CN105461693B - CRTH2 agonist compounds and application thereof - Google Patents

CRTH2 agonist compounds and application thereof Download PDF

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Publication number
CN105461693B
CN105461693B CN201510621564.1A CN201510621564A CN105461693B CN 105461693 B CN105461693 B CN 105461693B CN 201510621564 A CN201510621564 A CN 201510621564A CN 105461693 B CN105461693 B CN 105461693B
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compound
base
methyl
group
acid
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CN105461693A (en
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余天柱
刘兵
张英俊
张翔宇
张仕国
郑常春
张健存
雷健华
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Guangdong HEC Pharmaceutical
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Ruyuan Yongxing Technical Service Co Ltd
Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Abstract

Present invention relates particularly to the compound (structure shown in formula (I)) or its stereoisomer as CRTH2 receptor antagonist, geometric isomer, tautomers, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug.The invention further relates to the compounds of CRTH2 receptor antagonist to treat and prevent the purposes in asthma, allergic rhinitis and atopic dermatitis and other diseases mediated by the prostaglandin D2 (PGD2) to work on cell CRTH2 receptor.

Description

CRTH2 agonist compounds and application thereof
Invention field
Present invention relates particularly to the compounds as CRTH2 receptor antagonist, and its are treating and preventing allergic disease Such as asthma, allergic rhinitis and atopic dermatitis and other by the prostaglandin D2 that works on cell CRTH2 receptor (PGD2) mediate inflammatory disease in purposes, wherein the cell includes that eosinophils, basophil and Th2 lymph are thin Born of the same parents.
Background of invention
CRTH2 is the chemoattractant receptor of G-protein coupling, is expressed on Th2 cell, eosinophil.In allergy Property disease, as in asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis have observed that Th2- polarization.Th2 is thin Born of the same parents adjust anaphylactia such as IL-4, IL-5 and IL-3 by generating Th2 cell factor.In anaphylactia, these Th2 cell factor directly or indirectly induction of effector cell, as the migration of eosinophil and basophilic granulocyte, activation, Triggering and extended survival.
PGD2(prostaglandin D2), the aglucon of CRTH2 are by mast cell and other important in anaphylactia What effector cell generated.In people's cell, PGD2Pass through CRTH2 moving induction of Th2 cell, eosinophil and basophilla It moves and activates.Thus, the antagonism PGD on CRTH2 receptor2For treating Th2- dependence allergic disease such as asthma, allergic effect Property rhinitis and atopic dermatitis are a very attractive approach.It has been reported that CRTH2 receptor antagonist is other to treatment The relevant disease of eosinophil, if Churg-Strauss syndrome and nasosinusitis are also useful.
As CRTH2 inhibitor, it has been reported that Indoleacetic derivative (referring to WO2005/019171), phenoxy group Acetogenin (referring to WO2005/115382), pyrimidinyl acrylic acid derivatives (referring to WO2004/096777), two and ring are derivative Object (referring to CN103373996), isoquinilone derivatives (WO2010/074244) etc..
It is on CRTH2 receptor that the present invention, which provides a series of indole nitrogen indole derivatives replaced alkyl-carboxylic acid, PGD2Antagonist and can be used for treating by the PGD on CRTH2 receptor2The disease and situation of mediation.
Summary of the invention
It is on CRTH2 receptor that the present invention, which provides a series of indole nitrogen indole derivatives replaced alkyl-carboxylic acid, PGD2Antagonist and can be used for treating by the PGD on CRTH2 receptor2The disease and situation of mediation.The compounds of this invention tool The activity having had can be effectively used for treating the PGD by CRTH2 receptor2The disease and situation of mediation.
On the one hand, the present invention provides a kind of compound, is the structure as shown in formula (I) or the structure as shown in formula (I) Stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmacy Upper acceptable salt or its prodrug,
Wherein, A, E, h, w, L, L1、L2And L3With meaning as described in the present invention.
In some embodiments, A is arlydene, inferior heteroaryl, sub- heterocycle or cycloalkylidene；A is optionally by 1,2,3 or 4 It is a to be independently selected from R2Substituent group replaced；Wherein, R2With meaning as described in the present invention.
In some embodiments, compound of the present invention, wherein A C6-12Arlydene, C1-9Inferior heteroaryl, C2-10It is sub- Heterocycle or C3-12Cycloalkylidene；A is optionally independently selected from R by 1,2,3 or 42Substituent group replaced；Wherein R2With such as Meaning of the present invention.
In some embodiments, compound of the present invention, wherein A is following subformula:
Subformula representated by A is optionally independently selected from R by 1,2,3 or 42Substituent group replaced；
Wherein,When for singly-bound,For
When for double bond,For
Each X1, X2And X3It independently is-(CR3R3a)b,-O- ,-N (R4)-or-S (=O)t1-；
Each X4, X5, X6, X7, X and X8It independently is-C (R3)-or-N-；
Each b independently is 0,1,2,3 or 4；
Each q, m, f1, p and r independently are 0,1,2,3 or 4；
Each t1 independently is 0,1 or 2；
Wherein, R2、R4、R3aAnd R3With meaning as described in the present invention.
In some embodiments, compound of the present invention, wherein
A is
Wherein, subformula representated by A is optionally independently selected from R by 1,2,3 or 42Substituent group replaced；Its In, R2With meaning as described in the present invention.
In some embodiments, E is heterocycle, and naphthenic base condenses miscellaneous bicyclic group, the miscellaneous bicyclic group of bridge, the miscellaneous bicyclic group of spiral shell, aryl Or heteroaryl；E is optionally independently selected from R by 1,2,3 or 42cSubstituent group replaced；Wherein, R2cWith as described herein Meaning.
In some embodiments, compound of the present invention, wherein E C2-10Heterocycle, C5-12The miscellaneous bicyclic group of spiral shell, C5-12 Condense miscellaneous bicyclic group, C5-12The miscellaneous bicyclic group of bridge, C3-12Naphthenic base, C6-12Aryl or C1-12Heteroaryl；E is optionally by 1,2,3 or 4 It is a to be independently selected from R2cSubstituent group replaced；Wherein, R2cWith meaning as described in the present invention.
In some embodiments, wherein E is following subformula:
Wherein, Y, Y1, Y2, Y3, Y4, Y5And Y6It is each independently N or CH；
T1, T2, T3- O- ,-S- ,-NH- or-CH are each independently with T2-；
Each e and f independently are 0,1,2,3 or 4；
The subformula that the E is represented optionally is independently selected from R by 1,2,3 or 42cSubstituent group replaced；Wherein, R2cWith meaning as described in the present invention.
In some embodiments, compound of the present invention, wherein E is following subformula:
The subformula that the E is represented optionally is independently selected from R by 1,2,3 or 42cSubstituent group replaced；Wherein, R2cWith meaning as described in the present invention.
In some embodiments, L3For-O- ,-S- ,-S (=O)t,-C (OH) H- ,-N (R1)-or-C (=O)-；Wherein, R1With meaning as described in the present invention.
In some embodiments, each L independently is-O- ,-S (=O)t,-S- ,-N (R1)-,-CH2,-C (=O)-,-OC (=O)-,-C (=S)-,-C (=O)-N (R1)-,-C (=S)-N (R1)-or-(CH2)n- C (=O)-；Wherein, t, n and R1Tool There is meaning as described in the present invention.
In some embodiments ,-L3-(L)hIt is-O- ,-S- ,-S (=O)t,-C (OH) H- ,-NH- ,-NH-C (=O)-,-C (=O)-NH- ,-C (=O)-C (=O)-or-C (=O)-.
In some embodiments, L1For-O- ,-S (=O)t,-S- ,-N (R1a)-,-CH2,-C (=O)-,-OC (=O)-,-C (=S)-,-C (=O)-N (R1a)-,-C (=S)-N (R1a)-or-(CH2)n- C (=O)-；Wherein, t, n and R1aWith such as originally The invention meaning.
In some embodiments, each L2It independently is key ,-O- ,-S (=O)t,-S- ,-N (R1a)-,-CH2,-C (=O)-,- OC (=O)-,-C (=S)-,-C (=O)-N (R1a)-,-C (=S)-N (R1a)-or-(CH2)n- C (=O)-；Wherein, t, n and R1aWith meaning as described in the present invention.
In some embodiments ,-L1-(L2)wIt is-NH-C (=O)-,-C (=O)-,-S (=O)2,-NH-S (=O)2,-C (=O)-NH-CH2Or-C (=O)-NH-.
In some embodiments, h 0,1,2,3 or 4.
In some embodiments, w 0,1,2,3 or 4.
In some embodiments, each n independently is 0,1,2,3 or 4.
In some embodiments, each t independently is 0,1 or 2.
In some embodiments, each R1aIt independently is hydrogen, C1-4Alkyl, halogenated C1-4Alkyl, C1-4Alkyl acyl or hydroxyl.
In some embodiments, each R1It independently is hydrogen, C1-4Alkyl, halogenated C1-4Alkyl, C1-4Alkyl acyl or hydroxyl.
In some embodiments, each R2It independently is hydrogen, alkyl, halogenated alkyl, hydroxyl, nitro, cyano, halogen, carboxyl, alkane Oxygroup, alkylamino, alkylthio group, alkyl acyl, naphthenic base, heterocycle, aryl, heteroaryl, aminoalkyl, amino, hydroxy alkyl, Sulfonic group, amino-sulfonyl or aminoacyl.
In some embodiments, each R2It independently is hydrogen, C1-4Alkyl, C1-4Halogenated alkyl, hydroxyl, nitro, amino, cyano, Halogen, carboxyl, C1-4Alkoxy, C1-4Alkylamino, C1-4Alkylthio group, C1-4Alkyl acyl, C3-12Naphthenic base, C3-9Heterocycle, C6-12 Aryl, C1-9Heteroaryl, amino C1-4Alkyl, hydroxyl C1-4Alkyl, sulfonic group, amino-sulfonyl or aminoacyl.
In some embodiments, each R2It independently is hydrogen, methyl, ethyl, propyl, butyl, trifluoromethyl, hydroxyl, nitro, ammonia Base, cyano, fluorine, chlorine, bromine, carboxyl, methoxyl group, ethyoxyl, methylamino, ethylamino, dimethylamino, methylacyl, amino methyl, Hydroxymethyl, sulfonic group, amino-sulfonyl or aminoacyl.
In some embodiments, each R2cIt independently is hydrogen, alkyl, halogenated alkyl, hydroxyl, nitro, cyano, halogen, carboxyl, alkane Oxygroup, alkylamino, alkylthio group, alkyl acyl, naphthenic base, heterocycle, aryl, heteroaryl, aminoalkyl, amino, hydroxy alkyl, Sulfonic group, amino-sulfonyl or aminoacyl.
In some embodiments, each R2cIt independently is hydrogen, C1-4Alkyl, C1-4Halogenated alkyl, hydroxyl, nitro, amino, cyano, Halogen, carboxyl, C1-4Alkoxy, C1-4Alkylamino, C1-4Alkylthio group, C1-4Alkyl acyl, C3-12Naphthenic base, C3-9Heterocycle, C6-12 Aryl, C1-9Heteroaryl, amino C1-4Alkyl, hydroxyl C1-4Alkyl, sulfonic group, amino-sulfonyl or aminoacyl.
In some embodiments, each R2cIt independently is hydrogen, methyl, ethyl, propyl, butyl, trifluoromethyl, hydroxyl, nitro, ammonia Base, cyano, fluorine, chlorine, bromine, carboxyl, methoxyl group, ethyoxyl, methylamino, ethylamino, dimethylamino, methylacyl, amino methyl, Hydroxymethyl, sulfonic group, amino-sulfonyl or aminoacyl.
In some embodiments, compound of the present invention, for the structure as shown in formula (II) or as shown in formula (II) Structure stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, Ester, pharmaceutically acceptable salt or its prodrug,
Wherein,When for singly-bound,For
When for double bond,For
Each X1, X2And X3It independently is-(CR3R3a)b,-O- ,-N (R4)-or-S (=O)t-；
X4For-C (R3)-or-N-；
Each b independently is 0,1,2,3 or 4；
Wherein, E, h, w, L, L1、L2、L3、R3、R3a、R4There is meaning as described in the present invention with t.
In some embodiments, each R3aAnd R3It independently is hydrogen, C1-4Alkyl, C1-4Halogenated alkyl, hydroxyl, nitro, cyano, halogen Element, amino, carboxyl, C1-4Alkoxy, C1-4Alkylamino, C1-4Alkylthio group, C1-4Alkyl acyl, C3-12Naphthenic base, C3-9Heterocycle, C6-12Aryl, C1-9Heteroaryl, amino C1-4Alkyl, hydroxyl C1-4Alkyl, sulfonic group, amino-sulfonyl or aminoacyl.
In some embodiments, each R4It independently is hydrogen, C1-4Alkyl, C1-4Halogenated alkyl, hydroxyl, C3-12Naphthenic base, C3-9It is miscellaneous Ring group, C6-12Aryl, C1-9Heteroaryl, amino C1-4Alkyl or hydroxyl C1-4Alkyl.
In some embodiments, each R3aAnd R3It independently is hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary fourth Base, hydroxyl, nitro, cyano, fluorine, chlorine, bromine, carboxyl, methoxyl group, ethyoxyl, amino, trifluoromethyl, amino C1-4Alkyl, hydroxyl C1-4Alkyl, sulfonic group, amino-sulfonyl or aminoacyl.
In some embodiments, each R4It independently is hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl, three Methyl fluoride, hydroxyl, amino C1-4Alkyl or hydroxyl C1-4Alkyl.
In some embodiments, compound of the present invention, for the structure as shown in formula (III) or such as formula (III) institute The stereoisomer for the structure shown, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, Ester, pharmaceutically acceptable salt or its prodrug,
X5- CH- or-N- are each independently with X；
Wherein, p and f1 are each independently 0,1,2,3 or 4；
Wherein, L1, L2, w and E have meaning as described in the present invention.
In some embodiments, compound of the present invention, wherein the pharmaceutically acceptable salt is formula (I)- (III) salt that compound shown in and inorganic acid, organic acid, inorganic base, metal base or organic base are formed.
In some embodiments, compound of the present invention, wherein the pharmaceutically acceptable salt is hydrochloride, Hydrobromate, hydriodate, nitrate, sulfate, disulfate, phosphate, acetate, propionate, butyrate, lactate, Mesylate, tosilate, maleate, benzoate, succinate, tartrate, citrate, oxalates are rich Horse hydrochlorate, taurate, sodium salt, sylvite or ammonium salt.
On the one hand, the present invention provides a kind of pharmaceutical composition, and it includes any compounds as described in the present invention.
In some embodiments, pharmaceutical composition of the present invention further includes pharmaceutically acceptable carrier, figuration At least one of agent, diluent, adjuvant and medium.
In some embodiments, pharmaceutical composition of the present invention, further comprising it is one or more for treat by PGD on CRTH2 receptor2Other active agents of the disease mediated.
In other embodiment, pharmaceutical composition of the present invention, wherein other described active agents are TNF-α Inhibitor, COX-1/COX-2 inhibitor, cox 2 inhibitor, glucocorticoid, the inactivation antibody of interleukin, chemokine receptors Regulator, histamine H 1 receptor antagonist/antihistaminic, leukotriene D receptor antagonist, LTD4 antagonist, VLA-4 antagonist, skin Matter steroids analog, theophylline, inhibitors of leukotriene biosynthesis, epoxy enzyme-2 inhibitor, opium kind analgesics, anticoagulation Agent, beta blocker, beta-adrenergic agonist, angiotensin converting enzyme inhibitors, HMG-CoA reductase inhibitor, β 2 Agonist, corticosteroid, antihistaminic, leukotriene antagonist, ant-IgE antibody therapeutic agent, anti-infectious agent, antifungal are exempted from Epidemic disease inhibitor acts on other PGD of other receptors2Antagonist, the inhibitor of 4 type phosphodiesterases adjust cell factor and produce Raw drug adjusts the active drug of Th2 cell factor IL-4 and IL-5,5- lipoxidase inhibitor.
In other embodiment, pharmaceutical composition of the present invention, wherein the active agents are salmeterol, fluorine For Kathon CG, Loratadine, montelukast, omalizumab, Fusidic Acid, clotrimazole, tacrolimus, Elidel, DP antagonism Agent, cilomilast, TNF-α invertase (TACE) inhibitor, the blocking monoclonal antibody or soluble recepter of IL-4 or IL-5 And Zileuton.
On the one hand, the present invention provides a kind of use any compound of the present invention or any drug of the present invention Composition is used to prepare for protecting, handling, treat or mitigating patient by PGD on CRTH2 receptor2The medicine of the disease mediated The purposes of product.
In some embodiments, purposes of the present invention, wherein by PGD on CRTH2 receptor2The disease mediated is to roar Asthma, allergic asthma, perennial allergic rhinitis, pollinosis, atopic dermatitis, contact hypersensitivity, knot Film is scorching, eosinophil driven's bronchitis, food hypersenstivity, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crow Grace disease, mastocytosis, autoimmune disease, psoriasis, acne, multiple sclerosis, allograft row Reprimand, reperfusion injury, chronic obstructive pulmonary disease, rheumatoid arthritis, arthritic psoriasis or osteoarthritis.
In other embodiment, purposes of the present invention, wherein the autoimmune disease is psoriasis, it is more Hair property hardening illness, allograft rejection, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus and bone Arthritis.
Still further aspect, the present invention provide a kind of comprising any compound of the present invention and one or more hairs Combined pharmaceutical preparation of the bright any medicament as combination formulations, simultaneously, respectively or in succession for protecting, handling, treating Or mitigate by PGD on CRTH2 receptor2The purposes of the disease mediated.
Another aspect, the present invention provide it is a kind of protection, processing, treatment or mitigate patient by PGD on CRTH2 receptor2It is situated between The method of the disease and situation led, method include to give patient's any chemical combination as described in the present invention of the infectious disease Effective therapeutic dose of object or any pharmaceutical composition of the present invention.
Still further aspect, any compound or any pharmaceutical composition of the present invention are used for according to the present invention Protection, processing, treatment mitigate patient by PGD on CRTH2 receptor2The disease and situation mediated.
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This hair Bright intention covers all replacement, modification and equivalent technical solutions, they are included in the model of the present invention defined such as claim In enclosing.Those skilled in the art will appreciate that many can be used in practicing with similar or equivalent method and material described herein The present invention.The present invention is not limited to method described herein and material.At one of the document, patent and the similar material that are combined More it is different from the application or in the case where contradicting it is (term defined in including but not limited to, term application, described Technology, etc.), it is subject to the application.
It will further be appreciated that certain features of the invention, are clearly visible, the progress in multiple independent embodiments Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.
Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise stated, following definition should be obtained using used herein.For purposes of the present invention, chemical element with The periodic table of elements CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can join It examines " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, New York:2007, entire contents are incorporated herein by reference.
There is apparent conflict unless otherwise indicated or in context, the article " one " used herein, " one (kind) " " described " is intended to include "at least one" or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one Component be taken into account in the embodiment of the embodiment and use or use.
Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise Content.
Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley&Sons, Inc., New York, 1994.
Many organic compounds exist with optical active forms, i.e., they, which have, rotates the plane of linearly polarized light Ability.When describing optically active compound, indicate molecule about one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols for the rotation of linearly polarized light caused by appointed compound, Wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50:50 mixture of enantiomter Referred to as racemic mixture or racemic modification, when chemical reaction or in the process without stereoselectivity or stereospecificity when, It may occur in which such case.
Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess or at least 99% enantiomer mistake Amount.
According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Optically active (R)-or (S)-isomers can be used chiral synthon or chiral reagent preparation or torn open using routine techniques Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or trans configuration.
The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.
The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Object can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, can refer to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the recombination of some bonding electrons come The mutual inversion of phases carried out.The specific example of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyl are mutual The interconversion of tautomeric.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the interconversion of pure and mild pyridine -4 (1H) the -one tautomer of pyridine -4-.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.
" cis-trans-isomer " refers to that there is the factors that limitation carbon atom rotates freely in molecule, such as double bond (such as oximes, idol Nitrogen class, alkenes etc.) or ring (such as alicyclic ring)；With connect that there are two different atoms or atom on the atom that cannot rotate freely respectively Group.Cis-trans isomerism belongs to configurational isomer, and two mutually different isomers of generation are referred to as cis- (cis) and trans- (trans) isomers.The presence of alicyclic ring prevents the carbon atom for constituting ring from rotating freely, on ring at least 2 carbon atoms When being respectively connected with 2 different atoms or atomic group, just there may be cis-trans isomerisms.In cyclic compound, if two identical Substituent group is located at the ipsilateral of plane of a loop, then the compound is referred to as cis-；If two identical substituent groups are located at the heteropleural of plane of a loop, Then the compound is referred to as trans-.Although different cis-trans-isomers has identical functional group, there is different physical properties (as melted Point, boiling point and dipole moment etc.), chemical property and bioactivity.Unless otherwise noted, all along anti-existing for the compounds of this invention Isomeric forms are within the scope of the present invention.
