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CN1406225A - Quinoline-4-carboxamide derivatives as NK-3 and NK-2 receptor antagonists - Google Patents

Quinoline-4-carboxamide derivatives as NK-3 and NK-2 receptor antagonists Download PDF

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Publication number
CN1406225A
CN1406225A CN99815753A CN99815753A CN1406225A CN 1406225 A CN1406225 A CN 1406225A CN 99815753 A CN99815753 A CN 99815753A CN 99815753 A CN99815753 A CN 99815753A CN 1406225 A CN1406225 A CN 1406225A
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Prior art keywords
compound
formula
phenyl
methyl
1har
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CN99815753A
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Inventor
C·法里纳
G·吉尔蒂纳
M·格鲁格尼
M·莫尔范
G·M·M·G·纳德勒
L·F·拉维格利尔
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Glaxo Smith Kline Laboratory
GlaxoSmithKline SpA
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Glaxo Smith Kline Laboratory
GlaxoSmithKline SpA
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Priority claimed from GBGB9825553.2A external-priority patent/GB9825553D0/en
Priority claimed from GBGB9825552.4A external-priority patent/GB9825552D0/en
Application filed by Glaxo Smith Kline Laboratory, GlaxoSmithKline SpA filed Critical Glaxo Smith Kline Laboratory
Publication of CN1406225A publication Critical patent/CN1406225A/en
Pending legal-status Critical Current

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Abstract

A compound, or a solvate or a salt thereof, of formula (I): wherein, Ar is an optionally substituted aryl or a C5-7 cycloalkdienyl group, or an optionally substituted C5-7 cycloalkyl group, or an optionally substituted single or fused ring aromatic heterocyclic group; R is hydrogen, linear or branched C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylalkyl, R1 represents hydrogen or up to three optional substituents selected from the list consisting of: C1-6 alkyl, C1-6 alkenyl, aryl, C1-6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, C1-6 alkoxycarbonyl, trifluoromethyl, acyloxy, amino or mono- and di-C1-6 alkylamino; R2 represents a moiety -(CH2)n-NY1Y2 wherein n is an integrer in the range of from 1 to 9, Y1 and Y2 are independently selected from C1-6- alkyl; C1-6 alkyl substituted with hydroxy, alkoxy, C1-6 alkylamino or bis (C1-6 alkyl)amino; C3-6 cycloalkyl; C4-6 azacycloalkyl; C1-6-alkenyl; aryl or aryl-C1-6-alkyl or Y1 and Y2 together with the nitrogen atom to which they are attached represent an optionally substituted N-linked single or fused ring heterocyclic group; R3 is branched or linear C1-6 alkyl, C3-7 cycloalkyl, C4-7 cycloalkylalkyl, optionally substituted aryl, or an optionally substituted single or fused ring aromatic heterocyclic group; and R4 represents hydrogen or C1-6 alkyl, R5 represents hydrogen or halogen; a process for preparing such compounds, a pharmaceutical composition comprising such compounds and the use of such compounds and composition in medicine.

Description

Quinoline-4-carboxamides derivatives as NK-3 and NK-2 receptor antagonist
The present invention relates to new compound, particularly new quinoline, prepare the method for described compound, contain the pharmaceutical composition of described compound, and the application of described compound in medicine.
Mammalian-derived peptides neurokinin B (NKB) belongs to tachykinin (TK) peptide family, and TK peptide family also comprises P material (SP) and neurokinin A (NKA).Existing pharmacology and molecular biology evidence show three kinds of hypotype (NK that exist the TK acceptor 1, NK 2And NK 3), and NKB preferentially is attached on the NK3 acceptor, though its also with lower avidity identification in addition two kinds of acceptors (people such as Maggi, 1993, J.Auton.Pharmacol., 13,23-93).
Peptide class NK optionally 3Receptor antagonist is known (Drapeau, 1990 Regul.Pept., 31,125-135), and the discovery based on peptide class NK3 receptor stimulant has proposed play a crucial role in the NKB adjusting that the nerve in tracheae, skin, spinal cord and black striatum path is imported by activating the NK3 acceptor (Myers and Undem, 1993, J.Physiol., 470,665-679; People such as Counture, 1993, Regul.Peptides, 46,426-429; Mccarson and Krause, 1994, J Neurosci., 14 (2), 712-720; People such as Arenas, 1991, J.Neurosci., 11,2332-8).Yet from metabolic angle, the peptide sample character of these known antagonists makes that their may be because too unstable and can not be as actual therapeutical agent.
Still autre action pendante International Patent Application PCT/EP98/03014 discloses some as non-peptide class NK-3 antagonist and have the compound of NK-2 antagonistic activity.Therefore think that these compounds have the potential application that prevents and treat the various clinical diseases that it is characterized in that tachykinin receptor, particularly NK-3 and NK-2 excessive activation.
We have found that the non-peptide class NK-3 agonist that an other class is new now, wherein from metabolic angle, the new antagonist of this class is much more stable than known peptide class NK-3 receptor antagonist, and has potential treatment application.The compounds of this invention also has the NK-2 antagonistic activity, thinks that therefore they have the potential application that prevents and treat the various clinical diseases that it is characterized in that tachykinin receptor, particularly NK-3 and NK-2 excessive activation.
These illnesss comprise respiratory disease, and for example chronic obstruction tuberculosis (COPD), asthma, tracheae reacted by force, cough; Inflammatory diseases is inflammatory bowel, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis and inflammatory pain for example; Neurogenic inflammation or peripheral neurophaty, transformation reactions be eczema and rhinitis for example; Disease of eye is eyes inflammation, conjunctivitis, vernal conjunctivitis etc. for example; Tetter, skin disorder and itch, for example skin pomphus and flush, contact dermatitis, atopic dermatitis, urticaria and other eczema-like dermatitis; Adverse immune response, for example the repulsion of transplanted tissue with immunostimulant or suppress for example systemic lupus erythematosus of relevant illness; Stomach and intestine (GI) obstacle and GI tract disease for example with the relevant illness of the former control of splanchnic nerve, for example ulcerative colitis, regional ileitis, irritable bowel syndrome (IBS), gastro oesophageal reflux disease (GORD) (GERD); The urinary incontinence and bladder function illness; Kidney disease (hereinafter being called " primary disease ").
Some The compounds of this invention also show the CNS activity, therefore can be used in particular for treating central nervous system disorder, for example anxiety, dysthymia disorders, psychosis and schizophrenia; Neurodegenerative disease is AIDS dependency dementia, Alzheimers type senile dementia, Alzheimer, mongolism, huntington's chorea, Parkinson's disease, dyskinesia and convulsibility disease (for example epilepsy) for example; Demyelinating disease is the sclerosis of multiple sclerosis and the amyotrophic lateral sclerosis outside and other neuropathy neuropathy and neurodynia of causing of diabetic neuropathy, AIDS dependency neuropathy, chemotherapy for example for example; Habituation venereal disease disease is alcoholism for example; The body illness relevant with stress; Reflex sympathetic dystrophy is for example takeed on/hand syndrome; Dysthymia; Eating disorder (for example ingestion of food disease); Fibrous tissue forms and collagen diseases, for example scleroderma and acidophilia fascioliasis; The blood flow venereal disease disease that is caused by vasorelaxation and vasospasm disease is stenocardia, migraine and Raynaud disease and pain or nociception for example, for example cause by above-mentioned illness or pain, the especially migraine relevant with above-mentioned disease in pain transmission (hereinafter being called " secondary disease ").
Formula (I) compound also can be used as the diagnostic tool of the degree (normal, excessively active or active deficiency) of mensuration neurokinin-3 and neurokinin-2 receptor active participation patient symptom.
The invention provides formula (I) compound or its solvate or salt: Wherein Ar is optional substituted aryl or C 5-7Cycloalkadienyl (cycloalkdienyl), or optional substituted C 5-7Cycloalkyl, or optional substituted monocycle or fused rings aromatic heterocyclic; R is hydrogen, straight or branched C 1-6Alkyl, C 3-7Cycloalkyl, C 3-7Cycloalkylalkyl; R 1Represent hydrogen or be selected from 3 optional substituting group: the C that are up to of following radicals 1-6Alkyl, C 1-6Alkenyl, aryl, C 1-6Alkoxyl group, hydroxyl, halogen, nitro, cyano group, carboxyl, formamyl, amino-sulfonyl, C 1-6Alkoxy carbonyl, trifluoromethyl, acyloxy, amino or a C 1-6Alkylamino or two C 1-6Alkylamino; R 2Representative-(CH 2) n-NY 1Y 2, wherein n is the integer of 1-9, Y 1And Y 2Be independently selected from C 1-6Alkyl; By hydroxyl, alkoxyl group, C 1-6Alkylamino or two (C 1-6Alkyl) the amino C that replaces 1-6Alkyl; C 3-6Cycloalkyl; C 4-6Azacycloalkyl; C 1-6Alkenyl; Aryl or aryl-C 1-6Alkyl, perhaps Y 1And Y 2Represent monocycle or the fused rings heterocyclic radical of choosing substituted N-connection wantonly with the nitrogen-atoms that they connected; R 3Be straight or branched C 1-6Alkyl, C 3-7Cycloalkyl, C 4-7Cycloalkylalkyl, optional substituted aryl or optional substituted monocycle or fused rings aromatic heterocyclic; And R 4Represent hydrogen or C 1-6Alkyl, R 5Represent hydrogen or halogen.
R 5The preferred hydrogen of representing.Another preferred aspect, R 5It is chlorine or bromine.
Suitably, optional substituted phenyl, unsubstituted phenyl or cyclohexyl of Ar representative.
Suitably, Ar represents cyclohexyl.
Ar preferably represents phenyl or cyclohexyl.
Suitably, R represents C 1-6Alkyl, for example methyl, ethyl or sec.-propyl.
One preferred aspect, R is an ethyl.Another preferred aspect, R is methyl or sec.-propyl.
Suitably, R 1Represent hydrogen, C 1-6Alkoxyl group is methoxyl group or hydroxyl for example.
R 1The preferred hydrogen of representing.Another preferred aspect, R 1Be methoxyl group or hydroxyl.
Suitably, NY 1Y 2Monocycle or fused rings heterocyclic radical that the optional substituted N-of representative connects.
List or annelated heterocycles base that suitable N-connects comprise such group, arbitrary monocycle wherein or fused rings are saturated or undersaturated, and form by 5 or 6 annular atomses, described annular atoms is chosen wantonly and is comprised the other heteroatoms that one or two is selected from O and N, and one of them or two annular atomses are chosen wantonly and replaced by following radicals: one or two oxo base or one or two hydroxyl, carboxyl, carboxyl C 1-6Alkyl, C 1-6Alkoxy carbonyl, aminocarboxyl, the optional C that is replaced by aromatic heterocyclic 1-6Alkyl-carbonyl, aryl carbonyl, aryl C 1-6Alkyl-carbonyl, carboxyl C 1-6Alkyl-carbonyl, carboxyl aryl carbonyl, amino, C 1-6Alkyl-carbonyl-amino, C 1-6Alkyl, C 1-6Hydroxyalkyl, aryl, aryl C 1-6Alkyl, C 3-7Cycloalkyl, optional substituted C 4-7Cycloalkenyl group, optional substituted C 4-7Azacycloalkyl, optional substituted C 4-7Diazacyclo alkyl, optional substituted C 4-7Oxa-azacycloalkyl, optional substituted C 4-7Thia azacycloalkyl, optional substituted C 4-7Thia nitrogen heterocyclic thiazolinyl, C 3-7Cycloalkylalkyl, hydroxyl C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkyl, two C 1-6Alkyl amino-carbonyl, two C 1-6Alkylamino C 1-6Alkyl-carbonyl, optional substituted C 4-7Azacycloalkyl C 1-6Alkyl-carbonyl, optional substituted C 4-7Diazacyclo alkyl C 1-6Alkyl-carbonyl, optional substituted C 4-7Oxa-azacycloalkyl C 1-6Alkyl-carbonyl, optional substituted carbonamidine, C 1-6Thio-alkyl amino-carbonyl, optional substituted nitroethylene base, amino-sulfonyl, two C 1-6Alkyl amino sulfonyl or optional substituted spiroheterocyclic or monocycle or fused rings aromatic heterocyclic, perhaps the substituting group on the adjacent ring atom forms carbocyclic ring; Described aryl or aromatic heterocyclic are optional by one or two C 1-6Alkyl, alkoxyl group, hydroxyl, halogen or haloalkyl replace; Wherein unless otherwise noted, otherwise defined optional being substituted is that expression is up to 3 substituting groups that are selected from following radicals and replaces: amino, alkylamino, alkyl, aryl, heterocyclic radical, alkylaryl, aralkyl, oxo, hydroxyl and nitrile.
Other heteroatoms is preferably N.
For list or annelated heterocycles base that N-connects, favourable optional substituting group is selected from carboxyl C 1-6Alkyl, aminocarboxyl, the optional C that is replaced by aromatic heterocyclic 1-6Alkyl-carbonyl, aryl carbonyl, aryl C 1-6Alkyl-carbonyl, carboxyl C 1-6Alkyl-carbonyl, carboxyl aryl carbonyl, amino, C 1-6Alkyl-carbonyl-amino, C 1-6Alkyl, C 1-6Hydroxyalkyl, aryl, aryl C 1-6Alkyl, C 3-7Cycloalkyl, optional substituted C 4-7Cycloalkenyl group, optional substituted C 4-7Azacycloalkyl, optional substituted C 4-7Diazacyclo alkyl, optional substituted C 4-7Oxa-azacycloalkyl, optional substituted C 4-7Thia azacycloalkyl, optional substituted C 4-7Thia nitrogen heterocyclic thiazolinyl, C 3-7Cycloalkylalkyl, hydroxyl C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkyl, two C 1-6Alkyl amino-carbonyl, two C 1-6Alkylamino C 1-6Alkyl-carbonyl, optional substituted C 4-7Azacycloalkyl C 1-6Alkyl-carbonyl, optional substituted C 4-7Diazacyclo alkyl C 1-6Alkyl-carbonyl, optional substituted C 4-7Oxa-azacycloalkyl C 1-6Alkyl-carbonyl, optional substituted carbonamidine, C 1-6Thio-alkyl amino-carbonyl, optional substituted nitroethylene base, amino-sulfonyl, two C 1-6Alkyl amino sulfonyl or optional substituted spiroheterocyclic; Wherein unless otherwise noted, otherwise defined optional being substituted is that expression is up to 3 substituting groups that are selected from following radicals and replaces: amino, alkylamino, alkyl, aryl, heterocyclic radical, alkylaryl, aralkyl, oxo, hydroxyl and nitrile.For list or fused ring heterocycle base that N-connects, the preferred optional substituting group comprises the sec.-propyl carbonyl; hydroxyethyl; cyclohexyl; phenyl; benzyl; sec.-propyl; styroyl; piperidino; hydroxyl ethoxy ethyl; (4-hydroxyl)-piperidino; the 4-piperidyl; (1-methyl)-4-piperidyl; the dimethylaminomethyl carbonyl; diethylamino ethyl carbonyl; (4-methyl)-1-piperazinyl methyl carbonyl; 4-morpholinyl ethyl carbonyl; amino; (4-methyl)-1-piperazinyl; the 1-piperazinyl; N-methyl-N '-cyano group carbonamidine; the 2-thiazolinyl; pyrrolidyl-N-cyano group methylenimine; pyrrolidyl-N-methyl methylenimine; 1-pyrrolidyl-2-nitroethylene base; carbonamidine; the carboxy ethyl carbonyl; pyrrolidyl-N-methyl sulphonyl methylenimine; (2-carboxyl) phenylcarbonyl group; amino-sulfonyl; the dimethylamino alkylsulfonyl; the carboxyl methyl.
When existing, the α position of the list that the oxo substituting group preferably connects at N-or the tie point of annelated heterocycles base.
When the list that connects as N-or the heteroatoms of annelated heterocycles base were substituted, preferred substituted was selected from: C 1-6Alkyl, hydroxyl C 1-6Alkyl is hydroxyethyl, C for example 3-7Cycloalkyl, C 3-7Cycloalkylalkyl, aryl and arylalkyl, for example methyl, ethyl, sec.-propyl, phenyl, styroyl or benzyl are chosen substituted C wantonly 4-7Azacycloalkyl is 4-piperidyl or (1-methyl)-4-piperidyl for example, and the dialkyl aminoalkyl carbonyl is dimethylaminomethyl carbonyl or diethylamino ethyl carbonyl for example, hydroxyl C 1-6Alkoxy C 1-6Alkyl is hydroxyl ethoxy ethyl for example, optional substituted C 4-7Diazacyclo alkyl C 1-6Alkyl-carbonyl or C 4-7Oxa-azacycloalkyl C 1-6Alkyl-carbonyl is (4-methyl)-1 piperazinyl methyl carbonyl, 4-morpholinyl ethyl carbonyl for example; optional substituted carbonamidine is carbonamidine or N-methyl-N '-cyano group carbonamidine for example; or pyrrolidyl-N-cyano group methylenimine or pyrrolidyl-N-methyl methylenimine or pyrrolidyl-N-methyl sulphonyl methylenimine; optional substituted nitroethylene base is 1-pyrrolidyl-2-nitroethylene base for example, optional substituted C 4-7Thia nitrogen heterocyclic alkenyl is the 2-thiazolinyl for example, carboxyl C 1-6Alkyl-carbonyl is the carboxy ethyl carbonyl for example, and the carboxyl aryl carbonyl is (2-carboxyl) phenylcarbonyl group, amino-sulfonyl for example, two C 1-6Alkyl amino sulfonyl is the dimethylamino alkylsulfonyl for example, carboxyl C 1-6Alkyl is the carboxyl methyl for example.
The annelated heterocycles base comprises such group, and they have one or more rings, and these rings are shared one or more atoms, and for example the spiro-condensed ring is perhaps shared one or more keys.
The suitable N-connection monocyclic heterocycles base that comprises 5 yuan of saturated heterocyclics is tetramethyleneimine-1-base.
The suitable N-connection monocyclic heterocycles base that comprises 6 yuan of saturated heterocyclics is optional substituted piperidines-1-base, for example 4-(piperidines-1-yl) piperidines-1-base or 4-amino piperidine-1-base.
Comprising other heteroatomic suitable 6 yuan of saturated heterocyclyls of N-connection monocycle is optional substituted piperazine-1-bases, for example optional substituted 4-alkylpiperazine-1-base.
Suitable N-connects the fused rings heterocyclic radical and comprises 5 yuan or 6 yuan of saturated or unsaturated heterocycles that are fused on the phenyl ring.
The suitable N-connection fused rings heterocyclic radical that comprises 6 yuan of saturated heterocyclics that are fused on the phenyl ring is 2-(1,2,3, a 4-tetrahydrochysene) isoquinolyl.
Suitable N-connects the annelated heterocycles base and comprises the spiro-condensed group, for example 1,4-two oxa-s-8-azaspiro [4.5] last of the ten Heavenly stems-8-base, 3-oxo-2,8-diaza spiro [4.5] last of the ten Heavenly stems-8-base, 2,4-dioxo-1,3,8-thriazaspiro [4.5] last of the ten Heavenly stems-8-base, 2,7-diaza spiro [4.4] ninth of the ten Heavenly Stems-2-base or 2,3-two oxa-s-1,8-diaza spiro [4.5] last of the ten Heavenly stems-8-base.
-NY 1Y 2A preferred value be piperazine-1-base, especially 4-hydroxyalkyl piperazine-1-base or 4-(dialkyl aminoalkyl carbonyl) piperazine-1-base or 4-(azacycloalkyl) piperazine-1-base, wherein said piperazinyl can be substituted or not replace.
-NY 1Y 2Particularly preferred value be formula (a) and (b), (c) or (d) group:
Figure A9981575300121
T wherein 1Represent the sec.-propyl carbonyl; hydroxyethyl; cyclohexyl; phenyl; benzyl; sec.-propyl; styroyl; the I-piperidyl; hydroxyl ethoxy ethyl; (4-hydroxyl)-piperidino; the 4-piperidyl; (1-methyl)-4-piperidyl; the dimethylaminomethyl carbonyl; diethylamino ethyl carbonyl; (4-methyl)-1-piperazinyl methyl carbonyl; 4-morpholinyl ethyl carbonyl; amino; (4-methyl)-1-piperazinyl; the 1-piperazinyl; N-methyl-N '-cyano group carbonamidine; the 2-thiazolinyl; pyrrolidyl-N-cyano group methylenimine; pyrrolidyl-N-methyl methylenimine; 1-pyrrolidyl-2-nitroethylene base; carbonamidine; the carboxy ethyl carbonyl; pyrrolidyl-N-methyl sulphonyl methylenimine; (2-carboxyl) phenylcarbonyl group; amino-sulfonyl; the dimethylamino alkylsulfonyl; the carboxyl methyl, perhaps
Figure A9981575300131
T wherein 1And T 2The atom that connects respectively with them forms optional substituted monocycle or fused rings heterocyclic radical, T 3With T 4Form optional substituted monocycle or fused rings heterocyclic radical together;
Suitably, T 1Represent one of them following radicals:
Figure A9981575300132
R wherein 6Represent H or low alkyl group, preferably represent H or methyl, m is the integer of 1-5, and R 7And R 8Represent low alkyl group, preferable methyl or ethyl, perhaps the two forms heterocycle together, for example piperidines, morpholine or optional substituted piperazine.
