CN101151239A - Novel biaromatic compounds, inhibitors of the P2X7-receptor - Google Patents
Novel biaromatic compounds, inhibitors of the P2X7-receptor Download PDFInfo
- Publication number
- CN101151239A CN101151239A CNA2006800100357A CN200680010035A CN101151239A CN 101151239 A CN101151239 A CN 101151239A CN A2006800100357 A CNA2006800100357 A CN A2006800100357A CN 200680010035 A CN200680010035 A CN 200680010035A CN 101151239 A CN101151239 A CN 101151239A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- chloro
- amino
- compound
- carbonyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ar<1> represents a group (II), (III), (IV) or (V), and A, Ar<2>, n, R<1>, R<2>, R<3>, R<4> and R<5> are as defined in the specification; a process for their preparation; pharmaceutical compositions containing them; and their use in therapy.
Description
Technical field
The present invention relates to two novel aromatic derivatives, prepare their method, comprise their pharmaceutical composition, prepare the method for this pharmaceutical composition, and their purposes in treatment.
Background technology
P2X
7Acceptor (being called the P2Z acceptor in the past) is a kind of ligand-gated ion channel, is present in the various cell types, mainly is those known cells that relate to inflammation/immunologic process, specifically, is scavenger cell, mastocyte and lymphocyte (T and B).P2X
7Acceptor is by extracellular Nucleotide, when particularly Triphosaden activates, can cause discharging il-1 β (IL-1 β) and form giant cells (scavenger cell/microgliacyte), threshing (mastocyte) and propagation (T cell), apoptosis and L-select albumen come off (lymphocyte).P2X
7Acceptor also is positioned on antigen presenting cell (APC), keratinocyte, sialisterium cystencyte (parotid gland cell), liver cell and the mesangial cell.
Effectively as P2X
7The compound of receptor antagonist is advantageously used in treatment inflammation, immunity or cardiovascular disorder, P2X in the cause of disease of these diseases
7Acceptor can work.The P2X that therefore, need have the pharmaceutical properties of improvement
7Receptor antagonist.
The invention provides the P2X of new class
7Antagonist, it comprises two aromatic groups (biaromatic group) of replacement.These new compounds show in treatment inflammation, immunity or cardiovascular disorder as P2X
7The excellent properties of receptor antagonist.Though described P2X in the past
7Antagonist, for example WO 00/61569, WO 01/42194, WO 01/44170, WO 01/44213, WO 01/46200, WO 01/94338, WO 03/041707, WO 03/042190, WO 03/042191, WO03/080579, WO 04/058270, WO 04/058731, WO 04/074224 and WO 04/099146, but before the present invention, do not hint that the compound that comprises two aromatic groups of replacement of the present invention can make effective P2X
7Antagonist.
U.S. Patent application 2004/0214888 has been described the carboxylic acid derivative as insulin sensitizer, and U.S. Patent application 2003/0134885 has been described the biphenyl ligand activator as the carboxyl substituted of PPAR γ acceptor.These two pieces of documents are not all mentioned P2X
7Acceptor.
Summary of the invention
The invention provides formula (I) compound or its pharmacy acceptable salt,
Ar wherein
1The expression group
A represents C (O) NH or NHC (O);
R
1Expression 3-to 9-unit's carbocyclic ring or 4-to 10-unit heterocycle, at least one substituting group that described carbocyclic ring or heterocycle randomly independently are selected from the following radicals replaces: halogen, hydroxyl, cyano group, nitro, NR
6R
7, C
1-6Alkyl sulphonyl, C
1-6Alkoxyl group, and C
1-6Alkyl, described C
1-6At least one substituting group that alkyl randomly is independently selected from halogen and the hydroxyl replaces;
N is 0,1,2 or 3;
At each CR
2R
3Combination in, R
2And R
3Represent hydrogen, halogen, phenyl or C independently of one another
1-6Alkyl, perhaps R
2And R
3The carbon atom that the two all connects with them forms 3-to 8-unit cycloalkyl ring;
R
4And R
5One of expression halogen, nitro, NR
6R
7, hydroxyl, the C that randomly replaced by at least one halogen
1-6Alkoxyl group, or the C that is randomly replaced by at least one halogen
1-6Alkyl, and R
4And R
5In another expression hydrogen, halogen or the C that is randomly replaced by at least one halogen
1-6Alkyl;
Ar
2The expression phenyl, its at least one substituting group that independently is selected from the following radicals replaces: carboxyl, MC
1-6Alkyl CO
2H, C
1-6The amino carbonyl of alkyl sulfonyl, C (O) NHOH, NHR
8, R
9, XR
10And NR
17R
18, or Ar
2Expression comprises 1 to 2 the heteroatomic 5-or the 6-unit aromatic heterocycle that are independently selected from nitrogen, oxygen and sulphur, and at least one substituting group that described aromatic heterocycle independently is selected from the following radicals replaces: carboxyl, MC
1-6Alkyl CO
2H, C
1-6The amino carbonyl of alkyl sulfonyl, C (O) NHOH, NHR
8And NR
19R
20
Wherein phenyl or aromatic heterocycle Ar
2At least one substituting group that can further randomly independently be selected from the following radicals replaces: halogen, nitro, NR
6R
7, S (O)
0-2R
11, the C that randomly replaced by at least one halogen
1-6Alkoxyl group, and randomly independently be selected from halogen, hydroxyl, NR
6R
7, SO
2NR
6R
7, NR
11SO
2R
11, NHCOR
11And CONR
6R
7In the C that replaces of at least one substituting group
1-6Alkyl;
R
8Expression CN, C
1-6Alkoxy carbonyl, C
1-6Alkyl amino sulfonyl, or C
1-6Alkyl amino sulfonyl or two-C
1-6Alkyl amino sulfonyl;
R
9And R
10Represent tetrazyl, 1 independently of one another, 2,3-triazolyl, 1,2,4-triazolyl or comprise 1 to 4 heteroatomic 5-to 6-unit heterocycle that is independently selected from nitrogen, oxygen and sulphur, at least one substituting group that described heterocycle independently is selected from the following radicals replaces: hydroxyl ,=O and=S, and described heterocycle can further randomly independently be selected from least one substituting group replacement in the following radicals: halogen, nitro, amino, cyano group, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl and C
1-6Alkyl, described C
1-6At least one substituting group that alkyl randomly independently is selected from the following radicals replaces: halogen, hydroxyl and amino;
M represents key, oxygen, S (O)
0-2Or NR
11
X represents oxygen, S (O)
0-2, NR
11, C
1-6Alkylidene group, O (CH
2)
1-6, NR
11(CH
2)
1-6Or S (O)
0-2(CH
2)
1-6
R
6And R
7Represent hydrogen atom or C independently of one another
1-6Alkyl, described C
1-6Alkyl randomly is independently selected from hydroxyl, halogen and C
1-6At least one substituting group in the alkoxyl group replaces, or R
6And R
7The nitrogen-atoms that connects with them forms 3-to 8-unit saturated heterocyclic;
R
11Expression hydrogen atom or C
1-6Alkyl, described C
1-6Alkyl randomly is independently selected from hydroxyl, halogen and C
1-6At least one substituting group in the alkoxyl group replaces;
R
17And R
18The nitrogen-atoms that connects with them forms 3-to 8-unit saturated heterocyclic, and at least one substituting group that described heterocycle independently is selected from the following radicals replaces: carboxyl, MC
1-6Alkyl CO
2H, C
1-6The amino carbonyl of alkyl sulfonyl, C (O) NHOH, NHR
8, R
9And XR
10, described 3-to 8-unit saturated heterocyclic can further randomly independently be selected from least one substituting group replacement in the following radicals: hydroxyl, halogen, the C that is randomly replaced by at least one halogen
1-6Alkoxyl group, and C
1-6Alkyl, described C
1-6At least one substituting group that alkyl randomly is independently selected from halogen and the hydroxyl replaces;
R
19And R
20The nitrogen-atoms that connects with them forms 3-to 8-unit saturated heterocyclic, and at least one substituting group that described heterocycle independently is selected from the following radicals replaces: carboxyl, MC
1-6Alkyl CO
2H, C
1-6The amino carbonyl of alkyl sulfonyl, C (O) NHOH and NHR
8, described 3-to 8-unit saturated heterocyclic can further randomly independently be selected from least one substituting group replacement in the following radicals: hydroxyl, halogen, the C that is randomly replaced by at least one halogen
1-6Alkoxyl group, and C
1-6Alkyl, described C
1-6At least one substituting group that alkyl randomly is independently selected from halogen and the hydroxyl replaces;
Condition is that formula (I) compound is not
(3-{4-chloro-3-[(1-hydroxyl-suberyl methyl)-formamyl]-phenyl }-5-methyl-pyrazol-1-yl)-acetate,
3-[4-methoxyl group-3-({ [4-(trifluoromethyl) benzyl] amino } carbonyl) phenyl] phenylformic acid, or
3-[4-methoxyl group-3-({ [2, the 4-dichloro benzyl] amino } carbonyl) phenyl] phenylformic acid.
Some compound of formula (I) can exist with stereomeric form.Should be appreciated that the formula of the present invention includes (I) compound all how much and optical isomer and composition thereof, comprise racemic modification.Its tautomer and mixture also constitute one aspect of the present invention.
It should be understood that some compound of the present invention can be with the solvation form, for example hydrated form and non-solvent form exist.It should be understood that all this solvation forms that the present invention includes.
In the context of the present specification, " carbocyclic ring " is list undersaturated, saturated or fractional saturation or dicyclo, and it only comprises carboatomic ring atom, and can have aliphatic series or aromatic series characteristic." heterocycle " is list undersaturated, saturated or fractional saturation or dicyclo, and its at least one atom is the heteroatoms that is selected from oxygen, sulphur or nitrogen, and can have aliphatic series or aromatic series characteristic." aromatic heterocycle " is meant that at least one atom is the heteroatomic aromatic ring that is selected from oxygen, sulphur or nitrogen." cycloalkyl " is meant saturated alkyl ring.Unless otherwise noted, alkyl can be a straight or branched.When describing a group is " randomly being replaced by at least one substituting group ", and then this group can be unsubstituted or has one or more (for example one, two or three) substituting group.
In one embodiment of the present invention, A represents NHC (O).In another embodiment of the invention, A represents C (O) NH.
R
1Expression 3-to 9-unit's carbocyclic ring or 4-to 10-unit heterocycle, at least one substituting group that described carbocyclic ring or heterocycle randomly independently are selected from the following radicals replaces: halogen (for example fluorine, chlorine, bromine or iodine), hydroxyl, cyano group, nitro, NR
6R
7, C
1-6Alkyl sulphonyl (MeSO for example
2-), C
1-6Alkoxyl group (preferred C
1-4Alkoxyl group) (for example methoxyl group, oxyethyl group, positive propoxy, n-butoxy, n-pentyloxy or positive hexyloxy) and C
1-6Alkyl (preferred C
1-4Alkyl) (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or n-hexyl), described C
1-6Alkyl is randomly replaced by at least one (for example one, two or three) substituting group, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine or iodine) and hydroxyl.
In one embodiment of the invention, R
1Expression 3-to 9-unit aliphatic carbocycle, it is randomly replaced by at least one (for example one, two or three) substituting group, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine or iodine), hydroxyl, cyano group, nitro, NR
6R
7, C
1-6Alkyl sulphonyl (MeSO for example
2-), C
1-6Alkoxyl group (preferred C
1-4Alkoxyl group) (for example methoxyl group, oxyethyl group, positive propoxy, n-butoxy, n-pentyloxy or positive hexyloxy) and C
1-6Alkyl (preferred C
1-4Alkyl) (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or n-hexyl), described C
1-6Alkyl is randomly replaced by at least one (for example one, two or three) substituting group, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine or iodine) and hydroxyl.At this embodiment on the other hand, R
1Representative ring propyl group, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group or two suberyl (bicycloheptyl), it is randomly replaced by at least one (for example one, two or three) substituting group separately, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine or iodine), hydroxyl, C
1-6Alkoxyl group (preferred C
1-4Alkoxyl group) (for example methoxyl group, oxyethyl group, positive propoxy, n-butoxy, n-pentyloxy or positive hexyloxy) and C
1-6Alkyl (preferred C
1-4Alkyl) (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or n-hexyl), described C
1-6Alkyl is randomly replaced by at least one (for example one, two or three) substituting group, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine or iodine) and hydroxyl.Radicals R according to this embodiment
1Example comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group,
In another embodiment of the present invention, R
1The expression phenyl, it is randomly replaced by at least one (for example one, two or three) substituting group, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine or iodine), hydroxyl, cyano group, nitro, NR
6R
7, C
1-6Alkyl sulphonyl (MeSO for example
2-), C
1-6Alkoxyl group (preferred C
1-4Alkoxyl group) (for example methoxyl group, oxyethyl group, positive propoxy, n-butoxy, n-pentyloxy or positive hexyloxy) and C
1-6Alkyl (preferred C
1-4Alkyl) (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or n-hexyl), described C
1-6Alkyl is randomly replaced by at least one (for example one, two or three) substituting group, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine or iodine) and hydroxyl.Radicals R according to this embodiment
1Example be phenyl or 2-chloro-phenyl-.
In another embodiment of the present invention, R
1Expression 4-to 10-unit aromatic heterocycle, it contains 1 to 3, or 1 to 2 heteroatoms, described heteroatoms is selected from nitrogen, oxygen and sulphur, described aromatic heterocycle is randomly replaced by at least one (for example one, two or three) substituting group, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine or iodine), hydroxyl, cyano group, nitro, NR
6R
7, C
1-6Alkyl sulphonyl (MeSO for example
2-), C
1-6Alkoxyl group (preferred C
1-4Alkoxyl group) (for example methoxyl group, oxyethyl group, positive propoxy, n-butoxy, n-pentyloxy or positive hexyloxy) and C
1-6Alkyl (preferred C
1-4Alkyl) (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or n-hexyl), described C
1-6Alkyl is randomly replaced by at least one (for example one, two or three) substituting group, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine or iodine) and hydroxyl.Example according to the aromatic heterocycle of this embodiment comprises pyridyl, pyridazinyl, pyrazinyl, pyrimidyl, pyrazolyl and quinolyl.
In another embodiment of the present invention, R
1Expression monocycle aliphatic series 5-to 8-unit heterocycle, it contains 1 to 3, or 1 to 2 heteroatoms that is selected from nitrogen, oxygen and sulphur, described heterocycle is randomly replaced by at least one (for example one, two or three) substituting group, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine or iodine), hydroxyl, cyano group, nitro, NR
6R
7, C
1-6Alkyl sulphonyl (MeSO for example
2-), C
1-6Alkoxyl group (preferred C
1-4Alkoxyl group) (for example methoxyl group, oxyethyl group, positive propoxy, n-butoxy, n-pentyloxy or positive hexyloxy) and C
1-6Alkyl (preferred C
1-4Alkyl) (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or n-hexyl) is described
1-6Alkyl is randomly replaced by at least one (for example one, two or three) substituting group, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine or iodine) and hydroxyl.Heterocyclic example according to this embodiment comprises pyrrolidyl, piperidyl, piperazinyl, high piperazinyl (homopiperazinyl) and homopiperidinyl (homopiperidinyl).
In one embodiment of the invention, n is 0,1 or 2.In another embodiment of the present invention, n is 0.In another embodiment of the present invention, n is 1 or 2.
At each CR
2R
3Combination in, R
2And R
3Represent hydrogen, halogen (for example fluorine, chlorine, bromine or iodine), phenyl or C independently of one another
1-6Alkyl (preferred C
1-4Alkyl) (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or n-hexyl), perhaps R
2And R
3The carbon atom that the two all connects with them forms 3-to 8-unit cycloalkyl ring (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl).
In one embodiment of the invention, R
2And R
3Represent hydrogen, C independently of one another
1-4Alkyl or R
2And R
3The carbon atom that the two all connects with them forms cyclopropyl rings.In another embodiment of the present invention, R
2And R
3Represent hydrogen independently of one another.
R
4And R
5One of expression halogen (for example fluorine, chlorine, bromine or iodine), nitro, NR
6R
7, hydroxyl, the C that randomly replaced by at least one (for example one, two or three) halogen (for example fluorine, chlorine, bromine or iodine)
1-6Alkoxyl group (preferred C
1-4Alkoxyl group) (for example methoxyl group, oxyethyl group, positive propoxy, n-butoxy, n-pentyloxy or positive hexyloxy), or the C that is randomly replaced by at least one (for example one, two or three) halogen (for example fluorine, chlorine, bromine or iodine)
1-6Alkyl (preferred C
1-4Alkyl) (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or n-hexyl), and R
4And R
5In another expression hydrogen, halogen (for example fluorine, chlorine, bromine or iodine) or the C that is randomly replaced by at least one (for example one, two or three) halogen (for example fluorine, chlorine, bromine or iodine)
1-6Alkyl (preferred C
1-4Alkyl) (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or n-hexyl).
In one embodiment of the invention, R
4Expression halogen, nitro, NH
2, hydroxyl, or the C that is randomly replaced by one to three halogenic substituent
1-4Alkyl; And R
5The expression hydrogen atom.
In one embodiment of the invention, Ar
1Expression group (II) or (III).
In one embodiment of the invention, Ar
1Expression group (II)
According to the present invention, Ar
2The expression phenyl, it is replaced by at least one (for example one or two) substituting group, and described substituting group is independently selected from carboxyl, MC
1-6Alkyl CO
2H, C
1-6The amino carbonyl of alkyl sulfonyl (MeSO for example
2NHCO-), C (O) NHOH, NHR
8, R
9, XR
10And NR
17R
18, perhaps Ar
2Expression comprises 1 to 2 heteroatomic 5-that is independently selected from nitrogen, oxygen and sulphur or 6-unit aromatic heterocycle, and described aromatic heterocycle is replaced by at least one (for example one or two) substituting group, and described substituting group is independently selected from carboxyl, MC
1-6Alkyl CO
2H, C
1-6The amino carbonyl of alkyl sulfonyl (MeSO for example
2NHCO-), C (O) NHOH, NHR
8And NR
19R
20
Wherein phenyl or aromatic heterocycle Ar
2Can be further replaced by at least one (for example one or two) substituting group, described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine or iodine), nitro, NR
6R
7, S (O)
0-2R
11, C
1-6Alkoxyl group (preferred C
1-4Alkoxyl group) randomly halogen (for example fluorine, chlorine, bromine or iodine) replaces, and C by at least one (for example one, two or three) for (for example methoxyl group, oxyethyl group, positive propoxy, n-butoxy, n-pentyloxy or positive hexyloxy), described alkoxyl group
1-6Alkyl (preferred C
1-4Alkyl) (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or n-hexyl), described alkyl is randomly replaced by at least one (for example one, two or three) substituting group, and described substituting group is independently selected from halogen (for example fluorine, chlorine, bromine or iodine), hydroxyl, NR
6R
7, SO
2NR
6R
7, NR
11SO
2R
11, NHCOR
11And CONR
6R
7
In one embodiment of the invention, Ar
2The optional as defined above phenyl that replaces of expression.
In another embodiment of the present invention, Ar
2Expression 5-to 6-unit aromatic heterocycle, it is selected from pyrryl, thienyl, furyl, imidazolyl, thiazolyl, azoles base, isothiazolyl, different azoles base, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl and pyrazinyl, and described aromatic heterocycle is randomly by substituting group replacement as defined above.
In the further embodiment of the present invention, Ar
2The optional as defined above pyridyl that replaces of expression.
In one embodiment of the invention, Ar
2Being selected from following substituting group replaces: carboxyl, MC
1-6Alkyl CO
2H and C
1-6The amino carbonyl of alkyl sulfonyl.
In another embodiment of the present invention, Ar
2By carboxyl substituted.
In another embodiment of the present invention, Ar
2For being substituted basic NR
17R
18The phenyl that replaces, wherein R
17And R
18The nitrogen-atoms that connects with them forms 3-to 8-unit saturated heterocyclic, and at least one substituting group that described heterocycle independently is selected from the following radicals replaces: carboxyl, MC
1-6Alkyl CO
2H and C
1-6The amino carbonyl of alkyl sulfonyl.At this embodiment on the other hand, this NR
17R
18Heterocycle by carboxyl substituted.
In another embodiment of the present invention, Ar
2For being substituted basic NR
19R
20The pyridyl that replaces, wherein R
19And R
20The nitrogen-atoms that connects with them forms 3-to 8-unit saturated heterocyclic, and at least one substituting group that described heterocycle independently is selected from the following radicals replaces: carboxyl, MC
1-6Alkyl CO
2H and C
1-6The amino carbonyl of alkyl sulfonyl.At this embodiment on the other hand, this NR
19R
20Heterocycle by carboxyl substituted.
In one embodiment of the invention, M represents key or oxygen.In another embodiment of the present invention, M represents key.
In one embodiment of the invention, X represents oxygen or C
1-4Alkylidene group.
R
8Expression CN, C
1-6Alkoxy carbonyl (preferred C
1-4Alkoxy carbonyl) (for example methoxycarbonyl, ethoxy carbonyl, positive propoxy carbonyl, n-butoxy carbonyl, n-pentyloxy carbonyl or positive hexyloxy carbonyl), C
1-6Alkyl amino sulfonyl (preferred C
1-4Alkyl amino sulfonyl) (MeNHSO for example
2Or EtNHSO
2-), or C
1-6Alkyl amino sulfonyl or two-C
1-6Alkyl amino sulfonyl (is preferably C
1-4Alkyl amino sulfonyl or two-C
1-4Alkyl amino sulfonyl) (Me for example
2NSO
2Or Et
2NSO
2-or EtMeNSO
2-).
