actual compound amount given, and described correlation circumstance includes treated disease, the route of administration of selection, gives Actual compound, individual patient age, body weight and reaction, the seriousness etc. of patients symptomatic.

Pharmaceutical composition provided herein can be given by all means, including being administered orally, rectum, transdermal, subcutaneous, vein In, intramuscular and intra-nasal route.According to the difference of designated delivery approach, preferably compound provided herein is configured to injectable or Orally administered composition or be used to the ointment of transdermal administration, lotion or patch.

Compounds for oral administration can be to use bulk liquids solution or suspension or the form of powder in bulk.So And, more commonly compositions is formed with the unit dosage forms being beneficially accurately administered.Term " unit dosage forms " means to be suitable for making For the physical dispersion unit for people experimenter He the unit dose of other mammals, each unit comprises being computed of scheduled volume Produce the active substance of expectation therapeutic effect and the pharmaceutical excipient being suitable for.Typical unit dosage forms includes the pre-of fluid composition Filling, the ampoule of premeasuring or syringe, or be pill, tablet, capsule etc. for solid composite.In this compositions In, furane sulfonic acid compound is typically a small amount of composition (about 0.1-about 50% weight or preferably from about 1-about 40% weight), remaining Contribute to form the various vehicles of desired form of medication or carrier and processing aid.

The liquid form being suitable for oral administration can include containing buffer agent, suspending agent and dispersant, coloring agent, taste masking The water being suitable for of agent etc. or nonaqueous carrier.Solid form can include, such as arbitrary following ingredients or the chemical combination of similarity Thing: adhesive, such as microcrystalline Cellulose, gum tragacanth or gelatin；Excipient, such as starch or lactose；Disintegrating agent, such as algae Acid, Primogel or corn starch；Lubricant, such as magnesium stearate；Fluidizer, such as colloidal silica；Sweeting agent, such as Sucrose or saccharin；Or correctives, such as Herba Menthae, methyl salicylate or orange correctives.

Injectable composition will be typically based on injectable Sterile Saline or phosphate-buffered saline or well known in the art other Injectable carrier.As it has been described above, reactive compound in such a composition is typically a small amount of composition, normally about 0.05- 10% weight, remaining is injectable carrier etc..

Transdermal composition is typically configured to topical ointments or cream, and it comprises active component, general active component Consumption is about 0.01-about 20% weight, preferably from about 0.1-about 20% weight, preferably from about 0.1-about 10% weight, and more preferably About 0.5-about 15% weight.When being configured to ointment, typically by active component and paraffin or the ointment the most miscible with water Substrate mixes.Or, by such as oil-in-water type cream base, active component is configured to cream.This preparation capable of permeating skin is this area Well-known and generally comprise promotion active component or other compositions of preparation epidermal penetration stability.All this transdermals In the range of preparation and composition are included in provided herein is.

Compound provided herein can also be given by transdermal device.Therefore, it is possible to use bank or perforated membrane type Or the patch of various solid matrix carries out transdermal administration.

The composition of the above-mentioned compositions for Orally-administrable, injection or topical is only representational.Other materials Material and process technology etc. existRemington’s PharmaceuticalSciences, the 17th edition, 1985, Mack Publishing Company, enumerates in the 8th part of Easton, Pennsylvania, by quoting, the document is incorporated to this Literary composition.

The composition of the above-mentioned compositions for Orally-administrable, injection or topical is only representational.Other materials Material and process technology etc. are at Remington ' s The Science and Practice of Pharmacy, 21st 8th part of edition, 2005, Publisher:Lippincott Williams&Wilkins is enumerated, by quote by The document is expressly incorporated herein.

Can also be with sustained release forms or the compound giving the present invention from slow releasing pharmaceutical delivery system.To representational The description of slow-release material can be found in Remington ' s Pharmaceutical Sciences.

Following formulation examples illustrates can be with representational pharmaceutical composition prepared in accordance with the present invention.But, this Bright it is not limited to agents compositions.

Preparation 1 tablet

The compound of the present invention can be mixed into dry powder as with dry gelatin adhesive according to the weight ratio of about 1:2.Add Enter a small amount of magnesium stearate as lubricant.This mixture is made to form 240-270mg tablet (80-90mg active ingredient with tablet machine Thing/sheet).

Preparation 2 capsule

The compound of the present invention and starch diluent can be mixed into dry powder according to the weight ratio of about 1:1.By this mixing Thing is packed into 250mg capsule (125mg reactive compound/capsule).

Preparation 3 liquid

The compound (125mg) of the present invention can be mixed with sucrose (1.75g) and xanthan gum (4mg), can blend The mixture arrived so that it is by No. 10 U.S. sieves, then with previously prepared microcrystalline Cellulose and sodium carboxymethyl cellulose (11: Aqueous solution 89,50mg).Dilute with water sodium benzoate (10mg), correctives and coloring agent and stirring while add Enter.It is subsequently adding enough water to produce 5mL cumulative volume.

Preparation 4 tablet

The compound of the present invention and dry gelatin adhesive can be mixed into dry powder according to the weight ratio of about 1:2.Add few Amount magnesium stearate is as lubricant.With tablet machine make this mixture formed 450-900mg tablet (150-300mg reactive compound/ Sheet).

Preparation 5 injection

The compound of the present invention can be dissolved in or is suspended in buffering Sterile Saline injectable aqueous medium to about 5mg/mL's Concentration.

Preparation 6 topical preparation

The compounds of this invention can be subsequently adding by octadecanol (250g) and white vaseline (250g) about 75 DEG C of fusings (50g), methyl parahydroxybenzoate (0.25g), propyl p-hydroxybenzoate (0.15g), sodium lauryl sulphate (10g) and third Glycol (120g) is dissolved in the mixture of water (about 370g), the mixture stirring obtained being condensed to it.

Therapeutic Method

The compound of the present invention is used as the therapeutic agent for the treatment of mammalian diseases.Therefore, compound provided herein and medicine Compositions is used as prevention and/or the neural degeneration for the treatment of mammal (including people and inhuman mammal), autoimmune Therapeutic agent with inflammatory diseases.Therefore with as it has been described above, the present invention includes in the range of it and extends to described Therapeutic Method, With the compound for this method, and this compound preparation for this method medicine in application.

In an aspect of Therapeutic Method, there is provided herein and treat susceptible or suffer from and arthritis, asthma, cardiac muscle stalk Extremely, the method for the mammal of disease that inflammatory bowel is relevant with autoimmune disease, the method includes give effective dose one Plant or multiple described pharmaceutical composition.

In another aspect of Therapeutic Method, there is provided herein and treat susceptible or suffer from generation painful response or relate to sense Feel neural basal activity maintains the method for the mammal of unbalance disease.The compound of the present invention be used as treat various origins or The analgesic of the pain of the cause of disease, described pain is the most acute, inflammatory pain is (such as with osteoarthritis and rheumatoid arthritis phase The pain closed)；Various neuropathic pain syndrome (such as postherpetic neuralgia, trigeminal neuralgia, sympathetic reflex nutrition Obstacle, diabetic neuropathy, Guillain-Barr é syndrome, fibromyalgia, phantom pain, post mastectomy pain, many Neuropathy, HIV neuropathy and the neuropathy of chemotherapy induction and other iatrogenic neuropathys)；Encelialgia is (such as with gastroesophageal reflux Disease, irritable bowel syndrome, inflammatory bowel, Encelialgia that pancreatitis is relevant with urological disorders with various gynecological), have a toothache and have a headache (such as migraine, cluster headache and tension headache).

In other aspects of Therapeutic Method, there is provided herein and treat the food in one's mouth that is susceptible or that suffer from neurodegenerative disease and obstacle The method of breast animal, described neurodegenerative disease and obstacle such as parkinson disease, Alzheimer and multiple sclerosis；By god Through inflammation mediated or cause disease and the obstacle of neuroinflamation, such as encephalitis；The neuropsychopathy of maincenter mediation and obstacle, such as Depressed, manic, bipolar disorder, anxiety, schizophrenia, eating disorders, sleep disorder and cognitive disorder；Epilepsy and insane Epilepsy is shown effect；Prostate, bladder and intestinal dysfunction, such as urinary incontinence, hesitancy in urination, rectum anaphylaxis, fecal incontinence, optimum Prostate hyperplasia and inflammatory bowel；Breathe and airway disorders and obstacle, such as allergic rhinitis, asthma and RAD and Chronic obstructive pulmonary disease；By inflammation mediated or cause disease and the obstacle of inflammation, such as rheumatoid arthritis and osteoarthrosis Inflammation, myocardial infarction, various autoimmune disease and obstacle；Itch/pruritus, such as psoriasis；Fat；Disorders of lipid metabolism；Cancer； And nephropathy, the method includes giving effectively to treat disease or one or more described pharmaceutical compositions of prevention disease consumption.

As another aspect, it is provided that be used as to treat especially or prevent of the present inventionization of the medicine of above-mentioned disease and disease Compound.We additionally provide the compounds of this invention in preparation for treating or preventing in the medicine of one of above-mentioned disease and disease Application.

Injection dosage level was at about 0.1mg/kg/ hour-at least 10mg/kg/ hour, all about 1-about 120 hours, especially It is to complete in 24-96 hour.The preload bolus injection of about 0.1mg/kg-about more than 10mg/kg can also be given to reach To enough steady-state level.For 40-80kg people patient, undesirably maximum accumulated dose exceedes about 2g/ days.

In order to prevent and/or treat prolonged sickness, such as neural degeneration and autoimmune disease, therapeutic scheme typically lasts for Multiple moons or for many years, therefore, in order to compliance and the toleration preferred oral of patient are administered.Owing to using oral administration, so Every day 1-5 time and especially 2-4 time and typically 3 oral doses are representational schemes.These are used to be administered mould Formula, each dosage provides about 0.01-about 20mg/kg compound provided herein, and wherein preferred dose each provides about 0.1-about 10mg/kg, especially about 1-about 5mg/kg.

It is typically chosen transdermal dosage compositions to provide similar or lower than the blood level using injection dosage to reach.

When being used for preventing neural degeneration, autoimmune or inflammatory diseases outbreak, to being in the trouble developed in this disease risk Person gives compound provided herein, typically carries out with above-mentioned dosage level under the sincere advice and supervision of clinicist.It is in Occur the patient in disease specific risk to generally comprise there is family's medical history or be identified the easiest through genetic testing or screening There is the patient of this disease in sense.

Compound provided herein can be given as single-activity agent, maybe they can be given with other drug combination Give, including other activity amine and derivant.Administering drug combinations can be by those skilled in the art's obviously any technology Carry out, including, the most individually, successively, simultaneously and alternating delivery.

General synthetic method

Can by the raw material that can be easily obtained, use following conventional method and operation prepare compound provided herein.Such as, See following synthetic schemes 1-11.To be understood that, and there is shown typical case or preferably processing conditions (i.e. reacts temperature Degree, time, the mol ratio of reactant, solvent, pressure etc.), unless separately stated, other conditions otherwise can also be used.Most preferably Reaction condition changes according to concrete reactant used or the difference of solvent, but this condition can be led to by those skilled in the art Cross classical algorithm to determine.

It addition, as apparent to a person skilled in the art, need conventional protection group to prevent functional group from occurring not Desired reaction.The protection group being suitable for for particular functional group and the selection for protection and the applicable condition of deprotection are these Field is well-known.Such as, a large amount of protection groups and introducing and removing thereof are described in T.W.Greene and P.G.M.Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991 and its In the list of references of middle citation.

For example, it is possible to prepare compound provided herein as follows: make carboxylic acid react with suitable substituted amine, separate product, By known standard method purification.This method includes, but is not limited to recrystallization, column chromatography or HPLC.Use for preparation The detailed description of the representational substituted biaryl amide-type enumerated herein provides following synthetic schemes.Can be by organic Compound provided herein prepared by synthesis skilled person known or that be purchased raw material and reagent.

Can be according to well known to a person skilled in the art that any technology prepares enantiopure compound provided herein.Example As, can be prepared by the optical voidness precursor being suitable for by chirality or asymmetric synthesis or (such as be passed through by any conventional technique Use the Chromatographic resolution of chiral column, TLC or by prepare diastereomer, its separate and regenerate desired enantiomer) obtain They." Enantiomers, the Racemates and for example, with reference to J.Jacques, A.Collet and S.H.Wilen Resolutions"(Wiley-Interscience,New York,1981)；S.H.Wilen, A.Collet and J.Jacques, Tetrahedron,2725(1977)；E.L.Eliel Stereochemistry of Carbon Compound(McGraw- Hill,NY,1962)；With S.H.Wilen Tables of Resolving Agents and Optical Resolutions268 (E.L.Eliel ed., Univ.of Notre Dame Press, Notre Dame, IN, 1972, Stereochemistry of Organic Compound, Ernest L.Eliel, Samuel H.Wilen and Lewis N.Manda (1994John Wiley&Sons, Inc.) and Stereoselective Synthesis A Practical Approach,Mihály Nógrádi(1995VCH Publishers,Inc.,NY,NY)。

In some embodiments, the right of formula 1 can be obtained by the optically-active acid or the alkali reaction that make racemate and be suitable for Reflect body pure compound.Be suitable for acid or alkali include Bighley et al. 1995, Salt Forms of Drugs and Adsorption,in Encyclopedia of Pharmaceutical Technology,vol.13,Swarbrick& Boylan,eds.,Marcel Dekker,New York；ten Hoeve&H.Wynberg,1985,Journal of Organic Chemistry50:4508-4514；Dale&Mosher,1973,J.Am.Chem.Soc.95:512；And CRC Those described in Handbook of Optical Resolution via Diastereomeric Salt Formation, By quoting, the content intact of these documents is expressly incorporated herein.

Dissolubility according to specific acid resolution reagent used and the difference of specific acid enantiomer used, it is also possible to from crystallization Diastereomer or mother solution reclaim enantiopure compound.Polarimetry well known in the art or other points can be passed through Analysis method measures feature and the optical purity of the particular compound so reclaimed.Then, chromatography or classification can such as be passed through Crystallization Separation diastereomer and by making desired enantiomer regenerate with applicable alkali or acid treatment.Can be according to similar Mode obtains other enantiomer from racemate, or post-treated from the liquid separated for the first time obtains.

In some embodiments, can be closed by chiral chromatography enantiomer separation purification from racemic compound Thing.Various chiral columns and eluant for enantiomer separation are available and can pass through as well known to those skilled in the art Method empirically determined for separate applicable condition.It is applied to separate the typical chiral column of enantiomer provided herein Include, but are not limited toOB、OB-H、 OD、OD-H、OF、OG、OJ andOK。

Following conventional method or synthetic schemes can be used to prepare various substituted biaryl amide-type.

General synthetic schemes

Synthetic schemes 1

Synthetic schemes 2

Synthetic schemes 3

Synthetic schemes 4

Synthetic schemes 5

Synthetic schemes 6

Synthetic schemes 7

Synthetic schemes 8

Synthetic schemes 9

Synthetic schemes 10

Synthetic schemes 11

In above-mentioned synthetic schemes 1-11, X and X¹It is each independently selected from F, Cl, Br, I and OTf；X " be F, Cl, Br, I, Ts or OH；Or R is selected from C₁-C₆Alkyl and benzyl；A、B、W、X’、L、R¹、R^3a、R^3b、R^4b, L and m ' as described herein.

The synthesis of intermediate

Intermediate 1

(S)-2-amino-2-(6-(difluoromethyl) pyridin-3-yl) ethanol

A) the bromo-2-of 5-(difluoromethyl) pyridine

5-bromo-2-pyridyl aldehyde (10g, 54mmol) is processed with DAST (9.2g, 70mmol) at-78 DEG C (Org.Lett.2004,6,4905) at anhydrous CH₂Cl₂(100mL) solution of the stirring in, the reaction that will obtain within the 5h time limit Mixture warms to room temperature.After having reacted, make this reactant mixture quencher with ice cold water, use CH₂Cl₂Extraction.Use anhydrous Na₂SO₄ It is dried organic layer, vacuum evaporating solvent.By column chromatography (SiO₂, 5%Et₂O/ petroleum ether) purification residue, obtain titled Compound (6g, 54% yield).MS:210[M+1]⁺；¹H-NMR(300MHz,CDCl₃): δ 8.72 (s, 1H), 7.93 (d, 1H, J= 8.3Hz), 7.54 (d, 1H, J=8.3Hz), 6.60 (t, 1H, J=55.1Hz).

B) 2-(difluoromethyl)-5-vinylpyridine

To vinyl potassium trifluoborate (3.32g, 24.8mmol), PdCl₂(0.1g, 0.56mmol) and PPh₃(0.45g, 1.71mmol) at the THF-H of 60mL₂Stirred suspension in O (9:1) adds Cs₂CO₃(20.2g, 62mmol) and the bromo-2-of 5- (difluoromethyl) pyridine (4.3g, 20.7mmol).The reactant mixture obtained is heated to 80 DEG C, stirs 16h.Reaction completes After, this reactant mixture is cooled to room temperature, processes with water, use CH₂Cl₂Extraction.Use anhydrous Na₂SO₄It is dried organic layer, vacuum Evaporation solvent.By column chromatography (SiO₂, 5%Et₂O/ pentane) purification residue, (2.46g, 75% receives to obtain title compound Rate).MS:156[M+1]⁺；¹H-NMR(300MHz,CDCl₃): δ 8.64 (s, 1H), 7.86 (d, 1H, J=8.3Hz), 7.60 (d, 1H, J=8.3Hz), 6.74 (dd, 1H, J=18,11.2Hz), 6.63 (t, 1H, J=55.6Hz), 5.91 (d, 1H, J= 18Hz), 5.48 (d, 1H, J=11.2Hz).

C) (R)-1-(6-(difluoromethyl) pyridin-3-yl) second-1,2-glycol

0 DEG C to AD-mixture-β (21.67g) at 30mL t-BuOH-H₂Stirred suspension in O (1:1) adds 2-(difluoromethyl)-5-vinylpyridine (2.4g, 15.5mmol), stirs 5h by the reactant mixture obtained at 0 DEG C, then exists It is stirred at room temperature.After 16h, use Na₂SO₃Solution processes this reactant mixture, then extracts with EtOAc (3x).Use anhydrous Na₂SO₄Dry The organic layer of dry merging, vacuum evaporating solvent, obtain title compound (2.6g, 87% yield).MS:190[M+1]⁺；¹H-NMR (300MHz,CDCl₃): 8.64 (s, 1H), 7.89 (d, 1H, J=7.8Hz), 7.64 (d, 1H, J=7.8Hz), 6.64 (t, 1H, J =55.4Hz), 4.91-4.96 (m1H), 3.84 (dd, 1H, J=11,3.6Hz), 3.67 (dd, 1H, J=11,7.8Hz).

D) (R)-2-(t-butyldimethylsilyloxy base)-1-(6-(difluoromethyl) pyridin-3-yl) ethanol

In room temperature to (R)-1-(6-(difluoromethyl) pyridin-3-yl) second-1,2-glycol (2.5g, 13.2mmol) anhydrous CH₂Cl₂In agitating solution in add tert-butyldimethylsilyl chloride (2.19g, 14.5mmol) and imidazoles (0.99g, 14.5mmol).The reactant mixture stirring 16h that will obtain.After having reacted, process this reactant mixture with water, use CH₂Cl₂Extraction Take.Use anhydrous Na₂SO₄It is dried organic layer, vacuum evaporating solvent.By column chromatography (SiO₂, 20%EtOAc/ petroleum ether) and purification Residue, obtains title compound (3g, 75% yield).MS:304[M+1]⁺；¹H-NMR(300MHz,CDCl₃):8.63(s, 1H), 7.89 (d, 1H, J=8.2Hz), 7.63 (d, 1H, J=8.2Hz), 6.64 (t, 1H, J=55.4Hz), 4.82-4.86 (m, 1H), 3.82 (dd, 1H, J=10.1,3.7Hz), 3.58 (dd, 1H, J=10.1,7.8Hz), 0.9 (s, 9H), 0.06 (s, 6H).

E) methanesulfonic acid (R)-2-(t-butyldimethylsilyloxy base)-1-(6-(difluoromethyl) pyridin-3-yl) ethyl ester

At 0 DEG C to (R)-2-(t-butyldimethylsilyloxy base)-1-(6-(difluoromethyl) pyridin-3-yl) ethanol (3.0g, 9.90mmol) is at anhydrous CH₂Cl₂In agitating solution in add MeSO₂Cl (1.2g, 10.9mmol) and Et₃N (1.3g,12.9mmol).The reactant mixture obtained was warmed to room temperature within the 2h time limit.After having reacted, process this with water anti- Answer mixture, use CH₂Cl₂Extraction.Use anhydrous Na₂SO₄It is dried organic layer, vacuum evaporating solvent.By column chromatography (SiO₂, 10%EtOAc/ petroleum ether) purification residue, obtain title compound (2.26g, 60% yield).MS:381[M+1]⁺；¹H-NMR (300MHz,CDCl₃): 8.67 (s, 1H), 7.90 (d, 1H, J=8.3Hz), 7.68 (d, 1H, J=8.3Hz), 6.65 (t, 1H, J =55.2Hz), 5.62-5.66 (m, 1H), 3.98 (dd, 1H, J=11.2,6.8Hz), 3.87 (dd, 1H, J=11.2, 4.9Hz),3.028(s,3H),0.87(s,9H),0.04-0.05(m,6H)。

F) (S)-5-(1-azido-2-(t-butyldimethylsilyloxy base) ethyl)-2-(difluoromethyl) pyridine

To methanesulfonic acid (R)-2-(t-butyldimethylsilyloxy base)-1-(6-(difluoromethyl) pyridin-3-yl) ethyl ester (2.24g, 5.87mmol) agitating solution in dry DMF (15mL) adds NaN₃(0.45g, 7.05mmol), will obtain Reactant mixture 60 DEG C heat 2h.After having reacted, process this reactant mixture with ice cold water, use Et₂O extracts.By nothing Water Na₂SO₄It is dried organic layer, vacuum evaporating solvent, obtains title compound (1.63g, 85% yield).MS:328[M+1]⁺；¹H-NMR(300MHz,CDCl₃): 8.60 (s, 1H), 7.82 (d, 1H, J=8.3Hz), 7.64 (d, 1H, J=8.3Hz), 6.64 (t, 1H, J=55.7Hz), 4.65-4.70 (m1H), 3.80-3.86 (m, 2H), 0.89 (s, 9H), 0.04-0.06 (m, 6H).

G) (S)-2-azido-2-(6-(difluoromethyl) pyridin-3-yl) ethanol

At 0 DEG C to (S)-5-(1-azido-2-(t-butyldimethylsilyloxy base) ethyl)-2-(difluoromethyl) pyrrole The pyridine (1.9g, 5.79mmol) agitating solution in 20mL EtOH adds 5mL6N HCl, anti-by obtain within the 2h time limit Mixture is answered to be slowly to warm to room temperature.Evaporation solvent, makes residue distribute at 10%NaHCO₃Solution and CH₂Cl₂Between.With anhydrous Na₂SO₄It is dried organic layer, vacuum evaporating solvent, obtains title compound (1.1g, 89% yield).MS:215[M+1]⁺；¹H- NMR(300MHz,CDCl₃): 8.63 (s, 1H), 7.86 (d, 1H, J=8.3Hz), 7.68 (d, 1H, J=8.3Hz), 6.65 (t, 1H, J=55.2Hz), 4.75-4.79 (m1H), 3.70-3.90 (m, 2H).

H) (S)-2-amino-2-(6-(difluoromethyl) pyridin-3-yl) ethanol

To (S)-2-azido-2-(6-(difluoromethyl) pyridin-3-yl) ethanol (1g, 4.67mmol) in 15mL THF Agitating solution in add PPh₃(2.45g,9.39mmol).The reactant mixture stirring 3h that will obtain, processes with 0.5mL water, Stirring 16h.After having reacted, process this reactant mixture with 2N HCl (15mL), extract with EtOAc.Use NH₃Water processes water Layer, evaporation of volatile substances, obtain residue.By column chromatography (little neutral Al₂O₃Pad, NH₃Water/MeOH/CH₂Cl₂,1:14: 85) purification residue, obtains title compound (0.74g, 85% yield).MS:189[M+1]⁺；.¹H-NMR(300MHz, CD₃OD): 8.72 (s, 1H), 8.09 (d, 1H, J=8.3Hz), 7.75 (d, 1H, J=8.3Hz), 6.73 (t, 1H, J= 55.0Hz), 4.39-4.43 (m1H), 3.90 (dd, 1H, J=10.9,4.7Hz), 3.80 (dd, 1H, J=10.9,6.2Hz).

Intermediate 2

(S)-2-amino-2-(6-(trifluoromethyl) pyridin-3-yl) ethanol

A) 2-(trifluoromethyl)-5-vinylpyridine

At-78 DEG C, in nitrogen atmosphere, within the 12min time limit, by the hexane solution of 2.5M n-BuLi (27mL, 67.5mmol) add Diethylaminoethyl triphenIn (24.4g, 68.4mmol) suspension in THF (150mL).By this reaction Warm to room temperature, obtain peony ylide solution, be cooled with ice, by 6-(trifluoromethyl) nicotine aldehyde (10g, 57mmol) at THF (50mL) solution in imports ylide solution.This reactant mixture is warmed to room temperature, stirs 3 hours.To in 30 minutes To suspension be heated to 60 DEG C, then 60 DEG C stir 1 hour.After cooling, dilute this mixture with water (400mL), use EtOAc extracts.Wash organic layer with saline, be dried (MgSO₄), concentrate.By silicagel column (0-10%EtOAc/ hexane) purification Residue, obtains title compound.

B) (R)-1-(6-(trifluoromethyl) pyridin-3-yl) second-1,2-glycol

The tert-butyl alcohol (49mL), water (49mL) and AD-mixture-β (13.78g) is added in 100mL flask.Stir in room temperature Mix generation two clarification phase.This mixture is cooled to 0 DEG C, at once add 2-(trifluoromethyl)-5-vinylpyridine (1.7g, 9.8mmol).At-20 DEG C by uneven slurry vigorous stirring overnight.TLC display reaction completes.This mixture is stirred at 0 DEG C Meanwhile, add solid sodium sulfite (15g, 0.12mol), by this mixture temperature to rt, stir 1 hour.EtOAc is joined this In reactant mixture, after separating each layer, then use EtOAc aqueous phase extracted.Use anhydrous MgSO₄Being dried the organic layer merged, vacuum is dense Contracting.By silicagel column (MeOH/CH₂Cl₂: 0-10%) purification residue, obtain title compound, for white solid.

C) 4-methylbenzene sulphur sulfonic acid (R)-2-hydroxyl-2-(6-(trifluoromethyl) pyridin-3-yl) ethyl ester

At 0 DEG C to (R)-1-(6-(trifluoromethyl) pyridin-3-yl) second-1,2-glycol (6.4g, 31mmol) and pyridine (20mL) at CH₂Cl₂(200mL) agitating solution in divides and adds p-toluenesulfonyl chloride (7.0g, 37mmol) in small batches.This is mixed Compound is slowly to warm to rt, stirs 40 hours, then uses CH₂Cl₂(100mL) dilution.Use NaHCO₃The washing of aqueous solution, saline is organic Phase, is dried (Na₂SO₄), concentrate, obtain crude title compound.

D) (R)-5-(oxirane-2-base)-2-(trifluoromethyl) pyridine

To 4-toluene sulfonic acide (R)-2-hydroxyl-2-(6-(trifluoromethyl) pyridin-3-yl) ethyl ester (1.0g, 2.77mmol) Point small batch dropping powdered potassium hydroxide (464mg, 8.28mmol) in agitating solution in THF (50mL).By this mixture Stirring 40 minutes, TLC display reaction completes.Filter this mixture by Celite, wash filter cake with acetonitrile (50mL).By filtrate It is concentrated into half volume with caution, the epoxide solution obtained is directly used in next step reaction.

E) (S)-2-azido-2-(6-(trifluoromethyl) pyridin-3-yl) ethanol

To (R)-5-(oxirane-2-base)-2-(trifluoromethyl) pyridine (2.72g, 14.4mmol) at acetonitrile (200mL) In agitating solution in add lithium perchlorate (20g, 0.19mol) and Hydrazoic acid,sodium salt (3.7g, 57mmol).By this mixture 60 DEG C being stirred overnight, TLC display reaction completes.After cooling, filter this mixture, concentrated filtrate by Celite.Process residual with water Excess, extracts with EtOAc.It is dried the organic layer merged, concentrates.By silica column purification residue, obtain title compound.

F) (S)-2-amino-2-(6-(trifluoromethyl) pyridin-3-yl) ethanol

By (S)-2-azido-2-(6-(trifluoromethyl) pyridin-3-yl) ethanol (604mg, 2.60mmol) in acetic acid second Mixture in ester (28mL) and 10%Pd-C (70mg) is at H₂Stirring 1hr in atmosphere (1atm).Filter out catalyst, concentrate filter Liquid, obtains title compound.¹H-NMR(300MHz,CDCl₃): 8.64 (s, 1H), 7.86 (d, 1H, J=8.1Hz), 7.60 (d, 1H, J=8.1Hz), 4.16 (m, 1H), 3.73 (dd, 1H, J=10.5,4.2Hz), 3.56 (dd, 1H, J=10.4,7.2Hz).

Intermediate 3

C-(1,1-dioxo-2,3-dihydro-1H-benzo [b] thiophene-6-base)-methylamine

A) 6-cyano group benzo [b] thiophene-2-carboxylic acid methyl ester

To round-bottomed flask adds 3-fluoro-4-formylbenzonitrile (9.00g, 60.4mmol), dimethyl sulfoxide (90mL), triphen Phosphine (18.0mL, 129mmol), is subsequently adding 2-methyl thioglycolate (5.40mL, 60.4mmol).By this reactant mixture 80 DEG C heating 2 hours.After cooling, this reactant mixture is poured into water, the product of precipitation is collected by filtration, be dried, by its without It is further purified for next step.

B) 6-cyano group benzo [b] thiophene-2-carboxylic acid

To round-bottomed flask is added in water (200mL) 6-cyano group benzo [b] thiophene-2-carboxylic acid methyl ester (4.00g, 17.9mmol), methanol (130mL) and sodium hydroxide (23g, 0.58mol).This reaction system is stirred at room temperature 20 minutes.Will This reaction system is concentrated into half volume, is acidified with 6N HCl/water solution.Use CHCl₃/ i-PrOH (90:10) extracts this mixing Thing, concentrating under reduced pressure organic facies, obtain title compound, for brown solid.

C) benzo [b] thiophene-6-nitrile

6-cyano group benzo [b] thiophene-2-carboxylic acid (1.90g, 9.35mmol), 1,8-diaza pair is added in microwave vial Ring [5.4.0] 11-7-alkene (5.6mL, 37.4mmol) and N,N-dimethylacetamide (15mL), by this reaction system 190 DEG C carry out microwave irradiation 1 hour.After cooling, this reactant mixture is poured into 1N HCl/water solution, is extracted with ethyl acetate.Decompression Concentrate organic facies, obtain product, for light tan solid.

D) 1,1-dioxo-1H-benzo [b] thiophene-6-nitrile

In 20 minutes, in round-bottomed flask, branch divides addition benzo [b] thiophene-6-nitrile (1.35g, 8.48mmol), dichloro Methane (270mL) and metachloroperbenzoic acid (70% purity, 5.85g, 23.73mmol).By this reactant mixture 45 DEG C of heating Overnight.This reaction system produces the mixture of the 2:1 ratio of sulfoxide and sulfone.By this reaction system of diluted ethyl acetate, with saturated Sodium thiosulfate solution makes reaction stop, and stirs 1 hour.Then being extracted with ethyl acetate this mixture, concentrating under reduced pressure is organic Phase.By purified by flash chromatography residue, obtain title compound, for white solid.

E) C-(1,1-dioxo-2,3-dihydro-1H-benzo [b] thiophene-6-base)-methylamine

1,1-dioxo-1H-benzo [b] thiophene-6-nitrile (0.30g, 1.57mmol), second is added in hydrogenation par container Alcohol (25mL) and palladium dydroxide (66mg).This container is placed at 5h on the agitator in the hydrogen atmosphere of 40Psi.Pass through Celite filters this reactant mixture, washs filter cake with methanol.Concentrated filtrate, obtains product, for white solid.

Intermediate 4

(S)-2-(t-butyldimethylsilyloxy base)-1-(6-picoline-3-base) ethamine

A) (6-methyl-3-pyridine radicals) methanol

In nitrogen atmosphere, in room temperature, to molten in ether (620mL) of 6-methyinicotinate (25g, 0.16mol) Double (2-methoxy ethoxy) aluminum sodium of dropping hydrogenation in liquid(toluene solution of 65wt.%, 110mL, 0.37mol).Then this mixture is heated to backflow, continues 1.5hr.After cooling, this reaction is made to mix at 0 DEG C with water (500mL) Compound quencher, uses EtOAc aqueous layer extracted.Use anhydrous MgSO₄It is dried the organic layer merged, filters, concentrate.Pass through silica column purification Residue, obtains title compound.

B) 6-methylnicotinamide aldehyde

In nitrogen atmosphere, to dimethyl sulfoxide (25.3mL, 0.357mol) and CH at-78 DEG C₂Cl₂(600mL) stirring Solution is slowly added to oxalyl chloride (16mL, 0.19mol).After having added, this mixture is stirred for 10min.To obtain Solution drips (6-methyl-3-pyridine radicals) methanol (20g, 0.162mol) at CH₂Cl₂(10mL) solution in, then mixes this Compound stirs 2.5hr at-78 DEG C.It is slowly added to triethylamine (110mL, 0.82mol), then by slow for this mixture at-78 DEG C Warm to room temperature, be stirred for 1hr.Process this mixture with water, use CH₂Cl₂(3x500mL) aqueous phase extracted.With saline washing merging Organic layer, uses anhydrous MgSO₄It is dried, filters, concentrate.By silica column purification residue, obtain title compound.

C) 2-methyl-5-vinylpyrine

At-78 DEG C, in nitrogen atmosphere, within the 1hr time limit, to Diethylaminoethyl triphen(62.54g,0.175mol) Suspension in THF (150mL) adds the hexane solution (69mL, 0.17mol) of 2.5M n-BuLi.By this mixture temperature To room temperature, obtain buff ylide solution.Be cooled with ice, in this ylide solution add 6-methylnicotinamide aldehyde (18.63g, 0.146mol) the solution in THF (50mL).This reactant mixture is warmed to room temperature, stirs 2 hours.To in 30 minutes To suspension be heated to 60 DEG C, 60 DEG C stir 1 hour.After cooling, this reactant mixture of dilute with water, extract with EtOAc. Separate organic layer, wash with saline, be dried (MgSO₄), concentrate.Remaining by silicagel column (0-10%EtOAc/ hexane) purification Thing, obtains title compound.

D) (R)-1-(6-picoline-3-base) second-1,2-glycol

The tert-butyl alcohol (480mL), water (480mL) and AD-mixture-β (138g) is added in 100mL flask.Stir in room temperature Mix generation two clarification phase, then this mixture is cooled to 0 DEG C.At once add 2-methyl-5-vinylpyrine (11.72g, 0.0934mol), by uneven slurry at-20 DEG C of vigorous stirring overnight.TLC display reaction completes.This mixture is stirred at 0 DEG C While, add solid sodium sulfite (117.8g, 0.934mol), by this mixture temperature to rt, stir 1 hour.Add EtOAc, after separating each layer, uses EtOAc aqueous phase extracted.Use anhydrous MgSO₄It is dried the organic layer merged, is concentrated in vacuo, obtains two Unit's alcohol, for brown oil.

E) (R)-2-(t-butyldimethylsilyloxy base)-1-(6-picoline-3-base) ethanol

At 0 DEG C to (R)-1-(6-picoline-3-base) second-1,2-glycol (13.72g, 0.085mol), 1H-imidazoles (13.55g, 0.197mol) and CH₂Cl₂(180mL) stirring mixture adds tert-butyldimethylsilyl chloride (15.31g,0.098mol).This reactant mixture is stirred 30 minutes at 0 DEG C, is then allowed to warm to room temperature, is stirred overnight.Use water (300mL) wash this mixture, use CH₂Cl₂Extraction.It is dried the organic layer of merging with sodium sulfate, concentrates.Pass through flash chromatography (0-50%EtOAc/ hexane) purification residue, obtains colorless oil.

F) (S)-5-(1-azido-2-(t-butyldimethylsilyloxy base) ethyl)-2-picoline

0 DEG C to (R)-2-(t-butyldimethylsilyloxy base)-1-(6-picoline-3-base) ethanol (15.6g, 0.055mol) and the diphenylphosphine azide (62.8mL, 0.292mol) stirring mixture in toluene (200mL) adds 1,8-diazabicyclo [5.4.0] 11-7-alkene (44.5mL, 0.292mol).By this mixture 0 DEG C of stirring 30 minutes, so After 60 DEG C of heated overnight.After cooling, wash this mixture with water.It is dried organic layer, is concentrated in vacuo.Pass through flash chromatography (0-15%EtOAc/ hexane) purification residue, obtains colorless oil.

G) (S)-2-(t-butyldimethylsilyloxy base)-1-(6-picoline-3-base) ethamine

By (S)-5-(1-azido-2-(t-butyldimethylsilyloxy base) ethyl)-2-picoline (11.21g, 0.036mol), the mixture of ethyl acetate (400mL) and 10%Pd-C (7g) is at H₂Stirring 1 hour in atmosphere (1atm).Filter Go out catalyst, concentrated filtrate, obtain title product, for grease.¹H NMR(CD₃OD, 400MHz): 8.39 (d, 1H, J= 2.0Hz), 7.74 (dd, 1H, J=8.0,2.4Hz), 7.28 (d, J=8.0Hz, 1H), 3.98 (t, 1H, J=6.0Hz), 3.73 (d, 2H, J=6.0Hz), 2.51 (s, 3H), 0.86 (s, 9H) ,-0.02 (s, 6H).

Intermediate 5

Imidazo [1,2-a] pyridin-7-yl methylamine

A) imidazo [1,2-a] pyridin-7-yl methanol

Lithium tetrahydroaluminate (0.50g, 13.2mmol) point fraction is slowly added into imidazo [1,2-a] pyridine-7-first In the acetoacetic ester (2.20g, 11.6mmol) ice cold solution in THF (150mL).This mixture is slowly to warm to rt, stirs at rt Mix overnight.This solution is cooled to 0 DEG C, with 1N HCl/water solution (10mL) quencher with caution.Add solid K₂CO₃With anhydrous Na₂SO₄, this mixture is stirred 30min at rt.Filter this mixture, wash filter cake with THF.Concentrated filtrate, obtains crude product, For solid (1.68g, 80% purity), it is used for next step without further purification.

B) 7-(azido methyl) imidazo [1,2-a] pyridine

0 DEG C to imidazo [1,2-a] pyridin-7-yl methanol (80% purity, 1.68g, 9.07mmol) at toluene (40mL) and CH₂Cl₂(40mL) agitating solution in adds diphenylphosphine azide (3.5mL, 16mmol), is subsequently adding 1,8-diazabicyclo [5.4.0] 11-7-alkene (2.5mL, 17mmol).This mixture is stirred 2h at 0 DEG C, then stirs at rt Mix 16h.With water (200mL) and CH₂Cl₂(200mL) this reactant mixture is diluted.Separate organic layer, wash with saline, be dried (Mg₂SO₄), filter, concentrate.By silica column purification residue, obtain title compound, for colorless oil (1.5g, two steps Yield 75%).

C) imidazo [1,2-a] pyridin-7-yl methylamine

7-(azido methyl) imidazo [1,2-a] pyridine (1.5g, 8.7mmol), acetic acid second is added in round-bottomed flask Ester (200mL) and 10%Pd/C (250mg).By this mixture in hydrogen capsule, it is stirred at room temperature 40 minutes.Pass through Celite Filter this mixture, concentrated filtrate, obtain title product (1.2g).¹H NMR (400MHz, DMSO-d6): 8.48 (d, 1H, J= 7.2Hz), 7.88 (s, 1H), 7.52 (d, 1H, J=1.2Hz), 7.51 (s, 1H), 6.89 (dd, 1H, J=7.2,1.6Hz), 3.83(s,2H)。

Intermediate 6

(4-methyl-3-(methyl sulphonyl) phenyl) methylamine

A) methyl-4-methyl-3-(methyl sulphonyl) benzoate

0^℃In round-bottomed flask add chlorosulfonic acid (170mL, 2.57mol), be dividedly in some parts 4-ar-Toluic acid (50g, 0.37mol).This reactant mixture is heated 5h at 130 DEG C.Then this reactant mixture is poured on ice, stirs 10 minutes. Filter the solid formed, wash with cold water, be dried, obtain 4-methyl-3-(chlorosulfonyl) benzoic acid, for white powder.Then This compound (80g, 0.34mol) is dividedly in some parts the round bottom comprising sodium sulfite (200g, 2.05mol) and water (80mL) burn In Ping.Then sodium hydrate aqueous solution (6N) is dripped, until the pH of this reactant mixture reaches 10, by stirred for this reaction system Night.Then make this reaction system in acid (pH2) by interpolation 2N HCl.Filter formed solid, be dried, obtain 4-methyl- 3-sulfino benzoic acid, for white solid.This compound (55g, 0.275mol) is joined comprise potassium carbonate (75.8g, 0.55mol) and N,N-dimethylformamide (450mL) round-bottomed flask in.It is slowly added to iodomethane (68.1mL, 1.10mol), This reaction system is stirred 4 hours.Then this reactant mixture of dilute with water, extracts with EtOAc.Removal of solvent under reduced pressure, obtains Title compound, for white solid.

B) (4-methyl-3-(methyl sulphonyl) phenyl) methanol

In round-bottomed flask, methyl-4-methyl-3-(methyl sulphonyl) benzoate (1.5g, 7.0mmol) is added at 0 DEG C With methanol (15mL).Branch divides addition sodium borohydride (3.7g, 100mmol), and this reaction system is stirred at room temperature 12h.Use ice Make reaction stop, extracting with MTBE.The organic facies that concentrating under reduced pressure merges, by purified by flash chromatography residue, obtains title Compound.

C) 4-(1-azido methyl)-1-methyl-2-(methyl sulphonyl) benzene

(4-methyl-3-(methyl sulphonyl) phenyl) methanol (6.0g, 30.14mmol), toluene is added in round-bottomed flask (70mL).Diphenyl phosphoryl azide (7.8mL, 36.1mmol) and 1,8-diazabicyclo [5.4.0] ten is added at 0 DEG C One-7-alkene (5.3mL, 36.1mmol), is stirred at room temperature overnight this reactant mixture.Removal of solvent under reduced pressure, dilute with water is residual Excess, extracts with EtOAc.The organic facies that concentrating under reduced pressure merges, by column chromatography eluting residue, obtains title compound (4g, 62% yield).

D) (4-methyl-3-(methyl sulphonyl) phenyl) methylamine

0 DEG C in round-bottomed flask add 4-(1-azido methyl)-1-methyl-2-(methyl sulphonyl) benzene (5.0g, 22.17mmol), THF (40mL), triphenyl phasphine (6.4g, 24.3mmol) and water (1.6mL, 34.2mmol), by this reactant mixture It is stirred at room temperature overnight.Remove solvent, residue is dissolved in MTBE, at the two of 0 DEG C of dropping 20%HClAlkane solution, collects The salt arrived, washs with EtOAc.Then use in 6N NaOH aqueous solution and salt, use CH₂Cl₂Extraction.Concentrating under reduced pressure organic layer, obtains Title compound, for the most thick grease.¹H NMR(400MHz,CDCl₃): 7.98 (s, 1H), 7.50 (d, 1H, J= 8.0Hz), 7.32 (d, 1H, J=8.0Hz), 3.93 (s, 2H), 3.08 (s, 3H), 2.69 (s, 3H).

Intermediate 7

1-(4-chloro-3-(methyl sulphonyl) phenyl) ethamine

A) 4-chloro-3-sulfino benzoic acid

0^℃In round-bottomed flask, add chlorosulfonic acid (6.36g, 96.0mmol), be dividedly in some parts 4-chlorobenzoic acid.This is anti- Mixture is answered to heat 5h at 130 DEG C.Then this reactant mixture is poured on ice, stirs 10 minutes.Filter the solid formed, Wash with cold water, be dried, obtain 4-chloro-3-(chlorosulfonyl) benzoic acid, for white powder.Then this compound is dividedly in some parts In the round-bottomed flask comprising sodium sulfite (7.1g, 56.4mmol) and water (40mL).Then sodium hydrate aqueous solution is dripped (6N), until the pH of this reactant mixture reaches 10, this reaction system is stirred overnight.Then make this anti-by interpolation 2N HCl Answer system in acid (pH2).Filter the solid formed, be dried, obtain title compound, for white solid.

B) the chloro-3-of 4-(methyl sulphonyl) benzoic acid

In round-bottomed flask add 4-chloro-3-sulfino benzoic acid (12g, 54.0mmol), potassium carbonate (15.4g, 109mmol) with N,N-dimethylformamide (170mL).It is slowly added to iodomethane (16.1mL, 218mmol), by this reaction system Stir 4 hours.Then this reactant mixture of dilute with water, extracts with EtOAc.The organic layer that concentrating under reduced pressure merges, obtains centre Body methyl-4-chloro-3-(methyl sulphonyl) benzoate, for pale solid.This solid is dissolved in methanol (100mL), adds 6N sodium hydroxide (50mL), stirs this reaction system 3 hours.Decompression removes methanol, adds water in residue.Then 0 DEG C it is acidified, with 2N HCl, the mixture that obtains, filters the solid formed, be dried, obtain title compound, for white solid.

C) 4-chloro-N-methoxy-. N-methyl-3-(methyl sulphonyl) Benzoylamide

4-chloro-3-(methyl sulphonyl) benzoic acid (7.5g, 30.24mmol), dichloromethane is added in round-bottomed flask (75mL) with N,N-dimethylformamide (0.25mL).It is slowly added to oxalyl chloride (4.0mL, 45.36mmol), this reaction is mixed Thing is stirred at room temperature 1 hour.Remove solvent, obtain intermediate acid chloride, be dissolved in dichloromethane (50mL), add N, O-diformazan Base hydroxylamine (10.0g, 122.9mmol), is stirred at room temperature overnight this reactant mixture.