Q 1Represent 2-phthalic acid, saturated or unsaturated C 1-6Carboxylic acid or heterocycle be 2-imidazolyl or thiazolyl for example.
In formula (a) group, T 1Also suitably represent heterocycle for example imidazolyl, thiazolyl, pyridyl, pyrimidyl, tetrazyl, perhaps T 1Optional substituted carbonamidine of representative or corresponding tetravalence carboxamidine derivatives.
In formula (a) group, T 1Also suitably represent one of them following chemical entities:
Figure A9981575300133
R wherein 9And R 10Represent hydrogen, alkyl, perhaps R 9And R 10Form 5-7 unit ring, preferred tetramethyleneimine or piperidine ring, and R with the N atom that they connected 11Represent C 1-6Straight or branched alkyl or optional substituted aryl, wherein Q 2Be hydrogen, alkyl, aralkyl, aryl, cyano group.
In formula (a) group, suitable T 1Also represent sulphonamide shown in the following formula:
SO 2NR 12R 13R wherein 12And R 13Be independently selected from hydrogen; C 1-6Alkyl; Optional substituted aryl, perhaps R 12And R 13Represent monocycle or the fused rings heterocyclic radical of choosing substituted N-connection wantonly with the N atom that they connected.
One special aspect ,-NY 1Y 2It is formula (a) part.
One special aspect ,-NY 1Y 2It is formula (b) part.
One special aspect ,-NY 1Y 2It is formula (c) part.
One special aspect ,-NY 1Y 2It is formula (d) part.
Suitably, R 3Be optional substituted aryl, preferred unsubstituted aryl is phenyl for example.
Suitably, R 4Be hydrogen.
Suitably, n is the integer of 1-6, is the integer of 1-4 advantageously, most preferably is 1,2 or 3.
Advantageously, n ' represents 1.
Advantageously, n ' represents 2.
Advantageously, n ' represents 3.
Preferred formula (I) compound is the compound that is defined as follows: wherein Ar is phenyl or cyclohexyl, and R is methyl, ethyl or sec.-propyl, R 1Be hydrogen or methoxyl group or hydroxyl, R 2Be (CH 2) nPart, wherein n is 1,2,3 or 4, R 3Be phenyl, R 4Be hydrogen, and NY 1Y 2Be: (i) optional substituted piperazinyl, the formula of especially above-mentioned definition (a) part; The (ii) formula of above-mentioned definition (b) part; Or the formula of (iii) above-mentioned definition (c) part; Or the formula of (iv) above-mentioned definition (d) part.
Further preferred formula (I) compound is the compound that is defined as follows: wherein Ar is phenyl or cyclohexyl, and R is methyl, ethyl or sec.-propyl, R 1Be hydrogen, methoxyl group or hydroxyl, R 2Be-(CH 2) n-NY 1Y 2Part, wherein n is 1, R 3Be phenyl, R 4Be hydrogen, and NY 1Y 2Be: (i) optional substituted piperazinyl, the formula of especially above-mentioned definition (a) part; Or the formula of (ii) above-mentioned definition (b) part.
The compound that should mention especially is the compound of embodiment 20,29,32,33,34,46,47,48,53,55,62,67,78,79,80,81 and 95.
Formula (I) compound can have at least one asymmetric center-for example and therefore can exist with more than one stereoisomeric forms in any ratio in the lump with the carbon atom of asterisk (*) sign in formula (I) compound.The present invention includes all such stereoisomeric forms in any ratio and their mixture, comprise racemic modification.The present invention has stereochemical compound shown in the formula (Ia) particularly including the carbon atom with the asterisk sign in its Chinese style (I):
Figure A9981575300151
Wherein Ar, R, R 1, R 2, R 3, R 4And R 5Suc as formula defining in (I).
Formula (I) compound or its salt or solvate preferably are pharmaceutically acceptable or pure basically form.Pharmaceutically acceptable form is expression, the standard drug additive for example thinner and carrier disregard under interior prerequisite, have pharmaceutically acceptable purity level, and do not contain virose any material under the standard dose level.
Basically pure form contains at least 50% (the standard drug additive is disregarded interior), preferred 75%, more preferably 90% even more preferably 95% formula (I) compound or its salt or solvate usually.
A preferred pharmaceutically acceptable form is a crystalline form, is included in the crystalline form in the pharmaceutical composition.For salt and solvate, additional ion and solvent partly also must not have toxicity.
Suitable salt is pharmacologically acceptable salt.
Suitable pharmacologically acceptable salt comprises the acid salt that forms with conventional pharmaceutically acceptable acid, and described acid has for example toxilic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, acetate, fumaric acid, Whitfield's ointment, citric acid, lactic acid, amygdalic acid, tartrate, succsinic acid, phenylformic acid, xitix and methylsulfonic acid.
Suitable pharmacologically acceptable salt comprises the salt of the acidic moiety (if present) of formula (I) compound, for example salt of carboxyl or phenolic hydroxyl group.
The salt of suitable acidic moiety comprises metal-salt, aluminium salt for example, an alkali metal salt is lithium salts for example, sodium salt or sylvite, alkaline earth salt is calcium salt or magnesium salts for example, or the ammonium salt of ammonium salt or replacement, for example ammonium salt that forms with following substances: low-grade alkylamine is triethylamine for example, and hydroxyalkyl amine is 2 hydroxy ethylamine for example, two (2-hydroxyethyl) amine or three (2-hydroxyethyl) amine, Cycloalkyl amine is dicyclohexylamine for example, PROCAINE HCL, PHARMA GRADE, the dibenzyl piperidines, the N-benzyl is to styroyl amine, dehydrogenation rosin Amine D (abietylamine), N, N '-two dehydrogenation rosin Amine D, glycosamine, N-methylglucosamine, or pyridine type alkali pyridine for example, collidine, quinine or quinoline.
Suitable solvate is the acceptable solvent thing.
Suitable acceptable solvent thing comprises hydrate.
Use separately or when forming other group (for example " alkoxyl group ") a part of, term " alkyl " (unless indicating on the contrary) comprises the straight or branched alkyl that contains 1-12 carbon atom, preferred 1-6 carbon atom, and the example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl.
Term " carbocyclic ring " is meant cycloalkyl or aryl rings.
Term " cycloalkyl " comprises the cycloalkyl with individual, preferred 4-6 the ring carbon atom of 3-12.
Term " aryl " comprises phenyl and naphthyl, preferred phenyl, unless indicate on the contrary, otherwise aryl can be chosen wantonly to comprise and is up to 5, preferably is up to 3 substituting groups that are selected from following radicals: halogen, alkyl, phenyl, alkoxyl group, haloalkyl, hydroxyalkyl, hydroxyl, amino, nitro, cyano group, carboxyl, alkoxy carbonyl, alkoxy carbonyl alkyl, alkyl-carbonyl oxygen base or alkyl-carbonyl.
Term " aromatic heterocyclic " comprises and comprises fragrant heterocycle and should the virtue heterocycle contain 5-12,5 or 6 annular atomses and contain and be up to 4 heteroatomic groups that are selected from S, O or N suitably in this ring or in each encircles.
Unless indicate on the contrary, otherwise for any heterocyclic radical, its suitable substituents comprises and is up to 4 substituting groups that are selected from alkyl, alkoxyl group, aryl and halogen, perhaps any two substituting groups on adjacent carbons form aryl, preferred phenyl with the carbon atom that they connected, and can be substituted or not replacement by the carbon atom self on the aryl of these two described substituting group representatives.
When using in this article, term " halogen " is meant fluorine, chlorine, bromine and iodine, preferred fluorine, chlorine or bromine.
When using in this article, term " acyl group " comprises the residue for example alkyl-carbonyl or the aryl carbonyl of the residue, particularly carboxylic acid of acid.
The present invention also provides the method for preparation formula (I) compound or its salt and/or its solvate, and described method comprises with formula (II) compound or its activated derivatives: R ' wherein 1, R ' 2, R ' 3And R ' 5Be respectively suc as formula defined R in (I) 1, R 2, R 3And R 5, perhaps be respectively to change into R 1, R 2, R 3, R 5Group; React with formula (III) compound: Wherein R ', R 4' and Ar ' be respectively suc as formula defined R, R in (I) 4And Ar, perhaps be respectively to change into R, R 4Group with Ar; With production (Ib) compound:
Figure A9981575300173
Wherein Ar ', R ', R ' 1, R ' 2, R ' 3, R ' 4And R ' 5As defined above, carry out one or more following optional step then: (i) as required with arbitrary Ar ', R ', R ' 1, R ' 2, R ' 3, R ' 4And R ' 5Change into Ar, R, R respectively 1, R 2, R 3, R 4Or R 5, with acquisition formula (I) compound; (ii) formula (I) compound is changed into another formula (I) compound; (iii) salt and/or its solvate of preparation formula (I) compound.
The suitable group that can change into other group comprises the protection form of described group.
Suitably, Ar ', R ', R ' 1, R ' 2, R ' 3, R ' 4Or R ' 5Represent Ar, R, R respectively 1, R 2, R 3, R 4Or R 5, or their protection form.
It is favourable that formula (II) compound exists as its activated derivatives.
The suitable activated derivatives of formula (II) compound is the transition activated form of formula (II) compound, or the carboxyl of its Chinese style (II) compound is by different groups or atom for example carboxylic acid halides, preferred acyl chlorides or acid azide or the displaced derivative of carboxylic acid anhydride.
Other suitable activated derivatives comprises: the mixed acid anhydride that forms between the carboxy moiety of formula (II) compound and alkyl chloroformate; Acibenzolar, for example cyano group methyl esters, benzene thioesters, p-nitrophenyl ester, p-nitrophenyl thioesters, 2,4,6-trichlorine phenyl ester, pentachlorophenyl ester, pentafluorophenyl esters, N-hydroxyl phthalimido ester, N-hydroxy piperidine ester, N-hydroxy-succinamide ester, N-hydroxybenzotriazole ester; Perhaps, available carbodiimide or N, N '-carbonyl dimidazoles is with the activated carboxylic of formula (II) compound.
The reaction of formula (II) compound or its activated derivatives and formula (III) compound is to carry out under the normal condition of selected specific compound being suitable for.When formula (II) compound is when existing as activated derivatives, normally use the solvent used solvent identical and condition to carry out this reaction with condition with preparing activated derivatives, the preferred activated derivatives of preparation earlier, form formula (Ib) compound then in position, afterwards preparation formula (I) compound or its salt and/or its derivative.
For example, can followingly carry out the activated derivatives of formula (II) compound and the reaction between formula (III) compound: (a) at first in the presence of mineral alkali or the organic bases, for example under-70-50 ℃ (preferred-10-20 ℃) temperature, prepare acyl chlorides in the dimethyl formamide (DMF) at suitable aprotonic solvent, then with the coupling of formula (III) compound; Perhaps (b) is at suitable condensing agent N for example, N '-carbonyl dimidazoles (CDI) or carbodiimide for example dicyclohexylcarbodiimide (DCC) or N-dimethylaminopropyl-N '-ethyl carbodiimide exist down, preferably at N-hydroxybenzotriazole (HOBT) (to increase productive rate to greatest extent and to prevent racemization) (referring to Synthesis, 453,1972) or O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU) exists down, at aprotonic solvent, the mixture of acetonitrile (MeCN) and tetrahydrofuran (THF) (THF) for example, as volume ratio is 1: 9-7: 3 (MeCN: in mixture THF), under the arbitrary temp of the suitable formation speed that required product can be provided, for example at-70-50 ℃, preferably-and 10-25 ℃ for example 0 ℃, with formula (III) compound treatment formula (II) compound.
Shown preferred reaction in the following reaction scheme 1: reaction scheme 1
Figure A9981575300191
Wherein Ar ', R ', R ' 1, R ' 2, R ' 3, R ' 4And R ' 5As defined above.
Should be appreciated that by mutual conversion suitable substituents formula (Ib) compound can be transformed an accepted way of doing sth (I) compound, perhaps a kind of formula (I) compound can change into another kind (I) compound.Therefore, some formulas (I) and (Ib) compound can be used as the intermediate for preparing other The compounds of this invention.
Therefore, further, the invention provides the method for preparation formula (I) compound or its salt and/or its solvate, described method comprises, incites somebody to action wherein at least one Ar ', R ', R ' 1, R ' 2, R ' 3, R ' 4Or R ' 5Not respectively Ar, R, R 1, R 2, R 3, R 4Or R 5Above-mentioned (Ib) compound transform an accepted way of doing sth (I) compound; Carry out one or more following optional step then as required: (i) formula (I) compound is changed into another formula (I) compound; (ii) salt and/or its solvate of preparation formula (I) compound.
Suitably, in formula (Ib) compound, variables A r ', R ', R ' 1, R ' 2, R ' 3, R ' 4And R ' 5Be respectively Ar, R, R 1, R 2, R 3, R 4Or R 5, or its protection form.
Above-mentioned conversion, protection and deprotection are to carry out with suitable conventional reagent and condition, hereinafter this are discussed further.
Wherein n is that 1 formula (II) compound or corresponding alkyl (for example methyl or ethyl) ester are by using formula (IV) compound or corresponding alkyl (for example methyl or ethyl) ester: R ' wherein 1, R ' 3And R ' 5As defined above, and L 1Represent for example bromine atoms of halogen atom, make with formula V compound reaction:
HNY ' 1Y ' 2(V) Y ' wherein 1And Y ' 2Be respectively suc as formula defined Y in (I) 1And Y 2Or its protection form.
Suitably, Y ' 1And Y ' 2Be Y 1And Y 2
Suitably, the reaction between formula (IV) compound or corresponding alkyl (for example methyl or ethyl) ester and the formula V compound is carried out under conventional amination condition, for example, works as L 1When being bromine atoms, this reaction is, under the arbitrary temp of the suitable formation speed that required product can be provided, normally to carry out easily at normal temperatures for example in tetrahydrofuran (THF) or the dimethyl formamide at aprotonic solvent; Preferably at triethylamine (TEA) or K 2CO 3Carry out this reaction under existing.
Formula (IV) compound or corresponding alkyl (for example methyl or ethyl) ester by with formula (VI) compound or corresponding alkyl (for example methyl or ethyl) ester suitably halogenation make: R ' wherein 1, R ' 3And R ' 5Suc as formula defining in (II).
Suitable halogenating agent is the conventional reagent that depends on the character of required halogen atom, for example works as L 1When being bromine atoms, preferred halogenating agent is a N-bromine succinimide (NBS).
The halogenation of formula (VI) compound or corresponding alkyl (for example methyl or ethyl) ester is carried out under normal condition, and for example, bromination is by at inert solvent for example 1,2-ethylene dichloride or CH 3Among the CN, under the arbitrary temp of the suitable formation speed that required product can be provided, suitably at high temperature for example 60 ℃-100 ℃ as 80 ℃, handle with NBS and to carry out; Preferably in the presence of the benzoyl peroxide of catalytic amount, carry out this reaction.
In reaction scheme 1,, before transforming an accepted way of doing sth (Ib) compound, need formula (II) compound hydrolysis when use formula (VI), (IV) with (II) during the corresponding alkyl of compound (for example methyl or ethyl) ester.Hydrolysis can for example carried out under 30-100 ℃ of temperature in the presence of the 10-36% hydrochloric acid under acidic conditions.R ' wherein 2Representative (CH 2) 2-9-NY 1Y 2Formula (II) compound as described belowly make easily: with formula (VII) compound: R ' wherein 1And R ' 5Suc as formula defining in (II), react with formula (VIII) compound:
R 3'-CO-CH 2-(CH 2) p-T 5(VIII) R ' wherein 3Suc as formula in (II) define T 5Be suc as formula defined group-NY in (I) 1Y 2Or its protection form maybe can change into its group, and p is the integer of 2-9;
Remove protecting group then as required and/or incite somebody to action group T arbitrarily 5Change into NY 1Y 2
The available Pfitzinger reaction conditions of reaction between formula (VII) compound and formula (VIII) compound carries out easily (referring to for example J.Prakt.Chem.33,100 (1886), J.Prakt.Chem.38,582 (1888), J.Chem.Soc.106 (1948) and Chem.Rev.35,152 (1944)), for example at the alkanol solvent for example in the ethanol, under the arbitrary temp of the suitable formation speed that required product can be provided, but usually at high temperature for example under the reflux temperature of solvent, and preferably for example carry out this reaction in the presence of potassium hydroxide or the potassium tert.-butoxide at alkali.
-NY 1Y 2The protection form will become according to this special properties of desiring blocking group, but should establishing criteria the chemistry practice select.
Can change into-NY 1Y 2Group comprise basis-NY 1Y 2Special properties, be essential and suitable group from the standard chemical practical term.
Be used for NY 1Y 2Protection form deprotection proper method and be used for T 5Change into NY 1Y 2Method for transformation be depend on consider this area common method of special groups, but the reference standard textbook is Greene for example, T.W. and Wuts, " protecting group in the organic synthesis " of P.G.M. (Protective Groups in Organic Synthesis), John Wiley﹠amp; Sons Inc.New York, 1991 (Second Edt.) or Kocienski, P.J. " protecting group " (Protecting groups), George Thieme Verlag, New York, 1994, " amino chemistry " (the amino Group of Chemistry of the), Patais (Ed.), Interscience, New York 1968; Or " organic chemistry progress " (AdvancedOrganic Chemistry), March J, John Wiley ﹠amp; Sons, New York, 1992.
Formula (VIII) compound makes with formula (IX) compound:
R 3'-CO-CH 2-(CH 2) p-OH (IX) is R ' wherein 3Define suc as formula institute in (II), and p is suc as formula defining in (VIII), at first with the halogenation of formula (IX) compound, preferred bromination, perhaps methylsulfonylization is then with formed halogenation or methylsulfonyl product and can form group T 5Compound reaction, to generate required formula (VII) compound.
Work as T 5Be group-NY 1Y 2The time, can form group T 5Compound be formula V compound as defined above.
The halogenation of formula (IX) compound is suitably carried out with conventional halogenating agent.Methylsulfonylization be with methylsulfonyl chloride at inert solvent for example in the methylene dichloride, under subambient temperature for example 0 ℃, preferably in the presence of triethylamine, carry out.
Formula (IX) compound with can form group T 5Compound between reaction conditions be normal condition by reactant decision, for example as required T 5Be group-NY 1Y 2, and can form group T 5Required compound be as defined above during the formula V compound, then the halogenation of formula (IX) compound or the reaction between methylsulfonyl product and the formula V compound are to carry out being similar under the condition of above describing about the reaction between formula (IV) compound and the formula V compound.
Other can form group T 5Compound will depend on T 5Special properties, but should be suitable compound by conventional chemical practice decision, the reference standard textbook is " amino chemistry " (the amino Group of Chemistry of the) for example, Patais (Ed.), Interscience, New York 1968; " organic chemistry progress " (Advanced Organic Chemistry), March J, John Wiley ﹠amp; Sons, New York, 1992.
Formula (IX) compound can pass through with formula (X) compound: Wherein p makes with the reaction of formula (XI) lithium salts suc as formula defining in (VIII):
R ' 3Li (XI) is R ' wherein 3Suc as formula defining in (II).
Reaction between formula (X) compound and formula (XI) compound can be at aprotonic solvent for example in the ether, under the arbitrary temp of the suitable formation speed that required product can be provided, usually for example-10 ℃ at low temperature--and 30 ℃ as-20 ℃ are carried out.
Formula (III) compound is known commercial compound, perhaps can pass through currently known methods, or be similar to the method for preparing known compound, and for example at Liebigs Ann.der Chemie, (1936), the method for describing in 523,199 makes.
J.Org.Chem. (1996), 61 (12), having described wherein among the 4130-4135, Ar is C 5Or C 7Cycloalkyl, R is a methyl, and R 4It is formula (III) chipal compounds of H.Wherein Ar is a phenyl, and R is a sec.-propyl, and R 4Be formula (III) chipal compounds of H bright be to be described in for example Tetrahedron Lett. (1994), 35 (22), the known compound among the 3745-6.