R
9And R
10Represent tetrazyl, 1 independently of one another, 2,3-triazolyl, 1,2,4-triazolyl or comprise 1 to 4 heteroatomic 5-to 6-unit heterocycle that is independently selected from nitrogen, oxygen and sulphur, described heterocycle is replaced by at least one (for example one, two or three) substituting group, described substituting group be independently selected from hydroxyl ,=O and=S, and described heterocycle is randomly further replaced by at least one (for example one or two) substituting group, and described substituting group is independently selected from halogen (for example chlorine, fluorine, bromine or iodine), nitro, amino, cyano group, C
1-6Alkyl sulphonyl (preferred C
1-4Alkyl sulphonyl) (MeSO for example
2-or EtSO
2-), C
1-6Alkoxy carbonyl (preferred C
1-4Alkoxy carbonyl) (for example methoxyl group-, oxyethyl group-, positive propoxy-, n-butoxy-, n-pentyloxy-or positive hexyloxy carbonyl) and C
1-6Alkyl (preferred C
1-4Alkyl) (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or n-hexyl), described C
1-6Alkyl is randomly replaced by at least one (for example one, two or three) substituting group, and described substituting group is independently selected from halogen (for example chlorine, fluorine, bromine or iodine), hydroxyl and amino.
Work as R
9And R
10When representing 5-to 6-unit heterocycle independently of one another, assorted ring nitrogen can have hydroxyl substituent, and the sulphur atom in the ring can be S, SO (promptly having one=O substituting group) or SO
2The form of (promptly having two=O substituting group).
Work as R
9Or R
10Expression comprises the heteroatomic 5-to 6-of 1-4 unit heterocycle, and described heteroatoms is independently selected from nitrogen, oxygen and sulphur, described heterocycle be selected from hydroxyl ,=O and=when at least one substituting group among the S replaced, example comprised:
In one embodiment of the invention, R
9And R
10Represent 5-to 6-unit heterocycle independently, it comprises 2 to 3 nitrogen-atoms and 1 other heteroatoms that is selected from oxygen and sulphur randomly, described heterocycle independently be selected from hydroxyl ,=O and=at least one substituting group replacement among the S.
R
6And R
7Represent hydrogen atom or C independently of one another
1-6Alkyl (preferred C
1-4Alkyl) (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or n-hexyl), described alkyl is randomly replaced by at least one (for example one, two or three) substituting group, and described substituting group is independently selected from hydroxyl, halogen (for example fluorine, chlorine, bromine or iodine) and C
1-6Alkoxyl group (preferred C
1-4Alkoxyl group) (for example methoxyl group, oxyethyl group, positive propoxy, n-butoxy, n-pentyloxy or positive hexyloxy), perhaps R
6And R
7The nitrogen-atoms that connects with them forms 3-to 8-unit saturated heterocyclic.
R
11Expression hydrogen atom or C
1-6Alkyl (preferred C
1-4Alkyl) (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or n-hexyl), described alkyl is randomly replaced by at least one (for example one, two or three) substituting group, and described substituting group is independently selected from hydroxyl, halogen (for example fluorine, chlorine, bromine or iodine) and C
1-6Alkoxyl group (preferred C
1-4Alkoxyl group) (for example methoxyl group, oxyethyl group, positive propoxy, n-butoxy, n-pentyloxy or positive hexyloxy).
R
17And R
18The nitrogen-atoms that connects with their forms 3-to 8-unit, perhaps 4-to 7-unit saturated heterocyclic, and described heterocycle is replaced by at least one (for example one, two or three) substituting group, and described substituting group is independently selected from carboxyl, MC
1-6Alkyl CO
2H, C
1-6The amino carbonyl of alkyl sulfonyl, C (O) NHOH, NHR
8, R
9And XR
10, described 3-to 8-unit saturated heterocyclic randomly further independently is selected from least one substituting group replacement in the following radicals: hydroxyl, halogen, the C that is randomly replaced by at least one halogen
1-6Alkoxyl group, and C
1-6Alkyl, described C
1-6At least one substituting group that alkyl randomly is independently selected from halogen and the hydroxyl replaces.R
17And R
18The example of the saturated heterocyclic that the nitrogen-atoms that connects with their can form is ring for example pyrrolidyl, piperidyl, piperazinyl, high piperazinyl, homopiperidinyl and the azetidinyl that contains one or two nitrogen-atoms.
R
19And R
20The nitrogen-atoms that connects with their forms 3-to 8-unit, perhaps 4-to 7-unit saturated heterocyclic, and described heterocycle is replaced by at least one (for example one, two or three) substituting group, and described substituting group is independently selected from carboxyl, MC
1-6Alkyl CO
2H, C
1-6The amino carbonyl of alkyl sulfonyl, C (O) NHOH and NHR
8, described 3-to 8-unit saturated heterocyclic randomly further independently is selected from least one substituting group replacement in the following radicals: hydroxyl, halogen, the C that is randomly replaced by at least one halogen
1-6Alkoxyl group, and C
1-6Alkyl, described C
1-6At least one substituting group that alkyl randomly is independently selected from halogen and the hydroxyl replaces.R
19And R
20The example of the saturated heterocyclic that the nitrogen-atoms that connects with their can form is ring for example pyrrolidyl, piperidyl, piperazinyl, high piperazinyl, homopiperidinyl and the azetidinyl that contains one or two nitrogen-atoms.
In one embodiment of the invention, when n is 1, Ar
1Be group (II), Ar
2For at Ar
1Contraposition on by XR
10The phenyl that replaces, and X is CH
2The time, R so
10Be not 2,4-dioxo thiazolyl; With working as n is 1, Ar
1Be group (II), and Ar
2For at Ar
1Contraposition on by MC
1-6Alkyl CO
2During phenyl that H replaces, M does not represent key so.
The present invention provides compound or its pharmacy acceptable salt of formula (I) on the other hand,
Ar wherein
1The expression group
A represents C (O) NH or NHC (O);
R
1Expression phenyl or 3-to 9-unit aliphatic carbocycle, at least one substituting group that described phenyl or aliphatic carbocycle randomly independently are selected from the following radicals replaces: halogen, hydroxyl, C
1-6Alkoxyl group, and C
1-6Alkyl, described C
1-6At least one substituting group that alkyl randomly is independently selected from halogen and the hydroxyl replaces;
N is 0,1,2 or 3;
At each CR
2R
3Combination in, R
2And R
3Represent hydrogen independently of one another, or C
1-6Alkyl, perhaps R
2And R
3The carbon atom that the two all connects with them forms 3-to 6-unit cycloalkyl ring;
R
4And R
5One of expression halogen, nitro, NR
6R
7, hydroxyl, or the C that is randomly replaced by at least one halogen
1-6Alkyl, and R
4And R
5In another the expression hydrogen;
Ar
2The expression phenyl, its at least one substituting group that independently is selected from the following radicals replaces: carboxyl, MC
1-6Alkyl CO
2H and NR
17R
18,
Or Ar
2Expression 5-or 6-unit aromatic heterocycle, it is selected from thienyl, furyl, imidazolyl, thiazolyl, azoles base, isothiazolyl, different azoles base, pyridyl, pyridazinyl, pyrimidyl and pyrazinyl, and at least one substituting group that described phenyl or aromatic heterocycle independently are selected from the following radicals replaces: carboxyl, MC
1-6Alkyl CO
2H and NR
19R
20
M represents key, oxygen, S (O)
0-2Or NR
11
R
6And R
7Represent hydrogen atom or C independently of one another
1-6Alkyl
R
11Expression hydrogen atom or C
1-6Alkyl;
R
17And R
18The nitrogen-atoms that connects with them forms 6-unit saturated heterocyclic, and at least one substituting group that described heterocycle independently is selected from the following radicals replaces: carboxyl and MC
1-6Alkyl CO
2H; With
R
19And R
20The nitrogen-atoms that connects with them forms 6-unit saturated heterocyclic, and at least one substituting group that described heterocycle independently is selected from the following radicals replaces: carboxyl and MC
1-6Alkyl CO
2H.
Another aspect of the invention provides compound or its pharmacy acceptable salt of formula (I),
Ar wherein
1The expression group
A represents NHC (O);
R
1Expression phenyl or 3-to 9-unit aliphatic carbocycle, at least one substituting group that described phenyl or aliphatic carbocycle randomly independently are selected from the following radicals replaces: halogen, hydroxyl and C
1-4Alkyl, described C
1-4Alkyl is randomly replaced by hydroxyl;
N is 0,1 or 2;
At each CR
2R
3Combination in, R
2And R
3Represent hydrogen or C independently of one another
1-4Alkyl;
R
4And R
5One of expression halogen, nitro, NR
6R
7, hydroxyl or the C that randomly replaced by at least one halogen
1-6Alkyl, and R
4And R
5Another represents hydrogen;
Ar
2The expression phenyl, its at least one substituting group that independently is selected from the following radicals replaces: carboxyl and NR
17R
18,
Or Ar
2The expression pyridyl, its at least one substituting group that independently is selected from the following radicals replaces: carboxyl and NR
19R
20,
R
6And R
7Represent hydrogen atom or C independently of one another
1-6Alkyl
R
17And R
18The nitrogen-atoms that connects with them forms 6-unit saturated heterocyclic, and described heterocycle independently is selected from carboxyl and C
1-6Alkyl CO
2At least one substituting group among the H replaces; With
R
19And R
20The nitrogen-atoms that connects with them forms 6-unit saturated heterocyclic, and described heterocycle independently is selected from carboxyl and C
1-6Alkyl CO
2At least one substituting group among the H replaces.
In one embodiment of the invention, the compound of formula (I) is selected from:
4 '-chloro-3 '-[[[2-(2-chloro-phenyl-) ethyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[(cyclohexyl methyl) amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[[(2S)-and the 2-phenyl propyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[[[(1S, 2R, 5S)-6, and 6-dimethyl dicyclo [3.1.1] heptan-2-yl] methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[(suberyl methyl) amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[[(1-hydroxy-cyclohexyl) methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[[[cis-2-hydroxyl suberyl] methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[(2-cyclohexyl ethyl) amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
3-[4-chloro-3-[[(suberyl methyl) amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid,
3-[4-chloro-3-[[(2-cyclohexyl ethyl) amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid
4 '-chloro-3 '-[[[(1R)-and 1-cyclohexyl ethyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[[(1-methyl suberyl) methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[[[1-(hydroxymethyl) suberyl] methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
3-[4-chloro-3-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid,
3 '-[[(suberyl methyl) amino] carbonyl]-4 '-methyl-[1,1 '-xenyl]-the 2-carboxylic acid,
1-[3-[3-[[(suberyl methyl) amino] carbonyl]-the 4-aminomethyl phenyl]-the 2-pyridyl]-the 4-piperidine carboxylic acid,
3-chloro-6-[3-[[(suberyl methyl) amino] carbonyl]-the 4-aminomethyl phenyl]-2-Pyridinecarboxylic Acid,
5-chloro-2-[4-chloro-3-[[(2-cyclohexyl ethyl) amino] carbonyl] phenyl]-the 3-pyridine carboxylic acid,
5-chloro-2-[4-chloro-3-[[(suberyl methyl) amino] carbonyl] phenyl]-the 3-pyridine carboxylic acid,
5-chloro-2-[4-chloro-3-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl] phenyl]-the 3-pyridine carboxylic acid,
3-chloro-6-[4-chloro-3-[[(2-cyclohexyl ethyl) amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid,
3-chloro-6-[4-chloro-3-[[(suberyl methyl) amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid,
3-chloro-6-[4-chloro-3-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid,
1-[3-[4-chloro-3-[[(2-cyclohexyl ethyl) amino] carbonyl] phenyl]-the 2-pyridyl]-the 4-piperidine carboxylic acid,
1-[3-[4-chloro-3-[[(suberyl methyl) amino] carbonyl] phenyl]-the 2-pyridyl]-the 4-piperidine carboxylic acid,
1-[3-[4-chloro-3-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl] phenyl]-the 2-pyridyl]-the 4-piperidine carboxylic acid,
Or its pharmacy acceptable salt.
The present invention also provides the method for preparing formula (I) compound as defined above or its pharmacy acceptable salt, and it comprises:
(a) compound of formula (VI), (VII), (VIII) or compound (IX) and formula (X) is reacted,
Perhaps
Z-Ar
2(X)
One of Y and Z replaceable group of expression (displaceable group) metal, organo-metallic or organosilicon radical (copper, lithium, organic boron group B (OH) for example for example for example wherein
2, B (O
iPr)
2, BEt
2Or boric acid tetramethyl ethylene ketone cyclic ester (boronic acid pinacol cyclic ester), perhaps organotin group SnMe for example
3Or SnBu
3, organosilicon radical Si (Me) F for example
2, organoaluminum group AlEt for example
2, organic-magnesium group for example MgCl, MgBr or MgI, perhaps for example ZnCl, ZnBr or ZnI of organic zinc group) and another expression leavings group (leaving group) among Y and the Z for example halogen or sulfonyloxy (for example chlorine, bromine, iodine, trifluoro-methanesulfonyl oxy, mesyloxy or tolysulfonyl oxygen base) and Ar
2, R
1, R
2, R
3, n, A, R
4And R
5Suc as formula defining in (I); Or
(b) work as Ar
2During by carboxyl substituted, make the compound reaction of defined formula (VI), (VII), (VIII) or compound (IX) and formula (XI) in above-mentioned (a),
Z-Ar
2a-CO
2R
12 (XI)
Wherein Z suc as formula in (X) define Ar
2aRepresent phenyl or comprise 1 to 2 heteroatomic 5-or 6-unit aromatic heterocycle that is independently selected from nitrogen, oxygen and sulphur, and R
12Be C
1-6Alkyl, then temperature and the alkali (for example sodium hydroxide or lithium hydroxide) in 0-150 ℃ of scope reacts in solvent (for example water or methyl alcohol), the perhaps then temperature in 0-150 ℃ of scope and acid (for example hydrochloric acid, Hydrogen bromide or trifluoroacetic acid) reaction in solvent (for example water, 1,4-two alkane, tetrahydrofuran (THF), acetate or methylene dichloride); Perhaps
(c) work as Ar
2During by carboxyl substituted, make the compound reaction of defined formula (VI), (VII), (VIII) or compound (IX) and formula (XII) in above-mentioned (a), then temperature and the alkali (for example sodium hydroxide or lithium hydroxide) in 0-150 ℃ of scope reacts in solvent (for example water or methyl alcohol), perhaps then the temperature in 0-150 ℃ of scope is reacted in solvent (for example water) with acid (for example hydrochloric acid)
Z-Ar
2b-CN (XII)
Wherein Z defines suc as formula (X) is middle, and Ar
2bRepresent phenyl or comprise 1 to 2 heteroatomic 5-or 6-unit aromatic heterocycle that is independently selected from nitrogen, oxygen and sulphur; Perhaps
(d) work as R
8Expression CN, C
1-6Alkoxy carbonyl, C
1-6Alkyl amino sulfonyl or C
1-6Alkyl amino sulfonyl or two-C
1-6During alkyl amino sulfonyl, make the compound reaction of defined formula (VI), (VII), (VIII) or compound (IX) and formula (XIII) in above-mentioned (a), then with the compound reaction of formula (XIV),
L
1-Ar
2c-Z (XIII)
L wherein
1The expression leavings group is halogen or sulfonyloxy (for example chlorine, bromine, iodine, trifluoro-methanesulfonyl oxy, mesyloxy or tolysulfonyl oxygen base) for example, Ar
2cThe expression phenyl, comprise 1 to 2 heteroatomic 5-that is independently selected from nitrogen, oxygen and sulphur or 6-unit aromatic heterocycle, and Z is suc as formula defining in (X),
Wherein W represents hydrogen or metal group, for example sodium, and R
8Suc as formula defining in (I); Perhaps
(e) work as Ar
2During by carboxyl substituted, make the compound of defined formula (XIII) reaction in defined formula (VI), (VII), (VIII) or the compound (IX) and above-mentioned (d) in above-mentioned (a), then with suitable cyanide source (for example sodium cyanide, potassium cyanide, cupric cyanide or zinc cyanide) reaction, then temperature and the alkali (for example sodium hydroxide or lithium hydroxide) in 0-150 ℃ of scope reacts in solvent (for example water or methyl alcohol), and perhaps then the temperature in 0-150 ℃ of scope is reacted in solvent (for example water) with acid (for example hydrochloric acid); Perhaps
(f) work as Ar
2During by carboxyl substituted, make the compound of defined formula (XIII) reaction in defined formula (VI), (VII), (VIII) or the compound (IX) and above-mentioned (d) in above-mentioned (a), then react with carbon monoxide and alcohol in the presence of appropriate catalyst (for example palladium catalyst), then temperature and the alkali (for example sodium hydroxide or lithium hydroxide) in 0-150 ℃ of scope reacts in solvent (for example water or methyl alcohol); Perhaps
(g) compound of formula (XV), (XVI), (XVII) or compound (XVIII) and formula (XIX) is reacted
Perhaps
R wherein
13And R
14One of the expression NH
2, R
13And R
14In another the expression CO
2H, COBr or COCl, and R
1, R
2, R
3, n, R
4, R
5And Ar
2Suc as formula defining in (I); Perhaps
(h) compound of defined formula (XIX) among formula (XX), (XXI), (XXII) or compound (XXIII) and above-mentioned (g) is reacted, then temperature and the alkali (for example sodium hydroxide or lithium hydroxide) in 0-150 ℃ of scope reacts in solvent (for example water or methyl alcohol), the perhaps then temperature in 0-150 ℃ of scope and acid (for example hydrochloric acid, Hydrogen bromide or trifluoroacetic acid) reaction in solvent (for example water, 1,4-two alkane, tetrahydrofuran (THF), acetate or methylene dichloride)
Ar wherein
2dRepresent phenyl or comprise 1 to 2 heteroatomic 5-or 6-unit aromatic heterocycle that is independently selected from nitrogen, oxygen and sulphur, R
12Suc as formula in (XI) define R
4And R
5Define suc as formula (I) is middle, and R
13Define suc as formula (XV)-(XVIII) is middle,
(i) work as R
19And R
20Connect nitrogen-atoms with them and form 3-to 8-unit saturated heterocyclic, described heterocycle is during by carboxyl substituted, and (wherein Y represents for example organic boron group of replaceable group (B (OH) for example to make defined formula (VI), (VII), (VIII) or compound (IX) in above-mentioned (a)
2, B (O
iPr)
2, BEt
2Or boric acid tetramethyl ethylene ketone cyclic ester)) compound with formula (XXXXV) reacts,
R wherein
21Expression C
1-6Alkyl, Ar
2eExpression comprises 1 to 2 the heteroatomic 5-or the 6-unit aromatic heterocycle that are independently selected from nitrogen, oxygen and sulphur, L
2The expression leavings group is halogen or sulfonyloxy (for example chlorine, bromine, iodine, trifluoro-methanesulfonyl oxy, mesyloxy or tolysulfonyl oxygen base) for example, and R
19And R
20Suc as formula defining in (I), randomly then temperature and the alkali (for example sodium hydroxide or lithium hydroxide) in 0-150 ℃ of scope reacts in solvent (for example water or methyl alcohol), the perhaps randomly then temperature in 0-150 ℃ of scope and acid (for example hydrochloric acid, Hydrogen bromide or trifluoroacetic acid) reaction in solvent (for example water, 1,4-two alkane, tetrahydrofuran (THF), acetate or methylene dichloride); Perhaps
(j) work as R
19And R
20Connect nitrogen-atoms with them and form 3-to 8-unit saturated heterocyclic, described heterocycle is during by carboxyl substituted, make the compound and the formula (XXXXVI) of defined formula (XIX) in above-mentioned (g), (XXXXVII), (XXXXVIII) or compound (IL) reaction, then temperature and the alkali (for example sodium hydroxide or lithium hydroxide) in 0-150 ℃ of scope reacts in solvent (for example water or methyl alcohol), the perhaps then temperature in 0-150 ℃ of scope and acid (hydrochloric acid for example, Hydrogen bromide or trifluoroacetic acid) at solvent (water for example, 1,4-two alkane, tetrahydrofuran (THF), acetate or methylene dichloride) middle reaction
Ar wherein
2fExpression comprises 1 to 2 the heteroatomic 5-or the 6-unit aromatic heterocycle that are independently selected from nitrogen, oxygen and sulphur, R
22Be C
1-6Alkyl, R
4, R
5, R
19And R
20Define suc as formula (I) is middle, and R
13Define suc as formula (XV)-(XVIII) is middle,
And randomly or (j) afterwards, carry out one or more following step at (a) and (b), (c), (d), (e), (f), (g), (h), (i):
This compound is changed into other compound of the present invention
Form this compound pharmacy acceptable salt.
In above-mentioned formula (XI), (XII), (XIII), (XX), (XXI), (XXII) with (XXIII), represent the Ar of phenyl or 5-or 6-unit aromatic heterocycle independently
2a, Ar
2b, Ar
2cAnd Ar
2dRandomly replaced by at least one substituting group, described at least one substituting group suc as formula in (I) to Ar
2Going up further optional substituting group defines.
In above-mentioned formula (XXXXV), (XXXXVI), (XXXXVII), (XXXXVIII) with (IL), represent the Ar of 5-or 6-unit aromatic heterocycle independently
2eAnd Ar
2fRandomly replaced by at least one substituting group, described at least one substituting group suc as formula in (I) to Ar
2Going up further optional substituting group defines.
At method (a) and (b), (c), (d), (e), (f) with (i), coupled reaction is in the presence of the catalyzer, carry out easily in the presence of suitable solvent, described catalyzer is tetrakis triphenylphosphine palladium (0), palladium chloride (II), dibrominated palladium (II), two (triphenylphosphine) palladium chloride (II), Nickel Chloride (II), Nickel Bromide (II) or two (triphenylphosphine) Nickel Chloride (II) for example, described suitable solvent is tetrahydrofuran (THF), 1 for example, 4-two alkane, 1,2-glycol dimethyl ether, benzene,toluene,xylene, methyl alcohol, ethanol or water.Reaction is preferred, and temperature in preferred 60 to 120 ℃ of scopes is carried out in the presence of suitable alkali and at 10 to 250 ℃, and described suitable alkali is yellow soda ash or salt of wormwood, pyridine, 4-dimethylaminopyridine, triethylamine or morpholine for example.