Removal of solvent under reduced pressure, by purified by flash chromatography residue, obtains title compound.

D) 1-(4-chloro-3-(methyl sulphonyl) phenyl) ethyl ketone

In round-bottomed flask, 4-chloro-N-methoxy-. N-methyl-3-(methyl sulphonyl) Benzoylamide is added at 0 DEG C (18.0g, 64.9mmol) and oxolane (200mL).Be slowly added to methylmagnesium-bromide (THF solution of 1M, 78mL, 78mmol), this reaction system is stirred 3h at such a temperature.Then make reaction stop with aqueous ammonium chloride solution, use ethyl acetate Extraction.Concentrating under reduced pressure organic layer, by purified by flash chromatography residue, obtains title compound.

E) 1-(4-chloro-3-(methyl sulphonyl) phenyl) ethanol

In round-bottomed flask, 1-(4-chloro-3-(methyl sulphonyl) phenyl) ethyl ketone (12.0g, 50.0mmol) is added at 0 DEG C With oxolane (100mL).Branch divides addition sodium borohydride (3.7g, 100mmol), and this reaction system is stirred at room temperature 12h. Make reaction stop with ice, extract with MTBE.Decompression removes organic solvent, by purified by flash chromatography residue, obtains title Compound.

F) 4-(1-Azidoethyl)-1 chloro-2-(methyl sulphonyl) benzene

1-(4-chloro-3-(methyl sulphonyl) phenyl) ethanol (8.5g, 32.44mmol) and toluene is added in round-bottomed flask (100mL).Diphenyl phosphoryl azide (8.4mL, 38.93mmol) and 1,8-diazabicyclo [5.4.0] is added at 0 DEG C 11-7-alkene (5.8mL, 38.93mmol), are stirred at room temperature overnight this mixture.It is dilute that decompression removes volatile material water Release residue, extract with EtOAc.The organic layer that concentrating under reduced pressure merges, by column chromatography eluting residue, obtains product (2.4g, 28% yield).

G) 1-(4-chloro-3-(methyl sulphonyl) phenyl) ethamine

0 DEG C in round-bottomed flask add 4-(1-Azidoethyl)-1 chloro-2-(methyl sulphonyl) benzene (2.1g, 7.7mmol), THF (20mL), triphenyl phasphine (2.4g, 8.5mmol) and water (0.6mL, 34.2mmol), by this reaction system in room Temperature is stirred overnight.Remove solvent, residue is dissolved in MTBE, at the two of 0 DEG C of dropping 20%HClAlkane solution.Collection obtains Salt.Wash with EtOAc.Then use in 6N NaOH and salt, use CH₂Cl₂Extraction.The organic layer that concentrating under reduced pressure merges, obtains title Compound, for the most thick grease.¹H NMR(400MHz,CDCl₃): 8.14 (d, 1H, J=2.0Hz), 7.63 (dd, 1H, J=8.4,2.4Hz), 7.52 (d, 1H, J=8.0Hz), 4.24 (q, 1H, J=6.4Hz), 3.28 (s, 3H), 1.40 (d, 3H, J =6.4Hz).

Intermediate 8

5-(amino methyl)-2-chloro-N-cyclopropyl-phenyl sulfonamide

A) the chloro-3-of 4-(chlorosulfonyl) essence of Niobe

In round-bottomed flask, 4-chloro-3-(chlorosulfonyl) benzoic acid (16.0g, 63.24mmol) and first it is slowly added at 0 DEG C Alcohol (100mL) and thionyl chloride (9.3mL, 126.5mmol).Then this reactant mixture is heated to backflow, continues 1.5 little Time.Decompression removes volatile material, dilute with water residue, extracts with EtOAc.Removal of solvent under reduced pressure, obtains title compound, For solid.

B) the chloro-3-of 4-(N-Cyclopropylsulfamoyl base) essence of Niobe

In round-bottomed flask, 4-chloro-3-(chlorosulfonyl) essence of Niobe (12.0g, 44.32mmol) and 1 is added at 0 DEG C, 4-bis-Alkane (100mL).Dropping cyclopropylamine (9.31mL, 137.8mmol), stirs 3h by this mixture in this temperature.Remove Solvent, processes residue with EtOAc.Washing organic facies with saline, be dried, concentrate, (4.5g, 32% receives to obtain title compound Rate).

C) 2-chloro-N-cyclopropyl-5-(hydroxymethyl) benzsulfamide

In nitrogen atmosphere, in round-bottomed flask, add lithium aluminium hydride reduction (2.36g, 62.2mmol), add THF at 0 DEG C (50mL).The chloro-3-of 4-(the N-Cyclopropylsulfamoyl base) essence of Niobe that is slowly added in THF (20mL) (4.5g, 15.57mmol), this mixture is stirred 3h at such a temperature.With the THF/H of 1:1₂O mixture and 6N NaOH make this reaction mix Compound quencher, is filtered by Celite.Concentrating under reduced pressure filtrate, by purified by flash chromatography residue, obtains title compound (2.5g, 63% yield), for solid.

D) 5-(azido methyl)-2-chloro-N-cyclopropyl-phenyl sulfonamide

2-chloro-N-cyclopropyl-5-(hydroxymethyl) benzsulfamide (2.4g, 10mmol) and toluene is added in round-bottomed flask (30mL).Diphenyl phosphoryl azide (2.19mL, 10.1mmol) and 1,8-diazabicyclo [5.4.0] is added at 0 DEG C 11-7-alkene (1.31mL, 10.1mmol), are stirred at room temperature overnight this mixture.Decompression removes volatile material, dilute with water Release residue, extract with EtOAc.Decompression removes organic solvent, by column chromatography eluting residue, obtains title compound (1.4g, 53% yield).

D) 5-(amino methyl)-2-chloro-N-cyclopropyl-phenyl sulfonamide

0 DEG C in round-bottomed flask add 5-(azido methyl)-2-chloro-N-cyclopropyl-phenyl sulfonamide (1.40g, 4.87mmol), THF (40mL), triphenyl phasphine (1.6g, 6.43mmol) and water (0.11mL, 6.43mmol), by this reactant mixture In ambient temperature overnight.Remove solvent, residue is dissolved in MTBE, at the two of 0 DEG C of dropping 20%HClAlkane solution.Collection obtains Salt, washs with EtOAc.Then use in 6N NaOH and salt, use CH₂Cl₂Extraction.The organic facies that concentrating under reduced pressure merges, obtains title Product, for the most thick grease.¹H NMR(400MHz,DMSO-d6):8.00(s,1H),7.58(s,2H),3.78(s, 2H),2.18(m,1H),0.50-0.35(m,4H)。

The synthesis of representative compound

Compound 1

(S)-N-(1-hydroxyl acrylate-2-yl)-N-isobutyl group-N, 4'-dimethyl diphenyl-3,5-dicarboxamide

A) 4'-methyl biphenyl-3,5-dimethyl dicarboxylate

To the different dimethyl phthalate of 5-bromine (2.50g, 9.15mmol), p-tolyl boric acid in argon gas atmosphere (1.37g, 10.1mmol), toluene (50mL), ethanol (10mL), cesium carbonate (3.28g, 10.1mmol) and the mixing of water (5mL) Thing adds four (triphenyl phasphine)-palladiums (0) (529mg, 0.458mmol).This mixture is heated to backflow, continues 6h, the coldest But to room temperature, filtered by Celite.Concentrated filtrate, by silicagel column (0-50%EtOAc/ hexane) purification residue, obtains White solid.¹H NMR(400MHz,CDCl₃): δ 8.63 (s, 1H), 8.45 (s, 2H), 7.57 (d, 2H, J=8.0Hz), 7.29 (d, 2H, J=8.0Hz), 3.98 (s, 6H), 2.42 (s, 3H).

B) 5-(methoxycarbonyl)-4'-methyl biphenyl-3-carboxylic acid

By 4'-methyl biphenyl-3,5-dimethyl dicarboxylate (1.70g, 5.98mmol), MeOH (100mL) and 2N NaOH water To LC-MS, the mixture of solution (8mL) shows that this diester is the most completely depleted 60 DEG C of stirrings.After cooling, this is concentrated in vacuo and mixes Compound, is acidified to pH < 4 with 1N HCl/water solution, extracts with EtOAc (100mL x3).The organic layer merged with saline washing, dry Dry (Na₂SO₄), concentrate, obtain white solid (comprising some dicarboxylic acids).

C) (S)-5-(1-hydroxyl acrylate-2-base carbamoyl)-4'-methyl biphenyl-3-carboxylate methyl ester

To 5-(methoxycarbonyl)-4'-methyl biphenyl-3-carboxylic acid (0.60g, 2.2mmol), N-(3-dimethylamino third Base)-N'-ethyl-carbodiimide hydrochloride (470mg, 2.4mmol), I-hydroxybenzotriazole hydrate (340mg, 2.2mmol) And CH₂Cl₂(5mL) mixture adds (S)-2-aminopropan-1-ols (180mg, 2.4mmol) and N, N-diisopropylethylamine (0.58mL,3.3mmol).This mixture is stirred at room temperature overnight, then dilutes with EtOAc, use NaHCO₃Aqueous solution, saline Washing, is dried (Na₂SO₄), concentrate.By silicagel column (0-80%EtOAc/ hexane) purification residue, obtain white solid.LC- MS:328.2[M+1]⁺；¹HNMR (400MHz, DMSO-d6): δ 8.48 (d, 1H, J=8.0Hz), 8.40 (t, 1H, J=1.6Hz), 8.37 (t, 1H, J=1.6Hz), 8.28 (t, 1H, J=1.6Hz), 7.69 (d, 2H, J=8.0Hz), 7.34 (d, 2H, J= 8.0Hz), 4.78 (t, 1H, J=5.6Hz), 4.07 (m, 1H), 3.92 (s, 3H), 3.49 (m, 1H), 3.38 (m, 1H), 2.37 (s, 3H), 1.16 (d, 3H, J=6.8Hz).

D) (S)-5-(1-hydroxyl acrylate-2-base carbamoyl)-4'-methyl biphenyl-3-carboxylic acid

By (S)-5-(1-hydroxyl acrylate-2-base carbamoyl)-4'-methyl biphenyl-3-carboxylate methyl ester (105mg, 0.321mmol), the mixture of Lithium hydrate (9.98mg, 0.417mmol), THF (3mL) and water (1mL) is stirred at room temperature 12h. LC-MS display reaction completes.Dilute this reactant mixture with water (5mL), be acidified to pH=3 with 1N HCl/water solution, use EtOAc (50mL x3) extracts.The organic layer merged with saline washing, is dried (Na₂SO₄), concentrate, obtain white solid.LC-MS: 314.4[M+1]⁺。

E) (S)-N3-(1-hydroxyl acrylate-2-yl)-N5-isobutyl group-N5,4'-dimethyl diphenyl-3,5-dicarboxamide

To (S)-5-(1-hydroxyl acrylate-2-base carbamoyl)-4'-methyl biphenyl-3-carboxylic acid (32mg, 0.10mmol), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (29mg, 0.15mmol), I-hydroxybenzotriazole are hydrated Thing (16mg, 0.10mmol), CH₂Cl₂(3mL) and DMF (0.5mL) mixture in add N-methyl-isobutyl amine (13mg, 0.15mmol) and N, N-diisopropylethylamine (0.027mL, 0.15mmol).This mixture is stirred at room temperature overnight, then uses EtOAc dilutes, and uses NaHCO₃Aqueous solution, saline wash, and are dried (Na₂SO₄), concentrate.By preparation HPLC (100x21.2mm C18 post, 40-80%MeCN/ water [10mM Et₂NH]) purification residue, obtain white foam.

LC-MS:383.3[M+1]⁺；¹H NMR(400MHz,CDCl₃): (rotamer) δ 8.00 (d, 1H, J= 5.2Hz), 7.66 (m, 2H), 7.50 (d, 2H, J=8.0Hz), 7.27 (d, 2H, J=8.0Hz), 6.52 (m, 1H), 4.30 (m, 1H), 3.81 (dd, 1H, J=11.2,3.6Hz), 3.67 (dd, 1H, J=11.2,5.6Hz), 3.41 (d, 1H, J=7.2Hz), 3.11 (d, 1H, J=7.6Hz), 3.08 and 2.95 (s, 3H), 2.41 (s, 3H), 2.10 and 1.94 (m, 1H), 1.31 (d, 3H, J =6.8Hz), 1.01 and 0.77 (d, 6H, J=6.8Hz).

Compound 2

(S)-N3-(1-hydroxyl acrylate-2-yl)-N5-isobutyl group-4'-methyl biphenyl-3,5-dicarboxamide

To (S)-5-(1-hydroxyl acrylate-2-base carbamoyl)-4'-methyl biphenyl-3-carboxylic acid (25m_g,0.080mmol)、 N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (30mg, 0.16mmol), I-hydroxybenzotriazole are hydrated Thing (12mg, 0.080mmol), CH₂Cl₂(3mL) and DMF (0.5mL) mixture in add 2-methyl isophthalic acid-propylamine (12mg, 0.16mmol) and N, N-diisopropylethylamine (0.021mL, 0.12mmol).This mixture is stirred at room temperature overnight, then uses EtOAc dilutes, and uses NaHCO₃Aqueous solution, saline wash, and are dried (Na₂SO₄), concentrate.By preparation HPLC (100x21.2mm C18 post, 30-70%MeCN/ water [10mM Et₂NH]) purification residue, obtain white foam.

LC-MS:369.1[M+1]⁺；¹H NMR(400MHz,CDCl₃):8.08(m,3H),7.52(m,2H),7.28(m, 2H), 4.32 (m, 1H), 3.81 (dd, 1H, J=11.2,3.6Hz), 3.68 (dd, 1H, J=11.2,5.6Hz), 3.30 (d, 2H, J=6.4Hz), 2.41 (s, 3H), 1.93 (m, 1H), 1.32 (d, 3H, J=6.8Hz), 0.99 (d, 6H, J=6.4Hz).

Compound 3

(S)-N-(1-hydroxyl acrylate-2-yl)-4'-methyl-5-(methyl sulphonyl) biphenyl-3-carboxylic acid amides

A) 3-bromo-5-methylsulfanyl-benzoic acid

By 3,5-dibromobenzoic acid (2.5g, 8.9mmol), methyl sodium sulfide (1.4g, 20mmol) and dimethyl sulfoxide (10mL) mixture is sealed in microwave tube, heats 4h at 100 DEG C in oil bath.TLC display reaction completes.By this reaction Mixture is poured in water, extracts with EtOAc (3x50mL).The organic layer merged with saline washing, is dried (Na₂SO₄), concentrate.Will Residue is the most purified for next step.¹H NMR(400MHz,CDCl₃): δ 7.97 (t, 1H, J=1.6Hz), 7.87 (t, 1H, J =1.6Hz), 7.57 (t, 1H, J=1.6Hz), 2.53 (s, 3H).

B) the bromo-5-of 3-(methyl mercapto) essence of Niobe

At 0 DEG C to 3-bromo-5-methylsulfanyl-benzoic acid (2.2g, 8.9mmol), dichloromethane (100mL) and DMF (5 Drip) stirring mixture in add oxalyl chloride (1.0mL, 12mmol).This mixture is slowly to warm to room temperature, was stirred at room temperature Night.Add methanol (5.0mL, 120mmol) and DIPEA (5.0mL, 29mmol), this mixture is stirred in room temperature Mix 3h, then concentrate.By silicagel column (0-50%EtOAc/ hexane) purification residue, obtain grease.¹H NMR (400MHz,CDCl₃): δ 7.91 (t, 1H, J=1.6Hz), 7.81 (t, 1H, J=1.6Hz), 7.52 (t, 1H, J=1.6Hz), 3.92(s,3H),2.52(s,3H)。

C) the bromo-5-of 3-(methyl sulphonyl) essence of Niobe

By bromo-for 3-5-(methyl mercapto) essence of Niobe (1.6g, 6.1mmol), metachloroperbenzoic acid (75% purity, 4.2g, 18mmol) mixture with dichloromethane (100mL) is stirred at room temperature overnight.Use Na₂CO₃Aqueous solution and saline wash this reaction Mixture, is dried (Na₂SO₄), concentrate.By silicagel column (EtOAc/ hexane: 0-70%) purification residue, obtain white solid 。¹H NMR(400MHz,CDCl₃):δ8.52(s,1H),8.44(s,1H),8.27(s,1H),3.98(s,3H),3.10(s,3H)。

D) 4'-methyl-5-(methyl sulphonyl) biphenyl-3-carboxylate methyl ester

To 3-bromo-5-(methyl sulphonyl) essence of Niobe (0.65g, 2.2mmol), p-tolyl in argon gas atmosphere The mixture of boric acid (0.332g, 2.44mmol), toluene (10mL), cesium carbonate (0.795g, 2.44mmol) and water (1mL) adds Enter four (triphenyl phasphine)-palladiums (0) (128mg, 0.111mmol).This mixture is heated 15h at reflux.After cooling, pass through Celite filters this mixture, washs filter cake with EtOAc.Use saline wash filtrate, be dried (Na₂SO₄), concentrate.Pass through silicagel column (0-100%EtOAc/ hexane) purification residue, obtains white solid.LC-MS:3.26min,305.3[M+1]⁺(weak).

E) 4'-methyl-5-(methyl sulphonyl) biphenyl-3-carboxylic acid

By 4'-methyl-5-(methyl sulphonyl) biphenyl-3-carboxylate methyl ester (0.55g, 1.8mmol), MeOH (50mL) and 2N The mixture of NaOH aqueous solution (4mL) stirs 3h at 50 DEG C.After cooling, this mixture is concentrated in vacuo, by 1N HCl/water solution acid Change to pH < 4, extract with EtOAc (100mL).Wash organic layer with saline, be dried (Na₂SO₄), concentrate, obtain white solid. LC-MS:289.3[M-1]^-；¹H NMR(400MHz,CDCl₃): δ 8.61 (t, 1H, J=1.6Hz), 8.59 (t, 1H, J= 1.6Hz), 8.39 (t, 1H, J=1.6Hz), 7.58 (d, 2H, J=8.0Hz), 7.33 (d, 2H, J=8.0Hz), 3.15 (s, 3H),2.44(s,3H)。

F) (S)-N-(1-hydroxyl acrylate-2-yl)-4'-methyl-5-(methyl sulphonyl) biphenyl-3-carboxylic acid amides

To 4'-methyl-5-(methyl sulphonyl) biphenyl-3-carboxylic acid (50mg, 0.17mmol), N-(3-dimethylamino third Base)-N'-ethyl-carbodiimide hydrochloride (36mg, 0.19mmol), I-hydroxybenzotriazole hydrate (26mg, 0.17mmol) And CH₂Cl₂(2mL) mixture adds (S)-2-aminopropan-1-ols (19mg, 0.26mmol) and N, N-diisopropylethylamine (0.045mL,0.26mmol).This mixture is stirred at room temperature overnight, is then concentrated in vacuo.Pass through preparation HPLC (100x20.2mm, C18 post；30-60%MeCN-water [10mM Et₂NH]) purification residue, obtain white solid.

LC-MS:348.2[M+1]⁺；¹H NMR (400MHz, DMSO-d6): δ 8.55 (d, 1H, J=8.0Hz), 8.42 (t, 1H, J=1.6Hz), 8.33 (t, 1H, J=1.6Hz), 8.26 (t, 1H, J=1.6Hz), 7.75 (d, 2H, J=8.0Hz), 7.37 (d, 2H, J=8.0Hz), 4.80 (bs, 1H), 4.08 (m, 1H), 3.49 (m, 1H), 3.39 (m, 1H), 2.50 (s, 3H), 2.38 (s, 3H), 1.17 (d, 3H, J=6.8Hz).

Compound 6

(S)-5-(1-hydroxyl acrylate-2-base carbamoyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester

A) 5-(ethoxy carbonyl)-4'-methyl biphenyl-3-carboxylic acid

4'-methyl biphenyl-3,5-dimethyl dicarboxylate (14.3g, 50.3mmol) is dissolved in 1,4-bis-Alkane (160mL) With ethanol (200proof, 450mL).In the solution of stirring, add Lithium hydrate (2.41g, 100mmol), this is stirred at room temperature Reactant mixture, monitors with LC-MS.A main ethyl ester and some dicarboxylic acids (5-10%) are obtained exhausting about 90% dimethyl ester While, cool down this mixture, neutralize with 2N HCl/water solution, be concentrated in vacuo to about 100mL.Remnants are processed with water (100mL) Thing, is acidified to pH2-3 with 2N HCl/water solution, extracts with EtOAc (100mL x3).The organic layer merged with saline washing, dry Dry (Na₂SO₄), concentrate, obtain a rough ethyl ester, for white solid.LC-MS:283.1[M-1]^-。

B) (S)-5-(1-hydroxyl acrylate-2-base carbamoyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester

To 5-(ethoxy carbonyl)-4'-methyl biphenyl-3-carboxylic acid (35mg, 0.12mmol), N-(3-dimethylamino third Base)-N'-ethyl-carbodiimide hydrochloride (47mg, 0.25mmol), I-hydroxybenzotriazole hydrate (19mg, 0.12mmol) And CH₂Cl₂(3mL) mixture adds (S)-2-aminopropan-1-ols (10mg, 0.14mmol) and N, N-diisopropylethylamine (0.032mL,0.18mmol).This mixture is stirred at room temperature overnight, then concentrates.Pass through preparation HPLC (100x21.2mm C18 post, 30-70%MeCN/ water [10mM Et₂NH]) purification residue, obtain white solid.

LC-MS:342.4[M+1]⁺；¹H NMR(400MHz,CDCl₃): 8.38 (t, 1H, J=1.6Hz), 8.29 (t, 1H, J =1.6Hz), 8.24 (t, 1H, J=1.6Hz), 7.55 (d, 2H, J=8.0Hz), 7.29 (d, 2H, J=8.0Hz), 4.44 (q, 2H, J=7.2Hz), 4.34 (m, 1H), 3.83 (dd, 1H, J=11.2,3.6Hz), 3.70 (dd, 1H, J=11.2,6.0Hz), 2.41 (s, 3H), 1.43 (t, 3H, J=7.2Hz), 1.34 (d, 3H, J=6.8Hz).

Compound 7

(S)-N3-(2-hydroxyl-1-(6-methoxypyridine-3-base) ethyl)-N5-isobutyl group-N5,4'-two

Methyl-biphen-3,5-dicarboxamide

A) 5-(isobutyl group (methyl) carbamoyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester

To 5-(ethoxy carbonyl)-4'-methyl biphenyl-3-carboxylic acid (260mg, 0.91mmol), N-(3-dimethylamino third Base)-N'-ethyl-carbodiimide hydrochloride (350mg, 1.8mmol), I-hydroxybenzotriazole hydrate (140mg, 0.91mmol)、CH₂Cl₂(5mL) mixture adds N-methyl-isobutyl amine (120mg, 1.4mmol) and N, N-diisopropyl Ethamine (0.24mL, 1.4mmol).This mixture is stirred at room temperature overnight, is then concentrated in vacuo.By silicagel column (0-60% EtOAc/ hexane) purification residue, obtain syrup.LC-MS:354.2[M+1]⁺。

B) 5-(isobutyl group (methyl) carbamoyl)-4'-methyl biphenyl-3-carboxylic acid

By 5-(isobutyl group (methyl) carbamoyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester (165mg, 0.467mmol), The mixture of Lithium hydrate (55mg, 2.3mmol), ethanol (10mL) and water (1mL) is stirred at room temperature 5h.LC-MS shows reaction Complete.Solvent removed in vacuo, processes residue with water, is acidified to pH=3 with 1N HCl/water solution, extracts with EtOAc (50mL x3) Take.The organic layer merged with saline washing, is dried (Na₂SO₄), it is concentrated into and obtains product, for white foam.LC-MS:326.0[M +1]⁺。

C) (S)-N3-(2-hydroxyl-1-(6-methoxypyridine-3-base) ethyl)-N5-isobutyl group-N5,4'-dimethyl connection Benzene-3,5-dicarboxamide

To 5-(isobutyl group (methyl) carbamoyl)-4'-methyl biphenyl-3-carboxylic acid (35mg, 0.11mmol), N-(3- Dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (41mg, 0.22mmol), I-hydroxybenzotriazole hydrate (16mg,0.11mmol)、CH₂Cl₂(3mL) mixture adds (S)-2-amino-2-(6-methoxypyridine-3-base) ethanol (27mg, 0.16mmol) (WO 2008/130481) and N, N-diisopropylethylamine (28 μ L, 0.16mmol).This mixture is existed Stirred overnight at room temperature, is then concentrated in vacuo.By preparation HPLC (100x21.2mm C18 post, 30-70%MeCN/ water [10mM Et₂NH]) purification residue, obtain white solid.

LC-MS:476.4[M+1]⁺；¹H NMR(400MHz,CD₃OD): (rotamer) 8.19 (m, 2H), 7.82- 7.70 (m, 3H), 7.59 (m, 2H), 7.30 (d, 2H, J=8.0Hz), 6.80 (d, 1H, J=8.4Hz), 5.19 (t, 1H, J= 6.4Hz), 3.94-3.83 (m, 5H), 3.42 (d, 1H, J=7.6Hz), 3.18 (d, 1H, J=7.6Hz), 3.10 and 3.00 (s, 3H), 2.38 (s, 3H), 2.15 and 1.98 (m, 1H), 1.01 and 0.77 (d, 6H, J=6.8Hz).

Compound 8

N3-isobutyl group-N3,4'-dimethyl-N5-(1-(pyrazine-2-base) ethyl) biphenyl-3,5-dicarboxamide

To 5-(isobutyl group (methyl) carbamoyl)-4'-methyl biphenyl-3-carboxylic acid (21mg, 0.064mmol), N-(3- Dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (25mg, 0.13mmol), I-hydroxybenzotriazole hydrate (9.9mg, 0.064mmol) and CH₂Cl₂(3mL) mixture adds 1-(pyrazine-2-base) ethamine (12mg, 0.097mmol) And N, N-diisopropylethylamine (17 μ L, 0.097mmol).This mixture is stirred at room temperature overnight, is then concentrated in vacuo.Pass through Preparation HPLC (100x21.2mm C18 post, 30-70%MeCN/ water [10mM Et₂NH]) purification residue, obtain white bubble Foam.

LC-MS:431.1[M+1]⁺；¹H NMR(400MHz,CD₃OD): (rotamer) δ 8.70 (s, 1H), 8.59 (m, 1H), 8.49 (d, 1H, J=2.8Hz), 8.20 (t, 1H, J=1.6Hz), 7.84-7.75 (m, 2H), 7.62-7.57 (m, 2H), 7.30 (d, 2H, J=8.0Hz), 5.36 (q, 1H, J=7.2Hz), 3.42 (d, 1H, J=7.6Hz), 3.19 (d, 1H, J= 7.6Hz), 3.10 and 3.01 (s, 3H), 2.39 (s, 3H), 2.15 and 1.98 (m, 1H), 1.66 (d, 3H, J=7.2Hz), 1.02 With 0.78 (d, 6H, J=6.4Hz).

Compound 9

N3-((6-chloropyridine-3-base) methyl)-N5-isobutyl group-N5,4'-dimethyl diphenyl-3,5-dicarboxamide

To 5-(isobutyl group (methyl) carbamoyl)-4'-methyl biphenyl-3-carboxylic acid (21mg, 0.064mmol), N-(3- Dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (25mg, 0.13mmol), I-hydroxybenzotriazole hydrate (9.9mg, 0.064mmol) and CH₂Cl₂(3mL) in mixture add 2-chloro-5-aminomethyl pyridine (14mg, 0.097mmol) and N, N-diisopropylethylamine (17 μ L, 0.097mmol).This mixture is stirred at room temperature overnight, the most very Empty concentration.By preparation HPLC (100x21.2mm C18 post, 40-80%MeCN/ water [10mM Et₂NH]) purification residue, Obtain white foam.

LC-MS:450.4[M+1]⁺；¹H NMR(400MHz,CD₃OD): (rotamer) δ 8.39 (d, 1H, J= 2.0Hz), 8.18 (m, 1H), 7.85 (dd, 1H, J=8.0,2.4Hz), 7.82-7.75 (m, 2H), 7.58 (m, 2H), 7.44 (d, 1H, J=8.0Hz), 7.30 (d, 2H, J=7.6Hz), 4.61 (s, 2H), 3.42 (d, 1H, J=7.6Hz), 3.19 (d, 1H, J= 7.2Hz), 3.10 and 3.01 (s, 3H), 2.38 (s, 3H), 2.15 and 1.98 (m, 1H), 1.01 and 0.77 (d, 6H, J= 6.8Hz)。

Compound 10

(R)-N3-isobutyl group-N3,4'-dimethyl-N5-(1-(6-(trifluoromethyl) pyridin-3-yl) ethyl) biphenyl-3, 5-dicarboxamide

To 5-(isobutyl group (methyl) carbamoyl)-4'-methyl biphenyl-3-carboxylic acid (21mg, 0.064mmol), N-(3- Dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (25mg, 0.13mmol), I-hydroxybenzotriazole hydrate (9.9mg, 0.064mmol) and CH₂Cl₂(3mL) mixture adds (R)-1-(6-(trifluoromethyl) pyridin-3-yl) ethamine (18mg, 0.097mmol) (WO2008/130481) and N, N-diisopropylethylamine (17 μ L, 0.097mmol).By this mixture It is stirred at room temperature overnight, is then concentrated in vacuo.By preparation HPLC (100x21.2mm C18 post, 40-80%MeCN/ water [10mM Et₂NH]) purification residue, obtain white foam.

LC-MS:498.6[M+1]⁺；¹H NMR(400MHz,CD₃OD): (rotamer) δ 8.77 (d, 1H, J= 1.6Hz), 8.19 (t, 1H, J=1.6Hz), 8.07 (dd, 1H, J=8.0,2.0Hz), 7.83-7.75 (m, 3H), 7.59 (m, 2H), 7.30 (d, 2H, J=8.4Hz), 5.36 (q, 1H, J=6.4Hz), 3.42 (d, 1H, J=7.6Hz), 3.18 (d, 1H, J= 7.6Hz), 3.10 and 3.00 (s, 3H), 2.39 (s, 3H), 2.15 and 1.98 (m, 1H), 1.66 (d, 3H, J=7.2Hz), 1.01 With 0.77 (d, 6H, J=6.8Hz).

Compound 11

N3-(imidazo [1,2-a] pyridin-7-yl methyl)-N5-isobutyl group-N5,4'-dimethyl diphenyl-3,5-dicarboxylic dihydrazides Amine

To 5-(isobutyl group (methyl) carbamoyl)-4'-methyl biphenyl-3-carboxylic acid (15mg, 0.046mmol), N-(3- Dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (18mg, 0.092mmol), I-hydroxybenzotriazole hydrate (7.0mg, 0.046mmol) and CH₂Cl₂(2mL) in mixture add imidazo [1,2-a] pyridin-7-yl methylamine (10mg, 0.069mmol) and N, N-diisopropylethylamine (12 μ L, 0.069mmol).This mixture is stirred at room temperature overnight, the most very Empty concentration.By preparation HPLC (100x21.2mm C18 post, 40-70%MeCN/ water [10mM Et₂NH]) purification residue, Obtain white foam.

LC-MS:455.4[M+1]⁺；¹H NMR(400MHz,CD₃OD): (rotamer) δ 8.40 (d, 1H, J= 7.2Hz), 8.22 (s, 1H), 7.87-7,76 (m, 3H), 7.62-7.57 (m, 2H), 7.52 (d, 1H, J=1.6Hz), 7.49 (s, 1H), 7.30 (d, 2H, J=8.0Hz), 6.96 (dd, 1H, J=7.2,1.6Hz), 4.66 (s, 2H), 3.43 (d, 1H, J= 8.0Hz), 3.20 (d, 1H, J=7.6Hz), 3.10 and 3.02 (s, 3H), 2.39 (s, 3H), 2.15 and 1.98 (m, 1H), 1.01 With 0.78 (d, 6H, J=6.4Hz).

Compound 12

N3-isobutyl group-N3,4'-dimethyl-N5-((2-methylpyrimidine-5-base) methyl) biphenyl-3,5-dicarboxamide

To 5-(isobutyl group (methyl) carbamoyl)-4'-methyl biphenyl-3-carboxylic acid (15mg, 0.046mmol), N-(3- Dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (18mg, 0.092mmol), I-hydroxybenzotriazole hydrate (7.0mg, 0.046mmol) and CH₂Cl₂(2mL) in mixture add (2-methylpyrimidine-5-base) methylamine (8.5mg, 0.069mmol) (WO2008/130481) and N, N-diisopropylethylamine (12 μ L, 0.069mmol).By this mixture in room temperature It is stirred overnight, is then concentrated in vacuo.By preparation HPLC (100x21.2mmC18 post, 40-70%MeCN/ water [10mM Et₂NH]) purification residue, obtain white foam.

LC-MS:431.3[M+1]⁺；¹H NMR(400MHz,CD₃OD): (rotamer) δ 8.72 (s, 2H), 8.17 (s, 1H), 7.82-7.75 (m, 2H), 7.60-7.55 (m, 2H), 7.30 (d, 2H, J=8.4Hz), 4.59 (s, 2H), 3.42 (d, 1H, J=7.6Hz), 3.18 (d, 1H, J=7.6Hz), 3.10 and 3.00 (s, 3H), 2.67 (s, 3H), 2.38 (s, 3H), 2.15 Hes 1.98 (m, 1H), 1.01 and 0.77 (d, 6H, J=6.4Hz).

Compound 13

(R)-N3-(3-hydroxyl-1-(6-picoline-3-base) propyl group)-N5-isobutyl group-N5,4'-dimethyl diphenyl-3, 5-dicarboxamide

To 5-(isobutyl group (methyl) carbamoyl)-4'-methyl biphenyl-3-carboxylic acid (15mg, 0.046mmol), N-(3- Dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (18mg, 0.092mmol), I-hydroxybenzotriazole hydrate (7.0mg, 0.046mmol) and CH₂Cl₂(2mL) mixture adds (R)-3-amino-3-(6-picoline-3-base) acrylate- 1-alcohol (11mg, 0.069mmol) (WO2008/130481) and N, N-diisopropylethylamine (12 μ L, 0.069mmol).This is mixed Compound is stirred at room temperature overnight, and is then concentrated in vacuo.By preparation HPLC purification residue (100x21.2mm C18 post, 40- 70%MeCN/ water [10mM Et₂NH]), obtain white foam.

LC-MS:474.6[M+1]⁺；¹H NMR(400MHz,CD₃OD): (rotamer) δ 8.47 (d, 1H, J= 1.6Hz), 8.15 (s, 1H), 7.80-7.73 (m, 3H), 7.60-7.55 (m, 2H), 7.30 (d, 3H, J=8.0Hz), 5.32 (m, 1H), 3.72-3.57 (m, 2H), 3.42 (d, 1H, J=7.6Hz), 3.17 (d, 1H, J=7.6Hz), 3.09 and 3.00 (s, 3H), 2.51 (s, 3H), 2.38 (s, 3H), 2.24-1.94 (m, 3H), 1.01 and 0.77 (d, 6H, J=6.4Hz).

Compound 14

(R)-N3-isobutyl group-N3,4'-dimethyl-N5-(1-(2-methylpyrimidine-5-base) ethyl) biphenyl-3,5-dicarboxyl Amide

To 5-(isobutyl group (methyl) carbamoyl)-4'-methyl biphenyl-3-carboxylic acid (15mg, 0.046mmol), N-(3- Dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (18mg, 0.092mmol), I-hydroxybenzotriazole hydrate (7.0mg, 0.046mmol) and CH₂Cl₂(2mL) in mixture add (R)-1-(2-methylpyrimidine-5-base) ethamine (9.5mg, 0.069mmol) (WO2008/130481) and N, N-diisopropylethylamine (12 μ L, 0.069mmol).By this mixture in room temperature It is stirred overnight, is then concentrated in vacuo.By preparation HPLC (100x21.2mm C18 post, 40-70%MeCN/ water [10mM Et₂NH]) purification residue, obtain white foam.

LC-MS:445.6[M+1]⁺；¹H NMR(400MHz,CD₃OD): (rotamer) δ 8.77 (s, 2H), 8.17 (t, 1H, J=1.6Hz), 7.81-7.74 (m, 2H), 7.61-7.55 (m, 2H), 7.30 (d, 2H, J=8.4Hz), 5.27 (q, 1H, J =7.2Hz), 3.42 (d, 1H, J=7.6Hz), 3.18 (d, 1H, J=7.6Hz), 3.09 and 3.00 (s, 3H), 2.67 (s, 3H), 2.39 (s, 3H), 2.15 and 1.98 (m, 1H), 1.65 (d, 3H, J=6.8Hz), 1.01 and 0.77 (d, 6H, J=6.8Hz).

Compound 15

4'-methyl-5-((2-methylpyrimidine-5-base) methylcarbamoyl) biphenyl-3-carboxylic acid, ethyl ester

To rough 5-(ethoxy carbonyl)-4'-methyl biphenyl-3-carboxylic acid (450mg, 1.6mmol), N-(3-dimethylamino Base propyl group)-N'-ethyl-carbodiimide hydrochloride (610mg, 3.2mmol), I-hydroxybenzotriazole hydrate (240mg, 1.6mmol),CH₂Cl₂(5mL) mixture adds (2-methylpyrimidine-5-base) methylamine (290mg, 2.4mmol) and N, N-bis- Wopropyl ethyl amine (0.41mL, 2.4mmol).This reactant mixture is stirred at room temperature overnight, then uses NaHCO₃Aqueous solution and EtOAc (100mL) dilutes.Separate organic layer, wash with saline, be dried with anhydrous sodium sulfate, be concentrated in vacuo.Pass through silicagel column (0-20%MeOH/CH₂Cl₂) purification residue, obtain title product, for white foam.

LC-MS:390.4[M+1]⁺；¹H NMR(400MHz,CDCl₃): 8.73 (s, 2H), 8.40 (t, 1H, J=1.6Hz), 8.29 (t, 1H, J=1.6Hz), 8.26 (t, 1H, J=1.6Hz), 7.54 (d, 2H, J=8.0Hz), 7.28 (d, 2H, J= 8.0Hz), 6.72 (bs, 1H), 4.67 (d, 2H, J=6.0Hz), 4.43 (q, 2H, J=7.2Hz), 2.76 (s, 3H), 2.41 (s, 3H), 1.42 (t, 3H, J=7.2Hz).

Compound 16

Double ((2-methylpyrimidine-5-base) methyl) biphenyl-3,5-dicarboxamide of 4'-methyl-N3, N5-

Title compound is separated from the preparation of compound 15, for white foam, because rough 5-(ethoxy carbonyl)- 4'-methyl biphenyl-3-carboxylic acid comprises some 4'-methyl biphenyl-3,5-dicarboxylic acids.

LC-MS:467.4[M+1]⁺；¹H NMR(400MHz,CDCl₃):8.66(s,4H),8.09(s,2H),8.06(s, 1H), 7.46 (d, 2H, J=8.4Hz), 7.25 (d, 2H, J=8.8Hz), 6.95 (t, 2H, J=5.6Hz), 4.61 (d, 4H, J= 6.0Hz),2.71(s,6H),2.39(s,3H)。

Compound 17

5-(3,3-difluoro azetidine-1-carbonyl)-4'-methyl-N-((2-methylpyrimidine-5-base) methyl) biphenyl- 3-carboxylic acid amides

To 4'-methyl-5-((2-methylpyrimidine-5-base) methylcarbamoyl) biphenyl-3-carboxylic acid (11mg, 0.030mmol), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (12mg, 0.061mmol), 1-hydroxyl Benzotriazole hydrate (4.7mg, 0.030mmol), CH₂Cl₂(2mL) mixture adds 3,3-difluoro azetidine (4.2mg, 0.046mmol) and N, N-diisopropylethylamine (11 μ L, 0.061mmol).This mixture is stirred at room temperature overnight, Then it is concentrated in vacuo.By preparation HPLC (100x21.2mm C18 post, 30-70%MeCN/ water [10mM Et₂NH]) purification Residue, obtains white foam.

LC-MS:437.3[M+1]⁺；¹H NMR(400MHz,CD₃OD): δ 8.73 (s, 2H), 8.26 (t, 1H, J= 1.6Hz), 8.06 (m, 2H), 7.60 (d, 2H, J=8.4Hz), 7.31 (d, 2H, J=8.0Hz), 4.77 (bs, 2H), 4.59 (s, 2H),4.56(bs,2H),2.67(s,3H),2.38(s,3H)。

Compound 18

4'-methyl-N-((2-methylpyrimidine-5-base) methyl)-5-(piperidines-1-carbonyl) biphenyl-3-carboxylic acid amides

To 4'-methyl-5-((2-methylpyrimidine-5-base) methylcarbamoyl) biphenyl-3-carboxylic acid (11mg, 0.030mmol), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (12mg, 0.061mmol), 1-hydroxyl Benzotriazole hydrate (4.7mg, 0.030mmol) and CH₂Cl₂(2mL) in mixture add piperidines (3.9mg, 0.046mmol) and N, N-diisopropylethylamine (11 μ L, 0.061mmol).This mixture is stirred at room temperature overnight, the most very Empty concentration.By preparation HPLC (100x21.2mm C18 post, 30-70%MeCN/ water [10mM Et₂NH]) purification residue, Obtain white foam.

LC-MS:429.3[M+1]⁺；¹H NMR(400MHz,CD₃OD): δ 8.72 (s, 2H), 8.17 (t, 1H, J= 1.6Hz), 7.80 (t, 1H, J=1.6Hz), 7.78 (t, 1H, J=1.6Hz), 7.58 (d, 2H, J=8.0Hz), 7.30 (d, 2H, J=8.0Hz), 4.58 (s, 2H), 3.74 (bs, 2H), 3.41 (bs, 2H), 2.67 (s, 3H), 2.38 (s, 3H), 1.71 (bs, 4H),1.56(bs,2H)。

Compound 19

5-(azepan-1-carbonyl)-4'-methyl-N-((2-methylpyrimidine-5-base) methyl) biphenyl-3-carboxylic acid amides

To 4'-methyl-5-((2-methylpyrimidine-5-base) methylcarbamoyl) biphenyl-3-carboxylic acid (11mg, 0.030mmol), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (12mg, 0.061mmol), 1-hydroxyl Benzotriazole hydrate (4.7mg, 0.030mmol) and CH₂Cl₂(2mL) mixture adds hexahydro-1 H-azepines (4.5mg, 0.046mmol) and N, N-diisopropylethylamine (11 μ L, 0.061mmol).This mixture is stirred at room temperature overnight, Then it is concentrated in vacuo.By preparation HPLC (100x21.2mm C18 post, 30-70%MeCN/ water [10mM Et₂NH]) purification Residue, obtains white foam.

LC-MS:443.5[M+1]⁺；¹H NMR(400MHz,CD₃OD): δ 8.72 (s, 2H), 8.17 (t, 1H, J= 1.6Hz), 7.80 (t, 1H, J=1.6Hz), 7.77 (t, 1H, J=1.6Hz), 7.58 (d, 2H, J=8.4Hz), 7.30 (d, 2H, J=8.0Hz), 4.58 (s, 2H), 3.70 (t, 2H, J=6.0Hz), 3.45 (t, 2H, J=5.6Hz), 2.67 (s, 3H), 2.38 (s,3H),1.90-1.80(m,2H),1.73-1.58(m,6H)。

Compound 20

4'-methyl-N-((2-methylpyrimidine-5-base) methyl)-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid amides

To 4'-methyl-5-((2-methylpyrimidine-5-base) methylcarbamoyl)-biphenyl-3-carboxylic acid (11mg, 0.030mmol), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (12mg, 0.061mmol), 1-hydroxyl Benzotriazole hydrate (4.7mg, 0.030mmol) and CH₂Cl₂(2mL) in mixture add pyrrolidine (3.2mg, 0.046mmol) and N, N-diisopropylethylamine (11 μ L, 0.061mmol).This mixture is stirred at room temperature overnight, the most very Empty concentration.By preparation HPLC (100x21.2mm C18 post, 30-70%MeCN/ water [10mM Et₂NH]) purification residue, Obtain white foam.

LC-MS:415.2[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.27 (t, 1H, J=5.6Hz), 8.68 (s, 2H), 8.20 (t, 1H, J=1.6Hz), 7.93 (t, 1H, J=1.4Hz), 7.90 (t, 1H, J=1.5Hz), 7.67 (d, 2H, J= 8.1Hz), 7.31 (d, 2H, J=8.0Hz), 4.49 (d, 2H, J=5.6Hz), 3.50 (t, 2H, J=6.7Hz), 3.42 (t, 2H, J=6.4Hz), 2.60 (s, 3H), 2.36 (s, 3H), 2.00-1.78 (m, 4H).

Compound 21

4'-methyl-5-((2-methylpyrimidine-5-base) methylcarbamoyl) biphenyl-3-carboxylic acid

By 4'-methyl-5-((2-methylpyrimidine-5-base) methylcarbamoyl)-biphenyl-3-carboxylic acid, ethyl ester (275mg, 0.706mmol), the mixture of Lithium hydrate (85mg, 3.5mmol), THF (10mL) and water (1mL) is stirred at room temperature 5h.LC- MS display reaction completes.Solvent removed in vacuo, processes residue with water, is acidified to pH=4-5 with 1N HCl/water solution.By mistake Precipitation is collected in filter, is dried, obtains title compound, for white solid.Filtrate is extracted with EtOAc (100mL).Wash with water organic Layer, concentrates, some products of getting back.