The formula V compound is known commercial compound, perhaps can make by being similar to the method for preparing known compound; For example at " amino chemistry " (the amino Group of Chemistry of the), Patais (Ed.), Interscience, New York 1968; " organic chemistry progress " (Advanced Organic Chemistry), March J, John Wiley ﹠amp; Sons, New York, 1992; J.Heterocyclic Chem. (1990), 27,1559; Synthesis (1975); 135; Bioorg.Med.Chem.Lett. (1997); 7; 555; or " protecting group in the organic synthesis " (Protecctive Groups in OrganicSynthesis) (second edition), Wiley Interscience, the method for mentioning in the method for describing in (1991) or these documents.
The amino piperidines that replaces of 4-generally is by making with the 4-oxo-piperidine or by the 4-oxo-piperidine reduction amination that the due care base replaces with suitable amine, and representative instance can be referring to J.Org.Chem. (1990), 55 (8), and 2552-4 or ibid.(1995)，60(15)，4928-9。
Some diaza spiro nonane intermediates of Shi Yonging are known compounds in the present invention, and the compound that for example is used to prepare embodiment 68 is described in J.Med.Chem. (1990), 33 (8), and among the 2270-2275.
Be used to generate the succinyl oxide of embodiment 83 and 85-87 and the condensation of Tetra hydro Phthalic anhydride is described in J.Indian Chem.Soc. (1979), 56 (2), among the 171-2.The piperidines that is used for preparing the 4-heterocyclic substituted of embodiment 77 is described in US 4329348 A 19820511.
Formula (VII) compound is a known compound, perhaps can be according to the method that is used to prepare known compound, and for example at J.Org.Chem.21,171 (1955); J.Org.Chem.21,169 (1955) the middle methods of describing make.
Formula (X) is a known compound with (XI) compound, perhaps can be according to the method that is used to prepare known compound, and for example Krow G.R. is at Organic Reactions, 43, the 251 pages of Vol, John Wiley ﹠amp; Sons Inc.1994 (for formula (X) compound) and Organometallics in Synthesis, Schlosser M. (Ed), John Wiley﹠amp; Disclosed method makes among the Sons Inc.1994 (for formula (XI) compound).
R wherein 2Representative-(CH 2) n-NY 1Y 2, and-NY 1Y 2Formula (I) compound that is formula (a) piperazinyl can be by using formula XII compound Wherein Ar ', R ', R ' 1, R ' 2, R ' 3, R ' 4And R ' 5As defined above, suitably make with formula (XIII) class reactant reaction, for example:
Figure A9981575300251
L wherein 2With L ' 2Represent leavings group for example-the S alkyl or-the O alkyl, for example-SCH 3With-the O butyl, and R is as defined above.
Still carry a leavings group L ' by formula (XIII) compound list being replaced to generate with formula (XII) compound 2New texture, then can be with the reaction of compound shown in itself and the following formula:
HNR 9R 10R wherein 9And R 10As defined above, with production (I) compound.
Preferably as described below the making of amidino piperazine that replaces: according to method shown in the reaction scheme 2, with the lsothiocyanates reaction of formula (XII) compound and replacement
Reaction scheme 2
Figure A9981575300252
R wherein 12Represent low alkyl group, optional substituted aryl or aralkyl, use aforesaid formula HNR then 9R 10Compound substituent group-SCH 3(it has substituted leavings group L 2).
The unsubstituted amidino piperazine of formula (XVI)
Figure A9981575300261
By making with formula (XII) compound and the reaction of formula (XVII) benzotriazole derivatives. (dimethylamino ethylidene) shown in the formula (XVIII) Dimethyl Ammonium piperazine By for example in the presence of the TEA, in appropriate solvent, formula (XII) compound and HBTU heating are made a kind of solvent or solvent mixture that wherein said solvent normally uses in the peptide coupled reaction at alkali.R wherein 2Representative-(CH 2) n-NY 1Y 2, and-NY 1Y 2Be formula (a) piperazinyl, T 1Formula (I) compound of representation carboxy, alkoxy carbonyl, the optional alkyl that replaces, the optional aryl that replaces, aralkyl, cycloalkyl can be by suitably making with the reaction of compound shown in formula XII compound and the following formula
T 1L 3T wherein 1Represent a group as defined above, L 3Be for example halogen or sulfonate radical of leavings group, preferred chlorine, bromine or methanesulfonate.Formula (XII) compound is to make by the protecting group on the formula of removing (XIX) compound Wherein Ar ', R ', R ' 1, R ' 2, R ' 3, R ' 4And R ' 5As defined above, P is an amine protecting group, for example fmoc or benzyl, preferably fmoc.Remove protecting group by the standard method of describing in the literature, for example can come cracking to fall the fmoc residue by for example handling piperidines in the acetonitrile at solvent.As mentioned above, can there be more than one stereoisomeric forms in any ratio in formula (I) compound, and the inventive method can make the form of racemic modification and enantiomer-pure.Therefore, the pure enantiomer of formula (I) compound can make by following method: with formula (II) compound as defined above and suitable formula (IIIa) or (IIIc) enantiomer-pure primary amine reaction Wherein R ', R ' 4And Ar ' is as defined above, with acquisition formula (I ' a) or (I ' c) compound:
Figure A9981575300273
Wherein Ar ', R ', R ' 1, R ' 2, R ' 3, R ' 4And R ' 5As defined above.
Can formula (I ' a) or (I ' c) compound be transformed an accepted way of doing sth (Ia) or (Ic) compound by above-mentioned method for transformation then:
Figure A9981575300281
Wherein Ar, R, R 1, R 2, R 3, R 4And R 5As defined above.
Suitably, at above-mentioned formula (Ia), (Ic), (I ' a), (I ' c), (IIIa) with (IIIc) in the compound, R 4Represent hydrogen.
The other method of separating optical isomers is to use conventional fractional separation method, particularly fractionation crystallization.Therefore, the pure enantiomer of formula (I) compound can obtain like this: suitable alcoholic solvent for example ethanol or methyl alcohol or ketones solvent for example in the acetone will by with formula (I) racemic compound and optically-active strong acid resolving agent for example camphorsulfonic acid react the diastereo-isomerism salt classification crystallization that forms.Salification process should be carried out under 20-80 ℃, preferred 50 ℃ of temperature.
When existing other basic functionality for example when primary amine, secondary amine or tertiary amine in the molecule, can use the optically-active acid resolving agent of wider scope, comprise tartrate, O, O '-two pair of toluyl tartrate and amygdalic acid.
A kind of formula (I) compound comprises by following method for example a radicals R to the suitable conversion of another kind of formula (I) compound 2Change into another radicals R 2: (i), use for example dilute hydrochloric acid, ketone acetal is changed into ketone by for example appropriate acidic hydrolysis; (ii) use the borohydride reductive agent that ketone is reduced into hydroxyl; (iii) use alkaline hydrolysis that carboxylic acid ester groups is changed into carboxyl; And/or (iv) use the borohydride reductive agent that carboxylic acid ester groups is reduced into hydroxymethyl.
As mentioned above, when needs, incite somebody to action normally Ar, R, R 1, R 2, R 3, R 4Or R 5Any group Ar ', R ', the R ' of protection form 1, R ' 2, R ' 3, R ' 4And R ' 5Change into Ar, R, R 1, R 2, R 3, R 4Or R 5Can adopt for example suitable deprotection means of suitable normal condition to carry out.
Be to be understood that, in any above-mentioned reaction, can be according to the conventional chemical practice with any reactive group protection and deprotection in the reactant molecule, for example according to Greene, T.W. and Wuts, P.G.M. " protecting group in the organic synthesis " (Protective Groups inOrganic Synthesis), John Wiley ﹠amp; Sons Inc. New York, 1991 (Second Edt.), or Kocienski, P.J. " protecting group " (Protecting groups) .George Thieme Verlag, New York, the method for describing in 1994 is protected and deprotection.
In any above-mentioned reaction, suitable protecting group is this area protecting group commonly used.Therefore, for example suitable hydroxyl protecting group comprises benzyl or trialkylsilkl.
The method that forms and remove such protecting group is the ordinary method that is suitable for desire protection molecule.For example, benzyloxy can by benzyl halogenide for example bromotoluene handle suitable compound and form, then if necessary, available catalytic hydrogenation or weak ether cracking agent for example TMS iodine or boron tribromide are removed benzyl in a usual manner.
As mentioned above, formula (I) compound has useful pharmaceutical properties.
Therefore, the present invention also provides formula (I) compound or its pharmacologically acceptable salt or the solvate as the active treatment material.
The present invention also provides formula (I) compound or its pharmacologically acceptable salt or the solvate that is used for the treatment of or prevents primary and Secondary cases illness.
The present invention also provides the pharmaceutical composition that comprises formula (I) compound or its pharmacologically acceptable salt or solvate and pharmaceutically acceptable carrier.
The present invention also provides formula (I) compound or its pharmacologically acceptable salt or solvate to be used for the treatment of application in the medicine of primary and Secondary cases illness in preparation.
As mentioned above, the primary illness comprises respiratory disease, and for example chronic obstruction tuberculosis (COPD), asthma, tracheae reacted by force, cough; Inflammatory diseases is inflammatory bowel, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis and inflammatory pain for example; Neurogenic inflammation or peripheral neurophaty, transformation reactions be eczema and rhinitis for example; Disease of eye is eyes inflammation, conjunctivitis, vernal conjunctivitis etc. for example; Tetter, skin disorder and itch, for example skin pomphus and flush, contact dermatitis, atopic dermatitis, urticaria and other eczema-like dermatitis; Adverse immune response, for example the repulsion of transplanted tissue with immunostimulant or suppress for example systemic lupus erythematosus of relevant illness; Stomach and intestine (GI) obstacle and GI tract disease for example with the relevant illness of the former control of splanchnic nerve, for example ulcerative colitis, regional ileitis, irritable bowel syndrome (IBS), gastro oesophageal reflux disease (GORD) (GERD); The urinary incontinence and bladder function illness; Kidney disease.
As mentioned above, the Secondary cases illness comprises central nervous system disorder, for example anxiety, dysthymia disorders, psychosis and schizophrenia; Neurodegenerative disease is AIDS dependency dementia, Alzheimers type senile dementia, Alzheimer, mongolism, huntington's chorea, Parkinson's disease, dyskinesia and convulsibility disease (for example epilepsy) for example; Demyelinating disease is the sclerosis of multiple sclerosis and the amyotrophic lateral sclerosis outside and other neuropathy neuropathy and neurodynia of causing of diabetic neuropathy, AIDS dependency neuropathy, chemotherapy for example for example; Habituation venereal disease disease is alcoholism for example; The body illness relevant with stress; Reflex sympathetic dystrophy is for example takeed on/hand syndrome; Dysthymia; Eating disorder (for example ingestion of food disease); Fibrous tissue forms and collagen diseases, for example scleroderma and acidophilia fascioliasis; The blood flow venereal disease disease that is caused by vasorelaxation and vasospasm disease is stenocardia, migraine and Raynaud disease and pain or nociception for example, for example cause by above-mentioned illness or pain, the especially migraine relevant with above-mentioned disease in the pain transmission.
The such medicine and the present composition can make by The compounds of this invention is mixed with carrier suitably.It can contain thinner commonly used, tackiness agent, weighting agent, disintegrating agent, correctives, tinting material, lubricant or sanitas.
Can use and resemble these usual excipients of in the composition of the sanatory known active of preparation, using.
Pharmaceutical composition of the present invention preferably is unit dosage and is applicable to the formulation of medical treatment and veterinary applications.For example, such preparation can be packaged form, uses the sanatory written or printing description of promoting agent with instructing in this packing.
The suitable dose scope of The compounds of this invention depends on used compound and patient's illness.Also depend on especially and absorb effectiveness and administration frequency and approach.
For by any administration, can prepare The compounds of this invention or composition, preferably be mixed with unit dosage, or human patients can be with the formulation of single dose to self-administer.For the purpose of favourable, that the present composition is suitable for is oral, rectum, part, parenteral route, intravenously or intramuscular administration.Preparation can be designed so that active ingredient slowly discharges.
Composition can be for example form of solution or suspension agent or suppository of for example tablet, capsule, sachet, bottled preparation, pulvis, granula, lozenge, the pulvis that can prepare again or liquid preparation.
Composition for example is suitable for liquid preparations for oral administration and can contains conventional excipients for example tackiness agent such as syrup, gum arabic, gelatin, sorbyl alcohol, tragakanta or polyvinylpyrrolidone; Weighting agent is lactose, sugar, W-Gum, calcium phosphate, sorbyl alcohol or glycine for example; The film-making lubricant is Magnesium Stearate for example; Disintegrating agent is starch, polyvinylpyrrolidone, sodium starch glycolate or Microcrystalline Cellulose for example; Or pharmaceutically acceptable peptizer sodium lauryl sulphate for example.
Solids composition can make by ordinary methods such as mixing, filling, film-makings.Can promoting agent be distributed in the composition that has adopted a large amount of weighting agents by married operation repeatedly.When composition is the form of tablet, pulvis or lozenge, can use any carrier that is suitable for preparing solid composite medicament, the example has Magnesium Stearate, starch, glucose, lactose, sucrose, ground rice and chalk.But the well-known process in the establishing criteria medicinal practice is particularly used the enteric coating dressing with tablet coating.But the present composition can also be the form of swallowable capsule, for example contains the active compound and the gelatine capsule of carrier or other vehicle if necessary.
The liquid composition of oral administration can be the form of example emulsion, syrup or elixir, perhaps can be to face the drying products of preparing again with preceding water or other suitable carrier.Such liquid composition can contain conventional suspension agent for example sorbyl alcohol, syrup, methylcellulose gum, gelatin, Natvosol, carboxymethyl cellulose, aluminium stearate gel, hydrogenation edible-fat; Emulsifying agent is Yelkin TTS, anhydro sorbitol monooleate or gum arabic for example; Water or nonaqueous carrier comprise edible oil for example Prunus amygdalus oil, fractionated coconut oil, and grease is glyceryl ester, propylene glycol or ethylene glycol for example, glycerine, water or physiological saline; Sanitas, for example methyl p-hydroxybenzoate or propylparaben or Sorbic Acid; If necessary, correctives commonly used or tinting material.
The compounds of this invention can also pass through non-oral administration.According to the conventional medicine operation, composition can be mixed with the suppository that is used for rectal administration.Also composition can be mixed with at for example aseptic water that does not contain pyrogen of pharmaceutically acceptable liquid or non-enteron aisle and can accept water in oil or the liquid mixture or the injection type in non-aqueous solution, suspension agent or the solution.Liquid can contain bacteriostatic agent, antioxidant or other sanitas, buffer reagent or make solution and the isoosmotic solute of blood, thickening material, suspension agent or other pharmaceutically acceptable additive.Such formulation can present unit dosage form, and for example ampoule or disposable syringe device, or multiple doses form for example can therefrom take out the medicine bottle of suitable dosage, perhaps can be used to prepare the solid dosage or the enriched material of injection.
The compounds of this invention also can pass through inhalation via a nose or a mouthful approach.Such administration can optional be suspended in The compounds of this invention in the hydrocarbon propellants for example and the sprays of suitable carrier is carried out with comprising.
Preferred sprays comprises the micronized compound particle that mixes with tensio-active agent, solvent or dispersion agent (preventing the suspended particle deposition).The granula of compound particle is preferably about 2-10 micron.
The alternative mode of administration of The compounds of this invention comprises the transdermal administration that uses skin patch.Contain The compounds of this invention in the preferred pressure sensitive adhesive of preparation on being adhered to skin, therefore make compound from tackiness agent, to be diffused in patient's body via skin.In order to absorb through skin, can use pressure sensitive adhesive known in the art for example natural rubber or silicone with constant speed.
As mentioned above, the effective dose of compound depends on used specific compound, patient's illness and administration frequency and approach.Unitary dose contains 20-1000mg usually, preferably contains 30-500mg, particularly 50,100,150,200,250,300,350,400,450 or 500mg.But composition is administered once every day or repeatedly for example 2,3 or 4 times, and for the adult of 70kg, total per daily dose is generally 100-3000mg.Perhaps unitary dose contains the 2-20mg active ingredient, and administration every day if necessary is repeatedly to reach above-mentioned per daily dose.
Estimate when according to administration of the present invention, can not occur any unacceptable toxic action.
The present invention also provides the method that treats and/or prevents primary and Secondary cases illness in Mammals, particularly people, comprises formula (I) compound or pharmaceutically acceptable salt thereof of effective, nontoxic pharmaceutically acceptable amount or solvate this Mammals administration that treats and/or prevents of needs.
Suppress radiolabeled NK by measuring it 3Part-[ 125I]-[Me-Phe 7]-NKB or [ 3H]-Senktide and cavy and people NK 3The ability of receptors bind determines that The compounds of this invention is as NK 3The activity of part (people such as Renzetti, 1991, Neuropeptide, 18,104-114; People such as Buell, 1992, FEBS, 299 (1), 90-95; People such as Chung, 1994, Biochem.Biophys.Res.Commun., 198 (3), 967-972).
This used binding assay can determine with [ 125I]-[Me-Phe 7]-NKB or [ 3H]-Senktide and NK 3The specificity of acceptor under equilibrium conditions is in conjunction with reducing by 50% each required compound concentrations (IC 50).
For each test compounds, binding assay has provided 2-5 with in duplicate or the average IC of the independent experiment that carries out in triplicate 50Value.The most virtuous The compounds of this invention shows the IC between 0.1-1000nM 50Value.The NK of The compounds of this invention 3-antagonistic activity is to suppress senktide inductive guinea pig ileum and shrink (people such as Maggi, 1990, Br.I.Pharmacol. by measuring it, 101,996-1000) and isolating rabbit iris sphincters contract (people such as Hall, 1991, Eur.J.Pharmacol., 199,9-14) and people NK 3Receptor-mediated Ca ++Movable (people such as Mochizuki, 1994, J.Biol.Chem., 269, ability 9651-9658) is measured.For each test compounds, the external functional examination of cavy and rabbit has provided the average K of 3-8 independent experiment BValue, wherein K BBe in concentration-response curve of senktide, to produce 2 times of each compound concentrations that moves to right required.People's function of receptors assay method can determine and will pass through the exciting NKB inductive Ca of institute ++50% o'clock each required compound concentrations (IC of movable reduction 50Value).In this was measured, The compounds of this invention played antagonist action.
The compounds of this invention as the activity of NK-2 part be by measure its suppress radiolabeled NK-2 part, [ 125I]-NKA or [ 3H]-the bonded ability of NKA and people NK-2 acceptor and definite (people such as Aharony, 1992, Neuropeptide, 23,121-130).
Used binding assay can determine with [ 125I]-NKA and [ 3H]-NKA and people NK2 acceptor combining under equilibrium conditions reduce by 50% each required compound concentrations (IC 50).
Binding assay has provided 2-5 with in duplicate or the average IC of the independent experiment that carries out in triplicate 50Value.The most virtuous The compounds of this invention shows between 0.5-1000nM, the IC of for example 1-1000nm 50Value.The NK-2 antagonistic activity of The compounds of this invention is to suppress the receptor-mediated Ca of people NK-2 by measuring it ++Movable (people such as Mochizuki, 1994, J.Biol.Chem., 269, ability 9651-9658) is measured.People's function of receptors assay method can determine and will pass through the exciting NKA inductive Ca of institute ++50% o'clock each required compound concentrations (IC of movable reduction 50Value).In this was measured, The compounds of this invention played antagonist action.
Can use the rodent disease model to measure the treatment potentiality of The compounds of this invention in the treatment illness.
As mentioned above, formula (I) compound also can be used as diagnostic tool.Therefore, the present invention includes formula (I) compound of the diagnostic tool that is used as the degree (normal, active excessive or active deficiency) of measuring neurokinin-3 and neurokinin-2 receptor active participation patient symptom.Such application comprises the application of formula (I) compound as described active antagonist, and the myo-inositol phosphates of tachykinin agonist induction that for example described activity includes but not limited to derive from patient's cell sample transforms or electric physiology activates.Exist such activity down to know that in this tissue NK-3 and the participation of NK-2 acceptor mediate the degree of agonist effect by relatively being in or be not in formula (I) compound.
The preparation of intermediate is for example understood in following description, and following embodiment for example understands the preparation of The compounds of this invention.