In method (d), can be in the presence of suitable alkali, randomly in the presence of appropriate catalyst, randomly in the presence of suitable part, in the presence of suitable solvent and at 10 to 250 ℃, temperature in preferred 60 to 150 ℃ of scopes is carried out replacement(metathesis)reaction, described suitable alkali is potassium tert.-butoxide for example, sodium hydride, salt of wormwood or cesium carbonate, described appropriate catalyst is palladium catalyst such as tetrakis triphenylphosphine palladium (0) for example, palladium chloride (II), dibrominated palladium (II), palladium (II), two (triphenylphosphine) dichloro palladium (II) or three (dibenzalacetone) palladium (0) (tris (dibenzylideneacetone) palladium (0)), or copper catalyst cuprous iodide (I) for example, described suitable part for example 1,1 '-two ((diphenylphosphino) ferrocene, 9,9-dimethyl-4,5-pair ((diphenylphosphino) Xanthene or 2-dicyclohexyl phosphino--2 '-(N, the N-dimethylamino) biphenyl, described suitable solvent is 1-Methyl-2-Pyrrolidone (pyrrolidinone) for example, 1,4-two alkane, 1, the 2-glycol dimethyl ether, tetrahydrofuran (THF) or acetonitrile.
In method (e), can be in the presence of suitable cyanide source, randomly in the presence of the appropriate catalyst, in the presence of suitable solvent and at 10 to 250 ℃, temperature in preferred 60 to 150 ℃ of scopes is carried out replacement(metathesis)reaction, described suitable cyanide source is sodium cyanide, potassium cyanide, cupric cyanide or zinc cyanide for example, described appropriate catalyst is palladium catalyst such as tetrakis triphenylphosphine palladium (0), palladium (II) for example, described suitable solvent is N for example, dinethylformamide, 1-Methyl-2-Pyrrolidone or methyl-sulphoxide.
In method (f), can be in the presence of alcohol, in the presence of catalyzer, randomly in the presence of part, in the presence of suitable alkali, randomly in the presence of the cosolvent and the temperature in 10 to 150 ℃ of scopes carry out carbonylation reaction, described alcohol is butanols for example, propyl alcohol, ethanol or methyl alcohol, described catalyzer is tetrakis triphenylphosphine palladium (0) for example, palladium chloride (II), dibrominated palladium (II), palladium (II), two ((triphenylphosphine) palladium chlorides (II) or [1,1 '-two ((diphenylphosphino) ferrocene] palladium chloride (II), described part is triphenylphosphine or 1 for example, two ((diphenylphosphino) propane of 3-, described suitable alkali is triethylamine for example, described suitable cosolvent is 1-Methyl-2-Pyrrolidone or N for example, dinethylformamide.
In method (g), (h) with (j), can in the presence of the suitable coupler, in the presence of the alkali, in solvent and the temperature in 0-150 ℃ of scope carry out the acid amides coupled reaction, described coupler for example 1,1 '-carbonyl dimidazoles or dicyclohexyl carbodiimide and I-hydroxybenzotriazole, described alkali is triethylamine, N-methylmorpholine, diisopropylethylamine or salt of wormwood for example, and described solvent is methylene dichloride, N-Methyl pyrrolidone, N-N-dimethyl formamide or tetrahydrofuran (THF) for example.
It should be appreciated by those skilled in the art that in the method for the invention, may need for example hydroxyl, carboxyl or amino with some functional group in protecting group protection raw material reagent (starting reagent) or the midbody compound.Therefore, the preparation of the compound of formula (I) can be included in certain stage interpolation and/or remove one or more protecting groups.The protection of functional group and deprotection are at " Protective Groups in OrganicSynthesis "; 2nd edition; T.W.Greene and P.G.M.Wuts; Wiley-Interscience (1991) and " Protecting Groups "; P.J.Kocienski has description among the Georg Thieme Verlag (1994).
The compound of above-mentioned formula (I) can be changed into its pharmacy acceptable salt.When compound is enough tart, suitable salt comprises basic salt (base salts) for example basic metal such as salt, alkaline-earth metal such as the calcium of sodium or potassium or the salt of magnesium, the salt of organic amine, described organic amine is triethylamine, morpholine, N-methyl piperidine, N-ethylpiperidine, PROCAINE HCL, PHARMA GRADE, dibenzyl amine, N for example, and N-dibenzyl ethamine or amino acid is Methionin for example.When compound is enough alkalescence time, suitable salt comprises acid salt for example hydrochloride, hydrobromate, phosphoric acid salt, acetate, fumarate, maleate, tartrate, Citrate trianion, oxalate, mesylate or tosilate.According to number and the positively charged ion or the anionic valence state of charged functional group, more than one positively charged ion or negatively charged ion can be arranged.Can use conventional other pharmacy acceptable salt of method, and for example pharmaceutically acceptable ester of prodrug and pharmaceutically acceptable acid amides.
(wherein Y represents for example B (OH) of organic boron group can be prepared as follows the compound of formula (VI)-(IX)
2Or B (O
iPr)
2): in the presence of the trialkyl borate, in the presence of the suitable solvent and the temperature in-100 ℃ to 30 ℃ scopes, make the compound (wherein Y represents for example bromine or iodine of replaceable group) of formula (VI)-(IX) and suitable for example lithium methide and tert-butyl lithium reaction of organometallic reagent, described trialkyl borate is tri-isopropylborate for example, and described suitable solvent is tetrahydrofuran (THF) for example; And randomly then by making the boric acid ester hydrolysis with acid (for example ammonium chloride) thermotonus in 0 to 150 ℃ of scope in solvent (for example water or tetrahydrofuran (THF)).
Alternatively, (wherein Y represents for example B (OH) of organic boron group can be prepared as follows the compound of formula (VI)-(IX)
2Or boric acid tetramethyl ethylene ketone cyclic ester): in the presence of catalyzer, in the presence of alkali, in the presence of suitable solvent and the temperature in 25-250 ℃ of scope, (wherein Y represents replaceable group for example halogen or sulfonyloxy such as chlorine to make the compound of formula (VI)-(IX), bromine, iodine, trifluoro-methanesulfonyl oxy, mesyloxy or tolysulfonyl oxygen base) react as two (tetramethyl ethylene ketone closes) diboron hexahydride with suitable two borane reagents (diboron reagent), described catalyzer is palladium or [1 for example, 1 '-two ((diphenylphosphino) ferrocene] palladium chloride (II), described alkali is Potassium ethanoate or Tripotassium phosphate (tripotassium phosphate) for example, described suitable solvent is methyl-sulphoxide for example, N, dinethylformamide, 1,4-two alkane or tetrahydrofuran (THF)s; And randomly then by making the boric acid ester hydrolysis with acid (for example ammonium chloride) thermotonus in 0 to 150 ℃ of scope in solvent (for example water or tetrahydrofuran (THF)).
Compound (wherein Y represents leavings group for example halogen or sulfonyloxy) that can following preparation formula easily (VI)-(IX): randomly in the presence of suitable coupler, make compound and formula (XXIV), (XXV), (XXVI) or the reaction of compound (XXVII) of formula (XIX)
Wherein Y represents suc as formula (VI), (VII), (VIII) or for example halogen or sulfonyloxy of defined leavings group (IX), R
4And R
5Define suc as formula (I) is middle, and R
13Suc as formula defining in (XV)-(XVIII), described coupler is 1,1 '-carbonyl dimidazoles or dicyclohexyl carbodiimide and I-hydroxybenzotriazole for example.
Can be prepared as follows the compound (R wherein of formula (XV)-(XVIII)
13Be carboxyl): make formula (XXVIII), (XXIX), (XXX) or compound (XXXI) (R wherein
15Be C
1-6Alkyl, Ar
2, R
4And R
5Suc as formula defining in (I)) and alkali (for example sodium hydroxide or lithium hydroxide) thermotonus in 0-150 ℃ of scope in solvent (for example water or methyl alcohol), perhaps with acid (for example hydrochloric acid, Hydrogen bromide or trifluoroacetic acid) thermotonus in 0-150 ℃ of scope in solvent (for example water, 1,4-two alkane, tetrahydrofuran (THF), acetate or methylene dichloride)
Can be prepared as follows the compound (R wherein of formula (XX)-(XXIII)
13Be carboxyl): make formula (XXXII), (XXXIII), (XXXIV) or compound (XXXV) (Ar wherein
2dSuc as formula in (XX)-(XXIII) define R
12Suc as formula in (XI) define R
4And R
5Define suc as formula institute in (I)) and sour (for example hydrochloric acid, Hydrogen bromide or trifluoroacetic acid) thermotonus in 0-150 ℃ of scope in solvent (for example water, 1,4-two alkane, tetrahydrofuran (THF), acetate or methylene dichloride)
Can be prepared as follows the compound of formula (XXVIII)-(XXXI): in the presence of catalyzer and in the presence of suitable solvent, make formula (XXXVI), (XXXVII), (XXXVIII) or compound (XXXIX) with as the compound of defined formula (X) in above (a) (wherein Y suc as formula (VI)-(IX) middle definition, R
15Define suc as formula (XXVIII)-(XXXI) is middle, and R
4And R
5Suc as formula defining in (I)) reaction,
Described catalyzer is tetrakis triphenylphosphine palladium (0), palladium chloride (II), dibrominated palladium (II), two (triphenylphosphine) dichloro palladium (II), Nickel Chloride (II), Nickel Bromide (II) or two (triphenylphosphine) Nickel Chloride (II) for example, described suitable solvent is tetrahydrofuran (THF), 1 for example, 4-two alkane, 1,2-glycol dimethyl ether, benzene,toluene,xylene, methyl alcohol, ethanol or water.Reaction is preferred, and temperature in preferred 60 to 120 ℃ of scopes is carried out in the presence of suitable alkali and at 10 to 250 ℃, and described suitable alkali is yellow soda ash or salt of wormwood, pyridine, 4-dimethylaminopyridine, triethylamine or morpholine for example.
Can be prepared as follows the compound of formula (XXXII)-(XXXV): in the presence of catalyzer and in the presence of suitable solvent, make the compound (R wherein of formula (XXXVI)-(XXXIX)
15Be the tertiary butyl) with the reaction of the compound of formula (XXXX),
Z-Ar
2d-CO
2R
12(XXXX)
Wherein Z suc as formula in (X) define Ar
2dSuc as formula defining and R in (XX)-(XXIII)
12Suc as formula defining in (XI), described catalyzer is tetrakis triphenylphosphine palladium (0), palladium chloride (II), dibrominated palladium (II), two (triphenylphosphine) palladium chloride (II), Nickel Chloride (II), Nickel Bromide (II) or two (triphenylphosphine) Nickel Chloride (II) for example, described suitable solvent is tetrahydrofuran (THF), 1 for example, 4-two alkane, 1,2-glycol dimethyl ether, benzene,toluene,xylene, methyl alcohol, ethanol or water.Reaction is preferred, and temperature in preferred 60 to 120 ℃ of scopes is carried out in the presence of suitable alkali and at 10 to 250 ℃, and described suitable alkali is yellow soda ash or salt of wormwood, pyridine, 4-dimethylaminopyridine, triethylamine or morpholine for example.
(wherein Y represents for example B (OH) of organic boron group can be prepared as follows the compound of formula (XXXVI)-(XXXIX)
2Or B (O
iPr)
2): trialkyl borate for example in the presence of the tri-isopropylborate, at suitable solvent for example in the presence of the tetrahydrofuran (THF) and the temperature in-100 ℃ to 30 ℃ scopes, make the compound (wherein Y represents for example bromine or iodine of replaceable group) of formula (XXXVI)-(XXXIX) and suitable organometallic reagent reaction, described organometallic reagent is lithium methide and tert-butyl lithium for example; And randomly then by making the boric acid ester hydrolysis with acid (for example ammonium chloride) thermotonus in 0 to 150 ℃ of scope in solvent (for example water or tetrahydrofuran (THF)).
Alternatively, (wherein Y represents for example B (OH) of organic boron group can be prepared as follows the compound of formula (XXXVI)-(XXXIX)
2Or boric acid tetramethyl ethylene ketone cyclic ester): in the presence of catalyzer, in the presence of alkali, in the presence of the suitable solvent and the temperature in 25-250 ℃ of scope, (wherein Y represents replaceable group for example halogen or sulfonyloxy such as chlorine to make the compound of formula (XXXVI)-(XXXIX), bromine, iodine, trifluoro-methanesulfonyl oxy, mesyloxy or tolysulfonyl oxygen base) react with for example two (tetramethyl ethylene ketone closes) diboron hexahydrides of two suitable borane reagents, described catalyzer is palladium or [1 for example, 1 '-two ((diphenylphosphino) ferrocene] palladium chloride (II), described alkali is Potassium ethanoate or Tripotassium phosphate for example, described suitable solvent is methyl-sulphoxide for example, 1,4-two alkane or tetrahydrofuran (THF)s; And randomly then by making the boric acid ester hydrolysis with acid (for example ammonium chloride) thermotonus in 0 to 150 ℃ of scope in solvent (for example water or tetrahydrofuran (THF)).
Compound (wherein Y represents leavings group for example halogen or sulfonyloxy) that can following preparation formula easily (XXXVI)-(XXXIX): randomly in the presence of suitable reagent, make formula (XXXXI), (XXXXII), (XXXXIII) or compound (XXXXIV) (R wherein
16Expression CO
2H, COBr or COCl, Y are suc as formula defined leavings group in (VI)-(IX), R
4And R
5Suc as formula defining in (I)) and alcohol or for example potassium tert.-butoxide reaction of metal alkoxide, described suitable reagent is dicyclohexyl carbodiimide and 4-dimethylaminopyridine for example,
Compound that can following preparation formula easily (XXXXV): the compound (R wherein that makes formula (L)
21Suc as formula in (XXXXV) define R
19And R
20Define suc as formula institute in (I)) and the compound of formula (LI) (L wherein
3The expression leavings group is halogen or sulfonyloxy (for example chlorine, bromine, iodine, trifluoro-methanesulfonyl oxy, mesyloxy or tolysulfonyl oxygen base) for example, L
2And Ar
2eSuc as formula defining in (XXXXV)) reaction,
Can be prepared as follows the compound (R wherein of formula (XXXXVI)-(IL)
13The expression carboxyl): the temperature in 0-150 ℃ of scope makes formula (LII), (LIII), (LIV) or compound (LV) (Ar wherein
2fAnd R
22Define suc as formula (XXXXVI)-(IL) is middle, and R
4, R
5, R
19And R
20Define suc as formula institute in (I)) with acid (for example hydrochloric acid, Hydrogen bromide or trifluoroacetic acid) middle reaction of solvent (for example water, 1,4-two alkane, tetrahydrofuran (THF), acetate or methylene dichloride)
Can be prepared as follows the compound of formula (LII)-(LV): in the presence of catalyzer and in the presence of suitable solvent, (wherein Y represents for example B (OH) of for example organic boron group of replaceable group to make the compound of formula (XXXVI)-(XXXIX)
2, B (O
iPr)
2, BEt
2Or boric acid tetramethyl ethylene ketone cyclic ester, R
15Be the tertiary butyl) with the reaction of the compound of formula (XXXXV), described catalyzer is tetrakis triphenylphosphine palladium (0), palladium chloride (II), dibrominated palladium (II), two (triphenylphosphine) palladium chloride (II), Nickel Chloride (II), Nickel Bromide (II) or two (triphenylphosphine) Nickel Chloride (II) for example, described suitable solvent is tetrahydrofuran (THF), 1 for example, 4-two alkane, 1,2-glycol dimethyl ether, benzene,toluene,xylene, methyl alcohol, ethanol or water.Reaction is preferred, and temperature in preferred 60 to 120 ℃ of scopes is carried out in the presence of suitable alkali and at 10 to 250 ℃, and described suitable alkali is yellow soda ash or salt of wormwood, pyridine, 4-dimethylaminopyridine, triethylamine or morpholine for example.
Formula (X), (XI), (XII), (XIII), (XIV), (XIX), (XXIV), (XXV), (XXVI), (XXVII), (XXXX), (XXXXI), (XXXXII), (XXXXIII), (XXXXIV), (L) and compound (LI) or commercially available, be known in the document, perhaps can use known technology easily to prepare.
Compound of the present invention or its pharmacy acceptable salt can be used for following treatment:
1. respiratory tract: airway obstructive disease, comprise: asthma, comprise that bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced asthma (comprising what acetylsalicylic acid and NSAID-brought out) and dust bring out asthma, intermittent and persistence, all are severities; Airway hyperreactivity with other reason; Chronic obstructive pulmonary disease (COPD); Bronchitis comprises infectious bronchitis and acidophilia bronchitis; Pulmonary emphysema; Bronchiectasis; Cystic fibrosis; Sarcoidosis; Farmer lung and relative disease; Hypersensitivity pneumonitis; Pulmonary fibrosis comprises CFA, idiopathic interstitial pneumonia, concurrent antineoplaston and chronically infected fibrosis, comprises tuberculosis and aspergillosis and other fungi infestation; Complication of transplanted lung; Lung vascular system vasculitis and thrombotic disease; And pulmonary hypertension; Antitussive activity comprises for a long time cough and iatrogenic cough relevant with the secretion symptom of treatment and airway inflammation; Acute and chronic rhinitis comprises medicamentous rhinitis and vasomotor rhinitis; Perennial rhinitis and seasonal allergic rhinitis comprise nervous rhinitis's (pollinosis); Nasal polyposis; Acute viral infection comprises flu and the infection that causes because of respiratory syncytial virus, influenza, coronavirus (comprising SARS) and adenovirus;
2. bone and joint: relevant with osteoarthritis/osteoarthropathy or comprise their sacroiliitis, not only comprised idiopathic but comprise insecondary, congenital hip dysplasia for example; Neck and lumbar spine scorching and lumbago and backache and cervicodynia; Rheumatoid arthritis and Still disease (Still ' sdisease); Seronegative spondyloanthropathy comprises ankylosing spondylitis, arthritic psoriasis, reactive arthritis and does not break up SpA (undifferentiatedspondarthropathy); Septic arthritis infects relevant joint disease (arthopathies) and osteopathia with other, such as tuberculosis, comprises Pott's disease (Potts ' disease) and Poncet syndrome (Poncet ' s syndrome); The synovitis that acute and chronic crystal brings out comprises gout, tendon, mucous bursa and synovia inflammation that calcium pyrophosphate deposition disease is relevant with apatite calcium; Behcet's disease (Behcet ' s disease); Primary and Secondary cases xerodermosteosis (Sjogren ' s syndrome); Sjogren's syndrome and local scleroderma; Systemic lupus erythematous, MCTD and undifferentiated connective tissue disease; Inflammatory myopathy comprises dermatomyositis and polymyositis; The rheumatic polymyopathy; Juvenile arthritis (juvenile arthritis) comprises primary inflammatory arthritis and related syndromes and rheumatic fever and whole body complication thereof that no matter which kind of joint distributes; Vasculitis (vasculitide), comprise giant cell arteritis, aortic arch syndrome (Takayasu ' s arteritis), Qiu-Shi syndrome (Churg-Strauss syndrome), polyarteritis nodosa, microcosmic polyarteritis, with the vasculitis relevant with virus infection, allergy, cryoglobulin and M-band; Lumbago and backache; Familial Mediterranean fever, Mu-Wei syndrome (Muckle-Wells syndrome) and familial Ireland heat (Familial Hibernian Fever), Kikuchi disease (kikuchi); Drug-induced arthrodynia, tendonitis (tendonititides) and myopathy;
3. because the flesh skeleton illness that pain that damage [for example sport injury] or disease cause and reticular tissue reproduce: sacroiliitis (rheumatoid arthritis for example, osteoarthritis, gout or crystal joint disease), other joint disease (for example disc degenerates or temporomandibular degenerative joint), bone remodelling disease (for example osteoporosis, scleromalacia or osteonecrosis), polychondritis, scleroderma, mixed connective tissue disease disease, spondyloarthropathy or periodontopathy (for example periodontitis);
4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczema dermatoses and delayed type hypersensitivity; Vegetalitas dermatitis and solar dermatitis; Seborrheic dermatitis, dermatitis herpetiformis, lichen planus, atrophic sclerosis lichen, PG, skin tag disease, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema toxicum, epidermis eosinophilia, alopecia areata, male pattern baldness disease, sweet's syndrome (Sweet ' s syndrome), Wei-Ke syndrome (Weber-Christian syndrome), erythema multiforme; Cellulitis comprises communicable and noninfectious; Pimelitis; Lymphoma cutis; Non-melanoma skin cancer and other dysplasia infringement; Drug-induced disease comprises fixed drug eruption;
The eye: blepharitis; Conjunctivitis comprises property and spring allergic conjunctivitis for many years; Iritis; Anterior uveitis and posterior uveitis; Choroiditis; Autoimmune disorder; Influence amphiblestroid sex change or inflammatory diseases; Ophthalmia comprises sympathetic ophthalmia; Sarcoidosis; Infect, comprise virus, fungi and infectation of bacteria;
6. gi tract: glossitis, oulitis, periodontitis; Esophagitis comprises and backflowing; Eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis comprise ulcerative colitis, rectitis, pruritus ani; Coeliac disease, irritable bowel syndrome and can have food related allergic (for example migraine, rhinitis or eczema) away from the intestines effect;
7. belly: hepatitis comprises autoimmunity, alcohol and viral hepatitis; Hepatic fibrosis and liver cirrhosis; Cholecystitis; Pancreatitis comprises acute pancreatitis and chronic pancreatitis;
8. urogenital system: ephritis comprises interstitial nephritis and glomerulonephritis; Nephrotic syndrome; Urocystitis comprises acute and chronic (matter) urocystitis and hunner's ulcer (Hunner ' sulcer); Acute and chronic urethritis, prostatitis, epididymitis, ovaritis and salpingitis; Vulvo-vaginitis; Peyronie disease (Peyronie ' s disease); Erectile dysfunction (masculinity and femininity);
9. allograft rejection: acute and chronic allograft rejection, for example after kidney, heart, liver, lung, marrow, skin or the corneal transplantation or the acute and chronic allograft rejection after the blood transfusion; Or chronic graft versus host disease;
10.CNS: alzheimer's disease and other dementia disease comprise CJD and nvCJD; Amyloidosis; Multiple sclerosis and other demyelination syndrome; Cerebral atherosclerosis and vasculitis (vasculitis); Temporal arteritis; Myasthenia gravis; Acute and chronic pain be (acute, intermittence or persistence, no matter derive from maincenter or periphery), comprise Encelialgia, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and ostalgia, invade pain, the neuropathic pain syndrome that causes, comprise after diabetes, the bleb and the DPN relevant with HIV-because of cancer and tumour; Neurosarcoidosis; The maincenter and the peripheral nervous system complication of pernicious, infectivity and self-immunprocess;
11. other autoimmune disorder and allergic disorder comprise Hashimoto thyroiditis (Hashimoto ' s thyroiditis), Graves disease (Graves ' disease), bronzed disease (Addison ' s disease), diabetes, idiopathic thrombocytopenic purpura, eosinophilic fasciitis, height-IgE syndrome, antiphospholipid syndrome;
12. the disease that other has inflammatory or immunity composition comprises acquired immune deficiency syndrome (AIDS) (AIDS), leprosy, malignant cutaneous reticulosis syndrome (ezary syndrome) and paraneoplastic syndrome;
13. it is cardiovascular; Atherosclerosis, influence the pericarditis of coronary artery and peripheral circulation; Myocarditis, inflammatory and autoimmunity myocardosis comprise myocardial sarcoisosis; The ischemic reperfusion injury; Endocarditis, cardiovalvulitis and aortitis comprise communicable (for example plum is toxic); Vasculitis; Nearly vein and peripheral vein disease comprise phlebitis and thrombosis, comprise that dvt forms and the varix complication;
14. tumour: treatment common cancer, the malignant tumour that comprises prostate gland, mammary gland, lung, ovary, pancreas, intestines and colon, stomach, skin and cerebral tumor and infringement marrow (comprising leukemia) and lymphadenosis system is such as hodgkin lymphoma (Hodgkin ' s lymphoma) and non-hodgkin lymphoma (non-Hodgkin ' s lymphoma); Comprise prevention and treatment metastatic disease and tumor recurrence and paraneoplastic syndrome; With
15. gi tract: coeliac disease, rectitis, acidophilia gastroenteritis, mast cell disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome (irritable bowel disorder), irritable bowel syndrome (irritable bowel syndrome), non-inflammatory diarrhoea or have the relevant allergy of food away from the effect of intestines, for example, migraine, rhinitis and eczema.