LC-MS:362.4[M+1]⁺；¹H NMR (400MHz, DMSO-d6): δ 13.33 (s, 1H), 9.36 (t, 1H, J= 5.6Hz), 8.69 (s, 2H), 8.41 (t, 1H, J=1.6Hz), 8.36 (t, 1H, J=1.6Hz), 8.29 (t, 1H, J= 1.6Hz), 7.67 (d, 2H, J=8.0Hz), 7.33 (d, 2H, J=8.0Hz), 4.50 (d, 2H, J=5.6Hz), 2.60 (s, 3H),2.37(s,3H)。

Compound 22

4'-methyl-N-((2-methylpyrimidine-5-base) methyl)-5-(methyl sulphonyl) biphenyl-3-carboxylic acid amides

To 4'-methyl-5-(methyl sulphonyl) biphenyl-3-carboxylic acid (45mg, 0.15mmol), N-(3-dimethylamino third Base)-N'-ethyl-carbodiimide hydrochloride (59mg, 0.31mmol), I-hydroxybenzotriazole hydrate (24mg, 0.15mmol) And CH₂Cl₂(3mL) mixture adds (2-methylpyrimidine-5-base) methylamine (29mg, 0.23mmol) and N, N-diisopropyl Ethamine (54 μ L, 0.31mmol).This mixture is stirred at room temperature overnight, then concentrates.Pass through preparation HPLC (100x20.2mm, C18 post；30-60%MeCN-water [10mM Et₂NH]) purification residue, obtain white solid.

LC-MS:396.3[M+1]⁺；¹H NMR (400MHz, DMSO-d6): δ 9.45 (t, 1H, J=5.6Hz), 8.70 (s, 2H), 8.45 (t, 1H, J=1.6Hz), 8.33 (t, 1H, J=1.6Hz), 8.29 (t, 1H, J=1.6Hz), 7.75 (d, 2H, J= 8.4Hz), 7.36 (d, 2H, J=8.0Hz), 4.52 (d, 2H, J=5.6Hz), 2.60 (s, 3H), 2.50 (s, 3H), 2.38 (s, 3H)。

Compound 28

3-(5-picoline-2-base)-N-((2-methylpyrimidine-5-base) methyl)-5-(pyrrolidine-1-carbonyl) benzoyl Amine

A) the bromo-5-of 3-(methoxycarbonyl) benzoic acid

The different dimethyl phthalate of 5-bromine (0.50g, 1.8mmol), barium hydroxide octahydrate is added in round-bottomed flask (0.43g, 1.4mmol) and methanol (10mL).This mixture is stirred at room temperature overnight.Addition HCl (2N diethyl ether solution, 10mL), decompression removes volatile material.By purified by flash chromatography residue, obtain expecting product, for white solid.¹H NMR (400MHz, DMSO-d6): 13.70 (Br, 1H), 8.42 (t, J=1.5Hz, 1H), 8.31-8.24 (m, 2H), 3.90 (s, 3H)。

B) the bromo-5-of 3-(pyrrolidine-1-carbonyl) essence of Niobe

To 3-bromo-5-(methoxycarbonyl) benzoic acid (1.8g, 5.6mmol), N-(3-dimethylaminopropyl)-N'-second Base carbodiimide hydrochloride (2.1g, 11mmol), I-hydroxybenzotriazole hydrate (1.7g, 11mmol), dichloromethane (20mL) mixture adds pyrrolidine (0.58g, 8.2mmol) and N, N-diisopropylethylamine (1.9mL, 11mmol).Will This mixture is stirred at room temperature overnight, and then dilutes with dichloromethane (200mL).Use BaHCO₃Aqueous solution and K₂HPO₄Aqueous solution, Saline washing organic facies, uses Na₂SO₄It is dried, concentrates.Residual by flash chromatography (silicagel column, 0-100EtOAc/ hexane) purification Excess, obtains expecting product, for clear oil thing.¹H NMR (400MHz, DMSO-d6): 8.12 (t, J=1.8Hz, 1H), 7.80-7.98 (m, 2H), 3.88 (s, 3H), 3.47 (t, J=6.7Hz, 2H), 3.36 (t, J=6.5Hz, 2H), 1.89-1.80 (m,4H)。

C) the bromo-5-of 3-(pyrrolidine-1-carbonyl) benzoic acid

The bromo-5-of 3-(pyrrolidine-1-carbonyl) essence of Niobe (0.86g, 2.5mmol), hydrogen-oxygen is added in round-bottomed flask Change lithium (0.071g, 3.0mmol), methanol (5mL) and water (5mL).This mixture is stirred at room temperature 2h.Decompression removes methanol. With 1N HCl/water solution, water layer is acidified to pH=1, then uses CH₂Cl₂Extraction.Use Na₂SO₄It is dried the organic facies separated, mistake Filter, is concentrated to dryness, and obtains expecting product, for white solid.¹H NMR(400MHz,DMSO-d6):13.54(Br、1H),8.09 (t, J=1.6Hz, 1H), 7.98 (t, J=1.5Hz, 1H), 7.94 (t, J=1.8Hz, 1H), 3.47 (t, J=6.7Hz, 2H), 3.37 (t, J=6.5Hz, 2H), 1.90-1.80 (m, 4H).

D) the bromo-N-of 3-((2-methylpyrimidine-5-base) methyl)-5-(pyrrolidine-1-carbonyl) Benzoylamide

The bromo-5-of 3-(pyrrolidine-1-carbonyl) benzoic acid (340mg, 1.0mmol), N-(3-diformazan is added in round-bottomed flask Base aminopropyl)-N'-ethyl-carbodiimide hydrochloride (0.39g, 2.0mmol), I-hydroxybenzotriazole (0.30g, 2.2mmol), N, N-diisopropylethylamine (0.2g, 1.5mmol), dichloromethane (10mL), 4-dimethylaminopyridine (5mg, 0.04mmol) with (2-methylpyrimidine-5-base) methylamine (240mg, 1.5mmol).This mixture is stirred at room temperature overnight, then Use CH₂Cl₂Dilution.Use Na₂HPO₄The organic facies that the washing of aqueous solution, saline separates, uses Na₂SO₄It is dried, concentrates.By quick color Spectrometry purification residue, obtains expecting product, for grease.LC-MS:404.8[M+1]⁺；¹H NMR(400MHz,CDCl₃): 8.68 (s, 2H), 7.95 (t, J=1.6Hz, 1H), 7.76 (t, J=1.3Hz, 1H), 7.74-7.71 (m, 1H), 7.61 (t, J= 1.5Hz, 1H), 4.57 (d, J=5.8Hz, 2H), 3.56 (t, J=6.8Hz, 2H), 3.37 (t, J=6.4Hz, 2H), 2.73 (s, 3H),1.96-1.89(m,4H)。

E) 3-(5-picoline-2-base)-N-((2-methylpyrimidine-5-base) methyl)-5-(pyrrolidine-1-carbonyl) benzene first Amide

By bromo-for 3-N-((2-methylpyrimidine-5-base) methyl)-5-(pyrrolidine-1-carbonyl) benzoyl in nitrogen atmosphere Amine (25mg, 0.059mmol), 5-methyl-2-(tributylstamlyl) pyridine (40mg, 0.10mmol), four (triphenyl phasphine) palladium (0) mixture of (5mg, 0.0043mmol) and toluene (1mL) carries out microwave irradiation 1 hour at 120 DEG C.After cooling, dilute with water Release this mixture, extract with EtOAc.Use Na₂SO₄It is dried the organic layer merged, concentrates.By purified by flash chromatography residue, Obtain title compound, for white solid.

LC-MS:416.3[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.29 (t, J=5.4Hz, 1H), 8.67 (s, 2H), 8.62 (t, J=1.7Hz, 1H), 8.54 (d, J=2.2Hz, 1H), 8.32 (t, J=1.6Hz, 1H), 8.01-7.99 (m, 2H), 7.75 (dd, J=1.7,8.0Hz, 1H), 4.49 (d, J=5.6Hz, 2H), 3.50 (t, J=6.7Hz, 2H), 3.41 (t, J =6.3Hz, 2H), 2.60 (s, 3H), 2.36 (s, 3H), 1.91-1.81 (m, 4H).

Compound 29

5-(3-hydroxy azetidine-1-carbonyl)-4'-methyl-N-((2-methylpyrimidine-5-base) methyl) biphenyl-3- Carboxylic acid amides

A) 5-(3-hydroxy azetidine-1-carbonyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester

To 5-(ethoxy carbonyl)-4'-methyl biphenyl-3-carboxylic acid (2.0g, 7.0mmol), N-(3-dimethylamino third Base)-N'-ethyl-carbodiimide hydrochloride (2.7g, 14mmol), I-hydroxybenzotriazole hydrate (1.1g, 7.0mmol) and CH₂Cl₂(50mL) mixture adds 3-hydroxy azetidine hydrochlorate (1.2g, 10mmol) and N, N-diisopropyl second Amine (3.7mL, 21mmol).This mixture is stirred at room temperature 5h, then with saline and Na₂CO₃Solution washing, is dried (Na₂SO₄), it is concentrated in vacuo.By silica column purification residue (0-10%MeOH/CH₂Cl₂), obtain syrup.LC-MS: 340.4[M+1]⁺；¹H NMR(400MHz,CDCl₃): 8.34 (t, 1H, J=1.6Hz), 8.19 (t, 1H, J=1.6Hz), 8.04 (t, 1H, J=1.6Hz), 7.52 (d, 2H, J=8.4Hz), 7.28 (d, 2H, J=8.4Hz), 4.75 (bs, 1H), 4.50 (m, 2H), 4.41 (q, 2H, J=7.2Hz), 4.25 (bs, 1H), 4.10 (bs, 1H), 2.82 (bs, 1H), 2.41 (s, 3H), 1.42 (t, 3H, J=7.2Hz).

B) 5-(3-hydroxy azetidine-1-carbonyl)-4'-methyl biphenyl-3-carboxylic acid

By 5-(3-hydroxy azetidine-1-carbonyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester (2.0g, 5.9mmol), hydrogen The mixture of lithium oxide (0.56g, 24mmol), methanol (100mL) and water (10mL) stirs 4h at rt.LC-MS display has been reacted Become.Solvent removed in vacuo, processes residue with water, is acidified to pH2-3 with 1N HCl/water solution, extracts with EtOAc (50mL x3) Take.The organic layer merged with saline washing, is dried (Na₂SO₄), concentrate, obtain white solid.LC-MS:312.4[M+1]⁺；¹H NMR(400MHz,DMSO-d6):13.30(bs,1H),8.26(s,1H),8.09(s,1H),8.03(s,1H),7.64(d,2H,J =8.0Hz), 7.32 (d, 2H, J=8.0Hz), 5.79 (bs, 1H), 4.52 (s, 2H), 4.30 (bs, 1H), 4.10 (bs, 1H), 3.84 (d, 1H, J=9.6Hz), 2.37 (s, 3H).

C) 5-(3-hydroxy azetidine-1-carbonyl)-4'-methyl-N-((2-methylpyrimidine-5-base) methyl) biphenyl- 3-carboxylic acid amides

To 5-(3-hydroxy azetidine-1-carbonyl)-4'-methyl biphenyl-3-carboxylic acid (350mg, 1.1mmol), N-(3- Dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (430mg, 2.2mmol), I-hydroxybenzotriazole hydrate (170mg,1.1mmol),CH₂Cl₂(50mL) mixture adds (2-methylpyrimidine-5-base) methylamine (210mg, 1.7mmol) And N, N-diisopropylethylamine (0.39mL, 2.2mmol).This mixture is stirred at room temperature 4h, then with water and Na₂CO₃Water-soluble Liquid washs, and is dried (Na₂SO₄), it is concentrated in vacuo.By preparation HPLC (100x21.2mm C18 post, 20-60%MeCN/ water [10mM Et₂NH]) purification residue, obtain white solid.

LC-MS:417.5[M+1]⁺；¹H NMR(400MHz,CD₃OD): 8.73 (s, 2H), 8.22 (t, 1H, J=1.6Hz), 8.03 (t, 1H, J=1.6Hz), 8.01 (t, 1H, J=1.6Hz), 7.59 (d, 2H, J=8.0Hz), 7.30 (d, 2H, J= 8.0Hz),4.66-4.55(m,4H),4.42(m,1H),4.18(m,1H),3.97(m,1H),2.67(s,3H),2.39(s, 3H)。

Compound 31

4'-methyl-5-(2-methylaziridine-1-carbonyl)-N-((2-methylpyrimidine-5-base) methyl) biphenyl-3-carboxylic acyl Amine

To 4'-methyl-5-((2-methylpyrimidine-5-base) methylcarbamoyl)-biphenyl-3-carboxylic acid (11mg, 0.030mmol), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (12mg, 0.061mmol), 1-hydroxyl Benzotriazole hydrate (4.7mg, 0.030mmol), CH₂Cl₂(2mL) in mixture add 2-methyl-aziridin (3.5mg, 0.061mmol) and N, N-diisopropylethylamine (11 μ L, 0.061mmol).This mixture is stirred at room temperature overnight, the most very Empty concentration.By preparation HPLC purification residue (100x21.2mm C18 post, 30-70%MeCN/ water [10mM Et₂NH]), Obtain white foam.

LC-MS:401.3[M+1]⁺；¹H NMR(400MHz,CD₃OD):8.74(s,2H),8.28-8.13(m,3H),7.62 (m, 2H), 7.31 (d, 2H, J=8.4Hz), 5.02 (m, 1H), 4.71 (m, 1H), 4.60 (s, 2H), 3.84 (m, 1H), 2.67 (s, 3H), 2.40 (s, 3H), 1.50 and 1.45 (d, 3H, J=6.8Hz).

Compound 34

5-(3,3-difluoropyrrolidin-1-carbonyl)-4'-methyl-N-((2-methylpyrimidine-5-base) methyl) biphenyl-3-carboxylic Amide

To 4'-methyl-5-((2-methylpyrimidine-5-base) methylcarbamoyl)-biphenyl-3-carboxylic acid (11mg, 0.030mmol), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (12mg, 0.061mmol), 1-hydroxyl Benzotriazole hydrate (5mg, 0.030mmol), CH₂Cl₂(2mL) mixture adds 3,3-difluoropyrrolidine hydrochloride (9mg, 0.061mmol) and N, N-diisopropylethylamine (21 μ L, 0.12mmol).This mixture is stirred at room temperature overnight, so Final vacuum concentrates.By preparation HPLC (100x21.2mm C18 post, 30-70%MeCN/ water [10mM Et₂NH]) purification is residual Excess, obtains white foam.

LC-MS:451.2[M+1]⁺；¹H NMR(400MHz,CD₃OD):8.73(s,2H),8.22(s,1H),7.94(s, 2H), 7.60 (d, 2H, J=8.0Hz), 7.30 (d, 2H, J=8.0Hz), 4.59 (s, 2H), 4.03-3.75 (m, 4H), 2.67 (s,3H),2.45(m,2H),2.38(s,3H)。

Compound 37

4'-methyl-5-(methyl sulphonyl)-N-((6-(trifluoromethyl) pyridin-3-yl) methyl) biphenyl-3-carboxylic acid amides

To 4'-methyl-5-(methyl sulphonyl) biphenyl-3-carboxylic acid (40mg, 0.14mmol), N-(3-dimethylamino third Base)-N'-ethyl-carbodiimide hydrochloride (53mg, 0.28mmol), I-hydroxybenzotriazole hydrate (21mg, 0.14mmol) And CH₂Cl₂(3mL) mixture adds C-(6-trifluoromethylpyridin-3-base)-methylamine (36mg, 0.21mmol) and N, N- Diisopropylethylamine (48 μ L, 0.28mmol).This mixture is stirred at room temperature overnight, then concentrates.Pass through preparation HPLC (100x20.2mm, C18 post；40-80%MeCN-water [10mMEt₂NH]) purification residue, obtain white solid.

LC-MS:449.4[M+1]⁺；¹H NMR(400MHz,CDCl₃): 8.77 (s, 1H), 8.35 (t, 1H, J=1.6Hz), 8.28 (t, 1H, J=1.6Hz), 8.21 (t, 1H, J=1.6Hz), 7.95 (d, 1H, J=8.0Hz), 7.70 (d, 1H, J= 8.0Hz), 7.55 (d, 2H, J=8.0Hz), 7.31 (d, 2H, J=8.0Hz), 6.89 (t, 1H, J=6.0Hz), 4.78 (d, 2H, J=6.0Hz), 3.12 (s, 3H), 2.42 (s, 3H).

Compound 39

2'-cyano group-4'-methyl-N-((2-methylpyrimidine-5-base) methyl)-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic Amide

The bromo-N-of 3-((2-methylpyrimidine-5-base) methyl)-5-(pyrrolidine-1-carbonyl is added in Parr pressure reactor Base) Benzoylamide (240mg, 0.48mmol), 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2- Base) benzonitrile (160mg, 0.58mmol) (WO2008/130481), toluene (5mL), ethanol (1mL), cesium carbonate (170mg, 0.52mmol) with water (0.5mL).Deaerate to this mixture, purge several times with nitrogen, be subsequently adding four (triphenyl phasphine) palladium (0) (28mg,0.024mmol).Seal test tube, by this mixture 90 DEG C of heated overnight.After cooling, filter this by Celite and mix Compound, concentrated filtrate.By flash chromatography, then by preparation HPLC purification residue, obtain expecting product, for white Solid.

LC-MS:440.3[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.26 (t, J=5.9Hz, 1H), 8.67 (s, 2H), 8.10-8.07 (m, 2H), 7.83 (dd, J=1.6,9.7Hz, 2H), 7.62 (t, J=8.0Hz, 2H), 4.48 (d, J= 5.7Hz,2H),3.51-3.43(m,4H),2.59(s,3H),2.41(s,3H),1.90-1.82(m,4H)。

Compound 45

N-(1-(4-chloro-3-(methyl sulphonyl) phenyl) ethyl)-4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl-3- Carboxylic acid amides

A) 5-(chloroformyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester

0 DEG C to 5-(ethoxy carbonyl)-4'-methyl biphenyl-3-carboxylic acid (5.0g, 18mmol), DMF (0.05mL) and CH₂Cl₂(150mL) agitating solution in adds oxalyl chloride (2.23mL, 26.4mmol).This mixture is stirred at room temperature 6h, Then it is concentrated in vacuo, obtains the crude acid chloride reacted for next step.

B) 4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid, ethyl ester

0 DEG C to 5-(chloroformyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester (5.5g, 18mmol) at dichloromethane (100mL) agitating solution in is slowly added to pyrrolidine (2.6g, 36mmol) and triethylamine (7.6mL, 54mmol).This is mixed Compound is stirred at room temperature 2h, then with saline, Na₂CO₃Aqueous solution and water washing.It is dried the organic facies (Na separated₂SO₄), dense Contracting.By silicagel column (30-100%EtOAc/ hexane) purification residue, obtain desired compound.

C) 4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid

By 4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid, ethyl ester (3.94g, 11.7mmol), Lithium hydrate The mixture of (0.65g, 27.1mmol), MeOH (250mL) and water (40mL) stirs 20hr at rt.LC-MS display reaction completes. Solvent removed in vacuo, processes residue with water, is acidified to pH=2-3 with 1N HCl/water solution.Extract with EtOAc (3x100mL) Aqueous phase.The organic layer merged with water, saline washing, is dried, is concentrated into and obtains product, for white solid.LC-MS:310.4[M+ 1]⁺；¹H NMR (400MHz, DMSO-d6): 13.29 (s, 1H), 8.21 (t, 1H, J=1.6Hz), 7.99 (t, 1H, J= 1.6Hz), 7.98 (t, 1H, J=1.5Hz), 7.64 (d, 2H, J=8.2Hz), 7.31 (d, 2H, J=7.9Hz), 3.50 (t, 2H, J=6.7Hz), 3.43 (t, 2H, J=6.5Hz), 2.36 (s, 3H), 1.98-1.78 (m, 4H).

D) N-(1-(4-chloro-3-(methyl sulphonyl) phenyl) ethyl)-4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl- 3-carboxylic acid amides

To 4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid (17mg, 0.055mmol) at N, N-dimethyl methyl Solution in amide (0.5mL) adds 1-(4-chloro-3-(methyl sulphonyl) phenyl) ethamine (50mg, 0.21mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (80mg, 0.21mmol) and N, N-diisopropyl Ethamine (80 μ L, 0.46mmol).This reactant mixture is stirred 16 hours at 50 DEG C.LC-MS display reaction completes.By preparation This mixture of type HPLC purification, obtains end-product, for pale solid.

LC-MS:525.6[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.18 (d, 1H, J=7.3Hz), 8.21 (s, 1H), 8.10 (d, 1H, J=1.8Hz), 8.0-7.85 (m, 2H), 7.80-7.65 (m, 4H), 7.32 (d, 2H, J=7.9Hz), 5.30-5.20 (m, 1H), 3.50 (t, 2H, J=6.5Hz), 3.46-3.35 (m, 5H), 2.36 (s, 3H), 2.00-1.78 (m, 4H), 1.53 (d, 3H, J=7Hz).

Compound 49

4'-methyl-5-(pyrrolidine-1-carbonyl)-N-(quinoline-7-ylmethyl) biphenyl-3-carboxylic acid amides

To 4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid (17mg, 0.055mmol) at N, N-dimethyl methyl Solution in amide (0.5mL) adds quinoline-7-base methylamine (34mg, 0.22mmol) (WO 2008/130481), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (80mg, 0.21mmol) and N, N-diisopropyl second Amine (80 μ L, 0.46mmol).This reactant mixture is stirred 16 hours at 50 DEG C.LC-MS display reaction completes.Pass through preparative This reactant mixture of HPLC purification, obtains title compound.

LC-MS:450.5[M+1]⁺；¹H NMR(400MHz,CDCl₃): 8.92 (dd, 1H, J=4.1,1.4Hz), 8.19 (d, 1H, J=8.1Hz), 8.12 (t, 1H, J=1.7Hz), 8.09 (s, 1H), 7.92-7.80 (m, 3H), 7.60 (dd, 1H, J= 9.9,1.4Hz), 7.52 (d, 2H, J=8.1Hz), 7.43 (dd, 1H, J=8.3,4.3Hz), 7.26 (d, 2H, J=7.8Hz), 6.76 (t, 1H, J=5.7Hz), 4.91 (d, 2H, J=5.8Hz), 3.66 (t, 2H, J=6.9Hz), 3.47 (t, 2H, J= 6.6Hz),2.40(s,3H),2.10-1.80(m,4H)。

Compound 58

4'-methyl-N-((6-picoline-3-base) methyl)-5-(methyl sulphonyl) biphenyl-3-carboxylic acid amides

To 4'-methyl-5-(methyl sulphonyl) biphenyl-3-carboxylic acid (40mg, 0.14mmol), N-(3-dimethylamino third Base)-N'-ethyl-carbodiimide hydrochloride (53mg, 0.28mmol), I-hydroxybenzotriazole hydrate (21mg, 0.14mmol) And CH₂Cl₂(3mL) mixture adds (6-picoline-3-base) methylamine (25mg, 0.21mmol) and N, N-diisopropyl Ethamine (48 μ L, 0.28mmol).This mixture is stirred at room temperature overnight, then concentrates.Pass through preparation HPLC (100x20.2mm, C18 post；30-80%CH₃CN-water [10mM Et₂NH]) purification residue, obtain white solid.

LC-MS:395.5[M+1]⁺；¹H NMR(400MHz,CDCl₃):8.52(s,1H),8.34(s,1H),8.26(s, 1H), 8.18 (s, 1H), 7.65 (dd, 1H, J=8.0,2.0Hz), 7.54 (d, 2H, J=8.0Hz), 7.30 (d, 2H, J= 8.0Hz), 7.17 (d, 1H, J=8.0Hz), 6.73 (bs, 1H), 4.66 (d, 2H, J=5.6Hz), 3.11 (s, 3H), 2.56 (s, 3H),2.42(s,3H)。

Compound 62

2'-cyano group-4'-methyl-5-(pyrrolidine-1-carbonyl)-N-((6-(trifluoromethyl) pyridin-3-yl) methyl) joins Benzene-3-carboxylic acid amides

A) 2'-cyano group-4'-methyl biphenyl-3,5-dimethyl dicarboxylate

The different dimethyl phthalate of 5-bromine (1.3g, 4.8mmol), 5-methyl-2-is added in Parr pressure reactor (4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-base) benzonitrile (2.0g, 5.9mmol), toluene (25mL), ethanol (5mL), cesium carbonate (1.7g, 5.2mmol) and water (2.5mL).Deaerate to this mixture, purge several times with nitrogen, be subsequently adding Four (triphenyl phasphine)-palladiums (0) (280mg, 0.24mmol).Seal test tube, by this mixture 90 DEG C of heated overnight.After cooling, use EtOAc (200mL) dilutes this mixture, washs with saline, uses Na₂SO₄It is dried, concentrates.Remaining by purified by flash chromatography Thing, obtains expecting product, for white solid.LC-MS:310.5[M+1]⁺；¹H NMR(400MHz,CDCl₃):8.75(s,1H), 8.39 (d, J=1.6Hz, 2H), 7.61 (s, 1H), 7.49 (dd, J=1.1,8.5Hz, 1H), 7.43 (d, J=7.9Hz, 1H), 3.98(s,6H),2.46(s,3H)。

B) 2'-cyano group-5-(methoxycarbonyl)-4'-methyl biphenyl-3-carboxylic acid

2'-cyano group-4'-methyl biphenyl-3,5-dimethyl dicarboxylate (1.5g, 4.4mmol), second is added in round-bottomed flask Alcohol (100mL), 1,4-bis-Water (10mL) solution of alkane (20mL) and sodium hydroxide (0.17g, 4.4mmol).By this mixture 3h is stirred at room temperature.Decompression removes volatile material, with 1N HCl/water solution by residue acidified to pH=4, uses CH₂Cl₂Extraction Take.It is dried the organic layer merged, concentrates.By purified by flash chromatography residue, obtain expecting product 2'-cyano group-5-(methoxy Base carbonyl)-4'-methyl biphenyl-3-carboxylic acid, for white solid.¹HNMR(400MHz,DMSO-d6):13.58(Br、1H),8.56 (t, J=1.3Hz, 1H), 8.34-8.31 (m, 2H), 7.85 (s, 1H), 7.65 (d, J=2.6Hz, 2H), 3.92 (s, 3H), 2.42(s,3H).Also having separated 2'-cyano group-4'-methyl biphenyl-3,5-dicarboxylic acids 3-ethyl 5-methyl ester, for white solid.

C) 2'-cyano group-4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylate methyl ester

To 2'-cyano group-5-(methoxycarbonyl)-4'-methyl biphenyl-3-carboxylic acid (0.20g, 0.68mmol), N-(3-diformazan Base aminopropyl)-N'-ethyl-carbodiimide hydrochloride (0.26g, 1.4mmol), I-hydroxybenzotriazole hydrate (0.21g, 1.4mmol) add pyrrolidine (0.072g, 1.0mmol) and N, N-diisopropyl second with in the mixture of dichloromethane (10mL) Amine (0.24mL, 1.4mmol).This mixture is stirred at room temperature overnight, then concentrates.By flash chromatography (silicagel column, 0- 100%EtOAc/ hexane) purification residue, obtain expecting product, for white solid.LC-MS:349.0[M+1]⁺；¹H NMR (400MHz, DMSO-d6) 8.14 (s, 1H), 8.12 (t, J=1.6Hz, 1H), 7.96 (t, J=1.7Hz, 1H), 7.83 (s, 1H),7.66-7.60(m,2H),3.91(s,3H),3.52-3.43(m,4H),2.42(s,3H),1.90-1.81(m,4H)。

B) 2'-cyano group-4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid

2'-cyano group-4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylate methyl ester is added in round-bottomed flask (0.17g, 0.46mmol), Lithium hydrate (17mg, 0.70mmol), methanol (5mL) and water (1mL).By this mixture in room temperature It is stirred overnight.Decompression removes volatile material, is acidified residue with 1N HCl, uses CH₂Cl₂Extraction.Use Na₂SO₄It is dried merging Organic layer, filters, and concentrates, and obtains expecting product, for white solid.LC-MS:335.4[M+1]⁺；¹H NMR(400MHz,DMSO- D6): 8.14 (t, J=1.6Hz, 1H), 8.10 (t, J=1.5Hz, 1H), 7.93 (t, J=1.7Hz, 1H), 7.83 (t, J= 0.8Hz,1H),7.66-7.60(m,2H),3.51-3.42(m,4H),2.42(s,3H),1.91-1.83(m,4H)。

C) 2'-cyano group-4'-methyl-5-(pyrrolidine-1-carbonyl)-N-((6-(trifluoromethyl) pyridin-3-yl) methyl) connection Benzene-3-carboxylic acid amides

In round-bottomed flask add 2'-cyano group-4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid (50mg, 0.1mmol), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (52mg, 0.27mmol), 1-hydroxy benzo Triazole (36mg, 0.27mmol), N, N-diisopropylethylamine (35mg, 0.27mmol), dichloromethane (4mL), 4-dimethylamino Yl pyridines (1mg) and C-(6-trifluoromethylpyridin-3-base)-methylamine (47mg, 0.27mmol).This mixture is stirred in room temperature Mix overnight, then use CH₂Cl₂Dilution, uses Na₂HPO₄Aqueous solution, saline wash, and use Na₂SO₄It is dried, concentrates.Pass through preparative HPLC purification residue, obtains expecting product, for white solid.

LC-MS:493.2[M+1]⁺；¹H NMR(400MHz,CDCl₃): 8.67 (s, 1H), 8.07 (dd, J=1.6Hz, 6.0Hz, 2H), 7.87 (dd, J=1.1,8.4Hz, 1H), 7.72-7.71 (m, 1H), 7.59-7.57 (m, 2H), 7.47 (dd, J =0.44,8.1Hz, 1H), 7.41 (d, J=8Hz, 1H), 4.67 (s, 2H), 3.54-3.49 (m, 4H), 2.44 (s, 3H), 1.95-1.88(m,4H)。

Compound 63

2'-cyano group-5-(3-hydroxy azetidine-1-carbonyl)-4'-methyl-N-((6-picoline-3-base) methyl) Biphenyl-3-carboxylic acid amides

A) 2'-cyano group-5-(ethoxy carbonyl)-4'-methyl biphenyl-3-carboxylic acid

In round-bottomed flask add 2'-cyano group-4'-methyl biphenyl-3,5-dicarboxylic acids 3-ethyl 5-methyl ester (0.12g, 0.33mmol), 1,4-bis-Water (2mL) solution of alkane (10mL) and Lithium hydrate (9mg, 0.4mmol).This mixture is existed 2h is stirred at room temperature.Decompression removes volatile material, is acidified residue with 1N HCl, uses CH₂Cl₂Extraction.It is dried the organic of separation Phase, concentrates.By purified by flash chromatography residue, obtain expecting product, for white solid.

B) 2'-cyano group-5-(3-hydroxy azetidine-1-carbonyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester

To 2'-cyano group-5-(ethoxy carbonyl)-4'-methyl biphenyl-3-carboxylic acid (90mg, 0.29mmol), N-(3-diformazan Base aminopropyl)-N'-ethyl-carbodiimide hydrochloride (120mg, 0.61mmol), I-hydroxybenzotriazole hydrate (93mg, 0.61mmol) and dichloromethane (5mL) mixture in add 3-hydroxy azetidine hydrochlorate (67mg, 0.61mmol) and N, N-diisopropylethylamine (0.21mL, 1.2mmol).This mixture is stirred at room temperature overnight, then concentrating under reduced pressure.By soon Speed chromatography purification residue, obtains expecting product, for white solid.LC-MS:365.4[M+1]⁺；¹H NMR(400MHz, DMSO-d6): 8.24 (d, J=1.6Hz, 1H), 8.18 (t, J=1.7Hz, 1H), 8.00 (t, J=1.7Hz, 1H), 7.84 (s, 1H), 7.64-7.61 (m, 2H), 5.79 (d, J=6.0Hz, 1H), 4.54-4.52 (m, 2H), 4.37 (q, J=7.2Hz, 2H), 4.35-4.34 (m, 1H), 4.29-4.27 (m, 1H), 3.84-3.82 (m, 1H), 2.42 (s, 3H), 1.35 (t, J=7.2Hz, 3H)。

C) 2'-cyano group-5-(3-hydroxy azetidine-1-carbonyl)-4'-methyl biphenyl-3-carboxylic acid

2'-cyano group-5-(3-hydroxy azetidine-1-carbonyl)-4'-methyl biphenyl-3-carboxylic is added in round-bottomed flask Acetoacetic ester (25mg, 0.066mmol), sodium hydroxide (10mg, 0.25mmol), acetonitrile (2mL) and water (2mL).By this mixture It is stirred at room temperature overnight.Adding 1N HCl/water solution (3mL), decompression removes volatile material.Use CH₂Cl₂Extracted residues, will CH₂Cl₂Layer is concentrated to dryness, and obtains expecting product, for white solid.LC-MS:337.5[M+1]⁺。

D) 2'-cyano group-5-(3-hydroxy azetidine-1-carbonyl)-4'-methyl-N-((6-picoline-3-base) first Base) biphenyl-3-carboxylic acid amides

2'-cyano group-4'-methyl-5-((6-picoline-3-base) methylcarbamoyl) connection is added in round-bottomed flask Benzene-3-carboxylic acid (80mg, 0.24mmol), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (80mg, 0.42mmol), I-hydroxybenzotriazole hydrate (64mg, 0.42mmol), N, N-diisopropylethylamine (110mg, 0.83mmol), dichloromethane (5mL) and 3-hydroxy azetidine hydrochlorate (45mg, 0.42mmol).By this mixture in room Temperature is stirred overnight, and then concentrates.By purified by flash chromatography residue, obtain expecting product, for white solid.

LC-MS:441.5[M+1]⁺；¹H NMR(400MHz,CDCl₃): 8.54 (s, 1H), 8.10 (d, J=8.3Hz, 2H), 7.81 (s, 1H), 7.72 (d, J=7.9Hz, 1H), 7.58 (s, 1H), 7.49-7.42 (m, 3H), 7.18 (d, J=7,9Hz, 1H),4.68-4.57(m,4H),4.44-4.41(m,1H),4.29-4.28(m,1H),4.05-4.02(m,1H),2.57(s, 3H),2.45(s,3H)。

Compound 65

(R)-2,4'-dimethyl-N-(1-(2-methylpyrimidine-5-base) ethyl)-5-(pyrrolidin-1-yl sulfonyl) connection Benzene-3-carboxylic acid amides

A) 5-(chlorosulfonyl)-3-iodo-2-ar-Toluic acid

In round-bottomed flask, add chlorosulfonic acid (3.80mL, 57.2mmol), be dividedly in some parts 3-iodo-2-methylbenzene first at 0 DEG C Acid (5.00g, 19.1mmol).This reaction system is heated 2 hours at 95 DEG C, is then stirred at room temperature overnight.This reaction is mixed Compound is poured on ice, collects the solid formed, and is dried, and obtains expecting product, for white solid.

B) 3-iodo-2-methyl-5-(pyrrolidin-1-yl sulfonyl) benzoic acid

5-(chlorosulfonyl)-3-iodo-2-ar-Toluic acid (1.00g, 2.77mmol), pyrrolidine is added in round-bottomed flask (0.278mL, 3.33mmol), 1,4-bis-Alkane (4mL) and pyridine (0.20mL, 2.5mmol).This mixture is stirred 30 points Clock.Remove solvent, by purified by flash chromatography residue, obtain compound, for yellow solid.

C) 2,4'-dimethyl-5-(pyrrolidin-1-yl sulfonyl) biphenyl-3-carboxylic acid

In argon gas atmosphere to 3-iodo-2-methyl-5-(pyrrolidin-1-yl sulfonyl) benzoic acid (1.00g, 2.53mmol), p-tolyl boric acid (0.378g, 2.78mmol), toluene (10mL), ethanol (3mL), cesium carbonate (0.907g, 2.78mmol) add four (triphenyl phasphine) palladium (0) (146mg, 0.126mmol) with in water (1mL).This mixture is heated to back Stream, is continued 6h, is then cooled to room temperature, is filtered by Celite.Concentrated filtrate, by silicagel column (0-50%EtOAc/ hexane) Purification residue, obtains yellow solid.

D) (R)-2,4'-dimethyl-N-(1-(2-methylpyrimidine-5-base) ethyl)-5-(pyrrolidin-1-yl sulfonyl) connection Benzene-3-carboxylic acid amides

To reaction bottle in add 2,4'-dimethyl-5-(pyrrolidin-1-yl sulfonyl) biphenyl-3-carboxylic acid (40mg, 0.11mmol), (R)-1-(2-methylpyrimidine-5-base) ethamine (20mg, 0.14mmol), N, N, N ', N '-tetramethyl-O-(7-nitrogen Miscellaneous benzotriazole-1-base) urea hexafluorophosphate (106mg, 0.28mmol), N, N-diisopropylethylamine (39 μ L, 0.22mmol) With DMF (1.33mL), this reactant mixture is stirred at room temperature overnight.Should by preparation HPLC purification Reactant mixture, obtains compound, for light tan solid.

LC-MS:479.4[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.13 (t, J=7.34Hz, 1H), 8.73 (s, 2H), 7.61 (d, J=1.87Hz, 1H), 7.54 (d, J=1.87Hz, 1H), 7.31 (d, J=7.68Hz, 2H), 7.25 (d, J= 7.68Hz, 2H), 5.15 (t, J=7.45Hz, 1H), 3.16 (t, J=6.72Hz, 4H), 2.60 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H), 1.70 (t, J=6.72Hz, 4H), 1.50 (d, J=6.72Hz, 3H).

Compound 67

2,4'-dimethyl-N-((2-methylpyrimidine-5-base) methyl)-5-(pyrrolidin-1-yl sulfonyl) biphenyl-3-carboxylic Amide

To reaction bottle in add 2,4'-dimethyl-5-(pyrrolidin-1-yl sulfonyl) biphenyl-3-carboxylic acid (40mg, 0.11mmol), (2-methylpyrimidine-5-base) methylamine (18mg, 0.15mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo Triazol-1-yl) urea hexafluorophosphate (106mg, 0.28mmol), N, N-diisopropylethylamine (39 μ L, 0.22mmol) and N, N- Dimethylformamide (1.33mL), is stirred overnight this reactant mixture.By this reactant mixture of preparation HPLC purification, To compound, for white solid.

LC-MS:465.3[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.14 (t, J=6.16Hz, 1H), 8.69 (s, 2H), 7.65 (d, J=1.93Hz, 1H), 7.54 (d, J=1.93Hz, 1H), 7.30 (d, J=7.73Hz, 2H), 7.26 (d, J= 7.73Hz, 2H), 4.46 (d, J=5.64Hz, 2H), 3.16 (t, J=6.78Hz, 4H), 2.60 (s, 3H), 2.37 (s, 3H), 2.22 (s, 3H), 1.70 (t, J=6.67Hz, 4H).

Compound 73

N-(the chloro-3-of 4-(N-Cyclopropylsulfamoyl base) benzyl)-4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic Amide

To 4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid (60mg, 0.19mmol) at N, N-dimethyl formyl Solution in amine (1.0mL) adds 5-(amino methyl)-2-chloro-N-cyclopropyl-phenyl sulfonamide (80mg, 0.31mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (150mg, 0.39mmol) and N, N-diisopropyl Base ethamine (150 μ L, 0.86mmol).This reactant mixture is stirred 16 hours at 50 DEG C.By preparation HPLC purification, this is anti- Answer mixture, obtain pale solid.

LC-MS:552.6[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.39 (t, 1H, J=5.9Hz), 8.23 (t, 2H, J=1.4Hz), 8.00 (d, 1H, J=1.6Hz), 7.95 (t, 1H, J=1.3Hz), 7.92 (t, 1H, J=1.5Hz), 7.70-7.55 (m, 4H), 7.32 (d, 2H, J=8.0Hz), 4.58 (d, 2H, J=5.8Hz), 3.50 (t, 2H, J=6.5Hz), 3.43 (t, 2H, J=6.4Hz), 2.36 (s, 3H), 2.28-2.12 (m, 1H), 2.00-1.78 (m, 4H), 0.50-0.32 (m, 4H)。

Compound 83

N-(3-hydroxyl-1-(6-(trifluoromethyl) pyridin-3-yl) propyl group)-4'-methyl-5-(pyrrolidine-1-carbonyl) joins Benzene-3-carboxylic acid amides

To 4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid (17mg, 0.055mmol) at N, N-dimethyl methyl In solution in amide (0.5mL) add 3-amino-3-(6-(trifluoromethyl) pyridin-3-yl) acrylate-1-alcohol (47mg, 0.21mmol) (WO2008/130481), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (80mg, 0.21mmol) and N, N-diisopropylethylamine (80 μ L, 0.46mmol).This reactant mixture is little 30 DEG C of stirrings 16 Time.By this reactant mixture of preparation HPLC purification, obtain white solid.

LC-MS:512.4[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.15 (d, 1H, J=7.6Hz), 8.81 (s, 1H), 8.19 (s, 1H), 8.09 (dd, 1H, J=8.0,1.3Hz), 8.0-7.85 (m, 3H), 7.66 (d, 2H, J=8.1Hz), 7.32 (d, 2H, J=8.0Hz), 5.4-5.25 (m, 1H), 4.71 (t, 1H, J=4.5Hz), 3.60-3.35 (m, 6H), 2.36 (s,3H),2.25-2.10(m,1H),2.05-1.95(m,1H),1.94-1.78(m,4H)。

Compound 86

4'-methyl-N-((6-picoline-3-base) methyl)-5-(3-morpholino pyrrolidine-1-carbonyl) biphenyl-3-carboxylic Amide

To 4'-methyl-5-((6-picoline-3-base) methylcarbamoyl)-biphenyl-3-carboxylic acid (55mg, 0.15mmol), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (58mg, 0.30mmol), 1-hydroxy benzenes And triazole hydrate (23mg, 0.15mmol) and CH₂Cl₂(3mL) mixture adds 4-(pyrrolidin-3-yl) morpholine (48mg, 0.30mmol) and N, N-diisopropylethylamine (53 μ L, 0.30mmol).This mixture is stirred at room temperature overnight, so Final vacuum concentrates.By preparation HPLC (100x21.2mm C18 post, 30-60%MeCN/ water [10mM Et₂NH]) purification is residual Excess, obtains white foam.

LC-MS:499.7[M+1]⁺；¹H NMR(400MHz,CD₃OD): 8.43 (d, 1H, J=2.0Hz), 8.19 (s, 1H), 7.92 (d, 2H, J=1.6Hz), 7.76 (dd, 1H, J=8.0,2.0Hz), 7.59 (d, 2H, J=8.0Hz), 7.31-7.27 (m, 3H),4.59(s,2H),3.95-3.20(m,8H),2.90(m,1H),2.65-2.10(m,11H),1.85(m,1H)。

Compound 87

4'-methyl-5-((6-picoline-3-base) methylcarbamoyl) biphenyl-3-carboxylic acid

A) 4'-methyl-5-((6-picoline-3-base) methylcarbamoyl) biphenyl-3-carboxylic acid, ethyl ester

To 5-(ethoxy carbonyl)-4'-methyl biphenyl-3-carboxylic acid (1.5g, 5.3mmol), N-(3-dimethylamino third Base)-N'-ethyl-carbodiimide hydrochloride (2.0g, 10mmol), I-hydroxybenzotriazole hydrate (0.32g, 2.1mmol) and CH₂Cl₂(50mL) mixture adds (6-picoline-3-base) methylamine (0.97g, 7.9mmol) and N, N-diisopropyl second Amine (1.8mL, 10mmol).This mixture is stirred at room temperature 4h, then with water and Na₂CO₃Solution washing, is dried (Na₂SO₄), it is concentrated in vacuo.By silica column purification residue, obtain white foam.

LC-MS:389.4[M+1]⁺；¹H NMR(400MHz,CDCl₃): 8.53 (d, 1H, J=2.0Hz), 8.39 (t, 1H, J =1.6Hz), 8.29 (t, 1H, J=1.6Hz), 8.26 (t, 1H, J=1.6Hz), 7.66 (dd, 1H, J=8.0,2.0Hz), 7.55 (d, 2H, J=8.4Hz), 7.28 (d, 2H, J=8.0Hz), 7.17 (d, 1H, J=8.0Hz), 6.64 (m, 1H), 4.67 (d, 2H, J=5.6Hz), 4.42 (q, 2H, J=7.2Hz), 2.57 (s, 3H), 2.41 (s, 3H), 1.42 (t, 3H, J= 7.2Hz)。

B) 4'-methyl-5-((6-picoline-3-base) methylcarbamoyl) biphenyl-3-carboxylic acid

By 4'-methyl-5-((6-picoline-3-base) methylcarbamoyl) biphenyl-3-carboxylic acid, ethyl ester (1.02g, 2.62mmol), the mixture of Lithium hydrate (310mg, 13mmol), EtOH (100mL) and water (10mL) is stirred overnight at rt. LC-MS display reaction completes.Solvent removed in vacuo, processes residue with water (50mL), is acidified to pH=with 1N HCl/water solution 4.The solid of precipitation is collected by filtration, washes with water, be dried, obtain white solid.

LC-MS:361.3[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 13.5 (bs, 1H), 9.34 (t, 1H, J= 5.6Hz), 8.44 (d, 1H, J=2.0Hz), 8.41 (t, 1H, J=1.6Hz), 8.34 (t, 1H, J=1.6Hz), 8.29 (t, 1H, J=1.6Hz), 7.67 (d, 2H, J=8.4Hz), 7.64 (dd, 1H, J=8.0,2.0Hz), 7.33 (d, 2H, J=8.0Hz), 7.22 (d, 1H, J=8.0Hz), 4.49 (d, 2H, J=5.6Hz), 2.44 (s, 3H), 2.37 (s, 3H).