As described in the invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound or the example special as embodiment the inside, subclass, and a kind of compound that the present invention is included above.It answers Understanding " optionally replacing " this term, this term can be used interchangeably with " substituted or non-substituted ".In general, term " substituted " the one or more hydrogen atoms indicated in given structure are replaced specific substituent group.Unless otherwise indicated, One optional substituent group can be replaced at various substitutable position of that group.When in given structural formula not only one It a position can be replaced one or more substituent groups selected from specific group, then substituent group can be identical or differently each A position replaces.It only includes the substitution for forming stable compound that the present invention considered, which replaces,.In some embodiments, certain suitable Optional substituent group 1 can further be replaced by corresponding suitable optional substituent group 2.In other embodiments, corresponding to close Suitable optional substituent group 2 is not further substituted.Wherein the substituent group can be, but be not limited to: hydrogen, alkyl are halogenated Alkyl, hydroxyl, nitro, cyano, halogen, carboxyl, alkoxy, alkylamino, alkylthio group, alkyl acyl, naphthenic base, heterocycle, virtue Base, heteroaryl, aminoalkyl, amino, hydroxy alkyl, sulfonic group, sulfoamido or aminoacyl.
It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-6Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each section of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then respectively represents it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.
Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1 to 20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention Replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-12 A carbon atom；In another embodiment, alkyl group contains 1-6 carbon atom；In another embodiment, alkyl group contains 1- 4 carbon atoms；Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group includes, but and unlimited In, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, 2- amyl, 3- amyl, 2- methyl-2- butyl, 3- methyl-2- butyl, 3- methyl-1-butyl, 2-methyl-1-butene base, n-hexyl, 2- hexyl, 3- hexyl, 2- methyl -2- amyl, 3- methyl -2- amyl, 4- methyl -2- amyl, 3- methyl -3- amyl, 2- methyl -3- amyl, 2,3- bis- Methyl -2- butyl, 3,3- dimethyl -2- butyl, n-heptyl, n-octyl, etc..
Terminology used in the present invention " halogen ", " halogen atom " or " halogen atom " include fluorine, chlorine, bromine, iodine.
Term " hetero atom " refers to O, S, N, P and Si, the form including any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N is (as in 3,4- dihydro-2 h-pyrrole base N), NH (as the NH in pyrrolidinyl) or NR (NR in pyrrolidinyl replaced as N-).
Term used in the present invention " alkoxy ", is related to alkyl, as defined in the present invention, is connected by oxygen atom It is connected in main carbochain.Some of embodiments are that alkoxy is the C of lower level1-3Alkoxy, some embodiments include, but It is not limited to, methoxyl group, ethyoxyl, propoxyl group etc..
Term " halogenated alkyl " or " halogenated alkoxy " indicate that alkyl or alkoxy can be by one or more identical or not With situation replaced halogen atom.Wherein alkyl and alkoxy base have meaning as described in the present invention, such example Include, but is not limited to trifluoromethyl, trifluoromethoxy etc..
Term " alkylthio group " includes C1-10The alkyl of linear chain or branched chain is connected on the sulphur atom of divalent, wherein alkyl group With meaning as described in the present invention.Some of embodiments are that alkylthio group is the C of lower level1-3Alkylthio group, such example It includes, but is not limited to, methyl mercapto (CH3S-), ethylmercapto group etc..
Term " alkyl acyl " includes C1-10The alkyl of linear chain or branched chain is connected on-C (=O)-, and wherein alkyl group has There is meaning as described in the present invention.Some of embodiments are that alkyl acyl is the C of lower level1-3Alkyl acyl, such reality Example includes, but is not limited to, acetyl group, propiono etc..
Term " aminoacyl " refers to-C (=O) NH2。
Term " amino-sulfonyl " refers to-S (=O)2NH2。
Term " amino " refers to formula-NH2。
Term " aminoalkyl " refers to formula R ' R " group of N- alkyl, wherein R ' and R " is separately hydrogen, alkane Base or halogenated alkyl.Alkyl has meaning as described in the present invention.Some of embodiments are that aminoalkyl is the ammonia of lower level Base C1-4Alkyl, some of embodiments are, but are not limited to, amino-ethyl, amino methyl, aminopropyl etc..
Term " alkylamino " or " alkyl amino " include " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino Group is separately replaced one or two alkyl group, and wherein alkyl group has meaning as described in the present invention. Some of embodiments are that alkyl amino is one or two C1-6Alkyl is connected to the alkyl amino of the lower level on nitrogen-atoms Group.Other embodiment is that alkyl amino is C1-3Lower level alkylamino group.Suitable alkylamino group It can be alkyl monosubstituted amino or dialkyl amido, such example includes, but is not limited to, N- methylamino, N- ethylamino, N, N- Dimethylamino, N, N- lignocaine etc..
Term " hydroxy alkyl " or " hydroxy alkoxy base " indicate that alkyl or alkoxy can be taken by one or more hydroxyls For the case where.Wherein alkyl and alkoxy base have meaning as described in the present invention, and some of embodiments are hydroxy alkyls It is the hydroxyl C of lower level1-4Alkyl, such example include, but is not limited to methylol, 1- ethoxy, hydroxypropyl, and 1,2- bis- Hydroxypropyl, hydroxyl methoxyl group, 1- hydroxy ethoxy etc..
Term " aryl " can be used alone or as " aralkyl ", a big portion of " aralkoxy " or " aryloxy alkyl " Point, it can be monocycle, bicyclic and tricyclic carbocyclic ring system, in certain embodiments of the present invention, can substitute arlydene makes With.Wherein, at least one ring system of aryl is aromatic, and wherein each ring system includes 3-7 atom.Term " aryl " It can be used interchangeably with term " aromatic rings ", if aromatic rings may include phenyl, naphthalene and anthracene.Depending on structure, aryl can be Monoradical or bivalent group (that is, arlydene).Hydrogen atom on one or more rings is individually optionally by one or more sheets It invents replaced described substituent group.
Term " heteroaryl ", " hetero-aromatic ring " are used interchangeably here, can be used alone or as " heteroaryl alkyl " Or a part of " heteroarylalkoxy " can substitute inferior heteroaryl use in certain embodiments of the present invention.All refer to list Ring, bicyclic, tricyclic or tetracyclic ring system, wherein Bicyclic heteroaromatic rings, tricyclic hetero-aromatic ring or Fourth Ring heteroaromatic ring systems are with condensed Form cyclization.Wherein, heteroaromatic ring systems are armaticity, and one or more atoms are individually optionally replaced hetero atom on ring (hetero atom is selected from N, O, P, S, optionally obtains replaced one or more oxygen atoms in this S or P as SO, SO2, PO, PO2's Group).Heteroaryl system can be connected in main structure to form stable compound on any hetero atom or carbon atom. Heteroaryl system group can be 3-7 former molecular monocycle or 7-10 former molecular bicyclic or 10-15 atom composition Tricyclic.It can be two rings [4,5] with 7-10 the bicyclic of atom, [5,5], [5,6] or [6,6] system, there are 10-15 The tricyclic of atom can be tricyclic [5,5,6], [5,6,6] or [6,5,6] system.Depending on structure, heteroaryl can be monovalent radical Group or bivalent group (that is, inferior heteroaryl).Hydrogen atom on one or more rings is individually optionally by one or more present invention Replaced described substituent group.
Other embodiment is that heteroaryl system (including heteroaryl, hetero-aromatic ring) includes following example, but is not limited to this A little examples: 2- furyl, 3- furyl, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyl, 4- are different Oxazolyl, 5- isoxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazolyl, 4- methylisoxazole -5- base, N- pyrrole radicals, 2- pyrrole Cough up base, 3- pyrrole radicals, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine radicals, 4- pyrimidine radicals, pyrimidine -5- base, pyridazinyl (such as 3- pyridazinyl) base, 2- thiazolyl, 4- thiazolyl, 5- thiazolyl, tetrazole radical (such as 5- tetrazole radical), triazolyl (such as 2- triazole Base and 5- triazolyl), 2- thienyl, 3- thienyl, pyrazolyl (such as 2- pyrazolyl), isothiazolyl, 1,2,3-oxadiazoles base, 1, 2,5- oxadiazoles bases, 1,2,4- oxadiazoles base, 1,2,3-triazoles base, 1,2,3- thio biphosphole base, 1,3,4- thio biphosphole base, 1, 2,5- thio biphosphole bases, 1,3,4- thiadiazoles -2- base, pyrazinyl, pyrazine -2- base, 1,3,5-triazines base, benzo [d] thiazole -2- Base, imidazo [1,5-a] pyridine -6- base, benzimidazolyl, benzoxazolyl, quinoxalinyl, 1,8- phthalazinyl, benzo Furyl, benzothienyl, benzothiazolyl, indoles (such as 2- indyl) base, purine radicals, quinolyl (such as 2- quinolyl, 3- quinoline Quinoline base, 4- quinoline), isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl), tetralyl, benzopyrazoles Base, acridinyl, benzimidazolyl, benzindole base, benzo isooxazine base, benzo thiopyranyl, benzoxazinyl-, benzo are disliked Oxazolyl, benzothiazolyl, B-carboline base, carbazyl, cinnoline base, dibenzofuran group, imidazopyridyl, imidazo Thiazolyl, indazolyl, indolizine base, indyl, different benzo thienyl, iso-dihydro-indole-group, isoquinolyl, isothiazole alkyl, Isothiazolyl, naphthyridines base, oxazolidinyl, oxazole and pyridyl group, oxazolyl, embedding two pyridyl of tea, phenanthridinyl, phenanthroline base, pheno Arsenic piperazine base, phenazinyl, phenothiazinyl, phenoxazine base, phthalazinyl, pteridyl, pyridopyridine base, quinazolyl, quinoxaline base, Thio-phenyl, triazine radical, 2H- pyrrolo- [3,4-c] pyridyl group, pyrazolo [2 ', 1 ': 2,3] oxazole simultaneously [4,5-c] pyridyl group, Imidazo [2', 1':2,3] thiazole simultaneously [4,5-b] pyrazinyl, imidazo [2', 1':2,3] thiazole simultaneously [5,4-b] pyridyl group, miaow Azoles simultaneously [2', 1':2,3] thiazole simultaneously [4,5-c] pyridyl group etc..
Term " carbocylic radical " or " annular aliphatic ", " carbocyclic ring ", " naphthenic base " refer to monovalence or multivalence, and non-aromatic is satisfied And/or part unsaturated ring, and do not include hetero atom, two of monocycle or 7-12 carbon atom including 3-12 carbon atom Ring or tricyclic.Bicyclic carbocyclic ring with 7-12 atom can be two rings [4,5], [5,5], and [5,6] or [6,6] system has simultaneously There is the bicyclic carbocyclic ring of 9 or 10 atoms to can be two rings [5,6] or [6,6] system.Depending on structure, " carbocylic radical " or " cyclic annular rouge That is, in certain embodiments of the present invention fat race ", " carbocyclic ring ", " naphthenic base " can substitute for monoradical or bivalent group Or as sub- carbocylic radical, cycloalkylidene is used.Suitable cyclic aliphatic group includes, but is not limited to, naphthenic base, cycloalkenyl And cycloalkynyl radical.The example of cyclic aliphatic group further comprises, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, 1- ring Amyl -1- alkenyl, 1- cyclopenta -2- alkenyl, 1- cyclopenta -3- alkenyl, cyclohexyl, 1- cyclohexyl -1- alkenyl, 1- cyclohexyl - 2- alkenyl, 1- cyclohexyl -3- alkenyl, cyclohexadienyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, ring ten Dialkyl group, adamantyl etc..Hydrogen atom on one or more rings is individually optionally by one or more described in the invention Substituent group replaced.
Term " cycloalkylidene " refers to the non-aromatic of divalent, saturation or part unsaturated ring, and does not include hetero atom, In include the monocycle of 3-12 carbon atom or two rings or tricyclic of 7-12 carbon atom.Bicyclic ring system can be [4,5], [5,5], [5,6] or [6,6] system.In some embodiments, cycloalkylidene is the unsaturated list of saturation monocycle or part of 4-7 carbon atom Ring, in other embodiment, cycloalkylidene is the saturation monocycle of 6 carbon atoms or the monocycle containing a degree of unsaturation.Sub- ring The example of alkyl includes, but are not limited to cyclopropylidene, sub- cyclobutyl, cyclopentylene, 1- cyclopentylene -1- alkenyl, the Asia 1- ring penta Base -2- alkenyl, 1- cyclopentylene -3- alkenyl, cyclohexylidene, 1- cyclohexylidene -1- alkenyl, 1- cyclohexylidene -2- alkenyl, 1- are sub- Cyclohexyl -3- alkenyl, cyclohexadienylene, cycloheptylidene, cyclooctylene, sub- cyclononyl, sub- cyclodecyl, sub- ring undecyl, Sub- cyclo-dodecyl, sub- adamantyl etc..Hydrogen atom on one or more rings is individually optionally by one or more present invention Replaced described substituent group.
Term " heterocycle ", " heterocycle ", " heteroalicyclic " or " heterocycle " are used interchangeably here, all refer to monocycle, Bicyclic, tricyclic or tetracyclic ring system, one or more atoms are substituted by hetero atom individually optionally in middle ring, and ring can be It is fully saturated or comprising one or more degrees of unsaturation, but definitely not aromatic.Depending on structure, " heterocycle " is " miscellaneous Ring ", " heteroalicyclic " can be monoradical or bivalent group, i.e., in certain embodiments of the present invention, can substitute or as Sub- heterocycle uses.Heterocyclic system can be connected in main structure to be formed on any hetero atom or carbon atom stable Compound.Hydrogen atom on one or more rings is taken by one or more substituent groups described in the invention individually optionally Generation.Some of embodiments are " heterocycles ", " heterocycle ", " sub- heterocycle " " heteroalicyclic " or " heterocycle " group is 3-7 member Ring monocycle (1-6 carbon atom and be selected from N, O, P, the 1-3 hetero atom of S；When the ring is a three-membered ring, wherein only having One hetero atom) or 7-10 former molecular bicyclic (4-9 carbon atom and selected from N, O, P, the 1-3 hetero atom of S).
" heterocycle " can be carbon-based or heteroatom group." heterocycle " equally also include heterocyclic group and saturation or part not Saturated rings or heterocycle and close be formed by group.The example of heterocycle includes, but is not limited to, 1,2,3,6- tetrahydro pyridyl, piperazine Piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, Tetrahydro thiapyran base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, glycidyl, azacycloheptyl, oxa- Suberyl, thiocycloheptyl, N- morpholinyl, 2- morpholinyl, morpholinyl, thio-morpholinyl, high piperazine base, oxygen azatropylidene base, Diazepine base, sulphur azatropylidene base, pyrrolin -1- base, 2- pyrrolinyl, 3- pyrrolinyl, indolinyl, 2H- pyranose, 4H- pyranose, dioxacyclohexyl, 1,3- dioxymyl, dithianyl, dithienyl group, dihydrothiophene, 1,2,3,4- tetra- Hydrogen isoquinoline base, hexahydro -2H- [1,4] dioxin [2,3-c] pyrrole radicals, 2,3,3a, 7a- tetrahydro -1H- isoindolyl, 1,2,3, 4- tetrahydric quinoline group, dioxolanyl, 3,7- diazabicyclo [3.3.0] octyl, 2,6- diazabicyclo [3.3.0] octane Base, 2,7- diazabicyclo [3.3.0] octyl, 2,8- diazabicyclo [4.3.0] nonyl, 3- oxygen -8- azabicyclo [4.3.0] nonyl, 2- oxygen -8- azabicyclo [4.3.0] nonyl, 2,8- phenodiazine -5- oxabicyclo [4.3.0] nonyl, 4,9- diazabicyclo [4.3.0] nonyl, 2,9- diazabicyclo [4.3.0] nonyl, 3,8- diazabicyclo [4.3.0] Nonyl, 3,7- diazabicyclo [4.3.0] nonyl, 3,9- diazabicyclo [4.3.0] nonyl, 3- oxygen -8- azepine are double Ring [4.3.0] nonyl, 3- sulphur -8- azabicyclo [4.3.0] nonyl, 5,6- dihydro -4H- pyrrolo- [3,4-c] isoxazole Base, [1,2,4] triazole [4,3-a] and piperidyl, isoxazole simultaneously [4,3-c] piperidyl, 4,5,6,7- tetrahydro isoxazole simultaneously [3, 4-c] pyridyl group, [1,2,4] triazole simultaneously [4,3-a] piperazinyl, 2- oxygen -7- azabicyclo [4.4.0] decyl, 1,5- bis- Oxygen -9- azabicyclo [4.4.0] decyl, 3- azabicyclo [4.4.0] decyl, 5- benzyl -2- oxygen -5,8- diazabicyclo [4.3.0] nonyl, 2,7- diaza decahydro naphthalene, 2- oxygen -8- azabicyclo [4.4.0] decyl, 2- oxygen -5- azabicyclo Thio -5- azabicyclo [2.2.1] the heptane base of [2.2.1] heptane base, 2-, 2- oxo -5- azabicyclo [2.2.1] heptane base, 2,5- diazabicylo [2.2.1] heptane base, 4- azaspiro [2.4] heptane base, 4- oxaspiro [2.4] heptane base, 5- azaspiro [2.4] heptane base, 2- azaspiro [4.5] decyl, 2- azepine spiroheptane base, 2- azaspiro [4.4] nonyl, 3- nitrogen Miscellaneous spiral shell [5.4] decyl, 2- oxygen -6- azepine spiroheptane base, 2,6- diaza spiroheptane base, 2- sulphur -6- azepine Spiral shell [3.3] heptane base 2- monoxide, 2- sulphur -6- azepine spiroheptane base 2,2- dioxide etc..
Term " sub- heterocycle " refers to monocycle, bicyclic, tricyclic or tetracyclic ring system, and one or more atoms are independent in middle ring Optionally replaced hetero atom, ring can be fully saturated or fragrant comprising one or more degrees of unsaturation, but definitely not The same clan.Sub- heterocycle be bivalent group, heterocyclic system can be connected on any hetero atom or carbon atom in main structure from And form stable compound.Hydrogen atom on one or more rings is individually optionally by one or more described in the invention Replaced substituent group.Some of embodiments are, " sub- heterocycle " group is that the monocycle of 3-7 member ring (1-6 carbon atom and is selected from The 1-3 hetero atom of N, O, P, S optionally obtain replaced one or more oxygen atoms in this S or P as SO, SO2, PO, PO2 Group；When the ring is a three-membered ring, only one of them hetero atom) or 7-10 former molecular bicyclic (4-9 carbon Atom and it is selected from N, O, P, the 1-3 hetero atom of S optionally obtain picture replaced one or more oxygen atoms in this S or P SO, SO2, PO, PO2Group).In some embodiments, sub- heterocycle is the unsaturated list of saturation monocycle or part of 4-7 atom Ring, in other embodiment, sub- heterocycle is the saturation monocycle of 6 atoms or the monocycle containing a degree of unsaturation.
" sub- heterocycle " can be carbon-based or heteroatom group." sub- heterocycle " equally also includes heterocyclic group and saturation or portion Point unsaturated ring or heterocycle simultaneously close and are formed by group.The example of sub- heterocycle includes, but is not limited to, and 1,2,3,6- tetrahydro is sub- Pyridyl group, piperidylidene, sub- piperazinyl, pyrrolidinylidene, sub- tetrahydrofuran base, furylidene, sub- tetrahydro-thienyl, Asia THP trtrahydropyranyl, sub- dihydro pyranyl, sub- tetrahydro thiapyran base, sub- azelidinyl, sub- oxetanylmethoxy, sub- thietanyl, Sub- homopiperidinyl, sub- glycidyl, sub- azacycloheptyl, sub- oxetane, sub- thiocycloheptyl, Asia N- morpholinyl, Asia 2- Morpholinyl, sub- morpholinyl, sub- thio-morpholinyl, sub- high piperazine base, Asia 4- Methoxy-piperidin -1- base, Asia oxygen azatropylidene base, Sub- diazepine base, sulfurous azatropylidene base, Asia pyrrolin -1- base, Asia 2- pyrrolinyl, Asia 3- pyrrolinyl, sub- indoline Base, Asia 2H- pyranose, Asia 4H- pyranose, sub- dioxacyclohexyl, Asia 1,3- dioxymyl, sub- dithianyl, sub- dithiode Alkyl, sub- dihydrothiophene, Asia 1,2,3,4- tetrahydro isoquinolyl, Asia 1,2,6- thiadiazine alkane 1,1- dioxy -2- base, Asia six Hydrogen -2H- [1,4] dioxin [2,3-c] pyrrole radicals, sub- dihydropyridine base, sub- pyrazoline base, sub- dihydro-pyrimidin base, sub- dihydro Pyrrole radicals, Asia 1,4- dithianyl, sub- morpholinyl, sub- decahydro indyl, Asia 2- oxygen -8- azabicyclo [4.3.0] nonyl, Asia 2,8- phenodiazine -5- oxabicyclo [4.3.0] nonyl, Asia 4,9- diazabicyclo [4.3.0] nonyl, Asia 2,9- diaza are double Ring [4.3.0] nonyl, Asia 3- oxo -2,4,8- three azabicyclo [4.3.0] nonyl, Asia 3- oxo -4- oxygen -2,8- phenodiazine Miscellaneous bicyclic [4.3.0] nonyl, Asia 3- oxo -2,8- diazabicyclo [4.3.0] nonyl, Asia 3,8- diazabicyclo [4.3.0] nonyl, Asia 3,7- diazabicyclo [4.3.0] nonyl, Asia 3,9- diazabicyclo [4.3.0] nonyl, Asia 3- oxygen -8- azabicyclo [4.3.0] nonyl, Asia 3- sulphur -8- azabicyclo [4.3.0] nonyl, Asia 5,6- dihydro -4H- pyrrole Cough up simultaneously [3,4-c] isoxazolyl, Asia [1,2,4] triazole [4,3-a] and piperidyl, sub- isoxazole simultaneously [4,3-c] piperidyl, Asia 4,5,6,7- tetrahydro isoxazole simultaneously [3,4-c] pyridyl group, Asia [1,2,4] triazole simultaneously [4,3-a] piperazinyl, Asia 2- oxo -3- Oxygen -8- azabicyclo [4.3.0] nonyl, Asia 2- oxygen -7- azabicyclo [4.4.0] decyl, Asia 1,5- dioxy -9- azepine are double Ring [4.4.0] decyl, Asia 3- azabicyclo [4.4.0] decyl, Asia 2,7- diaza decahydro naphthalene, Asia 2- oxygen -8- azepine Bicyclic [4.4.0] decyl, Asia 2- oxygen -5- azabicyclo [2.2.1] heptane base, Asia 5- azaspiro [2.4] heptane base, Asia 2- nitrogen Miscellaneous spiral shell [4.5] decyl, Asia 2- azepine spiroheptane base, Asia 2- azaspiro [4.4] nonyl, Asia 3- azaspiro [5.4] last of the ten Heavenly stems Alkyl, Asia 2- oxygen -6- azepine spiroheptane base, Asia 2,6- diaza spiroheptane base, Asia 2- sulphur -6- azaspiro [3.3] heptane base 2- monoxide, Asia 2- sulphur -6- azepine spiroheptane base 2,2- dioxide etc..