Description and embodiment describe A:3-methyl-2-phenylquinoline-4-methyl-formiate
30g (114mmol) 3-methyl-2-phenylquinoline-4-formic acid (CAS[43071-45-0]) is suspended in the 250ml anhydrous methylene chloride; Dropping is dissolved in 20ml (230mmol) oxalyl chloride in the 120ml methylene dichloride, with this reaction mixture stirring at room 30 minutes.Add 2 N, dinethylformamide (DMF) was with this reaction mixture restir 30 minutes.Solvent vacuum-evaporation to doing, is placed the 100ml methylene dichloride to resistates, and drip the 100ml MeOH that is dissolved in the 400ml methylene dichloride.Stir after 18 hours, solvent vacuum-evaporation to doing, is placed methylene dichloride to resistates, and washs with 1% sodium bicarbonate; Use the dried over sodium sulfate organic layer, filter also vacuum-evaporation and extremely do, obtained this title compound of 31.6g, be solid, need not be further purified and be directly used in next reaction.C 18H 15NO 2MW 277.31MP=73-75 ℃ IR (KBr) 3441,3051,2954,1731,1582,1556cm -1. B:3-brooethyl-2-phenylquinoline-4-methyl-formiate is described
10g (36mmol) 3-methyl-2-phenylquinoline-4-methyl-formiate (describing the A compound) is dissolved in 500ml CH 3Among the CN; Add 13g (72mmol) of N-bromine succinimide, this reaction mixture is heated to backflow.After adding 1g (4.1mmol) dibenzoyl superoxide, should react and reflux 24 hours; And then added 4g (22.5mmol) N-bromine succinimide and 0.5g (2.0mmol) dibenzoyl superoxide, and should react and reflux 4 hours.Solvent vacuum-evaporation to doing, has been obtained 26.1g 3-brooethyl-2-phenylquinoline-4-methyl-formiate crude product (theoretical amount is 12.8g), need not be further purified and be directly used in next reaction.C 8H 14BrNO 2MW=356.23 prepares 1:3-[1,4 '] connection piperidines-1 '-ylmethyl-2-phenylquinoline-4-methyl-formiate
5g (14mmol) 3-brooethyl-2-phenylquinoline-4-methyl-formiate (describing the B compound), 2.9g (15.4mmol) 90%4-piperidino-(1-position only) piperidines (Aldrich), 2.7ml (15.4mmol) diisopropylethylamine are dissolved among the anhydrous THF of 100ml, this mixture is spent the night 50 ℃ of stirrings.Solvent is concentrated, resistates is dissolved in the methylene dichloride, wash with water, the organic phase dried over mgso.After solvent concentrated, (eluent was CH to the purified by flash chromatography resistates by using 160g silica gel 2Cl 2/ MeOH/NH 4OH:95/5/0.5), obtain this title compound of 3.5g (productive rate 56%), be white solid.C 28H 33N 3O 2MW=443.59 δ (CDCl 3): 1.29-2.02 (12H); 2.25 (1H); 2.47 (4H); 2.78 (2H); 3.66 (2H); 4.05 (3H); 7.38-7.55 (5Har); 7.58 (1Har); 7.72 (1Har); 7.88 (1Har); 8.17 (1Har) ppm. describes 2:3-[1,4 '] connection piperidines-1 '-ylmethyl-2-phenylquinoline-4-formic acid dihydrochloride
With 3.5g (7.9mmol) 3-[1,4 '] connection piperidines-1 '-ylmethyl-2-phenylquinoline-4-methyl-formiate (describing 1 compound) and 50ml 6N HCl backflow 1.5 hours, be concentrated into dried then.Resistates is developed in acetone.This operation repeats 2 times, after the vacuum-drying, has obtained this title compound of 4.5g, is the dihydrochloride crude product, need not be further purified and be directly used in next step.C 27H 3N 3O 2.2HClMW=502.56 δ (DMSOd 6): 1.16-2.29 (10H); 2.62-3.38 (8H); 4.46 (2H); (5.77 1Hexch with D2O); 7.45-8.30 (9Har); 11.12 (1Hexch with D 2O) ppm. describes 3:2-phenyl-3-(4-Phenylpiperidine-1-ylmethyl) quinoline-4-methyl-formiate
Under nitrogen atmosphere, 5.4g 3-brooethyl-2-phenylquinoline-4-methyl-formiate (describing the B compound) is dissolved among the anhydrous THF of 30ml.This solution is cooled to 10 ℃, drips 4.0g (24.8mmol) the 4-Phenylpiperidine that is dissolved among the 5ml THF.This reaction mixture is risen to room temperature, and stir and spend the night.Filter out salt, filtrate vacuum-evaporation to doing, is placed 2N HCl, and washs with EtOAc; With 10%NaOH water layer is alkalized, and use dichloromethane extraction.Use the dried over sodium sulfate organic layer, filter also vacuum-evaporation and extremely do, obtained crude product, by using the gradient flash column chromatography purifying of 230-400 order silica gel, at first with containing 0.5%NH 410: 90 mixture wash-outs of the EtOAc/ hexane of OH (28%) are at last with containing 0.5%NH 415: 85 mixture wash-outs of the EtOAc/ hexane of OH (28%).Collect this title compound of 3.0g, be white-yellowish solid.C 29H 28N 2O 2MW=436.56IR:(KBr) 3440,3062,2945,1731,1577,1555cm -1. 4:2-phenyl-3-(4-Phenylpiperidine-1-ylmethyl) quinoline-4-formate hydrochlorate is described
3.0g (6.87mmol) 2-phenyl-3-(4-Phenylpiperidine-1-ylmethyl) quinoline-4-methyl-formiate (describing 3 compounds) is dissolved among the 100ml 6N HCl, and refluxed 1 hour.Be evaporated to do after, obtained the crude product of this title compound of 3.5g, need not be further purified and be directly used in next reaction.C 28H 26N 2O 2.HClMW=459.00MP=175-178 ℃ IR:(KBr) 3385,3062,2495,1973,1718,1630cm -1. 5:3-(4-sec.-propyl piperazine-1-ylmethyl)-2-phenylquinoline-4-methyl-formiate is described
Under nitrogen atmosphere, 7.8g 3-brooethyl-2-phenylquinoline-4-methyl-formiate (describing the B compound) is dissolved among the anhydrous THF of 130ml.This solution is cooled to 10 ℃, drips 2.8g (21.6mmol) the 1-sec.-propyl piperazine that is dissolved among the 20ml THF.This reaction mixture is risen to room temperature, and stir and spend the night.Filter out salt, filtrate vacuum-evaporation to doing, is placed 2NHCl, and washs with EtOAc; With 10%NaOH water layer is alkalized, and use dichloromethane extraction.Use the dried over sodium sulfate organic layer, filter also vacuum-evaporation and extremely do, obtained crude product, by using the flash column chromatography purifying of 230-400 order silica gel, with containing 0.3%NH 4The Et of OH (28%) 2O/iPr 270: 30 mixture wash-outs of O.Collect this title compound of 3.8g, be white-yellowish solid.C 25H 29N 3O 2MW=403.54IR:(KBr) 3441,3065,2946,1731,1580,1555cm -1. 6:3-(4-sec.-propyl piperazine-1-ylmethyl)-2-phenylquinoline-4-formic acid dihydrochloride is described
3.8g (9.42mmol) 3-(4-sec.-propyl piperidines-1-ylmethyl)-2-phenylquinoline-4-methyl-formiate (describing 5 compounds) is dissolved among the 100ml 6N HCl, and refluxed 4 hours.Be evaporated to do after, obtained this title compound of 4.0g, be directly used in next reaction without purifying.C 24H 27N 3O 2.2HCIMW=389.50MP=177-180 ℃ IR:(KBr) 3408,2928,2666,1716,1632cm -1. 7:(S is described)-1-cyclohexyl-propylamin hydrochloride
With 2.0g (14.8mmol) (S)-the 1-phenylpropylamine is dissolved in 250ml 4% aqueous citric acid solution.Add 0.6g 20%Pd (OH) 2/ C, with this reaction mixture in steel autoclave in 50 crust and 60 ℃ of hydrogenation 24 hours.Filter out catalyzer,, resistates is placed 40%NaOH the filtrate evaporation, and with water extraction for several times.With the organic layer of dried over sodium sulfate merging, and use HCl/Et 2The O acidifying.Be evaporated to driedly, obtained this title compound of 0.3g, be solid.C 9H 19N.HClMW=389.50 describes 8:3-(4-Fmoc-piperazine-1-ylmethyl)-2-phenylquinoline-4-methyl-formiate
According to describing the method for using in 3,6.6g (18.5mmol) 3-brooethyl-2-phenylquinoline-4-methyl-formiate (describing the B compound) is reacted in 150ml THF with 6.8g (20mmol) Fmoc piperazine, obtained 7.5g (productive rate: this title compound 69%).C 37H 33N 3O 4MW=583.68 1H NMR δ (DMSOd 6): 1.99 (4H); 3.10 (4H); 3.62 (2H); 3.97 (3H); 4.20 (1H); 4.42 (2H); 7.18-7.40 (4Har); 7.45-7.92 (12Har); 8.09 (1Har) ppm. describes 9:3-(4-Fmoc-piperazine-1-ylmethyl)-2-phenylquinoline-4-formate hydrochlorate
According to describing the method for using in 4, with 6N hydrochloric acid 7.5g (13mmol) is described by 8 ester hydrolysis, obtained the crude product of this title compound of 9.5g, be directly used in next step without purifying.C 36H 31N 3O 4.HClMW=606.12 1H NMR δ (DMSOd 6): 2.50 (4H); 3.32 (4H); 4.22 (2H); 4.23 (1H); 4.35 (2H); (6.50 1Hexch with D2O); 7.22-7.88 (14Har); 7.98 (1Har); 8.17 (2Har) ppm. describes 10:3-(4-Fmoc-piperazine-1-ylmethyl)-2-phenylquinoline-4-formic acid ((S)-1-phenyl propyl) acid amides
According to the method for embodiment 2, with 5.35g (8.3mmol) describe 9 sour crude product and 1.7ml (12.5mmol) (S)-condensation of 1-phenylpropylamine, behind the fast silica gel chromatogram purifying, obtained this title compound of 3.2g (productive rate 56%).C 45H 42N 4O 3MW=686.86 1H NMR δ (DMSOd 6): 0.94 (3H); 1.40-2.18 (6H); 2.57-3.13 (4H); 3.50 (2H); 4.21 (1H); 4.34 (2H); 5.08 (1H); 7.09-7.98 (21Har); 8.03 (1Har); 9.12 (1Hexch with D2O) ppm. describes 11:3-(4-Fmoc-piperazine-1-ylmethyl)-2-phenylquinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides
According to the method for embodiment 2, with 4.75g (8.3mmol) describe 9 sour crude product and 1.65ml (11mmol) (S)-condensation of 1-cyclohexyl ethamine, behind the fast silica gel chromatogram purifying, obtained this title compound of 2.2g (productive rate 43.9%).C 44H 46N 4O 3MW=678.87 1H NMR δ (DMSOd 6): 0.95 (3H); 1.68-4.00 (21H); 2.60 (3H); 5.08 (1H); 7.22-8.24 (13Har); 9.32 (1Hexch with D 2O); 10.82 (2Hexchwith D 2O) ppm. describes 12:3-(4-Fmoc-piperazine-1-ylmethyl)-2-phenylquinoline-4-formic acid ((S)-2-methyl isophthalic acid-phenyl propyl) acid amides
According to the method for embodiment 2, with 6.95g (10.8mmol) describe 9 sour crude product and 2g (13.5mmol) (S)-2-methyl isophthalic acid-phenylpropylamine condensation, behind the fast silica gel chromatogram purifying, obtained this title compound of 5.4g (productive rate 71%).C 46H 44N 4O 3MW=700.86 1H NMR δ (DMSOd 6): 0.96 (3H); 1.18 (3H); 1.56-2.98 (4H); 2.28 (1H); 3.04 (4H); 3.53 (2H); 4.20 (1H); 4.35 (2H); 5.17 (1H); 7.18-7.63 (18Har); 7.74 (3Har); 7.97 (1Hexch with D 2O); 8.14 (1Har) ppm. describes 13:2-phenyl-3-piperazine-1-ylmethyl quinoline-4-formic acid ((S)-2-methyl isophthalic acid-phenyl propyl) acid amides
The Fmoc derivative and the 1.25ml piperidines of 5.4g (7.7mmol) description 12 are spent the night in room temperature reaction in the 200ml acetonitrile.This reaction mixture is concentrated into dried, by fast silica gel chromatogram method purifying resistates (eluent: CH 2Cl 2/ CH 3OH/NH 4OH; 90/10/2), obtained this title compound of 2.55g (productive rate 69.3%).C 31H 34N 4OMW=478.64 1H NMR δ (DMSOd 6): 0.79 (3H); 1.06 (3H); 1.49-2.55 (2H and 1HexchwithD 2O); 4.88 (1H); 7.12-8.10 (14Har); 9.16 (1Hexch with D 2O) ppm. describes 14:2-phenyl-3-piperazine-1-ylmethyl quinoline-4-formic acid ((S)-1-phenyl propyl) acid amides
Adopt 13 the method for describing, use 2.75g (41mmol) to describe 12 Fmoc protection derivative, obtained this title compound of 1.14g (productive rate 60%).C 30H 32N 4OMW=464.61 1H NMR δ (DMSOd 6): 0.94 (3H); 1.57-2.08 (6H); 2.31 (4H); 3.36 (2H and 1Hexch with D 2O); 5.07 (1H); 7.13-7.94 (13Har); 9.17 (1Hexch with D 2O) ppm. describes 15:3-[4-(1-cyanoimino-1-methyl sulfane ylmethyl) piperazine-1-ylmethyl-2-phenylquinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides
With 0.5g (1.1mmol) 2-phenyl-3-piperazine-1-ylmethyl quinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides (embodiment 34 compounds) and 0.16g (1.1mmol) N-cyano group dithio imido-carbonic acid dimethyl ester (Aldrich) reflux 6 hours in the mixture of 2.2ml DMF and 8.8ml EtOH.
Solvent is concentrated, by fast silica gel chromatogram method purifying resistates (CH 2Cl 2/ MeOH:98/2), obtained this title compound of 0.56g (productive rate 91.8%), be directly used in next step without purifying.C 33H 34N 6OSMW=562.74 1H NMR δ (CDCl 3): 1.00-1.39 (5H); 1.24 (3H); 1.48 (1H); 1.63-1.96 (5H); 2.25 (4H); 2.69 (4H); 3.57 (4H); 3.72 (2H); 4.25 (1H); 6.42 (1Hexch with D 2O); 7.38-7.55 (5Har); 7.60 (1Har); 7.75 (1Har); 7.95 (1Har); 8.14 (1Har) ppm. describes 16:3-[4-(1-methylsulfonyl imino--1-methyl sulfane ylmethyl) piperazine-1-ylmethyl]-2-phenylquinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides
With 0.48g (1.05mmol) 2-phenyl-3-piperazine-1-ylmethyl quinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides (embodiment 34 compounds) and 0.21g (1.05mmol) imido dithio formic acid (methyl sulphonyl) dimethyl ester (RN 13068-10-5) reflux 5 hours in the mixture of 2ml DMF and 8ml EtOH.