Compound 94

(R)-5-(3-hydroxyl pyrrolidine-1-carbonyl)-4'-methyl-N-((6-picoline-3-base) methyl) biphenyl-3- Carboxylic acid amides

A) (R)-5-(3-hydroxyl pyrrolidine-1-carbonyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester

To 5-(ethoxy carbonyl)-4'-methyl biphenyl-3-carboxylic acid (1.50g, 5.28mmol), N-(3-dimethylamino third Base)-N'-ethyl-carbodiimide hydrochloride (2.0g, 10mmol), I-hydroxybenzotriazole hydrate (0.404g, 2.64mmol) And CH₂Cl₂(30mL) mixture adds (R)-3-hydroxyl pyrrolidine (0.92g, 10mmol) and N, N-diisopropylethylamine (1.8mL,10mmol).This mixture is stirred at room temperature overnight, then uses CH₂Cl₂(100mL) dilution, uses NaHCO₃Water-soluble Liquid, saline wash, and are dried (Na₂SO₄), it is concentrated in vacuo.By silicagel column (100%EtOAc) purification residue, obtain white bubble Foam.LC-MS:354.2[M+1]⁺；¹H NMR(400MHz,CDCl₃): 8.32 (s, 1H), 8.16 and 8.12 (bs, 1H), 7.92 (m, 1H), 7.53 (d, 2H, J=7.6Hz), 7.28 (d, 2H, J=8.4Hz), 4.63 and 4.49 (bs, 1H), 4.41 (q, 2H, J= 7.2Hz), 3.95-3.40 (m, 4H), 2.41 (s, 3H), 2.20-1.90 (m, 2H), 1.41 (t, 3H, J=7.2Hz).

B) (R)-5-(3-hydroxyl pyrrolidine-1-carbonyl)-4'-methyl biphenyl-3-carboxylic acid

By (R)-5-(3-hydroxyl pyrrolidine-1-carbonyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester (1.25g, 3.54mmol), The mixture of Lithium hydrate (0.42g, 18mmol), methanol (50mL) and water (5mL) stirs 4h at rt.LC-MS display has been reacted Become.Volatiles removed in vacuo, processes residue with water, is acidified to pH2-3 with 1N HCl/water solution, with EtOAc (50mL X3) extraction.The organic layer merged with saline washing, is dried (Na₂SO₄), concentrate, obtain white foam.LC-MS:326.3[M+1 ]⁺；¹H NMR(400MHz,CD₃: 8.33 (m, 1H), OD) 8.11 and 8.10 (t, 1H, J=1.6Hz), 7.98 and 7.97 (t, 1H, J =1.6Hz), 7.57 (d, 2H, J=7.6Hz), 7.30 (d, 2H, J=8.0Hz), 4.51 and 4.38 (m, 1H), 3.85-3.35 (m,4H),2.39(s,3H),2.20-1.90(m,2H)。

C) (R)-5-(3-hydroxyl pyrrolidine-1-carbonyl)-4'-methyl-N-((6-picoline-3-base) methyl) biphenyl- 3-carboxylic acid amides

To 4'-methyl-5-((6-picoline-3-base) methylcarbamoyl)-biphenyl-3-carboxylic acid (55mg, 0.15mmol), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (58mg, 0.30mmol), 1-hydroxy benzenes And triazole hydrate (23mg, 0.15mmol) and CH₂Cl₂(3mL) in mixture add (R)-3-hydroxyl pyrrolidine (26mg, 0.30mmol) and N, N-diisopropylethylamine (53 μ L, 0.30mmol).This mixture is stirred at room temperature overnight, then vacuum Concentrate.By preparation HPLC (100x21.2mm C18 post, 30-60%MeCN/ water [10mM Et₂NH]), then use silicagel column (0-20%MeOH/CH₂Cl₂) purification residue, obtain white foam.

LC-MS:430.3[M+1]⁺；¹H NMR(400MHz,CD₃OD): 8.44 (d, 1H, J=2.0Hz), 8.19 (m, 1H), 7.95-7.90 (m, 2H), 7.77 (dd, 1H, J=8.0,2.4Hz), 7.59 (d, 2H, J=8.0Hz), 7.29 (d, 3H, J= 8.0Hz), 4.59 (s, 2H), 4.50 and 4.37 (m, 1H), 3.85-3.30 (m, 4H), 2.51 (s, 3H), 2.38 (s, 3H), 2.20-1.90(m,2H)。

Compound 95

(S)-5-(3-hydroxyl pyrrolidine-1-carbonyl)-4'-methyl-N-((6-picoline-3-base) methyl) biphenyl-3- Carboxylic acid amides

To 4'-methyl-5-((6-picoline-3-base) methylcarbamoyl)-biphenyl-3-carboxylic acid (55mg, 0.15mmol), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (58mg, 0.30mmol), 1-hydroxy benzenes And triazole hydrate (23mg, 0.15mmol) and CH₂Cl₂(3mL) in mixture add (S)-3-hydroxyl pyrrolidine (26mg, 0.30mmol) and N, N-diisopropylethylamine (53 μ L, 0.30mmol).This mixture is stirred at room temperature overnight, then vacuum Concentrate.By preparation HPLC (100x21.2mm C18 post, 30-60%MeCN/ water [10mM Et₂NH]), then use silicagel column (0-20%MeOH/CH₂Cl₂) purification residue, obtain white foam.

LC-MS:430.3[M+1]⁺；¹H NMR(400MHz,CD₃OD): 8.44 (d, 1H, J=2.0Hz), 8.19 (m, 1H), 7.95-7.90 (m, 2H), 7.77 (dd, 1H, J=8.0,2.4Hz), 7.59 (d, 2H, J=8.0Hz), 7.29 (d, 3H, J= 8.0Hz), 4.59 (s, 2H), 4.50 and 4.37 (m, 1H), 3.81-3.30 (m, 4H), 2.51 (s, 3H), 2.38 (s, 3H), 2.20-1.90(m,2H)。

Compound 108

(R)-N-(1-(5-chloro-1-methyl isophthalic acid H-pyrazoles-4-base) ethyl)-4'-methyl-5-(pyrrolidine-1-carbonyl) connection Benzene-3-carboxylic acid amides

In 20mL bottle add 4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid (30mg, 0.097mmol), (R)-1-(5-chloro-1-methyl isophthalic acid H-pyrazoles-4-base) ethylamine hydrochloride (24mg, 0.12mmol), N, N, N ', N '-tetramethyl-O- (7-azepine benzo triazol-1-yl) urea hexafluorophosphate (92mg, 0.24mmol), N, N-diisopropylethylamine (0.068mL, 0.39mmol) with DMF (1.0mL), this reactant mixture is stirred at room temperature overnight.Pass through preparative This reactant mixture of HPLC purification, obtains product, for faint yellow solid.

LC-MS:451.3[M+1]⁺；¹H NMR (DMSO-d6): 8.87 (d, J=7.77Hz, 1H), 8.16 (t, J= 1.83Hz, 1H), 7.92 (t, J=1.61Hz, 1H), 7.87 (t, J=1.61Hz, 1H), 7.66 (d, J=8.22Hz, 2H), 7.59 (s, 1H), 7.31 (d, J=8.22Hz, 2H), 5.16-5.12 (m, 1H), 3.76 (s, 3H), 3.49 (t, J=6.70Hz, 2H), 3.40 (t, J=6.70Hz, 2H), 2.36 (s, 3H), 1.90-1.80 (m, 4H), 1.47 (d, J=7.45Hz, 3H).

Compound 111

4'-methyl-N-(1-(2-methylthiazol-4-base) ethyl)-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid amides

In 20mL bottle add 4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid (30mg, 0.097mmol), 1-(2-methylthiazol-4-base)-ethylamine hydrochloride (22mg, 0.12mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo Triazol-1-yl) urea hexafluorophosphate (92mg, 0.24mmol), N, N-diisopropylethylamine (0.068mL, 0.39mmol) and N, Dinethylformamide (1.0mL), is stirred at room temperature overnight this reactant mixture.Mixed by this reaction of preparation HPLC purification Compound, obtains product, for pinkish solid.

LC-MS:434.4[M+1]⁺；¹H NMR (DMSO-d6): 9.01 (d, J=8.50Hz, 1H), 8.24 (t, J= 1.59Hz, 1H), 7.97 (t, J=1.99Hz, 1H), 7.88 (t, J=1.99Hz, 1H), 7.68 (d, J=8.35Hz, 2H), 7.31 (d, J=7.95Hz, 2H), 7.25 (d, J=0.99Hz, 1H), 5.31-5.27 (m, 1H), 3.50 (t, J=6.53Hz, 2H), 3.42 (t, J=6.53Hz, 2H), 2.63 (s, 3H), 2.36 (s, 3H), 1.91-1.81 (m, 4H), 1.53 (d, J= 7.26Hz,3H)。

Compound 113

3-(5-picoline-2-base)-N-((6-picoline-3-base) methyl)-5-(methyl sulphonyl) Benzoylamide

A) the bromo-5-of 3-(methyl sulphonyl) benzoic acid

By bromo-for 3-5-(methyl sulphonyl) essence of Niobe (0.65g, 2.2mmol), Lithium hydrate (0.26g, 11mmol), the mixture of oxolane (25mL) and water (5mL) is stirred at room temperature 3h.Add water (50mL), molten with 1N HCl/water This mixture is acidified to pH2-3 by liquid, extracts with EtOAc (100mL).Separate organic layer, wash with saline, be dried (Na₂SO₄), Concentrate, obtain white solid.LC-MS:278.6[M-1]^-；¹H NMR(400MHz,CDCl₃):8.59(m,1H),8.50(m, 1H),8.33(m,1H),3.13(s,3H)。

B) the bromo-N-of 3-((6-picoline-3-base) methyl)-5-(methyl sulphonyl) Benzoylamide

To 3-bromo-5-(methyl sulphonyl) benzoic acid (630mg, 2.2mmol), N-(3-dimethylaminopropyl)-N'-second Base carbodiimide hydrochloride (860mg, 4.5mmol), I-hydroxybenzotriazole hydrate (140mg, 0.90mmol) and CH₂Cl₂ (25mL) mixture adds (6-picoline-3-base) methylamine (550mg, 4.5mmol) and N, N-diisopropylethylamine (0.79mL,4.5mmol).This mixture is stirred at room temperature overnight, then uses CH₂Cl₂(50mL) dilution.With water and Na₂CO₃ Solution washing organic facies, is dried (Na₂SO₄), it is concentrated in vacuo.Remaining by silicagel column (50-100%EtOAc/ hexane) purification Thing, obtains white solid.LC-MS:385.2[M+1]⁺；¹H NMR(400MHz,CDCl₃): 8.51 (d, 1H, J=1.6Hz), 8.28 (t, 1H, J=1.6Hz), 8.23 (t, 1H, J=1.6Hz), 8.19 (t, 1H, J=1.6Hz), 7.66 (dd, 1H, J= 8.0,2.0Hz), 7.19 (d, 1H, J=8.0Hz), 6.93 (bs, 1H), 4.63 (d, 2H, J=5.6Hz), 3.09 (s, 3H), 2.57(s,3H)。

C) 3-(5-picoline-2-base)-N-((6-picoline-3-base) methyl)-5-(methyl sulphonyl) benzoyl Amine

In argon gas atmosphere, by bromo-for 3-N-((6-picoline-3-base) methyl)-5-(methyl sulphonyl) Benzoylamide (71mg, 0.18mmol), 5-methyl-2-(tributylstamlyl) pyridine (91mg, 0.23mmol), four (triphenyl phasphine) palladium (0) The mixture of (11mg, 0.0093mmol) and toluene (2.0mL) carries out microwave irradiation 2 hours at 120 DEG C.This mixture is cooled down So that product precipitation.Discard solvent, rinse the solid of precipitation with hexane, then by preparation HPLC (100x21.2mm C18 Post, 30-70%CH₃CN/ water [10mM Et₂NH]) purification, obtain white foam.

LC-MS:396.4[M+1]⁺；¹H NMR(400MHz,CDCl₃): 8.72 (t, 1H, J=1.6Hz), 8.69 (t, 1H, J =1.6Hz), 8.53 (m, 2H), 8.34 (t, 1H, J=1.6Hz), 7.76 (d, 1H, J=8.0Hz), 7.68-7.62 (m, 2H), 7.17 (d, 1H, J=8.0Hz), 6.86 (bs, 1H), 4.67 (d, 2H, J=6.4Hz), 3.13 (s, 3H), 2.57 (s, 3H), 2.41(s,3H)。

Compound 116

(R)-4'-methyl-N-(1-(2-methylpyrimidine-5-base) ethyl)-5-(methyl sulphonyl) biphenyl-3-carboxylic acid amides

To 4'-methyl-5-(methyl sulphonyl) biphenyl-3-carboxylic acid (1.0g, 3.44mmol) at N,N-dimethylformamide (10mL) solution in adds (R)-1-(2-methylpyrimidine-5-base) ethamine (900mg, 5.58mmol), N, N, N ', N '-four Methyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (3.0g, 7.89mmol) and N, N-diisopropylethylamine (3.0mL,17.22mmol).This reactant mixture is stirred 16 hours at 25 DEG C.LC-MS display reaction completes.Dilute with EtOAc Release this reaction solution, with water, saturated NaHCO₃Aqueous solution, saline wash, and use anhydrous MgSO₄It is dried.By silicagel column and preparative HPLC purification residue, obtains end-product, for pale solid.

LC-MS:410.1[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.26 (d, 1H, J=7.4Hz), 8.75 (s, 2H), 8.44 (t, 1H, J=1.6Hz), 8.33 (t, 1H, J=1.6Hz), 8.28 (t, 1H, J=1.6Hz), 7.75 (d, 2H, J= 8.2Hz), 7.37 (d, 2H, J=7.9Hz), 5.22 (m, 1H), 3.34 (s, 3H), 2.60 (s, 3H), 2.38 (s, 3H), 1.58 (d, 3H, J=7.1Hz).

Compound 122

3-(5-picoline-2-base)-N-((6-picoline-3-base) methyl)-5-(pyrrolidine-1-carbonyl) benzoyl Amine

A) 3-(5-picoline-2-base)-5-(pyrrolidine-1-carbonyl) essence of Niobe

In argon gas atmosphere by bromo-for 3-5-(pyrrolidine-1-carbonyl) essence of Niobe (1.2g, 3.8mmol), 5-methyl- 2-(tributylstamlyl) pyridine (0.90mL, 2.6mmol), the mixing of four (triphenyl phasphine) palladium (0) (100mg, 0.086mmol) Thing carries out microwave irradiation 2 hours at 120 DEG C.This mixture is cooled to room temperature, precipitation is collected by filtration, rinse with hexane, Obtain title compound, for white solid.Concentrated filtrate, by purified by flash chromatography, a collection of expectation product of getting back.LC- MS:325.1[M+1]⁺。

B) 3-(5-picoline-2-base)-5-(pyrrolidine-1-carbonyl) benzoic acid

3-(5-picoline-2-base)-5-(pyrrolidine-1-carbonyl) essence of Niobe is added in round-bottomed flask (0.80g, 2.47mmol), methanol (40mL), sodium hydroxide (0.20g, 5.0mmol) and water (10mL).By this mixture in room Temperature stirring 1h.Decompression removes volatile material.Process residue with 1NHCl (10mL), concentrate, by preparation HPLC purification, Obtain expecting product.LC-MS:311.5[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 8.61 (t, J=1.7Hz, 1H), 8.52 (t, J=0.8Hz, 1H), 8.16 (t, J=1.8Hz, 1H), 7.99 (t, J=1.5Hz, 1H), 7.80 (d, J=8.2Hz, 1H), 7.72-7.69 (m, 1H), 3.50 (t, J=6.7Hz, 2H), 3.41 (t, J=6.5Hz, 2H), 2.35 (s, 3H), 1.91-1.81 (m,4H)。

C) 3-(5-picoline-2-base)-N-((6-picoline-3-base) methyl)-5-(pyrrolidine-1-carbonyl) benzene first Amide

In round-bottomed flask add 3-(5-picoline-2-base)-5-(pyrrolidine-1-carbonyl) benzoic acid (80mg, 0.26mmol), (6-picoline-3-base) methylamine (60mg, 0.49mmol), N-(3-dimethylaminopropyl)-N'-ethyl carbon Diimmonium salt hydrochlorate (90mg, 0.47mmol), I-hydroxybenzotriazole hydrate (80mg, 0.52mmol), N, N-diisopropyl Ethamine (80mg, 0.62mmol) and dichloromethane (5mL).This mixture is stirred at room temperature overnight, then concentrates.By preparation Type HPLC purification residue, obtains expecting product, for white solid.

LC-MS:415.5[M+1]⁺；¹H NMR(400MHz,CD₃OD): 8.56 (t, J=1.7Hz, 1H), 8.53-8.52 (m, 1H), 8.46 (d, J=2.1Hz, 1H), 8.29 (t, J=1.6Hz, 1H), 8.04 (t, J=1.6Hz, 1H), 7.89 (d, J= 8.1Hz, 1H), 7.81-7.77 (m, 2H), 7.32 (d, J=8.0Hz, 1H), 4.63 (s, 2H), 3.66 (t, J=7.0Hz, 2H), 3.54 (t, J=6.7Hz, 2H), 2.54 (s, 3H), 2.43 (s, 3H), 2.05-1.94 (m, 4H).

Compound 127

4'-methyl-N-((6-picoline-3-base) methyl)-5-(4-(thiazol-2-yl) piperazine-1-carbonyl) biphenyl-3- Carboxylic acid amides

To 4'-methyl-5-((6-picoline-3-base) methylcarbamoyl) biphenyl-3-carboxylic acid (30mg, 0.083mmol) in the solution in N,N-dimethylformamide (1mL) add 2-(piperazine-1-base) thiazole (40mg, 0.24mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (80mg, 0.21mol) And N, N-diisopropylethylamine (100 μ L, 0.57mmol).This reactant mixture is stirred 16 hours at 25 DEG C.Pass through preparative This reactant mixture of HPLC purification, obtains end-product, for white solid.

LC-MS:512.4[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.27 (t, 1H, J=5.6Hz), 8.44 (bs, 1H), 8.24 (bs, 1H), 7.90-7.84 (m, 2H), 7.70-7.60 (m, 3H), 7.32 (d, 2H, J=7.9Hz), 7.22 (d, 1H, J=8.0Hz), 7.19 (d, 1H, J=3.6Hz), 6.89 (d, 1H, J=3.6Hz), 4.49 (d, 2H, J=5.6Hz), 3.90-3.70(m,2H),3.60-3.40(m,6H),2.44(s,3H),2.36(s,3H)。

Compound 130

5-(3-hydroxy azetidine-1-carbonyl)-4'-methyl-N-((6-(trifluoromethyl) pyridin-3-yl) methyl) joins Benzene-3-carboxylic acid amides

To 5-(3-hydroxy azetidine-1-carbonyl)-4'-methyl biphenyl-3-carboxylic acid (80mg, 0.26mmol) at N, N- In solution in dimethylformamide (1.5mL) add C-(6-trifluoromethylpyridin-3-base)-methylamine (70mg, 0.40mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (200mg, 0.53mmol) and N, N-diisopropylethylamine (200 μ L, 1.15mmol).This reactant mixture is stirred 16 hours at 25 DEG C.Logical Cross this reactant mixture of preparation HPLC purification, obtain white solid.

LC-MS:470.5[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.42 (t, 1H, J=5.7Hz), 8.78 (d, 1H, J=1.3Hz), 8.28 (t, 1H, J=1.6Hz), 8.06 (t, 1H, J=1.4Hz), 8.04 (dd, 1H, J=8.0, 1.5Hz), 7.96 (t, 1H, J=1.5Hz), 7.89 (d, 1H, J=8.1Hz), 7.67 (d, 2H, J=8.2Hz), 7.33 (d, 2H, J=8.0Hz), 5.79 (d, 1H, J=5.7Hz), 4.65 (d, 2H, J=5.7Hz), 4.60-4.45 (m, 2H), 4.28 (m, 1H), 4.09(m,1H),3.82(m,1H),2.36(s,3H)。

Compound 140

4'-methyl-N-((6-picoline-3-base) methyl)-5-((3aR, 6aS)-octahydro pyrrolo-[3,4-c] pyrroles- 2-carbonyl) biphenyl-3-carboxylic acid amides

To 4'-methyl-5-((6-picoline-3-base) methylcarbamoyl)-biphenyl-3-carboxylic acid (25mg, 0.069mmol) solution in N,N-dimethylformamide (1mL) adds (3aR, 6aS)-hexahydropyrrolo also [3,4-c] pyrrole Cough up-2 (1H)-carboxylic acid tert-butyl esters (30mg, 0.14mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea Hexafluorophosphate (60mg, 0.16mmol) and N, N-diisopropylethylamine (100 μ L, 0.57mmol).This reactant mixture is existed 25 DEG C are stirred 16 hours.By this reactant mixture of preparation HPLC purification, obtain the product protected by Boc, for white solid, It is dissolved in dichloromethane (3.0mL), adds trifluoroacetic acid (0.20mL, 2.6mmol).This reactant mixture is stirred at rt Night.Volatiles removed in vacuo, by preparation HPLC (100x21.2mm C18 post, 20-60%MeCN/ water [10mM Et₂NH]) purification residue, obtain product, for white foam.

LC-MS:455.4[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.26 (t, 1H, J=5.3Hz), 8.44 (bs, 1H), 8.21 (bs, 1H), 7.95-7.80 (m, 2H), 7.70-7.60 (m, 3H), 7.31 (d, 2H, J=7.9Hz), 7.22 (d, 1H, J=7.9Hz), 4.48 (d, 1H, J=5.5Hz), 3.90-3.15 (m, 4H), 2.90 (m, 1H), 2.85-2.60 (m, 4H), 2.50-2.30(m,2H),2.44(s,3H),2.36(s,3H)。

Compound 162

N3,4'-dimethyl-N5-((6-picoline-3-base) methyl)-N3-(pyridin-4-yl methyl) biphenyl-3,5-two Carboxylic acid amides

To 4'-methyl-5-((6-picoline-3-base) methylcarbamoyl)-biphenyl-3-carboxylic acid (60mg, 0.16mmol) in the solution in N,N-dimethylformamide (1mL) add methvl-pyridinium-4-ylmethyl-amine (50mg, 0.41mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (140mg, 0.37mmol) and N, N-diisopropylethylamine (140 μ L, 0.80mmol).This reactant mixture is stirred 16 hours at 25 DEG C.Logical Cross this reactant mixture of preparation HPLC purification, obtain product, for light tan solid.

LC-MS:465.5[M+1]⁺；¹H NMR (400MHz, DMSO-d6): (rotamer (rotomers)) 9.29 (m, 1H),8.57(m,2H),8.44(bs,1H),8.20(m,1H),8.95-7.55(m,5H),7.48-7.15(m,5H),4.74 (bs, 1H), 4.60-4.40 (m, 3H), 3.00 and 2.94 (s, 3H), 2.44 (s, 3H), 2.37 and 2.33 (s, 3H).

Compound 163

N3,4'-dimethyl-N5-((6-picoline-3-base) methyl)-N3-(pyridin-4-yl) biphenyl-3,5-dicarboxylic dihydrazides Amine

To 4'-methyl-5-((6-picoline-3-base) methylcarbamoyl)-biphenyl-3-carboxylic acid (50mg, 0.134mmol) in the solution in N,N-dimethylformamide (1mL) add N-picoline-4-amine (40mg, 0.37mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (120mg, 0.32mmol) and N, N-diisopropylethylamine (120 μ L, 0.69mmol).This reactant mixture is stirred 16 hours at 25 DEG C.Logical Cross this reactant mixture of preparation HPLC purification, obtain end-product, for pale solid.

LC-MS:451.6[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.20 (t, 1H, J=5.7Hz), 8.48-8.38 (m, 3H), 8.12 (t, 1H, J=1.6Hz), 7.87 (t, 1H, J=1.4Hz), 7.65 (t, 1H, J=1.5Hz), 7.59 (dd, 1H, J=8.0,2.3Hz), 7.42 (d, 2H, J=8.1Hz), 7.30-7.15 (m, 5H), 4.45 (d, 2H, J=5.7Hz), 3.45 (s,3H),2.44(s,3H),2.33(s,3H)。

Compound 165

(R)-N3,4'-dimethyl-N5-((6-picoline-3-base) methyl)-N3-(pyrrolidin-3-yl) biphenyl-3,5- Dicarboxamide

To 4'-methyl-5-((6-picoline-3-base) methylcarbamoyl) biphenyl-3-carboxylic acid (50mg, 0.14mmol) in the solution in N,N-dimethylformamide (1mL) add (R)-N-methylpyrrolidin-3-amine (50mg, 0.50mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (120mg, 0.32mmol) and N, N-diisopropylethylamine (120 μ L, 0.69mmol).This reactant mixture is stirred 16 hours at 25 DEG C.Logical Cross preparation HPLC purification reaction solution, obtain end-product, for pale solid.

LC-MS:443.5[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.26 (t, 1H, J=5.8Hz), 8.43 (bs, 1H), 8.22 (bs, 1H), 7.94 (bs, 1H), 7.88 (bs, 1H), 7.70-7.60 (m, 3H), 7.31 (d, 2H J=7.9Hz), 7.21 (d, 1H, J=8.0Hz), 4.48 (d, 2H, J=5.7Hz), 3.65-3.05 (m, 5H), 2.44 (s, 3H), 2.36 (s, 3H), 2.29 and 2.17 (rotamers: s, 3H), 2.05-1.65 (m, 3H).

Compound 166

N3, N3,4'-trimethyl-N5-((6-picoline-3-base) methyl) biphenyl-3,5-dicarboxamide

To 4'-methyl-5-((6-picoline-3-base) methylcarbamoyl) biphenyl-3-carboxylic acid (50mg, 0.14mmol) solution in N,N-dimethylformamide (1mL) adds dimethylamine hydrochloride (60mg, 0.74mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (120mg, 0.32mmol) and N, N-bis-are different Propylethylamine (0.50mL, 2.87mmol).This reactant mixture is stirred 16 hours at 25 DEG C.Anti-by preparation HPLC purification Answer solution, obtain end-product, for light tan solid.

LC-MS:388.5[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.26 (t, 1H, J=5.8Hz), 8.44 (bs, 1H), 8.21 (bs, 1H), 7.90-7.60 (m, 5H), 7.31 (d, 2H, J=7.3Hz), 7.21 (d, 1H, J=8.0Hz), 4.49 (d, 2H, J=4.9Hz), 3.02 (s, 3H), 2.94 (s, 3H), 2.44 (s, 3H), 2.36 (s, 3H).

Compound 168

N3,4'-dimethyl-N5-((6-picoline-3-base) methyl)-N3-(2,2,2-trifluoroethyl) biphenyl-3,5- Dicarboxamide

To 4'-methyl-5-((6-picoline-3-base) methylcarbamoyl) biphenyl-3-carboxylic acid (50mg, 0.14mmol) solution in N,N-dimethylformamide (1.5mL) adds 2,2,2-trifluoro-N-methyl ethylamine hydrochloride (60mg, 0.40mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (120mg, 0.32mmol) and N, N-diisopropylethylamine (0.50mL, 2.87mmol).This reactant mixture is stirred 16 hours at 25 DEG C. By this reactant mixture of preparation HPLC purification, obtain end-product, for faint yellow solid.

LC-MS:456.3[M+1]⁺；¹H NMR(400MHz,DMSO-d6):9.31(bs,1H),8.44(bs,1H),8.25 (bs, 1H), 7.90-7.60 (m, 5H), 7.32 (d, 2H, J=8.1Hz), 7.21 (d, 1H, J=8.0Hz), 4.49 (d, 2H, J= 5.7Hz),4.45-4.10(m,2H),3.07(bs,3H),2.44(s,3H),2.36(s,3H)。

Compound 181

(R)-3-(5-picoline-2-base)-5-(methyl sulphonyl)-N-(1-(6-(trifluoromethyl) pyridin-3-yl) second Base) Benzoylamide

A) 3-(5-picoline-2-base)-5-(methyl sulphonyl) essence of Niobe

By bromo-for 3-5-(methyl sulphonyl) essence of Niobe (1.0g, 3.4mmol), 5-methyl-2-in argon gas atmosphere (tributylstamlyl) pyridine (1.2mL, 3.5mmol), four (triphenyl phasphine) palladium (0) (200mg, 0.17mmol) and toluene (10mL) mixture carries out microwave irradiation 2 hours at 120 DEG C.This mixture is cooled to room temperature.Precipitation is collected by filtration, Rinse with hexane, obtain title compound, for light tan solid (432mg).Concentrated filtrate, remaining by purified by flash chromatography Thing, a collection of product of getting back, for faint yellow solid (200mg).¹HNMR(400MHz,CDCl₃): 8.91 (t, J=1.4Hz, 1H), 8.80 (d, J=1.7Hz, 1H), 8.61 (s, 1H), 8.58 (d, J=0.8Hz, 1H), 7.76 (d, J=8.1Hz, 1H), 7.65 (d, J=8.1Hz, 1H), 4.00 (s, 3H), 3.15 (s, 3H), 2.42 (s, 3H).

B) 3-(5-picoline-2-base)-5-(methyl sulphonyl) benzoic acid (HCl salt)

In round-bottomed flask add 3-(5-picoline-2-base)-5-(methyl sulphonyl) essence of Niobe (0.60g, 1.96mmol), barium hydroxide octahydrate (1.23g, 3.90mmol) and methanol (50mL).This mixture is stirred at room temperature to instead Should complete.It is acidified this mixture with HCl (2M diethyl ether solution, 20mL).Concentrate this mixture, obtain expecting product and BaCl₂'s Mixture, for white solid (1.4g, 40% purity).LC-MS:291.5[M+1]；¹H NMR(400MHz,DMSO-d6):8.90 (s, 1H), 8.80 (d, J=1.7Hz, 1H), 8.63 (s, 1H), 8.43 (d, J=1.5Hz, 1H), 8.16 (d, J=8.1Hz, 1H), 7.89 (d, J=7.8Hz, 1H), 7.64-7.55 (m, 1H), 3.38 (s, 3H), 2.40 (s, 3H).

C) (R)-3-(5-picoline-2-base)-5-(methyl sulphonyl)-N-(1-(6-(trifluoromethyl) pyridin-3-yl) Ethyl) Benzoylamide

(40% contains BaCl to add 3-(5-picoline-2-base)-5-(methyl sulphonyl) benzoic acid in round-bottomed flask₂ Mixture, 250mg, 0.34mmol), (R)-1-(6-(trifluoromethyl) pyridin-3-yl) ethamine (130mg, 0.69mmol), N- (3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (130mg, 0.69mmol), I-hydroxybenzotriazole hydrate (100mg, 0.69mmol), triethylamine (87mg, 0.86mmol) and CH₂Cl₂(3mL).This mixture is stirred at room temperature overnight, Then concentrate.By purified by flash chromatography residue, obtain expecting product, for white solid.

LC-MS:464.8[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.41 (d, J=7.3Hz, 1H), 8.86 (t, J =1.6Hz, 2H), 8.74 (t, J=1.6Hz, 1H), 8.60 (d, J=2.2Hz, 1H), 8.43 (t, J=1.6Hz, 1H), 8.13- 8.10 (m, 2H), 7.91 (d, J=8.1Hz, 1H), 7.82 (dd, J=2.2,8.7Hz, 1H), 5.34 (p, J=7.1Hz, 1H), 3.33 (s, 3H), 2.38 (s, 3H), 1.60 (d, J=7.1Hz, 3H).

Compound 185

5-(isoindoline-2-carbonyl)-4'-methyl-N-((6-picoline-3-base) methyl) biphenyl-3-carboxylic acid amides

To 4'-methyl-5-((6-picoline-3-base) methylcarbamoyl) biphenyl-3-carboxylic acid (50mg, 0.14mmol) solution in N,N-dimethylformamide (1mL) adds isoindoline (40mg, 0.34mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (120mg, 0.32mmol) and N, N-diisopropyl Base ethamine (120 μ L, 0.69mmol).This reactant mixture is stirred 16 hours at 25 DEG C.By preparation HPLC purification reaction Solution, obtains end-product, for yellow solid.

LC-MS:461.9[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.27 (t, 1H, J=5.7Hz), 8.45 (d, 1H, J=2.0Hz), 8.26 (t, 1H, J=1.5Hz), 8.02 (bs, 2H), 7.72-7.62 (m, 3H), 7.42 (d, 1H, J= 7.2Hz), 7.35-7.25 (m, 5H), 7.22 (d, 1H, J=8.0Hz), 4.90 (s, 2H), 4.81 (s, 2H), 4.49 (d, 2H, J =5.7Hz), 2.44 (s, 3H), 2.36 (s, 3H).

Compound 187

4'-methyl-N-((6-picoline-3-base) methyl)-5-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl) biphenyl- 3-carboxylic acid amides

To 4'-methyl-5-((6-picoline-3-base) methylcarbamoyl)-biphenyl-3-carboxylic acid (50mg, 0.14mmol) in the solution in N,N-dimethylformamide (1mL) add 1,2,3,4-tetrahydroisoquinoline (50mg, 0.38mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (120mg, 0.32mmol) and N, N-diisopropylethylamine (120 μ L, 0.69mmol).This reactant mixture is stirred 16 hours at 25 DEG C.Logical Cross preparation HPLC purification reaction solution, obtain end-product, for yellow solid.

LC-MS:476[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.27 (t, 1H, J=5.6Hz), 8.44 (d, 1H, J =1.8Hz), 8.25 (bs, 1H), 7.88 (m, 2H), 7.72-7.62 (m, 3H), 7.35-7.00 (m, 7H), 4.81 and 4.61 (bs, 2H), 4.48 (d, 2H, J=5.7Hz), 3.88 and 3.60 (bs, 2H), 2.85 (m, 2H), 2.44 (s, 3H), 2.36 (s, 3H)。

Compound 191

4'-methyl-N-((R)-1-(2-methylpyrimidine-5-base) ethyl)-5-(octahydro pyrrolo-[1,2-a] pyrazine-2-carbonyl Base) biphenyl-3-carboxylic acid amides

A) 4'-methyl-5-(octahydro pyrrolo-[1,2-a] pyrazine-2-carbonyl) biphenyl-3-carboxylic acid

To 5-(ethoxy carbonyl)-4'-methyl biphenyl-3-carboxylic acid (300mg, 1.06mmol) at N,N-dimethylformamide (6mL) solution in adds octahydro pyrrolo-[1,2-a] pyrazine (200mg, 1.58mmol), N, N, N ', N '-tetramethyl-O- (7-azepine benzo triazol-1-yl) urea hexafluorophosphate (1.0g, 2.63mmol) and N, N-diisopropylethylamine (1.0mL, 5.74mmol).This reactant mixture is stirred 16 hours at 25 DEG C.LC-MS display reaction completes.This reaction is diluted with EtOAc Mixture, with water, saturated NaHCO₃Aqueous solution, saline wash, and use anhydrous MgSO₄It is dried, concentrates.Remaining by silica column purification Thing, obtains ethyl ester product, for brown foam.By the ethyl ester (480mg, 1.22mmol) obtained, Lithium hydrate (75mg, 3.1mmol), the mixture of MeOH (25mL) and water (4mL) stirs 20hr at rt.LC-MS display reaction completes.Vacuum removes and waves Volatile material, processes residue with water, is acidified to pH=5 with 1N HCl/water solution.By EtOAc (3x100mL) aqueous phase extracted, use The organic layer that saline washing merges, is dried, is concentrated into and obtains acid product, for pale solid.

B) 4'-methyl-N-((R)-1-(2-methylpyrimidine-5-base) ethyl)-5-(octahydro pyrrolo-[1,2-a] pyrazine-2- Carbonyl) biphenyl-3-carboxylic acid amides

To 4'-methyl-5-(octahydro pyrrolo-[1,2-a] pyrazine-2-carbonyl) biphenyl-3-carboxylic acid (50mg, 0.14mmol) In solution in N,N-dimethylformamide (1.0mL) add (R)-1-(2-methylpyrimidine-5-base) ethamine (35mg, 0.25mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (120mg, 0.32mmol) and N, N-diisopropylethylamine (120 μ L, 0.69mmol).This reactant mixture is stirred 16 hours at 25 DEG C.Logical Cross this reactant mixture of preparation HPLC purification, obtain end-product, for faint yellow solid.

LC-MS:484.1[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.07 (d, 1H, J=7.5Hz), 8.73 (s, 2H), 8.19 (bs, 1H), 7.82 (bs, 1H), 7.77 (bs, 1H), 7.66 (d, 2H, J=7.8Hz), 7.32 (d, 2H, J= 8.0Hz), 5.20 (m, 1H), 4.63 and 4.49 (bs, 1H), 3.70-2.80 (m, 4H), 2.64 (s, 3H), 2.36 (s, 3H), 2.20-1.10 (m, 8H), 1.55 (d, 3H, J=7.1Hz).

Compound 200

The bromo-N-of 4'-((6-picoline-3-base) methyl)-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid amides

A) the bromo-5-of 4'-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid, ethyl ester

To the bromo-5-of 3-(pyrrolidine-1-carbonyl) ethyl benzoate (3.20g, 9.81mmol), 4-bromobenzene in argon gas atmosphere Ylboronic acid (2.17g, 10.8mmol), toluene (40mL), cesium carbonate (3.52g, 10.8mmol) and water (5mL) add four (three Phosphniline) palladium (0) (567mg, 0.49mmol).This mixture is heated 15h at reflux.After cooling, by Celite mistake Filter this mixture, wash filter cake with EtOAc.Use saline wash filtrate, be dried (Na₂SO₄), concentrate.Remaining by silica column purification Thing (0-80%EtOAc/ hexane), obtains syrup.LC-MS:404.0[M+1]⁺。

B) the bromo-5-of 4'-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid

By bromo-for 4'-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid, ethyl ester (3.3g, 8.2mmol), MeOH (100mL), water (20mL) mixture with Lithium hydrate (0.90g, 38mmol) is stirred at room temperature 3h.This mixture is concentrated in vacuo, uses 1N HCl Aqueous solution, extracts residue acidified to pH2-3 with EtOAc (2x100mL).It is dried the organic layer (Na merged₂SO₄), concentrate, Obtain white foam.LC-MS:376.1[M+1]⁺。

C) the bromo-N-of 4'-((6-picoline-3-base) methyl)-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid amides

To the bromo-5-of 4'-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (1.65g, 4.41mmol), N-(3-dimethylamino Propyl group)-N'-ethyl-carbodiimide hydrochloride (1.7g, 8.8mmol), I-hydroxybenzotriazole hydrate (0.20g, 1.3mmol) And CH₂Cl₂(50mL) mixture adds (6-picoline-3-base) methylamine (0.81g, 6.6mmol) and N, N-diisopropyl Ethamine (1.5mL, 8.8mmol).This mixture is stirred at room temperature overnight, then washes with water, be dried (Na₂SO₄), concentrate.Logical Cross silicagel column (0-15%MeOH/CH₂Cl₂) purification residue, by preparation HPLC (100x20.2mm, C18 post；30-80% CH₃CN-water [10mMEt₂NH]) purity analysis sample, obtain white foam.

LC-MS:480.1[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.26 (t, 1H, J=5.6Hz), 8.44 (d, 1H, J=2.0Hz), 8.23 (t, 1H, J=1.6Hz), 7.99 (t, 1H, J=1.6Hz), 7.94 (t, 1H, J=1.6Hz), 7.77-7.66 (m, 4H), 7.63 (dd, 1H, J=8.0,2.0Hz), 7.22 (d, 1H, J=8.0Hz), 4.49 (d, 2H, J= 5.6Hz), 3.50 (t, 2H, J=6.8Hz), 3.42 (t, 2H, J=6.8Hz), 2.44 (s, 3H), 1.93-1.79 (m, 4H).

Compound 203

4'-methyl-d3-N-((6-picoline-3-base) methyl)-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid amides

A) N-((6-picoline-3-base) methyl)-5-(pyrrolidine-1-carbonyl)-4'-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolanes-2-base) biphenyl-3-carboxylic acid amides

In argon gas atmosphere to the bromo-N-of 4'-((6-picoline-3-base) methyl)-5-(pyrrolidine-1-carbonyl) biphenyl- 3-carboxylic acid amides (0.47g, 0.98mmol), double (frequency which acid) two boron (0.37g, 1.5mmol), potassium acetate (0.29g, 2.9mmol), 1,4-bis-The mixture of alkane (20mL) and dimethyl sulfoxide (0.2mL) adds [double (diphenylphosphino) ferrocene of 1,1'-] two Chlorine palladium (II) and the complex (1:1) (24mg, 0.029mmol) of dichloromethane.By this mixture in argon gas atmosphere at 85 DEG C Lower heated overnight.After cooling, filter this mixture by Celite, wash filter cake with EtOAc.Concentrated filtrate, passes through silicagel column (0-10%EtOH/CH₂Cl₂) purification residue, obtain brown foam.LC-MS:526.2[M+1]⁺。

B) 4'-methyl-d3-N-((6-picoline-3-base) methyl)-5-(pyrrolidine-1-carbonyl) biphenyl-3-carboxylic acid amides

K ₃ PO ₄ Solution: to 2.0M K ₃PO₄Aqueous solution deaerates, and purges with argon.BorateSolution: by N-((6-methyl pyrrole Pyridine-3-base) methyl)-5-(pyrrolidine-1-carbonyl)-4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-base) Biphenyl-3-carboxylic acid amides (100mg, 0.19mmol) is dissolved in DMF (0.8mL).Deaerate to this solution, purge with argon.Catalyst is molten Liquid: will [1,1'-double (diphenylphosphino) ferrocene] dichloro palladium (II) with and the complex of dichloromethane (1:1) (10mg, 0.012mmol) it is substantially soluble in the N,N-dimethylformamide (5.0mL) of degassing.Deaerate to this solution, purge with argon.Reaction: At room temperature with in argon gas atmosphere, add in little reaction bulb 1mL orange-red catalyst solution (i.e. use 2mg catalyst) and Iodomethane-d3 (55mg, 0.38mmol).It is subsequently adding borate solution (0.19mmol), is subsequently adding 0.30mL2.0M K₃PO₄ Aqueous solution.The reactant mixture obtained is heated 20min in argon gas atmosphere, in 100 DEG C of oil baths.LC-MS display is without residue Borate.After cooling, reaction is made to stop with 1.0mL MeOH, the solution being filtrated to get, passes through preparation HPLC (100x20.2mm, C18 post；30-80%MeCN-water [10mM Et₂NH]；Flow velocity: 20mL/min) purification.

LC-MS:417.2[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.25 (t, 1H, J=6.0Hz), 8.44 (d, 1H, J=2.0Hz), 8.21 (t, 1H, J=1.6Hz), 7.94 (t, 1H, J=1.6Hz), 7.89 (t, 1H, J=1.6Hz), 7.67 (d, 2H, J=8.4Hz), 7.63 (dd, 1H, J=8.0,2.4Hz), 7.31 (d, 2H, J=8.4Hz), 7.22 (d, 1H, J= 8.0Hz), 4.48 (d, 2H, J=6.0Hz), 3.50 (t, 2H, J=6.8Hz), 3.42 (t, 2H, J=6.4Hz), 2.44 (s, 3H),1.93-1.78(m,4H)。

Compound 206

(S)-N-(2-hydroxyl-1-(6-methoxypyridine-3-base) ethyl)-4'-methyl-5-(methyl sulphonyl) biphenyl- 3-carboxylic acid amides

To 4'-methyl-5-(methyl sulphonyl) biphenyl-3-carboxylic acid (35mg, 0.12mmol), N-(3-dimethylamino third Base)-N'-ethyl-carbodiimide hydrochloride (46mg, 0.24mmol), I-hydroxybenzotriazole hydrate (18mg, 0.12mmol) And CH₂Cl₂(3mL) mixture adds (S)-2-amino-2-(6-methoxypyridine-3-base) ethanol (30mg, 0.18mmol) And N, N-diisopropylethylamine (42 μ L, 0.24mmol).This mixture is stirred at room temperature overnight, then concentrates.By preparation Type HPLC (100x20.2mm, C18 post；30-80%CH₃CN-water [10mM Et₂NH]) purification residue, obtain white foam.

LC-MS:440.9[M+1]⁺；¹H NMR(400MHz,CDCl₃):8.32(m,1H),8.27-8.23(m,3H),7.65 (dd, 1H, J=8.4,2.8Hz), 7.53 (d, 2H, J=8.4Hz), 7.30 (d, 2H, J=8.0Hz), 7.16 (d, 1H, J= 7.2Hz), 6.77 (d, 1H, J=8.8Hz), 5.26 (m, 1H), 4.11-4.00 (m, 2H), 3.93 (s, 3H), 3.13 (s, 3H), 2.42(s,3H)。

Compound 219

(R)-5-(Cyclopentylsulfonyl)-4'-methyl-N-(1-(2-methylpyrimidine-5-base) ethyl) biphenyl-3-carboxylic acid amides

A) the bromo-5-of 3-(ring penta sulfenyl) benzoic acid

At 0 DEG C to the sodium hydride (mineral oil solution of 60%, 0.82g, 20.5mmol) in salable flask and DMSO (15mL) stirring mixture is slowly added to cyclopentanethiol (1.23mL, 11.9mmol).This mixture is stirred at room temperature 30min, is subsequently adding 3, the 5-dibromobenzoic acid (2.5g, 8.9mmol) solution in DMSO (10mL).Seal this reactant System, is stirred overnight at 80 DEG C.After cooling, this reactant mixture is poured in water, adjusts to pH5-6 with 15%HCl (aqueous solution), Extract with EtOAc.The organic layer merged with saline washing, uses anhydrous MgSO₄It is dried, concentrates, obtain crude product, by it without entering One step purification reacts for next step.

B) the bromo-5-of 3-(ring penta sulfenyl) essence of Niobe

0 DEG C with chloroacetic chloride (3.87mL, 54.4mmol) process the bromo-5-of 3-(ring penta sulfenyl) benzoic acid (1.49g, 4.95mmol) the solution in methanol (40mL).It is heated to refluxing overnight by this reactant mixture, then concentrating under reduced pressure.Pass through Flash chromatography (0-20%EtOAc/ hexane) purification residue, obtains title compound, for colorless oil.

C) the bromo-5-of 3-(Cyclopentylsulfonyl) essence of Niobe

0 DEG C to the bromo-5-of 3-(ring penta sulfenyl) essence of Niobe (1.2g, 3.8mmol) in dichloromethane (20mL) In agitating solution, slow branch divides addition metachloroperbenzoic acid (70% purity, 2.35g, 9.52mmol).By slow for this mixture Warm to room temperature, be stirred overnight.Use Na₂CO₃Aqueous solution and saline wash this reactant mixture, use anhydrous MgSO₄It is dried, concentrates.Logical Cross silicagel column (EtOAc/ hexane) purification residue, obtain colorless oil.