Therefore, the invention provides as mentioned in defined formula (I) compound or its pharmacy acceptable salt, it is used for the treatment of.
On the other hand, the invention provides as mentioned in the purposes of defined formula (I) compound or its pharmacy acceptable salt, it is used for the employed medicine of preparation treatment.
In the context of the present specification, term " treatment " also comprises " prevention " is unless exist opposite specific description.Term " treatment " and " remedially " are also answered respective explanations.
The purposes of defined formula (I) compound or its pharmacy acceptable salt during an embodiment of the invention provide as mentioned, it is used for preparing the employed medicine of treatment of rheumatoid arthritis.
The purposes of defined formula (I) compound or its pharmacy acceptable salt during one embodiment of the present invention provide as mentioned, it is used to prepare the medicine that is used for the treatment of osteoarthritis.
The purposes of defined formula (I) compound or its pharmacy acceptable salt during one embodiment of the present invention provide as mentioned, it is used for the medicine that preparation is used for the treatment of asthma or chronic obstructive pulmonary disease (chronicobstructive pulmonary disease).
The purposes of defined formula (I) compound or its pharmacy acceptable salt during one embodiment of the present invention provide as mentioned, it is used for preparation and is used for the treatment of atherosclerotic medicine.
The present invention also provides and carries out immunosuppressant method (for example in rheumatoid arthritis, osteoarthritis, irritable bowel syndrome, atherosclerosis or psoriasis treatment), and it comprises that (I) compound of formula as hereinbefore defined or its pharmacy acceptable salt with the treatment significant quantity deliver medicine to the patient.
The present invention also provides the method for treatment obstructive airway diseases (for example asthma or COPD), and this method comprises treatment (I) compound of formula as hereinbefore defined of significant quantity or its pharmacy acceptable salt medicine in the patient.
Use for all above-mentioned treatments, the dosage of administration changes along with the illness of the compound that is adopted, administering mode, desired treatment and adaptation certainly.The per daily dose of formula (I) compound/salt (" activeconstituents ") can be 0.001mg/kg to 30mg/kg.
Formula (I) compound and pharmacy acceptable salt thereof can use separately, but common form administration with pharmaceutical composition, in this pharmaceutical composition, formula (I) compound/salt/solvate (" activeconstituents ") combines with acceptable accessories, diluent or carrier.According to administering mode, pharmaceutical composition comprises preferred 0.05～99%w (weight percentage), the more preferably activeconstituents of 0.10～70%w, and preferred 1～99.95%w, the more preferably acceptable accessories of 30～99.90%w, diluent or carrier, all wt percentage number average is based on whole composition.
Thereby the present invention also provides pharmaceutical composition, and it comprises front defined formula (I) compound or its pharmacy acceptable salt, and is combined with pharmaceutical excipient, diluent or carrier.
Pharmaceutical composition of the present invention can solution, the form topical (for example delivering medicine to lung and/or air flue or skin) of outstanding mixture, Sevoflurane hydrocarbon gas colloidal sol and dry powder formulations; Perhaps whole body administration, for example, with tablet, capsule, syrup, pulvis or particulate form oral administration, perhaps with the form parenteral admin of solution or outstanding mixture, perhaps subcutaneous administration is perhaps with the form rectal administration or the percutaneous dosing of suppository.
The invention further relates to combination therapy, wherein with The compounds of this invention or its pharmacy acceptable salt or comprise the pharmaceutical composition of The compounds of this invention or preparation and another kind of or multiple therapeutical agent simultaneously or in order or as the combination preparation administration, to be used for the treatment of one or more cited illnesss.
Especially, with regard to the treatment of inflammatory diseases, (but being not limited to) rheumatoid arthritis for example, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis and inflammatory bowel, The compounds of this invention can with following agent combination: non-steroidal anti-inflammatory agents (hereinafter referred to as NSAID), comprise nonselective cyclooxygenase COX-1/COX-2 inhibitor, no matter part or whole body are used (piroxicam for example, diclofenac, propionic acid is Naproxen Base for example, flurbiprofen, fenoprofen, Ketoprofen and Ibuprofen BP/EP, fragrant that acid is mefenamic acid for example, INDOMETHACIN (Indomethacin), sulindac, azapropazone (azapropazone), pyrazolone is Phenylbutazone for example, and salicylate is Asprin for example); Selective COX-2-2 inhibitor (meloxicam for example, celecoxib, rofecoxib, valdecoxib, Lu Makao former times (lumarocoxib), former times examined by handkerchief and support is examined former times); Cyclooxygenase suppresses nitric oxide donors (CINOD); Glucocorticosteroid (no matter by local, oral, intramuscular, intravenously or the administration of IA path); Methotrexate, leflunomide; Oxychloroquine, d-Trolovol, auranofin or other parenteral or oral gold preparation; Anodyne; Diacerein (diacerein); The intraarticular therapy is derivatives of hyaluronic acids for example; With accessory substance glycosamine for example.
The present invention further relates to the combination of compound of the present invention or its pharmacy acceptable salt and following cytokine or cytokine function agonist or antagonist (comprise and act on for example medicine of SOCS system modifier of cytokine signaling pathway): comprise α-, β-and gamma-interferon; Insulin-like growth factor I type (IGF-1); Interleukin (IL) comprises for example Kineret of IL1 to 17 and interleukin antagonist or inhibitor; Tumor necrosis factor alpha (TNF-α) inhibitor is anti-tumor necrosis factor monoclonal antibody (infliximab (infliximab) for example for example; Adalimumab (adalimumab), and CDP-870) and the TNF receptor antagonist comprise for example pentoxifylline (pentoxyfylline) of immunoglobulin molecules (for example etanercept) and low-molecular-weight drug.
In addition, the present invention relates to the combination of the monoclonal antibody of The compounds of this invention or its pharmacy acceptable salt and target B-lymphocyte (for example CD20 (Rituximab (rituximab)), MRA-aIL16R) and T-lymphocyte (CTLA4-Ig, HuMax Il-15).
The invention further relates to the combination of The compounds of this invention or its pharmacy acceptable salt and following chemokine receptor function conditioning agent, for example CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (C-X-C family); And CX
3CR1 (C-X
3-C family) antagonist.
The present invention further relates to the combination of The compounds of this invention or its pharmacy acceptable salt and following inhibitor: matrix metallo-proteinase inhibitor, the inhibitor of instant stromatin enzyme (stromelysins), collagenase and gelatinase and proteoglycan enzyme (aggrecanase); Collagenase-1 (MMP-1) particularly, collagenase-2 (MMP-8), collagenase-3 (MMP-13), molten stromatin enzyme-1 (MMP-3), molten stromatin enzyme-2 (MMP-10) and molten stromatin enzyme-3 (MMP-11) and MMP-9 and MMP-12 comprise Vibravenos etc.
The present invention further relates to compound of the present invention or its pharmacy acceptable salt and following drug regimen: leukotrienes biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activated protein (FLAP) antagonist for example: abandon stay logical; ABT-761; Fenleuton; Tepoxalin; Abbott-79175; Abbott-85761; N-(5-replaces)-thiophene-2-alkyl sulfonamide; 2,6-two-tert-butyl phenol hydrazone; The methoxyl group tetrahydropyrans is Zeneca ZD-2138 for example; Compound S B-210661; The 2-cyano group naphthalene compound of pyridyl-replacement is L-739 for example, and 010; 2-cyano quinolines compound is L-746 for example, and 530; Indoles and quinoline compound be MK-591 for example, MK-886, and BAYx1005.
The present invention further relates to The compounds of this invention or its pharmacologically acceptable salts and the combination that is selected from the receptor antagonist of following leukotrienes (LT) B4, LTC4, LTD4 and LTE4: thiodiphenylamine-3-ketone is L-651 for example, and 392; Amidino compounds is CGS-25019c for example; Benzo amine (benzoxalamine) is Ontazolast for example; Benzenyl amidine (benzenecarboximidamides) is BIIL 284/260 for example; Compound is Zafirlukast, Ro 23-3544, Singulair, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A) and BAYx 7195 for example.
The present invention further relates to the combination of The compounds of this invention or its pharmacy acceptable salt and following medicine: phosphodiesterase (PDE) inhibitor for example methyl xanthine (methyl xanthanines) comprises theophylline and aminophylline; Optionally PDE isozyme inhibitor comprises the inhibitor of PDE4 inhibitor and isoform PDE4D and the inhibitor of PDE5.
The present invention further relates to the combination of The compounds of this invention or its pharmacy acceptable salt and following medicine: histamine 1 receptor antagonist, alerlisin for example, Loratadine, Desloratadine, fexofenadine, Acrivastine, terfenadine, astemizole, azelastine, levocabastine, Toldrin, promethazine, marezine (cyclizine), or mizolastine; Oral, part or parenteral are used.
The present invention further relates to the combination of The compounds of this invention or its pharmacy acceptable salt and proton pump inhibitor (for example omeprazole) or stomach protection histamine 2 receptor antagonist.
The invention further relates to the combination of The compounds of this invention or its pharmacy acceptable salt and histamine 4 receptor antagonists.
The present invention further relates to the combination of The compounds of this invention or its pharmacy acceptable salt and following medicine: α-1/ α-2 adrenoceptor agonists, vasoconstrictor, sympathomimetic drug, propylhexedrine (propylhexedrine) for example, synephrine, Phenylpropanolamine, ephedrine, pseudo-ephedrine, naphcon, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorephinephrine hydrochloride.
The invention further relates to the combination of The compounds of this invention or its pharmacy acceptable salt and following medicine: anticholinergic agents, comprise muscarinic receptor (M1, M2 and M3) antagonist, coromegine for example, Scopolamine (hyoscine), GLYCOPYRRONIUM (glycopyrrrolate), SCH 1000, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
The present invention further relates to the combination of The compounds of this invention or its pharmacy acceptable salt and following medicine: receptor, agonist (comprising beta receptor hypotype 1-4) is Racemic isoproterenol for example, salbutamol (salbutamol), formoterol, Salmeterol, terbutaline (terbutaline), Metaprel, bitolterol mesilate, and pirbuterol, or its chirality enantiomorph.
The present invention further relates to for example combination of sodium cromoglycate or sodium nedocromil of compound of the present invention or its pharmacy acceptable salt and chromone.
The present invention further relates to the combination of this compound of the present invention or its pharmacy acceptable salt and following medicine: glucocorticosteroid, flunisolide for example, Triamcinolone Acetonide, Viarox, budesonide, fluticasone propionate, ciclesonide, or furancarboxylic acid Mo Meisong.
The present invention further relates to compound of the present invention or its pharmacy acceptable salt and for example combination of the medicine of PPAR of adjusting nuclear hormone receptor.
The present invention further relates to the combination of compound of the present invention or its pharmacy acceptable salt and following medicine: immunoglobulin (Ig) (Ig) or Ig preparation or antagonist or antibody are regulated for example anti-IgE of Ig function (horse pearl monoclonal antibody for example difficult to understand).
The present invention further relates to compound of the present invention or its pharmacy acceptable salt and other system or topical application for example combination of Thalidomide (thalidomide) or derivatives thereof, retinoid, anthratriol (dithranol) or calcipotriol (calcipotriol) of anti-inflammatory agent.
The present invention further relates to the combination of compound of the present invention or its pharmacy acceptable salt and following medicine: aminosalicylate and sulfapyridine be sulfasalazine for example, mesalazine, Balsalazide, and olsalazine; With immunoregulation druge thio-purine (thiopurines) and corticosteroid budesonide for example for example.
The present invention further relates to the combination of compound of the present invention or its pharmacy acceptable salt and following medicine: antiseptic-germicide comprises penicillin derivative, tsiklomitsin, macrolide, beta-lactam, fluoroquinolone, metronidazole and suction aminoglycoside; And antiviral drug, comprise acyclovir, Famciclovir, valacyclovir, ganciclovir, cidofovir; Amantadine, Rimantadine; Virazole; Zanamivir (zanamavir) and special quick clothes (oseltamavir); Proteinase inhibitor, Indinavir for example, viracept see nelfinaivr, ritonavir, and Saquinavir; Nucleoside reverse transcriptase inhibitor, didanosine for example, Lamivudine, stavudine (stavudine), zalcitabine or zidovudine; Or non-nucleoside reverse transcriptase inhibitor, for example nevirapine (nevirapine) or efavirenz (efavirenz).
The present invention further relates to the combination of compound of the present invention or its pharmacy acceptable salt and following medicine: cardiovascular agent, calcium channel blocker for example, the receptor, blocker, angiotensin-converting enzyme (ACE) inhibitor, Angiotensin-2 receptor antagonist; Lipid reduces medicine, for example the special class (fibrates) of statin or shellfish; The blood cell shape conditioning agent is for example joined the appropriate western film; Thrombolytics, and anti-coagulant comprise anticoagulant.
The present invention further relates to the combination of compound of the present invention or its pharmacy acceptable salt and following medicine: the CNS medicine, thymoleptic (for example Sertraline) for example, antiparkinsonian medicine (selegiline for example, levodopa, Ropinirole, pramipexole, the MAOB inhibitor is Si Lanjilan (selegine) and rasagiline for example, the comP inhibitor is tolcapone (tasmar) for example, A-2 inhibitor, dopamine reuptake inhibitor, nmda antagonist, or anti-Alzheimer medicine E2020 (donepezil) for example nicotinic agonist, the inhibitor of dopamine agonist or neuronal nitric oxide synthase (inhibitors of neuronal nitric oxide synthase)),, Li Fansi's is bright, tacrine, cox 2 inhibitor, propentofylline or metrifonate.
The present invention further relates to compound of the present invention or its pharmacy acceptable salt is acute with treatment and the combination of the medicine of chronic pain, as maincenter and peripheral action pain killer (for example opioid or derivatives thereof), Carbamzepine, Phenytoin Sodium Salt, Sodium Valproate, amitriptyline (amitryptiline) or other thymoleptic, Paracetamol or non-steroidal anti-inflammatory agents.
The present invention further relates to for example combination of lignocaine (lignocaine) or derivatives thereof of local anesthetic of compound of the present invention or its pharmacy acceptable salt and parenteral or topical application (comprising suction).
Compound of the present invention or its pharmacy acceptable salt also can comprise for example Reynolds former times sweet smell of hormonal medicaments with anti-osteoporosis agents, or diphosphonate (biphosphonate) being used in combination of alendronate (alendronate) for example.
The present invention further relates to the combination of compound of the present invention or its pharmacy acceptable salt and following medicine: (i) tryptase inhibitors; (ii) platelet activation factor (PAF) antagonist; (iii) interleukin is changed enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) the adhesion molecule inhibitor comprises the VLA-4 antagonist; (vi) kethepsin; (vii) kinase inhibitor, comprise tyrosine kinase inhibitor (Btk for example, Itk, Jak3 MAP, the example of inhibitor can comprise Gefitinib (Gefitinib), imatinib mesylate), the serine/threonine kinase inhibitor (for example, map kinase is the inhibitor of p38, JNK, protein kinase A, B and C and IKK for example), or relate to the inhibitor of the kinases (for example, cell cycle protein dependent kinase) of Cycle Regulation; (viii) glucose-6 monophosphate dehydrogenase inhibitor; (ix) kassinin kinin-B1-or B2-receptor antagonist body; (x) antigout agent, for example, colchicine; (xi) xanthine oxidase inhibitor, for example, Zyloric; (xii) uricosuric agent, for example probenecid or sulphur arsenic ketone or benzbromarone; (xiii) tethelin succagoga; (xiv) transforming growth factor (TGF β); (xv) Thr6 PDGF BB (PDGF); (xvi) fibroblast growth factor, for example basic fibroblast growth factor (bFGF); (xvii) rHuGM-CSF (GM-CSF); (xviii) capsicum vegetable oil (capsaicincream); (xix) tachykinin NK-1 1 or NK3 receptor antagonist for example are selected from NKP-608C, SB-233412 (Talnetant) or D-4418; (xx) elastase inhibitor is selected from UT-77 or ZD-0892; (xxi) TNF-α converting enzyme inhibitor (TACE); (xxii) inductive nitric oxide synthase inhibitor activity (iNOS); Or the chemoattractant receptor homolog molecule (CRTH2 antagonist) of (xxiii) expressing on the TH2 cell; (xxiv) inhibitor of P38; (xxv) medicine of adjusting Toll receptoroid (TLR) function and (xxvi) the active medicine of adjusting purinergic receptor, for example P2X7; Or (xxvii) transcription factor activatory inhibitor, for example NFkB, API or STATS.
Compound of the present invention or its pharmacy acceptable salt can also with the combination of existing therapeutical agent of treatment cancer in use, for example suitable therapeutical agent comprises:
(i) antiproliferative/antitumour drug or its combination as being used for the medical science oncology, for example alkylating agent (as cis-platinum, carboplatin, endoxan, mustargen, L-PAM, Chlorambucil, busulfan or nitrosourea); (antifol for example is as fluorinated pyrimidine such as 5 FU 5 fluorouracil or Tegafur, Raltitrexed, Rheumatrex, cytosine arabinoside, hydroxyurea, gemcitabine or taxol for metabolic antagonist; Antitumor antibiotics (for example anthracycline antibiotics, as Zorubicin, bleomycin, Dx, daunorubicin, epirubicin, idarubicin, Mitomycin-C, gengshengmeisu or Plicamycin); Antimitotic agent (catharanthus alkaloid class for example, as vincristine(VCR), vincaleucoblastine, vindesine or vinorelbine, or taxanes, as taxol or docetaxel); Or topoisomerase enzyme inhibitor (for example epipodophyllotoxin class, as Etoposide and teniposide, Amsacrine, topotecan or camptothecin);
(ii) cytostatic agent such as antiestrogen (tamoxifen for example, toremifene, raloxifene, droloxifene or iodoxyfene), estrogen receptor is born conditioning agent (as fulvestrant), antiandrogen (bicalutamide for example, flutamide, Nilutamide or cyproterone acetate), lhrh antagonist or LHRH agonist (goserelin for example, Leuprolide or buserelin), progestogens (as Magace), aromatase inhibitor (anastrozole for example, letrozole, vorozole (vorazole) or Exemestane) or 5 inhibitor such as finasteride;
The (iii) medicine (for example inhibitor of inhibitors of metalloproteinase such as Marimastat or UPA function of receptors) of anticancer invasion;
(iv) somatomedin depressant of functions, for example such as following inhibitor: growth factor antibodies (for example anti--erbb2 antibody trastuzumab or anti--erbb1 antibody Cetuximab [C225]), farnesyl transferase inhibitor, tyrosine kinase inhibitor or serine/threonine kinase inhibitor, the inhibitor of epidermal growth factor family (EGFR family tyrosine kinase inhibitor for example, as N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (Gefitinib, AZD1839), N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy) quinazoline-4-amine (erlotinib, OSI-774) or 6-acryl amino-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033)), the inhibitor of the inhibitor of platelet-derived growth factor family or pHGF family;
(v) anti-angiogenic agent, for example those suppress the medicine of vascular endothelial growth factor effect, (for example anti-VEGF antibody rhuMAb-VEGF is for example asked those disclosed compound among WO 97/22596, WO 97/30035, WO 97/32856 or the WO 98/13354 in international monopoly) or the compound (for example inhibitor or the angiostatin of linomide, beta 2 integrin alpha v β 3 functions) that works with other mechanism;
(vi) vascular damages disclosed compound among agent such as combretastatin A4 or International Patent Application WO 99/02166, WO00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or the WO 02/08213;
(those materials of target spot such as ISIS 2503, anti--ras antisense thing are listed in vii) antisense therapy agent above for example being oriented to;
(the viii) medicament that uses in the gene therapy method, the medicament that uses in for example following method: for example those use the method for Isocytosine deaminase, thymidine kinase or bacterium nitroreductases and increase the method for example multidrug resistance gene treatment of patient to chemotherapy or radiotherapy tolerance to replace method, GDEPT (the enzyme prodrug treatment of the gene orientation) method of aberrant gene such as unusual p53 or unusual BRCA1 or BRCA2; Perhaps
(ix) be used in medicine in the following immunotherapy method, comprise the method that for example increases the patient tumors cell immunogenicity in vitro and in vivo, as with cytokine such as interleukin-22, interleukin 4 or rHuGM-CSF transfection, the method that reduces T-cell anergy, the immunocyte that uses transfection such as transfection cytokine dendritic cell method, use cytokine transfection tumor cell line method and use the method for antiidiotypic antibody.