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " or " condensed ring radical " indicate saturated or unsaturated condensed ring body System, is related to the bicyclic system of non-aromatic, at least one ring is nonaromatic.Depending on structure, " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " or " condensed ring radical " can that is, in certain embodiments of the present invention can be with for unit price or bivalent group Substitution is used as sub- condensed-bicyclic base.Such system may include independent or conjugation undersaturated condition, but its core Core structure does not include aromatic rings or heteroaromatic (but aromatic series can be used as substituent group thereon).Each of condensed-bicyclic Ring is either carbocyclic ring or is heteroalicyclic, and such example includes, but is not limited to, hexahydro-furans [3,2-b] furyl, 2,3,3a, 4,7,7a- hexahydro -1H- indenyls, 7- azabicyclo [2.2.1] heptane base, condensed-bicyclic [3.3.0] octyl condense Bicyclic [3.1.0] hexyl, 1,2,3,4,4a, 5,8,8a- octahydro naphthalenes, these are included within the system of condensed-bicyclic. Hydrogen atom on one or more rings is individually optionally replaced one or more substituent groups described in the invention.
Term " condensing miscellaneous bicyclic group " indicates saturated or unsaturated fused ring system, is related to the bicyclic body of non-aromatic System, at least one ring is nonaromatic.Such system may include independent or conjugation undersaturated condition, but its core Core structure does not include aromatic rings or heteroaromatic (but aromatic series can be used as substituent group thereon).Depending on structure, " condense miscellaneous That is, in certain embodiments of the present invention bicyclic group " can be substituted or be condensed as Asia miscellaneous bicyclic for unit price or bivalent group Base uses.And at least one ring system includes one or more hetero atoms, wherein each ring system includes 3-7 atom composition Ring, i.e., comprising 1-6 carbon atom and selected from N, O, P, the 1-3 hetero atom of S, in this S or P optionally by one or more oxygen It is obtained replaced atom as SO, SO2, PO, PO2Group, in addition, carbon atom can also be by oxo formation-C (=O)-；It is such Example includes, but is not limited to, hexahydro -2H- [Isosorbide-5-Nitrae] dioxin [2,3-c] pyrrole radicals, 3- azabicyclo [3.3.0] octyl, 3- methyl -3,7- diazabicyclo [3.3.0] octyl, 8- azabicyclo [4.3.0] nonyl, 8- azabicyclo [4.3.0] Nonane 3- base, 3- azabicyclo [4.3.0] nonane -3- base, 1,5- dioxy -8- azabicyclo [4.3.0] nonyl, (1R, 6S) - 2,5- dioxy -8- azabicyclo [4.3.0] nonyls, (1R, 6R) -2,5- dioxy -8- azabicyclo [4.3.0] nonyl are different Indoline base, 1,2,3,4- tetrahydric quinoline group, (1S, 5S) -1- hydroxyl -3- azabicyclo [3.1.0] hexyl, (1R, 5S) -1- Hydroxyl -3- azabicyclo [3.1.0] hexyl, (1R, 5S) -1-N, N- dimethylamino -3- azabicyclo [3.1.0] hexane Base, (1S, 5R, 6R) -1- methyl -6- alcohol -3- azabicyclo [3.2.0] heptane base, 3- nitrogen -7- oxabicyclo [3.3.0] octane Base, 3,7- diazabicyclos [3.3.0] octyl, 2,6- diazabicyclos [3.3.0] octyl, 2,7- diazabicyclos [3.3.0] octyl, 2,8- diazabicyclos [4.3.0] nonyl, 3- oxygen -8- azabicyclo [4.3.0] nonyl, 2- oxygen - 8- azabicyclo [4.3.0] nonyl, 2,8- phenodiazine -5- oxabicyclo [4.3.0] nonyls, 2,7- diaza decahydro naphthalenes or 2- oxygen -8- azabicyclo [4.4.0] decyl etc..Hydrogen atom on one or more rings is individually optionally by one or more sheets It invents replaced described substituent group.
Term " bridge bicyclic group " indicates saturated or unsaturated bridged-ring system, is related to the bicyclic system of non-aromatic.This The system of sample may include independent or conjugation undersaturated condition, but its nuclear structure do not include aromatic rings or hetero-aromatic ring (but It is that aromatic series can be used as substituent group thereon).Wherein each ring system includes 3-7 atom, and such example includes, but It is not limited to, bicyclic [2.2.1] heptane base, miscellaneous two ring [2.2.1] the heptane base of 2- methyl-, etc..Hydrogen on one or more rings is former Son is individually optionally replaced one or more substituent groups described in the invention.
Term " the miscellaneous bicyclic group of bridge " indicates saturated or unsaturated bridged-ring system, is related to the bicyclic system of non-aromatic. Depending on structure, that is, in certain embodiments of the present invention " the miscellaneous bicyclic group of bridge " can be replaced for monoradical or bivalent group In generation, uses as the miscellaneous bicyclic group of sub- bridge.Such system may include independent or conjugation undersaturated condition, but its core Structure does not include aromatic rings or heteroaromatic (but aromatic series can be used as substituent group thereon).And at least one ring system includes One or more hetero atoms, wherein each ring system includes 3-7 atom, i.e., comprising 1-6 carbon atom and selected from N, O, P, S 1-3 hetero atom, optionally obtained replaced one or more oxygen atoms in this S or P as SO, SO2, PO, PO2Group, In addition, carbon atom can also be by oxo formation-C (=O)-；Such example includes, but is not limited to 2- oxygen -5- azabicyclo [2.2.1] heptane base, thio -5- azabicyclo [2.2.1] the heptane base of 2-, 2- oxo -5- azabicyclo [2.2.1] heptane base, 2,5- diazabicylos [2.2.1] heptane base, 2- methyl -2,5- diazabicylo [2.2.1] heptane base etc..One or more rings On hydrogen atom individually optionally replaced one or more substituent groups described in the invention.
Term " loop coil base ", " loop coil ", " spiral shell bicyclic group ", " spiral shell is bicyclic " indicate a ring originating from special on another ring Cyclic annular carbon.For example, the bridged-ring system (ring B and B') of a saturation is referred to as " condensed-bicyclic ", on the contrary as disclosed below A carbon atom is shared in the ring system that ring A ' and ring B is saturated at two, then is referred to as " loop coil ".Each ring inside loop coil It is carbocyclic ring or is heteroalicyclic.Such example includes, but is not limited to, 4- azaspiro [2.4] heptane -5- base, 4- Oxaspiro [2.4] heptane -5- base, 5- azaspiro [2.4] heptane -5- base, spiral shell [2.4] heptane base, spiral shell [4.4] nonyl, 7- hydroxyl Base -5- azaspiro [2.4] heptane -5- base etc..Hydrogen atom on one or more rings is individually optionally by this one or more hair Replaced bright described substituent group.
Term " the miscellaneous bicyclic group of spiral shell " indicates a ring originating from particularly ring-shaped carbon on another ring.For example, as institute above Description, the bridged-ring system (ring B and B') of a saturation is referred to as " condensed-bicyclic ", on the contrary what ring A ' and ring B was saturated at two A carbon atom is shared in ring system, then is referred to as " loop coil ".And at least one ring system includes one or more hetero atoms, In each ring system include 3-7 atom, i.e., comprising 1-6 carbon atom and selected from N, O, P, the 1-3 hetero atom of S, in this S Or P is optionally obtained replaced one or more oxygen atoms as SO, SO2, PO, PO2Group, such example includes, but simultaneously It is not limited to 4- azaspiro [2.4] heptane base, 4- oxaspiro [2.4] heptane base, 5- azaspiro [2.4] heptane base, 2- azaspiro [4.5] decyl, 2- azepine spiroheptane base, 2- azaspiro [4.4] nonyl, 3- azaspiro [5.4] decyl, 2- first Base -2- azepine spiroheptane base, 2- oxygen -6- azepine spiroheptane base, 2,6- diaza spiroheptane bases, 2- sulphur - 6- azepine spiroheptane base 2- monoxide, 2- sulphur -6- azepine spiroheptane base 2,2- dioxide etc..One or more Hydrogen atom on a ring is individually optionally replaced one or more substituent groups described in the invention.
As described in the present invention, substituent R is keyed to the ring system formed on the ring at center by one and represents substituent R It any on ring can may replace or any reasonable position is replaced.For example, formula a represents any possibility on A ' ring or B ring Substituted position can be replaced by R, as shown in formula b, formula c, formula d, formula e, formula f, formula g and formula h.
As described in the present invention, substituent group (R)nThe ring system formed on the ring at center, which is keyed to, by one represents n Substituent R can be replaced any substitutive position on ring.For example, formula i represents any possibility quilt on A ' ring or B ' ring Substituted position can be replaced by n R.
As described in the invention, can be connected with molecule rest part on ring C there are two tie point, for example, such as formula j institute Show, indicate either E " end be also possible to E ' end be connected with the rest part of molecule, i.e. the connection type at both ends can be interchanged.
As described in the present invention, attachment point can be connect any attachable position on ring with molecule rest part.Example Such as, formula k, which represents any possible connected position on A ' ring or B ' ring, can be used as the point of connection.
As described in the present invention, attachment point can be connect any attachable position on ring with molecule rest part, together When the both ends that connect can be interchanged.For example, formula m, which represents any possible connected position on ring, can be used as the point of connection, together When tie point both ends can be interchanged.Dotted line in formula indicates not essential.
As described in the present invention, the "-(L occurred in general formula formula (I)2)w" indicate, when w takes different values, there are different Several L2, and each L2It is independent to represent identical or different group.For example, when w is 3, then L2There are three identical or different bases Group, for example, L2Welcome representative-NH- ,-C (=O)-and-CH2-.At this time in embodiment ,-(L2)wIt is-C (=O)-NH- CH2,-CH2The combination of-C (=O)-NH- or other these three groups.
In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both may be used To refer among the different groups, does not influence mutually, can also indicate in phase between expressed specific option between the same symbol In same group, do not influenced mutually between expressed specific option between the same symbol.For example, formula i represents A ' ring or B ' ring Upper any possible substituted position can be replaced by n R, wherein each R is each independently selected from identical or different base Group.In another example in formula (I), each L2Identical or different group can be taken.
" hydrate " of the invention refers to compound or its salt provided by the present invention, further includes chemical quantity or non-chemical The water that equivalent is combined by non-covalent intermolecular forces can also say be solvent molecule to be that water is formed by associated matter.
" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.
" ester " of the invention refers to that the formula (I) containing hydroxyl-(III) compound can form internal hydrolyzable ester.In this way Ester be for example in human or animal's body hydrolysis generate parent alcohol pharmaceutically acceptable ester.Formula (I)-containing hydroxyl (III) group of hydrolyzable ester includes, but are not limited to phosphate, acetoxymethoxy, 2,2- dimethyl in compound body Propionyloxy methoxyl group, alkanoyl, benzoyl, the first and second acyl group of benzene, alkoxy carbonyl, dialkyl carbamoyl and N- (two Alkylaminoethyl)-N- alkyl-carbamoyl etc..
" nitrogen oxides " of the invention refer to when compound is containing several amine functional groups, can nitrogen by 1 or greater than 1 it is former Son oxidation forms N- oxide.The particular example of N- oxide is the N- oxidation of the N- oxide or nitrogen-containing heterocycle nitrogen-atoms of tertiary amine Object.Available oxidant example, as hydrogen peroxide or peracid (such as peroxycarboxylic acid) handle corresponding amine formed N- oxide (referring to Advanced Organic Chemistry, Wiley Interscience, the 4th edition, Jerry March, pages).Especially It is that N- oxide can be prepared (Syn.Comm.1977,7,509-514) with the method for L.W.Deady, wherein for example molten in inertia In agent, such as methylene chloride, react amine compounds with metachloroperbenzoic acid (MCPBA).
A variety of different geometric isomers may be present in compound and tautomer, the formula (I)-(III) compound include All such forms.For the avoidance of doubt, when compound exists with one of several geometric isomers or tautomer and only has When body describes or shows a kind of, it is clear that all other form is included in formula (I)-(III).
Term " prodrug " used in the present invention represents a compound and is converted into shown in formula (I)-(III) in vivo Compound.Such conversion is hydrolyzed in blood by pro-drug or the shadow in blood or tissue through enzymatic conversion for precursor structure It rings.Pro-drug compounds of the present invention can be ester, and what ester can be used as pro-drug in existing invention has phenyl ester class, Aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention A compound include hydroxyl, it can be acylated to obtain the compound of prodrug form.Other pro-drug shapes Formula includes phosphate, if these phosphate compounds are obtaining through the di on parent.It is complete about pro-drug Whole discussion can refer to following documents: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008,51,2328-2345.
Unless otherwise indicated, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more different originals The enriched isotope of son.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
The various pharmaceutically acceptable salt forms of the compounds of this invention are all useful.Term is " pharmaceutically acceptable Salt " refers to that those salt forms are it will be apparent that i.e. they are substantially nontoxic and needed for capable of providing for pharmaceutical chemistry man Pharmacokinetic property, palatability, absorption, distribution, metabolism or excretion.Other factors, it is more practical in nature, for choosing Select also critically important, these are: the costs of raw material, being easy of crystallization, the stream of yield, stability, hygroscopicity and result bulk pharmaceutical chemicals Dynamic property.Simply, pharmaceutical composition can be prepared by effective component and pharmaceutically acceptable carrier.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66: 1-19,1977. documented.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, anti-with amino group The inorganic acid salt that should be formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetate, Oxalates, maleate, tartrate, citrate, succinate, malonate or by it is described in the books or literature its His method such as ion-exchange obtains these salt.Other pharmaceutically acceptable salts include adipate, malate, 2- hydroxyl Base propionate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyric acid Salt, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formic acid Salt, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydrogen iodine Hydrochlorate, 2- hydroxy-ethanesulfonate salt, lactobionate, lactate, laruate, lauryl sulfate, malonate, methanesulfonic acid Salt, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenyl third Hydrochlorate, picrate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, Etc..Salt obtained by an appropriate base includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to structure The compound for having thought the group of any included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can pass through Quaternization obtains.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt is into one Step includes appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylation Object, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Sulphonic acid compound and aromatic sulphonic acid compound.Amine salt, such as, but not limited to N, N '-dibenzyl-ethylenediamin, chloroprocanine, choline, ammonia, isopropylamine, tardocillin (benzathine), choline salt (cholinate), lysine, meglumine (meglumine), piperazine, tromethamine, diethanol amine and other hydroxyalkyl amines, second Diamines, N- methyl glucamine, procaine, N- benzyl-1-phenylethylamine, the p- chlorobenzyl -2- pyrrolidines -1 '-ylmethyl-benzene of 1- And imidazoles, diethylamine and other alkylamines, piperazine and three (methylol) aminomethanes；Alkali salt, such as, but not limited to barium, Calcium and magnesium；Transition metal salt, such as, but not limited to zinc.
Any disease of term " treatment " or illness as used in the present invention, some embodiment middle fingers improve disease wherein Or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).In further embodiments, it " controls Treat " refer to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.In other implementations Example in, " treatment " refer to from body (such as stablizing perceptible symptom) or physiologically (such as parameter of stable body) or on It states two aspects and adjusts disease or illness.In further embodiments, " treatment " refers to the breaking-out for preventing or delaying disease or illness, hair Raw or deterioration.
" inflammatory disease " used in the present invention refers to excessive inflammation caused by excessive or out of control inflammatory responses Property symptom, host tissue damage or function of organization any disease for losing, disorder or symptom." inflammatory disease " also refers to by leucocyte The pathologic state that inflow and/or Neutrophil chemotaxis mediate.
" inflammation " used in the present invention refers to by tissue damaged or topical protective response caused by destroying, it is for breaking Tissue that is bad, diluting or separate (isolation) harmful substance and be damaged.Inflammation is flowed into leucocyte and/or neutrophil cell becomes The property changed has significant connection.Inflammation can produce in the infection and non-infectious mode of pathogenic organism and virus, such as heart Wound or Reperfu- sion after muscle infarction or apoplexy, to the immune response and autoimmune response of exotic antigen.Therefore, this can be used The inflammatory disease of disclosure of the invention compound treatment includes: to react with specific system of defense and non-specific defense system reaction Relevant disease.
Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) it reacts or by making the free alkali form of these compounds and chemistry The suitable acid reaction of metered amount is to be prepared.Such reaction usually carries out in the mixture of water or organic solvent or both. Generally, in appropriate cases, it needs using non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook: property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list that other is suitable for salt can be found in.
In addition, compound disclosed by the invention, the salt including them, in the form of their hydrate or can also include it The form of solvent (such as ethyl alcohol, DMSO, etc.) obtains, for their crystallization.Disclosed compound of present invention can be with pharmacy Upper acceptable solvent (including water) forms solvate inherently or by design；Therefore, the present invention is intended to include solvations And unsolvated form.
Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H,3H,11C,13C,14C,15N,17O,18O,18F,31P,32P,35S,36Cl and125I。
On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In there are radioactive isotopes, such as3H,14C and18Wherein there is non radioactive isotope in those of F compound, such as2H and13C.The compound of such isotope enrichment can be used for being metabolized research and (use14C), Reaction kinetics research are (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including drug or substrate tissue measure of spread Single photon emission computed tomography (SPECT) can be used in the radiotherapy of patient.18The compound of F enrichment to PET or It is especially desirable for SPECT research.Compound shown in the formula (I) of isotope enrichment can be ripe by those skilled in the art It is substituted described by the embodiment and preparation process in routine techniques or the present invention known using suitable isotope labeling reagent former Carry out used unmarked reagent to prepare.
In addition, higher isotope especially deuterium (that is,2H or D) substitution can provide certain treatment advantages, these advantages are By the higher bring of metabolic stability.For example, Half-life in vivo increase or reduction of volume requirements or therapeutic index obtain improving band Come.It should be appreciated that the deuterium in the present invention is seen as the substituent group of formula (I) compound.It can be determined with isotope enrichment factor The concentration of such adopted higher isotope especially deuterium.Term " isotope enrichment factor " used in the present invention refers to specified same Ratio between the isotope abundance and natural abundance of position element.If the substituent group of the compounds of this invention is designated as deuterium, the change Object is closed for each specified D-atom at least 3500 (52.5% deuterium incorporations at each specified D-atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% deuterium incorporations), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporations), at least 6466.7 The isotope enrichment of (97% deuterium incorporation), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuterium incorporations) The factor.The pharmaceutical solvate of the present invention includes such as D that wherein recrystallisation solvent can be isotope substitution2O, acetone-d6、 DMSO-d6Those of solvate.