D) 5-(Cyclopentylsulfonyl)-4'-methyl biphenyl-3-carboxylate methyl ester

3-bromo-5-(Cyclopentylsulfonyl) essence of Niobe (0.50g, 1.44mmol), p-first is added in microwave vial Molten in water (0.3mL) of phenylboric acid (0.44g, 3.25mmol), toluene (7mL) and cesium carbonate (1.06g, 3.26mmol) Liquid.Deaerate to bottle, purge with argon, be subsequently adding four (triphenyl phasphine) palladium (0) (0.16g, 0.14mmol).This reaction is mixed Thing carries out microwave irradiation 2h at 100 DEG C.After cooling, filter this mixture, filtrate is concentrated in vacuo.By flash column (0-25% EtOAc/ hexane) purification residue, obtain title compound, for colorless oil.

E) 5-(Cyclopentylsulfonyl)-4'-methyl biphenyl-3-carboxylic acid

To 5-(Cyclopentylsulfonyl)-4'-methyl biphenyl-3-carboxylate methyl ester (0.34g, 0.95mmol) at oxolane (15mL) solution in adds 2.5M lithium hydroxide aqueous solution (1.0mL, 2.5mmol).This reactant mixture is stirred at 60 DEG C Mix overnight.With 15%HCl (aqueous solution), this aqueous solution is acidified to pH=5, extracts with EtOAc.Merging organic is concentrated in vacuo Layer, obtains title compound, for white solid.

F) (R)-5-(Cyclopentylsulfonyl)-4'-methyl-N-(1-(2-methylpyrimidine-5-base) ethyl) biphenyl-3-carboxylic acyl Amine

To 5-(Cyclopentylsulfonyl)-4'-methyl biphenyl-3-carboxylic acid (50mg, 0.14mmol) at N, N-dimethyl formyl Solution in amine (1mL) adds (R)-1-(2-methylpyrimidine-5-base) ethamine (40mg, 0.29mmol), N, N, N ', N '-four Methyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (120mg, 0.32mmol) and N, N-diisopropylethylamine (140μL,0.80mmol).This reactant mixture is stirred 16 hours at 25 DEG C.Mixed by this reaction of preparation HPLC purification Thing, obtains end-product, for pale solid.

LC-MS:464.1[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.26 (d, 1H, J=7.4Hz), 8.75 (s, 2H), 8.47 (t, 1H, J=1.5Hz), 8.29 (t, 1H, J=1.5Hz), 8.21 (t, 1H, J=1.6Hz), 7.74 (d, 2H, J= 8.2Hz), 7.36 (d, 2H, J=8.0Hz), 5.22 (m, 1H), 3.99 (m, 1H), 2.60 (s, 3H), 2.38 (s, 3H), 2.00- 1.75 (m, 4H), 1.70-1.50 (m, 4H), 1.57 (d, 3H, J=7.1Hz).

Compound 220

3-(5-picoline-2-base)-N-((6-picoline-3-base) methyl)-5-(trifluoromethoxy) Benzoylamide

A) the bromo-N-of 3-((6-picoline-3-base) methyl)-5-(trifluoromethoxy) Benzoylamide

The bromo-3-of 1-iodo-5-(trifluoromethoxy) benzene (98mg, 0.27mmol), (6-methyl is added in 5mL microwave vial Pyridin-3-yl) methylamine (50mg, 0.41mmol), molybdenum hexacarbonyl (160mg, 0.61mmol), acid chloride (8mg, 0.036mmol), 1, 8-diazabicyclo [5.4.0] 11-7-alkene (120mg, 0.79mmol) and 1,4-bis-Alkane (2mL).In nitrogen atmosphere close Seal this bottle, this reaction system is carried out microwave irradiation 20 minutes at 120 DEG C.After cooling, by purified by flash chromatography, this mixes Compound, obtains expecting product, for white solid.LC-MS:391.2[M+1]⁺；¹H NMR(CDCl₃, 400MHz): 8.43 (d, J= 2.1Hz, 1H), 7.85 (t, J=1.5Hz, 1H), 7.63-7.61 (m, 2H), 7.52 (s, 1H), 7.16 (d, J=8.0Hz, 1H), 6.74 (Br, 1H), 4.60 (d, J=5.8Hz, 2H), 2.55 (s, 3H).

B) 3-(5-picoline-2-base)-N-((6-picoline-3-base) methyl)-5-(trifluoromethoxy) benzoyl Amine

By bromo-for 3-N-((6-picoline-3-base) methyl)-5-(trifluoromethoxy) Benzoylamide in argon gas atmosphere (60mg, 0.15mmol), 5-methyl-2-(tributylstamlyl) pyridine (0.1mL, 0.3mmol), four (triphenyl phasphine) palladium (0) The mixture of (20mg, 0.02mmol) and toluene (4mL) carries out microwave irradiation 2 hours at 120 DEG C.LC-MS shows the strong of raw material Peak.Deaerate to this mixture with nitrogen, apply microwave irradiation again 2 hours at 120 DEG C.This mixture is cooled to room temperature, vacuum Concentrate.By preparation HPLC (100x21.2mm C18 post, CH₃CN/ water [10mM Et₂NH]) purification residue, expected Product, for white solid.

LC-MS:401.7[M+1]⁺；¹H NMR (DMSO-d6,400MHz): 9.36 (t, J=5.8Hz, 1H), 8.60 (t, J =1.4Hz, 1H), 8.56 (d, J=2.2Hz, 1H), 8.45 (d, J=1.9Hz, 1H), 8.21 (s, 1H), 8.04 (d, J= 8.1Hz, 1H), 7.85 (s, 1H), 7.78 (dd, J=1.6,8.2Hz, 1H), 7.65 (dd, J=2.4,8.0Hz, 1H), 7.22 (d, J=8.0Hz, 1H), 4.49 (d, J=5.6Hz, 2H), 2.44 (s, 3H), 2.36 (s, 3H).

Compound 221

(S)-N-(2-hydroxyl-1-(2-methylpyrimidine-5-base) ethyl)-4'-methyl-5-(methyl sulphonyl) biphenyl-3- Carboxylic acid amides

To 4'-methyl-5-(methyl sulphonyl) biphenyl-3-carboxylic acid (35mg, 0.12mmol), N-(3-dimethylamino third Base)-N'-ethyl-carbodiimide hydrochloride (46mg, 0.24mmol), I-hydroxybenzotriazole hydrate (18mg, 0.12mmol) And CH₂Cl₂(3mL) mixture adds (S)-2-(t-butyldimethylsilyloxy base)-1-(2-methylpyrimidine-5-base) Ethamine (48mg, 0.18mmol) (WO2008/130481) and N, N-diisopropylethylamine (42 μ L, 0.24mmol).By this mixing Thing is stirred at room temperature overnight, and then concentrates.Residue is dissolved in MeOH (5mL), concentrates, add HCl solution (0.5mL).Should Mixture is stirred at room temperature 2h, is then concentrated in vacuo.By preparation HPLC (100x20.2mm, C18 post；30-80%MeCN- Water [10mM Et₂NH]) purification residue, obtain white solid.

LC-MS:426[M+1]⁺；¹H NMR(CDCl₃, 400MHz): 8.78 (s, 2H), 8.32 (t, 1H, J=1.6Hz), 8.30-8.25 (m, 2H), 7.53 (d, 2H, J=8.0Hz), 7.47 (d, 1H, J=7.2Hz), 7.29 (d, 2H, J=8.0Hz), 5.30 (m, 1H), 4.17 (dd, 1H, J=10.8,4.0Hz), 4.05 (dd, 1H, J=10.8,4.8Hz), 3.13 (s, 3H), 2.73(s,3H),2.41(s,3H)。

Compound 224

2-methyl-5-((4'-methyl-5-(pyrrolidine-1-carbonyl) biphenyl-3-base formamido group) methyl) pyridine 1-aoxidizes Thing

4'-methyl-N-((6-picoline-3-base) methyl)-5-(pyrrolidine-1-carbonyl is added in 20mL reaction bottle Base) biphenyl-3-carboxylic acid amides (30mg, 0.073mmol) and dichloromethane (1.0mL).This mixture is cooled to 0 DEG C, between dropping The aqueous solution of chlorine benzylhydroperoxide (70% purity, 28mg, 0.11mmol).This reactant mixture is stirred for 3hr, is subsequently adding Water.Use dichloromethane aqueous layer extracted, be dried the organic layer merged, concentrate.The solid obtained by preparation HPLC purification, is obtained Title compound.

LC-MS:429.6[M+1]⁺。

Compound 225

(R)-3-methoxyl group-5-(5-picoline-2-base)-N-(1-(2-methylpyrimidine-5-base) ethyl) Benzoylamide

A) 3-bromo-5-methoxybenzoic acid

3,5-dibromobenzoic acid (1.0g, 3.6mmol), the methanol solution of 4M Feldalat NM is added in 3-neck flask (1.2mL, 4.8mmol), N,N-dimethylformamide (1.2mL).By this mixture 110 DEG C of heating, it is subsequently adding protobromide Copper (I) (51mg, 0.36mmol).This mixture is stirred at 110 DEG C in 4 days.After cooling, this mixture is poured into 1N HCl/water Solution, adjusts to low pH, uses CH₂Cl₂Extraction.Use Na₂SO₄It is dried organic layer, is concentrated to dryness.By crude product without the purest Change and react for next step.LC-MS:231.2[M-1]^-。

B) 3-bromo-5-methoxyl methyl benzoate

0 DEG C to rough 3-bromo-5-methoxybenzoic acid (40% purity, 0.8g, 1.4mmol) at CH₂Cl₂(50mL) in Stirring mixture in add DMF (0.1mL) and chloroacetic chloride (0.2mL, 3mmol).This mixture is slowly to warm to rt, stirred Night.Then this mixture is cooled to 0 DEG C, is slowly added to methanol (2mL).This mixture is stirred 3h at rt, then uses Na₂CO₃ Aqueous solution, saline wash, and are dried (Na₂SO₄), concentrate.By purified by flash chromatography residue, obtain expecting product, for white Solid.¹H NMR(CDCl₃, 400MHz): 7.76 (t, J=1.6Hz, 1H), 7.49 (t, J=1.3Hz, 1H), 7.24 (t, J= 2.2Hz,1H),3.92(s,3H),3.84(s,3H)。

C) 3-methoxyl group-5-(5-picoline-2-base) essence of Niobe

By bromo-for 3-5-methoxyl methyl benzoate (0.1g, 0.4mmol), 5-methyl-2-(tributyl in argon gas atmosphere Stannyl) pyridine (0.1mL, 0.3mmol), four (triphenyl phasphine) palladium (0) (20mg, 0.02mmol) and the mixing of toluene (4mL) Thing carries out microwave irradiation 2 hours at 120 DEG C.This mixture is cooled to room temperature, by purified by flash chromatography, obtains expectation and produce Thing, for pale yellow oil.LC-MS:257.9[M+1]⁺。

D) 3-methoxyl group-5-(5-picoline-2-base) benzoic acid

3-methoxyl group-5-(5-picoline-2-base) essence of Niobe (80mg, 0.2mmol), eight water are added in flask Close barium hydroxide (300mg, 0.95mmol) and methanol (10mL).This mixture is stirred at room temperature overnight.Add 2N HCl (second Ethereal solution, 30mL), decompression removes volatile material.LC-MS:244.1[M+1]⁺。

E) (R)-3-methoxyl group-5-(5-picoline-2-base)-N-(1-(2-methylpyrimidine-5-base) ethyl) benzoyl Amine

In round-bottomed flask add 3-methoxyl group-5-(5-picoline-2-base) benzoic acid (26mg, 0.11mmol), (R)-1-(2-methylpyrimidine-5-base) ethamine (29mg, 0.21mmol), N-(3-dimethylaminopropyl)-N'-ethyl carbon two Asia Amine hydrochlorate (41mg, 0.21mmol), I-hydroxybenzotriazole hydrate (33mg, 0.21mmol), triethylamine (22mg, 0.21mmol) with dichloromethane (3mL).This mixture is stirred at room temperature overnight, then concentrates.Pass through preparation HPLC (100x21.2mm C18 post, CH₃CN/ water [10mM Et₂NH]) purification residue, obtain expecting product, for white solid.

LC-MS:363.1[M+1]⁺；¹H NMR(400MHz,CD₃OD):8.65(s,1H),8.60(s,1H),8.38(d,J =1.9Hz, 1H), 7.87 (t, J=1.5Hz, 1H), 7.72 (d, J=8.1Hz, 1H), 7.65 (dd, J=1.6,8.1Hz, 1H), 7.58 (dd, J=1.6,2.4Hz, 1H), 7.34 (dd, J=1.6,2.4Hz, 1H), 5.17 (q, J=7.1Hz, 1H), 3.82 (s, 3H), 2.57 (s, 3H), 2.31 (s, 3H), 1.55 (d, J=7.1Hz, 3H).

Compound 227

5-(hydroxyl (phenyl) methyl)-4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl) biphenyl-3-carboxylic acyl Amine

A) 5-(hydroxymethyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester

In nitrogen atmosphere, at 0 DEG C to 5-(ethoxy carbonyl)-4'-methyl biphenyl-3-carboxylic acid (2.66g, 8.89mmol) in the agitating solution in anhydrous tetrahydro furan (40mL) add 1M borine tetrahydrofuran solution (20mL, 20mmol).After having added, this reaction system is stirred 30 minutes at 0 DEG C, then remove cooling bath.It is stirred at room temperature 2 hours After, by this reactant mixture 0 DEG C of cooling, by adding 2M HCl/water solution (30mL) quencher.This mixture is stirred in room temperature Mix 1 hour, then extract with EtOAc (50mL x3).The organic layer merged with saline washing, uses anhydrous MgSO₄It is dried, filters, Concentrate.By silica column purification residue, obtain title compound.

B) 5-formoxyl-4'-methyl biphenyl-3-carboxylic acid, ethyl ester

By 5-(hydroxymethyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester (400mg, 1.5mmol) and manganese oxide (IV) (660mg, 6.6mmol) mixture in dichloromethane (14mL) is stirred at room temperature overnight.This reactant mixture is passed through Celite filters, and washs with dichloromethane.Concentrated filtrate, obtains title compound.

C) 5-(hydroxyl (phenyl) methyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester

At 0 DEG C, phenyl-magnesium-bromide (850mg, 4.7mmol) joined 5-formoxyl-4'-methyl biphenyl-3-carboxylic acid, ethyl ester In (360mg, 1.3mmol) solution in oxolane (8mL).This reactant mixture is stirred at room temperature 3h, is subsequently adding Water (10mL).This mixture is extracted with EtOAc (20mLx2).Use anhydrous MgSO₄It is dried the organic layer merged, concentrates.Pass through silicon The column chromatography eluting residue of glue, obtains title compound.

D) 5-(hydroxyl (phenyl) methyl)-4'-methyl biphenyl-3-carboxylic acid

To 5-(hydroxyl (phenyl) methyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester (230mg, 0.66mmol) at 1,4-bis-Solution in alkane (2mL) and water (1mL) adds Lithium hydrate (48mg, 2mmol).This reactant mixture is stirred at 60 DEG C Mix overnight.After cooling, with 15%HCl (aqueous solution), this mixture is acidified to pH=5, extracts with EtOAc.It is dried organic layer, It is concentrated in vacuo, obtains title compound, for white solid.¹H NMR (300MHz, acetone-d6): 8.14 (t, 1H, J= 2.0Hz),8.09(m,1H),7.97(m,1H),7.60-7.47(m,4H),7.37-7.19(m,5H),6.00(s,1H),2.37 (s,3H)。

E) 5-(hydroxyl (phenyl) methyl)-4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl) biphenyl-3-carboxylic Amide

To 5-(hydroxyl (phenyl) methyl)-4'-methyl biphenyl-3-carboxylic acid (50mg, 0.16mmol) at N, N-dimethyl methyl Solution in amide (1mL) adds (R)-1-(6-picoline-3-base) ethylamine dihydrochloride (70mg, 0.34mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (120mg, 0.32mmol) and N, N-bis-are different Propylethylamine (500 μ L, 2.87mmol).This reactant mixture is stirred 16 hours at 30 DEG C.Pass through preparation HPLC (100x21.2mm C18 post, CH₃CN/ water [10mM Et₂NH]) this reactant mixture of purification, obtain pale solid.

LC-MS:437.2[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 8.92 (d, 1H, J=7.8Hz), 8.47 (d, 1H, J=2.1Hz), 7.98 (bs, 1H), 7.83 (bs, 1H), 7.79 (bs, 1H), 7.67 (dd, 1H, J=8.0,2.2Hz), 7.59 (d, 2H, J=8.1Hz), 7.42 (d, 2H, J=7.3Hz0,7.35-7.25 (m, 4H), 7.23-7.15 (m, 2H), 6.04 (m, 1H), 5.82 (d, 1H, J=4.0Hz), 5.17 (m, 1H), 2.43 (s, 3H), 2.35 (s, 3H), 1.50 (d, 3H, J= 7.1Hz)。

Compound 229

(R)-5-benzoyl-4'-methyl-N-(1-(6-picoline-3-base) ethyl) biphenyl-3-carboxylic acid amides

To 5-(hydroxyl (phenyl) methyl)-4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl) biphenyl-3-carboxylic The amide (20mg, 0.04mmol) solution in dichloromethane (2.0mL) adds Dess-Martin periodinane (26mg,0.061mmol).Being stirred 2 hours at 40 DEG C by this reactant mixture, LC-MS display reaction completes.Use CH₂Cl₂Dilution Reaction solution, uses 10%Na₂S₂O₃, saturated NaHSO₃Aqueous solution and saline washing.Use anhydrous MgSO₄It is dried organic layer, concentrates.Logical Cross silica column purification residue, obtain white solid.

LC-MS:435.3[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.13 (d, 1H, J=7.7Hz), 8.48 (d, 1H, J=2.2Hz), 8.42 (t, 1H, J=1.5Hz), 8.16 (bs, 1H), 8.06 (t, 1H, J=1.5Hz), 7.85-7.55 (m, 8H), 7.33 (d, 2H, J=8.1Hz), 7.21 (d, 1H, J=8.0Hz), 5.20 (m, 1H), 2.43 (s, 3H), 2.37 (s, 3H), 1.52 (d, 3H, J=7.1Hz).

Compound 232

(R)-4'-methyl-N-(1-(6-picoline-3-base) ethyl)-5-(pyrimidine-2-yloxy) biphenyl-3-carboxylic acyl Amine

A) 3-bromo-5-hydroxy-benzoic acid methyl ester

0 DEG C to 3-bromo-5-hydroxy benzoic acid (3.41g, 15mmol) (J.Chem.Soc.1955,463) at absolute methanol (80mL) solution in adds chloroacetic chloride (2.56mL, 36mmol).Then by this mixture heated overnight at reflux. Volatiles removed in vacuo, obtains title compound.

B) 5-hydroxyl-4'-methyl biphenyl-3-carboxylate methyl ester

Room temperature to 3-bromo-5-hydroxy-benzoic acid methyl ester (4.09g, 17.7mmol) and p-tolyl boric acid (2.86g, Agitating solution in toluene (36mL) 21mmol) adds water (3.6mL) solution of cesium carbonate (7.14g, 22mmol).Use nitrogen This mixture is swept in air-blowing, adds four (triphenyl phasphine) palladium (0) (1.05g, 0.906mmol).This reactant mixture is carried out at 110 DEG C Microwave irradiation 1 hour.After cooling, filter this mixture, concentrated filtrate by Celite.Remaining by purified by flash chromatography Thing, obtains title compound.

C) 4'-methyl-5-(pyrimidine-2-yloxy) biphenyl-3-carboxylate methyl ester

At 0 DEG C, within 10 minute time limit, to 5-hydroxyl-4'-methyl biphenyl-3-carboxylate methyl ester (300mg, 1.24mmol) Agitating solution in oxolane (20mL) adds sodium hydride (60% mineral oil solution, 55mg, 1.37mmol).This is anti- Answer mixture to be concentrated into and obtain green solid.Green solid, dimethyl sulfoxide (8mL) and the 2-chlorine obtained is added in microwave vial Pyrimidine (118mg, 0.98mmol).This mixture is carried out microwave irradiation 4 minutes at 100 DEG C.After cooling, filtered by Celite This mixture, concentrated filtrate.By purified by flash chromatography residue, obtain title compound.

D) 4'-methyl-5-(pyrimidine-2-yloxy) biphenyl-3-carboxylic acid

To 4'-methyl-5-(pyrimidine-2-yloxy) biphenyl-3-carboxylate methyl ester (60mg, 0.19mmol) at oxolane (3mL) agitating solution in adds 2.5M lithium hydroxide aqueous solution (0.77mL, 1.9mmol).This mixture is stirred in room temperature Mix overnight, be then acidified to pH=5 by interpolation 2N HCl/water solution, extract with EtOAc (50mL).Separate organic layer, use sulfur Acid sodium is dried, and filters, is concentrated into and obtains title product.¹H NMR(CD₃OD, 400MHz): 8.63 (d, 2H, J=4.8Hz), 8.16 (t, 1H, J=1.6Hz), 7.74 (t, 1H, J=2.0Hz), 7.65 (t, 1H, J=2.0Hz), 7.56 (d, 2H, J=8.0Hz), 7.29 (d, 2H, J=8.0Hz), 7.24 (t, 1H, J=4.8Hz), 2.39 (s, 3H).

E) (R)-4'-methyl-N-(1-(6-picoline-3-base) ethyl)-5-(pyrimidine-2-yloxy) biphenyl-3-carboxylic Amide

To 4'-methyl-5-(pyrimidine-2-yloxy) biphenyl-3-carboxylic acid (20mg, 0.065mmol) at N, N-dimethyl methyl Solution in amide (1mL) adds (R)-1-(6-picoline-3-base) ethylamine dihydrochloride (30mg, 0.143mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (60mg, 0.16mmol) and N, N-diisopropyl Base ethamine (200 μ L, 1.15mmol).This reactant mixture is stirred at room temperature 16 hours.LC-MS display reaction completes.Pass through Preparation HPLC (100x21.2mm C18 post, CH₃CN/ water [10mMEt₂NH]) this reactant mixture of purification, obtain pale solid.

LC-MS:425.1[M+1]⁺；¹H NMR (DMSO-d6,400MHz): 8.97 (d, 1H, J=7.8Hz), 8.67 (d, 2H, J=4.8Hz), 8.47 (d, 1H, J=2.2Hz), 8.06 (t, 1H, J=1.4Hz), 7.70-7.62 (m, 5H), 7.32- 7.25 (m, 3H), 7.21 (d, 1H, J=8.0Hz), 5.18 (m, 1H), 2.43 (s, 3H), 2.36 (s, 3H), 1.51 (d, 3H, J= 7.1Hz)。

Compound 236

(R)-4'-methyl-N-(1-(2-methylpyrimidine-5-base) ethyl)-5-(thiazol-2-yl epoxide) biphenyl-3-carboxylic acyl Amine

A) 4'-methyl-5-(thiazol-2-yl epoxide) biphenyl-3-carboxylate methyl ester

By 5-hydroxyl-4'-methyl biphenyl-3-carboxylate methyl ester (100mg, 0.41mmol), potassium carbonate (114mg, 0.83mmol), the mixture of 2-bromo thiazole (0.38mL, 4.2mmol) and dimethyl sulfoxide (2.5mL) is stirred overnight at 135 DEG C.Cold But, after, dilute this mixture with EtOAc, use NaHCO₃Aqueous solution (saturated) washs, and uses anhydrous MgSO₄It is dried, concentrates.By soon Speed chromatography (0-20%EtOAc/ hexane) purification residue, obtains title compound.

B) 4'-methyl-5-(thiazol-2-yl epoxide) biphenyl-3-carboxylic acid

To 4'-methyl-5-(thiazol-2-yl epoxide) biphenyl-3-carboxylate methyl ester (560mg, 1.6mmol) at oxolane (20mL) agitating solution in adds 2.5M lithium hydroxide aqueous solution (6.7mL, 17mmol).After being stirred at room temperature overnight, logical Cross interpolation 2N HCl/water solution and this mixture is acidified to pH=5, extract with EtOAc.It is dried organic layer with sodium sulfate, is concentrated into Obtain title product.¹H NMR(CD₃OD, 400MHz): 8.18 (t, 1H, J=1.6Hz), 7.82 (dd, 1H, J=2.4, 1.2Hz), 7.74 (t, 1H, J=2.0Hz), 7.57 (d, 2H, J=8.0Hz), 7.30 (d, 2H, J=8.4Hz), 7.28 (d, 1H, J=4.0Hz), 7.13 (d, 1H, J=4.0Hz), 2.39 (s, 3H).

C) (R)-4'-methyl-N-(1-(2-methylpyrimidine-5-base) ethyl)-5-(thiazol-2-yl epoxide) biphenyl-3-carboxylic Amide

To 4'-methyl-5-(thiazol-2-yl epoxide) biphenyl-3-carboxylic acid (50mg, 0.16mmol) at N, N-dimethyl formyl Solution in amine (1mL) adds (R)-1-(2-methylpyrimidine-5-base) ethamine (45mg, 0.33mmol), N, N, N ', N '-four Methyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (150mg, 0.39mmol) and N, N-diisopropylethylamine (200μL,1.15mmol).This reactant mixture is stirred at room temperature 16 hours.LC-MS display reaction completes.Pass through preparative HPLC (100x21.2mm C18 post, CH₃CN/ water [10mM Et₂NH]) this reactant mixture of purification, obtain pale solid.

LC-MS:431.2[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.07 (d, 1H, J=7.4Hz), 8.73 (s, 2H), 8.10 (t, 1H, J=1.4Hz), 7.82 (t, 1H, J=2.0Hz), 7.76 (t, 1H, J=1.5Hz), 7.68 (d, 2H, J= 8.2Hz), 7.35-7.25 (m, 4H), 5.18 (m, 1H), 2.59 (s, 3H), 2.36 (s, 3H), 1.55 (d, 3H, J=7.1Hz).

Compound 240

5-(hydroxyl (pyridine-2-base) methyl)-4'-methyl-N-((6-picoline-3-base) methyl) biphenyl-3-carboxylic acyl Amine

A) 5-(hydroxyl (pyridine-2-base) methyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester

In nitrogen atmosphere, at 60 DEG C, by with 2-bromopyridine (600mg, 3.8mmol) and iodine (30mg) at tetrahydrochysene furan The solution in (5mL) of muttering processes magnesium (100mg, 4.3mmol) and generates Grignard reagent in 1 hour.Cool down this mixture at 0 DEG C, add Enter 5-formoxyl-4'-methyl biphenyl-3-carboxylic acid, ethyl ester (332mg, 1.24mmol).This reactant mixture is stirred 2h at 0 DEG C, Then by adding 3mL2N H₂SO₄Aqueous solution quencher.This mixture is extracted with EtOAc (20mL x2).Water-soluble with 1N NaOH The organic layer that the washing of liquid, saline merges, uses anhydrous MgSO₄It is dried, filters, concentrate.Residue is carried out chromatography, obtains Huang Color grease.

B) 5-(Hydroxy-pyridine-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid

5-(hydroxyl (pyridine-2-base) methyl)-4'-methyl biphenyl-3-carboxylic acid, ethyl ester (319mg, 0.92mmol) is dissolved in 1,4-bis-Alkane (6mL) and water (0.3mL).Lithium hydrate (120mg, 5.0mmol) is added in the solution of stirring, this is anti- Answer mixture to be stirred at room temperature to reaction to complete.Cool down this mixture, use 2N H₂SO₄Aqueous solution is acidified to pH5-6, uses EtOAc (20mL x3) extracts.The organic layer merged with saline washing, is dried (MgSO₄), it is concentrated into and obtains faint yellow solid.¹H NMR (400MHz,CD₃OD): 8.47 (m, 1H), 8.13 (t, 1H, J=1.6Hz), 8.02 (t, 1H, J=1.6Hz), 7.91 (t, 1H, J =1.6Hz), 7.87 (td, 1H, J=7.6,1.6Hz), 7.71 (d, 1H, J=8.0Hz), 7.51 (d, 2H, J=8.0Hz), 7.31 (ddd, 1H, J=7.6,5.2,1.2Hz), 7.27 (d, 2H, J=8.0Hz), 5.93 (s, 1H), 2.37 (s, 3H).

C) 5-(hydroxyl (pyridine-2-base) methyl)-4'-methyl-N-((6-picoline-3-base) methyl) biphenyl-3-carboxylic Amide

To 5-(Hydroxy-pyridine-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid (35mg, 0.11mmol) at N, N-bis- Solution in methylformamide (1mL) adds (6-picoline-3-base) methylamine (40mg, 0.33mmol), N, N, N ', N '- Tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (100mg, 0.26mmol) and N, N-diisopropylethylamine (100μL,0.57mmol).This reactant mixture is stirred 16 hours at 25 DEG C.By preparation HPLC (100x21.2mm C18 Post, CH₃CN/ water [10mM Et₂NH]) this reactant mixture of purification, obtain pale solid.

LC-MS:424.1[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.15 (t, 1H, J=5.5Hz), 8.46 (d, 1H, J=4.0Hz), 8.41 (bs, 1H), 7.99 (bs, 1H), 7.88 (bs, 1H), 7.83 (bs, 1H), 7.79 (t, 1H, J= 7.8Hz), 7.65-7.55 (m, 4H), 7.30 (d, 2H, J=7.6Hz), 7.22 (m, 2H), 6.26 (bs, 1H), 5.83 (bs, 1H), 4.45 (d, 2H, J=5.4Hz), 2.43 (s, 3H), 2.35 (s, 3H).

Compound 241

5-(hydroxyl (pyridine-2-base) methyl)-4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl) biphenyl- 3-carboxylic acid amides

To 5-(Hydroxy-pyridine-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid (25mg, 0.078mmol) at N, N-bis- In solution in methylformamide (1mL) add (R)-1-(6-picoline-3-base) ethylamine dihydrochloride (35mg, 0.17mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (50mg, 0.13mmol) And N, N-diisopropylethylamine (200 μ L, 1.15mmol).This reactant mixture is stirred 16 hours at 25 DEG C, then by system Standby type HPLC (100x21.2mm C18 post, CH₃CN/ water [10mM Et₂NH]) purification, obtain pale solid.

LC-MS:438.1[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 8.92 (d, 1H, J=7.8Hz), 8.45 (bs, 2H), 7.98 (bs, 1H), 7.85 (bs, 1H), 7.81 (bs, 1H), 7.79 (t, 1H, J=7.2Hz), 7.70-7.55 (m, 4H), 7.30 (d, 2H, J=8.0Hz), 7.22 (m, 2H), 6.25 (bs, 1H), 5.83 (s, 1H), 5.20-5.10 (m, 1H), 2.43 (s, 3H), 2.35 (s, 3H), 1.50 (d, 3H, J=7.1Hz).

Compound 242

(R)-4'-methyl-N-(1-(6-picoline-3-base) ethyl)-5-(pyridine-2-base epoxide) biphenyl-3-carboxylic acyl Amine

A) 4'-methyl-5-(pyridine-2-base epoxide) biphenyl-3-carboxylate methyl ester

By 5-hydroxyl-4'-methyl biphenyl-3-carboxylate methyl ester (100mg, 0.41mmol), potassium carbonate (100mg, 0.72mmol), the mixture of 2-bromopyridine (0.40mL, 4.2mmol) and dimethyl sulfoxide (2mL) is stirred overnight at 135 DEG C.Cooling After, dilute this mixture with EtOAc, use NaHCO₃Aqueous solution (saturated) washs, and uses anhydrous MgSO₄It is dried, filters, concentrate.Pass through Flash chromatography (0-20%EtOAc/ hexane) purification residue, obtains title compound.

B) 4'-methyl-5-(pyridine-2-base epoxide) biphenyl-3-carboxylic acid

To 4'-methyl-5-(pyridine-2-base epoxide) biphenyl-3-carboxylate methyl ester (460mg, 1.4mmol) at oxolane (20mL) agitating solution in adds 2.5M lithium hydroxide aqueous solution (5.6mL, 14mmol).After being stirred at room temperature overnight, logical Cross interpolation 2N HCl/water solution and this mixture is acidified to pH=5, extract with EtOAc.It is dried organic layer with sodium sulfate, filters, Concentrate, obtain title compound.¹H NMR(CD₃OD, 300MHz): 8.17 (d, 1H, J=3.2Hz), 8.11 (s, 1H), 7.88 (td, 1H, J=8.0,2.0Hz), 7.65 (s, 1H), 7.58-7.52 (m, 3H), 7.29 (d, 2H, J=8.4Hz), 7.16 (dd, 1H, J=7.2,4.8Hz), 7.06 (d, 1H, J=8.0Hz), 2.38 (s, 3H).

C) (R)-4'-methyl-N-(1-(6-picoline-3-base) ethyl)-5-(pyridine-2-base epoxide) biphenyl-3-carboxylic Amide

To 4'-methyl-5-(pyridine-2-base epoxide) biphenyl-3-carboxylic acid (50mg, 0.16mmol) at N, N-dimethyl formyl Solution in amine (1mL) adds (R)-1-(6-picoline-3-base) ethylamine dihydrochloride (70mg, 0.34mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (150mg, 0.39mmol) and N, N-diisopropyl Base ethamine (400 μ L, 2.30mmol).This reactant mixture is stirred 16 hours at 25 DEG C, then by preparation HPLC purification, Obtain end-product, for pale solid.

LC-MS:424.0[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 8.97 (d, 1H, J=7.7Hz), 8.47 (bs, 1H), 8.15 (d, 1H, J=4.2Hz), 8.02 (bs, 1H), 7.89 (t, 1H, J=8.5Hz), 7.70-7.60 (m, 3H), 7.57 (bs, 2H), 7.30 (d, 2H, J=8.0Hz), 7.25-7.05 (m, 3H), 5.18 (m, 1H), 2.43 (s, 3H), 2.35 (s, 3H), 1.51 (d, 3H, J=7.1Hz).

Compound 248

5-(2-methoxy ethoxy)-4'-methyl-N-((6-picoline-3-base) methyl) biphenyl-3-carboxylic acid amides

A) 5-(2-methoxy ethoxy)-4'-methyl biphenyl-3-carboxylate methyl ester

By 5-hydroxyl-4'-methyl biphenyl-3-carboxylate methyl ester (400mg, 1.65mmol), 1-bromo-2-Ethyl Methyl Ether The mixture of (436mg, 3.14mmol), potassium carbonate (434mg, 3.14mmol) and dimethyl sulfoxide (5mL) is stirred at 135 DEG C Night.After cooling, dilute this mixture with EtOAc, use NaHCO₃Aqueous solution (saturated) washs, and uses anhydrous MgSO₄It is dried, filters, dense Contracting.By flash chromatography (0-100%EtOAc/ hexane) purification residue, obtain title compound.

B) 5-(2-methoxy ethoxy)-4'-methyl biphenyl-3-carboxylic acid

To 5-(2-methoxy ethoxy)-4'-methyl biphenyl-3-carboxylate methyl ester (703mg, 2.34mmol) at oxolane (40mL) agitating solution in adds 2.5M lithium hydroxide aqueous solution (9.6mL, 24mmol).After being stirred at room temperature overnight, logical Cross interpolation 2N HCl and this mixture is acidified to pH=5, extract with EtOAc.It is dried organic layer (Na₂SO₄), concentrate, obtain title Compound.¹H NMR(CD₃OD, 400MHz): 7.84 (t, 1H, J=1.6Hz), 7.55-7.51 (m, 3H), 7.34 (t, 1H, J= 2.0Hz), 7.27 (d, 2H, J=8.0Hz), 4.22 (m, 2H), 3.79 (m, 2H), 3.45 (s, 3H), 2.38 (s, 3H).

C) 5-(2-methoxy ethoxy)-4'-methyl-N-((6-picoline-3-base) methyl) biphenyl-3-carboxylic acid amides

To 5-(2-methoxy ethoxy)-4'-methyl biphenyl-3-carboxylic acid (50mg, 0.18mmol) at N, N-dimethyl methyl Solution in amide (1mL) adds (6-picoline-3-base) methylamine (45mg, 0.37mmol), N, N, N ', N '-tetramethyl- O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (150mg, 0.39mmol) and N, N-diisopropylethylamine (150 μ L, 0.86mmol).This reactant mixture is stirred 16 hours at 25 DEG C.LC-MS display reaction completes.By preparation HPLC purification This reactant mixture, obtains title product.

LC-MS:391.5[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.13 (t, 1H, J=5.8Hz), 8.42 (d, 1H, J=2.0Hz), 7.74 (bs, 1H), 7.66-7.60 (m, 3H), 7.40 (bs, 1H), 7.34 (bs, 1H), 7.29 (d, 2H, J =8.0Hz), 7.22 (d, 1H, J=8.0Hz), 4.47 (d, 2H, J=5.8Hz), 4.22 (t, 2H, J=4.4Hz), 3.69 (t, 2H, J=4.4Hz), 3.32 (s, 3H), 2.44 (s, 3H), 2.35 (s, 3H).

Compound 254

(R)-2'-cyano group-4'-methyl-N-(1-(2-methylpyrimidine-5-base) ethyl)-5-(thiazol-2-yl epoxide) connection Benzene-3-carboxylic acid amides

A) 2'-cyano group-5-hydroxyl-4'-methyl biphenyl-3-carboxylate methyl ester

In nitrogen atmosphere, in flask, add 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxane penta boron Alkane-2-base) benzonitrile (2.1g, 8.2mmol), 3-bromo-5-hydroxy-benzoic acid methyl ester (1.5g, 6.2mmol), potassium phosphate (2.8g, 13mmol), four (triphenyl phasphine) palladium (0) (400mg, 0.35mmol), 1,4-bis-Alkane (90mL) and water (20mL).By this reaction Mixture is stirred overnight at 85 DEG C.After cooling, filter this mixture by Celite, wash filter cake with EtOAc.Concentrated filtrate, By silica column purification residue, obtain title compound.

B) 2'-cyano group-4'-methyl-5-(thiazol-2-yl epoxide) biphenyl-3-carboxylate methyl ester

By 2'-cyano group-5-hydroxyl-4'-methyl biphenyl-3-carboxylate methyl ester (350mg, 1.2mmol), potassium carbonate (363mg, 2.63mmol), the stirring mixture of 2-bromo thiazole (431mg, 2.63mmol) and dimethyl sulfoxide (10mL) is heated at 135 DEG C Night.After cooling, dilute this reactant mixture with EtOAc.Use NaHCO₃Aqueous solution (saturated) washing organic facies, uses anhydrous MgSO₄Dry Dry, filter, concentrate.By purified by flash chromatography residue, obtain title compound.

C) 2'-cyano group-4'-methyl-5-(thiazol-2-yl epoxide) biphenyl-3-carboxylic acid

Exist to 2'-cyano group-4'-methyl-5-(thiazol-2-yl epoxide) biphenyl-3-carboxylate methyl ester (112mg, 0.32mmol) Solution in oxolane (2mL) adds 2.5M lithium hydroxide aqueous solution (0.72mL, 1.8mmol).By this reactant mixture It is stirred overnight at 60 DEG C.With 15%HCl (aqueous solution), this aqueous solution is acidified to pH=5, extracts with EtOAc.Conjunction is concentrated in vacuo And organic layer, obtain title compound, for white solid.

D) (R)-2'-cyano group-4'-methyl-N-(1-(2-methylpyrimidine-5-base) ethyl)-5-(thiazol-2-yl epoxide) connection Benzene-3-carboxylic acid amides

To 2'-cyano group-4'-methyl-5-(thiazol-2-yl epoxide) biphenyl-3-carboxylic acid (30mg, 0.089mmol) at N, N- Solution in dimethylformamide (1mL) adds (R)-1-(2-methylpyrimidine-5-base) ethamine (30mg, 0.22mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (100mg, 0.26mmol) and N, N-bis-are different Propylethylamine (100 μ L, 0.57mmol).This reactant mixture is stirred 16 hours at 25 DEG C, then pure by preparation HPLC Change, obtain brown solid.

LC-MS:455.9[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.07 (d, 1H, J=7.4Hz), 8.71 (s, 2H), 8.00 (bs, 1H), 7.94 (t, 1H, J=1.8Hz), 7.83 (bs, 1H), 7.76 (t, 1H, J=1.8Hz), 7.68-7.60 (m, 2H), 7.32 and 7.30 (AB, 2H, J=3.7Hz), 5.17 (m, 1H), 2.59 (s, 3H), 2.41 (s, 3H), 1.53 (d, 3H, J=7.1Hz).

Compound 256

2-methyl-5-((4'-methyl-5-(methyl sulphonyl) biphenyl-3-base formamido group) methyl) pyridine 1-oxide

4'-methyl-N-((6-picoline-3-base) methyl)-5-(methyl sulphonyl) is added in 20mL reaction bottle Biphenyl-3-carboxylic acid amides (40mg, 0.10mmol), metachloroperbenzoic acid (70% purity, 52mg, 0.21mmol), dichloromethane (3mL) with water (1mL).This reactant mixture is stirred at room temperature 12h.Add saturated sodium bicarbonate aqueous solution, separate each layer.With Sodium sulfate is dried organic layer, is concentrated in vacuo.Grease (0-10% methanol/the dichloromethane obtained by purified by flash chromatography Alkane), obtain title compound, for white solid.

LC-MS:411.2[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.5 (t, 1H, J=5.8Hz), 8.47 (t, 1H, J=1.5Hz), 8.34 (t, 1H, J=1.5Hz), 8.29 (t, 1H, J=1.5Hz), 8.27 (s, 1H), 7.75 (d, 2H, J= 8.1Hz), 7.49 (d, 1H, J=8.1Hz), 7.36 (d, 2H, J=8.1Hz), 7.26 (d, 1H, J=8.5Hz), 4.89 (d, 2H, J=5.8Hz), 3.37 (s, 3H), 2.82 (s, 3H), 2.32 (s, 3H).

Compound 257

(S)-N-(2-hydroxyl-1-(6-picoline-3-base) ethyl)-4'-methyl-5-(methyl sulphonyl) biphenyl-3- Carboxylic acid amides

To 4'-methyl-5-(methyl sulphonyl) biphenyl-3-carboxylic acid (37mg, 0.12mmol) at N,N-dimethylformamide (1mL) solution in adds (S)-2-(t-butyldimethylsilyloxy base)-1-(6-picoline-3-base) ethamine (80mg, 0.27mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (120mg, 0.32mmol) and N, N-diisopropylethylamine (120 μ L, 0.69mmol).This reactant mixture is stirred 16 hours at 25 DEG C. LC-MS display reaction completes.MeOH (2mL) and 12N HCl/water solution (0.5mL) is added in this reactant mixture.This is mixed Compound stirs 2hr at rt, is then concentrated in vacuo.By preparation HPLC (100x21.2mm C18 post, MeCN-water [10mM Et₂NH]) purification residue, obtain end-product, for pale solid.

LC-MS:425[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.16 (d, 1H, J=8.0Hz), 8.49 (d, 1H, J =2.1Hz), 8.47 (t, 1H, J=1.6Hz), 8.35 (t, 1H, J=1.6Hz), 8.28 (t, 1H, J=1.6Hz), 7.75 (d, 2H, J=8.2Hz), 7.71 (dd, 1H, J=8.0,2.2Hz), 7.37 (d, 2H, J=8.0Hz), 7.22 (d, 1H J= 8.0Hz),5.20-5.05(m,2H),3.85-3.65(m,2H),3.35(s,3H),2.44(s,3H),2.39(s,3H)。

Compound 264

(R)-3-(5-picoline-2-base)-N-(1-(6-picoline-3-base) ethyl)-5-(thiazol-2-yl epoxide) Benzoylamide

A) 3-hydroxyl-5-(5-picoline-2-base) essence of Niobe

By bromo-for 3-5-hydroxy-benzoic acid methyl ester (1.47g, 6.36mmol), 5-methyl-2-(tributylstamlyl) pyrrole Pyridine (3.0g, 7.85mmol), four (triphenyl phasphine)-palladiums (0) (300mg, 0.26mmol) are in toluene (20mL) and DMF (2mL) Mixture carries out microwave irradiation 1 hour at 110 DEG C.After cooling, this mixture of dilute with water, extract with EtOAc.With anhydrous MgSO₄It is dried the organic layer merged, is concentrated in vacuo.By purified by flash chromatography residue, obtain title compound, for white Solid.

B) 3-(5-picoline-2-base)-5-(thiazol-2-yl epoxide) essence of Niobe

By 3-hydroxyl-5-(5-picoline-2-base) essence of Niobe (290mg, 1.2mmol), 2-bromo thiazole (410mg, 2.5mmol), the stirring mixture of potassium carbonate (346mg, 2.5mmol) and dimethyl sulfoxide (5mL) is 135 DEG C of heated overnight.Then This reactant mixture is cooled to room temperature, dilutes with EtOAc.Use NaHCO₃Aqueous solution (saturated) washing organic facies, with anhydrous MgSO₄It is dried, filters, concentrate.By flash chromatography (0-30%EtOAc/ hexane) purification residue, obtain title compound Thing.

C) 3-(5-picoline-2-base)-5-(thiazol-2-yl epoxide) benzoic acid

To 3-(5-picoline-2-base)-5-(thiazol-2-yl epoxide) essence of Niobe (240mg, 0.74mmol) four Solution in hydrogen furan (6mL) adds 2.5M lithium hydroxide aqueous solution (1.6mL, 4.1mmol).By this reactant mixture 60 DEG C it is stirred overnight.With 15%HCl (aqueous solution), this aqueous solution is acidified to pH=5-6, extracts with EtOAc.Merging is concentrated in vacuo Organic layer, obtain title compound, for white solid.¹H NMR(CDCl₃,400MHz):8.77(s,1H),8.70(s,1H), 8.08 (s, 1H), 8.04 (s, 1H), 7.71 (d, J=8.0Hz, 1H), 7.64 (dd, J=8.0,2.0Hz, 1H), 7.25 (d, J= 4.8Hz, 1H), 6.85 (d, J=4.0Hz, 1H), 2.41 (s, 3H).