Solvent is concentrated, by fast silica gel chromatogram method purifying resistates (CH 2Cl 2/ MeOH:97/3), obtained this title compound of 0.52g, be directly used in next step without purifying.C 33H 37N 4O 3S 2MW=615.82 1H NMR δ (CDCl 3): 0.95-1.38 (5H); 1.28 (3H); 1.48 (1H); 1.62-1.94 (5H); 2.28 (4H); 2.47 (3H); 3.01 (3H); 3.54 (4H); 3.59 (2H); 4.25 (1H); (6.52 1Hexch with D2O); 7.36-7.53 (5Har); 7.59 (1Har); 7.75 (1Har); 7.95 (1Har); 8.14 (1Har) ppm. describes 17:4-[4-((S)-1-cyclohexyl ethylamino formyl radical)-2-phenylquinoline-3-ylmethyl]-N methyl piperazine-1-azomethine thio-methyl ester
0.05g (0.95mmol) 3-(4-methyl thiocarbamoyl piperazine-1-ylmethyl)-2-phenylquinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides (embodiment 75 compounds) is suspended in the 5ml acetone, adds 0.41g (2.85mmol) methyl-iodide.After 4 hours, this mixture becomes clarification in stirring at room.Solvent is concentrated, develop resistates, after filtration and the drying, obtained the hydrochloride of this title compound of 0.63g with ether.This compound need not be further purified and be directly used in next step.C 33H 37N 5OSMW=551.76 1H NMR δ (CDCl 3): 0.92-1.36 (5H); 1.75 (3H); 1.47 (1H); 1.58-1.92 (5H); 2.24 (4H); 2.46 (3H); 3.05 (3H); 3.36 (4H); 3.63 (2H); 4.02 (1H); 7.36-7.91 (8Har); 8.04 (1Har); 8.55 (1Hexch with D 2O) ppm. describes 18:3-(4-oxo-piperidine-1-ylmethyl)-2-phenylquinoline-4-formic acid ((S)-1-phenyl propyl) acid amides
Use 3-brooethyl-2-phenylquinoline-4-methyl-formiate (describing the B compound) and 4-oxo-piperidine as raw material, adopt earlier and describe 1 operation, adopt then and be similar to the operation of describing among description 2 and the embodiment 2, by silica gel purification (EtOAc/ heptane: obtained this title compound 1/1).C 31H 31N 3O 2MW=477.60 1H NMR δ (DMSOd 6): 0.83 (3H); 1.57-2.30 (8H); 2.45 (2H); 3.34-3.98 (2H); 5.08 (1H); 7.12-8.18 (14Har); 9.21 (1 Hexchwith D 2O) ppm. describes 19:4-tertiary butyl sulfamyl piperazine-1-t-butyl formate
6.1g (32.62mmol) piperazine-1-t-butyl formate (RN 76535-74-5) is dissolved in the 150ml methylene dichloride, and adds 4.5g (32.6mmol) salt of wormwood.This mixture is cooled to 0 ℃, drip 5.6g (32.62mmol) tertiary butyl sulfamyl chlorine be dissolved in the 50ml methylene dichloride (according to Catt, J.D.JOC, 1974,39,566-8), with this mixture stirring at room 2 hours.Add 50ml water, in separating funnel, separate two-phase, use the dichloromethane extraction water.Merge organic phase, use dried over sodium sulfate, and vacuum-evaporation is extremely dried, has obtained this title compound of 4.6g, is yellow solid.C 13H 27N 3O 4SMW=321.43IR:(KBr) 3273,2971,1701,1364,1137,1023,934,768cm -1. 20:4-dimethylamino alkylsulfonyl piperazine-1-t-butyl formate is described
As describe described in 19, made this title compound of 15.2g with 10.38g (55.7mmol) piperazine-1-t-butyl formate (RN 76535-74-5), 7.7g (55.7mmol) salt of wormwood and 8g (55.7mmol) dimethylamino SULPHURYL CHLORIDE, be yellow solid.C 11H 23N 3O 4SMW=293.39IR:(KBr) 2979,2866,1687,1142,952,752cm -1Describe 21: piperazine-1-sulfonic acid tert-butylamides
4.6g (14.3mmol) 4-tertiary butyl sulfamyl piperazine-1-t-butyl formate (describing 19 compounds) is dissolved in the 10ml methylene dichloride, and adds 50ml 30%HCl diethyl ether solution.With this solution stirring at room 2 hours.Solvent vacuum-evaporation to doing, is obtained this title compound of 1.5g, be white solid.C 8H 19N 3O 2SMW=221.32IR:(KBr) 3207,2730,1591,1326,1143,1001,917,720,631cm -1Describe 22: piperazine-1-sulfonic acid dimethylformamide
13g (44.31mmol) 4-dimethylamino alkylsulfonyl piperazine-1-t-butyl formate (describing 20 compounds) is dissolved in the 100ml methylene dichloride, and adds 20ml 30%HCl diethyl ether solution.With this solution stirring at room 2 hours.Solvent vacuum-evaporation to doing, is obtained this title compound of 9.2g, be white solid.C 6H 15N 3O 2SMW=193.27IR:(KBr) 2786,1688,1356,1152,1037,942,867,737,677cm -123:3-(4-tertiary butyl sulfamyl piperazine-1-ylmethyl)-2-phenylquinoline-4-methyl-formiate is described
1.5g (6.78mmol) piperazine-1-sulfonic acid tert-butylamides (describing 21 compounds) and 0.94g (6.78mmol) salt of wormwood are suspended in 70ml CH 3Among the CN.2.42g (6.78mmol) 3-brooethyl-2-phenylquinoline-4-methyl-formiate (describing the B compound) is dissolved in 30mlCH 3CN is added to this solution in the above-mentioned suspension.The gained mixture stirring at room 4 hours.Solvent vacuum-evaporation to doing, is placed 6N HCl to resistates and washs with EtOAc.With 1N NaOH water is alkalized, and extract with EtOAc.With the organic phase dried over sodium sulfate, and be evaporated to driedly, obtained the crude product of this title compound of 3.0g, need not be further purified direct use.C 26H 32N 4O 4SMW=496.63IR:(KBr) 3280,2974,1734,1575,1555,1444,1220,1146,940764cm -124:3-(4-dimethylamino alkylsulfonyl piperazine-1-ylmethyl)-2-phenylquinoline-4-methyl-formiate is described
1.6g (8.24mmol) piperazine-1-sulfonic acid dimethylformamide (describing 22 compounds) and 1.16g (8.24mmol) salt of wormwood are suspended in 70ml CH 3Among the CN.3.0g (8.42mmol) 3-brooethyl-2-phenylquinoline-4-methyl-formiate (describing the B compound) is dissolved in 30mlCH 3CN is added to this solution in the above-mentioned suspension.The gained mixture stirring at room 4 hours.Solvent vacuum-evaporation to doing, is placed 6N HCl to resistates and washs with EtOAc.With 1N NaOH water is alkalized, and extract with EtOAc.With the organic phase dried over sodium sulfate, and be evaporated to driedly, obtained crude product, by using the flash column chromatography purifying of 230-400 order silica gel, with 3: 7 mixture wash-outs of EtOAc/ hexane.After solvent evaporation, obtained this title compound of 3.0g, be yellow solid.C 24H 28N 4O 4SMW=468.58IR:(KBr) 2938,1736,1574,1552,1452,1244,1156,942 748cm -125:2-phenyl-3-(4-sulfamyl piperazine-1-ylmethyl) quinoline-4-formic acid is described
3.0g (6.04mmol) 3-(4-tertiary butyl sulfamyl piperazine-1-ylmethyl)-2-phenylquinoline-4-methyl-formiate (describing 23 compounds) is suspended among the 50ml 6N HCl, this mixture was refluxed 4 hours.Solvent vacuum-evaporation is extremely done.With ether resistates is handled 3 times, solvent evaporation to doing, has been obtained the crude product of 3.0 title compounds, need not be further purified direct use.C 21H 22N 4O 4SMW=426.44IR:(KBr) 3281,2974,1734,1556,1221,1146,1056,941,765cm -126:3-(4-dimethylamino alkylsulfonyl piperazine-1-ylmethyl)-2-phenylquinoline-4-formic acid is described
3.0g (6.40mmol) 3-(4-dimethylamino alkylsulfonyl piperazine-1-ylmethyl)-2-phenylquinoline-4-methyl-formiate (describing 24 compounds) is suspended among the 50ml 6N HCl, this mixture was refluxed 4 hours.Solvent vacuum-evaporation is extremely done.Use Me 2CO has collected 1.4 title compounds after resistates is developed, and is light yellow solid, need not be further purified direct use.C 23H 26N 4O 4SMW=454.55IR:(KBr) 3427,2658,1726,1632,1581,1452,1344,1151,932745cm -127:7-methoxyl group-3-methyl-2-phenylquinoline-4-methyl-formiate is described
16g (54.5mmol) 7-methoxyl group-3-methyl-2-phenylquinoline-4-formic acid (making with being similar to the raw material of describing A) is suspended in the 400ml anhydrous methylene chloride, drips 9.52ml (126.93mmol) oxalyl chloride.Add 2 N, dinethylformamide (DMF), with this reaction mixture stirring at room 3 hours.Solvent vacuum-evaporation to doing, is placed the 150ml methylene dichloride to resistates, and is added drop-wise to rapidly in the solution of 200ml MeOH and 200ml methylene dichloride.Stir after 1 hour, solvent evaporation to doing, is placed EtOAc to resistates, and uses 1%NaHCO 3Washing; With the organic layer drying, filter also vacuum-evaporation with sodium sulfate to doing.Resistates with after the ether development, is collected this title compound of 19g, be dark powder, need not be further purified direct use.C 19H 17NO 3MW=307.35IR (KBr) 3067,2947,1918,1729,1634,1581,1246,846cm -1. 28:3-[1 is described, 4 '] connection piperidines-1 '-ylmethyl-8-bromo-7-methoxyl group-2-phenylquinoline-4-methyl-formiate
According to describing B and describe the method for describing in 1, by with 4.7g (15.3mmol) 7-methoxyl group-3-methyl-2-phenylquinoline-4-methyl-formiate (describing 27 compounds), 5.5g (30.6mmol) N-bromine succinimide, 0.5g (2.05mmol) dibenzoyl superoxide, 3.85g (23mmol) 4-piperidino-(1-position only) piperidines and 3.18g (23.0mmol) salt of wormwood at CH 3In stirring at room 4 hours, made this title compound of 6.2g among the CN.C 29H 34BrN 3O 3MW=552.51IR (KBr) 3370,2938,1712,1612,1352,1268,1174,704cm -1. 29:3-[1 is described, 4 '] connection piperidines-1 '-ylmethyl-8-bromo-7-methoxyl group-2-phenylquinoline-4-formate hydrochlorate
According to the method for describing 4, by 6.0g (10.9mmol) 3-[1,4 '] connection piperidines-1 '-ylmethyl-8-bromo-7-methoxyl group-2-phenylquinoline-4-methyl-formiate (describing 28 compounds) and 50ml 6N HCl made the 4.7g light brown powder.C 28H 32BrN 3O 3.HclMW=574.94IR:(KBr) 3453,2939,2532,1714,1607,1598,1271,1072,960,779,705, cm -1. 30:3-[1 is described, 4 '] connection piperidines-1 '-ylmethyl-8-chloro-7-methoxyl group-2-phenylquinoline-4-methyl-formiate
According to describing B and describing the method for describing in 1, be prepared with 9.0g (15.3mmol) 7-methoxyl group-3-methyl-2-phenylquinoline-4-methyl-formiate hydrochloride (describing the hydrochloride of 27 compounds), 10.4g (58.6mmol) N-bromine succinimide, 1.0g (4.10mmol) dibenzoyl superoxide, 9.9g (58.6mmol) 4-piperidino-(1-position only) piperidines and 3.18g (23.0mmol) salt of wormwood.By using the flash column chromatography purifying of 230-400 order silica gel, with containing 0.1%NH 49: 1 mixture wash-outs of the EtOAc/MeOH of OH (28%) have obtained this title compound of 1.7g.C 29H 34ClN 3O 3MW=508.06IR (KBr) 2934,1730,1610,1501,1238,1079,774,706cm -1. 31:3-[1 is described, 4 '] connection piperidines-1 '-ylmethyl-8-chloro-7-methoxyl group-2-phenylquinoline-4-formic acid two hydrobromates
With 1.5g (3.0mmol) 3-[1,4 '] connection piperidines-1 '-ylmethyl-8-chloro-7-methoxyl group-2-phenylquinoline-4-methyl-formiate (describing 30 compounds) is dissolved among the 50ml 48%HBr, this solution refluxed 8 hours.Solvent vacuum-evaporation to doing, is obtained the crude product of this title compound of 2.2g, be dark powder, need not be further purified direct use.C 27H 31ClN 3O 3.2HBrMW＝736.76IR：(KBr)2948，1725，1624，1226，959，705cm -1.
Following embodiment for example understands the present invention; Table 1 has been summed up all embodiment 1-95 compound and analytical data thereof; Table 2 has been described the NMR spectroscopy data of embodiment 1-95 compound, and table 3 has been illustrated the chemical name of embodiment 1-95 compound.Embodiment 2:2-phenyl-3-(4-phenyl-piperidines-1-ylmethyl) quinoline-4-formic acid ((S)-1-phenyl propyl) acid amides
2.5g (5.0mmol) 2-phenyl-3-(4-Phenylpiperidine-1-ylmethyl) quinoline-4-formate hydrochlorate crude product (describing 4 compounds) is dissolved among the anhydrous THF of 50ml; Add 1.1ml (7.8mmol) triethylamine (TEA) and 2.4g (6.5mmol) O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU) is cooled to 0 ℃ with this reaction mixture.Dropping be dissolved in the 20ml anhydrous methylene chloride 0.72ml (5mmol) (S)-the 1-phenylpropylamine, this reaction mixture stirring at room 24 hours, and was stirred 2 hours at 50 ℃.Solvent vacuum-evaporation is extremely done, resistates is placed EtOAc, and water, 1N NaOH and salt water washing successively, use dried over sodium sulfate, and be evaporated to driedly, obtained crude product, by using the gradient flash column chromatography purifying of 230-400 order silica gel, with 3: 7 mixture wash-outs of EtOAc/ hexane, use 4: 6 mixture wash-outs of EtOAc/ hexane at last earlier.Use iPr 2After the O development, collect this title compound of 1.0g, be light yellow solid, need not be further purified direct use.C 37H 37N 3OMW=539.72IR:(KBr) 3279,3060,3028,2931,1633,1536,1494,757,699cm -1. embodiment 4:3-(4-sec.-propyl piperazine-1-ylmethyl)-2-phenylquinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides dihydrochloride
2.3g (5.0mmol) 3-(4-sec.-propyl piperazine-1-ylmethyl)-2-phenylquinoline-4-formic acid dihydrochloride (describing 6 compounds) is dissolved in 200ml CH 2Cl 2/ CH 3In 1: 1 mixture of CN, add 2.0ml (15mmol) triethylamine (TEA) and 2.5g (6.5mmol) O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU) is cooled to 0 ℃ with this reaction mixture.Dropping be dissolved in the 10ml anhydrous methylene chloride 0.74ml (5mmol) (S)-1-cyclohexyl ethamine, with this reaction mixture stirring at room 24 hours.Solvent vacuum-evaporation to doing, is placed EtOAc to resistates, and water, 1N NaOH and salt water washing successively, use dried over sodium sulfate, and be evaporated to driedly, obtained crude product, by the flash column chromatography purifying of use 230-400 order silica gel, with containing 0.5%NH 4The CH of OH (28%) 2Cl 295: 5 mixture wash-outs of/MeOH.Resistates is dissolved in the acetone, and uses HCl/Et 2The O acidifying; Collect formed precipitation by suction filtration, obtained this title compound of 0.9g, be yellow solid.C 32H 42N 4O.2HClMW=571.64IR:(KBr) 3411; 2927; 2851; 2667; 1650; 1546cm -1. embodiment 13:3-[1,4 '] connection piperidyl-1 '-ylmethyl-2-phenylquinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides dihydrochloride
With 4.0g (8.0mmol) 3-[1,4 '] connection piperidines-1 '-ylmethyl-2-phenylquinoline-4-formic acid dihydrochloride (describing 2 compounds) be dissolved in 300ml CH 2Cl 2/ CH 3In 1: 1 mixture of CN, add 3.4ml (24.6mmol) triethylamine (TEA) and 4.0g (10.7mmol) O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU) is cooled to 0 ℃ with this reaction mixture.Dropping be dissolved in the 10ml anhydrous methylene chloride 1.22ml (8.2mmol) (S)-1-cyclohexyl ethamine, with this reaction mixture stirring at room 24 hours.Add again 2.0g (5.3mmol) HBTU and 2.0ml (13.4mmol) (S)-1-cyclohexyl ethamine, with this reaction mixture 40 ℃ the heating 8 hours.Solvent vacuum-evaporation to doing, is placed EtOAc to resistates, and water, 1N NaOH and salt water washing successively, use dried over sodium sulfate, and be evaporated to driedly, obtained crude product, by the flash column chromatography purifying of use 230-400 order silica gel, with containing 0.5%NH 495: 5 mixture wash-outs of the EtOAc/MeOH of OH (28%).Resistates is dissolved in the acetone, and uses HCl/Et 2The O acidifying; Collect formed precipitation by suction filtration, obtained this title compound of 3.2g, be light yellow solid.C 35H 46N 4O.2HClMW=611.70IR:(KBr) 3422,2928,2852,2659,1647,1546cm -1. embodiment 34:2-phenyl-3-piperazine-1-ylmethyl quinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides
According to the method for describing 13, by describing 11 compounds cost title compounds.C 29H 36N 4OMW=456.63 embodiment 47:3-[4-(3-diethylamino propionyl) piperazine-1-ylmethyl]-2-phenylquinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides
With 0.4g (0.88mmol) 2-phenyl-3-piperazine-1-ylmethyl quinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides (embodiment 34 compounds), 0.5g (1.3mmol) HBTU, 360 microlitres (2.5mmol) triethylamine and 240mg 3-diethylamino propionic acid are dissolved among the anhydrous THF of 10ml, and stirring at room 16 hours.Solvent is concentrated into dried, resistates is dissolved among the 20ml EtOAc, and water, 0.5N aqueous sodium hydroxide solution and water washing successively.With the organic phase drying, be concentrated into dried with sal epsom.By fast silica gel chromatogram method purifying resistates (CH 2Cl 2/ MeOH:90/10).The fraction that will contain required compound concentrates, and with residue crystallized, has obtained this title compound of 250mg (productive rate 48.7%) with Di Iso Propyl Ether, is white crystals.C 36H 49N 5O 2MW=583.82 embodiment 53: phosphofluoric acid (4-[4-((S)-1-cyclohexyl ethylamino formyl radical)-2-phenylquinoline-3-ylmethyl] piperazine-1-yl }-the dimethylamino methylene) Dimethyl Ammonium
The piperazine of 50mg (0.11mmol) embodiment 34 and 62mg (0.16mmol) HBTU and 18mg (0.17mmol) triethylamine are reacted in the mixture of anhydrous THF of 1.2ml and 1ml methylene dichloride.Stirring at room 48 hours, be concentrated into dried then this mixture.Resistates is dissolved in 1ml water and the 1ml ethyl acetate., wash with water 2 times water extraction 2 times with EtOAc, use dried over mgso, and be concentrated into dried.By fast silica gel chromatogram method purifying resistates (CH 2Cl 2/ MeOH:95/5), obtained this title compound of 43mg, be white solid (productive rate 55.8%).C 34H 47N 6O.PF6MW=700.75 embodiment 55:3-(4-amino piperidine-1-ylmethyl)-2-phenylquinoline-4-formic acid ((S)-1-phenyl propyl) acid amides
0.477g (1mmol) 3-(4-oxo-piperidine-1-ylmethyl)-2-phenylquinoline-4-formic acid ((S)-1-phenyl propyl) acid amides (describing 18 compounds), 0.462g (6mmol) ammonium acetate are dissolved in the 10ml methyl alcohol, and stirring at room 1 hour.Add the 0.08g sodium cyanoborohydride then, with this mixture in stirred overnight at room temperature.This reaction mixture is poured in the 50ml water, filtered out the precipitation of formation.Use the dichloromethane extraction water.The solid of collecting is dissolved in the methylene dichloride, merges this two organic phases, wash with water, use dried over mgso, and be concentrated into dried.By quick silica gel microfluidic chromatography purifying resistates (CH 2Cl 2/ MeOH/NH 4OH:90/10/1), obtain this title compound of 47mg, be white solid (productive rate is about 10%).C 31H 34N 4OMW=478.64 embodiment 66:3-[1,4 '] connection piperidines-1 '-ylmethyl-8-bromo-7-methoxyl group-2-phenylquinoline-4-formic acid ((S)-1-phenyl propyl) acid amides
Method according to embodiment 2, with 2g (3.7mmol) 3-[1,4 '] connection piperidines-1 '-ylmethyl-8-bromo-7-methoxyl group-2-phenylquinoline-4-formic acid (describing 29 compound), 1.55ml (11.1mmol) triethylamine (TEA), 1.82g (4.8mmol) O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU) and 0.75g (5.5mmol) (S)-the 1-phenylpropylamine is prepared.By using the flash column chromatography purifying crude product of 230-400 order silica gel, with containing 0.05%NH 495: 5 mixture wash-outs of the EtOAc/MeOH of OH (28%) have obtained this title compound of 0.4g.Use iPr 2After the O development, collect this title compound of 0.3g, be light yellow solid.C 37H 43BrN 4O 2MW=655.68IR:(KBr) 3278,2936,1641,1276,1073,845,702cm -1. embodiment 67:3-[1,4 '] connection piperidyl-1 '-ylmethyl-7-methoxyl group-2-phenylquinoline-4-formic acid ((S)-1-phenyl propyl) amide hydrochloride
With 0.2g (0.31mmol) 3-[1,4 '] connection piperidines-1 '-ylmethyl-8-bromo-7-methoxyl group-2-phenylquinoline-4-formic acid ((S)-1-phenyl propyl) acid amides (embodiment 66 compounds) and 0.43ml (0.31mmol) TEA be dissolved among the 100ml EtOH.Under nitrogen atmosphere, add 20mg 10% palladium carbon, with this mixture 1psi hydrogenation 3 hours.Filter out catalyzer, to doing, by using the gradient flash column chromatography purifying resistates of 230-400 order silica gel, elder generation is with containing 0.05%NH with solvent vacuum-evaporation 4The EtOAc wash-out of OH (28%) is at last with containing 0.05%NH 495: 5 mixture wash-outs of the EtOAc/MeOH of OH (28%).Resistates is dissolved in the acetone, and uses HCl/Et 2The O acidifying; Collect formed precipitation by suction filtration, obtained this title compound of 0.1g, be light yellow solid.C 37H 44N 4O 2MW=576.78IR:(KBr) 3239,2943,2530,1619,1534,1222,1027,844,703cm -1. embodiment 72:3-[4-(3,4-dioxo-2-tetramethyleneimine-1-basic ring but-1-ene base) piperazine-1-ylmethyl]-2-phenylquinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides
With 0.25g (0.55mmol) 2-phenyl-3-piperazine-1-ylmethyl quinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides (embodiment 34 compounds) and 0.124g (0.55mmol) 3,4-two-N-butoxy-3-cyclobutene-1,2-diketone (Aldrich) in 3ml ethanol in stirring at room 7 hours.Add 0.15g (2.2mmol) tetramethyleneimine then, and continue to stir and spend the night.With this mixture vacuum concentration, by fast silica gel chromatogram method purifying resistates (CH 2Cl 2/ MeOH:98/2).After required fraction concentrated, with Di Iso Propyl Ether with residue crystallized.Once more the solid that is obtained by the silica gel chromatography purifying (with EtOAc as eluent).After required fraction concentrated, with the resistates recrystallization, obtained this title compound of 0.180g (productive rate 54%), be white crystal with Di Iso Propyl Ether.C 37H 43N 5O 3MW=605.78 embodiment 75:3-(4-methyl thiocarbamoyl piperazine-1-ylmethyl)-2-phenylquinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides
0.4g (0.87mmol) 2-phenyl-3-piperazine-1-ylmethyl quinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides (embodiment 34 compounds) is dissolved in the 10ml methylene dichloride, adds the 0.09g Trapex.With this mixture stirring at room 5 hours, with the solvent vacuum concentration, by fast silica gel chromatogram method purifying resistates (EtOAc/ heptane: 95/5), obtained this title compound of 0.43g (productive rate 92%), be white crystals.C3 31H 39N 5OSMW=529.75 embodiment 76:3-[4-(1-cyanoimino-1-tetramethyleneimine-1-ylmethyl) piperazine-1-ylmethyl]-2-phenylquinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides
With 0.25g (0.45mmol) 3-[4-(1-cyanoimino-1-methyl sulfane ylmethyl) piperazine-1-ylmethyl]-2-phenylquinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides (describing 15 compounds) and 1.5ml tetramethyleneimine reflux 2 hours.Vacuum is removed excessive tetramethyleneimine, by fast silica gel chromatogram purifying resistates (EtOAc/CH 2Cl 2: 80/20).After required fraction concentrated, with residue crystallized, obtained this title compound of 0.195g (productive rate 75%), be white crystals with Di Iso Propyl Ether.C 35H 43N 7OMW=577.77 embodiment 78:3-[4-(1-methyl-imino-1-tetramethyleneimine-1-ylmethyl) piperazine-1-ylmethyl]-2-phenylquinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides
The crude product of 0.2g (about 0.3mmol) being described 17 salt is dissolved in the 10ml acetonitrile, adds 1g tetramethyleneimine and 1.5g KF.This mixture backflow is spent the night.Behind the long-time vacuum concentration, resistates is dissolved in the methylene dichloride, filters out solid and discard.With this solution concentration, by fast silica gel chromatogram method purifying resistates (EtOAc/MeOH/NH 4OH:90/10/1).After required fraction concentrated, with residue crystallized, obtained this title compound of 0.120g (productive rate 71%), be white amorphous solid with ether.C 35H 46N 6OMW=566.79 embodiment 82:3-(4-imino-formamyl (carbamimidoyl)-piperazinyl-1-ylmethyl)-2-phenylquinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides sesquialter tosilate
With 0.3g (0.66mmol) 2-phenyl-3-piperazine-1-ylmethyl quinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides (embodiment 34 compounds), 0.313g (0.94mmol) benzotriazole-1-carbonamidine tosilate (at Synthetic Communications, 1995,25 (8), the reagent of describing among the 1173-1186), 0.167ml (0.94mmol) diisopropylethylamine stirred 3 days.Add ether and cause having formed precipitation, will precipitate further development with ether.By two these white solids of successive fast silica gel chromatogram purifying, use CH earlier 2Cl 2/ MeOH:90/10 wash-out is used CH then 2Cl 2/ MeOH/NH 4The OH:90/10/1 wash-out.Required fraction is concentrated, obtained solid, solid is developed, obtained this title compound of 0.225g, be tosilate with ether.The NMR spectroscopic analysis shows, for the parent compound of 1 molecule, produces 1.6 angelic acids (in table 2, NMR is meant the spectrum of this parent compound).C 30H 38N 6O.1.5C 7H 8O 3SMW=757.00 embodiment 84:3-[4-(1-methylsulfonyl imino--1-tetramethyleneimine-1-ylmethyl) piperazine-1-ylmethyl]-2-phenylquinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides
With 0.46g (0.76mmol) 3-[4-(1-methylsulfonyl imino--1-methyl sulfane ylmethyl) piperazine-1-ylmethyl]-2-phenylquinoline-4-formic acid ((S)-1-cyclohexyl ethyl) acid amides crude product (describing 16 compounds) and 5ml tetramethyleneimine reflux 5 hours.Vacuum is removed excessive tetramethyleneimine, by fast silica gel chromatogram purifying resistates (EtOAc/MeOH:97/3).After required fraction concentrated, with residue crystallized, obtained this title compound of 0.310g (productive rate 65%), be white crystals with Di Iso Propyl Ether.C 35H 46N 6O 3SMW=630.85 embodiment 85:4-{4-[4-((S)-2-methyl isophthalic acid-phenyl propyl formamyl)-2-phenylquinoline-3-ylmethyl piperazine-1-yl }-the 4-ketobutyric acid
200mg (0.42mmol) 2-phenyl-3-piperazine-1-ylmethyl quinoline-4-formic acid ((S)-1-phenyl propyl) acid amides (describing 13 compounds) is dissolved in the 5ml acetone, adds the 42mg succinyl oxide.This mixture was refluxed 10 hours.After the cooling, with this mixture diluted,, use dried over mgso, and be concentrated into dried with 30ml water washing 3 times with the 50ml methylene dichloride.By fast silica gel chromatogram method purifying resistates (CH 2Cl 2/ MeOH:90/10), obtained this title compound of 130mg, be white crystal (productive rate 54%).C 35H 38N 4O 4MW=578.71 embodiment 90:2-phenyl-3-(4-sulfamyl piperazine-1-ylmethyl) quinoline-4-formic acid ((S)-1-phenyl propyl) acid amides
3.0g (5.78mmol) 2-phenyl-3-(4-sulfamyl piperazine-1-ylmethyl) quinoline-4-formic acid crude product (describing 25 compounds) is dissolved in 1: 1 mixture of 150ml methylene dichloride and anhydrous THF; Add 2.41ml (17.34mmol) triethylamine (TEA) and 4.38g (11.56mmol) O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU) is cooled to 0 ℃ with this reaction mixture.Dropping be dissolved in the 20ml anhydrous methylene chloride 1.56g (11.56mmol) (S)-the 1-phenylpropylamine, this reaction mixture stirring at room 24 hours, was stirred 4 hours at 50 ℃.Solvent vacuum-evaporation to doing, is placed EtOAc to resistates, and water and 1N NaOH washing are with dried over sodium sulfate and be evaporated to dried.By using the flash column chromatography purifying crude product of 230-400 order silica gel, with 8: 2 mixture wash-outs of EtOAc/ hexane.Use iPr 2After the O development, collect this title compound of 1.05g, be light yellow solid.C 30H 33N 5O 3SMW=543.69IR:(KBr) 3270,3060,2967,1959,1644,1537,1492,1455,1354,1163,949,764,702cm -1Embodiment 91:3-(4-dimethylamino alkylsulfonyl piperazine-1-ylmethyl)-2-phenylquinoline-4-formic acid ((S)-1-phenyl propyl) acid amides
1.4g (2.85mmol) 3-(4-dimethylamino alkylsulfonyl piperazine-1-ylmethyl)-2-phenylquinoline-4-formic acid crude product (describing 26 compounds) is dissolved in 1: 1 mixture of 100ml methylene dichloride and anhydrous THF; Add 1.19ml (8.55mmol) triethylamine (TEA) and 2.16g (5.70mmol) O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU) is cooled to 0 ℃ with this reaction mixture.Dropping be dissolved in the 15ml anhydrous methylene chloride 0.77g (5.70mmol) (S)-the 1-phenylpropylamine, this reaction mixture stirring at room 24 hours, was stirred 4 hours at 50 ℃.Solvent vacuum-evaporation to doing, is placed EtOAc to resistates, water and 1N NaOH washing, with dried over sodium sulfate and be evaporated to dried, by using the flash column chromatography purifying crude product of 230-400 order silica gel, with 8: 2 mixture wash-outs of EtOAc/ hexane.Use iPr 2After the O development, collect this title compound of 0.3g, be white powder.C 32H 37N 5O 3SMW=571.74IR:(KBr) 3315,3059,2965,2813,1955,1661,1638,1533,1491,1455,1349,1152,947,748,702cm -1. table 1 R 3=Ph
Figure A9981575300541
Figure A9981575300611
Figure A9981575300641
Table 2
Table 1 embodiment compound 1H NMR data
Embodiment ???????????????????????????????????????????????????????? 1H NMR (solvent) δ ppm
????1 δ(DMSOd 6)：0.96(3H)；1.00-1.20(5H)；1.50-1.73(5H)；1.80-2.00(2H)；2.00-2.10(5H)；2.16(4H)；3.50(2H)；5.10(1H)；7.29(1H)； 7.38(1H)；7.40-7.58(8H)；7.72(2H)；8.00(1H)；8.83(1H).