" joint " indicates the medicine box of the fixed Combination in single dose unit form or the part for combined administration, Middle disclosed compound of present invention and combined partner can be in same time individual applications or can be at a certain time interval It applies respectively, so that joint is closed companion and show cooperation, for example act synergistically.Term " co-administered " as used herein Or " administering drug combinations " etc. are intended to include single individual (such as the patient) for being applied to selected COMBINATION OF THE INVENTION and needing it, and anticipate Be intended to include wherein substance without going through identical administration method or the therapeutic scheme being administered simultaneously.Term " drug as used herein Combination product " indicates to mix or combine obtained product for more than one active constituents, and both consolidating including active constituent Fixed combination also includes non-fixed combinations.Term " fixing joint " indicates active constituent such as disclosed compound of present invention and COMBINATION OF THE INVENTION It is administered simultaneously in the form of single entities or dosage in patient.Term " on-fixed joint " indicates that the active constituent such as present invention discloses Compound Compound and COMBINATION OF THE INVENTION are used as corpus separatum to be successively applied to trouble simultaneously, jointly or without specific time limitation ground Person, wherein this is applied in patient's body and provides the treatment effective level of two kinds of compounds.The latter applies also for cocktail therapy, Such as 3 kinds of application or more active constituent.
The description of the compounds of this invention
It is on CRTH2 receptor that the present invention, which provides a series of indole nitrogen indole derivatives replaced carboxylic moiety, PGD2Antagonist and can be used for treating by the PGD on CRTH2 receptor2The disease and situation of mediation.
Present invention offer such as compound of one of flowering structure or the stereoisomer of the compound, geometric isomer, mutually Tautomeric, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug:
On the one hand, the present invention provides a kind of pharmaceutical composition, and it includes any compounds as described in the present invention.
In some embodiments, pharmaceutical composition of the present invention further includes pharmaceutically acceptable carrier, figuration At least one of agent, diluent, adjuvant and medium.
In some embodiments, pharmaceutical composition of the present invention, further comprising it is one or more for treat by PGD on CRTH2 receptor2Other active agents of the disease mediated.
In other embodiment, pharmaceutical composition of the present invention, wherein other described active agents are TNF-α Inhibitor, COX-1/COX-2 inhibitor, cox 2 inhibitor, glucocorticoid, the inactivation antibody of interleukin, chemokine receptors Regulator, histamine H 1 receptor antagonist/antihistaminic, leukotriene D receptor antagonist, LTD4 antagonist, VLA-4 antagonist, skin Matter steroids analog, theophylline, inhibitors of leukotriene biosynthesis, epoxy enzyme-2 inhibitor, opium kind analgesics, anticoagulation Agent, beta blocker, beta-adrenergic agonist, angiotensin converting enzyme inhibitors, HMG-CoA reductase inhibitor, β 2 Agonist, corticosteroid, antihistaminic, leukotriene antagonist, ant-IgE antibody therapeutic agent, anti-infectious agent, antifungal are exempted from Epidemic disease inhibitor acts on other PGD of other receptors2Antagonist, the inhibitor of 4 type phosphodiesterases adjust cell factor and produce Raw drug adjusts the active drug of Th2 cell factor IL-4 and IL-5,5- lipoxidase inhibitor.
In other embodiment, pharmaceutical composition of the present invention, wherein the active agents are salmeterol, fluorine For Kathon CG, Loratadine, montelukast, omalizumab, Fusidic Acid, clotrimazole, tacrolimus, Elidel, DP antagonism Agent, cilomilast, TNF-α invertase (TACE) inhibitor, the blocking monoclonal antibody or soluble recepter of IL-4 or IL-5 And Zileuton.
On the one hand, the present invention provides a kind of use any compound of the present invention or any drug of the present invention Composition is used to prepare for protecting, handling, treat or mitigating patient by PGD on CRTH2 receptor2The medicine of the disease mediated The purposes of product.
In some embodiments, purposes of the present invention, wherein by PGD on CRTH2 receptor2The disease mediated is to roar Asthma, allergic asthma, perennial allergic rhinitis, pollinosis, atopic dermatitis, contact hypersensitivity, knot Film is scorching, eosinophil driven's bronchitis, food hypersenstivity, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crow Grace disease, mastocytosis, autoimmune disease, psoriasis, acne, multiple sclerosis, allograft row Reprimand, reperfusion injury, chronic obstructive pulmonary disease, rheumatoid arthritis, arthritic psoriasis or osteoarthritis.
In other embodiment, purposes of the present invention, wherein the autoimmune disease is psoriasis, it is more Hair property hardening illness, allograft rejection, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus and bone Arthritis.
Still further aspect, the present invention provide a kind of comprising any compound of the present invention and one or more hairs Combined pharmaceutical preparation of the bright any medicament as combination formulations, simultaneously, respectively or in succession for protecting, handling, treating Or mitigate by PGD on CRTH2 receptor2The purposes of the disease mediated.
Another aspect, the present invention provide it is a kind of protection, processing, treatment or mitigate patient by PGD on CRTH2 receptor2It is situated between The method of the disease and situation led, method include to give patient's any chemical combination as described in the present invention of the infectious disease Effective therapeutic dose of object or any pharmaceutical composition of the present invention.
Still further aspect, any compound or any pharmaceutical composition of the present invention are used for according to the present invention Protection, processing, treatment mitigate patient by PGD on CRTH2 receptor2The disease and situation mediated.
Unless otherwise indicated, the stereoisomer that the compound of the present invention is all, geometric isomer, tautomerism Body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug belong to model of the invention It encloses.Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " includes substance or composition must be suitable Combination or toxicologically, the mammal with the other components of composition preparation and for treatment are related.The compound of the present invention Salt further include being used to prepare or purifying compound shown in the intermediate or formula (I)-(III) of compound shown in formula (I)-(III) The salt of isolated enantiomter, but it is not necessarily pharmaceutically acceptable salt.
If the compound of the present invention be it is alkaline, conceivable salt can be by provided in the literature any suitable Method is prepared, for example, using inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid etc..Or using organic Acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, Lactic acid citric acid, Oxalic acid, glycolic acid and salicylic acid；Pyrans saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and winestone Acid；Amino acid, such as asparatate and glutamic acid；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, benzene Sulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid etc. or their combination.
If the compound of the present invention be it is acid, conceivable salt can be prepared by suitable method, e.g., Using inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide, ammonium, N+(R14)4Salt and alkaline earth gold Belong to hydroxide, etc..Suitable salt includes, but is not limited to, organic salt obtained from amino acids, such as glycine and smart ammonia Acid, ammonia, such as primaquine, parahelium and tertiary ammonia, N+(R14)4Salt, such as R14It is H, C1-4Alkyl, C6-10Aryl, C6-10Aryl C1-4Alkyl Deng and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtain inorganic salts from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium. It also include appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylation Object, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Sulphonic acid compound and aromatic sulphonic acid compound.
The purposes, preparation and composition of the compound of the present invention
The compounds of this invention may be used to treat the PGD by CRTH2 receptor2The method of the disease and situation of mediation, This method includes that compound shown in suitable logical formula (I)-(III) is applied to patient in need for the treatment of.
In another aspect of the present invention, new logical formula (I)-(III) compound represented is provided, is used for medical use On the way, especially for treating or preventing by the PGD on CRTH2 receptor2The disease and situation of mediation.
As described above, these diseases and situation include allergic asthma, perennial allergic rhinitis, seasonal allergia nose Inflammation, atopic dermatitis, contact hypersensitivity (including contact dermatitis), conjunctivitis, especially allergic conjunctivitis, acidophilus are thin Born of the same parents' property bronchitis, food hypersenstivity, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crohn disease, hypertrophy are thin Born of the same parents' hyperplasia disease and other PGD2The disease of mediation, such as autoimmune disease, such as hyper-IgE syndrome and generalized erythema wolf Sore, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease and class Rheumatic arthritis, arthritic psoriasis and osteoarthritis.
The compound of logical formula (I) must be prepared according to their institute diseases or situation to be treated with method appropriate.
Therefore, another aspect of the present invention provides a kind of pharmaceutical composition, and it includes shown in logical formula (I)-(III) Noval chemical compound and pharmaceutical excipient or carrier.Also may include be considered it is appropriate or suitable for treat or prevent above-mentioned disease or Other active materials of situation.Carrier or (if more than one carrier) each carrier all must be with preparations Other components have acceptable compatibility and harmless to receptor.
The preparation includes being suitable for oral cavity, rectum, nose, bronchus (sucking), locally (including eye drops, buccal With it is sublingual), the preparation of vagina or non-gastrointestinal (including subcutaneous, intramuscular, intravenous and intradermal) administration, and pharmaceutical field can be used Well-known any method prepares.
Administration route depends on institute's disease to be treated, but is preferably prepared into the composition and is used for oral cavity, nose, bronchus Or the preparation of local administration.
Above-mentioned active agents can be mixed with carrier to prepare the composition.Generally, active agents and liquid are carried Uniformly and closely mixing is to prepare said preparation for the mixture of body or the solid carrier finely separated or both, then if needed It wants, certain shapes is made in product.The present invention provides a kind of method for preparing pharmaceutical composition, including by logical formula (I)-(III) Shown in noval chemical compound in conjunction with pharmacy or veterinarily acceptable carrier or inert matter or combine.
Oral preparation in the present invention can be presented are as follows: discrete unit, such as each unit include predetermined amount active drug Capsule, wafer or the tablet of agent；Powder or particle；Solution or suspension of the active agents in waterborne liquid or non-aqueous liquid Liquid；Or oil-in-water liq emulsion or water-in-oil liquid emulsion；Or bolus etc..
For Orally administered composition (such as tablet and capsule), term " acceptable carrier " includes inert matter, such as common Excipient, such as adhesive, such as syrup, Arabic gum, gelatin, sorbierite, tragacanth, polyvinylpyrrolidone (poly- dimension Ketone), methylcellulose, ethyl cellulose, sodium carboxymethylcellulose, hydroxypropyl methyl cellulose, sucrose and starch；Filler and Carrier, such as cornstarch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, Dicalcium Phosphate, sodium chloride and seaweed Acid；And lubricant, such as magnesium stearate, odium stearate and other Metallic stearates, stearic acid glycerol stearate, silicone fluid, cunning Paraffin, oil and colloidal silicon.Also flavoring agent, such as peppermint, wintergreen, cherry flavor enhancement etc. can be used.If desired, can also Colorant is added so that dosage form is easy identification.Tablet can also be coated with method well-known in the art.
Tablet can be prepared optionally with one or more auxiliary agents by compression or molding.Prepare the method packet of compressed tablets It includes, active agents is compressed in machine appropriate, wherein active agents are the free-flowing forms of such as powder or particle, optionally Adhesive, lubricant, inert diluent, preservative, surfactant or dispersing agent can be also mixed into.The method for preparing press back tablet Including the mixture of the powder compounds moistened with inert liquid diluent is moulded in machine appropriate.Tablet optionally may be used Coating or indentation, and can be prepared into the preparation of sustained release or controlled release activity medicament.
It includes pastille of the active agents in flavoured base that other, which are suitable for oral preparation, and the flavoured base is usually Sucrose and Arabic gum or tragacanth；Pastille of the active agents in inert base, the inert base are, for example, gelatin With glycerol or sucrose and Arabic gum；With collutory of the active agents in appropriate liquid carrier.
In order to be applied topically to skin, logical formula (I)-(III) compound represented can be made emulsifiable paste, ointment, jelly, Solution or suspension etc..The emulsifiable paste or ointment formulation that can be used as drug are conventional formulations well-known in the art, for example, such as medicine Standard textbook is learned, such as described in British Pharmacopoeia.
Logical formula (I)-(III) compound represented can be by nose, bronchus or buccal administration for treating breathing Tract disease, such as aerosol or spray, can be pharmaceutical active in powder form or with solution or the liquid of suspension Drop form scatter.Pharmaceutical composition with powder dispersibility matter generally includes in addition to active component, and boiling point is lower than room temperature Liquid propellant and if desired, also include additive, such as liquid or solid nonionic or anionic surfactant and/or Diluent.The pharmaceutical composition of pharmaceutical active in the solution further includes appropriate push away in addition to solution and pharmaceutical active Into agent, furthermore if desired, also comprising other solvents and/or stabilizer.Propellant can also be replaced with compressed gas, if It needs, it can be prepared by compression appropriate and expansion device.
Non-gastrointestinal preparation is usually sterile.
In general, the dosage of the compound is about 0.01 to 100mg/kg；The dosage is enough drug is dense in blood plasma Degree maintains the PGD effectively inhibited on CRTH2 receptor2Concentration on.Compound shown in logical formula (I)-(III), which is accurately treated, to be had Effect amount and the optimal administration route of these compounds be those skilled in the art by comparing the haemoconcentration of preparation and Required concentration is assured that when with therapeutic effect.
The typically therapeutically effective amount serum that should generate about 0.1ng/ml to about 50-100 microgram/ml active constituent is dense Degree.Described pharmaceutical composition should typically be provided from about 0.001mg to the compound of about 2000mg/daily/kg body weight Dosage.Pharmaceutical quantities unit form can be prepared to provide every dosage unit form about 1mg to about 1000mg, in certain embodiments In, required active constituent from about 10mg to about 500mg, from about 20mg to about 250mg or from about 25mg to about 100mg or must Want the combination of ingredient.In certain embodiments, the pharmaceutical dosage unit forms can be prepared with provide about 1mg, 20mg, The required active constituent of 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg.In certain embodiments, it makes The standby pharmaceutical dosage unit forms are to provide the necessary active constituent of about 50mg.
The active constituent of reactive compound with once daily or can be divided into several smaller doses with one in pharmaceutical composition It fixes time and is spaced to be administered.It should be appreciated that accurate dosage and duration for the treatment of be disease to be treated function, can It is rule of thumb determined or acquisition of being extrapolated by internal or external experimental data using known experimental method.It should be noted that Concentration and dose value can also change with the seriousness degree of the symptom to be alleviated.It is to be further understood that for any Specific object should adjust at any time according to the professional judgement of individual demand and the people for being administered or supervising composition administration Specific dosage regimen, the concentration range proposed here have been only example effects, are not intended to limit claimed composition Range or implementation.
" effective quantity " of the present invention or " effective dose " refer to: one or more above-mentioned for treating or mitigating Disorder is effectively measured.Disclosed compound or composition according to the present invention can be used any effective quantity and any have The administration route treatment treatment of effect or the seriousness for mitigating disorder or disease.Required exact amount will be according to different themes And it is different, according to the ordinary circumstance of species, age and theme, the severity of infection, special preparation, administration mode etc..Chemical combination Object or composition can also be given together with one or more other drugs, as described above.
Compound shown in logical formula (I)-(III) can be with one or more for treating above-mentioned cited disease and situation Active agents be used in combination, although these active agents are not necessarily the PGD on CRTH2 receptor2Inhibitor.Therefore, on The pharmaceutical composition stated can also include one or more such active agents.
The present invention also provides compound shown in a kind of logical formula (I)-(III) in preparation for treating by CRTH2 receptor PGD2Purposes in the medicament of the disease and situation that are mediated, wherein the medicament also includes for treating same disease and situation Other active agents.It includes for allergia and other that these, which may have other active agents of entirely different binding mode, The existing therapeutic agent of inflammatory disease, comprising: β2agonists, such as salmeterol；Corticosteroid, such as fluticasone；Anti- group Amine agent, such as Loratadine；Leukotriene antagonist, such as montelukast；Ant-IgE antibody therapeutic agent, such as omalizumab； Anti-infectious agent, such as Fusidic Acid (especially for treating atopic dermatitis)；Antifungal, such as clotrimazole (are especially used In treatment atopic dermatitis)；Immunosuppressor, such as cosmo and the pyrrole U.S.A especially selected in inflammatory dermatosis are not Department.
CRTH2 antagonist can also be combined with the therapeutic agent for the treatment of inflammatory indication development, wherein the therapeutic agent includes: Act on other PGD of other receptors2Antagonist, such as DP antagonist；The inhibitor of 4 type phosphodiesterases, such as cilonilast；Adjust the drug that cell factor generates, such as TNF α invertase (TACE) inhibitor；Adjust Th2 cell factor The active drug of IL-4 and IL-5, such as blocking property monoclonal antibody and soluble recepter；PPAR- gamma agonist, such as Roger Column ketone；5- lipoxidase inhibitor, such as Zileuton.
In another aspect of the invention, a kind of product is provided, it includes noval chemical compounds and one shown in logical formula (I)-(III) Kind or a variety of above-mentioned medicaments are as combination formulations, simultaneously, respectively or in succession for treating by PGD on CRTH2 receptor2Effect institute The disease and situation of mediation.
The present invention also provides include compound, its pharmaceutically acceptable salt and its solid shown in logical formula (I)-(III) The pharmaceutical composition of isomers and one or more therapeutic active substances, the therapeutic active substance be selected from TNF-α inhibitor, COX-1/COX-2 inhibitor, cox 2 inhibitor, glucocorticoid, the inactivation antibody of interleukin, chemokine receptor modulators, Histamine H 1 receptor antagonist/antihistaminic, leukotriene D receptor antagonist, leukotriene antagonist, LTD4 antagonist, VLA-4 are short of money Anti-agent, corticosteroid, corticosteroid are similar to object, β 2- agonist, theophylline, inhibitors of leukotriene biosynthesis, cyclooxygenase-2 Inhibitor, phosphodiesteraseⅳ type inhibitor, opium kind analgesics, anticoagulant, beta blocker, beta-adrenergic excitement Agent, angiotensin converting enzyme inhibitors or HMG-CoA reductase inhibitor.
" composition " of the present invention, refers in pharmaceutical composition, it is intended to including carrying containing active constituent and composition The inertia of body is complexed or polymerization or from the decomposition of one or more ingredients or from the other types of of one or more ingredients Any product that reaction or interaction generate, therefore, pharmaceutical composition of the invention includes by will be shown in formula (I)-(III) Compound is mixed with one or more pharmaceutically acceptable excipient and any composition for preparing.
The pharmaceutical carrier used can be with are as follows: solid, liquid or gas.The example of solid carrier include: lactose, land plaster, Sucrose, talcum powder, gelatin, agar, pectin, Arabic gum, magnesium stearate, stearic acid etc..The example of liquid-carrier includes: sugar Slurry, peanut oil, olive oil, water etc..The example of gaseous carrier includes: carbon dioxide and/or nitrogen.Equally, carrier or diluent It may include time delay material disclosed in document, such as glycerin monostearate or glycerol stearate, individually or with wax use together.
On the other hand, the substance that can be used as pharmaceutically acceptable carrier includes, but is not limited to, ion-exchanger；Aluminium；Oxygen Change aluminium；Aluminum stearate；Lecithin；Haemocyanin such as human albumin；Buffer substance such as phosphate；Glycine；Sorbic acid；Sorb Sour potassium；The partial glyceride mixtures of saturated vegetable fatty acid；Water；Electrolyte such as protamine sulfate, disodium hydrogen phosphate, phosphoric acid Hydrogen potassium；Salt such as sodium chloride, zinc salt；Colloidal silicon；Magnesium trisilicate；Polyvinylpyrrolidone；Polyacrylate；Wax；Polyethylene-polyoxy Propylene-blocking condensate；Lanolin；Sugar such as lactose, dextrose and saccharose；Starch such as cornstarch and potato starch；Cellulose With its derivative such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Gum powder；Malt；Gelatin；Talcum powder； Auxiliary material such as cocoa butter and suppository wax；Oil such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil； Glycol compound, such as propylene glycol and polyethylene glycol；Esters such as ethyl oleate and ethyl laurate；Agar；Buffer is such as Magnesium hydroxide and aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge (family name) solution；Ethyl alcohol；Phosphate buffer solution；With Other nontoxic suitable lubricant such as Sodium Laurylsulfates and magnesium stearate, colorant, releasing agent, coating agents, sweetener are adjusted Taste agent and fragrance, preservative and antioxidant.
General synthetic method
Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I)-(III).Following reaction scheme and embodiment is for further illustrating Illustrate the contents of the present invention.
Those skilled in the art will realize that: chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention Or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Imperial chemistry examination is risen in factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Qingdao Agent Co., Ltd and Haiyang Chemical Plant, Qingdao are commercially available.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride It with chloroform is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDC13,d6-DMSO,CD3OD or d6Acetone is solvent (report is as unit of ppm), with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When there is multiplet, following abbreviation will be used: s (singlet, unimodal), d (doublet, it is double Peak), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant is indicated with hertz (Hz).
By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to low resolution mass spectrometry (MS) data DEG C) the spectrometer of Agilent 6320 series LC-MS measure, G1329A automatic sampler and G1315B DAD detector Applied to analysis, the source ESI is applied to LC-MS spectrometer.
Low resolution mass spectrometry (MS) data are by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C) 6120 series LC-MS of Agilent spectrometer come what is measured, G1329A automatic sampler and G1315D DAD detector are answered For analyzing, the source ESI is applied to LC-MS spectrometer.
Both the above spectrometer is provided with Agilent Zorbax SB-C18 column, and specification is 2.1 × 30mm, and 5 μm.Note Beam product is determined by sample concentration；Flow velocity is 0.6mL/min；The peak value of HPLC is by 210nm and 254nm UV-Vis wavelength records reading.Mobile phase is that 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid are ultrapure water-soluble Liquid (phase B).Condition of gradient elution is as shown in table 1:
Table 1
Compound purifying is by 1100 series of high efficiency liquid chromatogram (HPLC) of Agilent come what is evaluated, and wherein UV is detected At 210nm and 254nm, Zorbax SB-C18 column, specification be 2.1 × 30mm, 4 μm, 10 minutes, flow velocity 0.6mL/min, (0.1% aqueous formic acid) of (0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.