D) (R)-3-(5-picoline-2-base)-N-(1-(6-picoline-3-base) ethyl)-5-(thiazol-2-yl oxygen Base) Benzoylamide

To 3-(5-picoline-2-base)-5-(thiazol-2-yl epoxide) benzoic acid (40mg, 0.13mmol) at N, N-bis- In solution in methylformamide (1mL) add (R)-1-(6-picoline-3-base) ethylamine dihydrochloride (60mg, 0.29mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (120mg, 0.32mmol) and N, N-diisopropylethylamine (400 μ L, 2.3mmol).By this reactant mixture 25 DEG C of stirrings 16 hours, so Afterwards by preparation HPLC purification, obtain end-product, for light tan solid.

LC-MS:431[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.08 (d, 1H, J=7.8Hz), 8.55 (d, 1H, J =1.9Hz), 8.49 (m, 2H), 8.19 (t, 1H, J=2.0Hz), 8.01 (d, 1H, J=8.2Hz), 7.85 (t, 1H, J= 1.5Hz), 7.77 (dd, 1H, J=8.2,1.8Hz), 7.69 (dd, 1H, J=8.0,2.4Hz), 7.33 and 7.30 (AB, 2H, J= 3.8Hz), 7.21 (d, 1H, J=8.0Hz), 5.19 (m, 1H), 2.43 (s, 3H), 2.36 (s, 3H), 1.52 (d, 3H, J= 7.1Hz)。

Compound 269

(R)-3-(5-picoline-2-base)-N-(1-(2-methylpyrimidine-5-base) ethyl)-5-(thiazol-2-yl epoxide) Benzoylamide

To 3-(5-picoline-2-base)-5-(thiazol-2-yl epoxide) benzoic acid (40mg, 0.13mmol) at N, N-bis- Solution in methylformamide (1mL) adds (R)-1-(2-methylpyrimidine-5-base) ethamine (40mg, 0.29mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (120mg, 0.32mmol) and N, N-diisopropyl Base ethamine (120 μ L, 0.69mmol).This reactant mixture is stirred 16 hours at 25 DEG C, then by preparation HPLC purification, Obtain product, for pale solid.

LC-MS:432.2[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.12 (d, 1H, J=7.5Hz), 8.73 (s, 2H), 8.55 (d, 1H, J=2.0Hz), 8.49 (t, 1H, J=1.4Hz), 8.19 (t, 1H, J=2.1Hz), 8.01 (d, 1H, J= 8.2Hz), 7.84 (bs, 1H), 7.77 (dd, 1H, J=8.1,1.7Hz), 7.33 and 7.30 (AB, 2H, J=3.76Hz), 5.19 (m, 1H), 2.59 (s, 3H), 2.36 (s, 3H), 1.56 (d, 3H, J=7.1Hz).

Compound 274

(R)-3-(methoxy)-5-(5-picoline-2-base)-N-(1-(2-methylpyrimidine-5-base) ethyl) benzene Methanamide

A) 5-(5-picoline-2-base) different dimethyl phthalate

By different for 5-bromine dimethyl phthalate (1.0g, 3.66mmol), 5-methyl-2-(tributyl in nitrogen atmosphere Stannyl) pyridine (1.5mL, 4.5mmol), four (triphenyl phasphine) palladium (0) (200mg, 0.17mmol) and toluene (10mL) mixed Compound carries out microwave irradiation 2 hours at 120 DEG C.This mixture is cooled to room temperature, precipitation is collected by filtration, rush with hexane Wash, obtain white solid, for expectation product.By purified by flash chromatography filtrate, a collection of expectation product of getting back (amounts to 0.8g)。LC-MS:286.3[M+1]⁺；¹H NMR(400MHz,CDCl₃): 8.84 (d, J=1.6Hz, 2H), 8.71 (t, J= 1.6Hz, 1H), 8.56 (t, J=0.8Hz, 1H), 7.75 (d, J=8.0Hz, 1H), 7.61 (dd, J=2.0,8.1Hz, 1H), 3.98(s,6H),2.41(s,3H)。

B) 3-(hydroxymethyl)-5-(5-picoline-2-base) essence of Niobe

0 DEG C to 5-(5-picoline-2-base) different dimethyl phthalate (1.78g, 5.93mmol) at methanol (100mL) agitating solution in adds Sodium Borohydride (2.0g, 0.053mol).After 3h, use saturated NH₄Cl aqueous solution processes This reaction system, volatiles removed in vacuo.Residue is dissolved in water, by adding NaHCO₃Alkalization, to pH=9, is then used CH₂Cl₂(70mL x3) extracts.Use anhydrous MgSO₄It is dried the organic layer merged, concentrates.By purified by flash chromatography residue, Obtain title compound.

C) 3-(methoxy)-5-(5-picoline-2-base) essence of Niobe

0 DEG C to 3-(hydroxymethyl)-5-(5-picoline-2-base) essence of Niobe (110mg, 0.41mmol) at N, Agitating solution in dinethylformamide (2mL) adds sodium hydride (mineral oil solution of 60%, 21mg, 0.52mmol). After 30 minutes, add iodomethane (73mg, 0.51mmol) at 0 DEG C.This mixture is warmed to room temperature, stirs 30 minutes.Use water (2mL) make this mixture quencher, extract with EtOAc.Use anhydrous MgSO₄Be dried merge organic layer, be concentrated into obtain titled Compound.

D) 3-(methoxy)-5-(5-picoline-2-base) benzoic acid

To 3-(methoxy)-5-(5-picoline-2-base) essence of Niobe (75mg, 0.28mmol) at 1,4-bis-Agitating solution in alkane (3mL) and water (0.3mL) adds Lithium hydrate (66mg, 2.8mmol), by this reactant mixture It is stirred at room temperature 30 minutes.Use 2N H₂SO₄This reactant mixture is acidified to pH=7～8 by aqueous solution, then with EtOAc (20mL X3) extraction.The organic layer merged with saline washing, is dried (MgSO₄), concentrate, obtain title compound.¹H NMR(D₂O, 400MHz): 8.10 (s, 1H), 7.98 (s, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 7.40 (d, J=8.0Hz, 1H), 7.32 (d, J=8.4Hz, 1H), 4.41 (s, 2H), 3.32 (s, 3H), 2.13 (s, 3H).

E) (R)-3-(methoxy)-5-(5-picoline-2-base)-N-(1-(2-methylpyrimidine-5-base) ethyl) Benzoylamide

To 3-(methoxy)-5-(5-picoline-2-base) benzoic acid (30mg, 0.12mmol) at N, N-dimethyl Solution in Methanamide (1.5mL) adds (R)-1-(2-methylpyrimidine-5-base) ethamine (40mg, 0.29mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (100mg, 0.26mmol) and N, N-diisopropyl second Amine (100 μ L, 0.57mmol).This reactant mixture is stirred 16 hours at 25 DEG C, then by preparation HPLC purification, obtains End-product.

LC-MS:377.2[M+1]⁺；¹H NMR(400MHz,CDCl₃): 8.69 (s, 2H), 8.49 (d, 1H, J=1.1Hz), 8.30 (bs, 1H), 8.07 (bs, 1H), 7.80 (bs, 1H), 7.69 (d, 1H, J=8.1Hz), 7.58 (dd, 1H, J=8.1, 2.0Hz), 6.79 (d, 1H, J=7.2Hz), 5.34 (m, 1H), 4.56 (s, 2H), 3.43 (s, 3H), 2.72 (s, 3H), 2.38 (s, 3H), 1.65 (d, 3H, J=7.1Hz).

Compound 280

5-(hydroxyl (thiazol-2-yl) methyl)-4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl) biphenyl- 3-carboxylic acid amides

A) the bromo-5-of 3-(hydroxymethyl) essence of Niobe

At 0 DEG C in the different dimethyl phthalate of the 5-bromine (5.4g, 20mmol) agitating solution in methanol (300mL) Slowly add Sodium Borohydride (10g, 0.28mol).This mixture is stirred 3h at rt, then processes with water (300mL).Vacuum is removed Remove volatile material, use CH₂Cl₂(100mL x3) aqueous phase extracted.The organic layer merged with saline washing, uses anhydrous MgSO₄Dry Dry, it is concentrated in vacuo.The grease obtained by purified by flash chromatography, obtains title compound.

B) 3-bromo-5-acyl radical methyl benzoate

By bromo-for 3-5-(hydroxymethyl) essence of Niobe (149mg, 0.61mmol) and manganese oxide (IV) (529mg, 6.08mmol) and CH₂Cl₂(3mL) mixture is stirred overnight at rt.Filter this mixture by Celite, use CH₂Cl₂Washing Filter cake.Concentrated filtrate, obtains title compound.

C) the bromo-5-of 3-(hydroxyl (thiazol-2-yl) methyl) essence of Niobe

In nitrogen atmosphere, under rt, to the 2-bromo thiazole (0.40g, 24.4mmol) agitating solution in THF (60mL) The THF solution (10mL, 20mmol) of middle addition 2M isopropyl-magnesium chloride.This mixture is stirred 1h at rt, is subsequently cooled to 0 ℃.Add 3-bromo-5-acyl radical methyl benzoate (1.0g, 4.1mmol), this reactant mixture is stirred 30 minutes at 0 DEG C.With Water (30mL) makes this reactant mixture quencher, uses CH₂Cl₂(60mL x3) extracts.Use anhydrous MgSO₄It is dried the organic layer merged, Concentrate.By purified by flash chromatography residue, obtain title compound (0.90g).

D) 5-(hydroxyl (thiazol-2-yl) methyl)-4'-methyl biphenyl-3-carboxylate methyl ester

In argon gas atmosphere to the bromo-5-of 3-(hydroxyl (thiazol-2-yl) methyl) essence of Niobe (320mg, 0.98mmol), P-tolyl boric acid (0.16g, 1.2mmol), potassium carbonate (0.20g, 1.5mmol), 1,4-bis-Alkane (5mL) and water The mixture of (0.5mL, 0.03mol) adds four (triphenyl phasphine) palladium (0) (60mg, 0.052mmol).This reactant mixture is existed 95 DEG C of heating 8h.After cooling, process this mixture with water (15mL), extract with EtOAc (20mL x3).It is dried the organic of merging Layer (MgSO₄), concentrate.By purified by flash chromatography residue, obtain title compound.

E) 5-(hydroxyl (thiazol-2-yl) methyl)-4'-methyl biphenyl-3-carboxylic acid

To 5-(hydroxyl (thiazol-2-yl) methyl)-4'-methyl biphenyl-3-carboxylate methyl ester (170mg, 0.50mmol) 1, 4-bis-Agitating solution in alkane (1.5mL) and water (1.5mL) adds Lithium hydrate (42mg, 1.8mmol).Stir at rt After 4h, use NH₄Cl aqueous solution processes this reactant mixture, extracts with EtOAc (15mL x3).Use anhydrous MgSO₄It is dried merging Organic layer, by silica column purification, obtains title compound.¹H NMR(CDCl₃,400MHz):8.19(s,1H),8.16(s, 1H), 7.86 (s, 1H), 7.72 (d, J=2.4Hz, 1H), 7.41 (d, J=7.6Hz, 2H), 7.24 (m, 1H), 7.14 (d, J= 7.6Hz,2H),6.21(s,1H),5.28(s,1H),2.32(s,3H)。

F) 5-(hydroxyl (thiazol-2-yl) methyl)-4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl) connection Benzene-3-carboxylic acid amides

To 5-(hydroxyl (thiazol-2-yl) methyl)-4'-methyl biphenyl-3-carboxylic acid (31mg, 0.095mmol) at N, N-bis- In agitating solution in methylformamide (1mL) add (R)-1-(6-picoline-3-base) ethylamine dihydrochloride (50mg, 0.24mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (100mg, 0.26mmol) and N, N-diisopropylethylamine (300 μ L, 1.72mmol).By this reactant mixture 25 DEG C of stirrings 16 hours, so Afterwards by preparation HPLC purification, obtain end-product, for light tan solid.

LC-MS:444.1[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 8.96 (d, 1H, J=7.8Hz), 8.47 (d, 1H, J=2.0Hz), 8.05 (bs, 1H), 7.90 (bs, 1H), 7.85 (bs, 1H), 7.72-7.58 (m, 5H), 7.31 (d, 2H, J =8.0Hz), 7.21 (d, 1H, J=8.0Hz), 6.95 (d, 1H, J=3.7Hz), 6.08 (d, 1H, J=4.2Hz), 5.18 (m, 1H), 2.43 (s, 3H), 2.36 (s, 3H), 1.51 (d, 3H, J=7.0Hz).

Compound 290

(R)-2'-cyano group-5-(hydroxymethyl)-4'-methyl-N-(1-(6-picoline-3-base) ethyl) biphenyl-3-carboxylic Amide

A) 2'-cyano group-5-(hydroxymethyl)-4'-methyl biphenyl-3-carboxylate methyl ester

0 DEG C to 2'-cyano group-4'-methyl biphenyl-3,5-dimethyl dicarboxylate (343mg, 1.05mmol) at methanol (20mL) solution in is slowly added to Sodium Borohydride (0.60g, 16mmol).This mixture is stirred 6h at rt, then uses Water (20mL) processes.Volatiles removed in vacuo, uses CH₂Cl₂(30mL x3) aqueous phase extracted.The organic of merging is washed with saline Layer, uses anhydrous MgSO₄It is dried, is concentrated in vacuo.By purified by flash chromatography residue, obtain title compound.

B) 2'-cyano group-5-(hydroxymethyl)-4'-methyl biphenyl-3-carboxylic acid

To 2'-cyano group-5-(hydroxymethyl)-4'-methyl biphenyl-3-carboxylate methyl ester (220mg, 0.78mmol) at 1,4-bis-Agitating solution in alkane (5mL) and water (1mL) adds Lithium hydrate (60mg, 2.5mmol).This reactant mixture is existed Rt stirs 8h, then uses NH₄Cl aqueous solution and EtOAc process.Separate organic layer, use anhydrous MgSO₄It is dried, concentrates.Pass through silica gel Chromatography purification residue, obtains title compound.¹H NMR (acetone-d6,400MHz): 8.16 (m, 1H), 8.11 (m, 1H), 7.81 (m, 1H), 7.73 (m, 1H), 7.65-7.61 (m, 1H), 7.56 (d, 1H, J=8.0Hz), 4.81 (s, 2H), 2.46 (s, 3H)。

C) (R)-2'-cyano group-5-(hydroxymethyl)-4'-methyl-N-(1-(6-picoline-3-base) ethyl) biphenyl-3- Carboxylic acid amides

To 2'-cyano group-5-(hydroxymethyl)-4'-methyl biphenyl-3-carboxylic acid (40mg, 0.15mmol) at N, N-dimethyl In agitating solution in Methanamide (1mL) add (R)-1-(6-picoline-3-base) ethylamine dihydrochloride (60mg, 0.29mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (120mg, 0.32mmol) and N, N-diisopropylethylamine (400 μ L, 2.3mmol).By this reactant mixture 25 DEG C of stirrings 16 hours, so Afterwards by preparation HPLC purification, obtain end-product, for pale solid.

LC-MS:386.4[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 8.93 (d, 1H, J=7.8Hz), 8.47 (d, 1H, J=2.2Hz), 7.93 (bs, 1H), 7.91 (bs, 1H), 7.81 (bs, 1H), 7.70-7.60 (m, 3H), 7.57 (d, 1H, J =8.0Hz), 7.20 (d, 1H, J=8.0Hz), 5.41 (t, 1H, J=5.7Hz), 5.18 (m, 1H), 4.62 (d, 2H, J= 5.7Hz), 2.43 (s, 3H), 2.41 (s, 3H), 1.50 (d, 3H, J=7.1Hz).

Compound 295

2'-cyano group-4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl)-5-(2,2,2-tri-fluoro-1-hydroxyl Ethyl) biphenyl-3-carboxylic acid amides

A) the bromo-5-of 3-(2,2,2-tri-fluoro-1-hydroxyethyl) essence of Niobe

At-20 DEG C to 3-bromo-5-acyl radical methyl benzoate (0.60g, 2.5mmol), bromination four-N-butyl ammonium The stirring mixture of (0.90g, 2.8mol), potassium fluoride (10mg, 0.17mmol) and toluene (10mL) adds (trifluoromethyl) Trimethyl silane (0.74mL, 5.0mmol).This reactant mixture is stirred 20min, then uses water quencher.In this mixture Add 1M HCl/water solution (2mL) and 1,4-bis-Alkane (12mL), stirs 30min by this mixture.With EtOAc (3x20mL) Aqueous phase extracted.The organic layer merged with saline washing, uses anhydrous MgSO₄It is dried, concentrating under reduced pressure.Remaining by flash column purification Thing, obtains title compound.

B) 2'-cyano group-4'-methyl-5-(2,2,2-tri-fluoro-1-hydroxyethyl) biphenyl-3-carboxylate methyl ester

In nitrogen atmosphere by bromo-for 3-5-(2,2,2-tri-fluoro-1-hydroxyethyl) essence of Niobe (300mg, 0.96mmol), 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-base) benzonitrile (280mg, 1.1mmol), four (triphenyl phasphine) palladium (0) (60mg, 0.052mmol) is at N,N-dimethylformamide (0.75mL) and toluene (1.5mL) mixture in carries out microwave irradiation 1h at 110 DEG C.After cooling, dilute this mixture with water (15mL), use EtOAc (20mL x3) extracts.The organic layer merged with saline washing, uses anhydrous MgSO₄It is dried, concentrates.Pass through purified by flash chromatography Residue, obtains title compound.

C) 2'-cyano group-4'-methyl-5-(2,2,2-tri-fluoro-1-hydroxyethyl) biphenyl-3-carboxylic acid

To 2'-cyano group-4'-methyl-5-(2,2,2-tri-fluoro-1-hydroxyethyl) biphenyl-3-carboxylate methyl ester (250mg, 0.72mmol) at 1,4-bis-In agitating solution in alkane (5mL) and water (2.5mL) add Lithium hydrate (50mg, 2.1mmol).This reactant mixture is stirred 4h at rt, then uses NH₄Cl aqueous solution and EtOAc process.Separate organic layer, use Anhydrous MgSO₄It is dried, concentrates.By Silica gel chromatography residue, obtain title compound.¹H NMR(CDCl₃, 400MHz): 8.27 (s, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.58 (s, 1H), 7.48 and 7.43 (AB, J=8.0Hz, 2H), 5.17 (q, J=6.4Hz, 1H), 2.43 (s, 3H).

D) 2'-cyano group-4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl)-5-(2,2,2-tri-fluoro-1-hydroxyl Base ethyl) biphenyl-3-carboxylic acid amides

To 2'-cyano group-4'-methyl-5-(2,2,2-tri-fluoro-1-hydroxyethyl) biphenyl-3-carboxylic acid (32mg, 0.095mmol) solution in N,N-dimethylformamide (1mL) adds (R)-1-(6-picoline-3-base) ethamine two Hydrochlorate (50mg, 0.24mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (100mg, 0.26mmol) and N, N-diisopropylethylamine (300 μ L, 1.72mmol).This reactant mixture is stirred 16 at 25 DEG C Hour, by preparation HPLC purification, obtain end-product, for pale solid.

LC-MS:454.3[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.00 (d, 1H, J=7.7Hz), 8.48 (d, 1H, J=2.1Hz), 8.09 (s, 2H), 7.83 (s, 2H), 7.70-7.55 (m, 3H), 7.21 (d, 1H, J=8.0Hz), 7.07 (d, 1H, J=5.6Hz), 5.35 (m, 1H), 5.19 (m, 1H), 2.43 (s, 3H), 2.42 (s, 3H), 1.51 (d, 3H, J= 7.1Hz)。

Compound 297

2'-cyano group-5-(1,2-dihydroxy ethyl)-4'-methyl-N-((6-picoline-3-base) methyl) biphenyl-3-carboxylic Amide

A) 3-bromo-5-vinylbenzoate

At-78 DEG C, in nitrogen atmosphere to methyl triphenylphosphonium bromide(350mg, 0.97mmol) is in THF (3mL) Agitating solution drips the tetrahydrofuran solution (0.31mL, 0.78mmol) of 2.5M n-BuLi.By this mixture progressively temperature extremely Yellow persistently occurs.This mixture is cooled to 0 DEG C, dropping 3-bromo-5-acyl radical methyl benzoate (157mg, 0.65mmol) Solution in THF (2mL).After 0 DEG C of stirring 20min, use saturated NH₄Cl aqueous solution makes this mixture quencher, extracts with EtOAc Take.Separate organic layer, wash with saline, be dried, concentrate.By flash column purification residue, obtain title compound.

B) the bromo-5-of 3-(1,2-dihydroxy ethyl) essence of Niobe

To 3-bromo-5-vinylbenzoate (1.6g, 6.6mmol) and N-methylmorpholine N-oxide (2.0g, 17.1mmol) agitating solution in acetone (40mL) and water (10mL) drips 5% Osmic acid. aqueous solution (0.50g, 0.10mmol).This reactant mixture is stirred 3h at rt, is subsequently adding saturated Na₂S₂O₃Aqueous solution.After stirring 30min, use EtOAc (100mL x3) extracts this reactant mixture.Wash, with water and saline, the organic layer merged, be dried, concentrate.Pass through flash distillation Tower purification residue, obtains title compound.

C) 2'-cyano group-5-(1,2-dihydroxy ethyl)-4'-methyl biphenyl-3-carboxylate methyl ester

By bromo-for 3-5-(1,2-dihydroxy ethyl) essence of Niobe (100mg, 0.36mmol), 5-first in nitrogen atmosphere Base-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-base) benzonitrile (130mg, 0.54mmol), four (triphens Phosphine) palladium (0) (40mg, 0.035mmol), potassium carbonate (75mg, 0.54mmol), N,N-dimethylformamide (0.5mL) and toluene (1mL) mixture carries out microwave irradiation 1h at 110 DEG C.After cooling, dilute this mixture with water (5mL), with EtOAc (15mL X3) extraction.The organic layer merged with saline washing, uses anhydrous MgSO₄It is dried, is concentrated in vacuo.By flash column purification residue, Obtain title compound.

D) 2'-cyano group-5-(1,2-dihydroxy ethyl)-4'-methyl biphenyl-3-carboxylic acid

Exist to 2'-cyano group-5-(1,2-dihydroxy ethyl)-4'-methyl biphenyl-3-carboxylate methyl ester (140mg, 0.45mmol) 1,4-bis-Agitating solution in alkane (5mL) and water (2mL) adds Lithium hydrate (40mg, 1.67mmol).This reaction is mixed Compound stirs 6h at rt, then uses NH₄Cl aqueous solution processes, and extracts with EtOAc (3x).Use anhydrous MgSO₄It is dried the organic of merging Layer, concentrates, obtains title compound.¹H NMR (400MHz, acetone-d6): 8.21 (m, 1H), 8.13 (m, 1H), 7.87 (m, 1H), 7.73 (s, 1H), 7.66-7.61 (m, 1H), 7.58 (d, 1H, J=7.6Hz), 4.91 (dd, 1H, J=7.2,4.4Hz), 3.75 (dd, 1H, J=11.2,4.4Hz), 3.65 (dd, 1H, J=11.2,7.2Hz), 2.47 (s, 3H).

E) 2'-cyano group-5-(1,2-dihydroxy ethyl)-4'-methyl-N-((6-picoline-3-base) methyl) biphenyl-3- Carboxylic acid amides

To 2'-cyano group-5-(1,2-dihydroxy ethyl)-4'-methyl biphenyl-3-carboxylic acid (30mg, 0.10mmol) at N, N- Solution in dimethylformamide (1mL) adds (6-picoline-3-base) methylamine (35mg, 0.26mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (100mg, 0.26mmol) and N, N-diisopropyl second Amine (100 μ L, 0.57mmol).This reactant mixture is stirred 16 hours at 25 DEG C, then by preparation HPLC purification, obtains End-product, for pale solid.

LC-MS:402.1[M+1]⁺；¹H NMR(400MHz,DMSO-d6):9.14(m,1H),8.47(bs,1H),7.94 (m,2H),7.79(bs,1H),7.70-7.50(m,4H),7.20(m,1H),5.46(bs,1H),4,80(bs,1H),4.66 (bs,1H),4.46(bs,2H),3.49(bs,2H),2.43(s,3H),2.40(s,3H)。

Compound 308

4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl)-5-(oxolane-3-base epoxide) biphenyl-3- Carboxylic acid amides

A) 4'-methyl-5-(oxolane-3-base epoxide) biphenyl-3-carboxylate methyl ester

Rt to 5-hydroxyl-4'-methyl biphenyl-3-carboxylate methyl ester (120mg, 0.47mmol), triphenyl phasphine (120mg, 0.47mmol), 3-hydroxyl tetrahydrofuran (45mg, 0.50mmol) is at CH₂Cl₂(7mL) agitating solution in is slowly added to azo Dioctyl phthalate diisopropyl ester (100mg, 0.50mmol) is at CH₂Cl₂(2mL) solution in.This mixture is stirred overnight at rt, so Final vacuum concentrates.By purified by flash chromatography residue, obtain title compound.

B) 4'-methyl-5-(oxolane-3-base epoxide) biphenyl-3-carboxylic acid

To 4'-methyl-5-(oxolane-3-base epoxide) biphenyl-3-carboxylate methyl ester (150mg, 0.46mmol) at 1,4- TwoAgitating solution in alkane (5mL) and water (0.5mL) adds Lithium hydrate (55mg, 2.3mmol).This reaction is mixed Thing is stirred at room temperature 2 hours, then uses 2NH₂SO₄Aqueous solution is acidified to pH4-5, is concentrated in vacuo.Process residue with water, use CH₂Cl₂(10mL x3) extracts.It is dried the organic layer (MgSO merged₄), concentrate, obtain title compound.¹H NMR(CD₃OD, 400MHz): 7.85 (t, J=1.6Hz, 1H), 7.52 (d, 2H, J=8.4Hz), 7.48 (dd, 1H=2.4,1.2Hz), 7.34 (dd, 1H, J=2.4,1.6Hz), 7.28 (d, 2H, J=8.4Hz), 5.15 (m, 1H), 4.05-3.87 (m, 4H), 2.38 (s, 3H),2.36-2.27(m,1H),2.20-2.11(m,1H)。

C) 4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl)-5-(oxolane-3-base epoxide) biphenyl- 3-carboxylic acid amides

To 4'-methyl-5-(oxolane-3-base epoxide) biphenyl-3-carboxylic acid (40mg, 0.13mmol) at N, N-dimethyl In solution in Methanamide (1mL) add (R)-1-(6-picoline-3-base) ethylamine dihydrochloride (60mg, 0.29mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (120mg, 0.32mmol) and N, N-bis- Wopropyl ethyl amine (400 μ L, 2.3mmol).This reactant mixture is stirred 16 hours at 25 DEG C, by preparation HPLC purification, Obtain end-product, for pale solid.

LC-MS:417.1[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 8.90 (d, 1H, J=7.7Hz), 8.47 (d, 1H, J=2.2Hz), 7.73 (bs, 1H), 7.70-7.60 (m, 3H), 7.35 (bs, 1H), 7.32-7.25 (m, 3H), 7.21 (d, 1H, J=8.0Hz), 5.20 (m, 2H), 4.00-3.70 (m, 4H), 2.43 (s, 3H), 2.35 (s, 3H), 2.25 (m, 1H), 2.00 (m, 1H), 1.51 (d, 3H, J=7.1Hz).

Compound 310

4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl)-5-((oxolane-2-base) methoxyl group) joins Benzene_-3_-Carboxylic acid amides

A) 4'-methyl-5-((oxolane-2-base) methoxyl group) biphenyl-3-carboxylate methyl ester

At rt to 5-hydroxyl-4'-methyl biphenyl-3-carboxylate methyl ester (150mg, 0.59mmol), triphenyl phasphine (150mg, 0.59mmol), tetrahydrochysene-2-furancarbinol (60mg, 0.59mmol) is at CH₂Cl₂(8mL) agitating solution in is slowly added to idol Nitrogen dioctyl phthalate diisopropyl ester (200mg, 1.0mmol) is at CH₂Cl₂(3mL) solution in.This mixture is stirred at room temperature overnight, Then it is concentrated in vacuo.By purified by flash chromatography residue, obtain title compound.

B) 4'-methyl-5-((oxolane-2-base) methoxyl group) biphenyl-3-carboxylic acid

Exist to 4'-methyl-5-((oxolane-2-base) methoxyl group) biphenyl-3-carboxylate methyl ester (130mg, 0.40mmol) 1,4-bis-Agitating solution in alkane (5mL) and water (0.5mL) adds Lithium hydrate (50mg, 2.1mmol).By this reaction Mixture is stirred at room temperature 2 hours, then uses 2N H₂SO₄Aqueous solution is acidified to pH4-5, is concentrated in vacuo.Residue is processed with water, Use CH₂Cl₂(10mL x3) extracts.It is dried the organic layer (MgSO merged₄), concentrate, obtain title compound.¹H NMR(CD₃OD, 400MHz): 7.84 (t, J=1.6Hz, 1H), 7.54-7.50 (m, 3H), 7.38 (dd, 1H, J=2.8,1.6Hz), 7.27 (d, 2H, J=8.0Hz), 4.34-4.27 (m, 1H), 4.12 (dd, 1H, J=10.0,3.6Hz), 4.04 (dd, 1H, J=10.0, 6.4Hz),3.97-3.80(m,2H),2.38(s,3H),2.20-1.80(m,4H)。

4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl)-5-((oxolane-2-base) methoxyl group) joins Benzene-3-carboxylic acid amides

To 4'-methyl-5-((oxolane-2-base) methoxyl group) biphenyl-3-carboxylic acid (40mg, 0.13mmol) at N, N-bis- In agitating solution in methylformamide (1mL) add (R)-1-(6-picoline-3-base) ethylamine dihydrochloride (60mg, 0.29mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (120mg, 0.32mmol) and N, N-diisopropylethylamine (400 μ L, 2.3mmol).By this reactant mixture 25 DEG C of stirrings 16 hours, so Afterwards by preparation HPLC purification, obtain end-product, for light tan solid.

LC-MS:430.9[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 8.90 (d, 1H, J=7.7Hz), 8.47 (d, 1H, J=2.2Hz), 7.71 (bs, 1H), 7.70-7.60 (m, 3H), 7.38 (bs, 1H), 7.33 (t, 1H, J=1.6Hz), 7.29 (d, 2H, J=8.0Hz), 7.21 (d, 1H, J=8.0Hz), 5.18 (m, 1H), 4.19 (m, 1H), 4.15-3.95 (m, 2H), 3.79(m,1H),3.67(m,1H),2.43(s,3H),2.35(s,3H),2.02(m,1H),1.85(m,2H),1.70(m,1H), 1.51 (d, 3H, J=7.1Hz).

Compound 315

2'-cyano group-5-(2,3-dihydroxy propoxyl group)-4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl) Biphenyl-3-carboxylic acid amides

A) 2'-cyano group-5-((2,2-dimethyl-1,3-dioxolanes-4-base) methoxyl group)-4'-methyl biphenyl-3-carboxylic acid Methyl ester

In room temperature to 2'-cyano group-5-hydroxyl-4'-methyl biphenyl-3-carboxylate methyl ester (150mg, 0.56mmol), triphenyl phasphine (220mg, 0.84mmol), 2,2-dimethyl-1,3-dioxolanes-4-methanol (82mg, 0.62mmol) are at CH₂Cl₂(5mL) in Agitating solution in be slowly added to diisopropyl azodiformate (340mg, 1.7mmol) at CH₂Cl₂(3mL) solution in.Will This reactant mixture is stirred at room temperature overnight, and is then concentrated in vacuo.By purified by flash chromatography residue, obtain title compound Thing.

B) 2'-cyano group-5-((2,2-dimethyl-1,3-dioxolanes-4-base) methoxyl group)-4'-methyl biphenyl-3-carboxylic acid

To 2'-cyano group-5-((2,2-dimethyl-1,3-dioxolanes-4-base) methoxyl group)-4'-methyl biphenyl-3-carboxylic acid In the methyl ester (72mg, 0.19mmol) solution in oxolane (3mL) add 2.5M lithium hydroxide aqueous solution (1mL, 2.5mmol).This reactant mixture is stirred overnight at 60 DEG C.With 15%HCl (aqueous solution), this aqueous solution is acidified to pH=5, Extract with EtOAc.The organic layer of merging is concentrated in vacuo, obtains title compound.

C) 2'-cyano group-5-(2,3-dihydroxy propoxyl group)-4'-methyl biphenyl-3-carboxylic acid

To 2'-cyano group-5-((2,2-dimethyl-1,3-dioxolanes-4-base) methoxyl group)-4'-methyl biphenyl-3-carboxylic acid (63mg, 0.17mmol) agitating solution in THF (3mL) adds 1MHCl aqueous solution (3mL, 3mmol).This reaction is mixed Compound is stirred at room temperature 4 hours, is then concentrated in vacuo.Process residue with water, extract with EtOAc.Use anhydrous MgSO₄It is dried and closes And organic layer, concentrate, obtain title compound.¹H NMR(CD₃OD, 400MHz): 7.77 (t, 1H, J=1.6Hz), 7.67 (m, 2H), 7.58 (dd, 1H, J=8.0,2.0Hz), 7.51 (d, 1H, J=8.0Hz), 7.38 (t, 1H, J=2.0Hz), 4.19 (dd, 1H, J=9.6,4.0Hz), 4.10 (dd, 1H, J=9.6,6.0Hz), 4.02 (m, 1H), 3.72 (dd, 1H, J=11.2, 5.6Hz), 3.67 (dd, 1H, J=11.2,5.6Hz), 2.45 (s, 3H).

D) 2'-cyano group-5-(2,3-dihydroxy propoxyl group)-4'-methyl-N-((R)-1-(6-picoline-3-base) second Base) biphenyl-3-carboxylic acid amides

To 2'-cyano group-5-(2,3-dihydroxy propoxyl group)-4'-methyl biphenyl-3-carboxylic acid (30mg, 0.092mmol) at N, In solution in dinethylformamide (1mL) add (R)-1-(6-picoline-3-base) ethylamine dihydrochloride (60mg, 0.29mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (100mg, 0.26mmol) and N, N-diisopropylethylamine (400 μ L, 2.3mmol).This reactant mixture is stirred 16 hours at 25 DEG C, logical Cross preparation HPLC purification, obtain end-product, for pale solid.

LC-MS:446.6[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 8.92 (d, 1H, J=7.4Hz), 8.46 (bs, 1H), 7.79 (bs, 1H), 7.70-7.55 (m, 4H), 7.53 (bs, 1H), 7.27 (bs, 1H), 7.20 (d, 1H, J=7.8Hz), 5.17 (m, 1H), 5.00 (m, 1H), 4.70 (t, 1H, J=3.8Hz), 4.11 (m, 1H), 3.97 (m, 1H), 3.83 (m, 1H), 3.46 (t, 2H, J=4.8Hz), 2.43 (s, 3H), 2.41 (s, 3H), 1.49 (d, 3H, J=6.2Hz).

Compound 324

2'-cyano group-4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl)-5-(morpholine-2-ylmethoxy) joins Benzene-3-carboxylic acid amides

A) 2-((2'-cyano group-5-(methoxycarbonyl)-4'-methyl biphenyl-3-base epoxide) methyl) morpholine-4-carboxylic acid uncle Butyl ester

In nitrogen atmosphere, at room temperature, to 2'-cyano group-5-hydroxyl-4'-methyl biphenyl-3-carboxylate methyl ester (150mg, 0.56mmol), triphenyl phasphine (220mg, 0.84mmol), 2-(hydroxymethyl) morpholine-4-t-butyl formate (130mg, 0.62mmol) (Bioorg.Med.Chem.Lett.2007,17,533) is at CH₂Cl₂(5mL) agitating solution in is slowly added to Diisopropyl azodiformate (340mg, 1.7mmol) is at CH₂Cl₂(3mL) solution in.This mixture was stirred at room temperature At night, then it is concentrated in vacuo.By purified by flash chromatography residue, obtain title compound.

B) 5-((4-(tertbutyloxycarbonyl) morpholine-2-yl) methoxyl group)-2'-cyano group-4'-methyl biphenyl-3-carboxylic acid

To 2-((2'-cyano group-5-(methoxycarbonyl)-4'-methyl biphenyl-3-base epoxide) methyl) morpholine-4-formic acid uncle In the butyl ester (107mg, 0.23mmol) agitating solution in THF (2mL) add 2.5M lithium hydroxide aqueous solution (0.52mL, 1.3mmol).This reactant mixture is stirred overnight at 60 DEG C, is then acidified to pH=5 with 15%HCl (aqueous solution), use EtOAc extracts.The organic layer of merging is concentrated in vacuo, obtains title compound.¹H NMR(CDCl₃,400MHz):7.86(t,1H,J =1.6Hz), 7.70 (t, 1H, J=1.6Hz), 7.59 (s, 1H), 7.47 (dd, 1H, J=8.0,1.2Hz), 7.42 (d, 1H, J =8.0Hz), 7.37 (s, 1H), 4.20-3.56 (m, 7H), 3.10-2.90 (m, 2H), 2.45 (s, 3H), 1.49 (s, 9H).

C) 2'-cyano group-4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl)-5-(morpholine-2-ylmethoxy) Biphenyl-3-carboxylic acid amides

To 5-((4-(tertbutyloxycarbonyl) morpholine-2-yl) methoxyl group)-2'-cyano group-4'-methyl biphenyl-3-carboxylic acid (50mg, 0.11mmol) solution in N,N-dimethylformamide (1mL) adds (R)-1-(6-picoline-3-base) second Amine dihydrochloride (60mg, 0.29mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphoric acid Salt (120mg, 0.32mmol) and N, N-diisopropylethylamine (400 μ L, 2.3mmol).By this reactant mixture 25 DEG C of stirrings 16 hours, by preparation HPLC purification, obtain the product of Boc-protection, be dissolved in CH₂Cl₂(5mL), trifluoroacetic acid is added (1mL).Being stirred at room temperature overnight by this mixture, LC-MS display deprotection completes.This mixture is concentrated in vacuo, by preparation Type HPLC purification residue, obtains end-product, for white solid.

LC-MS:471.6[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 8.90 (d, 1H, J=7.7Hz), 8.46 (d, 1H, J=2.1Hz), 8.00 (bs, 1H), 7.70-7.55 (m, 4H), 7.53 (bs, 1H), 7.29 (bs, 1H), 7.21 (d, 1H, J =8.0Hz), 5.17 (m, 1H), 4.05 (m, 2H), 3.75 (m, 2H), 3.49 (m, 1H), 2.92 (m, 1H), 2.65 (m, 2H), 2.53 (m, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 1.50 (d, 3H, J=7.1Hz).

Compound 336

5-(4-hydroxyl tetrahydrofuran-3-base epoxide)-4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl) joins Benzene-3-carboxylic acid amides

A) 5-(4-hydroxyl tetrahydrofuran-3-base epoxide)-4'-methyl biphenyl-3-carboxylate methyl ester

By 5-hydroxyl-4'-methyl biphenyl-3-carboxylate methyl ester (370mg, 1.4mmol), potassium carbonate (421mg, 3.05mmol), the stirring mixture of DMSO (8mL) and 3,6-dioxa dicyclo [3.1.0] hexane (260mg, 3.0mmol) exists 110 DEG C of heated overnight.After cooling, dilute this reactant mixture with EtOAc.Use NaHCO₃Aqueous solution (saturated) washing organic facies, Use anhydrous MgSO₄It is dried, filters, concentrate.By purified by flash chromatography residue, obtain title compound.

B) 5-(4-hydroxyl tetrahydrofuran-3-base epoxide)-4'-methyl biphenyl-3-carboxylic acid

To 5-(4-hydroxyl tetrahydrofuran-3-base epoxide)-4'-methyl biphenyl-3-carboxylate methyl ester (140mg, 0.40mmol) At 1,4-bis-Agitating solution in alkane (2.8mL) and water (2.8mL) adds Lithium hydrate (50mg, 2.1mmol).Should Reactant mixture is stirred at room temperature 2 hours, then uses 2N H₂SO₄Aqueous solution is acidified to pH4-5, is concentrated in vacuo.Process residual with water Excess, extracts with EtOAc (10mL x2).It is dried the organic layer (MgSO merged₄), concentrate, obtain title compound.¹H NMR (CD₃OD, 400MHz): 7.87 (t, J=1.6Hz, 1H), 7.55-7.51 (m, 3H), 7.42 (t, J=2.0Hz, 1H), 7.28 (d, J=7.6Hz, 2H), 4.84 (d, J=4.4Hz, 1H), 4.38 (d, J=4.0Hz, 1H), 4.23 (dd, J=10.4, 4.4Hz, 1H), 4.05 (dd, J=9.6,4.4Hz, 1H), 3.94 (dd, J=10.4,1.6Hz, 1H), 3.77 (dd, J=9.6, 1.6Hz,1H),2.38(s,3H)。

C) 5-(4-hydroxyl tetrahydrofuran-3-base epoxide)-4'-methyl-N-((R)-1-(6-picoline-3-base) ethyl) Biphenyl-3-carboxylic acid amides

To 5-(4-hydroxyl tetrahydrofuran-3-base epoxide)-4'-methyl biphenyl-3-carboxylic acid (35mg, 0.11mmol) at N, N- In solution in dimethylformamide (1mL) add (R)-1-(6-picoline-3-base) ethylamine dihydrochloride (60mg, 0.29mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (100mg, 0.26mmol) and N, N-diisopropylethylamine (400 μ L, 2.3mmol).By this reactant mixture 25 DEG C of stirrings 16 hours, so Afterwards by preparation HPLC purification, obtain end-product, for white solid.

LC-MS:432.8[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 8.90 (d, 1H, J=7.8Hz), 8.47 (d, 1H, J=1.6Hz), 7.73 (bs, 1H), 7.70-7.60 (m, 3H), 7.41 (bs, 1H), 7.38 (bs, 1H), 7.29 (d, 2H, J =7.9Hz), 7.21 (d, 1H, J=8.0Hz), 5.53 (bs, 1H), 5.17 (m, 1H), 4.85 (d, 1H, J=3.7Hz), 4.24 (bs, 1H), 4.08 (dd, 1H, J=10.2,4.1Hz), 3.93 (dd, 1H, J=9.5,4.4Hz), 3.80 (d, 1H, J= 10.2Hz), 3.61 (d, 1H, J=9.4Hz), 2.43 (s, 3H), 2.36 (s, 3H), 1.50 (d, 3H, J=7.0Hz).

Compound 338

2'-cyano group-5-(4-hydroxyl pyrrolidine-3-base epoxide)-4'-methyl-N-((R)-1-(6-picoline-3-base) Ethyl) biphenyl-3-carboxylic acid amides

A) 3-(2'-cyano group-5-(methoxycarbonyl)-4'-methyl biphenyl-3-base epoxide)-4-hydroxyl pyrrolidine-1-formic acid The tert-butyl ester

By 2'-cyano group-5-hydroxyl-4'-methyl biphenyl-3-carboxylate methyl ester (300mg, 1.1mol), potassium carbonate (320mg, 2.4mmol), DMSO (8mL) and 6-oxa--3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (2.4mmol) (J.Am.Chem.Soc.2008,130,3900) stirring mixture is 135 DEG C of heated overnight.After cooling, should with EtOAc dilution Reactant mixture.Use NaHCO₃Aqueous solution (saturated) washing organic facies, uses anhydrous MgSO₄It is dried, filters, concentrate.By quick color Spectrometry (0-50%EtOAc/ hexane) purification residue, obtains title compound.

B) 5-(1-(tertbutyloxycarbonyl)-4-hydroxyl pyrrolidine-3-base epoxide)-2'-cyano group-4'-methyl biphenyl-3-carboxylic acid

To 3-(2'-cyano group-5-(methoxycarbonyl)-4'-methyl biphenyl-3-base epoxide)-4-hydroxyl pyrrolidine-1-formic acid In the tert-butyl ester (310mg, 0.68mmol) agitating solution in THF (3mL) add 2.5M lithium hydroxide aqueous solution (1.5mL, 3.8mmol).This reactant mixture is stirred overnight at 60 DEG C.With 15%HCl (aqueous solution), this aqueous solution is acidified to pH=5, Extract with EtOAc.The organic layer of merging is concentrated in vacuo, obtains title compound.

C) 2'-cyano group-5-(4-hydroxyl pyrrolidine-3-base epoxide)-4'-methyl-N-((R)-1-(6-picoline-3- Base) ethyl) biphenyl-3-carboxylic acid amides

To 5-(1-(tertbutyloxycarbonyl)-4-hydroxyl pyrrolidine-3-base epoxide)-2'-cyano group-4'-methyl biphenyl-3-carboxylic acid (60mg, 0.14mol) solution in N,N-dimethylformamide (1mL) adds (R)-1-(6-picoline-3-base) second Amine dihydrochloride (60mg, 0.29mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphoric acid Salt (120mg, 0.32mmol) and N, N-diisopropylethylamine (400 μ L, 2.3mmol).By this reactant mixture 25 DEG C of stirrings 16 hours, by preparation HPLC purification, obtain the product of Boc-protection, be dissolved in CH₂Cl₂(5mL), trifluoroacetic acid is added (1mL).This mixture is stirred at room temperature 2hr, is then concentrated in vacuo.By preparation HPLC purification residue, obtain whole product Thing, for pale solid.

LC-MS:457.3[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 8.90 (d, 1H, J=7.6Hz), 8.46 (bs, 1H), 7.80 (bs, 1H), 7.70-7.55 (m, 4H), 7.52 (bs, 1H), 7.33 (bs, 1H), 7.20 (d, 1H, J=8.2Hz), 5.28 (bs, 1H), 5.16 (m, 1H), 4.65 (bs, 1H), 4.16 (bs, 1H), 3.50-3.25 (m, 2H), 3.05 (dd, 1H, J= 11.7,4.4Hz), 2.88 (d, 1H, J=12.6Hz), 2.73 (d, 1H, J=11.7Hz), 2.43 (s, 3H), 2.41 (s, 3H), 1.49 (d, 3H, J=6.9Hz).