????2 δ(DMSOd 6)：0.99(3H)；1.20-1.35(2H)；1.43-1.51(2H)；1.70-1.80(2H)；1.80-2.05(2H)；2.25(1H)；2.50(2H)；3.55(2H)；5.12(1H)； 7.10(2H)；7.12(1H)；7.24(2H)；7.29(1H)；7.39(2H)；7.42-7.61(8H)；7.73(2H)；8.01(1H)；8.83(1H).
????3 δ(DMSOd 6)：1.10-1.30(9H)；1.45-1.85(5H)；2.50-2.60(4H)；2.75-2.90(4H)；3.68(2H)；4.00-4.10(1H)；4.19(2H)；7.39-7.59(11H)； 7.69(1H)；7.89(1H)；8.09(1H)；8.22(1H).
????4 δ(DMSOd 6)：1.10-1.40(15H)；1.50-1.88(5H)；2.50-2.60(8H)；3.25-3.35(1H)；3.79(2H)；4.00-4.10(1H)；7.45-7.80(7H)；7.90(1H)； 8.09(1H)；8.20(1H).
????5 δ(DMSOd 6)：1.10-1.35(8H)；1.50-1.70(2H)；1.70-1.88(4H)；2.58(4H)；2.90-3.35(8H)；3.73?and?3.80(2H)；4.01-4.12(1H)，7.20- 7.33(5H)；7.50-7.59(3H)；7.61-7.65(2H)；7.71(1H)；7.85(1H)；7.91(1H)；8.17(1H)；8.47(1H).
????6 δ(DMSOd 6)：0.85(6H)；0.97(3H)；1.21(2H)；1.53(1H)；1.80-2.01(2H)；2.01-2.07(8H)；3.50(2H)；5.10(1H)；7.29(1H)；7.38(2H)； 7.41-7.58(8H)；7.73(2H)；8.00(1H)；8.81(1H).
????7 δ(DMSOd 6)：0.87(9H)；0.98(3H)；1.23(2H)；1.80-2.00(2H)；2.01-2.09(8H)；2.14(2H)；3.50(2H)；5.10(1H)；7.28(1H)；7.38(2H)； 7.41-7.59(8H)；7.74(2H)；8.00(1H)；8.79(1H).
????8 δ(DMSOd 6)：0.80(6H)；0.98(3H)；1.63(1H)；1.80-2.00(4H)；2.00-2.09(8H)；3.50(2H)；5.10(1H)；7.28(1H)；738(2H)；7.41- 7.59(8H)；7.74(2H)；8.00(1H)；8.76(1H).
????9 δ(DMSOd 6)：0.76-0.9(2H)；0.98(3H)；1.10-1.40(4H)；1.55-1.70(5H)；1.80-2.07(12H)；3.50(2H)；5.11(1H)；7.28(1H)；7.38(2H)； 7.41-7.59(8H)；7.72(2H)；8.00(1H)；8.79(1H).
????10 δ(DMSOd 6)：0.80(6H)；0.98(3H)；1.18-1.32(6H)；1.80-2.05(11H)；3.50(2H)；5.11(1H)；7.28(1H)；7.35(2H)；7.41-7.59(8H)； 7.74(2H)；8.00(1H)；8.79(1H).
????11 δ(DMSOd 6)：0.96(3H)；1.65-1.99(9H)；2.35-2.43(2H)；2.76(3H)；-3.50(2H)；5.12(1H)；7.15-7.30(8H)；7.42-7.59(8H)；7.72(2H)； 8.01(1H)；8.81(1H).
????12 δ(DMSOd 6)：0.98(3H)；1.22-1.35(2H)；1.80-2.00(2H)；2.12-2.38(4H)；2.50-2.58(2H)；3.62(2H)；4.51(2H)；5.18(1H)；6.80(3H)； 7.23-7.32(3H)；7.38(2H)；7.41-7.62(8H)；7.73(2H)；8.01(1H)；8.14(1H)；8.81(1H).
????13 δ(DMSOd 6)：1.00-1.85(24H)；2.50(8H)；3.30(1H)；3.50(2H)；4.00(1H)；7.40-7.55(5H)；7.65(1H)；7.79(1H)；7.81(1H)；8.00(1H)； 8.58(1H).
????14 δ(DMSOd 6)：0.99(3H)；1.40-2.05(14H)；2.40-2.50(1H)；2.70-2.89(4H)；3.50(2H)；5.09(1H)；7.29(1H?)；7.38(2H)；7.41-7.59(8H)； 7.72(2H)；8.00(1H)；8.89(1H).
????15 δ(CDCl 3)：1.06(3H)；1.65-2.30(10H?and?1Hexch?with?D2O)；2.39(2H)；3.39-3.72(8H)；5.29(1H)；7.20-7.50(10Har?and?1Hexch with?D20)；7.55(1Har)；7.72(1Har)；8.02(1Har)；7.13(1Har).
????16 δ(CDCl 3)：1.04(3H)；1.62-2.55(10H)；2.37(2H)；3.28(3H)；3.37(2H)；3.64(2H)；5.31(1H)；7.18-7.50(10Har)；7.56(1Har)； 7.72(1Har)；8.00-8.16(2Har)；8.98(1Hexch?with?D2O).
????17 δ(CDCl 3)：1.00-1.32(5H)；1.28(3H)；1.42(1H)；1.52-1.95(5H)；2.03-2.58(10H)；3.30(3H)；3.43(2H)；3.77(2H)；4.26(1H)；7.35- 7.52(5Har)；7.62(1Har)；7.73(1Har)；8.12(2Har)；8.47(1Hexch?with?D20).
????18 δ(CDCl 3)：1.04(3H)；0.70-1.35(2H)；1.40-2.61(14H?and?1Hexch?with?D20)；2.73(2H)；3.57(2H)；3.71(2H)；5.30(1H)；7.22- 7.63(11Har)；7.72(1Har)；8.02(1Har)；8.12(1Har)；8.52(1Hexch?with?D2O).
????19 δ(CDCl 3)：1.04(3H)；1.32-1.73(6H)；1.75-2.22(4H)；2.37(4H)；2.50(1H)；3.58(2H)；3.67(4H)；5.32(1H)；7.20-7.62(1Har)； 7.71(1Har)；8.02(1Har)；8.11(1Har)；8.67(1Hexch?with?D2O).
????20 δ(CDCl 3)：0.93-1.35(5H)；1.29(3H)；1.45(1H)；1.57-2.67(15H?and?1Hexch?with?D2O)；3.43-3.71(6H)；3.76(2H)；4.25(1H)；7.32- 7.50(5Har)；7.48(1Har)；7.74(1Har)；7.60-7.90(1Hexch?with?D2O)；8.08(1Har)；8.13(1Har).
????21 δ(CDCl 3)：0.65-1.07(2H)；0.96(3H)；1.10-1.48(2H)；1.50-1.80(5H)；1.91(2H)；2.18(1H)；2.73(2H)；3.42(2H)；3.70(1H)；3.85(1H)； 5.22(1H)；7.12-7.60(16Har)；7.72(1Har)；8.02(1Har)；8.12(1Har)；8.69(1Hexch?with?D2O).
????22 δ(CDCl 3)：0.72-2.22(18H)；1.28(3H)；2.01(3H)；2.83(2H)；3.48(2H)；3.75(1H)；3.95(1H)；4.21(1H)；7.15-7.65(11Har?and?1Hexch with?D2O)；7.72(1Har)；8.06(1Har)；8.14(1Har).
????23 δ(CDCl 3)：1.03(3H)；1.52-2.25(6H)；1.93(3H)；2.93(2H)；3.14(2H)；3.59(2H)；5.30(1H)；7.20-7.82(13Har)；7.97(1Hexch?with D2O)；8.12(1Har).
????24 δ(CDCl 3)：0.95-1.37(5H)；1.28(3H)；1.45(1H)；1.60-1.96(5H)；2.22(4H)；3.32(2H)；3.48(1H)；3.75(2H)；4.28(1H)；6.90(1Hexch with?D2O)；7.20-7.66(11Har)；7.74(1Har)；7.00(1Har)；8.14(1Har).
????25 δ(CDCl 3)：0.92-1.36(5H)；1.05(6H)；1.30(3H)；1.46(1H)；1.53-1.95(5H)；2.19(4H)；2.67(1H)；3.27(2H)；3.39(2H)；3.73(2H)； 4.28(1H)；7.05(1Hexch?with?D2O)；3.37-7.54(5Har)；7.62(1Har)；7.78(1Har)；8.03(1Har)；8.17(1Har).
????26 δ(CDCl 3)：0.95-1.37(5H)；1.31(3H)；1.62(1H)；1.56-1.98(5H)；2.26(4H)；3.61(4H)；3.80(2H)；4.29(1H)；6.46(1Har)；7.33- 7.56(5Har)；7.60(1Har)；7.76(1Har)；7.83(1Hexch?with?D2O)；8.13(2Har)；8.25(2Har).
????27 δ(CDCl 3)：1.05(3H)；1.60(2H)；1.92-2.22(4H)；3.39(4H)；3.65(2H)；5.38(1H)；6.44(1Har)；7.20-7.53(10Har)；7.58(1Har)； 7.74(1Har)；8.07(1Har)；8.14(1Har)；8.28(2Har)；8.43(1Hexch?with?D2O).
????28 δ(CDCl 3)：1.03(3H)；1.73-2.30(10H?and?1Hexch?with?D2O)；2.41(2H)；3.54(2H)；3.63(2H)；5.29(1H)；7.25-7.50(10Har)； 7.55(1Har)；7.72(1Har)；8.03(1Har)；8.11(1Har)；8.16(1Hexch?with?D2O).
????29 δ(CDCl 3)：0.85-1.55(6H)；1.29(3H)；1.56-2.12(7H)；2.26(4H)；2.35(2H)；2.46(2H)；3.01(1Hexch?with?D2O)；3.55(2H)；3.76(2H)； 4.26(1H)；7.35-7.52(5Har)；7.59(1Har)；7.74(1Har)；7.92(1Hexch?with?D2O)；8.11(2Har).
????30 δ(DMSO，353K)：1.25(2H)；1.45(2H)；1.55(3H)；1.65(6H)；2.72(4H)；3.00(5H)；3.50(2H)；5.32(1H)；7.60-7.27(11Har)； 7.75(2Har)；8.01(1Har)；8.90(1Hexch?with?D2O).
????31 δ(DMSOd 6)(80℃)：0.98(3H)；1.92(2H)；2.23(4H)；3.23(4H)；3.80(2H)；5.03(1H)；7.15-7.90(18har)；8.08(1Har)；9.15(1Hexch?with D2O).
????32 δ(CDCl 3)：1.03(3H)；1.29-2.30(17H)；2.24(3H)；2.48(2H)；3.64(2H)；5.32(1H)；7.21-7.51(10Har)；7.58(1Har)；7.75(1Har)； 8.13(2Har)；9.00(1Hexch?with?D2O).
????33 δ(CDCl 3)：0.98-2.55(26H)；1.28(3H)；2.25(3H)；2.90(2H)；3.76(2H)；4.27(1H)；7.32-7.52(5Har)；7.59(1Har)；7.75(1Har)； 8.13(2Har)；8.46(1Hexch?with?D2O).
????34 δ(CDCl 3)：0.97-1.35(5H)；1.30(3H)；1.42(1H)；1.60-1.98(5H)；2.22(4H?and?1Hexch?with?D2O)；2.70(4H)；3.72(2H)；4.27(1H)； 7.35-7.52(5Har)；7.58(1Har)；7.75(1Har)；7.88(1Hexch?with?D2O)；8.08(1Har)；8.13(1Har).
????35 δ(CDCl 3)：0.78(12H)；1.01(3H)；1.92-2.42(18H)；3.60-3.95(2H)；5.28(1H)；7.22-7.56(11Har)；7.69(1Har)；7.82(1Har)； 8.10(1Har)；8.49(1Hexch?with?D2O).
????36 δ(CDCl 3)：0.70-2.03(20H)；1.42(3H)；3.43-3.64(3H)；7.37(1Hexch?with?D2O)；7.42-7.60(5Har)；7.66(1Har)；7.79(1Har)； 7.94(1Har)；7.98(1Hexch?with?D2O)；8.03(1Har)；8.17(1Hexch?with?D2O).
????37 δ(DMSO)：0.92(3H)；1.30-1.10(9H)；1.85-1.60(5H)；2.30-2.10(10H)；3.58(2H)；4.04(1H)；7.51-7.41(3Har)；7.57(2Har)； 7.62(1Har)；7.76(1Har)；7.87(1Har)；8.01(1Har)；8.30(1Hexch?with?D2O).
????38 δ(CDCl 3)：1.10(3H)；1.32-2.38(9H)；2.61(1H)；3.70(2H)；4.07(1H)；5.39(1H)；6.87-7.10(4Har)；7.22-7.64(11Har)；7.73(1Har)； 8.04(1Har)；8.15(1Har)；8.30(1Hexch?with?D20)；8.98(1Hexch?with?D2O).
????39 δ(CDCl 3)：1.02-1.43(5H)；1.34(3H)；1.45-2.36(12H)；2.26(1H)；2.38(1H)；3.82(2H)；4.19(1H)；4.37(1H)；7.02(4Har)；7.38- 7.86(7Har?and?1Hexch?with?D2O)；8.09(1Har)；8.16(1Har)；8.91(1hexch?with?D2O).
????40 δ(DMSOd 6)(80℃)：0.99(3H)；1.47(2H)；1.72(2H)；1.90(2H)；2.03(3H)；2.64(3H)；2.55-3.00(3H)；3.28(2H)；4.05(2H)；5.10(1H)； 7.25-7.95(13Har)；8.10(1Har)；9.49(1Hexch?with?D2O).
????41 δ(CDCl 3)：0.95-2.95(26H)；2.64-3.32(16H)；3.95(1H)；4.11(1H)；4.38(1H)；6.82(1Hexch?with?D2O)；7.42-7.20(6Har)；7.61- 7.87(2Har)；8.18(1Har).
????42 δ(CDCl 3)：0.92-1.94(17H)；1.29(3H)；2.04(1H)；2.43(4H)；2.53(1H)；2.79(1H)；3.52-3.82(6H)；4.28(1H)；7.34-7.55(5Har)； 7.60(1Har)；7.72(1Har)；8.00-8.30(2Har?and?1?Hexch?with?D2O).
????43 δ(CDCl 3)：0.95-2.07(23H?and?1Hexch?with?D2O)；1.28(3H)；2.13-2.45(2H)；2.53(1H)；2.77(2H)；3.68(3H)；4.25(1H)；7.33- 7.67(6Har)；7.75(1Har)；8.10(2Har)；7.70-8.20(1Hexch?with?D2O).