The use of logogram word below is through the present invention:
Boc tertbutyloxycarbonyl
CHCl3Chloroform
CDC13Deuterated chloroform
CD3OD deuterated methanol
d6- DMSO deuterated dimethyl sulfoxide
DMF N,N-dimethylformamide
DMAP 4-dimethylaminopyridine
DIPEA N, N- diisopropylethylamine
DMSO dimethyl sulfoxide
H2Hydrogen
HCl hydrogen chloride, hydrochloric acid
MeOH,CH3OH methanol
ML, ml milliliters
N2Nitrogen
Pd/C palladium/carbon
RT rt room temperature
Rt retention time
LiOH·H2O lithium hydroxide monohydrate
NaH sodium hydride
H2O water
Synthetic schemes 1
Compound (8) can be prepared according to the method for synthetic schemes 1.Wherein, A and E has as described in the present invention Meaning.The fluoro- 2- Methyl-1H-indole of 5- and DMF are in POCl3Reaction obtains compound (1) under the conditions of existing.Compound (1) with Methyl bromoacetate reaction under the conditions of alkaline (alkali can be sodium hydride, sodium hydroxide, organic base etc.) obtains compound (2).Change Object (2) are closed under the oxidation of potassium permanganate, obtain compound (3).Condensation reaction is passed through in compound (3) and compound (9) Compound (4) are obtained, then compound (4) obtains compound (5) by deprotection, then is condensed to yield chemical combination with compound (6) Object (7), compound (7) are deprotected under the conditions of alkaline (alkali can be lithium hydroxide, sodium hydroxide, aluminium hydroxide etc.), acid Under the conditions of post-processing obtain target product (8).
Synthetic schemes 2
Compound (14) can be prepared according to the method for synthetic schemes 2.Wherein, A and E has as described in the present invention Meaning.Compound (3) are obtained according to the related synthesis process of synthetic schemes 1.Compound (3) and compound (10) are in alkaline condition Under (alkali can be DIPEA, but be not limited to), obtain compound (11) by condensation reaction, (acid can be with using under acid condition Be HCl, but be not limited to) deprotection obtain compound (12).Then compound (12) and compound (6) are condensed to yield compound (13), compound (13) is deprotected under the conditions of alkaline (alkali can be lithium hydroxide, sodium hydroxide, aluminium hydroxide etc.) again, acid Property under the conditions of post-processing obtain target product (14).
Synthetic schemes 3
Compound (22) can be prepared according to the method for synthetic schemes 3.Wherein, L1, L2, m, A and E have such as this hair The bright meaning.Compound (3) are obtained according to the related synthesis process of synthetic schemes 1.Compound (3) and compound (20) are contracted Conjunction obtains compound (21), and then compound (21) is in alkaline (alkali can be lithium hydroxide, sodium hydroxide, aluminium hydroxide etc.) item It is deprotected under part, post-processing obtains target product (22) under acid condition.
Synthetic schemes 4
Compound (25) can be prepared according to the method for synthetic schemes 4.Wherein, A and E has as described in the present invention Meaning.Compound (5) are obtained according to the related synthesis process of synthetic schemes 1.Compound (5) again with compound (23) condensation reaction Compound (24) are obtained, then compound (24) is in alkaline (alkali can be lithium hydroxide, sodium hydroxide, aluminium hydroxide etc.) condition Lower deprotection, post-processing obtains target product (25) under acid condition.
Synthetic schemes 5
Compound (29) can be prepared according to the method for synthetic schemes 5.Wherein, A and E has as described in the present invention Meaning.Compound (12) are obtained according to the related synthesis process of synthetic schemes 2.Compound (12) is anti-with compound (23) condensation again Compound (28) should be obtained, then compound (28) is in alkaline (alkali can be lithium hydroxide, sodium hydroxide, aluminium hydroxide etc.) item It is deprotected under part, post-processing obtains target product (29) under acid condition.
The following examples can be with the present invention will be further described, however, these embodiments should not be used as to this hair The limitation of bright range.
Embodiment
1 compound 2- of embodiment (the fluoro- 2- methyl -3- of 5- (4- (quinoline -5- carbonyl) piperazine -1- carbonyl) -1H- indoles -1- Base) acetic acid hydrochloride synthesis
Step 1: the synthesis of the fluoro- 2- Methyl-1H-indole -3- formaldehyde of compound 5-
Under condition of ice bath to be added dropwise in the phosphorus oxychloride of nitrogen protection (3.7mL, 40.2mmol) anhydrous DMF (2.6mL, 33.5mmol), 5min is reacted under the conditions of 0 DEG C, and the anhydrous DMF solution of the fluoro- 2- Methyl-1H-indole (2g, 13.4mmol) of 5- is added dropwise (10mL), is stirred at room temperature 1.5h, and system is poured into ice water (20mL), and sodium hydroxide is added and is adjusted to alkalinity, solid is precipitated, mistake It filters, after filtration cakes torrefaction, obtains 1.97g pale solid, yield 82%.
1H NMR(400MHz,CD3OD):δppm 10.0(s,1H),7.77(dd,J1=9.6Hz, J2=2.3Hz, 1H), 7.33(dd,J1=8.8Hz, J2=4.4Hz, 1H), 6.97 (td, J1=9.3Hz, J2=2.5Hz, 1H), 2.71 (s, 3H)；MS- ESI:m/z 178.1[M+H]+.
Step 2: the synthesis of compound 2- (the fluoro- 3- aldehyde radical -2- Methyl-1H-indole -1- base of 5-) methyl acetate
To the fluoro- 2- Methyl-1H-indole -3- formaldehyde (1.11g, 6.26mmol) of compound 5- and sodium hydride under condition of ice bath Methyl bromoacetate (1.2mL, 12.5mmol) is added dropwise in the n,N-Dimethylformamide solution (14mL) of (451mg, 18.8mmol), 14h is stirred at room temperature, adds 20mL washing after removing solvent, ethyl acetate extracts (15mL × 2), and organic phase uses anhydrous slufuric acid after merging Sodium is dry, removes solvent, and concentrate carries out post separation (V (petroleum ether)/V (ethyl acetate)=2/1), it is faint yellow to obtain 1.32g Solid, yield 84%.
1H NMR(400MHz,CDCl3):δppm 10.2(s,1H),7.96(dd,J1=9.2Hz, J2=2.4Hz, 1H), 7.13(dd,J1=8.9Hz, J2=4.1Hz, 1H), 7.00 (td, J1=8.9Hz, J2=2.5Hz, 1H), 4.83 (s, 2H), 3.78(s,3H),2.66(s,3H)；MS-ESI:m/z250.2[M+H]+.
Step 3: the synthesis of the fluoro- 1- of compound 5- (2- methoxyl group -2- oxoethyl) -2- Methyl-1H-indole -3- carboxylic acid
Under condition of ice bath to compound 2- (the fluoro- 3- aldehyde radical -2- Methyl-1H-indole -1- base of 5-) methyl acetate (1.32g, The aqueous solution (6mL) of potassium permanganate (837mg, 5.30mmol) is added in acetone soln (12mL) 5.30mmol), is stirred at room temperature 3.5h is filtered using diatomite, and filtrate removes acetone, and after enriching hydrochloric acid is adjusted to acidity, stirring adds ethyl acetate to extract, organic It is mutually dry, it is concentrated to give 1.10g gray solid, yield 78%.
1H NMR(600MHz,d6-DMSO):δppm 7.66(dd,J1=10.1Hz, J2=2.6Hz, 1H), 7.52 (dd, J1 =8.9Hz, J2=4.4Hz, 1H), 7.03 (td, J1=9.1Hz, J2=2.7Hz, 1H), 5.23 (s, 2H), 3.71 (s, 3H), 2.64(s,3H)；MS-ESI:m/z 266.0[M+H]+
Step 4: compound 4- (the fluoro- 1- of 5- (2- methoxyl group -2- oxoethyl) -2- Methyl-1H-indole -3- carbonyl) piperazine The synthesis of piperazine -1- tert-butyl acetate
By the fluoro- 1- of compound 5- (2- methoxyl group -2- oxoethyl) -2- Methyl-1H-indole -3- carboxylic acid (460mg, 1.74mmol), N-Boc piperazine (388mg, 2.08mmol), 1- ethyl -3- (3- dimethylamine propyl) carbodiimide hydrochloride (498mg, 2.60mmol) and N- hydroxyl -7- azepine benzotriazole (590mg, 4.34mmol) are dissolved in methylene chloride (10mL) In, n,N-diisopropylethylamine (1.2mL, 6.94mmol) is added dropwise into this solution under the conditions of 0 DEG C, 17h is stirred at room temperature, adds washing (10mL × 3), organic phase is dry with anhydrous sodium sulfate, removes solvent, and concentrate carries out post separation (V (petroleum ether)/V (acetic acid second Ester)=1/1), 608mg white solid is obtained, yield: 80%.
1H NMR(400MHz,CDCl3):δppm 7.14(dd,J1=9.5Hz, J2=2.6Hz, 1H), 7.12-7.10 (m, 1H),6.96–6.92(m,1H),4.79(s,2H),3.76(s,3H),3.60–3.49(m,6H),3.43–3.39(m,2H), 2.46(s,3H),1.46(s,9H)；MS-ESI:m/z 434.3[M+H]+.
Step 5: compound 2- (the fluoro- 2- methyl -3- of 5- (piperazine -1- carbonyl) -1H- indoles -1- base) methyl acetate hydrochloric acid The synthesis of salt
By compound 4- (the fluoro- 1- of 5- (2- methoxyl group -2- oxoethyl) -2- Methyl-1H-indole -3- carbonyl) piperazine -1- Tert-butyl acetate (595mg, 1.37mmol) is dissolved in methylene chloride (6mL), and the ethyl acetate solution of 4mol/L HCl is added (6mL) stops reaction after 1.5h is stirred at room temperature.Solvent is removed, white solid 507mg pale solid, yield 99% are obtained.
1H NMR(400MHz,CD3OD):δppm 7.40(dd,J1=8.9Hz, J2=4.2Hz, 1H), 7.29 (dd, J1= 9.3Hz,J2=2.4Hz, 1H), 7.10 (td, J1=9.1Hz, J2=2.4Hz, 1H), 5.11 (s, 2H), 4.08-4.04 (m, 4H),3.92(s,3H),3.40–3.36(m,4H),2.61(s,3H)；MS-ESI:m/z 334.3[M+H-HCl]+.
Step 6: compound 2- (the fluoro- 2- methyl -3- of 5- (4- (quinoline -5- carbonyl) piperazine -1- carbonyl) -1H- indoles -1- Base) methyl acetate synthesis
By compound 2- (the fluoro- 2- methyl -3- of 5- (piperazine -1- carbonyl) -1H- indoles -1- base) acetate hydrochloride (155mg, 0.42mmol), quinoline-5-carboxylic acid (87mg, 0.50mmol), 1- ethyl -3- (3- dimethylamine propyl) carbodiimide salt Hydrochlorate (121mg, 0.63mmol) and N- hydroxyl -7- azepine benzotriazole (143mg, 1.05mmol) are dissolved in methylene chloride In (12mL), n,N-diisopropylethylamine (0.29mL, 1.68mmol) is added dropwise into this solution under the conditions of 0 DEG C, is stirred at room temperature Washing (10mL × 2) is added in 18h, and organic phase is dry with anhydrous sodium sulfate, removes solvent, and concentrate carries out post separation (V (dichloro Methane)/V (methanol)=30/1), 124mg white solid is obtained, yield: 60%.
1H NMR(600MHz,CDCl3): δ ppm 8.97 (s, 1H), 8.23 (br.s, 1H), 8.16 (d, J=8.5Hz, 1H), 7.74-7.72 (m, 1H), 7.52-7.46 (m, 2H), 7.14 (d, J=8.6Hz, 1H), 7.11 (dd, J1=8.8Hz, J2= 4.2Hz, 1H), 6.94 (t, J=8.0Hz, 1H), 4.79 (s, 2H), 4.02-3.90 (m, 2H), 3.84-3.78 (m, 2H), 3.75 (s,3H),3.55–3.49(m,2H),3.30–3.26(m,2H),2.47(s,3H)；MS-ESI:m/z 489.0[M+H]+.
Step 7: compound 2- (the fluoro- 2- methyl -3- of 5- (4- (quinoline -5- carbonyl) piperazine -1- carbonyl) -1H- indoles -1- Base) acetic acid hydrochloride synthesis
To compound 2- (the fluoro- 2- methyl -3- of 5- (4- (quinoline -5- carbonyl) piperazine -1- carbonyl) -1H- indoles -1- base) second A hydronium(ion) lithia is added in the tetrahydrofuran (8mL) of sour methyl esters (120mg, 0.25mmol) and the mixed solution of water (4mL) (52mg, 1.23mmol), 45 DEG C of reaction 2h are added 1mol/L salt acid for adjusting pH value to 1 or so, remove organic solvent, filter, filter Cake is drained after adding methanol to dissolve, and obtains yellow solid 69mg, yield 55%.
1H NMR(400MHz,d6- DMSO): δ ppm 8.99 (d, J=4.6Hz, 1H), 8.33 (d, J=8.1Hz, 1H), 8.11 (d, J=8.4Hz, 1H), 7.84 (t, J=7.7Hz, 1H), 7.66-7.62 (m, 2H), 7.47 (dd, J1=8.8Hz, J2= 4.3Hz, 1H), 7.20 (d, J=8.2Hz, 1H), 6.98 (t, J=8.2Hz, 1H), 5.03 (s, 2H), 3.90-3.75 (m, 2H), 3.70–3.65(m,3H),3.23–3.18(m,3H),2.37(s,3H)；
13C NMR(100MHz,d6-DMSO):δppm 170.3,167.5,166.4,157.2,151.2,147.4, 141.2,134.9,133.1,130.0,129.7,125.1,125.0,122.8,111.5,109.8,45.1,11.6；
MS-ESI:m/z 475.0[M+H-HCl]+.
2 compound 2- of embodiment (the fluoro- 3- of 5- (4- (the fluoro- 1- naphthalenecarboxamide of 5-) piperidines -1- carbonyl) -2- methyl-1 H- Yin Diindyl -1- base) acetic acid synthesis
Step 1: compound 2- (3- (4- ((tertbutyloxycarbonyl) amino) piperidines -1- carbonyl) fluoro- 2- methyl-1 H- Yin of -5- Diindyl -1- base) methyl acetate synthesis
By the fluoro- 1- of compound 5- (2- methoxyl group -2- oxoethyl) -2- Methyl-1H-indole -3- carboxylic acid (320mg, 1.2mmol), compound 4-N-Boc piperidines (290mg, 1.4mmol), 1- ethyl -3- (3- dimethylamine propyl) carbodiimide hydrochloride Salt (460mg, 2.4mmol) and N- hydroxyl -7- azepine benzotriazole (250mg, 1.8mmol) are dissolved in methylene chloride (10mL) In, n,N-diisopropylethylamine (0.65mL, 3.6mmol) is added dropwise into this solution under the conditions of 0 DEG C, 10h is stirred at room temperature, adds washing (10mL × 3), organic phase is dry with anhydrous sodium sulfate, removes solvent, and concentrate carries out post separation (V (petroleum ether)/V (acetic acid second Ester)=1/1), 500mg white solid is obtained, yield: 93%.
1H NMR(400MHz,CDCl3):δppm 7.17–7.19(m,1H),7.11(dd,J1=8.9Hz, J2=4.2Hz, 1H),6.93(td,J1=9.0Hz, J2=2.3Hz, 1H), 4.79 (s, 2H), 4.44-4.54 (m, 1H), 4.06-4.31 (m, 2H),3.76(s,3H),3.65–3.77(m,1H),3.00–3.11(m,2H),2.42–2.47(m,3H),1.98–2.00(m, 2H),1.44(s,9H)；MS-ESI:m/z 448.10[M+H]+.
Step 2: compound 2- (3- (4- amino piperidine -1- carbonyl) the fluoro- 2- Methyl-1H-indole -1- base of -5-) acetic acid first The synthesis of ester hydrochloride
By compound 2- (3- (4- ((tertbutyloxycarbonyl) amino) piperidines -1- carbonyl) fluoro- 2- Methyl-1H-indole -1- of -5- Base) methyl acetate (500mg, 1.1mmol) is dissolved in methylene chloride (4mL), the ethyl acetate solution of 4mol/L HCl is added (6mL) stops reaction after 2h is stirred at room temperature.Solvent is removed, 420mg white solid, yield 99% are obtained.
1H NMR(400MHz,CD3OD):δppm 7.28–7.31(m,1H),7.03–7.16(m,1H),6.89–6.94(m, 1H),4.92–5.06(m,2H),4.14–4.36(m,1H),3.72(s,2H),3.34–3.44(m,1H),3.03–3.22(m, 2H),2.35–2.42(m,3H),1.97–2.07(m,2H),1.45–1.65(m,2H)；MS-ESI:m/z 348.10[M+H- HCl]+.
Step 3: compound 2- (the fluoro- 3- of 5- (4- (the fluoro- 1- naphthalenecarboxamide of 5-) piperidines -1- carbonyl) -2- methyl-1 H- Yin Diindyl -1- base) methyl acetate synthesis
By compound 2- (3- (4- amino piperidine -1- carbonyl) the fluoro- 2- Methyl-1H-indole -1- base of -5-) methyl acetate salt Hydrochlorate (210mg, 0.55mmol), the fluoro- 1- naphthoic acid (125mg, 0.66mmol) of 5-, 1- ethyl -3- (3- dimethylamine propyl) carbon two Inferior amine salt hydrochlorate (157mg, 0.82mmol) and N- hydroxyl -7- azepine benzotriazole (186mg, 1.37mmol) are dissolved in dichloromethane In alkane (15mL), n,N-diisopropylethylamine (0.38mL, 2.19mmol) is added dropwise into this solution under the conditions of 0 DEG C, is stirred at room temperature Washing (10mL × 2) is added in 16h, and organic phase is dry with anhydrous sodium sulfate, removes solvent, and concentrate carries out post separation (V (dichloro Methane)/V (methanol)=30/1), 270mg white solid is obtained, yield: 94%.
1H NMR(400MHz,CDCl3): δ ppm 8.19 (d, J=8.4Hz, 1H), 8.04 (d, J=8.6Hz, 1H), 7.60–7.64(m,1H),7.53–7.44(m,2H),7.21–7.17(m,2H),7.11(dd,J1=8.9Hz, J2=4.2Hz, 1H),6.97–6.90(m,1H),6.11–6.09,5.96–5.93(m,m,0.5H,0.5H),4.79(s,2H),4.37–4.30 (m,2H),3.76(s,3H),3.22–3.10(m,2H),2.47(s,3H),2.20–2.18(m,2H),1.60–1.42(m,2H)； MS-ESI:m/z 520.3[M+H]+.
Step 4: compound 2- (the fluoro- 3- of 5- (4- (the fluoro- 1- naphthalenecarboxamide of 5-) piperidines -1- carbonyl) -2- methyl-1 H- Yin Diindyl -1- base) acetic acid synthesis
To compound 2- (the fluoro- 3- of 5- (4- (the fluoro- 1- naphthalenecarboxamide of 5-) piperidines -1- carbonyl) -2- Methyl-1H-indole -1- Base) hydronium(ion) is added in the tetrahydrofuran (10mL) of methyl acetate (260mg, 0.50mmol) and the mixed solution of water (5mL) Lithia (105mg, 2.50mmol), 45 DEG C of reaction 2.5h are added 1mol/L salt acid for adjusting pH value to 1 or so, add ethyl acetate It extracts (10mL × 2), removes solvent, obtain white solid 210mg, yield 83%.
1H NMR(600MHz,d6- DMSO): δ ppm 8.61-8.58 (m, 1H), 8.15 (d, J=8.1Hz, 1H), 8.00 (d, J=8.5Hz, 1H), 7.67-7.65 (m, 2H), 7.58-7.55 (m, 1H), 7.49 (dd, J1=8.9Hz, J2=4.4Hz, 1H), 7.41-7.38 (m, 1H), 7.13 (d, J=8.2Hz, 1H), 7.01-6.98 (m, 1H), 5.04 (s, 2H), 4.21-4.16 (m,1H),3.30–3.15(m,4H),2.37(s,3H),1.96–1.95(m,2H),1.57–1.47(m,2H)；
13C NMR(150MHz,d6-DMSO):δppm 172.5,170.4,167.9,159.2,157.6,139.7, 135.5,131.6,127.3,126.7,126.3,123.5,122.1,121.9,111.5,110.5,110.4,109.7, 109.5,108.9,67.5,46.9,45.1,30.9,11.5；
MS-ESI:m/z 506.2[M+H]+.