Compound 340

(R)-5-((dimethylamino) methyl)-4'-methyl-N-(1-(6-picoline-3-base) ethyl) biphenyl-3-carboxylic Amide

A) the bromo-5-of 3-((dimethylamino) methyl) essence of Niobe

By bromo-for 3-5-acyl radical methyl benzoate (200mg, 0.82mmol), methanol (3mL), the THF of 2.0M dimethylamine is molten Liquid (0.3mL, 6mmol), zinc dichloride (30mg, 0.22mmol) and the mixture of sodium cyanoborohydride (200mg, 3.2mmol) 1h is stirred at 0 DEG C.This mixture is diluted, by EtOAc (15mL x3) aqueous layer extracted with water (10mL).Use anhydrous MgSO₄It is dried and closes And organic layer, concentrate.By Silica gel chromatography residue, obtain title compound.

B) 5-((dimethylamino) methyl)-4'-methyl biphenyl-3-carboxylate

By bromo-for 3-5-((dimethylamino) methyl) essence of Niobe (50mg, 0.18mmol), p-in nitrogen atmosphere Tolyl boric acid (30mg, 0.22mmol), four (triphenyl phasphine)-palladiums (0) (10mg, 0.009mmol), N,N-dimethylformamide (0.5mL) mixture with toluene (1.5mL) carries out microwave irradiation 1h at 110 DEG C.After cooling, dilute this mixing with water (15mL) Thing, extracts with EtOAc (15mL x3).Use anhydrous MgSO₄It is dried the organic layer merged, is concentrated in vacuo.Pure by flash chromatography Change residue, obtain title compound.

C) 5-((dimethylamino) methyl)-4'-methyl biphenyl-3-carboxylic acid

To 5-((dimethylamino) methyl)-4'-methyl biphenyl-3-carboxylate methyl ester (90mg, 0.32mmol) at 1,4-bis-Agitating solution in alkane (1.5mL) and water (1.5mL) adds Lithium hydrate (20mg, 0.83mmol).This reaction is mixed Thing is stirred at room temperature 2h, then uses NH₄Cl aqueous solution processes, and extracts with EtOAc (15mL x3).Use anhydrous MgSO₄It is dried and merges Organic layer, concentrate.By Silica gel chromatography residue, obtain title compound.¹HNMR(CD₃OD,400MHz):8.29 (s, 1H), 7.79 (s, 1H), 7.60 (s, 1H), 7.59 (d, J=8.0Hz, 2H), 7.28 (d, J=8.0Hz, 2H), 4.27 (s, 2H),2.81(s,6H),2.38(s,3H)。

D) (R)-5-((dimethylamino) methyl)-4'-methyl-N-(1-(6-picoline-3-base) ethyl) biphenyl-3- Carboxylic acid amides

To 5-((dimethylamino) methyl)-4'-methyl biphenyl-3-carboxylic acid (20mg, 0.074mmol) at N, N-dimethyl In solution in Methanamide (1mL) add (R)-1-(6-picoline-3-base) ethylamine dihydrochloride (40mg, 0.19mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (60mg, 0.16mmol) and N, N-bis-are different Propylethylamine (200 μ L, 1.15mmol).This reactant mixture is stirred 16 hours at 25 DEG C, by preparation HPLC purification, To end-product.

LC-MS:388.3[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 8.93 (d, 1H, J=7.8Hz), 8.48 (d, 1H, J=2.2Hz), 8.01 (t, 1H, J=1.4Hz), 7.75 (bs, 1H), 7.70-7.65 (m, 2H), 7.62 (d, 2H, J= 8.1Hz), 7.31 (d, 2H, J=8.0Hz), 7.21 (d, 1H, J=8.0Hz), 5.19 (m, 1H), 3.48 (s, 2H), 2.43 (s, 3H), 2.36 (s, 3H), 2.17 (s, 6H), 1.52 (d, 3H, J=7.1Hz).

Compound 342

3-(2-(diethylamino)-1-hydroxyethyl)-5-(5-picoline-2-base)-N-((R)-1-(6-methyl pyrrole Pyridine-3-base) ethyl) Benzoylamide

A) the bromo-5-of 3-(oxirane-2-base) essence of Niobe

At 0 DEG C, within 10 minute time limit, to 3-bromo-5-vinylbenzoate (1.00g, 4.15mmol) at CH₂Cl₂ (40mL) in the agitating solution in, branch divides addition metachloroperbenzoic acid (70% purity, 1.43g, 5.80mmol).By this mixing Thing warms to room temperature, and stirs 2 hours, is then poured upon on saturated sodium bicarbonate (250mL).With ethyl acetate (3x100mL) Extract this mixture, use Na₂SO₄It is dried the extract merged, concentrates.By column chromatography (0-50%EtOAc/ hexane) purification Residue, obtains title compound, for yellow oil.¹H NMR (400MHz, DMSO-d6): 7.92 (t, 1H, J= 1.7Hz), 7.86 (t, 1H, J=1.5Hz), 7.78 (t, 1H, J=1.7Hz), 4.09 (q, 1H, J=2.5Hz), 3.87 (s, 3H),3.17-3.14(m,1H),2.92-2.90(m,1H)。

B) the bromo-5-of 3-(1-(diethylamino)-2-hydroxyethyl) essence of Niobe

In 20mL reaction vessel merge the bromo-5-of 3-(oxirane-2-base) essence of Niobe (0.10g, 0.39mmol), Ethanol (10mL) and diethylamine (120 μ L, 1.2mmol).By this mixture 50 DEG C of heated overnight, then concentrate.By preparation Type HPLC (100x21.2mmC18 post, CH₃CN/ water [10mM Et₂NH]) purification residue, obtain title compound.

LC-MS:331.7[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 7.95 (t, 1H, J=1.7Hz), 7.91 (t, 1H, J=1.7Hz), 7.80 (t, 1H, J=1.7Hz), 5.28 (brs, 1H), 4.66 (t, 1H, J=6.5Hz), 3.86 (s, 3H), 2.57-2.51 (m, 2H), 2.48-2.43 (m, 4H), 0.86 (t, 6H, J=7.0Hz).

C) 3-(2-(diethylamino)-1-hydroxyethyl)-5-(5-picoline-2-base) essence of Niobe

In argon gas atmosphere by bromo-for 3-5-(2-(diethylamino)-1-hydroxyethyl) essence of Niobe (80mg, 0.24mmol), 5-methyl-2-(tributylstamlyl) pyridine (100 μ L, 0.30mmol), four (triphenyl phasphine)-palladiums (0) The mixture of (14mg, 0.012mmol) and toluene (2.6mL) carries out microwave irradiation 2 hours at 120 DEG C.This mixture is cooled down To room temperature, it is poured into saline (20mL), extracts by ethyl acetate (3x20mL).Use Na₂SO₄Being dried the extract merged, vacuum is dense Contracting.By column chromatography (0-100%EtOAc/ hexane) purification residue, obtain title compound, for yellow oil.LC- MS:343.7[M+1]⁺。

D) 3-(2-(diethylamino)-1-hydroxyethyl)-5-(5-picoline-2-base) benzoic acid

3-(2-(diethylamino)-1-hydroxyethyl)-5-(5-picoline-2-base) is merged in 20mL reaction vessel Essence of Niobe (50mg, 0.15mmol), oxolane (10mL) and Lithium hydrate (8.7mg, 0.36mmol).By this mixture Heat 3 hours at 50 DEG C.After cooling, process this mixture with 7M HCl/water solution (52 μ L, 0.36mmol), concentrate, obtain thick Produced compounds, is directly used in next step.

E) 3-(2-(diethylamino)-1-hydroxyethyl)-5-(5-picoline-2-base)-N-((R)-1-(6-methyl Pyridin-3-yl) ethyl) Benzoylamide

To 3-(2-(diethylamino)-1-hydroxyethyl)-5-(5-picoline-2-base) benzoic acid (30mg, 0.075mmol) solution in N,N-dimethylformamide (5mL) adds (R)-1-(6-picoline-3-base) ethamine two Hydrochlorate (100mg, 0.48mmol), N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (160mg, 0.42mmol) and N, N-diisopropylethylamine (300 μ L, 1.7mmol).This reactant mixture is stirred 16 at 25 DEG C Hour, by preparation HPLC (100x21.2mm C18 post, CH₃CN/ water [10mM Et₂NH]) purification, obtain title product.

LC-MS:447.6[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 8.96 (d, 1H, J=8.0Hz), 8.54 (bs, 1H), 8.49 (bs, 1H), 8.38 (bs, 1H), 8.19 (bs, 1H), 7.93 (d, 1H, J=8.1Hz), 7.87 (bs, 1H), 7.77- 7.65 (m, 2H), 7.22 (d, 1H, J=8.1Hz), 5.21 (m, 1H), 5.06 (bs, 1H), 4.72 (bs, 1H), 3.40-3.30 (m, 2H), 2.65-2.50 (m, 4H), 2.43 (s, 3H), 2.35 (s, 3H), 1.53 (d, 3H, J=7.0Hz), 0.92 (t, 6H, J =7.1Hz).

Compound 365

5-(1-hydroxyl-2-morpholinoethyl)-4'-methyl-N-((6-picoline-3-base) methyl) biphenyl-3-carboxylic acyl Amine

A) 3-bromo-5-formylbenzoate

3-formylbenzoate (10.0g, 66.6mmol) and sulphuric acid (653g, 6.66mol) is merged in round-bottomed flask.? It is dividedly in some parts N-bromine butanimide (14.23g, 79.9mmol) in 10 minutes time limits, this reaction system is stirred in room temperature Mix 3h, then this mixture is poured on ice.Filter the white precipitate formed, wash with cold water (5x100mL), from water-second Recrystallization in alcohol, obtains title compound, for white solid (12.98g, 76.6%).LC-MS:227.0[M-1]^-；¹H NMR (400MHz, DMSO-d6): 10.05 (s, 1H), 8.40 (t, 1H, J=1.5Hz), 8.3 (d, 2H, J=1.5Hz).

B) 5-formoxyl-4'-methyl biphenyl-3-carboxylic acid

In nitrogen atmosphere to 3-bromo-5-formylbenzoate (8.0g, 34.9mmol), p-tolyl boric acid (9.5g, 70mmol), the mixture of toluene (300mL), cesium carbonate (28g, 87mmol) and water (25mL) adds four (triphenyl phasphine) palladium (0) (2.0g,1.7mmol).This mixture is heated 5h at reflux.After cooling, filter this mixture by Celite, use EtOAc washs filter cake.Use saline wash filtrate, be dried, concentrate.By using dichloromethane: the post color of methanol gradient (0-5%) Spectrometry purification residue, obtains title compound (4.8g, 51%).LC-MS:239.0[M-1]^-。

C) 5-formoxyl-4'-methyl-N-((6-picoline-3-base) methyl) biphenyl-3-carboxylic acid amides

5-formoxyl-4'-methyl biphenyl-3-carboxylic acid (3.00g, 12.5mmol), (6-methyl pyrrole is merged in round-bottomed flask Pyridine-3-base) methylamine (1.91g, 15.6mmol), N, N-diisopropylethylamine (6.46g, 49.9mmol) and N, N-dimethyl formyl Amine (97mL).Once add N, N, N ', N '-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea hexafluorophosphate (9.50g, 25.0mmol), this mixture is heated 2h at 60 DEG C.After cooling, this mixture is poured over saturated sodium bicarbonate (200mL) On.Extract by ethyl acetate (3x100mL).It is dried the extract of merging with sodium sulfate, is concentrated in vacuo.By using dichloromethane Alkane: the column chromatography eluting residue of methanol gradient (0-10%), obtains title compound.LC-MS:346.2[M+1]⁺；¹HNMR (400MHz, DMSO-d6): 10.14 (s, 1H), 8.46-8.43 (m, 2H), 8.37-8.33 (m, 2H), 7.72 (d, 2H, J= 8.0Hz), 7.64 (dd, 1H, J=8.0Hz), 7.34 (d, 2H, J=7.9Hz), 7.22 (d, 2H, J=7.9Hz), 4.51 (d, 2H, J=5.9Hz), 2.44 (s, 3H), 2.37 (s, 3H).

D) 4'-methyl-N-((6-picoline-3-base) methyl)-5-(oxirane-2-base) biphenyl-3-carboxylic acid amides

By cold for the sodium hydride (mineral oil solution of 60%, 0.85g, 21.2mmol) mixture in dimethyl sulfoxide (75mL) But to-10 DEG C.Iodate trimethyl sulfoxonium (4.66g, 21.2mmol) in DMSO (25mL) is dripped within the 10min time limit. This mixture is warmed to room temperature, is stirred for 1 hour.This mixture is cooled to 0 DEG C, dripped at DMSO within 10 minute time limit 5-formoxyl-4'-methyl-N-((6-picoline-3-base) methyl) biphenyl-3-carboxylic acid amides in (25mL) (3.65g, 10.6mmol).This mixture is warmed to room temperature, stirs 1 hour.This mixture is poured on ice, uses ethyl acetate (3x150mL) extraction.It is dried the extract of merging with sodium sulfate, is concentrated in vacuo.By using dichloromethane: methanol gradient (2- 10%) this mixture column chromatography eluting, obtains title compound, for yellow oil.LC-MS:358.8[M+1]⁺。

E) 5-(1-hydroxyl-2-morpholinoethyl)-4'-methyl-N-((6-picoline-3-base) methyl) biphenyl-3-carboxylic Amide

4'-methyl-N-((6-picoline-3-base) methyl)-5-(oxirane-2-is merged in 20mL reaction vessel Base) biphenyl-3-carboxylic acid amides (15mg, 0.042mmol), ethanol (2mL) and morpholine (13mg, 0.15mmol).This mixture is existed 50 DEG C of heated overnight.Decompression remove volatile material, by preparation HPLC purification residue (100x21.2mm C18 post, CH₃CN/ water [10mM Et₂NH]), obtain title product.

LC-MS:446.2[M+1]⁺；¹H NMR (400MHz, DMSO-d6): 9.13 (t, 1H, J=5.8Hz), 8.40 (d, 1H, J=2.3Hz), 8.00 (t, 1H, J=1.7Hz), 7.80 (s, 1H), 7.76 (s, 1H), 7.62 (d, 3H, J=8.2Hz), 7.30 (d, 2H, J=7.8Hz), 7.26 (d, 1H, J=7.8Hz), 5.21 (d, 1H, J=4.0Hz), 4.87-4.80 (m, 1H), 4.47 (d, 2H, J=5.8Hz), 3.56 (t, 4H, J=4.6Hz), 2.57-2.52 (m, 2H), 2.48-2.44 (m, 4H), 2.43 (s,3H),2.35(s,3H)。

Applicable reagent, raw material and pure can be well known to a person skilled in the art according to the above-mentioned method enumerated and use The change method synthesis representational compound of the present invention.

Test

Test based on cell (such as calcium current enters or electrophysiologic testing) can be used, use biochemical test (such as With P2X₂And P2X₃The binding tests of receptor) evaluate compound provided herein, or can be at ANIMAL PAIN or urinary function mould Type is evaluated compound provided herein.The example of test is as described below.

Including various sensation and sympathetic ganglion (such as Dorsal root (DRG), vagus nerve inferior ganglion (ND), trident god Through (TG) and superior cervical ganglion (SCG)) various tissues in, and also purine receptor can be expressed in smooth muscle cell P2X₂And P2X₃(Burnstock,Trends Pharmacol.Sci.27:166-76,2006).In several regions, coexpression P2X₂And P2X₃Receptor, functional study is confirmed the existence of different dimerization (heteromeric) P2X_2/3Receptor, its characteristic is different from those Same dimerization (homomeric) receptor.Comprise and P2X additionally, describe₃The P2X that first membrane-spanning domain merges₂N-terminal extracellular territory Chimeric P2X_2/3Receptor；These chimeric channel maintain same dimerization P2X₃The pharmacological characteristics of receptor, adds same dimerization simultaneously P2X₂Non-desensitization phenotype (Neelands et al. Br.J.Pharmacol.140:202-10,2003) of receptor.Chimerical receptor Non-desensitization performance is particularly suited for screening.

The member of P2X family be part gate non-selective cation channel, can by use electro physiology method or Its activity of sign is flowed into by using calcium sensitivity fluorescent dye to measure calcium ion.Agonist, such as ATP or ATP analog, example Application (α β MeATP, Sigma-Aldrich) such as α, β-methylene adenosine 5'-triphosphate causes channel opener, thus produces electricity Stream and calcium current enter (Bianchi et al. Eur.J.Pharmacol.376:127-38,1999).

The passage that the compounds affect that can provide by measuring the present invention is caused by ATP, α β MeATP or other agonist Open aptitude tests compound provided herein is to P2X₃And P2X_2/3The antagonist activities of receptor.Receptor active functional Test includes, but are not limited to: (i) is flowed into by the fluorimetric calcium ion of calcium sensitivity dyestuff；(ii) electro physiology is passed through The ion inflow produced because of channel opener that method measures.When associated receptor is allos in mammal or Amphibian cell During expression, these methods may be used for evaluating channel function.These methods can be also used in rodent primary neuronal and Other mammal primary cells being often expressed as paid close attention to receptor and cell line evaluate compound provided herein.

Biochemistry means can also be used to evaluate compound further and to combine P2X₃And P2X_2/3Energy in terms of receptor Power.

Compound ability in changing sensation and the conduction of autonomic nervous system signal, wherein known receptor can also be evaluated There is effect (such as bladder input signal conduction, the sensory nerve pain sensation).Finally, can be in phase well known by persons skilled in the art Close in animal model and test compound provided herein, such as nerve, inflammatory or visceral pain model or urinary incontinence mould in vivo Type.

Thering is provided following biological Examples is for example compound provided herein, pharmaceutical composition and method, but not It is considered as limiting its scope by any way.

Calcium pickup is tested

Clone and cell line:

By people P2X₃(registration number NM_002559), P2X₂(registration number NM_170682) and P of Rats 2X₃(registration number NM_ 031075) and P2X₂(registration number NM_053656) be cloned into mammalian expression vector (such as pcDNA5/TO or pcDNA3Invitrogen).People P2X is generated as described in Neelands et al._2/3Chimera is cloned, then as mentioned above by its gram Grand enter expression vector.By using the transient transfection of the transfection of standard liposomal mediation or by generating stable transfection of each receptor Expressed receptor in cell (such as HEK293 or 1321N1 (available from ECACC)).In order to express P2X_2/3Different dimerization receptor, will P2X₃Expression vector is stably transfected into the most stably expresses P2X₂Cell line.Pharmacological method is used to separate P2X_2/3Different aggressiveness Function.Cell line is maintained in DMEM+5%Glutamax, the selectivity antibiotic of proper level and 10% heat inactivation FBS.

P2X Antagonist assay:

The ability entered by measuring the calcium current of suppression agonist induction determines the compound functional activity to P2X receptor.Survey Examination compound is to P2X_2/3Chimera, P2X₃With aggressiveness or P2X_2/3The antagonist activities of different aggressiveness.When each screening sky starts, survey Determine agonist EC₅₀.Then predetermined agonist concentration (EC is used_50-90Depend on cell line) measure compound % as stimulus object Suppression or IC50s.Agonist used is α β MeATP, ATP or other ATP analog.Can survey under the concentration of 1pM-10 μM Examination compound.

In order to test antagonist activities, within 18-24 hour, it is seeded in 96 or 384 by expressing the cell being suitable for receptor before the test On orifice plate.On the same day of test, at most supplementing 10mM CaCl₂Hank buffer salt solution (HBSS) in cell load Calcium sensitivity fluorescent dye (such as Fluo-4no wash reagent-Invitrogen cat#F36206 or BD^TMPBX Calcium Assay Kit-BD cat#640175).At 37 DEG C of incubation plates, then at equilibrium at room temperature.Fluorescence imaging plate is used to read Go out device (such as FLIPR^TETRA, Molecular Devices, Sunnyvale, CA) measure the calcium current of agonist induction and enter antagonism and make With.This test includes two stages: the pretreatment phase, followed by process the phase.Compound can be tested as follows.With regard to the pretreatment phase Speech, joins in the cell comprising 100 μ L dye load media by the test compound in HBSS of 50 μ L 3x concentration, with Reach final concentration of 1x and test compound.For the process phase, setting interval (1-30 minute) after the pre-treatment, add 50 μ L 1x tests compound+4x Agonist solutions, produces 1X compound and the final concentration of 1X agonist.Glimmering at 0.1-3 second measuring space The excitation wavelength of light-wherein is 494nM and a length of 515nM of transmitted wave.Response is determined as (adding the peak fluorescence after agonist) Deduct (Baseline fluorescence before treatment).Percentage calculation will be suppressed as follows:

IC is determined by the dose response data using GraphPad Prizm to analyze in 4 parameter logistic fit₅₀Value.

Electro physiology is tested

Whole-cell patch-clamp:

Multiclamp700A patch clamp amplifier and Clampex is used to obtain program (Molecular Devices Corporation) whole-cell recording technique is carried out.Whole-cell recording technique is available from P2X₃And/or P2X₂Expression vector is stablized or transient transfection 1321N1 or HEK cell.Apply the solution 1-3s time limit by gravity flowing 8-valve delivery system or use speed to become Dynaflow Perfusion system (Cellectricon Inc.) applies the millisecond time limit.Internal pipette solution can include 140mM cesium chloride, 10mM EGTA and at the 5mM Hepes of pH7.2；Standard external solution is 140mM NaCl, 5mM KCl, 1mM CaCl₂、2mM MgCl₂, 25mM Hepes and 10mM glucose.By record as to the electricity being spaced the response of of short duration applying agonist at 1-3min Stream obtains concentration-response curve, wherein irrigates the external solution of routine in interval procedure.For the curve that is inhibited, short The time limit that cell pre-applied antagonist determines is given before applying agonist+antagonist temporarily.To whole experimental concentration series The time limit that speech antagonist pre-applied and agonist+agonist apply is constant.Measure-60 or-80 millivolts of voltage clampings The electric current that agonist in cell causes.By using GraphPad Prizm or Origin to analyze in 4 parameter logistic fit Dose response data determines IC₅₀Value.

Automatic two-electrode voltage pincers record:

By using the enzymolysis of collagenase (Worthington, 2mg/ml) from separating xenopus (Xenopus) ovum mother Cell (Nasco).Respectively inject P2X then to oocyte₃、P2X₂Or P2X₂And P2X₃The combination of mRNA.Each oocyte accepts ～the concentration of 64nl is～the RNA aqueous solution of 0.01 μ g/ μ l.At 16 DEG C, the oocyte through injection is stored in standard ovum mother carefully In born of the same parents Incubation solution ND96, it comprises (in terms of mM) 96NaCl, 2KCl, 1MgCl₂、1-5CaCl₂With 50 μ g/ml gentamycins.? In oocyte, within after injection 1-5 days, observe the electric current of the agonist induction that P2X channel opener produces.For automatic record, 8 oocytes are put into recording room.When filling 3M KCl solution, penetrate 2 to each oocyte and there is 0.5-1MOhm electricity The glass electrode of resistance.Electrode reach and oocyte puncture and are in (OPUSXPRESS1.1, Molecular under software control devices Corporation).In 96 orifice plates, prepare solution, and used 8 channel pipettor with machine mode aspirate into Oocyte recording room.Measure the inhibitory action of antagonist in the following manner: calculate when using in the presence of test compound Residual current % compared with the peak point current under agonist individualism when agonist stimulates oocyte.Oocyte is executed The order adding solution is as follows: be firstly added concrete concentration (such as EC₅₀、EC₈₀Or EC₉₀) agonist to cause peak response.? After pulse, with ND96, oocyte is washed a few minutes.It is subsequently adding the test compound of concrete concentration, is subsequently adding identical dense The compound of degree and agonist.Compound concentration can be 0.3-10,000nM.By use GraphPad Prizm or Dose response data in Origin software analysis 4 parameter logistic fit determines IC₅₀Value.

Manual two-electrode voltage clamps:

Manually puncture each oocyte with 2 electrodes and use oocyte to clamp amplifier (Warner Instrument Corp.) obtain software and measure, with Clampex (Molecular Devices Corporation), the electric current that agonist causes.Make Solution and applied as described above is delivered with gravity flowing.Without and with the electricity measuring agonist induction in the presence of antagonist Stream.Test the antagonist of a series of concentration so that curve suppressed as described above.

Selective screening:

Test suppression P2X₃And/or P2X_2/3The compound of the activation activity to other P2X receptors, to determine that they are to spy The selectivity of opposite sex P2X family member.Tested exemplary acceptors includes, but are not limited to P2X1, P2X₂、P2X4、P2X5、P2X6 And P2X7.Test type for selectively measuring may include that 1) in the cell of heterogenous expression associated receptor, agonist lures The calcium current led enters；2) receptor suppression in the mammalian cell or Xenopus oocytes of the paid close attention to receptor of heterogenous expression Electrophysiological detection.Method and data analysis are with above-mentioned to P2X₃And P2X_2/3Described similar.

Radioligand combines:

Carry out Radioligand binding assays to determine that test compound is to P2X₃With dimerization and P2X_2/3Different dimerization receptor affine Power.These researchs additionally provide to be seen clearly antagonism mechanisms is valuable.For P2X₃And P2X_2/3The radioligand of receptor The conventional method of Binding experiment is described by Jarvis et al. J.Pharmacol.Exp.Ther.10:407-16,2004.

In short, by instantaneous or stably express P2X₃Or P2X_2/3The cell of receptor prepares cell membrane.Cell is made to grow to converge Close, washing, separate, be stored in-80 DEG C to using as precipitation.Some researchs may need in cell membrane preparation process Add apyrase or hexokinase (Sigma-Aldrich) with by the receptor of ATP-mediation during film preparation Mistake sensitization is minimized.By cell precipitation is again suspended in homogenizing buffer, homogenizes, is centrifuged to obtaining film Precipitation prepares film.Standard method is used to measure total protein concentration.

Use revision carries out replacement binding from Jarvis et al. method.With optimal conditions, buffering is being combined In liquid, use radioligand ([3H] A-317491, Abbott) or other high-affinity radioligands and certain limit not Ligand Competition experiment is carried out with concentration determination compound.The radioligand using certain limit concentration carries out part saturation Research.By terminating whole association reactions through the filter of glass fibre filter speed.Washing film, incubation in scintillation solution, use scinticounting Device counts.4-parameter logistics Hill's equation is used to determine IC₅₀Value.

Drug metabolism and pharmacokinetics

Caco-2 permeability:

According to Yee, the method described in Pharm.Res.14:763-6,1997 measures Caco-2 permeability.Make Caco-2 Cell was filter support (filter support) (Falcon HTS porous adds system) upper growth 14 days.From top and the end Outer side chamber removes culture medium, at 37 DEG C, in water bath chader with 50 circulation/min 0.3ml top cushion of pre-warm Buffer precincubation monolayer 0.75 hour outside at the bottom of liquid and 1.0ml.Top buffer is by Hanks balanced salt solution, 25mM mono-water Close D-Glucose, 20mM MES biological buffer, 1.25mMCaCl₂With 0.5mM MgCl₂(pH6.5) composition.Buffer at the end Liquid is hydrated D-Glucose, 20mM HEPES biological buffer, 1.25mM CaCl by Hanks balanced salt solution, 25mM mono-₂With 0.5mM MgCl₂(pH7.4) composition.At the end of precincubation, remove culture medium, by buffer soln (10 μ of test compound M) join in top chamber.Make admixture move to comprising in the hole of buffer, incubation 1hr at fresh the end.Divided by LC/MS Analysis measures medicine concentration in buffer.

Occur that slope calculates flow velocity (F, quality/time), according to following equations meter according to the accumulation of substrate on receiver-side Calculation apparent permeability coefficients (Papp):

Papp (cm/sec)=(F*VD)/(SA*MD)

Wherein SA is the surface area (0.3cm of transhipment²), VD is donor volume (0.3ml), donor side medicine-feeding when MD is t=0 The total amount of thing.Total data represents 2 meansigma methodss added.Monolayer integrity is determined according to fluorescein transhipment.

People's dofetilide combines:

Can by express HERG product HEK-293 cell cell stick with paste be suspended in 10-times of volume at 25 DEG C with comprising 1mM MgCl₂, the 2M HCl of 10mM KCl adjusts to the 50mM Tris buffer of pH7.5.Use Polytron homogenizer even Changing cell (peak power 20 seconds), at 4 DEG C with 48,000g is centrifuged 20 minutes.Again suspendible precipitation, homogenizes, in the same fashion Recentrifuge.Discarding the supernatant obtained, suspendible finally precipitates (the 50mM Tris buffer of 10-times of volume) again, in maximum Power homogenizes 20 seconds.Decile film homogenate, is stored in-80 DEG C to using.It is used for using protein by aliquot Measure Quick kit and the determination of protein concentration of ARVO SX card reader (Wallac).All operations, stock solution and set For all remaining on ice.For saturation is tested, test with 200 μ l cumulative volumes.By at room temperature, do not having Or have incubation 20 μ l in the presence of 10 μMs of dofetilide final concentrations (20 μ l) [³H]-dofetilide and 160 μ l film homogenate (20- 30 μ g protein/hole) 60min measures the total or saturation of non-specific binding respectively.By soaking by Polyetherimide (PEI) The glass fiber filter paper of stain, use Skatron cellular collector rapid vacuum filtration terminate whole incubations, then use 50mM Tris buffer (pH7.5, at 25 DEG C) washes twice.Count being subject to by using Packard LS enumerator to carry out liquid scintillation The radioactivity that body combines is carried out quantitatively.

In order to being at war with property is tested, in semilog (semi-log) mode by diluted chemical compound on 96 hole polypropylene boards For 4-point diluent.First all dilute with DMSO, then proceed to comprise 1mM MgCl₂, the 50mM Tris of 10mM KCl Buffer (pH7.5, at 25 DEG C) so that final DMSO concentration is equal to 1%.Bread board distributes compound (4 μ in triplicate l).Respectively total binding and Non-Specific Binding wells are set in 6 holes as carrier and the dofetilide of 10 μMs of final concentrations.Preparation The radioligand of 5.6x final concentration, joins this solution in each hole (36 μ l).Flash by adding YSi poly-L-Lysine Proximity Assay (SPA) pearl (50 μ l, 1mg/ hole) and film (110 μ l, 20 μ g/ holes) firing test.At room temperature continued incubation 60min.By plate in room temperature incubation 3 hours again, so that pearl sedimentation.By counting WALLAC MICROBETA plate enumerator to receptor In conjunction with radioactivity carry out quantitatively.

HERG tests:

The HEK293 cell of stable expression HERG potassium channel is used for electrophysiologic study.Can be at its elsewhere (Zhou et al. Biophys.J.74:230-41,1998) method of this passage in stable transfection HEK cell is found.Previous test My god, from culture flask, gather cell, be placed in the standard limit dulbecco minimum essential medium Dulbecco (MEM) containing 10% hyclone (FCS) Glass cover-slip on.By the storage of cells of bed board 37 DEG C, maintain 95%O₂/ 5%CO₂In incubator in atmosphere.Adopting 15-28hr after collection studies cell.

Standard patch clamp techniques research HERG electric current is used in full cell pattern.In this experimentation, surpass to cell The standard external solution (mM) of perfusion (superfused) following composition: NaCl, 130；KCl,4；CaCl₂,2；MgCl₂,1；Fructus Vitis viniferae Sugar, 10；HEPES,5；PH7.4 and NaOH.When the standard internal solution of the following composition (mM) of perfusion, use patch clamp amplifier Whole-cell recording technique: KCl is carried out with the Patch pipettes (patch pipette) with 1-3MOhm resistance, 130；MgATP,5； MgCl₂,1.0；HEPES,10；EGTA5, pH7.2 and KOH.Only accept that there is the contact resistance (access less than 15MOhm Resistance) and tight resistance (seal resistance) > those cells of 1GOhm are for further experiment.By series electricity Resistance compensates (resistance compensation) and is applied to 80% maximum.Do not carry out leak subtraction.But, acceptable The size of current that contact resistance depends on record and the Series resistance compensation level that can use safely.Complete full cell structure With the enough time (> 5min using pipette solution to carry out cell dialysis) after, standard voltage protocol is applied to cell to draw Play membrane current.Voltage schemes is as follows.Make film from the holding current potential depolarization of-80mV to+40mV1000ms.It is to return after this step (speed 0.5mV msec-1) is declined to the voltage ramps (voltage ramp) keeping current potential.By this voltage schemes in whole reality Within during testing the most every 4 seconds, it is applied to cell (0.25Hz).Measure the peak of the pact-40mV caused during oblique line (ramp) Value current amplitude.In external solution, once obtain the stable current-responsive caused, then will be with peristaltic pump by vehicle (0.5% The standard external solution of DMSO) application 10-20min.As long as the current-responsive amplitude caused under the conditions of vehicle control changes Minimum, then apply the test compound 10min time limit of 0.3,1,3 or 10mM.The 10min time limit includes providing solution through pump from solution Reservoir is by the time of pipe to recording room.After indoor drug level sufficiently achieves trial concentration, cell and compound solution Time of contact is more than 5min.The washing phase of followed by 10-20min is to evaluate reversibility.Finally make cells contacting high dose many Fei Lite (5mM) i.e. one species specificity IKr blocker, to evaluate insensitive endogeneous electrical currents.

All experiments is all carried out in room temperature (23 ± 1 DEG C).The membrane current caused with computer on-line operation record, clamps with sheet Amplifier and special data are analyzed software and are filtered at 500-1KHz (Bessel-3dB), sample at 1-2KHz.Use computer from Line measures the peak current amplitude occurred at about-40mV.

Vehicle control condition and have in the presence of medicine calculate 10 amplitudes arithmetic mean of instantaneous value.According to calibration Current value, use equation below to be tested every time in the decline percentage ratio of IN: IN=(1-ID/IC) x100, wherein ID be Current average in the presence of medicine, IC is the meansigma methods of electric current under collating condition.Each drug level or time are matched Reference substance individually test, the arithmetic mean of instantaneous value every time tested is defined as result of study.

Half-life in people's hepatomicrosome (HLM):

Will test compound (1 μM) and 3.3mM MgCl₂At 100mM potassium phosphate together with 0.78mg/mLHLM (HL101) In buffer (pH7.4) at 37 DEG C, in 96-deep-well plates incubation.This reactant mixture is divided into two groups: non-P450 and P450 Group.Only NADPH is joined in the reactant mixture of P450 group.The sample of P450 group is gathered in 0,10,30 and 60min time point Aliquot, wherein 0min time point represents the time when NADPH joins P450 group reactant mixture.-10 and 65min time point gathers the aliquot of the sample of non-P450 group.Use and comprise the decile that the extraction of interior target acetonitrile solution gathers Part.Protein (2000rpm, 15min) by centrifuge rotation fall precipitation.By the change in LC/MS/MS system measurement supernatant Compound concentration.Elimination half life values is obtained with the figure of time relationship by drawing the compound/natural logrithm of internal standard peak area ratio.Pass through The slope of the line of best fit of each point creates metabolic rate (k).Equation below is used to convert it into elimination half life values:

Half-life=ln2/k.

Internal potency test

P2X can be tested in various human body diseases animal models₃、P2X_2/3Antagonist, described model include nerve, Inflammatory and visceral pain model and bladder functional mode.Difference according to concrete model and compound PK feature before guidance model or Give P2X afterwards₃Antagonist.Route of administration can include intraperitoneal (i.p.), subcutaneous (s.c.), oral (p.o.), intravenous (i.v.), in sheath in (i.t.) or vola.The terminal of these researchs can include that the mechanicalness being suitable for model as described below is different The painful response of perseverance pain, thermal hyperalgesia, cold allodynia, formalin induction reduces, writhing and contraction reduce or The bladder mechanical sense changed.

Formalin model:

In vola, give the different time before formalin give to test compound.By the weak solution (25-of formalin 1-2.5% formaldehyde/the saline of 50 μ L) s.c. is administered into the left back pawl plantar surface under slight compacting.At once by animal after injection Being placed in the screen deck in the observation ward of cleaning, it is sufficiently large so that animal is freely-movable in research process.Use hands Work scoring or automatic scoring are to behavior scoring.

Manual scoring: use triple channel intervalometer, observer records supported weight and declines (t₁), pawl lift (t₂) and lick/ Sting/shake (t₃) time (t in seconds).According to Dubuisson and Dennis, the method for Pain, 4:161-174,1977, Application formula t₁+2t₂+3t₃/ 180 weighted results, wherein 180s is to the estimation time being incremented by every time.It is incremented by with alternately 3min and obtains Take behavior, time started=0min (i.e. 0-3min, 6-9min etc.), terminate at 60min.

Automatic scoring: the little bonding jumper being weighed as 0.5g is placed in left claw.Give formalin, by animal not by about Put into use electromagnetic detector system (Automated Nociception Analyzer, University of bundle California, San Diego) observation ward inside.Electrically to record the number of times that pawl is shunk back.

The inflammatory pain that ATP and α β-methylene ATP (α β meATP) induces:

Rat is administered by most 1 μM ol α β meATP, ATP, adenosine or the PBS at most 100 μ L volumes through subcutaneous Enter the dorsal surface of rear solid end.At once being placed on by animal inside clear observation ward after injection, it is large enough to make animal free movement. Shrink back with 20 interval records and lick the time limit licked to evaluate anti-injury (nocifensive) behavior.Use above-mentioned to formalin Manually or automatically method described in test measures response.Other performance testings can include evaluating mechanical allodynia and heat Hyperpathia.In order to test, before injection agonist, give compound.

Freund's complete adjuvant model (CFA):

Animal accepts to comprise 100 μ g mycobacterium tuberculosis (Mycobacterium under isoflurane anesthesia Tuberculosis) the 100 μ L complete Freund's adjuvant s.c. of bacterial strain H37Ra inject the plantar surfaces of toe of right rear solid end.Swell in 1h after administration Swollen visible with inflammation.Impression injury test can start by 24h after CFA is administered.General 0.5-12hr before testing gives chemical combination Thing.

The acute pain of antler glue induction:

Animal accepts 100 μ L2% antler glues under isoflurane anesthesia and is subcutaneously injected into the plantar surfaces of toe of right rear solid end.1h after administration Interior swelling and inflammation are visible.Impression injury test can start (Hargreaves et al. by 3-24h after antler glue is administered Pain,32:77-88,1988).General 0.5-12hr before testing gives compound.

Chronic constriction injury (CCI or Bennett model):

According to Bennett and Xie, the method described in Pain, 33:87-107,1988 completes CCI model.In short, different Under halothane anesthesia, by making right sciatic nerves in big midleg horizontal exposed through the blunt dissection of biceps femoris.Ischium god There is no adhesion organization through bifurcated proximal the most about 7mm nerve, around nerve, tighten 4.0 chromic catguts of 4 loose ligation.Ligature it Between space be about 1mm.Close wound in layers and close skin with staple or non-silk suture line.In the same fashion Process the animal of sham operated, in addition to not ligaturing sciatic nerve.Impression injury test within 7-21 days, can be carried out after surgery.Typically 0.5-12hr gives compound before testing.

Spinal nerves crosscutting (SNT or Chung model):

Under anaesthesia, rat is placed in aseptic plane with ventricumbent position.Implement L4-S2 medisection and separate from spinous process Left paraspinal muscle.According to Kim and Chung, the silk suture of the 4-0 silicon of the method described in Pain, 50:355-363,1992-process Line firmly ligatures L5 and L6 spinal nerves.Protection L4 spinal nerves is to prevent surgical injury modestly.With wound clip close skin and Animal is put back in its cage.Will display postoperative nerve afunction (neurological deficits) or be difficult to ornamenting and prolong Long rat gets rid of from experiment.Evaluate impression injury response (baseline) before animal surgery, then give test compound After different time points evaluation impression injury response.Impression injury test within 7-21 days, can be carried out after surgery.Typically in test Front 0.5-12hr gives compound.

The pain neuropathy of chemotherapy-induction:

One times/day of induction chemother neuropathy (total agent of taxol (Taxol) that 1mg/kg gives is given by alternately 4 days i.p. Amount=4mg/kg) (Polomano et al. Pain, 94:293-304,2001).Within 9-30 days, can carry out after taxol administration starts Impression injury test.General 0.5-12hr before testing gives compound.

Impression injury test:

Mechanical allodynia: use the machine to Chaplan et al. J.Neurosci.Methods53:55-63,1994 Previous-next method (the up-of Dixon, Ann.Rev.Pharmacol.Toxicol.20:441-462,1980 that tool threshold is improved Down method) carry out mechanical allodynia test.In order to evaluate tactile allodynia, rat is put into sieve The bright and clean lucite of net bottom plate is indoor so that it is adapt at least 15 minutes time limits.After adaptation, to each rat left (operation) foot Plantar surfaces of toe provides a series of von Frey monofilament.There is provided every time and continue 4-8 time limit second or until observe shrinking back of impression injury Till behavior.To shrink back, pawl is shunk back or is licked pawl and is considered as impression injury behavior response.Use Chaplan et al. Method described in J.Neurosci.Methods53:55-63,1994 calculates 50% withdrawal threshold.

Thermal hyperalgesia: use plantar test instrument (Ugo Basile), according to Hargreaves et al. Pain32:77-88, Technical measurement described in 1988 reaches the rear solid end withdrawal latencies of harmful thermostimulation.Radiant heat concentrates on the plantar surfaces of toe of homonymy pawl, Measure pawl withdrawal latencies.Pawl withdrawal latencies increases display hyperpathia and reverses.

Mechanical nociceptive feel allergy: pawl pressure test may be used for evaluating mechanical nociceptive feel allergy.In order to carry out this examination Test, such as Stein et al. Pharmacol.Biochem.Behav.31:451-455, described in 1988, use analgesymeter (Ugo Basile) measures the rear solid end withdrawal threshold (PWT) for noxious mechanical sexual stimulus.To can put on the maximum of rear solid end Terminal, at 250g, is set to shrinking back completely of pawl by weight set.PWT is measured once by every rat at each time point.

Cold allodynia: in order to measure cold allodynia, uses 50 μ L Han Mierdunshi syringes to be led to by 1 acetone Cross and below grid, apply the plantar surfaces of toe at pawl, animal of having stood on grid.This process is carried out 5 times, every minor tick 3min. To be aggressively shaken and be recorded as positive response, the time that record shake spends.Or, it is possible to use psychrolusia method tests cold exception Property pain, wherein animal is put into the degree of depth be 1.5-2.0cm's and temperature be the psychrolusia of 3-4 degree Celsius, counting pawl lifts Number of times.

Colorectal Distension (CRD):

Before guidance model, make animal fasting, but can arbitrarily fetch water 16h, then guidance model.By 5cm latex balloon even It is connected to by effusion meter and the barostat system that forms through the pressure control program of duct length.Under isoflurane anesthesia, by gas The capsule per anum insert end colon distance away from anus 5cm and fixing with root of the tail portion with adhesive tape.After anesthesia, animal is unrestricted Put into cleaning polypropylene cage so that it is adapt to 30min.Make air bag the most swollen with the incremental change of 5mm every 30s from 0-75mmHg Swollen.The colon threshold of reaction is defined as the induction pressure that abdominal part shrinks for the first time.Instruction Encelialgia abdominal part shrink with swell, grand Rise position, lick lick hypogastric region, homonymy oblique system contraction wave repeatedly inwardly rotates with homonymy hind leg, stretch, by hypogastric region to ground Plate extruding is relevant (Wesselman, Neurosci.Lett., 246:73-76,1998).Or, can put the electrodes into outside abdomen oblique Flesh system is to shrink abdominal part and carrying out electromyogram graphy record.Thus, in colon air bag gas replenishment process, EMG activity is entered Row is quantitatively.General 0.5-12hr before testing gives compound.

Acetic acid twisting is tested:

Rat i.p. gives 0.6% acetum (10ml/kg), and the quantity shrinking abdomen in 30min counts.One As before testing 0.5-12hr give compound.

Bladder afferent record:

In order to measure P2X₃And P2X_2/3The receptor suppression accurate effect in response of urinating, verification test compound regulates Input signal from bladder conducts.At Vlaskovska et al. J.Neuroscience, 21:5670-7,2001 and Bladder described in Cockayne et al. J.Physiol.567:621-39,2005/pelvic nerve goods are evaluated compound.Letter speech It, the holocriny urethra that overall separation is connected with lower vertebra and surrounding tissue, recording indoor oxygenate (5%CO₂And 95%O₂) Krebs solution carries out super perfusion to it.Conduit is inserted to carry out infusion in tube chamber to bladder by urethra.By second double channel catheter Insert bladder to measure intraluminal pressure and empty bladder.After getting out bladder, cut open the luxuriant pelvic nerve opening vertebra, insert The glass electrode of suction.Standard electrophysiologic methods is used to measure neural activity.After 60min stable phase, carry out repeatedly oblique line expansion (ramp distension), until incoming response is stable.This stable incoming response be used for comparing different disposal group it Between the incoming mechanical sensitivity of bladder.

Test Deng holding bladder contraction:

Anesthesia Female Sprague Ge-Dao Li Mus, tracheostomize, cannulated in carotid artery and femoral vein.Pass through laparotomy Enter bladder and ligature and crosscutting ureter.In order to carry out fluid infusion and piezometry, cannulated to bladder.

Post operation, to Bladder infusion saline, until causing the bladder contraction that stable volume is induced.Once obtain steady Fixed threshold volumetric and contraction frequency, then give compound and measure contraction frequency animal.

Bladder function Reperfu-sion and cystitis models:

Anesthetized animal, per urethra proceeded as above Guan Bi cystometry (Dmitrieva et al. Neuroscience78: 449-59,1997；Cockayne et al. Nature407:1011-5,2000).Per urethra inserts PE-10 polypropylene catheter to bladder. Each cystometrogram is by slowly irrigating normal saline to bladder by transurethral catheter, then by pressure transducer record and filling The pressure composition that note is relevant.The contraction that will be greater than predetermined threshold is construed to Voiding Contractions.For each cystometrogram, record is main The dynamic volume (micturition threshold) shunk when occurring and the number of contractions of each cystometrogram.It is then determined that the effect of compound.