Now the present invention is described further with reference to following illustrative embodiment.In an embodiment, NMR spectrum is to measure on Varian Unity spectrograph with the proton frequency of 300 or 400 MHz.MS spectrum is measured on Agilent 1100 MSD G 1946D spectrographs or Hewlett Packard HP 1100 MSDG1946A spectrographs.It is to utilize Waters Symmetry that preparation HPLC separates
Perhaps Xterra
Chromatographic column is carried out, and adopts 0.1% trifluoroacetic acid aqueous solution: acetonitrile, 0.1% ammoniacal liquor: acetonitrile, perhaps 0.1% ammonium acetate solution: acetonitrile is as elutriant.Microwave reaction carries out in CEM Discover monotype microwave.In following examples, all compounds use the Chemical Abstracts Service Index Name function name in the ACD/Name software package.
Embodiment 1
4 '-chloro-3 '-[[[2-(2-chloro-phenyl-) ethyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid
A) [4-chloro-3-[[[2-(2-chloro-phenyl-) ethyl] amino] carbonyl] phenyl]-boric acid
To 5-bromo-2-chloro-N-[2-(2-chloro-phenyl-) ethyl that is stirring]-benzamide (preparing described in WO2003042191) is (1.5g) in-78 ℃ of solution in tetrahydrofuran (THF) (40mL), add lithium methide (the 1.6M diethyl ether solution, 3.0mL).After 10 minutes, add triisopropyl borate ester (4.8mL), then add tert-butyl lithium (the 1.7M pentane solution, 5.2mL).After-78 ℃ are stirred 2h, make this mixture be warming up to-30 ℃, add saturated aqueous ammonium chloride (40mL) carefully, and make this mixture last 16 hours to be warming up to room temperature.Add ethyl acetate (100mL), separate each layer, and (2 * 50mL) extractions contain water section with ethyl acetate.Dry (MgSO
4) organic fraction of merging, filter and vacuum concentration, obtain subtitle compounds, be colorless solid (1.3g).
MS：APCI(+ve)338(M+H
+).
B) 4 '-chloro-3 '-[[[2-(2-chloro-phenyl-) ethyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylate methyl ester
Under nitrogen atmosphere and 65 ℃, with [4-chloro-3-[[[2-(2-chloro-phenyl-) ethyl] amino] carbonyl] phenyl]-boric acid (600mg) (embodiment 1 (a)), 2-methyl-bromobenzoate (865mg), salt of wormwood (800mg) and two ((triphenylphosphine) palladium chloride (II) is (100mg) 1, the mixture heating up in 4-two alkane (9mL)/water (9mL) 3 hours.Product is filtered by diatomite, with methyl alcohol (3 * 30mL) washing).Solvent removed in vacuo, resistates chromatogram purification (SiO
2, methylene dichloride: methyl alcohol 99: 1 is as eluent), obtain subtitle compounds, be solid (230mg).
MS：APCI(+ve)430(M+H
+).
C) 4 '-chloro-3 '-[[[2-(2-chloro-phenyl-) ethyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid
With 4 '-chloro-3 '-[[[2-(2-chloro-phenyl-) ethyl] amino] carbonyl]-[1,1 '-xenyl]-2-carboxylate methyl ester (embodiment 1 (b)) (230mg), methyl alcohol (1mL) and aqueous sodium hydroxide solution (6M, mixture 1.0mL) in microwave in 65 ℃ of heating 30min.Chromatogram purification (SiO
2, methylene dichloride: methyl alcohol 99: 1, methylene dichloride then: methyl alcohol 97: 3 is as eluent), use Varian NH then
2Tube (it uses methyl alcohol (100mL), and 1% trifluoroacetic acid/methyl alcohol (100mL) is as eluent then) purifying, (acetonitrile: ammonium acetate aqueous solution, Symmetry) purifying obtains title compound, is solid (60mg) to use RP-HPLC then.
MS：APCI(+ve)414(M+H
+).
m.p.136-140℃
1H NMR(400MHz，d
6-DMSO)δ 8.59(1H，t)，7.75(1H，d)，7.58(1H，t)，7.51-7.21(9H，m)，3.49(2H，td)，2.97(2H，t).
Embodiment 2
4 '-chloro-3 '-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid
A) oxygen 1-[(trimethyl silyl)]-the suberane formonitrile HCN
According to J.Med.Chem., 1981,24, the method for 7-12 prepares subtitle compounds.Under nitrogen atmosphere and 0 ℃, (8.8g 12mL) lasts 30min and is added in the mixture of the suberone (10g) that stirring and zinc iodide (0.01g) with trimethylsilyl cyanide.Make mixture last 72 hours and be warming up to room temperature, and purifying does not just use subtitle compounds (18.8g).
1H NMR(400MHz，CDCl
3)δ1.91-1.82(2H，m)，1.75-1.64(2H，m)，1.53-1.26(8H，m)，0.00(9H，s).
B) 1-(amino methyl)-suberyl alcohol
According to J.Med.Chem., 1981,24, the method for 7-12 prepares subtitle compounds.Under nitrogen atmosphere and room temperature, with the 1-[(trimethyl silyl) oxygen]-ring formonitrile HCN in heptan (embodiment 2 (a)) tetrahydrofuran (THF) (120mL) solution (5.0g), last 10min be added to the lithium aluminum hydride that is stirring diethyl ether solution (72mL, 1.0M) in.With mixture 50 ℃ the heating 1 hour, make it in ice bath, be cooled to 0 ℃ then, and add entry (3mL) carefully, (3mL 15%wt/wt), then adds entry (9mL), makes its cancellation then to add aqueous sodium hydroxide solution.Vacuum is removed volatiles, and resistates is distributed between ether (100mL) and water (50mL).Separate each layer, (2 * 50mL) extractions contain water section, and concentrate the organic layer that merges, and obtain subtitle compounds, are liquid (3.3g) with ether.
1H NMR(400MHz，CDCl
3)δ4.61(2H，s)，2.44(2H，s)，1.63-1.15(12H，m).
C) methyl 2-chloro-N-[(1-hydroxyl suberyl)]-5-iodo-benzamide
In the 0 ℃ solution of 5-iodo-2-chloro-benzoic acid (730mg) in methylene dichloride (30mL), add triethylamine (0.72mL), I-hydroxybenzotriazole (435mg), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1g) and 1-(amino methyl)-suberyl alcohol (embodiment 2 (b)) (407mg).Make reaction mixture be warming up to room temperature, and under nitrogen, stirred 16 hours.Mixture is poured in the water (30mL) then.Separate each layer, and (2 * 30mL) extract this aqueous solution with methylene dichloride.With 2M hydrochloric acid (2 * 30mL), the organic layer that merges of saturated sodium bicarbonate aqueous solution (30mL) and salt solution (30mL) washing, make its drying then, filter also evaporation, obtain subtitle compounds, be colorless solid (900mg).
MS：APCI(-ve)406/408(M-H
+).
1H NMR(400MHz，d
6-DMSO)δ8.31(1H，t)，7.79-7.73(2H，m)，7.28(1H，dd)，4.24(1H，s)，3.19(2H，d)，1.67-1.27(12H，m).
D) 4 '-chloro-3 '-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid, ethyl ester
To the ethyl-2-(4 that is stirring, 4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) benzoic ether (204mg) and 2-chloro-N-[(1-hydroxyl suberyl) methyl]-5-iodo-benzamide (embodiment 2 (c)) (300mg) in the mixture in tetrahydrofuran (THF) (3mL), adds water (3mL) solution of salt of wormwood (204mg), adds then that two ((triphenylphosphine) palladium chloride (II) is (26mg).In this mixture of stirring at room 16 hours, concentrate then.Resistates is distributed between water (100mL) and methylene dichloride (100mL).Separate each layer, and with methylene dichloride (100mL) extraction water solution.The organic layer that merges is filtered by diatomite, concentrate then.Purifying (SiO
2, 3: 1 isohexanes: ethyl acetate is as eluent), obtain subtitle compounds, be solid (300mg).
MS：APCI(+ve)412/414(M+H-H
2O).
1H NMR(400MHz，d
6-DMSO)δ8.20(1H，t)，7.79(1H，dd)，7.66(1H，td)，7.56-7.51(2H，m)，7.47(1H，dd)，7.38-7.33(2H，m)，4.09(2H，q)，3.22(2H，d)，1.69-1.28(12H，m)，1.05(3H，t).
E) 4 '-chloro-3 '-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid
With 4 '-chloro-3 '-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl]-[1,1 '-xenyl]-2-carboxylic acid, ethyl ester (embodiment 2 (d)) (300mg) and methyl alcohol (1mL) place 10mL microwave bottle (microwave vial).Water (2mL) solution that adds potassium hydroxide (100mg), and with this mixture in CEM Discovery microwave in 50 ℃ of heating 15 minutes.Evaporate this mixture, and add water (5mL), with 2M hydrochloric acid it is acidified to pH 2 then to resistates.With the methylene dichloride (solution that 3 * 20mL) extractions obtain.Merge and concentrated extract.Purifying (Varian NH
2Tube (use methylene dichloride (100mL), 10% acetate/methylene dichloride (100mL) is as eluent then) obtains title compound, is solid (60mg).
MS：APCI(+ve)402/404(M+H
+).
m.p.113-116℃.
1H NMR(400MHz，d
6-DMSO)δ8.21(1H，t)，7.71(1H，d)，7.57-7.35(6H，m)，3.22(2H，d)，1.71-1.28(12H，m).
Embodiment 3
4 '-chloro-3 '-[[(cyclohexyl methyl) amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid
A) 2-chloro-5-iodo-phenylformic acid, 1,1-dimethyl ethyl ester
With N, dinethylformamide (1) and oxalyl chloride (4.8mL) are added in 0 ℃ of solution of 2-chloro-5-iodo-benzoic acid (5g) in methylene dichloride (20mL) that is stirring.Make reaction mixture be warming up to room temperature, under nitrogen, stir 2h, then it is evaporated to dried.Resistates is dissolved in the tetrahydrofuran (THF) (20mL), and is cooled to 0 ℃.Last 10 minutes, add potassium tert.-butoxide (22mL, 1M tetrahydrofuran solution).Make reaction mixture be warming up to room temperature and under nitrogen, stirred 2 hours, pour into then (50mL) in the sodium hydrogen carbonate solution.Separate each layer, and with ether (50mL) extraction water solution.The dry organic layer that merges filters and evaporation, obtains subtitle compounds, is oily matter (5.7g).
1H NMR(400MHz，d
6-DMSO)δ7.99(1H，d)，7.87(1H，dd)，7.34(1H，d)，1.54(9H，s).
B) 2-chloro-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-phenylformic acid 1,1-dimethyl ethyl ester
With 2-chloro-5-iodo-phenylformic acid 1,1-dimethyl ethyl ester (embodiment 3 (a)) (5g), two (tetramethyl ethylene ketone closes) diboron hexahydride (6g), [1,1 '-two ((diphenylphosphino) ferrocene] palladium chloride (II) methylene dichloride (600mg) and Potassium ethanoate (6.5g) be at N, mixture in the dinethylformamide (50mL) is in nitrogen atmosphere and 90 ℃ of heating 90 minutes.Make this mixture cooling, use 2: 1 ethyl acetate then: ether (250mL) dilution, and filter and pass through diatomite.Water (250mL) and salt solution (100mL) wash filtrate, evaporation then.Chromatogram purification (SiO
2, 1: 1 ether: isohexane is as eluent), obtain subtitle compounds, be solid (5.5g).
MS：APCI(+ve)282(M-C
4H
8+H
+).
1H NMR(300MHz，d
6-DMSO)δ7.88(1H，d)，7.76(1H，dd)，7.56(1H，d)，1.55(9H，s)，1.32(12H，s).
C) 4 '-chloro-[1,1 '-xenyl]-2,3 '-dicarboxylic acid 3 '-(1, the 1-dimethyl ethyl) ester 2-methyl esters
With 2-chloro-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-phenylformic acid 1,1-dimethyl ethyl ester (embodiment 3 (b)) (3.5g), 2-bromo-benzoic acid methyl ester (2.23g), salt of wormwood (2.87g), two ((triphenylphosphine) palladium chloride (II) (365mg), the mixture of tetrahydrofuran (THF) (20mL) and water (20mL), under nitrogen atmosphere and room temperature, stirred 16 hours.Solvent removed in vacuo, resistates chromatogram purification (SiO
2, 98: 2 isohexanes: ethyl acetate is as eluent), obtain subtitle compounds, be solid (2.15g).
1H NMR(300MHz，d
6-DMSO)δ7.82(1H，dd)，7.67(1H，td)，7.61-7.52(3H，m)，7.49-7.43(2H，m)，3.64(3H，s)，1.55(9H，s).
D) 4 '-chloro-[1,1 '-xenyl]-2,3 '-dicarboxylic acid 2-methyl esters
With trifluoroacetic acid (3.3mL) be added to stirring 4 '-chloro-[1,1 '-xenyl]-2,3 '-dicarboxylic acid 3 '-(1, the 1-dimethyl ethyl) ester 2-methyl esters (embodiment 3 (c)) methylene dichloride (10mL) solution (2.15g) in, and under nitrogen and room temperature, stirred this mixture 90 minutes.Then mixture is evaporated, obtain subtitle compounds, be solid (1.7g).
1H NMR(400MHz，d
6-DMSO)δ7.82(1H，dd)，7.69-7.64(2H，m)，7.59(1H，d)，7.55(1H，td)，7.49-7.44(2H，m)，3.63(3H，s).
E) 4 '-chloro-3 '-[[(cyclohexyl methyl) amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylate methyl ester
With N, dinethylformamide (1) and oxalyl chloride (0.16mL) be added to stirring 4 '-chloro-[1,1 '-xenyl]-2,3 '-dicarboxylic acid 2-methyl esters (embodiment 3 (d)) is (170mg) in 0 ℃ of solution of methylene dichloride (2mL).Make reaction mixture be warming up to room temperature, under nitrogen, stirred 2 hours, then it is evaporated to dried.Resistates is dissolved in the methylene dichloride (2mL), and is cooled to 0 ℃.Add cyclohexyl methyl amine (80mg), then add triethylamine (0.16mL).Make reaction mixture be warming up to room temperature and under nitrogen, stirred 2 hours, pour into then (20mL) in the sodium hydrogen carbonate solution.With methylene dichloride (3 * 20mL) extraction water solution.The dry organic layer that merges filters and evaporation.Purifying (SiO
2, 1: 3 ethyl acetate: isohexane), obtain subtitle compounds, be solid (190mg).
1H NMR(400MHz，d
6-DMSO)δ8.45(1H，t)，7.79(1H，dd)，7.66(1H，td)，7.56-7.50(2H，m)，7.47(1H，dd)，7.34(1H，dd)，7.29(1H，d)，3.63(3H，s)，3.08(2H，t)，1.79-1.45(6H，m)，1.29-1.07(3H，m)，1.02-0.87(2H，m).
F) 4 '-chloro-3 '-[[(cyclohexyl methyl) amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid
Water (1mL) solution of potassium hydroxide (100mg) is added to 4 '-chloro-3 '-[[(cyclohexyl methyl) amino] carbonyl]-[1,1 '-xenyl]-2-carboxylate methyl ester (embodiment 3 (e)) is (190mg) in the solution in methyl alcohol (1mL) and tetrahydrofuran (THF) (1mL).In stirring at room mixture 2 hours, concentrate then.Resistates is dissolved in the water (5mL), it is acidified to pH2 with 2M hydrochloric acid.Filter the solid of collecting gained, and water (10mL) washing, obtain title compound, be solid (150mg).
MS：APCI(-ve)370(M-H
+).
m.p.212-214℃.
1H NMR(400MHz，d
6-DMSO)δ12.92(1H，s)，8.45(1H，t)，7.79(1H，dd)，7.61(1H，td)，7.53-7.47(2H，m)，7.41(1H，dd)，7.37(1H，dd)，7.33(1H，d)，3.07(2H，t)，1.79-1.45(6H，m)，1.26-1.07(3H，m)，0.99-0.86(2H，m).
Embodiment 4-9
Use 4 '-chloro-[1,1 '-xenyl]-2,3 '-two-carboxylic acid 2-methyl esters (embodiment 3 (d)) and suitable amine, prepare following examples according to the general method of embodiment 3 (e)/(f).
Embodiment 10
3-[4-chloro-3-[[(suberyl methyl) amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid
A) 3-iodo-2-Pyridinecarboxylic Acid methyl esters
Last 10 minutes, butyllithium (32mL, 2.5M hexane solution) is dropped to 2,2,6 in nitrogen atmosphere, 6-tetramethyl piperidine (10.2mL) is in-78 ℃ of solution of tetrahydrofuran (THF) (100mL).Stirred this mixture 15 minutes at-78 ℃, last 10 minutes then and dropwise add pyridine carboxylic acid (2.4g).At-78 ℃ again after 10 minutes, make mixture be warming up to 0 ℃, and under nitrogen, stirred 30 minutes.Last 15 minutes then, reaction mixture is dropped in 0 ℃ of solution of iodine (15g) in tetrahydrofuran (THF) (100mL).Make it be warming up to room temperature then, and stirred 1 hour, add entry (20mL) then.Mixture is evaporated to dried, obtains the dark oil thing.Add methylene dichloride (50mL), and mixture is cooled to 0 ℃.Add N, dinethylformamide (1) and oxalyl chloride (4mL).Make reaction mixture be warming up to room temperature, and under nitrogen, stirred 2 hours, then it is evaporated to dried.Resistates is dissolved in the methylene dichloride (20mL), adds methyl alcohol (20mL) then.Stirred this mixture then 10 minutes, it is evaporated, obtain subtitle compounds, be oily matter (1.0g) that this oily matter is directly used in next step, and purifying not.
MS：APCI(+ve)264(M+H
+).
B) 3-[4-chloro-3-[(1,1-dimethyl oxyethyl group) carbonyl] phenyl]-the 2-Pyridinecarboxylic Acid methyl esters
With 2-chloro-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-phenylformic acid 1,1-dimethyl ethyl ester (embodiment 3 (b)) (500mg), 3-iodo-2-Pyridinecarboxylic Acid methyl esters (embodiment 10 (a)) (400mg) and tetrahydrofuran (THF) (2mL) place 10mL microwave bottle.Water (1mL) solution that adds salt of wormwood (400mg), then add two ((triphenylphosphine) palladium chloride (II) (50mg), and with this mixture in microwave in 130 ℃ of heating 3 hours.Resistates is distributed between methylene dichloride (20mL) and water (20mL).Separate each layer, and with methylene dichloride (2 * 20mL) extraction water solution.The dry organic layer that merges filters and evaporation.Chromatogram purification (SiO
2, 1: 4 ethyl acetate: isohexane is as eluent), obtain subtitle compounds, be solid (240mg).
MS：APCI(+ve)348/450(M+H
+).
1H NMR(400MHz，d
6-DMSO)δ8.68(1H，dd)，8.02(1H，dd)，7.71-7.63(3H，m)，7.54(1H，dd)，3.71(3H，s)，1.56(9H，s).
C) 3-(3-carboxyl-4-chloro-phenyl-)-2-Pyridinecarboxylic Acid 2-methyl esters
Method according to embodiment 3 (d), use 3-[4-chloro-3-[(1,1-dimethyl oxyethyl group) carbonyl] phenyl]-2-Pyridinecarboxylic Acid methyl esters (embodiment 10 (b)) (240mg), trifluoroacetic acid (1mL) and methylene dichloride (3mL) be prepared, obtain subtitle compounds, be oily matter (200mg).
MS：APCI(+ve)292/294(M+H
+).
1H NMR(300MHz，CDCl
3)δ8.97(1H，dd)，8.14(1H，dd)，8.00(1H，d)，7.91(1H，dd)，7.64(1H，d)，7.48(1H，dd)，3.88(3H，d).
D) amino 3-[4-chloro-3-[[(suberyl methyl)] carbonyl] phenyl]-the 2-Pyridinecarboxylic Acid methyl esters
Method according to embodiment 3 (e), use 3-(3-carboxyl-4-chloro-phenyl-)-2-Pyridinecarboxylic Acid 2-methyl esters (embodiment 10 (c)) (170mg), N, dinethylformamide (1), oxalyl chloride (1mL), (suberyl methyl) amine (90mg), triethylamine (0.2mL) and methylene dichloride (4mL) are prepared.Chromatogram purification (SiO
2, 2: 3 ethyl acetate: isohexane), obtain subtitle compounds, be solid (170mg).