3 compound 2- of embodiment (the fluoro- 2- methyl -3- of 5- (4- (quinoline-2-formamide) piperidines -1- carbonyl) -1H- indoles - 1- yl) acetic acid hydrochloride synthesis
Step 1: compound 2- (the fluoro- 2- methyl -3- of 5- (4- (quinoline-2-formamide) piperidines -1- carbonyl) -1H- indoles - 1- yl) methyl acetate synthesis
By compound 2- (3- (4- amino piperidine -1- carbonyl) the fluoro- 2- Methyl-1H-indole -1- base of -5-) methyl acetate salt Hydrochlorate (210mg, 0.55mmol), quinaldic acid (114mg, 0.66mmol), 1- ethyl -3- (3- dimethylamine propyl) carbon two Inferior amine salt hydrochlorate (157mg, 0.82mmol) and N- hydroxyl -7- azepine benzotriazole (186mg, 1.37mmol) are dissolved in dichloromethane In alkane (15mL), n,N-diisopropylethylamine (0.38mL, 2.19mmol) is added dropwise into this solution under the conditions of 0 DEG C, is stirred at room temperature Washing (10mL × 2) is added in 20h, and organic phase is dry with anhydrous sodium sulfate, removes solvent, and concentrate carries out post separation (V (petroleum Ether)/V (ethyl acetate)=1/3), 105mg faint yellow solid is obtained, yield: 38%.
1H NMR(600MHz,CDCl3): δ ppm 8.32-8.29 (m, 2H), 8.22-8.17 (m, 1H), 7.88 (d, J= 8.1Hz, 1H), 7.79-7.77 (m, 1H), 7.63 (t, J=7.3Hz, 1H), 7.30-7.28 (m, 1H), 7.12 (dd, J1= 8.9Hz,J2=4.1Hz, 1H), 6.96-6.93 (m, 1H), 4.81 (s, 2H), 4.32-4.28 (m, 1H), 3.76 (s, 3H), 3.25–3.15(m,2H),2.53(s,3H),2.16–2.14(m,2H),1.75–1.73(m,2H),1.66–1.60(m,2H)； MS-ESI:m/z 503.3[M+H]+.
Step 2: compound 2- (the fluoro- 2- methyl -3- of 5- (4- (quinoline-2-formamide) piperidines -1- carbonyl) -1H- indoles - 1- yl) acetic acid hydrochloride synthesis
To compound 2- (the fluoro- 2- methyl -3- of 5- (4- (quinoline-2-formamide) piperidines -1- carbonyl) -1H- indoles -1- base) Hydronium(ion) oxidation is added in the tetrahydrofuran (8mL) of methyl acetate (100mg, 0.20mmol) and the mixed solution of water (4mL) Lithium (42mg, 1.00mmol), 45 DEG C of reaction 2.5h are added 1mol/L salt acid for adjusting pH value to 1 or so, ethyl acetate are added to extract (10mL × 2) remove solvent, obtain yellow solid 85mg, yield, and 81.4%
1H NMR(600MHz,CD3OD): δ ppm 8.38-8.36 (m, 1H), 8.22 (d, J=8.3Hz, 1H), 8.17- 8.13(m,1H),7.92–7.90(m,1H),7.80–7.78(m,1H),7.65–7.63(m,1H),7.26–7.25(m,1H), 7.22-7.19 (m, 1H), 6.95 (t, J=8.3Hz, 1H), 4.84 (s, 2H), 4.27-4.25 (m, 1H), 3.29-3.22 (m, 2H),2.52(s,3H),2.13–2.10(m,2H),1.78–1.67(m,2H)；
13C NMR(150MHz,CD3OD):δppm 174.1,170.0,167.8,159.5,158.0,149.2,139.6, 137.8,132.7,130.3,129.4,128.1,127.7,118.5,110.0,108.4,47.0,44.6,11.0；
MS-ESI:m/z 489.0[M+H-HCl]+.
4 compound 2- of embodiment (the fluoro- 2- methyl -3- of 5- (4- (quinoline -2- carbonyl) piperazine -1- carbonyl) -1H- indoles -1- Base) acetic acid hydrochloride synthesis
Step 1: compound 2- (the fluoro- 2- methyl -3- of 5- (4- (quinoline -2- carbonyl) piperazine -1- carbonyl) -1H- indoles -1- Base) methyl acetate synthesis
By compound 2- (the fluoro- 2- methyl -3- of 5- (piperazine -1- carbonyl) -1H- indoles -1- base) acetate hydrochloride (200mg, 0.54mmol), quinaldic acid (112mg, 0.65mmol), 1- ethyl -3- (3- dimethylamine propyl) carbodiimide Hydrochloride (156mg, 0.81mmol) and N- hydroxyl -7- azepine benzotriazole (184mg, 1.35mmol) are dissolved in methylene chloride In (20mL), n,N-diisopropylethylamine (0.38mL, 2.16mmol) is added dropwise into this solution under the conditions of 0 DEG C, is stirred at room temperature Washing (10mL × 2) is added in 3.5h, and organic phase is dry with anhydrous sodium sulfate, removes solvent, and concentrate carries out post separation (V (two Chloromethanes)/V (methanol)=40/1), 225mg white solid is obtained, yield: 85%.
1H NMR(400MHz,CDCl3): δ ppm 8.28 (d, J=8.4Hz, 1H), 8.07 (d, J=8.5Hz, 1H), 7.86 (d, J=8.0Hz, 1H), 7.80-7.74 (m, 2H), 7.61 (t, J=7.5Hz, 1H), 7.18 (dd, J1=9.3Hz, J2= 2.3Hz,1H),7.12(dd,J1=8.9Hz, J2=4.1Hz, 1H), 6.97-6.92 (m, 1H), 4.80 (s, 2H), 3.98-3.94 (m,2H),3.89–3.80(m,6H),3.76(s,3H),2.50(s,3H)；MS-ESI:m/z 489.4[M+H]+.
Step 2: compound 2- (the fluoro- 2- methyl -3- of 5- (4- (quinoline -2- carbonyl) piperazine -1- carbonyl) -1H- indoles -1- Base) acetic acid hydrochloride synthesis
To compound 2- (the fluoro- 2- methyl -3- of 5- (4- (quinoline -2- carbonyl) piperazine -1- carbonyl) -1H- indoles -1- base) second A hydronium(ion) lithia is added in the tetrahydrofuran (10mL) of sour methyl esters (216mg, 0.44mmol) and the mixed solution of water (5mL) (93mg, 2.21mmol), 45 DEG C of reaction 5h are added 1mol/L salt acid for adjusting pH value to 1 or so, ethyl acetate are added to extract (10mL × 2) solvent, is removed, obtains yellow solid 73mg, yield 32.3%, purity 65% prepares chromatogram purification, obtains after processing 27mg faint yellow solid, yield 11.9%.
1H NMR(600MHz,CD3OD): δ ppm 8.48 (d, J=8.4Hz, 1H), 8.08 (d, J=8.4Hz, 1H), 7.99 (d, J=8.1Hz, 1H), 7.84 (t, J=7.5Hz, 1H), 7.72 (d, J=8.4Hz, 1H), 7.69 (t, J=7.5Hz, 1H), 7.36-7.32 (m, 1H), 7.20 (dd, J=9.4,2.1Hz, 1H), 6.98-6.95 (m, 1H), 4.98 (s, 2H), 3.85-3.63 (m,8H),2.48(s,3H)；
13C NMR(150MHz,CD3OD):δppm 170.4,168.3,168.1,159.6,158.0,153.1,138.0, 133.0,130.4,129.7,128.6,127.8,124.9,119.9,110.2,109.8,64.5,10.2；
MS-ESI:m/z 475.3[M+H-HCl]+.
5 compound 2- of embodiment (the fluoro- 2- methyl -3- of 5- (4- (quinoline -2- base carbamoyl) piperidines -1- carbonyl) - 1H- indoles -1- base) acetic acid hydrochloride synthesis
Step 1: the synthesis of compound N-(quinoline -2- base) piperidines -4- carboxamide dihydrochloride
By N-Boc-4- piperidinecarboxylic acid (200mg, 0.87mmol), 2- aminoquinoline (151mg, 1.05mmol), 1- ethyl- 3- (3- dimethylamine propyl) carbodiimide hydrochloride (251mg, 1.31mmol) and N- hydroxyl -7- azepine benzotriazole (297mg, 2.18mmol) is dissolved in methylene chloride (15mL), and n,N-diisopropylethylamine is added dropwise into this solution under the conditions of 0 DEG C 16h is stirred at room temperature in (0.61mL, 3.49mmol), and washing (10mL × 2) is added, and organic phase is dry with anhydrous sodium sulfate, removes molten Agent, concentrate carry out post separation (V (petroleum ether)/V (ethyl acetate)=3/1), obtain compound 4- (quinoline -2- Ji Anjijia Acyl group) piperidines -1- t-butyl formate: 290mg yellow oil, yield: 93%.
1H NMR(400MHz,CDCl3): δ ppm 8.42 (s, 1H), 8.18 (d, J=9.0Hz, 1H), 7.80 (t, J= 8.9Hz,2H),7.69–7.64(m,1H),7.47–7.44(m,1H),4.16–4.13(m,1H),2.77–2.71(m,2H), 2.47–2.41(m,1H),1.94–1.91(m,2H),1.78–1.72(m,4H),1.46(s,9H)；MS-ESI:m/z 356.3[M +H]+.
Compound 4- (quinoline -2- base carbamoyl) piperidines -1- t-butyl formate (295mg, 0.83mmol) is dissolved in The ethyl acetate solution (3mL) of 4mol/L HCl is added in methylene chloride (3mL), stops reaction after 2h is stirred at room temperature.It removes molten Agent obtains compound N-(quinoline -2- base) piperidines -4- carboxamide dihydrochloride 242mg white solid, yield 99%.
1H NMR(400MHz,CD3OD): δ ppm 8.97 (d, J=9.1Hz, 1H), 8.22 (t, J=7.7Hz, 2H), 8.09 (t, J=7.8Hz, 1H), 7.86 (t, J=7.8Hz, 1H), 7.69 (d, J=9.1Hz, 1H), 3.58-3.53 (m, 2H), 3.22 (td,J1=12.9, J2=3.0Hz, 2H), 3.15-3.12 (m, 1H), 2.35-2.31 (m, 2H), 2.18-2.09 (m, 2H)；MS- ESI:m/z 256.2[M+H-2HCl]+.
Step 2: compound 2- (the fluoro- 2- methyl -3- of 5- (4- (quinoline -2- base carbamoyl) piperidines -1- carbonyl) -1H- Indoles -1- base) methyl acetate synthesis
By the fluoro- 1- of compound 5- (2- methoxyl group -2- oxoethyl) -2- Methyl-1H-indole -3- carboxylic acid (261mg, 0.99mmol), compound N-(quinoline -2- base) piperidines -4- carboxamide hydrochloride (240mg, 0.82mmol), 1- ethyl -3- (3- Dimethylamine propyl) carbodiimide hydrochloride (237mg, 1.23mmol) and N- hydroxyl -7- azepine benzotriazole (280mg, 2.06mmol) be dissolved in methylene chloride (15mL), under the conditions of 0 DEG C into this solution be added dropwise n,N-diisopropylethylamine (0.57mL, 3.29mmol), 15h is stirred at room temperature, adds washing (10mL × 3), organic phase is dry with anhydrous sodium sulfate, removes solvent, concentrate It carries out post separation (V (methylene chloride)/V (methanol)=40/1), obtains 163mg faint yellow solid, yield: 39%.
1H NMR(400MHz,CDCl3): δ ppm 8.47-8.41 (m, 2H), 8.18 (d, J=8.9Hz, 1H), 7.80 (t, J =8.1Hz, 2H), 7.67 (t, J=7.7Hz, 1H), 7.46 (t, J=7.5Hz, 1H), 7.11 (dd, J1=8.8, J2=4.1Hz, 1H),6.94(td,J1=9.0, J2=2.4Hz, 1H), 4.79 (s, 2H), 4.33 (m, 1H), 3.76 (s, 3H), 3.10-2.98 (m,2H),2.59–2.55(m,1H),2.50(s,3H),2.00–1.90(m,3H),1.82–1.79(m,1H)；MS-ESI:m/z 503.2[M+H]+.
Step 3: compound 2- (the fluoro- 2- methyl -3- of 5- (4- (quinoline -2- base carbamoyl) piperidines -1- carbonyl) -1H- Indoles -1- base) acetic acid hydrochloride synthesis
To compound 2- (the fluoro- 2- methyl -3- of 5- (4- (quinoline -2- base carbamoyl) piperidines -1- carbonyl) -1H- Yin Diindyl -1- base) water is added in the tetrahydrofuran (8mL) of methyl acetate (161mg, 0.32mmol) and the mixed solution of water (4mL) It closes lithium hydroxide (67mg, 1.60mmol), 45 DEG C of reaction 2h, 1mol/L salt acid for adjusting pH value is added to 1 or so, adds ethyl acetate It extracts (10mL × 2), removes solvent, obtain crude yellow solid 93mg, yield 55.3% send and prepares chromatogram purification, obtains light Red solid 5mg, yield: 3%.
1H NMR(400MHz,CD3OD): δ ppm 8.47 (t, J=8.8Hz, 1H), 8.06 (d, J=9.0Hz, 1H), 7.97–7.94(m,2H),7.83–7.77(m,1H),7.63-7.57(m,1H),7.37(dd,J1=8.9Hz, J2=4.2Hz, 1H), 7.12 (d, J=9.2Hz, 1H), 6.98 (t, J=9.0Hz, 1H), 5.02 (s, 2H), 3.25-3.15 (m, 2H), 2.91- 2.88(m,1H),2.52(s,3H),2.05–2.00(m,2H),1.91–1.80(m,3H)；MS-ESI:m/z 489.3[M+H- HCl]+.
6 compound 2- of embodiment (the fluoro- 3- of 5- (4- (the fluoro- 1H- indole 2-carboxamides base of 5-) piperidines -1- carbonyl) -2- first Base -1H- indoles -1- base) acetic acid hydrochloride synthesis
Step 1: compound 2- (3- (4- ((tertbutyloxycarbonyl) amino) piperidines -1- carbonyl) fluoro- 2- methyl-1 H- Yin of -5- Diindyl -1- base) methyl acetate synthesis
By the fluoro- 1- of compound 5- (2- methoxyl group -2- oxoethyl) -2- Methyl-1H-indole -3- formic acid (320mg, 1.2mmol), compound piperidine -4- t-butyl carbamate (290mg, 1.4mmol), 1- ethyl -3- (3- dimethylamine propyl) carbon Diimmonium salt hydrochlorate (460mg, 2.4mmol) and N- hydroxyl -7- azepine benzotriazole (250mg, 1.8mmol) are dissolved in dichloromethane In alkane (10mL), n,N-diisopropylethylamine (0.65mL, 3.6mmol) is added dropwise into this solution under the conditions of 0 DEG C, is stirred at room temperature 10h adds washing (10mL × 3), and organic phase is dry with anhydrous sodium sulfate, removes solvent, and concentrate carries out post separation (V (petroleum Ether)/V (ethyl acetate)=1/1) 500mg white solid is obtained, yield: 93%.
1H NMR(400MHz,CDCl3):δppm 7.09-7.20(m,2H),6.91-6.96(m,1H),4.79(s,2H), 4.44-4.54(m,1H),4.06-4.31(m,2H),3.76(s,3H),3.65-3.77(m,1H),3.00-3.11(m,2H), 2.42-2.47(m,3H),1.97-2.05(m,2H),1.44(s,9H)；MS-ESI:m/z 448.10[M+H]+.
Step 2: compound 2- (3- (4- amino piperidine -1- carbonyl) the fluoro- 2- Methyl-1H-indole -1- base of -5-) acetic acid first The synthesis of ester hydrochloride
By compound 2- (3- (4- ((tertbutyloxycarbonyl) amino) piperidines -1- carbonyl) fluoro- 2- Methyl-1H-indole -1- of -5- Base) methyl acetate (500mg, 1.1mmol) is dissolved in methylene chloride (4mL), the ethyl acetate solution of 4mol/L HCl is added (6mL) stops reaction after 2h is stirred at room temperature.Solvent is removed, white solid 420mg white solid, yield 99% are obtained.
1H NMR(400MHz,CD3OD):δppm 7.29-7.31(m,1H),7.03-7.16(m,1H),6.89-6.94(m, 1H),4.96-5.02(m,2H),4.14-4.36(m,1H),3.26,3.72(s,2H,1H),3.34-3.44(m,1H),3.03- 3.22(m,2H),2.35-2.42(m,3H),1.97-2.07(m,2H),1.45-1.65(m,2H)；MS-ESI:m/z 348.10 [M+H-HCl]+.
Step 3: compound 2- (the fluoro- 3- of 5- (4- (the fluoro- 1H- indole 2-carboxamides base of 5-) piperidines -1- carbonyl) -2- first Base -1H- indoles -1- base) methyl acetate synthesis
By compound 2- (3- (4- amino piperidine -1- carbonyl) the fluoro- 2- Methyl-1H-indole -1- base of -5-) methyl acetate salt Hydrochlorate (210mg, 0.5mmol), the fluoro- 2 formic acid -1H- indoles (100mg, 0.5mmol) of compound 5-, 1- ethyl -3- (3- diformazan Amine propyl) carbodiimide hydrochloride (210mg, 1.1mmol) and N- hydroxyl -7- azepine benzotriazole (110mg, 0.8mmol) It is dissolved in methylene chloride (10mL), n,N-diisopropylethylamine (0.5mL, 2.2mmol) is added dropwise into this solution under the conditions of 0 DEG C, 10h is stirred at room temperature, adds washing (10mL × 3), organic phase is dry with anhydrous sodium sulfate, removes solvent, and concentrate carries out post separation (V (petroleum ether)/V (ethyl acetate)=1/1)=1/3) 70mg white solid is obtained, yield: 25%.
1H NMR(400MHz,CDCl3): δ ppm 11.65 (s, 1H), 8.37 (br.s, 1H), 7.49 (dd, J=8.9, 4.3Hz,1H),7.38-7.43(m,2H),7.10-7.20(m,2H),6.98-7.02(m,2H),5.18(s,2H),4.10- 4.18(m,2H),3.71(s,3H),3.00-3.21(m,2H),2.35-2.42(m,3H),1.86-1.89(m,2H),1.48- 1.56(m,2H)；MS-ESI:m/z 509.00[M+H]+.
Step 4: compound 2- (the fluoro- 3- of 5- (4- (the fluoro- 1H- indole 2-carboxamides base of 5-) piperidines -1- carbonyl) -2- first Base -1H- indoles -1- base) acetic acid hydrochloride synthesis
By compound 2- (the fluoro- 3- of 5- (4- (the fluoro- 1H- indole 2-carboxamides base of 5-) piperidines -1- carbonyl) -2- methyl-1 H- Indoles -1- base) methyl acetate (70mg, 0.14mmol) and LiOHH2O (42mg, 1.0mmol) be dissolved in tetrahydrofuran (5mL) and The in the mixed solvent of water (3mL), 45 DEG C of reaction 1h, add 1.0mol/L hydrochloric acid adjust pH=1, add ethyl acetate extraction (10mL × 3) dry with sodium sulphate after, organic phase merges, solvent is removed, 60mg white solid, yield 82.2% are obtained.
1H NMR(600MHz,d6-DMSO):δppm 11.64(s,1H),8.39(s,1H),7.37-7.49(m,3H), 7.10-7.20(m,2H),6.97-7.06(m,2H),5.03(s,2H),4.03-4.16(m,2H),3.07-3.14(m,3H), 2.35-2.42(m,3H),1.85-1.89(m,2H),1.48-1.55(m,2H)；MS-ESI:m/z 493.30[M-H-HCl]-.
7 compound 2- of embodiment (the fluoro- 3- of 5- (4- ((4- fluorophenyl) sulfonyl) piperazine -1- carbonyl) -2- methyl-1 H- Yin Diindyl -1- base) acetic acid synthesis
Step 1: compound 2- (the fluoro- 3- of 5- (4- ((4- fluorophenyl) sulfonyl) piperazine -1- carbonyl) -2- methyl-1 H- Yin Diindyl -1- base) methyl acetate synthesis
4- fluorobenzene sulfonic acid (110mg, 0.61mmol) is dissolved in methylene chloride (5mL), thionyl chloride is added at room temperature (120mg, 0.93mmol) is added DMF (1mL) after 10min, is spin-dried for solvent after reacting at room temperature 1h, is added at 0 DEG C to 2- (5- Fluoro- 2- methyl -3- (piperazine -1- carbonyl) -1H- indoles -1- base) acetate hydrochloride (150mg, 0.41mmol) and triethylamine In DMF (5mL) solution of (250mg, 2.43mmol), 3h is stirred at room temperature, screws out solvent, adds washing (15mL), ethyl acetate extraction It takes (10mL × 3), organic phase is dry with anhydrous sodium sulfate, removes solvent, and concentrate carries out post separation (V (petroleum ether)/V (acetic acid Ethyl ester)=1/1) 95mg white solid is obtained, yield: 47%.
1H NMR(400MHz,CDCl3): δ ppm 7.75-7.79 (m, 2H), 7.24 (t, J=8.8Hz, 2H), 7.10 (dd, J=8.9,4.2Hz, 1H), 7.02 (dd, J=9.3,2.4Hz, 1H), 6.93 (td, J=9.0,2.4Hz, 1H), 4.77 (s, 2H),3.76(s,3H),3.74(br.s,4H),3.04(br.s,4H),2.40(s,3H)；MS-ESI:m/z 492.95[M+H ]+.