????44 δ(CDCl 3)：0.94-2.02(27H)；2.30-2.61(2H)；2.98-3.40(4H)；3.73(2H)；4.25(1H)；7.32-7.52(5Har)；7.56(1Har)；7.72(1Har)；7.60- 7.80(1Hexch?with?D2O)；8.06(1Har)；8.13(1Har).
????45 δ(CDCl 3)：0.92-1.15(9H)；1.20-1.70(6H)；1.80-2.12(3H)；2.22(1H)；2.40(1H)；3.08(2H)；3.23(2H)；3.50(1H)；3.15(1H)；5.31(1H)； 7.21-7.62(11Har)；7.20(1Har)；7.33-8.22(2Har?and?1Hexch?with?D2O).
????46 δ(CDCl 3)：1.00-1.49(5H)；1.28(3H)；1.47(1H)；1.60-1.97(5H)；2.09-2.47(4H)；2.21(6H)；3.01(2H)；3.36(4H)；3.73(2H)；4.27(1H)； 7.06(1Hexch?with?D2O)；7.38-7.56(5Har)；7.60(1Har)；7.75(1Har)；8.02(1Har)；8.16(1Har).
????47 δ(CDCl 3)：0.85-1.38(5H)；1.03(6H)；1.28(3H)；1.44(1H)；1.60-1.95(5H)；2.19(4H)；2.35-2.67(6H)；2.78(2H)；3.24(2H)；3.38(2H)； 3.74(2H)；4.48(1H)；7.07(1Hexch?with?D2O)；7.34-7.59(5Har)；7.63(1Har)；7.78(1Har)；8.02(1Har)；8.14(1Har).
????48 δ(DMSOd 6)：0.93-1.35(5H)；1.16(3H)；1.48(1H)；1.58-1.92(5H)；1.98-2.29(4H)；2.24(3H)；2.40(8H)；3.07(2H)；2.96-3.65(4H)； 3.58(2H)；4.02(1H)；7.40-7.91(8Har)；8.04(1Har)；8.60(1Hexch?with?D2O).
????49 δ(DMSO)：0.95(3H)；1.10(2H)；2.00-1.50(9H)；2.22(1H)；2.41(1H)；2.59(1H)；2.81(1H)；3.55(2H)；5.10(1H)；7.59-7.25(11Har)； 7.75(2Har)；8.01(1Har)；8.83(1Hexch?with?D2O).
????50 δ(DMSO+TFA?353?K)：1.00(3H)；1.30-1.10(6H)；1.89-1.50(17H)；2.02(2H)；3.20-2.80(7H)；4.00(1H)；4.20(2H)；7.61- 7.51(3Har)；7.65(3Har)；7.88(1Har)；7.98(1Har)；8.10(1Har)；8.65(1Hexch?with?D2O).
????51 δ(DMSOd 6)：0.90-1.35(5H)；1.14(3H)；1.46(1H)；1.55-1.90(5H)；2.03(4H)；2.22-2.52(8H)；3.15(4H)；3.42-3.70(6H)；3.99(1H)； 7.32-8.12(6Har)；8.53(1Hexch?with?D2O).
????52 δ(DMSOd 6)：0.95-1.35(5H)；1.20(3H)；1.46(1H)；1.58-1.88(5H)；2.05(2H)；2.87(4H)；3.03-3.30(4H)；3.60(2H)； 4.01(1H)；6.86(1H)；7.30-8.10(10H?and?1Hexch?with?D2O)；8.54(1Hexch?with?D2O).
????53 δ(DMSOd 6)：0.95-1.32(5H)；1.17(3H)；1.47(1H)；1.55-1.95(5H)；2.26(4H)；2.82(12H)；3.03(4H)；3.62(2H)；4.01(1H)；7.38- 7.88(8Har)；8.03(1Har)；8.54(1Hexch?with?D2O).
????54 δ(DMSOd 6)：0.95-1.37(5H)；1.17(3H)；1.46(1H)；1.57-1.92(5H)；2.08(4H)；3.30(4H)；3.55(2H)；4.02(1H)；7.32-7.91(8Har)； 8.02(1Har)；8.53(1Hexch?with?D2O).
????55 δ(CDCl 3)：0.60-2.25(9H?and?2Hexch?with?D2O)；1.06(3H)；2.41(2H)；3.57(2H)；5.30(1H)；7.15-7.65(10Har)；7.72(1Har)； 8.02(1Har)；8.14(2Har)；8.80(1Hexch?with?D2O).
????56 δ(CDCl 3)：1.03(3H)；1.75-2.28(6H)；3.09(4H)；3.65(2H)；5.33(1H)；6.45(1Har)；6.58(1Har)；7.18-7.65(12Har)；7.75(1Har)；8.93- 8.20(3Har)；8.39(1Hexch?with?D2O).
????57 δ(CDCl 3)：0.97(3H)；2.02(2H)；2.33(4H)；2.94(6H)；3.03(4H)；3.88(2H)；5.23(1H)；7.19-7.60(10Har?and?1Hexch?with?D2O)； 7.68(1Har)；7.86(1Har)；8.02(1har)；8.22(1Har).
????58 δ(CDCl 3)：0.98-1.42(5H)；1.26(3H)；1.43-1.98(6H)；2.53(4H)；3.00(6H)；2.90-3.32(4H)；3.95(2H)；4.22(1H)；7.35-7.78(7Har?and 1Hexch?with?D2O)；7.98(1Har)；8.10(1Har).
????59 δ(CDCl 3)：1.30(3H)；0.95-2.02(11H)；2.31(4H)；3.32(4H)；3.80(2H)；4.28(1H)；6.48-6.68(2Har)；7.35-7.67(7Har)；7.73(1Har)； 7.65-7.69(1Hexch?with?D20)；8.02-8.22(3Har).
????60 δ(CDCl 3)：0.77(3H)；0.85(3H)；1.02(3H)；1.70-2.58(8H)；3.59(2H)；2.78(1H)；7.1?5-7.65(11Har?and?1Hexch?with?D2O)； 7.75(1Har)；8.05(1Har)；8.14(1Har)；8.58(1Hexch?with?D2O).
????61 δ(CDCl 3)：0.95-2.00(15H)；1.29(3H)；2.28(4H)；3.77(2H)；3.87(4H)；4.23(1H)；7.35-7.55(5Har)；7.60(1Har)；7.75(1Har)；7.95- 8.25(2Har?and?1Hexch?with?D2O).
????62 δ(CDCl 3)：0.70-1.70(6H)；1.04(3H)；1.82-2.22(5H)；2.28(3H)；2.35-2.65(8H)；3.57(2H)；5.32(1H)；7.20-7.64(11Har)；7.73(1Har)； 8.03(1Har)；8.13(1Har)；8.72(1Hexch?with?D2O).
????63 δ(DMSOd 6)：0.95(3H)；0.94-1.45(4H)；1.50-2.25(6H)；2.65-3.02(4H)；3.30(2H)；5.06(1H)；7.20-8.00(13Har?and?1Hexch?with D2O)；8.02(1Har)；9.14(1Hexch?wih?D2O).
????64 δ(CDCl 3)：1.02(3H)；1.10-1.88(6H)；1.90-2.28(3H)；2.45(1H)；3.59(2H)；5.30(1H)；5.91(1Hexch?with?D2O)；7.18-7.62(11Har?and 2Hexch?with?D2O)；7.72(1Har)；795(1har)；8.13(1Har).
????65 δ(CDCl 3)：1.29-2.22(15H)；2.27(3H)；2.88(2H)；3.66(2H)；4.74(2H)；7.22-7.52(10Har)；7.59(1Har)；7.77(1Har)；8.12(1Har)； 8.22(1Har)；9.64(1Hexch?with?D2O).
????66 δ(DMSO?343?k)：0.95(3H)；1.08(2H)；1.65-1.25(11H)；1.88-1.80(2H)；2.50-2.25(6H)；3.41(2H)；3.92(3H)；5.09(1H)；7.60- 7.15(13Har)；8.90(1Hexch?with?D2O).
????67 δ(DMSO)：0.95(3H)；1.08(2H)；1.65-1.25(11H)；2.00-1.80(2H)；2.50-2.25(6H)；3.49(2H)；4.00(3H)；5.09(1H)；7.71-7.25(12Har)； 8.90(1Hexch?with?D2O).
????68 δ(DMSOd 6)：0.94(3H)；1.15-2.45(14H)；2.11(3H)；3.60(2H)；5.05(1H)；7.15-7.59(13Har)；8.02(1Har)；9.16(1Hexch?with?D2O)
????69 δ(CDCl 3)：1.05-2.23(22H)；1.34(3H)；2.24-2.63(5H)；2.28(1H)；3.69(2H)；4.24(1H)；7.35-7.65(6Har)；7.73(1Har)；8.12(2Har)；
8.47(1Hexch?with?D2O).
????70 δ(CDCl 3)：0.80-1.44(4H)；1.04(3H)；1.53-2.29(7H)；2.50(1H)；2.89(2H)；3.20(2H)；3.63(2H)；4.02(1H)；4.49(1Hexch?with?D2O)； 5.29(1H)；7.18-7.55(10Har)；7.56(1Har)；7.74(1Har)；8.10(2Har)；8.74(1Hexch?with?D2O).
????71 δ(CDCl 3)：1.01(3H)；1.26(2H)；1.41-1.68(2H)；1.35-2.30(6H)；3.06(2H)；3.62(2H)；4.99(1Hexch?with?D2O)；5.26(1H)；7.22- 7.50(10Har)；7.57(1Har)；7.73(1Har)；7.41(1Hexch?with?D2O)；8.02(1Har)；8.12(1Har).
????72 δ(CDCl 3)：0.98-1.39(5H)；1.28(3H)；1.49(1H)；1.63-1.98(9H)；2.30(4H)；3.47(4H)；3.64(4H)；3.71(2H)；4.24(1H)；6.54(1Hexch with?D2O)；7.35-7.53(5Har)；7.60(1Har)；7.73(1Har)；7.94(1Har)；8.12(1Har).
????73 δ(CDCl 3)：0.99-1.37(5H)；1.27(3H)；1.48(1H)；1.63-1.90(5H)；2.23(4H)；2.93(3H)；3.19(4H)；3.70(2H)；4.24(1H)；4.84(1Hexch with?D20)；6.55(1Hexch?with?D2O)；7.36-7.52(5Har)；7.59(1Har)；7.73(1Har)；7.94(1Har)；8.13(1Har).
????74 δ(CDCl 3)：0.98-1.37(5H)；1.26(3H)；1.42(1H)；1.54-1.93(5H)；2.20(4H)；3.21(4H)；3.25(2H)；3.75(2H)；3.95(2H)；4.26(1H)；7.32- 7.67(5Har?and?1Hexch?with?D2O)；7.58(1Har)；7.73(1Har)；8.03(1Har)；8.13(1Har).
????75 δ(CDCl 3)：0.96-1.32(5H)；1.25(3H)；1.43(1H)；1.63-1.91(5H)；2.22(4H)；3.07(3H)；3.54(4H)；3.71(2H)；4.25(1H)；5.58(1Hexch with?D2O)；6.90(1Hexch?with?D2O)；7.38-7.52(5Har)；7.58(1Har)；7.72(1Har)；8.92(1Har)；8.10(1Har).
????76 δ(CDCl 3)：1.00-1.35(5H)；1.28(3H)；1.45(1H)；1.63-1.93(9H)；2.29(4H)；3.18(4H)；3.33(4H)；3.73(2H)；4.22(1H)；6.65(1Hexch with?D2O)；7.42-7.52(5Har)；7.61(1Har)；7.71(1Har)；7.76(1Har)；8.13(1Har).
????77 δ(DMSOd 6)：0.98(3H)；1.03-2.00(5H)；1.81(2H)；2.05-2.62(2H)；2.95-3.72(8H)；5.08(1H)；6.16(1Hexch?with?D2O)；7.17- 7.70(12Har)；7.77(1Har)；8.02(1Har)；9.12(1Hexch?with?D2O).
????78 δ(CDCl 3)：0.96-1.40(5H)；1.30(3H)；1.51(1H)；1.62-1.87(5H)；1.88-2.03(4H)；2.20-2.42(4H)；2.85，2.87(3H，2forms)；2.98- 3.15(4H)；3.38-3.62(4H)；3.75(2H)；4.23(1H)；6.27(1Hexch?with?D2O)；7.38-7.81(7Har)；7.92(1Har)；8.15(1Har).
????79 δ(CDCl 3)：0.93(3H)；1.19(3H)；1.05-1.65(8H)；1.68-1.83(4H)；1.90-2.55(8H)；3.52(2H)；5.14(1H)；7.33-7.60(11Har)；7.71(1Har)； 8.00(1Har)；8.11(1Har)；8.47(1Hexch?with?D2O).
????80 δ(CDCl 3)：0.94(3H)；1.08(6H)；1.17(3H)；1.86(4H)；2.23(1H)；2.46(2H)；2.63(4H)；2.83(2H)；3.02(2H)；3.17(2H)；3.53(2H)； 5.14(1H)；7.29-7.55(1Har?and?1Hexch?with?D2O)；7.73(1Har)；7.91(1Har)；8.13(1Har)
????81 δ(CDCl 3)：0.99-1.38(5H)；1.30(3H)；1.49(1H)；1.57-1.99(9H)；2.18-2.38(4H)；2.98-3.15(4H)；3.22-3.37(4H)；3.75(2H)；4.25(1H)； 6.28(1H)；6.63(1Hexch?with?D2O)；7.37-7.55(5Har)；7.60(1Har)；7.74(1Har)；7.98(1Har)；8.14(1Har).
????82 δ(DMSOd 6)：0.951-1.32(8H)；1.32(1H)；1.57-1.86(5H)；2.15-2.36(4H)；2.29(3H)；2.77(2H)；3.11(2H)；3.60(2H)；4.00(1H)； 7.11(2Har)；7.27(2Hexch?with?D2O)；7.48(2Har)；7.49-7.61(5Har)；7.62(1Har)；7.88(2Har)；8.03(1Har)；8.57(3Hexch?with?D2O).
????83 δ(CDCl 3)：0.98-1.36(5H)；1.28(3H)；1.45(1H)；1.60-1.95(5H)；2.08-2.27(4H)；2.47-2.66(4H)；3.00(1Hexch?with?D2O)；3.23(2H)；
?3.37(2H)；3.73(2H)；4.26(1H)；6.85(1Hexch?with?D2O)；7.39-7.54(5Har)；7.60(1Har)；7.75(1Har)；7.99(1Har)；8.15(1Har).
????84 δ(CDCl 3)：1.00-1.39(5H)；1.29(3H)；1.47(1H)；1.68-1.97(9H)；2.18-2.36(4H)；2.92(3H)；3.16-3.49(8H)；3.74(2H)；4.25(1H)； 6.93(1Hexch?with?D2O)；7.38-7.53(5Har)；7.59(1Har)；7.74(1Har)；8.00(1Har)；8.13(1Har).
????85 δ(CDCl 3)：0.93(3H)；1.17(3H)；1.71-2.03(4H)；2.21(1H)；2.40-2.66(4H)；300-3.50(1Hexch?with?D2O)；3.01(2H)；3.18(2H)； 3.51(2H)；5.13(1H)；7.01(1Hexch?with?D2O)；7.25-7.52(10Har)；7.55(1Har)；7.73(1Har)；7.89(1Har)；8.14(1Har).
????86 δ(CD 3COD)；0.84(3H)；1.19(3H)；1.36-2.41(5H)；2.65(2H)；2.80-3.70(2H)；3.24(1H)；3.45(1H)；4.96(1H)；7.00-8.15(18Har?and 2Hexch?with?D2O).
????87 δ(CD 3COD)：1.01-1.96(11H)；1.25(3H)；1.97-2.53(4H)；2.93(2H)；3.20-3.80(2H)；3.67(2H)；4.10(1H)；7.17(1Har)；7.37-8.14(12H and?2Hexch?with?D2O).
????88 δ(DMSO)：1.40-1.08(5H)；1.50(2H)；1.90-1.63(21H)；3.10-2.50(5H)；3.54(2H)；3.91(3H)；4.00(1H)；7.28(1Har)；7.41(1Har)；7.57- 7.42(5Har)；7.74(1Har)；8.29(1Hexch?with?D2O).
????89 δ(DMSO)：0.95(3H)；1.08(2H)；1.60-1.30(11H)；1.96-1.75(3H)；2.50-2.25(6H)；3.30(2H)；5.00(1H)；6.80(1Har)；7.42-7.12(9Har)； 7.54(2Har)；8.65(1Hexch?with?D2O).
????90 δ(DMSO?343?K)：0.97(3H)；2.10-1.80(6H)；2.69(4H)；3.51(2H)；5.09(1H)；6.40(2Hexch?with?D2O)；7.55-7.21(11Har)； 7.72(2Har)；8.00(1Har)；8.89(1Hexch?with?D2O).
????91 δ(DMSO?343?K)：0.98(3H)；2.10-1.80(6H)；2.70(6H)；2.79(4H)；3.55(2H)；5.10(1H)；7.57-7.21(11Har)；7.75(2Har)；8.00(1Har)； 8.89(1Hexch?with?D2O)；
????92 δ(DMSOd 6)：0.88-1.35(5H)；1.16(3H)；1.45(1H)；1.53-1.93(5H)；2.16(4H)；2.30(4H)；2.90(2H)；3.56(2H?and?1Hexch?with?D20)； 4.02(1H)；7.22-7.90(8Har)；8.03(1Har)；8.55(1Hexch?with?D2O)ppm.
????93 δ(CDCl 3)：0.94(3H)；0.98-1.34(2H)；1.19(3H)；1.36-1.67(2H)；1.70-2.56(6H?and?1Hexch?with?D2O)；2.43(4H)；2.88(4H)； 2.52(2H)；5.15(1H)；7.22-7.60(11Har)；7.71(1Har)；7.99(1Har)；8.11(1Har)；8.35(1Hexch?with?D2O).
????94 δ(CDCl3)：1.13-2.66(31H)；2.81(1H)；3.64(1H)；3.74(1H)；4.35(1H)；7.38-7.53(5Har)；7.58(1Har)；7.73(1Har)；8.13(1Har)；7.70- 8.50(1Hexch?with?D2O)
????95 δ(DMSOd 6)：0.95(3H)；1.09(2H)；1.34-1.50(8H)；1.50-1.65(2H)；1.80-1.98(3H)；2.35(4H)；2.42(2H)；3.40(2H)；5.09(1H)； 7.09(1Har)；7.22(1Har)；7.25-7.55(11Har)；8.88(1Hexch?with?D2O)；9.98(1Hexch?with?D2O).