MS：APCI(+ve)401/403(M+H
+).
1H NMR(400MHz，CDCl
3)δ8.72(1H，d)，7.75(1H，d)，7.67(1H，d)，7.51(1H，dd)，7.46(1H，d)，7.32(1H，dd)，6.32(1H，s)，3.85(3H，s)，3.34(2H，t)，1.86-1.40(11H，m)，1.35-1.20(2H，m).
E) amino 3-[4-chloro-3-[[(suberyl methyl)] carbonyl] phenyl]-2-Pyridinecarboxylic Acid
Method according to embodiment 3 (f), use 3-[4-chloro-3-[[(suberyl methyl) amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid methyl esters (embodiment 10 (d)) (175mg), potassium hydroxide (100mg), water (1mL), methyl alcohol (1mL) and tetrahydrofuran (THF) (1mL) be prepared, obtain title compound, be solid (150mg).
MS：APCI(-ve)385(M-H
+).
m.p.166-168℃.
1H NMR(400MHz，d
6-DMSO)δ13.45(1H，s)，8.64(1H，dd)，8.51(1H，t)，7.93(1H，dd)，7.63(1H，dd)，7.58(1H，d)，7.47(1H，dd)，7.44(1H，d)，3.07(2H，t)，1.80-1.33(11H，m)，1.25-1.13(2H，m).
Embodiment 11
3-[4-chloro-3-[[(2-cyclohexyl ethyl) amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid
A) amino 3-[4-chloro-3-[[(2-cyclohexyl ethyl)] carbonyl] phenyl]-the 2-Pyridinecarboxylic Acid methyl esters
Method according to embodiment 3 (e), use 3-(3-carboxyl-4-chloro-phenyl-)-2-Pyridinecarboxylic Acid 2-methyl esters (embodiment 10 (c)) (170mg), N, dinethylformamide (1), oxalyl chloride (1mL), (2-cyclohexyl ethyl) amine hydrochlorate (90mg), triethylamine (0.25mL) and methylene dichloride (4mL) are prepared.Chromatogram purification (SiO
2, 2: 3 ethyl acetate: isohexane), obtain subtitle compounds, be solid (170mg).
MS：APCI(+ve)401/403(M+H
+).
1H NMR(400MHz，CDCl
3)δ8.71(1H，dd)，7.74(1H，dd)，7.66(1H，d)，7.51(1H，dd)，7.45(1H，d)，7.32(1H，dd)，6.23(1H，s)，3.85(3H，s)，3.54-3.47(2H，m)，1.84-1.48(7H，m)，1.45-1.33(1H，m)，1.32-1.08(3H，m)，1.04-0.88(2H，m).
B) amino 3-[4-chloro-3-[[(2-cyclohexyl ethyl)] carbonyl] phenyl]-2-Pyridinecarboxylic Acid
Method according to embodiment 3 (f), use 3-[4-chloro-3-[[(2-cyclohexyl ethyl) amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid methyl esters (embodiment 11 (a)) (175mg), potassium hydroxide (100mg), water (1mL), methyl alcohol (1mL) and tetrahydrofuran (THF) (1mL) be prepared, obtain title compound, be solid (125mg).
MS：APCI(-ve)385(M-H
+).
m.p.104-107℃.
1H NMR(400MHz，d
6-DMSO)δ8.64(1H，dd)，8.44(1H，t)，7.93(1H，dd)，7.63(1H，dd)，7.58(1H，d)，7.47(1H，dd)，7.44(1H，d)，3.25(2H，q)，1.77-1.56(5H，m)，1.45-1.29(3H，m)，1.25-1.06(3H，m)，0.96-0.81(2H，m).
Embodiment 12
4 '-chloro-3 '-[[[(1R)-and 1-cyclohexyl ethyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid
A) 4 '-chloro-3 '-[[[(1R)-and 1-cyclohexyl ethyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylate methyl ester
Method according to embodiment 3 (e), use 4 '-chloro-[1,1 '-xenyl]-2,3 '-dicarboxylic acid 2-methyl esters (embodiment 3 (d)) (170mg), N, dinethylformamide (1), oxalyl chloride (0.16mL), (α R)-Alpha-Methyl hexanaphthene methylamine (90mg), triethylamine (0.16mL) and methylene dichloride (4mL) are prepared.Chromatogram purification (SiO
2, 1: 4 ethyl acetate: isohexane), obtain subtitle compounds, be colorless oil (190mg).
MS：APCI(+ve)400/402(M+H
+).
1H NMR(400MHz，CDCl
3)δ7.89(1H，dd)，7.61(1H，d)，7.55(1H，td)，7.44(1H，td)，7.41(1H，d)，7.35(1H，dd)，7.28(1H，dd)，6.05(1H，d)，4.18-4.04(1H，m)，3.72(3H，s)，1.91-1.63(5H，m)，1.50-1.38(1H，m)，1.30-1.00(8H，m).
B) 4 '-chloro-3 '-[[[(1R)-and 1-cyclohexyl ethyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid
Method according to embodiment 3 (f), use 4 '-chloro-3 '-[[[(1R)-and 1-cyclohexyl ethyl] amino] carbonyl]-[1,1 '-xenyl]-2-carboxylate methyl ester (embodiment 12 (a)) (190mg), potassium hydroxide (100mg), water (1mL), methyl alcohol (1mL) and tetrahydrofuran (THF) (1mL) be prepared, obtain title compound, be solid (160mg).
MS：APCI(+ve)386(M+H
+).
m.p.139-141℃.
1H NMR(300MHz，d
6-DMSO)δ12.92(1H，s)，8.27(1H，d)，7.79(1H，d)，7.61(1H，t)，7.54-7.46(2H，m)，7.43-7.33(2H，m)，7.29(1H，s)，3.88-3.71(1H，m)，1.87-1.52(5H，m)，1.45-1.29(1H，m)，1.28-0.88(8H，m).
Embodiment 13
4 '-chloro-3 '-[[[(1-methyl suberyl) methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid
A) 1-methyl-suberane formonitrile HCN
Under nitrogen atmosphere and-40 ℃, tetrahydrofuran (THF) (1mL) drips of solution of suberane formonitrile HCN (500mg) is added in the lithium diisopropylamine (lithium diisopropylamide) (2.8mL, 1.8M tetrahydrofuran solution).Make this mixture be warming up to-20 ℃ 10 minutes, again it is cooled to-40 ℃ then.Dropwise add methyl iodide (0.35mL), and make reaction mixture be warming up to room temperature and stirred 1 hour.Concentrated reaction mixture, and resistates distributed between ether (20mL) and 2M hydrochloric acid (20mL).Separate each layer, and dry organic layer, filter and evaporation, obtain subtitle compounds, yellow oil (600mg).
1H NMR(400MHz，CDCl
3)δ2.04-1.95(2H，m)，1.75-1.61(6H，m)，1.59-1.45(4H，m)，1.36(3H，s).
B) C-(1-methyl-suberane base) methylamine (1-Methyl-cycloheptanemethanamine)
Under nitrogen atmosphere and room temperature,, drop in the lithium aluminum hydride (12mL, 1M tetrahydrofuran solution) 1-methyl-suberane formonitrile HCN (embodiment 13 (a)) tetrahydrofuran (THF) (8mL) solution (550mg).With mixture heating up to 50 ℃ 3 hours, be cooled to 0 ℃ then, and, add entry (2mL) then and make its cancellation by adding entry (1mL) carefully, then adding 15% aqueous sodium hydroxide solution (1mL).This mixture is filtered by diatomite, it is distributed between water (50mL) and ether (50mL).Separate each layer, and dry organic layer, filter and evaporation, obtain subtitle compounds, yellow oil (500mg).
1H NMR(400MHz，CDCl
3)δ2.42(2H，s)，1.58-1.24(12H，m)，0.83(3H，s).
C) 4 '-chloro-3 '-[[[(1-methyl suberyl) methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylate methyl ester
Method according to embodiment 3 (e), use 4 '-chloro-[1,1 '-xenyl]-2,3 '-dicarboxylic acid 2-methyl esters (embodiment 3 (d)) (170mg), N, dinethylformamide (1), oxalyl chloride (0.16mL), C-(1-methyl-suberane base) methylamine (embodiment 13 (b)) are (165mg), triethylamine (0.17mL) and methylene dichloride (4mL) be prepared.Chromatogram purification (SiO
2, 1: 9 ethyl acetate: isohexane), obtain subtitle compounds, be solid (180mg).
MS：APCI(+ve)414/416(M+H
+).
1H NMR(300MHz，CDCl
3)δ7.90(1H，d)，7.65(1H，d)，7.55(1H，td)，7.44(1H，td)，7.42(1H，d)，7.35(1H，d)，7.28(1H，dd)，6.31(1H，s)，3.72(3H，s)，3.31(2H，d)，1.65-1.33(12H，m)，0.97(3H，s).
D) 4 '-chloro-3 '-[[[(1-methyl suberyl) methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid
Method according to embodiment 3 (f), use 4 '-chloro-3 '-[[[(1-methyl suberyl) methyl] amino] carbonyl]-[1,1 '-xenyl]-2-carboxylate methyl ester (embodiment 13 (c)) (180mg), potassium hydroxide (100mg), water (1mL), methyl alcohol (1mL) and tetrahydrofuran (THF) (1mL) be prepared.Concentrated reaction mixture is dissolved into resistates in the water (5mL), and with 2M hydrochloric acid this solution is acidified to pH 2.(3 * 10mL) extractions, the dry extraction liquid that merges filter and evaporation, and the solid with acetonitrile recrystallization gained obtains title compound, is solid (160mg) with methylene dichloride.
MS：APCI(+ve)400(M+H
+).
m.p.180-183℃.
1H NMR(300MHz，d
6-DMSO)δ12.93(1H，s)，8.40(1H，t)，7.78(1H，d)，7.61(1H，t)，7.56-7.46(2H，m)，7.44-7.30(3H，m)，3.08(2H，d)，1.59-1.18(12H，m)，0.88(3H，s).
Embodiment 14
4 '-chloro-3 '-[[[[1-(hydroxymethyl) suberyl] methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid
A) 1-cyano group-Cycloheptanoic acid's ethyl ester
Under nitrogen atmosphere, tetrahydrofuran (THF) (0.5mL) drips of solution of suberane formonitrile HCN (200mg) added in-40 ℃ the lithium diisopropylamine (1.1mL, 1.8M tetrahydrofuran solution).Make mixture be warming up to-20 ℃ 10 minutes, again it is cooled to-40 ℃ then.Dropwise add tetrahydrofuran (THF) (0.5mL) solution of Vinyl chloroformate (0.23mL), and make reaction mixture be warming up to room temperature and stir to spend the night.Concentrated reaction mixture, and resistates distributed between ether (20mL) and 2M hydrochloric acid (20mL).Separate each layer, and dry organic layer, purifying (SiO filtered and evaporation
2, 1: 49 ethyl acetate: isohexane), obtain subtitle compounds, be colorless oil (110mg).
1H NMR(400MHz，CDCl
3)δ4.25(2H，q)，2.21-2.12(2H，m)，2.09-2.00(2H，m)，1.83-1.65(6H，m)，1.63-1.53(2H，m)，1.32(3H，t).
B) 1-(amino methyl)-suberane methyl alcohol
Method according to embodiment 13 (b), use 1-cyano group-Cycloheptanoic acid's ethyl ester (embodiment 15 (a)) (110mg), lithium aluminum hydride (2.8mL, the 1M tetrahydrofuran solution) and tetrahydrofuran (THF) (0.5mL) be prepared, obtain subtitle compounds, be white solid (55mg).
1H NMR(400MHz，CDCl
3)δ3.51(2H，s)，2.76(2H，s)，1.60-1.37(10H，m)，1.35-1.24(2H，m).
C) 4 '-chloro-3 '-[[[[1-(hydroxymethyl) suberyl] methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylate methyl ester
Method according to embodiment 3 (e), use 4 '-chloro-[1,1 '-xenyl]-2,3 '-dicarboxylic acid 2-methyl esters (embodiment 3 (d)) (100mg), N, dinethylformamide (1), oxalyl chloride (0.16mL), 1-(amino methyl)-suberane methyl alcohol (embodiment 14 (b)) are (55mg), triethylamine (0.1mL) and methylene dichloride (2mL) be prepared.Chromatogram purification (SiO
2, 1: 4 ethyl acetate: isohexane), obtain subtitle compounds, be solid (80mg).
MS：APCI(+ve)430(M+H
+).
D) 4 '-chloro-3 '-[[[[1-(hydroxymethyl) suberyl] methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid
Method according to embodiment 3 (f), use 4 '-chloro-3 '-[[[[1-(hydroxymethyl) suberyl] methyl] amino] carbonyl]-[1,1 '-xenyl]-2-carboxylate methyl ester (embodiment 14 (c)) (80mg), potassium hydroxide (100mg), water (1mL), methyl alcohol (1mL) and tetrahydrofuran (THF) (1mL) be prepared.Concentrated reaction mixture is dissolved into resistates in the water (5mL), and with the 2M aqueous hydrochloric acid solution is acidified to pH 2.(3 * 10mL) extractions, the dry extraction liquid that merges filter and evaporation, and the solid with acetonitrile recrystallization gained obtains title compound, is solid (45mg) with methylene dichloride.
MS：APCI(-ve)414(M-H
+).
m.p.175-177℃.
1H NMR(300MHz，d
6-DMSO)δ8.41(1H，t)，7.79(1H，dd)，7.61(1H，td)，7.53(1H，d)，7.50(1H，td)，7.44-7.34(3H，m)，3.18-3.08(4H，m)，1.57-1.21(12H，m).
Embodiment 15
3-[4-chloro-3-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid
A) methyl 3-[4-chloro-3-[[[(1-hydroxyl suberyl)] amino] carbonyl] phenyl]-the 2-Pyridinecarboxylic Acid methyl esters is according to the method for embodiment 3 (e), use 3-(3-carboxyl-4-chloro-phenyl-)-2-Pyridinecarboxylic Acid 2-methyl esters (embodiment 10 (c)) (170mg), N, dinethylformamide (1), oxalyl chloride (1mL), 1-(amino methyl)-suberyl alcohol (embodiment 2 (b)) are (250mg), triethylamine (0.2mL) and methylene dichloride (4mL) be prepared.Chromatogram purification (SiO
2, 1: 30 methyl alcohol: methylene dichloride), obtain subtitle compounds, be solid (200mg).
MS：APCI(-ve)415/417(M-H
+).
1H NMR(400MHz，CDCl
3)δ8.72(1H，dd)，7.75(1H，dd)，7.67(1H，d)，7.51(1H，dd)，7.47(1H，d)，7.33(1H，dd)，6.78-6.68(1H，m)，3.84(3H，s)，3.49(2H，d)，1.78-1.42(12H，m).
B) methyl 3-[4-chloro-3-[[[(1-hydroxyl suberyl)] amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid
According to the method for embodiment 3 (f), use 3-[4-chloro-3-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid methyl esters (embodiment 15 (a)) (200mg), potassium hydroxide (100mg), water (1mL), methyl alcohol (1mL) and tetrahydrofuran (THF) (1mL) be prepared.(acetonitrile: moisture trifluoroacetic acid, Symmetry) purifying obtains title compound, is solid (45mg) by RP-HPLC.
MS：APCI(-ve)401(M-H
+).
m.p.95-100℃.
1H NMR(400MHz，d
6-DMSO)δ8.64(1H，dd)，8.26(1H，t)，7.95(1H，dd)，7.64(1H，dd)，7.58(1H，d)，7.51(1H，d)，7.47(1H，dd)，3.23(2H，d)，1.68-1.30(12H，m).
Embodiment 16
3 '-[[(suberyl methyl) amino] carbonyl]-4 '-methyl-[1,1 '-xenyl]-the 2-carboxylic acid
A) 5-bromo-N-(suberyl methyl)-2-methyl-benzamide
In the 5-bromo-2-methyl-phenylformic acid (US4282365) that is stirring methylene dichloride (20mL) solution (1g), add N, dinethylformamide (1) then adds oxalyl chloride (1.6mL).Reaction mixture was stirred 2 hours, and vacuum is removed volatile matter, and adds methylene dichloride (20mL), C-(suberane base) methylamine (649mg) and triethylamine (1.29mL).Reaction mixture was stirred 30 minutes, use 2M hydrochloric acid then its acidifying.Water phase separated with salt water washing organic phase once, through dried over mgso, is filtered and is removed and desolvate, and obtains subtitle compounds (1.48g).
MS：APCI(+ve)324(M+H
+).
1H NMR(300MHz，d
6-DMSO)δ8.43-8.33(1H，m)，7.50(1H，dd)，7.45-7.40(1H，m)，7.25-7.18(1H，m)，3.10-3.02(2H，m)，2.30-2.24(3H，m)，1.79-1.32(11H，m)，1.31-1.11(2H，m).
B) N-(suberyl methyl)-2-methyl-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-benzamide
Under nitrogen and 90 ℃, with 5-bromo-N-(suberyl methyl)-2-methyl-benzamide (embodiment 16 (a)) (1.48g), tetrakis triphenylphosphine palladium (15mg), Potassium ethanoate (2g), 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two-1,3,2-two oxa-boron heterocycle pentanes (1.85g) are at N, and the solution in the dinethylformamide (15mL) heated 3 hours.Add tetrakis triphenylphosphine palladium (130mg), Potassium ethanoate (200mg) and 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two-1,3,2-two oxa-boron heterocycle pentanes (200mg), and mixture continued to heat 15 hours at 90 ℃.Add ethyl acetate/treatment reaction thing, separate organic phase, and with twice of the further aqueous phase extracted of ethyl acetate.Organic fraction that water and salt solution wash merging respectively once through dried over mgso, is filtered and solvent removed in vacuo.Use the methylene dichloride wash-out, at SiO
2Enterprising circumstances in which people get things ready for a trip spectrum purifying obtains subtitle compounds (700mg).
MS：APCI(+ve)372(M+H
+).
C) 3 '-[[(suberyl methyl) amino] carbonyl]-4 '-methyl-[1,1 '-xenyl]-the 2-carboxylic acid
With N-(suberyl methyl)-2-methyl-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-benzamide (embodiment 16 (b)) (150mg), 2-bromo-methyl benzoate (130mg), tetrakis triphenylphosphine palladium (15mg), yellow soda ash (128mg), tetrahydrofuran (THF) (2mL) and water (1mL) in microwave in 120 ℃ of heating 40 minutes.48%w/v sodium hydroxide solution (0.3mL) and methyl alcohol (1mL) are added in the reaction mixture, and mixture was heated 30 minutes in 90 ℃ in microwave.Use the acetate acidizing product, and with RP-HPLC (0.2% trifluoroacetic acid/acetonitrile, Xterra post) purifying.Solvent removed in vacuo and the solid that obtains with the acetonitrile grinding filter and vacuum-drying, obtain title compound (32mg).
MS：APCI(+ve)366(M+H
+).
m.p.188-189℃.
1H NMR(400MHz，d
6-DMSO)δ12.81(1H，s)，8.28(1H，t)，7.72(1H，dd)，7.58(1H，td)，7.45(1H，td)，7.42(1H，dd)，7.28-7.25(3H，m)，3.06(2H，t)，2.36(3H，s)，1.76-1.33(11H，m)，1.25-1.12(2H，m).
Embodiment 17
1-[3-[3-[[(suberyl methyl) amino] carbonyl]-the 4-aminomethyl phenyl]-the 2-pyridyl]-the 4-piperidine carboxylic acid
A) 1-(3-bromo-2-pyridyl)-4-piperidine carboxylic acid methyl esters
With 2, the mixture of 3-two bromo-pyridines (3.0g) and 4-piperidine carboxylic acid methyl esters (5.4g) heated 30 minutes in 130 ℃ in microwave.The vacuum concentration product, and with chromatogram purification (SiO
2, methylene dichloride is as eluent), obtain subtitle compounds (2.4g), be colorless oil.
1H NMR(400MHz，d
6-DMSO)δ8.24(1H，dd)，7.95(1H，dd)，6.92(1H，dd)，3.63(3H，s)，3.62-3.59(2H，m)，2.88-2.79(2H，m)，2.60-2.52(1H，m)，1.97-1.89(2H，m)，1.78-1.66(2H，m).
B) amino 1-[3-[3-[[(suberyl methyl)] carbonyl]-the 4-aminomethyl phenyl]-the 2-pyridyl]-the 4-piperidine carboxylic acid
Method according to embodiment 16 (c), use N-(suberyl methyl)-2-methyl-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-benzamide (embodiment 16 (b)) (150mg) and 1-(3-bromo-2-pyridyl)-4-piperidine carboxylic acid methyl esters (133mg) be prepared, obtain title compound (114mg).
MS：APCI(-ve)448(M-H
+).
1H NMR(400MHz，d
6-DMSO)δ8.26(1H，t)，8.18(1H，dd)，7.72(1H，d)，7.58(1H，dd)，7.53(1H，d)，7.33(1H，d)，7.09(1H，dd)，3.46-3.39(2H，m)，3.07(2H，t)，2.79-2.70(2H，m)，2.37(3H，s)，2.36-2.29(1H，m)，1.77-1.33(15H，m)，1.25-1.13(2H，m).
Embodiment 18
3-chloro-6-[3-[[(suberyl methyl) amino] carbonyl]-the 4-aminomethyl phenyl]-2-Pyridinecarboxylic Acid
Method according to embodiment 16 (c), use N-(suberyl methyl)-2-methyl-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-benzamide (embodiment 16 (b)) is (150mg) and 3,6-two chloro-2-Pyridinecarboxylic Acid methyl esters (83mg) are prepared, and obtain title compound (22mg).
MS：APCI(-ve)399(M-H
+).
m.p.177-178℃.