Cystometrogram can also obtain in cystitis animal model, wherein injects ring by 24hr before cystometry Phosphamide (150mg/kg, i.p.) or stimulate bladder by being infused to many 1% acetic acid during cystometry.

Thering is provided synthesis described herein and biological Examples is for example compound provided herein, drug regimen Thing and method, but limit its scope never in any form.In these embodiments, all temperature all by degree Celsius (unless another There is instruction).The compound can prepared according to method provided herein and its biologically active data are as shown in following table.According to such as Upper described method synthesizes representational compound.

Typical compound provided herein

According to or following compounds can be prepared according to synthetic method as herein described.Calcium pickup proceeded as above is tested And the activity of each compound is expressed as:

+ compound display hP2X_2/3H IC₅₀>1000nM

++ compound display hP2X_2/3H IC₅₀501-1000nM

+++ compound display hP2X_2/3H IC₅₀100-500nM

++++compound display hP2X_2/3H IC₅₀<100

* compound display hP2X₃IC₅₀>1000nM

* compound display hP2X₃IC₅₀501-1000nM

* * compound display hP2X₃IC₅₀100-500nM

* * * compound display hP2X₃IC₅₀<100

Table 1: the Ca of typical compound flows into IC₅₀

From foregoing description, the apparent compositions provided herein of those skilled in the art and method can be carried out each Plant modification and change.All this modification belonged in scope of the appended claims are all designated and are included therein.

By quoting all open source literatures (including, but are not limited to patents and patent applications) quoted from this specification and Enter herein, just as by quote special with each single for each piece open source literature is completely introduced the same.

Based on automatization, it is purchased chemical name software program by use and generates at least specifying in the application and enumerating A little the compounds of this invention chemical names and and dependently verifying.The representational program performing this function includes Open Eye The Lexichem that Software, Inc. sell names the Autonom Software instrument that instrument and MDL, Inc. sell.Institute Show in the example that chemical name is different with described structure, be as the criterion with shown structure.

Use/ DRAW makes chemical constitution shown in this article.Herein structure occurs on carbon, oxygen or nitrogen-atoms Arbitrarily open quantivalence all indicate that to there is hydrogen former, during wherein chiral centre is present in structure, but do not show in chirality The concrete spatial chemistry of the heart, the enantiomer relevant to chiral structure is included by this structure.

Specific embodiments of the present invention include:

1. there is the compound of formula 1:

Wherein

A, B and W are each independently selected from CR⁴；

X ' is selected from CR^4aAnd N；

L is-C (R^2aR^2b)-；

R¹Selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxyl C₁-C₄Alkyl, C₃-C₇Cycloalkanes Base-C₁-C₄Alkyl or 4-7 unit Heterocyclylalkyl-C₁-C₄Alkyl；

R^2aAnd R^2bIt is each independently selected from hydrogen, C₁-C₄Alkyl or hydroxyl C₁-C₄Alkyl；

R³It is substituted or unsubstituted C₁-C₆Alkyl；CH(OH)R^3a、OR^3a、CN、COR^3a、COOR^3a、SOR^3a、SO₂R^3a、 CONR^3aR^3b、SONR^3aR^3bOr SO₂NR^3aR^3b；

R^3aIt is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, Substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl；

R^3bIt is H, substituted or unsubstituted C₁-C₆Alkyl；Or R^3aAnd R^3bForm the cycloheteroalkyl ring of 3-7 atom together；

R⁴It is each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted acyl group, replacement or unsubstituted Acylamino-, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio group, substituted or unsubstituted alkoxy carbonyl group, take Generation or unsubstituted alkyl virtue amino, substituted or unsubstituted amino, substituted or unsubstituted aryl alkyl, sulfo group, substituted Sulfo group, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted amino-sulfonyl, replacement or Unsubstituted alkyl sulphonyl, substituted or unsubstituted aryl sulfonyl, azido, substituted or unsubstituted carbamoyl, Carboxyl, cyano group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted dialkylamino, Halogen, nitro and sulfydryl；R^4aAnd R^4bBe each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted acyl group, Substituted or unsubstituted acylamino-, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio group, substituted or unsubstituted Alkoxyl, substituted or unsubstituted alkoxy carbonyl group, substituted or unsubstituted alkyl virtue amino, substituted or unsubstituted arylalkoxy Base, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, sulfo group, substituted sulphur Base, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted amino-sulfonyl, replacement or not Substituted alkyl sulphonyl, substituted or unsubstituted aryl sulfonyl, azido, substituted or unsubstituted carbamoyl, carboxylic Base, cyano group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halogen Element, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted miscellaneous alkyl, hydroxyl, nitro and sulfydryl；

And subscript m ' selected from 0-4；

Condition is

I) R is worked as³It is CO₂Me、SO₂Ph or OR^3aTime, R¹It it not unsubstituted phenyl；

Ii) R is worked as³It is SO₂-(4-methylpiperazine-1-yl) or SO₂-(thiomorpholine-1-base), and when X ' is CH, R^4bIt is not H；

Iii) R is worked as³Be Me or replaced by alkoxyl methyl time, R¹It it not substituted phenyl；

Iv) R is worked as³It is CO₂During H, R^4bIt is Cl, F, Br, Me, Et, OMe or CF₃；

V) working as X ' is CR^4a, R³It is CONR^3aR^3b, and R^3aWhen being H, R^3bIt not substituted n-pentyl, substituted pentynyl, take The benzyl in generation, substituted phenethyl, substituted thienyl ethyl or substituted thiazolylethyl；And

Vi) R is worked as¹It is 5-6 unit heterocycloalkylmethyl and R³It is CO₂During Me or n-Pr, R^4bIt not Cl or 4-F；

Or its pharmaceutically acceptable salt, N-oxide, solvate, prodrug, stereoisomer, tautomeride or coordination Element variant.

2. the compound of specific embodiments 1, wherein A, B and W are individually CH.

3. the compound of any one of specific embodiments 1-2, wherein L is selected from-CH₂-、

-CHMe-、-CMe₂-、-CH(CH₂OH)-and-CH (CH₂CH₂OH)-。

4. the compound of any one of specific embodiments 1-2, wherein L is selected from-CH₂-and

-CHMe-。

5. the compound of specific embodiments 1, wherein said compound be formula 2a, 2b, 2c,

The compound of 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m or 2n:

Wherein

X’、R¹、R^3a、R^3b、R^4a、R^4bWith m ' is as described in specific embodiments 1；R^2aIt is H, Me, CH₂OH or CH₂CH₂OH；And Het is substituted or unsubstituted Heterocyclylalkyl；Or it is its pharmaceutically acceptable salt, solvate, N-oxide, prodrug, vertical Body isomer, tautomeride or isotopic variations.

6. the compound of any one of specific embodiments 1-5, wherein subscript m ' it is 1,2 or 3.

7. the compound of any one of specific embodiments 1-5, wherein subscript m ' it is 1.

8. the compound of any one of specific embodiments 1-7, the most each R^4bIt is H, C independently₁-C₄Alkyl, halo C₁-C₄ Alkyl, CN, NO₂Or halogen.

9. the compound of specific embodiments 1, wherein said compound be formula 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, The compound of 3j, 3k, 3l, 3m or 3n:

Wherein

X’、R¹、R^3a、R^3b、R^4aAnd R^4bAs described in specific embodiments 1；R^2aIt is H, Me, CH₂OH or CH₂CH₂OH；And Het It it is substituted or unsubstituted Heterocyclylalkyl；Or it is its pharmaceutically acceptable salt, solvate, N-oxide, prodrug, three-dimensional different Structure body, tautomeride or isotopic variations.

10. the compound of any one of specific embodiments 5-9, wherein said compound be formula 2b, 2c, 2h, 2i, 3b, 3c, The compound of 3h or 3i；And R^3aIt is H.

The compound of 11. any one of specific embodiments 1-9, wherein R^3aIt it is substituted or unsubstituted alkyl.

The compound of 12. any one of specific embodiments 1-9, wherein R^3aBe Me, Et, i-Pr, n-Pr, i-Bu, t-Bu, CF₃、CH₂CF₃Or benzyl.

The compound of 13. any one of specific embodiments 1-9, wherein R^3aIt it is substituted methyl.

The compound of 14. any one of specific embodiments 1-9, wherein R^3aIt is methoxy, methoxy ethyl, dimethyl Amino methyl or dimethyl aminoethyl.

The compound of 15. any one of specific embodiments 1-9, wherein R^3aIt is hetervaromatic methyl, heteroarylethyl, heterocycle alkane Ylmethyl or Heterocyclylalkyl ethyl.

The compound of 16. any one of specific embodiments 1-9, wherein R^3aIt is pyridylmethyl, piperidino methyl, piperazinyl Methyl, pyrrolidinylmethyl, morpholinyl methyl, pyridyl-ethyl group, piperidinoethyl, piperazinyl, pyrrolidinyl ethyl or Morpholinyl ethyl.

The compound of 17. any one of specific embodiments 1-9, wherein R^3aIt is cyclopropyl, cyclopenta, Cvclopropvlmethvl or ring Phenyl-methyl.

The compound of 18. any one of specific embodiments 1-9, wherein R^3aIt it is substituted or unsubstituted heteroaryl.

The compound of 19. any one of specific embodiments 1-9, wherein R^3aIt is substituted or unsubstituted pyridine radicals, pyrazinyl Or pyrimidine radicals.

The compound of 20. any one of specific embodiments 1-9, wherein R^3aIt it is substituted or unsubstituted phenyl.

The compound of 21. any one of specific embodiments 1-9, wherein R^3aBe pyrrole radicals, furyl, thienyl, pyrazolyl, Imidazole radicals,Oxazolyl, thiazolyl, triazolyl, thiadiazolyl group, it is unsubstituted or is replaced by alkyl or haloalkyl.

The compound of 22. any one of specific embodiments 1-9, wherein R^3aSelected from substituted or unsubstituted quinolyl, isoquinoline Quinoline base, methylenedioxyphenyl, imidazopyridyl, benzoOxazolyl, benzothiazolyl and indyl.

The compound of 23. any one of specific embodiments 1-9, wherein R^3aIt is

And wherein subscript n 1 is selected from 1-5 and R^5aIt is each independently selected from hydrogen, substituted or unsubstituted alkyl, replacement or does not takes The acyl group in generation, substituted or unsubstituted acylamino-, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio group, replacement Or unsubstituted alkoxyl, aryloxy group, alkoxy carbonyl group, substituted alkoxy carbonyl group, substituted or unsubstituted alkyl virtue amino, aryl Alkoxyl, substituted alkoxy aryl, amino, aryl, substituted aryl, aryl alkyl, sulfo group, substituted sulfo group, substituted Sulfinyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted amino-sulfonyl, substituted or unsubstituted alkane Base sulfonyl, substituted or unsubstituted aryl sulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano group, Substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halogen, heteroaryl Epoxide, substituted or unsubstituted heteroaryl, substituted or unsubstituted miscellaneous alkyl, hydroxyl, nitro and sulfydryl.

The compound of 24. any one of specific embodiments 1-23, wherein R^3bIt is H or alkyl.

The compound of 25. any one of specific embodiments 1-23, wherein R^3bIt is H, Me, Et or i-Pr.

The compound of 26. any one of specific embodiments 1-23, wherein R^3bIt is H.

27. the compound of any one of specific embodiments 5-26, wherein Het is azetidine-1-base, pyrrolidine-1- Base, piperidin-1-yl, morpholine-1-base, piperazine-1-base and azepines-1-base, its unsubstituted or by one or more selected from alkane The group of base, alkoxyl, dialkylamino, halogen, haloalkyl, hydroxyl or hydroxy alkyl replaces.

The compound of 28. any one of specific embodiments 5-26, wherein Het is azetidine-1-base, pyrrolidine-1- Base, piperidin-1-yl, morpholine-1-base, piperazine-1-base and azepines-1-base, its unsubstituted or by one or more selected from Me, Et、i-Pr、OMe、NMe₂, Cl, F, OH or CF₃Group replace.

29. the compound of specific embodiments 1, wherein said compound is the compound of formula 4,5,6,7,8 or 9:

Wherein

X’、R¹、R^4bWith m ' is as described in specific embodiments 1；R^5cIt is R^5a；Subscript n 3 is 1,2 or 3；And R^5aAs being embodied as Described in scheme 23；

R^2aIt is H, Me, CH₂OH or CH₂CH₂OH；R^2bIt is H；And Q is-O-or-C (OH) H-；

Or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomeride or isotopic variations.

The compound of 30. specific embodiments 29, wherein subscript m ' it is 1,2 or 3.

The compound of 31. specific embodiments 29, wherein subscript m ' it is 1.

The compound of 32. specific embodiments 1, wherein said compound is the chemical combination of formula 10,11,12,13,14 or 15 Thing:

Wherein

X’、R¹、R^4aAnd R^4bAs described in specific embodiments 1；R^5cIt is H, Cl, F, Me, OMe or CF₃；And subscript n 3 be 1 or 2；

R^2aIt is H, Me, CH₂OH or CH₂CH₂OH；R^2bIt is H；And Q is-O-or-C (OH) H-；

Or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomeride or isotopic variations.

The compound of 33. specific embodiments 1, wherein Q is-O-.

34. the compound of specific embodiments 1, wherein Q is-C (OH) H-.

The compound of 35. any one of specific embodiments 1-34, wherein X ' is CR^4a；And R^4aIt is H, C₁-C₄Alkyl, halo C₁-C₄Alkyl, CN, NO₂Or halogen.

The compound of 36. any one of specific embodiments 1-34, wherein X ' is CR^4a；And R^4aIt is H, Me, CF₃、Cl、F、CN Or NO₂。

The compound of 37. any one of specific embodiments 1-34, wherein X ' is CR^4a；And R^4aIt is CN.

The compound of 38. any one of specific embodiments 1-34, wherein X ' is N.

The compound of 39. any one of specific embodiments 1-38, wherein R^4bIt is H, C₁-C₄Alkyl, halo C₁-C₄Alkyl or Halogen.

The compound of 40. any one of specific embodiments 1-38, wherein R^4bIt is H, Me, CF₃, Cl, Br or F.

The compound of 41. any one of specific embodiments 1-40, wherein R¹It is substituted or unsubstituted aryl or heteroaryl.

The compound of 42. any one of specific embodiments 1-40, wherein R¹It is substituted or unsubstituted bicyclic aryl, dicyclo Alkyl or bicyclic heteroaryl.

The compound of 43. any one of specific embodiments 1-40, wherein R¹It it is substituted or unsubstituted phenyl.

The compound of 44. any one of specific embodiments 1-40, wherein R¹It is substituted or unsubstituted pyridine radicals, pyrazine Base, thiazolyl or pyrimidine radicals.

The compound of 45. any one of specific embodiments 1-40, wherein R¹Selected from substituted or unsubstituted quinolyl, isoquinoline Quinoline base, methylenedioxyphenyl, imidazopyridyl, benzoOxazolyl, benzothiazolyl and indyl.

The compound of 46. any one of specific embodiments 1-40, wherein R¹It is

And wherein subscript n 2 is selected from 1-5 and R^5bIt is each independently selected from hydrogen, substituted or unsubstituted alkyl, replacement or does not takes The acyl group in generation, substituted or unsubstituted acylamino-, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio group, replacement Or unsubstituted alkoxyl, aryloxy group, alkoxy carbonyl group, substituted alkoxy carbonyl group, substituted or unsubstituted alkyl virtue amino, aryl Alkoxyl, substituted alkoxy aryl, amino, aryl, substituted aryl, aryl alkyl, sulfo group, substituted sulfo group, substituted Sulfinyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted amino-sulfonyl, substituted or unsubstituted alkane Base sulfonyl, substituted or unsubstituted aryl sulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano group, Substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halogen, heteroaryl Epoxide, substituted or unsubstituted heteroaryl, substituted or unsubstituted miscellaneous alkyl, hydroxyl, nitro and sulfydryl.

The compound of 47. specific embodiments 46, wherein subscript n 2 is 1,2 or 3.

The compound of 48. specific embodiments 46, wherein subscript n 2 is 1 or 2.

The compound of 49. any one of specific embodiments 1-40, wherein R¹It is

And wherein R^5bAs described in specific embodiments 40.

The compound of 50. any one of specific embodiments 46-49, the most each R^5bIndependently selected from H, alkyl, halogen, cyanogen Base, alkoxyl and haloalkyl.

The compound of 51. any one of specific embodiments 46-49, the most each R^5bIndependently selected from H, Me, Et, Pr, iso- Pr、Ph、Cl、F、Br、CN、OH、OMe、OEt、OPh、COPh、CO₂Me、CH₂-N-morpholino, CH₂-N-(4-Me-piperidino), NH₂、CONH₂、CF₃、CHF₂、OCF₃、OCHF₂, t-Bu, SMe, CH=CH-CO₂H、SOMe、SO₂Me、SO₂CF₃、SO₂NH₂、SO₃H、 SO₃Me, cyclopropyl, triazolyl, morpholinyl and pyridine radicals.

The compound of 52. any one of specific embodiments 46-49, the most each R^5bIndependently selected from H, Cl, F, Me, OMe or CF₃。

The compound of 53. any one of specific embodiments 1-40, wherein R¹Selected from hydroxyl C₁-C₄Alkyl, C₃-C₇Cycloalkyl- C₁-C₄Alkyl or 4-7 unit Heterocyclylalkyl-C₁-C₄Alkyl.

The compound of 54. any one of specific embodiments 1-40, wherein R¹Selected from hydroxymethyl, 1-hydroxyethyl and 2-hydroxyl Base ethyl.

The compound of 55. any one of specific embodiments 1-40, wherein R¹Selected from piperidin-1-yl methyl, piperazine-1-Ji Jia Base and morpholine-1-ylmethyl.

The compound of 56. any one of specific embodiments 1-55, wherein R^2aIt is hydrogen.

The compound of 57. any one of specific embodiments 1-55, wherein R^2aIt is methyl, hydroxymethyl or hydroxyethyl.

The compound of 58. any one of specific embodiments 1-55, wherein R^2aIt it is methyl.

The compound of 59. specific embodiments 1, the compound enumerated in table 1；

Or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomeride or isotopic variations.

The compound of 60. specific embodiments 1, is selected from

4'-methyl-5-(propane-1-sulfonyl)-biphenyl-3-carboxylic acid ((S)-2-hydroxyl-1-methyl-ethyl)-amide；

2,4'-dimethyl-5-(pyrrolidine-1-sulfonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-acyl Amine；

2'-cyano group-4'-methyl-5-(pyrrolidine-1-sulfonyl)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5- Base)-ethyl]-amide；

2'-cyano group-4'-methyl-5-(pyrrolidine-1-sulfonyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3-Ji Jia Base)-amide；

4'-methyl-5-(2-methyl-propan-1-sulfonyl)-biphenyl-3-carboxylic acid ((S)-2-hydroxyl-1-methyl-ethyl)- Amide；

5-Pentamethylene. sulfonyl-4'-methyl-biphen-3-carboxylic acid ((S)-2-hydroxyl-1-methyl-ethyl)-amide；

4'-methyl-5-(propane-2-sulfonyl)-biphenyl-3-carboxylic acid ((S)-2-hydroxyl-1-methyl-ethyl)-amide；

3-mesyl-5-(5-methvl-pyridinium-2-base)-N-(2-methyl-pvrimidine-5-ylmethyl)-Benzoylamide；

3-(4-hydroxy-pyrrolidine-3-base epoxide)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(2-methyl-phonetic Pyridine-5-base)-ethyl]-Benzoylamide；

5-(2-dimethylamino-1-hydroxy-ethyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-Ji Jia Base)-amide；

4'-methyl-5-(4-methyl-3-oxo-niperazin-1-carbonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-Ji Jia Base)-amide；

4'-methyl-5-(2-methyl-aziridin-1-carbonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-acyl Amine；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid ((S)-1-methyl-2-morpholine-4-base-ethyl)-acyl Amine；

5-[1-hydroxyl-2-(4-thyl-piperazin-1-base)-ethyl]-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium- 3-ylmethyl)-amide；With

5-{1-hydroxyl-2-[(2-hydroxy-ethyl)-Methyl-amino]-ethyl }-4'-methyl-biphen-3-carboxylic acid (6-first Base-pyridin-3-yl methyl)-amide；

Or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomeride or isotopic variations.

The compound of 61. specific embodiments 1, is selected from

4'-methyl-biphen-3,5-dicarboxylic acids 5-[(6-chloro-pyridin-3-yl methyl)-amide] 3-(isobutyl-methyl-acyl Amine)；

4'-methyl-biphen-3,5-dicarboxylic acids 3-(isobutyl-methyl-amide) 5-[(2-methyl-pvrimidine-5-ylmethyl)- Amide]；

4'-methyl-biphen-3,5-dicarboxylic acids 3-(isobutyl-methyl-amide) 5-{ [(R)-1-(2-methyl-pvrimidine-5- Base)-ethyl]-amide }；

4'-methyl-5-[(2-methyl-pvrimidine-5-ylmethyl)-carbamoyl]-biphenyl-3-carboxylic acid, ethyl ester；

5-(3,3-bis-fluoro-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (2-methyl-pvrimidine-5-Ji Jia Base)-amide；

4'-methyl-5-(piperidines-1-carbonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-amide；

5-(azepan-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [1-(4-chloro-3-Metlianesulfonyl-phenyl)-ethyl]-amide；

5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (2-methyl-pvrimidine-5-Ji Jia Base)-amide；

5-(azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-amide；

5-(3-methoxymethyl-pyrrolidin-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)- Amide；

4'-methyl-5-(2-Trifluoromethyl-pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-Ji Jia Base)-amide；

5-(3,3-difluoro-pyrrolidin-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)- Amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-trifluoromethylpyridin-3-base)-ethyl]-acyl Amine；

5-mesyl-4'-methyl-biphen-3-carboxylic acid 3-mesyl-4-methyl-benzylamide；

2'-cyano group-4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)- Amide；

4'-methyl-5-(propane-1-sulfonyl)-biphenyl-3-carboxylic acid 3-mesyl-4-methyl-benzylamide；

4'-methyl-5-(propane-1-sulfonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (2-methoxy-pyrimidine-5-ylmethyl)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (imidazo [1,2-a] pyridin-7-yl methyl)-acyl Amine；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (5-Methyl-pyrazin-2-ylmethyl)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]- Amide；

4'-methyl-5-(propane-1-sulfonyl)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]- Amide；

4'-methyl-5-(propane-1-sulfonyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-amide；

4'-methyl-5-(propane-1-sulfonyl)-biphenyl-3-carboxylic acid (imidazo [1,2-a] pyridin-7-yl methyl)-acyl Amine；

5-mesyl-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-amide；

2'-cyano group-4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)- Amide；

2'-cyano group-5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium- 3-ylmethyl)-amide；

2'-cyano group-5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-trifluoromethyl- Pyridin-3-yl methyl)-amide；

2'-cyano group-4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (6-chloro-pyridin-3-yl methyl)-acyl Amine；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid 3-mesyl-4-methyl-benzylamide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (1,1-dioxo-2,3-dihydro-1H-1 $ l%6& amp；-benzo [b] thiophene-6-ylmethyl)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (3-chloro-5-trifluoromethylpyridin-2-ylmethyl)- Amide；

5-(azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-trifluoromethylpyridin-3- Base)-ethyl]-amide；

5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine- 5-yl)-ethyl]-amide；

5-(azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methoxy-pyrimidine-5-base)- Ethyl]-amide；

5-(azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-second Base]-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (3,5-Dichloro-pendin-2-ylmethyl)-amide；

5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-trifluoromethyl-pyrrole Pyridine-3-base)-ethyl]-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [(S)-1-(6-difluoromethyl-pyridin-3-base)-2- Hydroxy-ethyl]-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (benzoAzoles-5-ylmethyl)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (6-chloro-pyridin-3-yl methyl)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [(S)-2-hydroxyl-1-(6-trifluoromethylpyridin- 3-yl)-ethyl]-amide；

5-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-Ji Jia Base)-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [(S)-2-hydroxyl-1-(2-methyl-pvrimidine-5- Base)-ethyl]-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid 4-chloro-3-[1,2,4] triazole-4-yl-benzyl acyl Amine；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [1-(6-methvl-pyridinium-3-base)-ethyl]-acyl Amine；

4'-methyl-5-(pyrrolidine-1-sulfonyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-amide；

3-(5-methvl-pyridinium-2-base)-N-(6-methvl-pyridinium-3-ylmethyl)-5-(pyrrolidine-1-sulfonyl)-benzene Methanamide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [(R)-1-(5-chloro-1-methyl isophthalic acid H-pyrazoles-4- Base)-ethyl]-amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]-amide；

3-(5-methvl-pyridinium-2-base)-N-[1-(6-methvl-pyridinium-3-base)-ethyl]-5-(pyrrolidine-1-carbonyl)- Benzoylamide；

3-(5-methvl-pyridinium-2-base)-N-(6-methvl-pyridinium-3-ylmethyl)-5-(pyrrolidine-1-carbonyl)-benzene first Amide；

3-(5-methvl-pyridinium-2-base)-5-(pyrrolidine-1-carbonyl)-N-(6-trifluoromethylpyridin-3-ylmethyl)- Benzoylamide；

5-(hexahydro-pyrrolo-[1,2-a] pyrazine-2-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3- Ylmethyl)-amide；

5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (3-chloro-5-trifluoromethyl-pyrrole Pyridine-2-ylmethyl)-amide；

5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-trifluoromethylpyridin-3-base Methyl)-amide；

5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-chloro-pyridin-3-yl methyl)- Amide；

5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-Ji Jia Base)-amide；

5-(3-Hydroxy-azetidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (3,5-Dichloro-pendin-2-Ji Jia Base)-amide；

3-(5-methvl-pyridinium-2-base)-5-(pyrrolidine-1-carbonyl)-N-[(R)-1-(6-trifluoromethylpyridin-3- Base)-ethyl]-Benzoylamide；

3-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-5-(5-methvl-pyridinium-2-base)-N-(6-trifluoromethylpyridin- 3-ylmethyl)-Benzoylamide；

3-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-fluoroform Base-pyridin-3-yl)-ethyl]-Benzoylamide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (6-methoxv-pyridine-3-ylmethyl)-amide；

5-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine- 5-yl)-ethyl]-amide；

5-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-trifluoromethyl-pyrrole Pyridine-3-base)-ethyl]-amide；

4'-methyl-biphen-3,5-dicarboxylic acids 3-(methvl-pyridinium-4-cyclohexylmethyl-amide) 5-[(6-methvl-pyridinium-3- Ylmethyl)-amide]；

4'-methyl-biphen-3,5-dicarboxylic acids 5-[(6-methvl-pyridinium-3-ylmethyl)-amide] 3-[methyl-(2,2,2- Trifluoro ethyl)-amide]；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-amide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-5-(pyrrolidine-1-carbonyl Base)-Benzoylamide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]-5-(pyrrolidine-1-carbonyl Base)-Benzoylamide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]- Amide；

3-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-Benzoylamide；

3-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-5-(5-methvl-pyridinium-2-base)-N-(6-methvl-pyridinium-3-base Methyl)-Benzoylamide；

4'-methyl-5-(2-methyl-propan-1-sulfonyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-acyl Amine；

4'-methyl-5-(2-methyl-propan-1-sulfonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-acyl Amine；

5-(2,5-dimethyl-pvrrolidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-Ji Jia Base)-amide；

5-(hexahydro-pyrrolo-[1,2-a] pyrazine-2-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl- Pyrimidine-5-base)-ethyl]-amide；

5-(hexahydro-pyrrolo-[1,2-a] pyrazine-2-carbonyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methyl- Pyridin-3-yl)-ethyl]-amide；

5-(7-aza-bicyclo [2.2.1] heptane-7-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3- Ylmethyl)-amide；

4'-methyl-5-(2-methyl-propan-1-sulfonyl)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5- Base)-ethyl]-amide；

5-((2R, 5R)-2,5-dimethyl-pvrrolidine-1-carbonyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium- 3-ylmethyl)-amide；

4'-methyl-5-(propane-2-sulfonyl)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]- Amide；

4'-methyl-5-(propane-2-sulfonyl)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]- Amide；

4'-methyl-5-(propane-2-sulfonyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-amide；

The bromo-5-of 4'-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-amide；

4'-methyl-5-(propane-2-sulfonyl)-biphenyl-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(R)-3-hydroxyl-1-(6-methvl-pyridinium-3-base)-propyl group]- Amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(S)-2-hydroxyl-1-(6-methoxv-pyridine-3-base)-second Base]-amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(S)-1-(6-difluoromethyl-pyridin-3-base)-2-hydroxyl-second Base]-amide；

5-ethylsulfonyl-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-amide；

5-ethylsulfonyl-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]-amide；

5-ethylsulfonyl-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-amide；

5-ethylsulfonyl-4'-methyl-biphen-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-amide；

The bromo-5-of 4'-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]-acyl Amine；

The bromo-5-of 4'-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-acyl Amine；

5-Pentamethylene. sulfonyl-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-acyl Amine；

5-Pentamethylene. sulfonyl-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]-acyl Amine；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(S)-2-hydroxyl-1-(2-methyl-pvrimidine-5-base)-ethyl]- Amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(R)-3-hydroxyl-1-(6-methoxv-pyridine-3-base)-the third Base]-amide；

4'-methyl-5-(pyrrolidine-1-carbonyl)-biphenyl-3-carboxylic acid (6-methyl isophthalic acid-epoxide-pyridin-3-yl methyl)-acyl Amine；

4'-methyl-5-(pyrimidine-2-yloxy)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]- Amide；

4'-methyl-5-(thiazol-2-yl epoxide)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]- Amide；

4'-methyl-5-(thiazol-2-yl epoxide)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]- Amide；

5-(Hydroxy-pyridine-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-acyl Amine；

5-(Hydroxy-pyridine-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)- Ethyl]-amide；

5-(2-Mehtoxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)-amide；

5-(2-Mehtoxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-second Base]-amide；

5-(2-Mehtoxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)-second Base]-amide；

2'-cyano group-5-(2-Mehtoxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

2'-cyano group-5-(2-Mehtoxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5- Base)-ethyl]-amide；

2'-cyano group-4'-methyl-5-(thiazol-2-yl epoxide)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5- Base)-ethyl]-amide；

2'-cyano group-4'-methyl-5-(thiazol-2-yl epoxide)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid (6-methyl isophthalic acid-epoxide-pyridin-3-yl methyl)-amide；

5-mesyl-4'-methyl-biphen-3-carboxylic acid [(S)-2-hydroxyl-1-(6-methvl-pyridinium-3-base)-ethyl]- Amide；

2'-cyano group-4'-methyl-5-(pyridine-2-base epoxide)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-5-(thiazol-2-yl oxygen Base)-Benzoylamide；

5-(Hydroxy-pyridine-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid (2-methyl-pvrimidine-5-ylmethyl)-acyl Amine；

5-(Hydroxy-pyridine-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)- Ethyl]-amide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]-5-(thiazol-2-yl oxygen Base)-Benzoylamide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(2-methyl-pvrimidine-5-base)-ethyl]-5-(pyridine-2-base oxygen Base)-Benzoylamide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-5-(pyridine-2-base oxygen Base)-Benzoylamide；

3-(HYDROXY-PHENYL-METHYL)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)- Ethyl]-Benzoylamide；

3-(HYDROXY-PHENYL-METHYL)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(2-methyl-pvrimidine-5-base)- Ethyl]-Benzoylamide；

2'-cyano group-5-(HYDROXY-PHENYL-METHYL)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5- Base)-ethyl]-amide；

2'-cyano group-5-(HYDROXY-PHENYL-METHYL)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

5-(Hydroxy-thiazol-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)- Ethyl]-amide；

5-(Hydroxy-thiazol-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)- Ethyl]-amide；

2'-cyano group-5-(Hydroxy-pyridine-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-amide；

2'-cyano group-5-(Hydroxy-pyridine-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-phonetic Pyridine-5-base)-ethyl]-amide；

3-(Hydroxy-pyridine-2-base-methyl)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(2-methyl-pvrimidine-5- Base)-ethyl]-Benzoylamide；

3-(Hydroxy-pyridine-2-base-methyl)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-Benzoylamide；

5-(1,2-dihydroxy-ethyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-second Base]-amide；

2'-cyano group-5-hydroxymethyl-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-second Base]-amide；

3-(Hydroxy-thiazol-2-base-methyl)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-Benzoylamide；

3-(Hydroxy-thiazol-2-base-methyl)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(2-methyl-pvrimidine-5- Base)-ethyl]-Benzoylamide；

2'-cyano group-5-(Hydroxy-thiazol-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-phonetic Pyridine-5-base)-ethyl]-amide；

2'-cyano group-5-(Hydroxy-thiazol-2-base-methyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-amide；

2'-cyano group-4'-methyl-5-(2,2,2-tri-fluoro-1-hydroxy-ethyl)-biphenyl-3-carboxylic acid [(R)-1-(6-methyl- Pyridin-3-yl)-ethyl]-amide；

2'-cyano group-4'-methyl-5-(2,2,2-tri-fluoro-1-hydroxy-ethyl)-biphenyl-3-carboxylic acid (6-methvl-pyridinium-3- Ylmethyl)-amide；

2'-cyano group-5-(1,2-dihydroxy-ethyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

5-(2-methoxyl group-1-methyl-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

5-(2-methoxyl group-1-methyl-ethoxy)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-ylmethyl)- Amide；

5-(2-Hydroxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]- Amide；

2'-cyano group-5-(2-Hydroxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

4'-methyl-5-(tetrahydro-furan-3-base epoxide)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)- Ethyl]-amide；

4'-methyl-5-(tetrahydro-furan-2-ylmethoxy)-biphenyl-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

2'-cyano group-5-(1-hydroxy-ethyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)- Ethyl]-amide；

2'-cyano group-4'-methyl-5-(tetrahydro-furan-2-ylmethoxy)-biphenyl-3-carboxylic acid [(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-amide；

2'-cyano group-4'-methyl-5-(tetrahydro-furan-3-ylmethoxy)-biphenyl-3-carboxylic acid [(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-amide；

2'-cyano group-4'-methyl-5-(tetrahydro-furan-3-base epoxide)-biphenyl-3-carboxylic acid [(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-amide；

2'-cyano group-5-(2-methoxyl group-1-methyl-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methyl- Pyridin-3-yl)-ethyl]-amide；

2'-cyano group-5-([1,4] twoAlkane-2-ylmethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methyl- Pyridin-3-yl)-ethyl]-amide；

5-(2,3-dihydroxy-propoxyl group)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-second Base]-amide；

5-(1-hydroxy-ethyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-acyl Amine；

5-(1-hydroxymethyl-2-Mehtoxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-amide；

3-(2-methoxyl group-1-methyl-ethoxy)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-Benzoylamide；

5-[hydroxyl-(3-methyl-3H-imidazol-4 yl)-methyl]-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-first Base-pyridin-3-yl)-ethyl]-amide；

3-(1-hydroxy-ethyl)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)-second Base]-Benzoylamide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-5-(tetrahydro-furan- 3-base epoxide)-Benzoylamide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-5-(tetrahydro-furan- 3-ylmethoxy)-Benzoylamide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-5-(tetrahydro-furan- 2-ylmethoxy)-Benzoylamide；

5-(4-dihydroxy-tetrahydro-furan-3-base epoxide)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium- 3-yl)-ethyl]-amide；

2'-cyano group-5-(4-dihydroxy-tetrahydro-furan-3-base epoxide)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-first Base-pyridin-3-yl)-ethyl]-amide；

3-(2-hydroxyl-1-methyl-ethoxy)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium- 3-yl)-ethyl]-Benzoylamide；

5-(2-hydroxyl-1-methyl-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-amide；

3-(2-hydroxyl-1-methoxy methyl-ethoxy)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methyl- Pyridin-3-yl)-ethyl]-Benzoylamide；

2'-cyano group-4'-methyl-5-(2,2,2-tri-fluoro-1-hydroxy-ethyl)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl- Pyrimidine-5-base)-ethyl]-amide；

5-[hydroxyl-(3-methyl-3H-imidazol-4 yl)-methyl]-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-first Base-pyrimidine-5-base)-ethyl]-amide；

2'-cyano group-4'-methyl-5-(tetrahydro-furan-3-base epoxide)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-phonetic Pyridine-5-base)-ethyl]-amide；

4'-methyl-5-(tetrahydro-furan-3-base epoxide)-biphenyl-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine-5-base)- Ethyl]-amide；

5-(4-dihydroxy-tetrahydro-furan-3-base epoxide)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-methyl-pvrimidine- 5-yl)-ethyl]-amide；

2'-cyano group-5-(4-dihydroxy-tetrahydro-furan-3-base epoxide)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(2-first Base-pyrimidine-5-base)-ethyl]-amide；

5-(1-hydroxyl-2-morpholine-4-base-ethyl)-4'-methyl-biphen-3-carboxylic acid (6-methvl-pyridinium-3-Ji Jia Base)-amide；

3-(5-Hydroxymethyl-thiazol-2-base epoxide)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-Benzoylamide；

2'-cyano group-4'-methyl-5-(4-methYl-thiazol-2-base epoxide)-biphenyl-3-carboxylic acid [(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-amide；

3-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-5-(4-methyl-thiophene Azoles-2-base epoxide)-Benzoylamide；

3-(benzothiazole-2-base epoxide)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-Benzoylamide；

2'-cyano group-5-(2-hydroxyl-1-methyl-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methyl-pyrrole Pyridine-3-base)-ethyl]-amide；

2'-cyano group-5-(1-hydroxymethyl-2-Mehtoxy-ethoxy)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6- Methvl-pyridinium-3-base)-ethyl]-amide；

5-(1-hydroxyl-propyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-ethyl]-acyl Amine；

5-(1,2-Dimethoxy-ethyl)-4'-methyl-biphen-3-carboxylic acid [(R)-1-(6-methvl-pyridinium-3-base)-second Base]-amide；With

3-(4-chloro-thiazol-2-yl epoxide)-5-(5-methvl-pyridinium-2-base)-N-[(R)-1-(6-methvl-pyridinium-3- Base)-ethyl]-Benzoylamide；

Or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomeride or isotopic variations.

62. pharmaceutical compositions, specific embodiments 1-61 comprising pharmaceutically acceptable carrier and pharmacy effective dose is arbitrary The compound of item.

The pharmaceutical composition of 63. specific embodiments 62, wherein said carrier is suitable for parenteral.

The pharmaceutical composition of 64. specific embodiments 62, wherein said carrier is suitable for oral administration.

The pharmaceutical composition of 65. specific embodiments 62, wherein said carrier is suitable for topical.

66. prevention or treatment have the disease of this mammal needed or the method for disease, it includes this mammal Give effectively to treat compound or the specific embodiment party of any one of specific embodiments 1-61 of disease or sanatory consumption The pharmaceutical composition of any one of case 62-65.

The method of 67. specific embodiments 66, wherein said disease or disease be selected from: pain, including acute, inflammatory and god Through property pain, chronic pain, have a toothache and have a headache, including migraine, cluster headache and tension headache, parkinson disease, A Er Ci Haimo disease and multiple sclerosis；Mediated or cause disease and the obstacle of neuroinflamation, encephalitis by neuroinflamation；Maincenter mediation Neuropsychopathy and obstacle, depressed, manic, bipolar disorder, anxiety, schizophrenia, eating disorders, sleep disorder and Cognitive disorder；Nerve and neurodegenerative disease and obstacle；Epilepsy and epilepsy；Prostate, bladder and intestinal dysfunction, urine loses Prohibit, hesitancy in urination, rectum anaphylaxis, fecal incontinence, benign prostatauxe and inflammatory bowel；Breathe and airway disorders and barrier Hinder, allergic rhinitis, asthma and RAD and chronic obstructive pulmonary disease；By inflammation mediated or cause the disease of inflammation And obstacle, arthritis, rheumatoid arthritis and osteoarthritis, myocardial infarction, autoimmune disease and obstacle；Itch/pruritus, Psoriasis；Fat；Disorders of lipid metabolism；Cancer；And nephropathy.

The method of 68. specific embodiments 67, wherein said disease or disease are parkinson disease.

The method of 69. specific embodiments 67, wherein said disease or disease are Alzheimer.

The method of 70. specific embodiments 67, wherein said disease or disease are pain.

The method of 71. specific embodiments 70, wherein said pain is relevant to selected from the following patient's condition: mastectomy is postoperative Pain syndrome, stump pain, phantom pain, oral cavity neuropathic pain, Charcot pain, toothache, venom, spider bites, insecticide Sting, postherpetic neuralgia, diabetic neuropathy, Reflex sympathetic dystrophy, trigeminal neuralgia, osteoarthrosis Inflammation, rheumatoid arthritis, fibromyalgia, Guillain-Barr é syndrome, Bernhards disease, Burning mouth syndrome (burning-mouth syndrome), two-way polyneuropathy, causalgia, sciatica, peripheral neuritis, polyneuritis, joint Section property neuritis (segmental neuritis), Gombault neuritis, neuronitis, cervico-brachial neuralgia, cranial neuralgia, knee joint Shape neuroglioma pain (geniculate neuralgia), glossopharyngeal neuralgia, migrainous neuralgia, idiopathic neuralgia Neuralgia (mammary neuralgia) in (idiopathic neuralgia), intercostal neuralgia, mammary gland, mandibular joint Neuralgia, Morton neuralgia, nasociliary neuralgia, occipital neuralgia, erythromelalgia, Sluder neuralgia, sphenopalatine god Dysmenorrhoea, supraorbital neuralgia, Vidian neuralgia, sinus headache (sinus headache), tension headache, childbirth (labor), Childbirth (childbirth), intestinal gas (intestinal gas), menstruation, cancer and wound.

The method of 72. specific embodiments 66, wherein said disease or disease are neuropathic pains.

The method of 73. specific embodiments 66, wherein said disease or disease are autoimmune diseases.

The method of 74. specific embodiments 66, wherein said disease or disease are inflammatory diseases or disease.

The method of 75. specific embodiments 66, wherein said disease or disease are neural or neurodegenerative disease or disease.

76. treatments suffer from the methods of mammal of at least one symptom, described symptom selected from contact capsaicin symptom, Because of burning of causing of contact conductane or irritation, because of contact burning of causing of light or irritation, symptoms of burns, because of contact tear-gas Bronchoconstriction that property poison causes or stimulation, and burn or irritation because of what contact acid caused, the method includes described Mammal gives effectively to treat compound or specific embodiments 62-of any one of specific embodiments 1-61 of symptom consumption The pharmaceutical composition of 65 any one.

77. for treating the compound of any one of specific embodiments 1-61 of disease or disease, wherein said disease or Disease is selected from: pain, including acute, inflammatory and neuropathic pain, chronic pain, has a toothache and has a headache, including migraine, cluster Headache and tension headache, parkinson disease, Alzheimer and multiple sclerosis；Mediated by neuroinflamation or cause neuritis The disease of disease and obstacle, encephalitis；The neuropsychopathy of maincenter mediation and obstacle, depressed, manic, bipolar disorder, anxiety, Schizophrenia, eating disorders, sleep disorder and cognitive disorder；Nerve and neurodegenerative disease and obstacle；Epilepsy and epilepsy are sent out Make；Prostate, bladder and intestinal dysfunction, urinary incontinence, hesitancy in urination, rectum anaphylaxis, fecal incontinence, benign prostate is fertile Big and inflammatory bowel；Breathe and airway disorders and obstacle, allergic rhinitis, asthma and RAD and chronic obstructive pulmonary Disease；By inflammation mediated or cause disease and the obstacle of inflammation, arthritis, rheumatoid arthritis and osteoarthritis, cardiac muscle stalk Extremely, autoimmune disease and obstacle, itch/pruritus, psoriasis；Fat；Disorders of lipid metabolism；Cancer；And nephropathy.

Claims (9)

1. compound, described compound is

Compound 28

Compound 99

Compound 106

Compound 113

Compound 118

Compound 122

Compound 123

Compound 135

Compound 145

Compound 146

Compound 150

Compound 151

Compound 155

Compound 160

Compound 173

Compound 174

Compound 175

Compound 178

Compound 179

Compound 180

Compound 181

Compound 182

Compound 202

Compound 220

Compound 225

Compound 244

Compound 264

Compound 265

Compound 266

Compound 269

Compound 270

Compound 271

Compound 272

Compound 273

Compound 274

Compound 275

Compound 276

Compound 277

Compound 286

Compound 287

Compound 291

Compound 292

Compound 307

Compound 319

Compound 322

Compound 328

Compound 329

Compound 331

Compound 332

Compound 333

Compound 334

Compound 335

Compound 339

Compound 342

Compound 344

Compound 345

Compound 347

Compound 348

Compound 349

Compound 350

Compound 351

Compound 352

Compound 355

Compound 356

Compound 357

Compound 364

Compound 369

Compound 371

Compound 372

Compound 374

Compound 375

Compound 376

Compound 384

Compound 385

Compound 386

Compound 387

And pharmaceutically acceptable salt.

2. pharmaceutical composition, it comprises the compound of claim 1 of pharmaceutically acceptable carrier and pharmacy effective dose.

3. the compound of claim 1 in preparation for treating the purposes in the medicine of disease or disease, wherein said disease or Disease is selected from: pain, by inflammation mediated or cause disease and the obstacle of inflammation, and autoimmune disease and obstacle.

4. the purposes of claim 3, wherein said disease or disease be selected from: acute, inflammatory and neuropathic pain, chronic pain, Toothache, headache and Encelialgia.

5. the purposes of claim 3, wherein said disease or disease be selected from: migraine, cluster headache and tension headache.

6. the purposes of claim 3, wherein said disease or disease be selected from: rheumatoid arthritis and osteoarthritis.

7. the purposes of claim 4, wherein said Encelialgia and gastroesophageal reflux disease, irritable bowel syndrome, inflammatory bowel, pancreas Gynecologys scorching, various or urologic complaints are correlated with.

8. the purposes of claim 3, wherein said disease or disease are selected from: mediated or cause the disease of neuroinflamation by neuroinflamation Disease and obstacle, and inflammatory bowel.

9. the purposes of claim 3, wherein said disease or disease are the pain relevant to menstruation.