Table 3
Table 1 Example Chemical name parent compound (Beilstein's Autonom name) Example chemical nomenclature 1 3 - (4 - cyclohexyl-piperazin-1 - ylmethyl)-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - phenyl-propyl Yl)-amide 2 2 - phenyl-3 - (4 - phenyl-piperidin-1 - yl methyl) quinoline-4 - carboxylic acid ((S) -1 - phenyl-propyl) Amide 3 3 - (4 - benzyl-piperazin-1 - ylmethyl)-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl-acetic Yl)-amide 4 3 - (4 - isopropyl-piperazin-1 - ylmethyl)-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl- Ethyl)-amide 5 3 - (4 - phenethyl-piperazin-1 - ylmethyl)-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl- Ethyl)-amide 6 3 - [4 - (3 - methylbutyl) piperazin-1 - yl methyl] -2 - phenyl-quinoline-4 - carboxylic acid ((S) - 1 - phenyl-propyl) amide 7 3 - [3 - (3,3 - dimethylbutyl) piperazin-1 - yl methyl] -2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 8 3 - (4 - iso-Butyl-piperazin-1 - ylmethyl)-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - phenyl-propyl Yl)-amide 9 3 - (4 - cyclohexylmethyl-piperazin-1 - ylmethyl)-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - phenyl Yl-propyl) amide 10 3 - [4 - (2 - ethylbutyl) piperazin-1 - yl methyl] -2 - phenyl-quinoline-4 - carboxylic acid ((S) - 1 - phenyl-propyl) amide 11 3 - [(acetyl-methyl-amino) phenyl-piperidin-1 - yl methyl] -2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 12 3 - (4 - oxo-1 - phenyl-1 ,3,8 - triaza-spiro [4.5] dec-8 - yl methyl) -2 - phenyl Quinoline-4-yl - carboxylic acid ((S) -1 - phenyl-propyl) amide 13 3 - [1,4 '] bipiperidinyl-1'-yl-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl- Ethyl)-amide 14 3 - [1,4 '] bipiperidinyl-1'-yl-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - phenyl-propyl Yl)-amide 15 3 - {4 - [2 - (2 - hydroxyethoxy) ethyl] piperazin-1 - ylmethyl}-2-phenyl - quinoline - 4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 16 3 - [4 - (2 - methoxyethyl) piperazin-1 - yl methyl] -2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 17 3 - [4 - (2 - methoxyethyl) piperazin-1 - yl methyl] -2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 18 3 - (4 - hydroxy - [1,4 '] bipiperidinyl-1'-yl)-2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 19 3 - (4 - morpholin-4 - yl-piperidin-1 - ylmethyl)-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - Phenyl-propyl) amide 20 3 - {4 - [2 - (2 - hydroxyethoxy) ethyl] piperazin-1 - ylmethyl}-2-phenyl - quinoline - 4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 21 3 - {[(1 - benzyl-piperidin-4 - yl) methylamino] methyl} -2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 22 3 - {[(1 - benzyl-piperidin-4 - yl) methylamino] methyl} -2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 cyclohexyl-ethyl) amide 23 3 - (4 - acetyl-piperazin-1 - ylmethyl)-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - phenyl- Propyl) amide 24 2 - phenyl-3 - [4 - (1 - phenyl-formyloxy) piperazin-1 - yl methyl] quinolin-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 25 3 - [4 - (2 - methyl-propionyl)-piperazin-1 - yl methyl] -2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 26 2 - phenyl-3 - (4 - pyrimidin-2 - piperazin-1 - yl methyl) quinoline-4 - carboxylic acid ((S) -1 - Cyclohexyl-ethyl) amide 27 2 - phenyl-3 - (4 - pyrimidin-2 - piperazin-1 - yl methyl) quinoline-4 - carboxylic acid ((S) -1 - Phenyl-propyl) amide 28 3 - [4 - (2 - hydroxyethyl) piperazin-1 - yl methyl] -2 - phenyl-quinoline-4 - carboxylic acid ((S) - 1 - phenyl-propyl) amide 29 3 - [4 - (2 - hydroxyethyl) piperazin-1 - yl methyl] -2 - phenyl-quinoline-4 - carboxylic acid ((S) - 1 - cyclohexyl-ethyl) amide 30 3 - [1,4 '] bipiperidinyl-1'-yl-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - phenyl-ethyl Yl)-amide 31 2 - phenyl-3 - [4 - (1 - phenyl-formyloxy) piperazin-1 - yl methyl] quinolin-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 32 3 - [4 - (1 - methyl-piperidin-4 - yl) piperazin-1 - yl methyl] -2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 33 3 - [4 - (1 - methyl-piperidin-4 - yl) piperazin-1 - yl methyl] -2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 34 2 - phenyl-3 - piperazin-1 - yl methyl-quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 35 3 - {[bis (2 - diethylaminoethyl) amino] methyl} -2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 36 3 - (4 - carbamoyl-piperidin-1 - ylmethyl)-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - Cyclohexyl-ethyl) amide 37 3 - (4 - ethyl-piperazin-1 - ylmethyl)-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl- Ethyl)-amide 38 3 - [4 - (2 - oxo-2 ,3 - dihydro-benzimidazol-1 - yl) piperidin-1 - yl methyl] -2 - phenyl Quinoline-4-yl - carboxylic acid ((S) -1 - phenyl-propyl) amide 39 3 - [4 - (2 - oxo-2 ,3 - dihydro-benzimidazol-1 - yl) piperidin-1 - yl methyl] -2 - phenyl Quinoline-4-yl - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 40 3 - {[methyl-(1 - methyl-piperidin-4 - yl) amino] methyl} -2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 41 3 - {[bis (2 - diethylaminoethyl) amino] methyl} -2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 42 3 - (4 - morpholin-4 - yl-piperidin-1 - ylmethyl)-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - Cyclohexyl-ethyl) amide 43 3 - (4 - hydroxy - [1,4 '] bipiperidinyl-1'-yl)-2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 44 3 - (3 - diethylamino-carbamoyl piperidin-1 - yl methyl) -2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 45 3 - (3 - diethylamino-carbamoyl piperidin-1 - yl methyl) -2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 46 3 - [4 - (2 - two methylaminoacetyl) piperazin-1 - yl methyl] -2 - phenyl-quinoline-4 - A Acid ((S) -1 - cyclohexyl-ethyl) amide 47 3 - [4 - (3 - diethylamino-propionyl) piperazin-1 - yl methyl] -2 - phenyl-quinolin-4 - methyl Acid ((S) -1 - cyclohexyl-ethyl) amide 48 3 - {4 - [2 - (4 - methyl-piperazin-1 - yl) acetyl] piperazin-1 - yl methyl} -2 - phenyl- Quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 49 3 - (hexahydro-pyrrolo [1,2-a] pyrazine-2 - ylmethyl) - phenyl-quinoline-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 50 3 - [1,4 '] bipiperidinyl-1'-yl-2 - phenyl-quinolin-4 - carboxylic acid 51 3 - [4 - (3 - morpholin-4 - yl-propionyl) piperazin-1 - yl methyl] -2 - phenyl-quinolin-4 - methyl Acid ((S) -1 - cyclohexyl-ethyl) amide 52 3 - [4 - (2-1H-imidazol-4 - yl-acetyl) piperazin-1 - yl methyl] -2 - phenyl-quinoline - 4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 53 ({4 - [4 - ((S) -1 - cyclohexyl-ethyl-carbamoyl)-2 - phenyl - quinolin-3 - yl methyl Yl] - piperazin-1 - yl} dimethyl aminomethylene) dimethyl ammonium 54 3 - morpholin-4 - yl-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 55 3 - (4 - amino-piperidin-1 - ylmethyl)-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - phenyl-propyl Yl)-amide 56 2 - phenyl-3 - (4 - pyridin-2 - piperazin-1 - yl methyl) quinoline-4 - carboxylic acid ((S) -1 - Phenyl-propyl) amide 57 3 - {[bis (2 - methoxyethyl) amino] methyl}-2 - phenyl-quinoline-4 - carboxylic acid ((S) - 1 - phenyl-propyl) amide 58 3 - {[bis (2 - methoxyethyl) amino] methyl}-2 - phenyl-quinoline-4 - carboxylic acid ((S) - 1 - cyclohexyl-ethyl) amide 59 2 - phenyl-3 - (4 - pyridin-2 - piperazin-1 - yl methyl) quinoline-4 - carboxylic acid ((S) -1 - Cyclohexyl-ethyl) amide 60 3 - ((3R, 5S) -3,5 - dimethyl-piperazin-1 - yl methyl) -2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 61 3 - (1,4 - dioxa-8 - aza-spiro [4.5] dec-8 - yl methyl) -2 - phenyl-quinolin-4 - Carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 62 3 - [4 - (4 - methyl-piperazin-1 - yl) piperidin-1 - yl methyl] -2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 63 3 - (3 - oxo -2,8 - diaza-spiro [4.5] dec-8 - yl methyl) -2 - phenyl-quinolin-4 - Carboxylic acid ((S) -1 - phenyl-propyl) amide 64 3 - (2,4 - dioxo-1 ,3,8 - triaza-spiro [4.5] dec-8 - yl)-2 - phenyl-quinoline -4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 65 3 - [4 - (1 - methyl-piperidin-4 - yl) piperazin-1 - yl methyl] -2 - phenyl-quinolin-4 - carboxylic acid Benzylamide 66 3 - [1,4 '] bipiperidinyl-1'-yl-8 - bromo-7 - methoxy-2 - phenyl-quinoline-4 - methyl Acid ((S) -1 - phenyl-propyl) amide 6 7 3 - [1,4 '] bipiperidinyl-1'-yl-7 - methoxy-2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 68 3 - (7 - methyl -2,7 - diaza-spiro [4.4] non-2 - ylmethyl)-2 - phenyl-quinolin-4 - Carboxylic acid ((S) -1 - phenyl-propyl) amide 69 3 - [1,4 '] bipiperidinyl-1'-yl-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - cyclopentyl- Ethyl)-amide 70 3 - [4 - (2 - oxo-tetrahydro-pyrimidin-1 - yl) piperidin-1 - yl methyl] -2 - phenyl-quinolin-4 - Carboxylic acid ((S) -1 - phenyl-propyl) amide 71 3 - (2 - oxo-3 - oxa-1, 8 - diaza-spiro [4.5] dec-8 - yl methyl) -2 - phenyl- Quinoline-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 72 3 - [4 - (3,4 - dioxo-2 - pyrrolidin-1 - yl ring but-1 - enyl) piperazin-1 - yl methyl Yl] -2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 73 3 - [4 - (1 - cyanoimino-1 - methyl-amino-methyl) piperazin-1 - yl methyl] -2 - phenyl- Quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 74 3 - [4 - (4,5 - dihydro-thiazol-2 - yl) piperazin-1 - yl methyl] -2 - phenyl-quinoline-4 - A Acid ((S) -1 - cyclohexyl-ethyl) amide 75 3 - (4 - methyl-thio-carbamoyl-piperazin-1 - yl methyl) -2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 76 3 - (4 - (1 - cyanoimino-1 - pyrrolidin-1 - ylmethyl) piperazin-1 - yl methyl] -2 - Phenyl-quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 77 3 - [4 - (2 - oxo - imidazolidin-1 - yl) piperidin-1 - yl methyl] -2 - phenyl-quinolin-4 - Carboxylic acid ((S) -1 - phenyl-propyl) amide 78 3 - [4 - (1 - methyl-1 - pyrrolidin-1 - ylmethyl) piperazin-1 - yl methyl] -2 - Phenyl-quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 79 3 - [1,4 '] bipiperidinyl-1'-yl-2 - phenyl-quinoline-4 - carboxylic acid ((S) -2 - methyl - 1 - phenyl-propyl) amide 80 3 - [4 - (3 - diethylamino-propionyl) piperazin-1 - yl methyl] -2 - phenyl-quinolin-4 - methyl Acid ((S) -2 - methyl-1 - phenyl-propyl) amide 81 3 - [4 - (2 - nitro-1 - pyrrolidin-1 - yl ethenyl) piperazin-1 - yl methyl] -2 - phenyl- Quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 82 3 - (4 - imino-carbamoyl-piperazin-1 - yl methyl) -2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 83 4 - {4 - (4 - ((S) -1 - cyclohexyl-ethyl-carbamoyl) -2 - phenyl-quinolin-3 - yl methyl Yl] piperazin-1 - yl} -4 - oxo-butyric acid 84 3 - [4 - (1 - methyl-1 sulfonylimino - pyrrolidin-1 - ylmethyl) piperazin-1 - yl methyl Yl] -2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 85 4 - {4 - [4 - ((S) -2 - methyl-1 - phenyl-propyl-carbamoyl)-2-phenyl - quinoline - ³ - methyl] piperazin-1 - yl} -4 - oxo-butyric acid 86 2 - (1 - {4 - [4 - ((S) -2 - methyl-1 - phenyl-propyl-carbamoyl)-2 - phenyl-quinoline -3 - yl-methyl]-piperazin-1 - yl} carbamoyl) benzoic acid 87 2 - (1 - {4 - [4 - ((S) -1 - cyclohexyl-ethyl-carbamoyl)-2 - phenyl-quinoline-3 - Ylmethyl]-piperazin-1 - yl} carbamoyl) benzoic acid 88 3 - [1,4 '] bipiperidinyl-1'-yl-7 - methoxy-2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 - cyclohexyl-ethyl) amide 89 3 - [1,4 '] bipiperidinyl-1'-yl-8 - chloro-7 - hydroxy-2 - phenyl-quinolin-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 90 2 - phenyl-3 - (4 - sulfamoyl-piperazin-1 - yl methyl) quinoline-4 - carboxylic acid ((S) -1 - phenyl Yl-propyl) amide 91 3 - (4 - two methylsulphamoyl piperazin-1 - yl methyl) -2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - phenyl-propyl) amide 92 {4 - [4 - ((S) -1 - cyclohexyl-ethyl-carbamoyl) -2 - phenyl-quinolin-3 - yl-methyl] Piperazin-1 - yl} acetic acid 93 2 - phenyl-3 - (4 - piperazin-1 - yl-piperidin-1 - yl methyl) quinoline-4 - carboxylic acid ((S) -2 - Methyl-1 - phenyl-propyl) amide 94 3 - [1,4 '] bipiperidinyl-1'-yl-2 - phenyl-quinoline-4 - carboxylic acid ((S) -1 - cycloheptyl Ethyl)-amide 95 3 - [1,4 '] bipiperidinyl-1'-yl methyl-7 - hydroxy-2 - phenyl-quinoline-4 - carboxylic acid ((S) - 1 - phenyl-propyl) amide ...

Claims (30)

1. formula (I) compound or its solvate or salt:
Wherein Ar is optional substituted aryl or C 5-7Cycloalkadienyl, or optional substituted C 5-7Cycloalkyl, or optional substituted monocycle or fused rings aromatic heterocyclic; R is hydrogen, straight or branched C 1-6Alkyl, C 3-7Cycloalkyl, C 3-7Cycloalkylalkyl; R 1Represent hydrogen or be selected from 3 optional substituting group: the C that are up to of following radicals 1-6Alkyl, C 1-6Alkenyl, aryl, C 1-6Alkoxyl group, hydroxyl, halogen, nitro, cyano group, carboxyl, formamyl, amino-sulfonyl, C 1-6Alkoxy carbonyl, trifluoromethyl, acyloxy, amino or a C 1-6Alkylamino or two C 1-6Alkylamino;
R 2Representative-(CH 2) n-NY 1Y 2, wherein n is the integer of 1-9, Y 1And Y 2Be independently selected from C 1-6Alkyl; By hydroxyl, alkoxyl group, C 1-6Alkylamino or two (C 1-6Alkyl) the amino C that replaces 1-6Alkyl; C 3-6Cycloalkyl; C 4-6Azacycloalkyl; C 1-6Alkenyl; Aryl or aryl-C 1-6Alkyl, perhaps Y 1And Y 2Represent monocycle or the fused rings heterocyclic radical of choosing substituted N-connection wantonly with the nitrogen-atoms that they connected;
R 3Be straight or branched C 1-6Alkyl, C 3-7Cycloalkyl, C 4-7Cycloalkylalkyl, optional substituted aryl or optional substituted monocycle or fused rings aromatic heterocyclic; And R 4Represent hydrogen or C 1-6Alkyl, R 5Represent hydrogen or halogen.
2. the compound of claim 1, wherein optional substituted phenyl, unsubstituted phenyl or cyclohexyl of Ar representative.
3. claim 1 or 2 compound, wherein Ar represents cyclohexyl.
4. claim 1 or 2 compound, wherein Ar represents phenyl.
5. each compound of claim 1-4, wherein R represents C 1-6Alkyl.
6. each compound of claim 1-5, wherein R 1Represent hydrogen or C 1-6Alkoxyl group.
7. each compound of claim 1-6, wherein R 1Represent hydrogen.
8. each compound of claim 1-6, wherein R 1Represent hydrogen methoxyl group or hydroxyl.
9. each compound of claim 1-8, wherein R 5Represent hydrogen.
10. each compound of claim 1-8, wherein R 5Represent chlorine or bromine.
11. each compound of claim 1-10, wherein NY 1Y 2Monocycle or fused rings heterocyclic radical that the optional substituted N-of representative connects.
12. each compound of claim 1-11, wherein-NY 1Y 2Representative replaces or unsubstituted piperazinyl.
13. each compound of claim 1-12, wherein-NY 1Y 2Representative formula (a) and (b), (c) or (d) group:
Figure A9981575300031
T wherein 1Represent the sec.-propyl carbonyl, hydroxyethyl, cyclohexyl, phenyl, benzyl, sec.-propyl, styroyl, piperidino, hydroxyl ethoxy ethyl, (4-hydroxyl)-piperidino, the 4-piperidyl, (1-methyl)-4-piperidyl, the dimethylaminomethyl carbonyl, diethylamino ethyl carbonyl, (4-methyl)-1-piperazinyl methyl carbonyl, 4-morpholinyl ethyl carbonyl, amino, (4-methyl)-1-piperazinyl, the 1-piperazinyl, N-methyl-N '-cyano group carbonamidine, the 2-thiazolinyl, pyrrolidyl-N-cyano group methylenimine, pyrrolidyl-N-methyl methylenimine, 1-pyrrolidyl-2-nitroethylene base, carbonamidine, the carboxy ethyl carbonyl, pyrrolidyl-N-methyl sulphonyl methylenimine, (2-carboxyl) phenylcarbonyl group, amino-sulfonyl, the dimethylamino alkylsulfonyl, the carboxyl methyl; Perhaps T wherein 1And T 2The atom that connects respectively with them forms optional substituted monocycle or fused rings heterocyclic radical, T 3With T 4Form optional substituted monocycle or fused rings heterocyclic radical together.
14. the compound of claim 13, wherein T 1Represent a following radicals:
Figure A9981575300041
R wherein 6Represent H or low alkyl group, m is the integer of 1-5, and R 7And R 8Represent low alkyl group, perhaps the two forms heterocycle, Q together 1Represent 2-phthalic acid, saturated or unsaturated C 1-6Carboxylic acid or heterocycle.
15. the compound of claim 13 or 14, wherein T 1Representative formula (a) part.
16. the compound of claim 13 or 14, wherein T 1Representative formula (b) part.
17. the compound of claim 13 or 14, wherein T 1Representative formula (c) part.
18. the compound of claim 13 or 14, wherein T 1Representative formula (d) part.
19. each compound of claim 1-18, wherein R 3It is phenyl.
20. each compound of claim 1-19, wherein R 4Be hydrogen.
21. the formula of claim 1 (I) compound is wherein:
Ar is phenyl or cyclohexyl, and R is methyl, ethyl or sec.-propyl, R 1Be hydrogen or methoxyl group or hydroxyl, R 2Be (CH 2) nPart, wherein n is 1,2,3 or 4, R 3Be phenyl, R 4Be hydrogen, and NY 1Y 2Be: (i) optional substituted piperazinyl, the formula of especially above-mentioned definition (a) part; The (ii) formula of above-mentioned definition (b) part; Or the formula of (iii) above-mentioned definition (c) part; Or the formula of (iv) above-mentioned definition (d) part.
22. the formula of claim 1 (I) compound, wherein:
Ar is a cyclohexyl, and R is methyl, ethyl or sec.-propyl, R 1Be hydrogen, methoxyl group or hydroxyl, R 2Be-(CH 2) n-NY 1Y 2Part, wherein n is 1, R 3Be phenyl, R 4Be hydrogen, and NY 1Y 2Be: (i) optional substituted piperazinyl, the formula of especially above-mentioned definition (a) part; The (ii) formula of above-mentioned definition (b) part; Or the formula of (iii) above-mentioned definition (c) part; Or the formula of (iv) above-mentioned definition (d) part.
23. be selected from formula (I) compound of the claim 1 of arbitrary embodiment 1-95 compound.
24. be selected from formula (I) compound of the claim 1 of arbitrary embodiment 20,29,32,33,34,46,47,48,53,55,62,67,78,79,80,81 and 95 compounds.
25. formula (I) compound of preparation claim 1 or the method for its salt and/or solvate, described method comprise with formula (II) compound or its activated derivatives:
Figure A9981575300051
R ' wherein 1, R ' 2, R ' 3And R ' 5Be respectively suc as formula defined R in (I) 1, R 2, R 3And R 5, perhaps be respectively to change into R 1, R 2, R 3, R 5Group; React with formula (III) compound: Wherein R ', R 4' and Ar ' be respectively suc as formula defined R, R in (I) 4And Ar, perhaps be respectively to change into R, R 4Group with Ar; With production (Ib) compound: Wherein Ar ', R ', R ' 1, R ' 2, R ' 3, R ' 4And R ' 5As defined above, carry out one or more following optional step then: (i) as required with arbitrary Ar ', R ', R ' 1, R ' 2, R ' 3, R ' 4And R ' 5Change into Ar, R, R respectively 1, R 2, R 3, R 4Or R 5, with acquisition formula (I) compound; (ii) formula (I) compound is changed into another formula (I) compound; (iii) salt and/or its solvate of preparation formula (I) compound.
26. comprise formula (I) compound of claim 1 or the pharmaceutical composition of its pharmacologically acceptable salt or solvate and pharmaceutically acceptable carrier.
27. formula (I) compound or its pharmacologically acceptable salt or solvate as the active treatment material.
28. be used for the treatment of or prevent formula (I) compound or its pharmacologically acceptable salt or the solvate of primary and Secondary cases illness.
29. formula (I) compound or its pharmacologically acceptable salt or solvate are used for the treatment of application in the medicine of primary and Secondary cases illness in preparation.
30. in Mammals, particularly people, treat and/or prevent the method for primary and Secondary cases illness, comprise formula (I) compound or pharmaceutically acceptable salt thereof of effective, nontoxic pharmaceutically acceptable amount or solvate to this Mammals administration that treats and/or prevents of needs.
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