1H NMR(400MHz，d
6-DMSO)δ13.90(1H，s)，8.38(1H，t)，8.13(2H，s)，8.03(1H，dd)，8.00(1H，d)，7.38(1H，d)，3.10(2H，t)，2.37(3H，s)，1.78-1.35(11H，m)，1.26-1.15(2H，m).
Embodiment 19
5-chloro-2-[4-chloro-3-[[(2-cyclohexyl ethyl) amino] carbonyl] phenyl]-the 3-pyridine carboxylic acid
A) 5-chloro-2-[4-chloro-3-[(1,1-dimethyl oxyethyl group) carbonyl] phenyl]-3-pyridine carboxylic acid methyl esters
Method according to embodiment 3 (c), use 2-chloro-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-phenylformic acid 1,1-dimethyl ethyl ester (embodiment 3 (b)) is (0.8g) with 2, and 5-two chloro-3-pyridine carboxylic acid methyl esters (0.49g) are prepared nitrogen and 65 ℃ of following stirrings 2 hours.Product is filtered by diatomite, with methyl alcohol (2 * 20mL) washings, and vacuum concentration.Resistates is distributed between methylene dichloride (50mL) and water (25mL).Separate each layer, and dry (MgSO
4) organic fraction, filter and vacuum concentration.Chromatogram purification (SiO
2, 98: 2 methylene dichloride: methyl alcohol is as eluent), obtain subtitle compounds, be colorless oil (0.59g).
1H NMR(400MHz，CDCl
3)δ8.73(1H，d)，8.13(1H，d)，7.90(1H，d)，7.55(1H，dd)，7.49(1H，d)，3.76(3H，s)，1.61(9H，s).
B) 2-(3-carboxyl-4-chloro-phenyl-)-5-chloro-3-pyridine carboxylic acid 3-methyl esters
According to the method for embodiment 3 (d), use 5-chloro-2-[4-chloro-3-[(1,1-dimethyl oxyethyl group) carbonyl] phenyl]-3-pyridine carboxylic acid methyl esters (embodiment 19 (a)) (0.59g) is prepared, and obtains subtitle compounds, be oily matter (0.50g).
MS：APCI(+ve)326/328(M+H
+).
C) amino 5-chloro-2-[4-chloro-3-[[(2-cyclohexyl ethyl)] carbonyl] phenyl]-3-pyridine carboxylic acid methyl esters
In 2-(3-carboxyl-4-chloro-phenyl-)-5-chloro-3-pyridine carboxylic acid 3-methyl esters (embodiment 19 (b)) methylene dichloride (5mL) solution (165mg), add triethylamine (0.40mL), then add 2-(1H-benzotriazole-1-yl)-1,1,3, the 3-tetramethyl-is melted a tetrafluoro borate (325mg) and C-(cyclohexyl) ethylamine hydrochloride (cyclohexaneethanamine hydrochloride) (159mg).Mixture stirring at room 24 hours, is added methylene dichloride (25mL) and 2M hydrochloric acid (10mL), and separates each layer.(10mL) washs organic fraction with saturated sodium bicarbonate aqueous solution, dry (MgSO
4), filter and vacuum concentration, use chromatogram purification (SiO then
2, methylene dichloride, 99: 1 methylene dichloride then: methyl alcohol is as eluent), obtain subtitle compounds, be membranoid substance (180mg).
MS：APCI(+ve)435/437(M+H
+).
D) amino 5-chloro-2-[4-chloro-3-[[(2-cyclohexyl ethyl)] carbonyl] phenyl]-the 3-pyridine carboxylic acid
To 5-chloro-2-[4-chloro-3-[[(2-cyclohexyl ethyl) amino] carbonyl] phenyl]-add water (1mL) solution of sodium hydroxide (49mg) in 3-pyridine carboxylic acid methyl esters (embodiment 19 (c)) methyl alcohol (3mL) solution (180mg).In this mixture of stirring at room 18 hours, vacuum concentration also added 2M hydrochloric acid (5mL).Filter the precipitation of gained, water (5mL) washing, and use the acetonitrile recrystallization, and obtain title compound, be solid (82mg).
MS：APCI(-ve)419/421(M-H
+).
m.p.208-211℃.
1H NMR(400MHz，d
6-DMSO)δ8.84(1H，d)，8.47(1H，t)，8.28(1H，d)，7.58-7.54(3H，m)，3.25(2H，dt)，1.75-0.82(13H，m).
Embodiment 20
5-chloro-2-[4-chloro-3-[[(suberyl methyl) amino] carbonyl] phenyl]-the 3-pyridine carboxylic acid
A) amino 5-chloro-2-[4-chloro-3-[[(suberyl methyl)] carbonyl] phenyl]-3-pyridine carboxylic acid methyl esters
Method according to embodiment 19 (c), use 2-(3-carboxyl-4-chloro-phenyl-)-5-chloro-3-pyridine carboxylic acid 3-methyl esters (embodiment 19 (b)) (165mg) and C-(suberane base) methylamine (cycloheptanemethanamine) (129mg) be prepared, obtain subtitle compounds, be membranoid substance (180mg).
MS：APCI(+ve)435/437(M+H
+).
B) amino 5-chloro-2-[4-chloro-3-[[(suberyl methyl)] carbonyl] phenyl]-the 3-pyridine carboxylic acid
According to the method for embodiment 19 (d), use 5-chloro-2-[4-chloro-3-[[(suberyl methyl) amino] carbonyl] phenyl]-3-pyridine carboxylic acid methyl esters (embodiment 20 (a)) (180mg) is prepared, and obtains title compound, be solid (63mg).
MS：APCI(-ve)419/421(M-H
+).
m.p.176-179℃.
1H NMR(400MHz，d6-DMSO)13.75(1H，s)，8.85(1H，d)，8.54(1H，t)，8.28(1H，d)，7.59-7.54(3H，m)，3.07(2H，t)，1.79-1.13(13H，m).
Embodiment 21
5-chloro-2-[4-chloro-3-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl] phenyl]-the 3-pyridine carboxylic acid
A) methyl 5-chloro-2-[4-chloro-3-[[[(1-hydroxyl suberyl)] amino] carbonyl] phenyl]-3-pyridine carboxylic acid methyl esters
Method according to embodiment 19 (c), use 2-(3-carboxyl-4-chloro-phenyl-)-5-chloro-3-pyridine carboxylic acid 3-methyl esters (embodiment 19 (b)) (165mg) and 1-(amino methyl)-suberyl alcohol (embodiment 2 (b)) (145mg) be prepared, obtain subtitle compounds, be membranoid substance (155mg).
MS：APCI(+ve)433/435(M-H
2O+H
+).
B) methyl 5-chloro-2-[4-chloro-3-[[[(1-hydroxyl suberyl)] amino] carbonyl] phenyl]-the 3-pyridine carboxylic acid
According to the method for embodiment 19 (d), use 5-chloro-2-[4-chloro-3-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl] phenyl]-3-pyridine carboxylic acid methyl esters (embodiment 21 (a)) (155mg) is prepared, and obtains title compound, be solid (10mg).
MS：APCI(+ve)437/439(M+H
+).
m.p.201-204℃.
1H NMR(400MHz，d
6-DMSO)δ8.50(1H，s)，8.19-8.12(1H，m)，7.88-7.80(2H，m)，7.70(1H，s)，7.46(1H，d)，4.34(1H，s)，3.23(2H，d)，1.67-1.22(12H，m).
Embodiment 22
3-chloro-6-[4-chloro-3-[[(2-cyclohexyl ethyl) amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid
A) 3-chloro-6-[4-chloro-3-[(1,1-dimethyl oxyethyl group) carbonyl] phenyl]-the 2-Pyridinecarboxylic Acid methyl esters
Method according to embodiment 3 (c), use 2-chloro-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-phenylformic acid, 1,1-dimethyl ethyl ester (embodiment 3 (b)) is (0.8g) with 3,6-two chloro-2-Pyridinecarboxylic Acid methyl esters (0.49g) nitrogen and 65 ℃ of following stirrings 2 hours, are prepared.Product is filtered by diatomite, with methyl alcohol (2 * 20mL) washings, and vacuum concentration.Resistates is distributed between methylene dichloride (50mL) and water (25mL).Separate each layer, and dry (MgSO
4) organic fraction, filter and vacuum concentration.Chromatogram purification (SiO
2, 80: 20 isohexanes: ethyl acetate is as eluent), obtain subtitle compounds, be colorless oil (0.82g).
1H NMR(400MHz，CDCl
3)δ8.31(1H，d)，8.06(1H，dd)，7.86(1H，d)，7.79(1H，d)，7.52(1H，d)，4.04(3H，s)，1.64(9H，s).
B) 6-(3-carboxyl-4-chloro-phenyl-)-3-chloro-2-Pyridinecarboxylic Acid 2-methyl esters
According to the method for embodiment 3 (d), use 3-chloro-6-[4-chloro-3-[(1,1-dimethyl oxyethyl group) carbonyl] phenyl]-2-Pyridinecarboxylic Acid methyl esters (embodiment 22 (a)) (0.82g) is prepared, and obtains subtitle compounds, be oily matter (0.69g).
MS：APCI(+ve)326/328(M+H
+).
C) amino 3-chloro-6-[4-chloro-3-[[(2-cyclohexyl ethyl)] carbonyl] phenyl]-the 2-Pyridinecarboxylic Acid methyl esters
With N, dinethylformamide (1) and oxalyl chloride (0.14mL) are added to 6-(3-carboxyl-4-chloro-phenyl-)-3-chloro-2-Pyridinecarboxylic Acid 2-methyl esters (embodiment 22 (b)) of stirring (172mg) in the suspension in methylene dichloride (5mL).Under nitrogen mixture was stirred 90 minutes, vacuum concentration adds methylene dichloride (5mL) then, then adds triethylamine (0.22mL) and C-(cyclohexyl) ethylamine hydrochloride (129mg).In stirring at room mixture 16 hours, add methylene dichloride (25mL) and 2M hydrochloric acid (10mL), and separate each layer.Wash organic fraction, drying (MgSO with saturated sodium bicarbonate aqueous solution (10mL)
4), filter and vacuum concentration.Chromatogram purification (SiO
2, 99: 1 methylene dichloride: methyl alcohol is as eluent), obtain subtitle compounds, be oily matter (160mg).
MS：APCI(+ve)435/437(M+H
+).
D) amino 3-chloro-6-[4-chloro-3-[[(2-cyclohexyl ethyl)] carbonyl] phenyl]-2-Pyridinecarboxylic Acid
According to the method for embodiment 19 (d), use 3-chloro-6-[4-chloro-3-[[(2-cyclohexyl ethyl) amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid methyl esters (embodiment 22 (c)) (160mg) is prepared, and obtains title compound, be solid (86mg).
MS：APCI(+ve)421/423(M+H
+).
m.p.189-190℃.
1H NMR(300MHz，d
6-DMSO)δ13.97(1H，s)，8.55-8.45(1H，m)，8.26-8.06(4H，m)，7.63(1H，d)，3.30-3.23(2H，m)，1.80-1.56(5H，m)，1.49-1.32(3H，m)，1.29-1.09(3H，m)，100-0.83(2H，m).
Embodiment 23
3-chloro-6-[4-chloro-3-[[(suberyl methyl) amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid
A) amino 3-chloro-6-[4-chloro-3-[[(suberyl methyl)] carbonyl] phenyl]-the 2-Pyridinecarboxylic Acid methyl esters
Method according to embodiment 22 (c), use 6-(3-carboxyl-4-chloro-phenyl-)-3-chloro-2-Pyridinecarboxylic Acid 2-methyl esters (embodiment 22 (b)) (172mg) and C-(suberane base) methylamine (100mg) be prepared, obtain subtitle compounds, be solid (220mg).
MS：APCI(+ve)435/437(M+H
+).
B) amino 3-chloro-6-[4-chloro-3-[[(suberyl methyl)] carbonyl] phenyl]-2-Pyridinecarboxylic Acid
According to the method for embodiment 19 (d), use 3-chloro-6-[4-chloro-3-[[(suberyl methyl) amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid methyl esters (embodiment 23 (a)) (220mg) is prepared.Grind to be further purified with methylene dichloride, obtain title compound, be solid (48mg).
MS：APCI(+ve)421/423(M+H
+).
m.p.189-190℃.
1H NMR(400MHz，d
6-DMSO)δ13.98(1H，s)，8.57(1H，t)，8.24-8.10(4H，m)，7.63(1H，d)，3.10(2H，t)，1.80-1.34(11H，m)，1.26-1.14(2H，m).
Embodiment 24
3-chloro-6-[4-chloro-3-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid
A) methyl 3-chloro-6-[4-chloro-3-[[[(1-hydroxyl suberyl)] amino] carbonyl] phenyl]-the 2-Pyridinecarboxylic Acid methyl esters
Method according to embodiment 22 (c), use 6-(3-carboxyl-4-chloro-phenyl-)-3-chloro-2-Pyridinecarboxylic Acid 2-methyl esters (embodiment 22 (b)) (172mg) and 1-(amino methyl)-suberyl alcohol (embodiment 2 (b)) (113mg) be prepared, obtain subtitle compounds, be oily matter (150mg).
MS：APCI(-ve)449(M-H
+).
B) methyl 3-chloro-6-[4-chloro-3-[[[(1-hydroxyl suberyl)] amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid
According to the method for embodiment 19 (d), use 3-chloro-6-[4-chloro-3-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid methyl esters (embodiment 24 (a)) (150mg) is prepared.Be further purified product by RP-HPLC, obtain title compound, be solid (46mg).
MS：APCI(-ve)435/437(M-H
+).
m.p.146-149℃.
1H NMR(400MHz，d
6-DMSO)8.35(1H，t)，8.23-8.12(4H，m)，7.63(1H，d)，3.26(2H，d)，1.70-1.32(12H，m).
Embodiment 25
1-[3-[4-chloro-3-[[(2-cyclohexyl ethyl) amino] carbonyl] phenyl]-the 2-pyridyl]-the 4-piperidine carboxylic acid
A) 1-[3-[4-chloro-3-[(1,1-dimethyl oxyethyl group) carbonyl] phenyl]-the 2-pyridyl]-4-piperidine carboxylic acid methyl esters
Method according to embodiment 3 (c), use 2-chloro-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-and phenylformic acid, 1,1-dimethyl ethyl ester (embodiment 3 (b)) is (0.8g) and 1-(3-bromo-2-pyridyl)-4-piperidine carboxylic acid methyl esters (embodiment 17 (a)) is (0.71g), nitrogen and 65 ℃ of following stirrings 2 hours, be prepared.Product is filtered by diatomite, with methyl alcohol (2 * 20mL) washings, and vacuum concentration.Resistates is distributed between methylene dichloride (50mL) and water (25mL).Separate each layer, and dry (MgSO
4) organic fraction, filter and vacuum concentration.Chromatogram purification (SiO
2, 80: 20 isohexanes: ethyl acetate is as eluent), obtain subtitle compounds, be colorless oil (0.82g).
1H NMR(400MHz，CDCl
3)δ8.24(1H，dd)，8.01(1H，d)，7.65(1H，dd)，7.47(1H，d)，7.46(1H，dd)，6.93(1H，dd)，3.67(3H，s)，3.52-3.44(2H，m)，2.72(2H，dd)，2.42-2.34(1H，m)，1.88-1.81(2H，m)，1.69-1.59(2H，m)，1.62(9H，s).
B) 1-[3-(3-carboxyl-4-chloro-phenyl-)-2-pyridyl]-4-piperidine carboxylic acid 4-methyl esters
Method according to embodiment 3 (d), use 1-[3-[4-chloro-3-[(1,1-dimethyl oxyethyl group) carbonyl] phenyl]-the 2-pyridyl]-4-piperidine carboxylic acid methyl esters (embodiment 25 (a)) (0.82g) is prepared, and obtains subtitle compounds, be oily matter (0.73g).
MS：APCI(+ve)375(M+H
+).
C) amino 1-[3-[4-chloro-3-[[(2-cyclohexyl ethyl)] carbonyl] phenyl]-the 2-pyridyl]-4-piperidine carboxylic acid methyl esters
Method according to embodiment 19 (c), use 1-[3-(3-carboxyl-4-chloro-phenyl-)-2-pyridyl]-4-piperidine carboxylic acid 4-methyl esters (embodiment 25 (b)) (180mg) and C-(cyclohexyl) ethylamine hydrochloride (117mg) be prepared, obtain subtitle compounds, be oily matter (230mg).
MS：APCI(+ve)485/487(M+H
+).
D) amino 3-chloro-6-[4-chloro-3-[[(2-cyclohexyl ethyl)] carbonyl] phenyl]-2-Pyridinecarboxylic Acid
According to the method for embodiment 19 (d), use 1-[3-[4-chloro-3-[[(2-cyclohexyl ethyl) amino] carbonyl] phenyl]-the 2-pyridyl]-4-piperidine carboxylic acid methyl esters (embodiment 25 (c)) (230mg) is prepared.By RP-HPLC purifying crude product, obtain title compound, be solid (53mg).
MS：APCI(-ve)468(M-H
+).
m.p.116-120℃
1H NMR(400MHz，d6-DMSO)δ8.38(1H，m)，8.20(1H，dd)，7.72(1H，dd)，7.61-7.57(2H，m)，7.55(1H，d)，7.01(1H，dd)，3.38(2H，d)，3.26(2H，td)，2.67(2H，t)，2.28(1H，t)，1.78-0.83(17H，m).
Embodiment 26
1-[3-[4-chloro-3-[[(suberyl methyl) amino] carbonyl] phenyl]-the 2-pyridyl]-the 4-piperidine carboxylic acid
A) amino 1-[3-[4-chloro-3-[[(suberyl methyl)] carbonyl] phenyl]-the 2-pyridyl]-4-piperidine carboxylic acid methyl esters
Method according to embodiment 19 (c), use 1-[3-(3-carboxyl-4-chloro-phenyl-)-2-pyridyl]-4-piperidine carboxylic acid 4-methyl esters (embodiment 25 (b)) (180mg) and C-(suberane base) methylamine (91mg) be prepared, obtain subtitle compounds, be oily matter (210mg).
MS：APCI(+ve)485/487(M+H
+).
B) amino 1-[3-[4-chloro-3-[[(suberyl methyl)] carbonyl] phenyl]-the 2-pyridyl]-the 4-piperidine carboxylic acid
According to the method for embodiment 19 (d), use 1-[3-[4-chloro-3-[[(suberyl methyl) amino] carbonyl] phenyl]-the 2-pyridyl]-4-piperidine carboxylic acid methyl esters (embodiment 26 (a)) (210mg) is prepared.By chromatogram (SiO
2, 96: 4 methylene dichloride: methyl alcohol is as eluent) and the purifying crude product, use Varian NH then
2Tube (it uses methyl alcohol (100mL), and 2% trifluoroacetic acid/methyl alcohol (100mL) is as eluent then) purifying obtains title compound, is solid (42mg).
MS：APCI(+ve)470(M+H
+).
m.p.164-167℃.
1H NMR(400MHz，d6-DMSO)δ8.45(1H，t)，8.21(1H，dd)，7.72-7.66(2H，m)，7.62(1H，d)，7.57(1H，d)，7.11-7.05(1H，m)，3.40(2H，d)，3.07(2H，t)，2.74(2H，t)，2.38-2.29(1H，m)，1.79-1.13(17H，m).
Embodiment 27
1-[3-[4-chloro-3-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl] phenyl]-the 2-pyridyl]-the 4-piperidine carboxylic acid
A) methyl 1-[3-[4-chloro-3-[[[(1-hydroxyl suberyl)] amino] carbonyl] phenyl]-the 2-pyridyl]-4-piperidine carboxylic acid methyl esters
Method according to embodiment 19 (c), use 1-[3-(3-carboxyl-4-chloro-phenyl-)-2-pyridyl]-4-piperidine carboxylic acid 4-methyl esters (embodiment 25 (b)) (180mg) and 1-(amino methyl)-suberyl alcohol (embodiment 2 (b)) (69mg) be prepared, obtain subtitle compounds, be oily matter (220mg).
MS：APCI(-ve)499/501(M-H
+).
B) methyl 1-[3-[4-chloro-3-[[[(1-hydroxyl suberyl)] amino] carbonyl] phenyl]-the 2-pyridyl]-the 4-piperidine carboxylic acid
According to the method for embodiment 19 (d), use 1-[3-[4-chloro-3-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl] phenyl]-the 2-pyridyl]-4-piperidine carboxylic acid methyl esters (embodiment 27 (a)) (220mg) is prepared.By chromatogram (SiO
2, 92: 8 methylene dichloride: methyl alcohol is as eluent) and the purifying crude product, use the RP-HPLC purifying then, obtain title compound, be solid (21mg).
MS：APCI(-ve)484(M-H
+).
m.p.117-119℃.
1H NMR(400MHz，d6-DMSO)δ8.24(1H，t)，8.21(1H，dd)，7.72(1H，dd)，7.67(1H，d)，7.61(1H，dd)，7.55(1H，d)，7.02(1H，dd)，4.26(1H，s)，3.43-3.35(2H，m)，3.23(2H，d)，2.67(2H，t)，2.35-2.25(1H，m)，1.77-1.22(16H，m).
Pharmacology analysis
Known some compound such as benzoyl benzoyl Triphosaden (bbATP) are P2X
7The agonist of acceptor, influence the plasma membrane mesopore formation (Drug Development Research (1996), 37 (3), p.126).Therefore, when this receptor utilized bbATP to activate in the presence of Eth Br (fluorescent DNA probe), the fluorescence of observing DNA bonded Eth Br in the cell strengthened.This fluorescence enhancing can be used as P2X
7Therefore measuring of receptor activation be used for the quantification compound to P2X
7The effect of acceptor.