Step 2: compound 2- (the fluoro- 3- of 5- (4- ((4- fluorophenyl) sulfonyl) piperazine -1- carbonyl) -2- methyl-1 H- Yin Diindyl -1- base) acetic acid synthesis
To compound 2- (the fluoro- 3- of 5- (4- ((4- fluorophenyl) sulfonyl) piperazine -1- carbonyl) -2- Methyl-1H-indole -1- Base) hydrated hydroxide is added in the tetrahydrofuran (5mL) of methyl acetate (90mg, 0.18mmol) and the mixed solution of water (3mL) Change lithium (40mg, 0.92mmol), 45 DEG C of reaction 1h, addition 1.0mol/L hydrochloric acid adjusting pH=1, ethyl acetate extraction (5mL × 3), organic phase is dry with anhydrous sodium sulfate, removes solvent, obtains light yellow solid 70mg, yield 80%.
1H NMR(600MHz,d6- DMSO): δ ppm 7.81-7.84 (m, 2H), 7.50 (t, J=8.8Hz, 2H), 7.46 (dd, J=8.9,4.4Hz, 1H), 7.08 (dd, J=9.7,2.4Hz, 1H), 6.97 (td, J=9.2,2.5Hz, 1H), 5.01 (s,2H),3.60(s,4H),3.04(br.s,2H),2.86(br.s,2H),2.28(s,3H)；MS-ESI:m/z 478.90[M+ H]+.
8 compound of embodiment (R) -2- (fluoro- 3- of 5- (4- ((4- fluorophenyl) sulfonyl) -2- methyl piperazine -1- carbonyl) - 2- Methyl-1H-indole -1- base) acetic acid synthesis
Step 1: compound (R) -4- (the fluoro- 1- of 5- (2- methoxyl group -2- oxoethyl) -2- Methyl-1H-indole -3- carbonyl Base) -3- methyl piperazine -1- t-butyl formate synthesis
By the fluoro- 1- of compound 5- (2- methoxyl group -2- oxoethyl) -2- Methyl-1H-indole -3- formic acid (450mg, 1.70mmol), (R) -4- tertbutyloxycarbonyl -2- methyl piperazine (400mg, 2.03mmol), 1- ethyl -3- (3- dimethylamine propyl) Carbodiimide hydrochloride (650mg, 3.39mmol) and N- hydroxyl -7- azepine benzotriazole (350mg, 2.55mmol) are dissolved in two In chloromethanes (10mL), n,N-diisopropylethylamine (0.9mL, 5.09mmol) is added dropwise into this solution under the conditions of 0 DEG C, room temperature is stirred 17h is mixed, is added washing (10mL × 3), organic phase is dry with anhydrous sodium sulfate, removes solvent, and concentrate carries out post separation (V (petroleum Ether)/V (ethyl acetate)=1/1) 330mg white solid is obtained, yield: 43%.
1H NMR(400MHz,CDCl3): δ ppm 7.08-7.20 (m, 2H), 6.96 (td, J=9.0,2.2Hz, 1H), 4.81(s,2H),3.31-3.44,4.41-4.56(m,0.5H,0.5H),3.84-4.00(m,2H),3.78(s,3H),3.12- 3.25(m,1H),2.73-2.94(m,1H),2.44-2.49(m,3H),1.49(s,9H),1.22-1.33(m,3H)；MS-ESI: m/z 448.10[M+H]+.
Step 2: compound (R) -2- (the fluoro- 2- methyl -3- of 5- (2- methyl piperazine -1- carbonyl) -1H- indoles -1- base) second The synthesis of acid methyl ester hydrochloride salt
By compound (R) -4- (the fluoro- 1- of 5- (2- methoxyl group -2- oxoethyl) -2- Methyl-1H-indole -3- carbonyl) -3- Methyl piperazine -1- t-butyl formate (320mg, 0.71mmol) is dissolved in methylene chloride (3mL), and the acetic acid second of 4mol/L HCl is added Ester solution (4mL) stops reaction after 1.5h is stirred at room temperature.Solvent is removed, 270mg white solid, yield 98% are obtained.
1H NMR(400MHz,CD3OD): δ ppm 7.38 (dd, J=8.9,4.2Hz, 1H), 7.05-7.13,7.25-7.32 (m, 0.5H, 0.5H), 7.00 (td, J=9.1,2.2Hz, 1H), 5.10 (s, 2H), 4.74-4.80 (m, 1H), 4.08-4.20 (m,1H),3.79(s,3H),3.51-3.67(m,1H),3.32-3.45(m,3H),3.04-3.26(m,1H),2.44-2.49 (m,3H),1.40-1.50(m,3H)；MS-ESI:m/z 348.10[M+H-HCl]+.
Step 3: compound (R) -2- (the fluoro- 3- of 5- (4- ((4- fluorophenyl) sulfonyl) -2- methyl piperazine -1- carbonyl) -2- Methyl-1H-indole -1- base) methyl acetate synthesis
4- fluorobenzene sulfonic acid (185mg, 1.06mmol) is added into methylene chloride (5mL), thionyl chloride is added at room temperature (192mg, 1.62mmol) is added DMF (1mL) after 10min, is spin-dried for solvent after reacting at room temperature 1h, is added at 0 DEG C to (R) -2- (the fluoro- 2- methyl -3- of 5- (2- methyl piperazine -1- carbonyl) -1H- indoles -1- base) acetate hydrochloride (270mg, 0.7mmol) In DMF (5mL) solution of triethylamine (430mg, 4.22mmol), 3h is stirred at room temperature, screws out solvent, adds washing (15mL), second Acetoacetic ester extracts (10mL × 3), and organic phase is dry with anhydrous sodium sulfate, removes solvent, and concentrate carries out post separation (V (petroleum Ether)/V (ethyl acetate)=2/1) 130mg white solid is obtained, yield: 37%.
1H NMR(400MHz,CDCl3): δ ppm 7.73-7.79 (m, 2H), 7.21-7.27 (m, 2H), 7.10 (dd, J= 8.9,4.1Hz,1H),6.92-7.01(m,2H),4.77(s,2H),4.45-4.69(m,1H),3.91-4.00(m,1H),3.77 (s, 3H), 3.74-3.79,3.64-3.67 (m, 0.5H, 0.5H), 3.58 (d, J=11.5Hz, 1H), 3.32-3.39,3.50- 3.57(m,0.5H,0.5H),2.48-2.59(m,1H),2.36-2.40(m,3H),2.18-2.23,2.36-2.39(m,0.5H, 0.5H),1.34-1.47(m,3H)；MS-ESI:m/z 506.30[M+H]+.
Step 4: compound (R) -2- (the fluoro- 3- of 5- (4- ((4- fluorophenyl) sulfonyl) -2- methyl piperazine -1- carbonyl) -2- Methyl-1H-indole -1- base) acetic acid synthesis
To compound (R) -2- (the fluoro- 3- of 5- (4- ((4- fluorophenyl) sulfonyl) -2- methyl piperazine -1- carbonyl) -2- first Base -1H- indoles -1- base) in the tetrahydrofuran (5mL) of methyl acetate (130mg, 0.26mmol) and the mixed solution of water (3mL) A hydronium(ion) lithia (60mg, 1.29mmol), 45 DEG C of reaction 1h, addition 1.0mol/L salt acid for adjusting pH value to 1, acetic acid is added Ethyl ester extracts (5mL × 3), and organic phase is dry with anhydrous sodium sulfate, removes solvent, obtain light yellow solid 120mg, yield 94%.
1H NMR(400MHz,CD3OD):δppm 7.81-7.88(m,2H),7.31-7.40(m,3H),6.91-7.05(m, 2H), 4.97 (s, 2H), 4.59-4.74 (m, 1H), 3.92-4.04 (m, 1H), 3.69-3.79 (m, 1H), 3.63 (d, J= 11.7Hz,1H),3.78-3.53(m,1H),2.50-2.64(m,1H),2.32-2.40(m,3H),2.27-2.45(m,1H), 1.34-1.45(m,3H)；MS-ESI:m/z 492.95[M+H]+.
9 compound 2- of embodiment (the fluoro- 3- of 5- (4- (4- fluorobenzene ylsulfonylamino) piperidines -1- carbonyl) -2- methyl-1 H- Yin Diindyl -1- base) acetic acid synthesis
Step 1: compound 2- (the fluoro- 3- of 5- (4- (4- fluorobenzene ylsulfonylamino) piperidines -1- carbonyl) -2- methyl-1 H- Yin Diindyl -1- base) methyl acetate synthesis
4- fluorobenzene sulfonic acid (140mg, 0.78mmol) is added into methylene chloride (5mL), thionyl chloride is added at room temperature (150mg, 1.19mmol) is added DMF (1mL) after 10min, is spin-dried for solvent after reacting at room temperature 1h, is added at 0 DEG C to compound 2- (3- (4- amino piperidine -1- carbonyl) the fluoro- 2- Methyl-1H-indole -1- base of -5-) acetate hydrochloride (200mg, 0.52mmol) and in DMF (5mL) solution of triethylamine (400mg, 3.13mmol), 3h is stirred at room temperature, screws out solvent, adds washing (15mL), ethyl acetate extract (10mL × 3), and organic phase is dry with anhydrous sodium sulfate, remove solvent, and concentrate carries out post separation (V (petroleum ether)/V (ethyl acetate)=2/1) obtains 168mg white solid, yield: 64%.
1H NMR(400MHz,CDCl3): δ ppm 7.87 (dd, J=8.8,5.0Hz, 2H), 7.16 (t, J=8.3Hz, 2H), 7.10 (dd, J=8.9,4.1Hz, 1H), 7.02-7.05 (m, 1H), 6.90-6.94 (m, 1H), 4.95-5.00,4.78- 4.83(m,0.5H,0.5H),4.77(s,2H),4.02-4.14(m,1H),3.75(s,3H),3.36-3.45(m,1H),2.97- 3.10(m,2H),2.39-2.45(m,3H),1.79-1.82(m,3H),1.32-1.52(m,2H)；MS-ESI:m/z 506.10 [M+H]+.
Step 2: compound 2- (the fluoro- 3- of 5- (4- (4- fluorobenzene ylsulfonylamino) piperidines -1- carbonyl) -2- methyl-1 H- Yin Diindyl -1- base) acetic acid synthesis
By compound 2- (the fluoro- 3- of 5- (4- (4- fluorobenzene ylsulfonylamino) piperidines -1- carbonyl) -2- Methyl-1H-indole -1- Base) methyl acetate (160mg, 0.32mmol) and LiOHH2O (710mg, 1.58mmol) is dissolved in tetrahydrofuran (5mL) and water The in the mixed solvent of (3mL), 45 DEG C of reaction 1h add 1.0mol/L hydrochloric acid to adjust pH=1, and ethyl acetate is added to extract (10mL × 3), Organic phase is dry with sodium sulphate after merging, and removes solvent, obtains 150mg white solid, yield 96%.
1H NMR(400MHz,CD3OD): δ ppm 7.94 (dd, J=8.8,5.1Hz, 2H), 7.27-7.33 (m, 3H), 7.10 (dd, J=39.6,8.9Hz, 1H), 6.92-6.97 (m, 1H), 4.96 (s, 2H), 4.49-4.87 (m, 1H), 3.94- 4.18(m,1H),3.36-3.42(m,1H),3.08-3.22(m,2H),2.37-2.45(m,3H),1.74-1.77(m,2H), 1.35-1.47(m,2H)；MS-ESI:m/z 492.10[M+H]+.
10 compound 2- of embodiment (the fluoro- 2- methyl -3- of 5- (4- (quinoline -5- formamido) piperidines -1- carbonyl) -1H- Yin Diindyl -1- base) acetic acid hydrochloride synthesis
Step 1: compound 2- (the fluoro- 2- methyl -3- of 5- (4- (quinoline -5- formamido) piperidines -1- carbonyl) -1H- Yin Diindyl -1- base) methyl acetate synthesis
By Compound Compound 2- (3- (4- amino piperidine -1- carbonyl) the fluoro- 2- Methyl-1H-indole -1- base of -5-) acetic acid Methyl ester hydrochloride (200mg, 0.52mmol), compound 5- carboxylic acid quinoline (108mg, 0.63mmol), 1- ethyl -3- (3- diformazan Amine propyl) carbodiimide hydrochloride (200mg, 1.05mmol) and N- hydroxyl -7- azepine benzotriazole (106mg, 0.78mmol) be dissolved in methylene chloride (10mL), under the conditions of 0 DEG C into this solution be added dropwise n,N-diisopropylethylamine (0.4mL, 2.09mmol), 10h is stirred at room temperature, adds washing (10mL × 3), organic phase is dry with anhydrous sodium sulfate, removes solvent, concentrate It carries out post separation (V (petroleum ether)/V (ethyl acetate)=1/1) and obtains 210mg light yellow solid, yield: 80%.
1H NMR(400MHz,CDCl3): δ ppm 8.93 (dd, J=4.1,1.5Hz, 1H), 8.71 (d, J=8.5Hz, 1H), 8.15-8.18 (m, 1H), 7.63-7.65 (m, 2H), 7.46 (dd, J=8.6,4.2Hz, 1H), 7.09-7.20 (m, 2H), 6.92-6.94(m,1H),6.09-6.30(m,1H),4.78(s,2H),4.30-4.34(m,2H),3.76(s,3H),3.08- 3.25 (m, 2H), 2.97-3.10 (m, 2H), 2.45 (d, J=10.6,3H), 2.15-2.20 (m, 2H), 1.53-1.63 (m, 2H)；MS-ESI:m/z 503.00[M+H]+.
Step 2: compound 2- (the fluoro- 2- methyl -3- of 5- (4- (quinoline -5- formamido) piperidines -1- carbonyl) -1H- Yin Diindyl -1- base) acetic acid hydrochloride synthesis
By compound 2- (the fluoro- 2- methyl -3- of 5- (4- (quinoline -5- formamido) piperidines -1- carbonyl) -1H- indoles -1- Base) methyl acetate (200mg, 0.4mmol) and LiOHH2O (83mg, 2.0mmol) is dissolved in tetrahydrofuran (5mL) and water (3mL) In the mixed solvent, 45 DEG C of reaction 1h, add 1.0mol/L hydrochloric acid adjust pH=1, add ethyl acetate extract (10mL × 3), it is organic It is dry with sodium sulphate after mutually merging, solvent is removed, 160mg light yellow solid, yield 76.6% are obtained.
1H NMR(600MHz,CD3OD): δ ppm 8.99-9.04 (m, 2H), 8.23 (d, J=8.4Hz, 1H), 7.90- 7.97 (m, 2H), 7.80-7.82 (m, 1H), 7.34-7.36 (m, 1H), 7.17 (dd, J=43.7,8.4Hz, 1H), 6.94- 6.99 (m, 1H), 5.01 (s, 2H), 4.30-4.34 (m, 1H), 3.25-3.36 (m, 2H), 2.47 (d, J=25.6,3H), 2.10-2.17(m,2H),1.62-1.71(m,2H)；MS-ESI:m/z 489.20[M+H-HCl]+.
11 compound 2- of embodiment (the fluoro- 2- methyl -3- of 5- (4- ((quinoline -2- methylene) carbamoyl) piperidines -1- Carbonyl) -1H- indoles -1- base) acetic acid hydrochloride synthesis
Step 1: the synthesis of compound 1- (tertbutyloxycarbonyl) piperidines -4- formic acid
By compound 4- methoxycarbonyl group piperidines -1- t-butyl formate (1.0g, 4.1mmol) and LiOHH2O(860mg, It 21mmol) is dissolved in the in the mixed solvent of tetrahydrofuran (10mL) and water (5mL), 45 DEG C of reaction 1h add 1.0mol/L hydrochloric acid to adjust PH=1 adds ethyl acetate to extract (10mL × 3), and organic phase is dry with sodium sulphate after merging, and removes solvent, obtains 860mg white Solid, yield 91%.
1H NMR(400MHz,CD3OD):δppm 3.97-4.02(m,2H),2.88-2.95(m,2H),2.48-2.55(m, 1H),1.88-1.92(m,2H),1.54-1.61(m,2H),1.47(s,9H)；MS-ESI:m/z 174.20[M-55]+.
Step 2: the synthesis of compound 4- ((quinoline -2- methylene) carbamoyl) piperidines -1- t-butyl formate
By compound 1- (tertbutyloxycarbonyl) piperidines -4- formic acid (200mg, 0.87mmol), compound quinoline -2- methylamine (165mg, 1.05mmol), 1- ethyl -3- (3- dimethylamine propyl) carbodiimide hydrochloride (334mg, 1.74mmol) and N- hydroxyl Base -7- azepine benzotriazole (180mg, 1.31mmol) is dissolved in methylene chloride (10mL), is dripped under the conditions of 0 DEG C into this solution Add n,N-diisopropylethylamine (0.45mL, 2.62mmol), 10h is stirred at room temperature, add washing (10mL × 3), organic phase is with anhydrous Sodium sulphate is dry, removes solvent, and concentrate carries out post separation (V (petroleum ether)/V (ethyl acetate)=1/1) and obtains 285mg white Solid, yield: 88%.
1H NMR(400MHz,CDCl3): δ ppm 8.14 (d, J=8.4Hz, 1H), 8.06 (d, J=8.5Hz, 1H), 7.82 (d, J=8.1Hz, 1H), 7.71-7.75 (m, 1H), 7.55 (t, J=7.5Hz, 1H), 7.33 (d, J=8.5Hz, 2H), 4.73 (d, J=4.5Hz, 2H), 4.11-4.23 (m, 2H), 2.78-2.84 (m, 2H), 2.40-2.47 (m, 1H), 1.91-1.94 (m, 2H),1.68-1.78(m,2H),1.46(s,9H).MS-ESI:m/z 370.20[M+H]+.
Step 3: the synthesis of compound N-(quinoline -2- methylene) piperidines -4- carboxamide hydrochloride
By compound 4- ((quinoline -2- methylene) carbamoyl) piperidines -1- t-butyl formate (280mg, It 0.76mmol) is dissolved in methylene chloride (4mL), the ethyl acetate solution (4mL) of 4mol/L HCl is added, stops after 2h is stirred at room temperature Reaction.Solvent is removed, 230mg white solid, yield 99% are obtained.
1H NMR(400MHz,CD3OD): δ ppm 9.17 (d, J=8.6Hz, 1H), 8.36 (t, J=8.6Hz, 2H), 8.20 (t, J=7.8Hz, 1H), 8.06 (d, J=8.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 4.98 (s, 2H), 3.46-3.49 (m,2H),3.11-3.17(m,2H),2.83-2.89(m,1H),2.15-2.18(m,2H),1.92-2.01(m,2H)；MS- ESI:m/z 270.20[M+H-HCl]+.
Step 4: compound 2- (the fluoro- 2- methyl -3- of 5- (4- ((quinoline -2- methylene) carbamoyl) piperidines -1- carbonyl Base) -1H- indoles -1- base) methyl acetate synthesis
By compound N-(quinoline -2- methylene) piperidines -4- carboxamide hydrochloride (200mg, 0.75mmol), compound N - (quinoline -2- methylene) piperidines -4- carboxamide hydrochloride (230mg, 0.75mmol), 1- ethyl -3- (3- dimethylamine propyl) carbon Diimmonium salt hydrochlorate (290mg, 1.51mmol) and N- hydroxyl -7- azepine benzotriazole (154mg, 1.13mmol) are dissolved in dichloro In methane (10mL), n,N-diisopropylethylamine (0.65mL, 3.77mmol) is added dropwise into this solution under the conditions of 0 DEG C, room temperature is stirred 10h is mixed, is added washing (10mL × 3), organic phase is dry with anhydrous sodium sulfate, removes solvent, and concentrate carries out post separation (V (dichloro Methane)/V (methanol)=30/1) 194mg white solid is obtained, yield: 49%.
1H NMR(400MHz,CDCl3): δ ppm 8.14 (d, J=8.4Hz, 1H), 8.06 (d, J=8.5Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.74 (t, J=7.7Hz, 1H), 7.55 (t, J=7.5Hz, 1H), 7.32-7.38 (m, 2H), 7.11 (dd, J=8.9,4.1Hz, 1H), 6.93 (td, J=9.0,2.1Hz, 1H), 4.79 (s, 2H), 4.74 (s, 2H), 4.22-4.48 (m,2H),3.76(s,3H),3.01-3.11(m,2H),2.52-2.63(m,1H),2.45-2.48(m,3H),1.94-2.07 (m,2H),1.73-1.84(m,2H)；MS-ESI:m/z 517.30[M+H]+.
Step 5: compound 2- (the fluoro- 2- methyl -3- of 5- (4- ((quinoline -2- methylene) carbamoyl) piperidines -1- carbonyl Base) -1H- indoles -1- base) acetic acid hydrochloride synthesis
By compound 2- (the fluoro- 2- methyl -3- of 5- (4- ((quinoline -2- methylene) carbamoyl) piperidines -1- carbonyl) - 1H- indoles -1- base) methyl acetate (190mg, 0.37mmol) and LiOHH2O (77mg, 1.84mmol) is dissolved in tetrahydrofuran The in the mixed solvent of (5mL) and water (3mL), 45 DEG C of reaction 1h add 1mol/L hydrochloric acid to adjust pH=1, ethyl acetate are added to extract (10mL × 3), organic phase is dry with sodium sulphate after merging, and removes solvent, obtains 134mg white solid, yield 67.7%.