According to this method, each title compound of experimental example is to P2X
7The antagonistic activity of acceptor.Thereby test is carried out on the flat-bottom microtiter plates of 96-hole, filling 250 μ l testing liquids in the hole, and this testing liquid comprises 200 μ l and contains 10
-4The THP-1 cell (2.5 * 10 of M Eth Br
6The suspension of cell/ml), 25 μ l contain 10
-5The high potassium buffered soln of M bbATP, and 25 μ l contain the high potassium buffered soln of the test compound of different concns (being generally 30 μ M to 0.001 μ M).Microtiter plate coated with plastics film, and was cultivated 1 hour at 37 ℃.Then microtiter plate is carried out reading in Perkin-Elmer fluorescent plate reader, excitation wavelength 520nm, emission wavelength 595nm, slit width: Ex15nm, Em 20nm.For relatively, use bbATP (P2X in the test respectively
7Receptor stimulant) and pyridoxal 5-phosphoric acid ester (P2X
7Receptor antagonist) in contrast.From the reading that is generated, calculate the pIC of each test compound
50Numerical value, this numerical value are the negative logarithms that reduces the concentration of bbATP agonist activity 50% needed test compound.Each compound of embodiment confirms to have antagonistic activity, its pIC
50Numerical value＞5.5.For example, following table shows the pIC of the compound of choosing typically
50Numerical value.
| The embodiment sequence number of compound | pIC 50 |
| 2 | 7.2 |
| 26 | 7.0 |
Claims (16)
1. formula (I) compound or its pharmacy acceptable salt,
Ar wherein
1The expression group
A represents C (O) NH or NHC (O);
R
1Expression 3-to 9-unit's carbocyclic ring or 4-to 10-unit heterocycle, at least one substituting group that described carbocyclic ring or heterocycle randomly independently are selected from the following radicals replaces: halogen, hydroxyl, cyano group, nitro, NR
6R
7, C
1-6Alkyl sulphonyl, C
1-6Alkoxyl group, and C
1-6Alkyl, described C
1-6At least one substituting group that alkyl randomly is independently selected from halogen and the hydroxyl replaces;
N is 0,1,2 or 3;
At each CR
2R
3Combination in, R
2And R
3Represent hydrogen, halogen, phenyl or C independently of one another
1-6Alkyl, perhaps R
2And R
3The carbon atom that the two all connects with them forms 3-to 8-unit cycloalkyl ring;
R
4And R
5One of expression halogen, nitro, NR
6R
7, hydroxyl, the C that randomly replaced by at least one halogen
1-6Alkoxyl group, or the C that is randomly replaced by at least one halogen
1-6Alkyl, and R
4And R
5In another expression hydrogen, halogen or the C that is randomly replaced by at least one halogen
1-6Alkyl;
Ar
2The expression phenyl, its at least one substituting group that independently is selected from the following radicals replaces: carboxyl, MC
1-6Alkyl CO
2H, C
1-6The amino carbonyl of alkyl sulfonyl, C (O) NHOH, NHR
8, R
9, XR
10And NR
17R
18, or Ar
2Expression comprises 1 to 2 the heteroatomic 5-or the 6-unit aromatic heterocycle that are independently selected from nitrogen, oxygen and sulphur, and at least one substituting group that described aromatic heterocycle independently is selected from the following radicals replaces: carboxyl, MC
1-6Alkyl CO
2H, C
1-6The amino carbonyl of alkyl sulfonyl, C (O) NHOH, NHR
8And NR
19R
20
Wherein phenyl or aromatic heterocycle Ar
2At least one substituting group that can further randomly independently be selected from the following radicals replaces: halogen, nitro, NR
6R
7, S (O)
0-2R
11, the C that randomly replaced by at least one halogen
1-6Alkoxyl group, and C
1-6Alkyl, described C
1-6Alkyl randomly independently is selected from halogen, hydroxyl, NR
6R
7, SO
2NR
6R
7, NR
11SO
2R
11, NHCOR
11And CONR
6R
7In at least one substituting group replace;
R
8Expression CN, C
1-6Alkoxy carbonyl, C
1-6Alkyl amino sulfonyl, or C
1-6Alkyl amino sulfonyl or two-C
1-6Alkyl amino sulfonyl;
R
9And R
10Represent tetrazyl, 1 independently of one another, 2,3-triazolyl, 1,2,4-triazolyl or comprise 1 to 4 heteroatomic 5-to 6-unit heterocycle that is independently selected from nitrogen, oxygen and sulphur, at least one substituting group that described heterocycle independently is selected from the following radicals replaces: hydroxyl ,=O and=S, and described heterocycle can further randomly independently be selected from least one substituting group replacement in the following radicals: halogen, nitro, amino, cyano group, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl and C
1-6Alkyl, described C
1-6At least one substituting group that alkyl randomly independently is selected from the following radicals replaces: halogen, hydroxyl and amino;
M represents key, oxygen, S (O)
0-2Or NR
11
X represents oxygen, S (O)
0-2, NR
11, C
1-6Alkylidene group, O (CH
2)
1-6, NR
11(CH
2)
1-6Or S (O)
0-2(CH
2)
1-6
R
6And R
7Represent hydrogen atom or C independently of one another
1-6Alkyl, described C
1-6Alkyl randomly is independently selected from hydroxyl, halogen and C
1-6At least one substituting group in the alkoxyl group replaces, perhaps R
6And R
7The nitrogen-atoms that connects with them forms 3-to 8-unit saturated heterocyclic;
R
11Expression hydrogen atom or C
1-6Alkyl, described C
1-6Alkyl randomly is independently selected from hydroxyl, halogen and C
1-6At least one substituting group in the alkoxyl group replaces;
R
17And R
18The nitrogen-atoms that connects with them forms 3-to 8-unit saturated heterocyclic, and at least one substituting group that described heterocycle independently is selected from the following radicals replaces: carboxyl, MC
1-6Alkyl CO
2H, C
1-6The amino carbonyl of alkyl sulfonyl, C (O) NHOH, NHR
8, R
9And XR
10, described 3-to 8-unit saturated heterocyclic can further randomly independently be selected from least one substituting group replacement in the following radicals: hydroxyl, halogen, the C that is randomly replaced by at least one halogen
1-6Alkoxyl group, and C
1-6Alkyl, described C
1-6At least one substituting group that alkyl randomly is independently selected from halogen and the hydroxyl replaces;
R
19And R
20The nitrogen-atoms that connects with them forms 3-to 8-unit saturated heterocyclic, and at least one substituting group that described heterocycle independently is selected from the following radicals replaces: carboxyl, MC
1-6Alkyl CO
2H, C
1-6The amino carbonyl of alkyl sulfonyl, C (O) NHOH and NHR
8, described 3-to 8-unit saturated heterocyclic can further randomly independently be selected from least one substituting group replacement in the following radicals: hydroxyl, halogen, the C that is randomly replaced by at least one halogen
1-6Alkoxyl group, and C
1-6Alkyl, described C
1-6At least one substituting group that alkyl randomly is independently selected from halogen and the hydroxyl replaces;
Condition is that formula (I) compound is not
(3-{4-chloro-3-[(1-hydroxyl-suberyl methyl)-formamyl]-phenyl }-5-methyl-pyrazol-1-yl)-acetate,
3-[4-methoxyl group-3-({ [4-(trifluoromethyl) benzyl] amino } carbonyl) phenyl] phenylformic acid, or
3-[4-methoxyl group-3-({ [2, the 4-dichloro benzyl] amino } carbonyl) phenyl] phenylformic acid.
2. the compound of claim 1, wherein A represents NHC (O).
3. claim 1 or 2 compound, wherein Ar
2Expression phenyl or pyridyl.
4. each compound, wherein Ar in the claim 1 to 3
2Being selected from following substituting group replaces: carboxyl, MC
1-6Alkyl CO
2H and C
1-6The amino carbonyl of alkyl sulfonyl.
5. each compound, wherein Ar in the claim 1 to 4
1The expression group
6. each compound, wherein R in the claim 1 to 5
4Expression halogen, nitro, NH
2, hydroxyl or the C that randomly replaced by one to three halogenic substituent
1-4Alkyl, and R
5The expression hydrogen atom.
7. the formula of claim 1 (I) compound or its pharmacy acceptable salt,
Ar wherein
1The expression group
A represents NHC (O);
R
1Expression phenyl or 3-to 9-unit aliphatic carbocycle, at least one substituting group that described phenyl or aliphatic carbocycle randomly independently are selected from the following radicals replaces: halogen, hydroxyl and C
1-4Alkyl, described C
1-4Alkyl is randomly replaced by hydroxyl;
N is 0,1 or 2;
At each CR
2R
3Combination in, R
2And R
3Represent hydrogen or C independently of one another
1-4Alkyl;
R
4And R
5One of expression halogen, nitro, NR
6R
7, hydroxyl or the C that randomly replaced by at least one halogen
1-6Alkyl, and R
4And R
5In another the expression hydrogen;
Ar
2The expression phenyl, its at least one substituting group that independently is selected from the following radicals replaces: carboxyl and NR
17RR
18,
Perhaps Ar
2The expression pyridyl, its at least one substituting group that independently is selected from the following radicals replaces: carboxyl and NR
19R
20,
R
6And R
7Represent hydrogen atom or C independently of one another
1-6Alkyl
R
17And R
18The nitrogen-atoms that connects with them forms 6-unit saturated heterocyclic, and described heterocycle independently is selected from carboxyl and C
1-6Alkyl CO
2At least one substituting group among the H replaces; And
R
19And R
20The nitrogen-atoms that connects with them forms 6-unit saturated heterocyclic, and described heterocycle independently is selected from carboxyl and C
1-6Alkyl CO
2At least one substituting group among the H replaces.
8. the compound of claim 1 or its pharmacy acceptable salt, described compound is selected from
4 '-chloro-3 '-[[[2-(2-chloro-phenyl-) ethyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[(cyclohexyl methyl) amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[[(2S)-and the 2-phenyl propyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[[[(1S, 2R, 5S)-6, and 6-dimethyl dicyclo [3.1.1] heptan-2-yl] methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[(suberyl methyl) amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[[(1-hydroxy-cyclohexyl) methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[[[cis-2-hydroxyl suberyl] methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[(2-cyclohexyl ethyl) amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
3-[4-chloro-3-[[(suberyl methyl) amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid,
3-[4-chloro-3-[[(2-cyclohexyl ethyl) amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid
4 '-chloro-3 '-[[[(1R)-and 1-cyclohexyl ethyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[[(1-methyl suberyl) methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
4 '-chloro-3 '-[[[[1-(hydroxymethyl) suberyl] methyl] amino] carbonyl]-[1,1 '-xenyl]-the 2-carboxylic acid,
3-[4-chloro-3-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid,
3 '-[[(suberyl methyl) amino] carbonyl]-4 '-methyl-[1,1 '-xenyl]-the 2-carboxylic acid,
1-[3-[3-[[(suberyl methyl) amino] carbonyl]-the 4-aminomethyl phenyl]-the 2-pyridyl]-the 4-piperidine carboxylic acid,
3-chloro-6-[3-[[(suberyl methyl) amino] carbonyl]-the 4-aminomethyl phenyl]-2-Pyridinecarboxylic Acid,
5-chloro-2-[4-chloro-3-[[(2-cyclohexyl ethyl) amino] carbonyl] phenyl]-the 3-pyridine carboxylic acid,
5-chloro-2-[4-chloro-3-[[(suberyl methyl) amino] carbonyl] phenyl]-the 3-pyridine carboxylic acid,
5-chloro-2-[4-chloro-3-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl] phenyl]-the 3-pyridine carboxylic acid,
3-chloro-6-[4-chloro-3-[[(2-cyclohexyl ethyl) amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid,
3-chloro-6-[4-chloro-3-[[(suberyl methyl) amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid,
3-chloro-6-[4-chloro-3-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl] phenyl]-2-Pyridinecarboxylic Acid,
1-[3-[4-chloro-3-[[(2-cyclohexyl ethyl) amino] carbonyl] phenyl]-the 2-pyridyl]-the 4-piperidine carboxylic acid,
1-[3-[4-chloro-3-[[(suberyl methyl) amino] carbonyl] phenyl]-the 2-pyridyl]-the 4-piperidine carboxylic acid and
1-[3-[4-chloro-3-[[[(1-hydroxyl suberyl) methyl] amino] carbonyl] phenyl]-the 2-pyridyl]-the 4-piperidine carboxylic acid.
The preparation as defined in claim 1 formula (I) compound or the method for its pharmacy acceptable salt, it comprises:
(a) compound of formula (VI), (VII), (VIII) or compound (IX) and formula (X) is reacted,
The replaceable group of one of Y and Z expression wherein, for example metal, organo-metallic or organosilicon radical,
And another expression leavings group among Y and the Z, for example halogen or sulfonyloxy, and Ar
2,
R
1, R
2, R
3, n, A, R
4And R
5Suc as formula defining in (I); Perhaps
(b) work as Ar
2During by carboxyl substituted, make the compound reaction of defined formula (VI), (VII), (VIII) or compound (IX) and formula (XI) in above-mentioned (a), then and alkali reaction,
Z-Ar
2a-CO
2R
12 (XI)
Wherein Z suc as formula in (X) define Ar
2aRepresent phenyl or comprise 1 to 2 heteroatomic 5-or 6-unit aromatic heterocycle that is independently selected from nitrogen, oxygen and sulphur, and R
12Be C
1-6Alkyl; Perhaps
(c) work as Ar
2During by carboxyl substituted, make the compound reaction of defined formula (VI), (VII), (VIII) or compound (IX) and formula (XII) in above-mentioned (a), then and alkali reaction,
Z-Ar
2b-CN (XII)
Wherein Z defines suc as formula (X) is middle, and Ar
2bRepresent phenyl or comprise 1 to 2 heteroatomic 5-or 6-unit aromatic heterocycle that is independently selected from nitrogen, oxygen and sulphur; Perhaps
(d) work as R
8Expression CN, C
1-6Alkoxy carbonyl, C
1-6Alkyl amino sulfonyl or C
1-6Alkyl amino sulfonyl or two-C
1-6During alkyl amino sulfonyl, make the compound reaction of defined formula (VI), (VII), (VIII) or compound (IX) and formula (XIII) in above-mentioned (a), then with the compound reaction of formula (XIV),
L
1-Ar
2c-Z (XIII)
L wherein
1The expression leavings group, for example halogen or sulfonyloxy, Ar
2cExpression phenyl or comprise 1 to 2 heteroatomic 5-that is independently selected from nitrogen, oxygen and sulphur or 6-unit aromatic heterocycle, and Z is suc as formula defining in (X),
Wherein W represents hydrogen or metal group, and R
8Suc as formula defining in (I); Perhaps
(e) work as Ar
2During by carboxyl substituted, make the compound of defined formula (XIII) reaction in defined formula (VI), (VII), (VIII) or the compound (IX) and above-mentioned (d) in above-mentioned (a), then and the reaction of suitable cyanide source, then and alkali reaction; Perhaps
(f) work as Ar
2During by carboxyl substituted, make the compound of defined formula (XIII) reaction in defined formula (VI), (VII), (VIII) or the compound (IX) and above-mentioned (d) in above-mentioned (a), then in appropriate catalyst, for example palladium catalyst exists down and carbon monoxide and alcohol reaction, follows and alkali reaction; Perhaps
(g) compound of formula (XV), (XVI), (XVII) or compound (XVIII) and formula (XIX) is reacted,
R wherein
13And R
14One of the expression NH
2, R
13And R
14Another the expression CO
2H, COBr or COCl, and R
1, R
2, R
3, n, R
4, R
5And Ar
2Suc as formula defining in (I); Perhaps
(h) compound of defined formula (XIX) among formula (XX), (XXI), (XXII) or compound (XXIII) and above-mentioned (g) is reacted, follow and alkali or acid-respons
Perhaps
Ar wherein
2dRepresent phenyl or comprise 1 to 2 heteroatomic 5-or 6-unit aromatic heterocycle that is independently selected from nitrogen, oxygen and sulphur, R
12Suc as formula in (XI) define R
4And R
5Define suc as formula (I) is middle, and R
13Suc as formula defining in (XV)-(XVIII); Perhaps
(i) work as R
19And R
20The nitrogen-atoms that connects with them forms 3-to 8-unit saturated heterocyclic, described heterocycle is during by carboxyl substituted, defined formula (VI), (VII), (VIII) or the compound (IX) in above-mentioned (a) (wherein Y represents for example organic boron group of replaceable group) and the compound of formula (XXXXV) are reacted, randomly follow and alkali or acid-respons
R wherein
21Expression C
1-6Alkyl, Ar
2eExpression comprises 1 to 2 the heteroatomic 5-or the 6-unit aromatic heterocycle that are independently selected from nitrogen, oxygen and sulphur, L
2The expression leavings group, for example halogen or sulfonyloxy, and R
19And R
20Suc as formula defining in (I); Perhaps
(i) work as R
19And R
20The nitrogen-atoms that connects with them forms 3-to 8-unit saturated heterocyclic, described heterocycle is during by carboxyl substituted, make compound and formula (XXXXVI), (XXXXVII), (XXXXVIII) or the reaction of compound (IL) of defined formula (XIX) in above-mentioned (g), then with alkali or acid-respons
Ar wherein
2fExpression comprises 1 to 2 the heteroatomic 5-or the 6-unit aromatic heterocycle that are independently selected from nitrogen, oxygen and sulphur, R
22Be C
1-6Alkyl, R
4, R
5, R
19And R
20Define suc as formula (I) is middle, and R
13Suc as formula defining in (XV)-(XVIII)
And randomly or (j) afterwards, carry out one or more following step at (a) and (b), (c), (d), (e), (f), (g), (h), (i):
This compound is changed into other compound of the present invention
Form this compound pharmacy acceptable salt.
10. pharmaceutical composition, it comprises as each defined formula (I) compound or its pharmacy acceptable salt in the claim 1 to 8, and is combined with acceptable accessories, diluent or carrier.
11. prepare the method for pharmaceutical composition as claimed in claim 10, it comprises and will mix with acceptable accessories, diluent or carrier as each defined formula (I) compound or its pharmacy acceptable salt in the claim 1 to 8.
12. each described formula (I) compound or its pharmacy acceptable salt in the claim 1 to 8, it is used for the treatment of.
13. each described formula (I) compound or its pharmacy acceptable salt purposes in the medicine of preparation treatment rheumatoid arthritis in the claim 1 to 8.
14. each described formula (I) compound or its pharmacy acceptable salt purposes in the medicine of preparation treatment osteoarthritis in the claim 1 to 8.
15. each described formula (I) compound or its pharmacy acceptable salt purposes in the medicine of preparation treatment asthma or chronic obstructive pulmonary disease in the claim 1 to 8.
16. each described formula (I) compound or its pharmacy acceptable salt purposes in the atherosclerotic medicine of preparation treatment in the claim 1 to 8.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE05002183 | 2005-01-27 | ||
| SE0500218 | 2005-01-27 | ||
| SE05007935 | 2005-04-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101151239A true CN101151239A (en) | 2008-03-26 |
Family
ID=39251229
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800100357A Pending CN101151239A (en) | 2005-01-27 | 2006-01-25 | Novel biaromatic compounds, inhibitors of the P2X7-receptor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101151239A (en) |
-
2006
- 2006-01-25 CN CNA2006800100357A patent/CN101151239A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2008528580A (en) | Novel bicyclic aromatic compounds that are inhibitors of P2X7 receptors | |
| CN101111488A (en) | Novel compounds | |
| CN101048369B (en) | Biphenyloxyacetic acid derivatives for the treatment of respiratory disease | |
| US7964616B2 (en) | Compounds 679 | |
| CN1938307B (en) | 9-substituted 8-oxoadenine compound | |
| CN101925584B (en) | Pyrimidine derivatives for treatment of asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, cancer, hepatitis B, hepatitis C, HIV, HPV, bacterial infections and dermatosis | |
| ES2314389T3 (en) | DERIVATIVES OF PHENOXYACETIC ACID TO TREAT RESPIRATORY DISORDERS. | |
| US20080153850A1 (en) | Adamantyl Derivates as P2x7 Receptor Antagonists | |
| ES2442523T3 (en) | New compounds 951: a biphenyloxypropanoic acid as a modulator of CRTh2 and intermediates | |
| CN101006057A (en) | Novel piperidine/8-azabicyclo [3.2.1] octan derivatives as moduilators of chemokine receptor CCR5 | |
| US9931324B2 (en) | Indolizine derivatives and their use in neurodegenerative diseases | |
| CN102625808B (en) | Spirocyclic amide derivatives | |
| CN101437795A (en) | Piperidine derivatives, their process for preparation, their use as therapeutic agents and pharmaceutical compositions containing them | |
| ES2342181T3 (en) | CHEMICAL COMPOUNDS I. | |
| US20080058309A1 (en) | Novel Compounds 171 | |
| CN101351448A (en) | Novel 1 -benzyl-4-piperidinamines that are useful in the treatment of COPD and asthma | |
| CN101151239A (en) | Novel biaromatic compounds, inhibitors of the P2X7-receptor | |
| JP2009529040A (en) | Piperidine derivatives, processes for their preparation, their use as therapeutic agents and pharmaceutical compositions containing them | |
| CN101490003A (en) | New alkyl esters of cyclic amino alcohols with muscarinic m3 receptor antagonist activity, useful for treating e.g. chronic bronchial obstruction, asthma and overactive bladder | |
| CN101535306B (en) | Quiniclidine derivatives of (hetero) arylcycloheptanecarboxylic acid as muscarinic receptor antagonists | |
| CN102245593A (en) | Isoquinolinone derivatives | |
| CN101437797A (en) | Piperidine derivatives, their process for preparation, their use as therapeutic agents and pharmaceutical compositions containing them | |
| CN101163673A (en) | New muscarinic receptor antagonists | |
| CN101356164A (en) | Novel compounds | |
| CN101268049A (en) | Novel piperidine derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20080326 |