1H NMR(400MHz,d6- DMSO): δ ppm 8.60-8.64 (m, 1H), 8.32 (d, J=8.4Hz, 1H), 7.95 (t, J=6.7Hz, 2H), 7.74 (t, J=7.3Hz, 1H), 7.57 (t, J=7.3Hz, 1H), 7.42 (d, J=8.3Hz, 1H), 7.27-7.31 (m, 1H), 6.89 (t, J=8.4Hz, 1H), 4.54 (s, 2H), 4.39 (s, 2H), 4.08-4.13 (m, 2H), 2.90-3.06(m,2H),2.50-2.60(m,1H),2.30-2.38(m,3H),1.46-1.67(m,2H),1.73-1.84(m, 2H)；MS-ESI:m/z 503.20[M+H-HCl]+.
12 compound of embodiment (R) -2- (the fluoro- 2- methyl -3- of 5- (3- methyl -4- (quinoline -2- carbonyl) piperazine -1- carbonyl Base) -1H- indoles -1- base) acetic acid hydrochloride synthesis
Step 1: the synthesis of compound (R) -3- methyl -4- (quinoline -2- carbonyl) piperazine -1- t-butyl formate
By compound (R) -3- methyl piperazine -1- t-butyl formate (530mg, 2.6mmol), compound quinoline -2- formic acid (450mg, 2.6mmol), 1- ethyl -3- (3- dimethylamine propyl) carbodiimide hydrochloride (996mg, 5.2mmol) and N- hydroxyl - 7- azepine benzotriazole (530mg, 3.9mmol) is dissolved in methylene chloride (10mL), and N is added dropwise into this solution under the conditions of 0 DEG C, N- diisopropylethylamine (1.3mL, 7.8mmol), is stirred at room temperature 10h, adds washing (10mL × 3), organic phase anhydrous sodium sulfate It is dry, solvent is removed, concentrate carries out post separation (V (petroleum ether)/V (ethyl acetate)=1/1) and obtains 820mg white solid, Yield: 88%.
1H NMR(400MHz,CDCl3): δ ppm 8.26 (d, J=8.3Hz, 1H), 8.09 (d, J=8.5Hz, 1H), 7.85 (d, J=8.1Hz, 1H), 7.76 (t, J=7.6Hz, 1H), 7.69 (d, J=8.4Hz, 1H), 7.61 (t, J=7.5Hz, 1H), 4.56-4.60,4.94-5.00(m,0.5H,0.5H),3.90-3.94,4.29-4.34(m,0.5H,0.5H),3.78-4.07 (m,2H),3.16-3.22,3.39-3.45(m,0.5H,0.5H),2.95-3.12(m,2H),1.48(s,9H),1.33-1.37 (m,3H)；MS-ESI:m/z 356.20[M+H]+.
Step 2: the synthesis of compound (R)-(2- methylpiperazine-1-yl) (quinoline -2- base) methanone hvdrochloric acid salt
Compound (R) -3- methyl -4- (quinoline -2- carbonyl) piperazine -1- t-butyl formate (250mg, 0.7mmol) is molten In methylene chloride (4mL), the ethyl acetate solution (4mL) of 4mol/L HCl is added, stops reaction after 2h is stirred at room temperature.It removes molten Agent obtains 230mg white solid, yield 99%.
MS-ESI:m/z 256.25[M+H-HCl]+.
Step 3: compound (R) -2- (fluoro- 2- methyl -3- of 5- (3- methyl -4- (quinoline -2- carbonyl) piperazine -1- carbonyl) - 1H- indoles -1- base) methyl acetate synthesis
By the fluoro- 1- of compound 5- (2- methoxyl group -2- oxoethyl) -2- Methyl-1H-indole -3- formic acid (200mg, 0.75mmol), compound (R)-(2- methylpiperazine-1-yl) (quinoline -2- base) methanone hvdrochloric acid salt (192mg, 0.75mmol), 1- Ethyl -3- (3- dimethylamine propyl) carbodiimide hydrochloride (290mg, 1.51mmol) and N- hydroxyl -7- azepine benzotriazole (154mg, 1.13mmol) is dissolved in methylene chloride (10mL), and n,N-diisopropylethylamine is added dropwise into this solution under the conditions of 0 DEG C (0.65mL, 3.77mmol), is stirred at room temperature 10h, adds washing (10mL × 3), and organic phase is dry with anhydrous sodium sulfate, removes molten Agent, concentrate carry out post separation (V (ethyl acetate)/V (methanol)=120/1) and obtain 150mg white solid, yield: 39%.
MS-ESI:m/z 503.25[M+H]+.
Step 4: compound (R) -2- (fluoro- 2- methyl -3- of 5- (3- methyl -4- (quinoline -2- carbonyl) piperazine -1- carbonyl) - 1H- indoles -1- base) acetic acid hydrochloride synthesis
By compound (R) -2- (the fluoro- 2- methyl -3- of 5- (3- methyl -4- (quinoline -2- carbonyl) piperazine -1- carbonyl) -1H- Indoles -1- base) methyl acetate (150mg, 0.3mmol) and LiOHH2O (63mg, 1.5mmol) be dissolved in tetrahydrofuran (5mL) and The in the mixed solvent of water (3mL), 45 DEG C of reaction 1h, add 1.0mol/L hydrochloric acid adjust pH=1, add ethyl acetate extraction (10mL × 3) dry with sodium sulphate after, organic phase merges, solvent is removed, 110mg light yellow solid, yield 70.3% are obtained.
1H NMR(400MHz,CD3OD):δppm 8.64-8.70(m,1H),8.07-8.16(m,2H),7.91-7.97(m, 1H),7.77-7.83(m,2H),7.32-7.37(m,1H),7.11-7.26(m,1H),6.94-7.00(m,1H),5.01(s, 2H),4.10-4.17(m,1H),3.48-3.710(m,2H),3.34-3.44(m,1H),3.15-3.27(m,1H),2.41- 2.53(m,3H),1.60-1.66(m,1H),1.30-1.35(m,3H)；
MS-ESI:m/z 489.30[M+H-HCl]+.
13 compound 2- of embodiment (the fluoro- 3- of 5- (8- ((4- fluorophenyl) sulfonyl) -2,8- diaza spiro [4.5] decane - 2- carbonyl) -2- Methyl-1H-indole -1- base) acetic acid synthesis
Step 1: compound 2- (the fluoro- 1- of 5- (2- methoxyl group -2- oxoethyl) -2- Methyl-1H-indole -3- carbonyl) -2, The synthesis of 8- diaza spiro [4.5] decane -8- t-butyl formate
By the fluoro- 1- of compound 5- (2- methoxyl group -2- oxoethyl) -2- Methyl-1H-indole -3- formic acid (170mg, 0.64mmol), 2,8- diaza spiro [4.5] decane -8- t-butyl formate (155mg, 0.64mmol), 1- ethyl -3- (3- diformazan Amine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) and N- hydroxyl -7- azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene chloride (10mL), under the conditions of 0 DEG C into this solution be added dropwise n,N-diisopropylethylamine (0.35mL, 1.92mmol), 10h is stirred at room temperature, adds washing (10mL × 3), organic phase is dry with anhydrous sodium sulfate, removes solvent, concentrate It carries out post separation (V (petroleum ether)/V (ethyl acetate)=1/1) and obtains 163mg white solid, yield: 52%.
1H NMR(400MHz,CDCl3): δ ppm 7.11-7.14 (m, 2H), 6.957.02 (td, J=9.0,2.3Hz, 1H),4.80(s,2H),3.77(s,3H),3.35–3.59(m,6H),2.47(s,3H),1.69–1.90(m,3H),1.41– 1.69(m,3H),1.46(m,9H)；MS-ESI:m/z488.35[M+H]+.
Step 2: compound 2- (the fluoro- 2- methyl -3- of 5- (2,8- diaza spiro [4.5] decane -2- carbonyl) -1H- indoles - 1- yl) acetate hydrochloride synthesis
By compound 2- (the fluoro- 1- of 5- (2- methoxyl group -2- oxoethyl) -2- Methyl-1H-indole -3- carbonyl) -2,8- two Azaspiro [4.5] decane -8- t-butyl formate (160mg, 0.33mmol) is dissolved in methylene chloride (4mL), and 4mol/L is added 50min is stirred at room temperature in the ethyl acetate solution (2mL) of HCl, removes solvent, obtains 121mg light yellow liquid, yield 95%.
1H NMR(400MHz,CD3OD):δppm 7.31–7.37(m,1H),7.14–7.16(m,1H),6.95–7.01(m, 1H),5.08–5.18(m,2H),3.78–3.79(m,3H),3.56–3.65(m,2H),3.02–3.28(m,5H),2.45(s, 3H),1.72–2.03(m,7H)；MS-ESI:m/z 388.30[M+H-HCl]+.
Step 3: compound 2- (the fluoro- 3- of 5- (8- ((4- fluorophenyl) sulfonyl) -2,8- diaza spiro [4.5] decane -2- Carbonyl) -2- Methyl-1H-indole -1- base) methyl acetate synthesis
4- fluorobenzene sulfonic acid (91mg, 0.52mmol) is added into methylene chloride (10mL), thionyl chloride is added at room temperature (92mg, 0.78mmol) is added DMF (1mL) after 10min, is spin-dried for solvent after reacting at room temperature 1h, is added at 0 DEG C to compound 2- (the fluoro- 2- methyl -3- of 5- (2,8- diaza spiro [4.5] decane -2- carbonyl) -1H- indoles -1- base) acetate hydrochloride In DMF (5mL) solution of (110mg, 0.26mmol) and triethylamine (0.36mL, 2.59mmol), 3h is stirred at room temperature, screws out molten Agent adds washing (10mL), and ethyl acetate extracts (10mL × 3), and organic phase is dry with anhydrous sodium sulfate, removes solvent, concentrate It carries out post separation (V (petroleum ether)/V (ethyl acetate)=1/3) and obtains white solid 104mg, yield: 73%.
1H NMR(400MHz,CDCl3):δppm 7.74–7.79(m,2H),7.18–7.25(m,2H),7.08–7.12(m, 1H), 7.01-7.04 (m, 1H), 6.93 (td, J=9.0,2.4Hz, 1H), 4.77 (s, 2H), 3.76 (s, 3H), 3.18-3.51 (m,4H),2.71–2.95(m,2H),2.43(s,3H),1.62–1.79(m,8H)；MS-ESI:m/z 546.80[M+H]+.
Step 4: compound 2- (the fluoro- 3- of 5- (8- ((4- fluorophenyl) sulfonyl) -2,8- diaza spiro [4.5] decane -2- Carbonyl) -2- Methyl-1H-indole -1- base) acetic acid synthesis
By compound 2- (the fluoro- 3- of 5- (8- ((4- fluorophenyl) sulfonyl) -2,8- diaza spiro [4.5] decane -2- carbonyl Base) -2- Methyl-1H-indole -1- base) methyl acetate (95mg, 0.18mmol) and LiOHH2O (36mg, 0.87mmol) be dissolved in The in the mixed solvent of tetrahydrofuran (5mL) and water (3mL), 45 DEG C of reaction 30min add 1N hydrochloric acid to adjust pH=1, add methylene chloride It extracts (10mL × 3), organic phase is dry with sodium sulphate after merging, and removes solvent, obtains 85mg white solid, yield 92%.
1H NMR(600MHz,d6-DMSO):δppm 7.74–7.83(m,2H),7.40–7.48(m,3H),7.04–7.06 (m, 1H), 6.96 (td, J=9.2,2.3Hz, 1H), 5.00 (s, 2H), 2.95-3.11 (m, 4H), 2.88-2.92 (m, 3H), 2.31(s,3H),1.46–1.64(m,7H)；
13CNMR(150MHz,d6-DMSO)δppm 170.4,166.1,164.1,158.9,157.3,139.9,133.1, 132.4,130.9,125.6,117.1,116.9,111.3,110.4,109.5,55.3,45.0,43.8,11.6；
MS-ESI:m/z 532.30[M+H]+.
14 compound 2- of embodiment (the fluoro- 2- methyl -3- of 5- (3- (quinoline -2- formamido group) azetidine -1- carbonyl Base)-indoles -1- base) acetic acid hydrochloride synthesis:
Step 1: the synthesis of compound N-(azetidine -3- base) quinoline-2-formamide hydrochloride
By compound 1-Boc-3- amino ring butylamine oxalates (500mg, 1.91mmol), quinaldic acid (396mg, 2.29mmol), 1- ethyl -3- (3- dimethylamine propyl) carbodiimide hydrochloride (658mg, 3.43mmol) and N- hydroxyl -7- nitrogen Miscellaneous benzotriazole (778mg, 5.72mmol) is dissolved in methylene chloride (15mL), and N, N- is added dropwise under the conditions of 0 DEG C into this solution 16h is stirred at room temperature in diisopropylethylamine (1.3mL, 7.63mmol), and washing (10mL × 2), organic phase anhydrous sodium sulfate is added It is dry, solvent is removed, concentrate carries out post separation (V (petroleum ether)/V (ethyl acetate)=4/1), obtains 454mg colourless liquid 3- (quinoline -2- formamido group) azetidine -1- carboxylic acid tert-butyl ester, yield: 72%.
1H NMR(600MHz,CDCl3): δ ppm 8.31 (d, J=8.5Hz, 1H), 8.26 (d, J=8.5Hz, 1H), 8.13 (d, J=8.5Hz, 1H), 7.88 (d, J=8.0Hz, 1H), 7.80-7.77 (m, 1H), 7.65-7.62 (m, 1H), 4.92-4.89 (m, 1H), 4.38 (t, J=8.6Hz, 2H), 3.99 (dd, J1=9.5Hz, J2=5.3Hz, 2H), 1.46 (s, 9H)；
To compound 3- (quinoline -2- formamido group) azetidine -1- carboxylic acid tert-butyl ester (440mg, 1.34mmol) The ethyl acetate solution (4N, 4mL) of hydrogen chloride is added in methylene chloride (4mL) solution, 1h is stirred at room temperature, removes solvent, obtains White solid 350mg, yield 98%.
1H NMR(400MHz,d6- DMSO): δ ppm 8.58 (d, J=8.5Hz, 1H), 8.18 (d, J=8.5Hz, 1H), 8.14 (d, J=8.5Hz, 1H), 8.09 (d, J=8.0Hz, 1H), 7.91-7.87 (m, 1H), 7.75-7.72 (m, 1H), 4.98- 4.92(m,1H),4.28–4.22(m,2H),4.20–4.14(m,2H)；MS-ESI:m/z 228.0[M+H-HCl]+.
Step 2: compound 2- (the fluoro- 2- methyl -3- of 5- (3- (quinoline -2- formamido group) azetidine -1- carbonyl) - Indoles -1- base) methyl acetate synthesis
By the fluoro- 1- of compound 5- (2- methoxyl group -2- oxoethyl) -2- Methvl-indole -3- carboxylic acid (170mg, 0.64mmol), N- (azetidine -3- base) quinoline-2-formamide hydrochloride (254mg, 0.96mmol), 1- ethyl -3- (3- Dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) and N- hydroxyl -7- azepine benzotriazole (218mg, 1.60mmol) be dissolved in methylene chloride (16mL), under the conditions of 0 DEG C into this solution be added dropwise n,N-diisopropylethylamine (0.45mL, 2.56mmol), 16h is stirred at room temperature, washing (10mL × 2) is added, organic phase is dry with anhydrous sodium sulfate, removes solvent, concentration Liquid carries out post separation (ethyl acetate), obtains 207mg faint yellow solid, yield: 68%.
1H NMR(400MHz,CDCl3): δ ppm 8.32 (d, J=8.5Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 8.16 (d, J=8.5Hz, 1H), 7.89 (d, J=8.1Hz, 1H), 7.82-7.78 (m, 1H), 7.64 (t, J=7.3Hz, 1H), 7.37 (dd,J1=9.5Hz, J2=2.4Hz, 1H), 7.11 (dd, J1=8.9Hz, J2=4.2Hz, 1H), 6.95 (td, J1=9.0Hz, J2=2.4Hz, 1H), 5.05-5.00 (m, 1H), 4.81 (s, 2H), 4.57-4.55 (m, 2H), 4.22-4.20 (m, 2H), 3.75 (s,3H),2.59(s,3H)；MS-ESI:m/z 475.2[M+H]+.
Step 3: compound 2- (the fluoro- 2- methyl -3- of 5- (3- (quinoline -2- formamido group) azetidine -1- carbonyl) - Indoles -1- base) acetic acid hydrochloride synthesis
To compound 2- (the fluoro- 2- methyl -3- of 5- (3- (quinoline -2- formamido group) azetidine -1- carbonyl)-indoles - 1- yl) hydronium(ion) is added in the tetrahydrofuran (8mL) of methyl acetate (202mg, 0.43mmol) and the mixed solution of water (4mL) Lithia (89mg, 1.00mmol), 45 DEG C of reaction 2h are added 1N salt acid for adjusting pH value to 1 or so, ethyl acetate are added to extract (10mL × 2) remove solvent, obtain yellow solid 184mg, yield 87%.
1H NMR(600MHz,CDCl3): δ ppm 8.74 (d, J=7.4Hz, 1H), 8.26 (d, J=8.5Hz, 1H), 8.20 (d, J=8.5Hz, 1H), 8.09 (d, J=8.5Hz, 1H), 7.84 (d, J=8.1Hz, 1H), 7.75 (t, J=7.6Hz, 1H), 7.61 (t, J=7.5Hz, 1H), 7.22 (dd, J1=9.3Hz, J2=2.1Hz, 1H), 7.07 (dd, J1=8.8Hz, J2= 4.1Hz,1H),6.85(td,J1=8.9Hz, J2=2.2Hz, 1H), 4.96-4.93 (m, 1H), 4.66 (s, 2H), 4.55-4.35 (m,2H),4.25–4.20(m,2H),2.30(s,3H)；
MS-ESI:m/z 461.9[M+H-HCl]+.
Embodiment 15-29
Using corresponding raw material, according to the similar synthetic method and synthesis described in the present invention of the embodiment of the present invention Method is prepared:
Biological activity test
Embodiment 1 passes through the inhibiting effect with intracellular calcium ion fluorescent technique detection compound to CRTH2 receptor
1. the configuration of solution:
Untested compound is accurately weighed, is dissolved in appropriate DMSO, 10mM storing liquid is configured to, solution clear divides Dress, freezes in -20 DEG C, spare.Before detection, with balance salt buffer solution (HBSS buffer, the second of hydroxyethyl piperazine containing 20mM Sulfonic acid) dilution untested compound, it is configured to be five times in the solution of detectable concentration.
2.FLIPR detects (real-time fluorescence imaging analysis)
The CHO-K1/G for stablizing expression CRTH2 receptor is configured to be five times in detectable concentration cell inoculation to 384 microwell plates, It is then placed into 37 DEG C/5%CO2Continue to cultivate in incubator.Cell is taken out after 18 hours, 20 μ L dyestuffs of addition, then plus After entering the 10 configured testing compound solutions of μ L, cell plates are put into 37 DEG C/5%CO2Incubator continues to be incubated for 1 hour, Finally in equilibrium at room temperature 15 minutes.The 5x EC of 12.5 μ L is added into each hole of cell plates80The positive agonist of concentration (PGD2) RFU (fluorescence intensity) value of untested compound is detected afterwards.
3. data are analyzed
After obtaining initial data by ScreenWorks (version 3.1), Excel and GraphPad Prism is used 6 software programs are acquired and analyze to data, to calculate IC50Value.
2 CRTH2 inhibitory activity of table
Experiment conclusion, from 2 data of table it is found that majority of compounds of the present invention has preferable CRTH2 inhibitory activity.
Drug activity is tested in 2 body of biological Examples
Experiment purpose: drug effect of the assessment test compound in the Rat Asthma Model that OVA (ovalbumin) is induced.
Experimental method:
1. sensitization process
Animal is randomly divided into control group, model group and administration group.At the 1st, 2,3 day, the mouse of control group was injected intraperitoneally 1 Milliliter PBS (phosphate buffer)；The rats by intraperitoneal injection sensitization solution of model group and administration group is (by 6 milliliters of 1%OVA solution (solution of 1%OVA phosphate buffer) and 54 milliliters of alum solutions are prepared by mixing into the solution of 1:9) progress sensitization (1 milliliter/ Mouse).
2. administration and attack process
Since the 19th day, once a day, continuous three days, administration group rat oral gavage doses untested compound is given； And the corresponding solvent for giving control group and model group rats stomach-filling corresponding dosage.Every time after administration 1 hour, with attack solution pair Rat carries out attack 20 minutes；Wherein the attack solution of model group and administration group is 1%OVA solution, the attack solution of control group For PBS.
3. Indexs measure and sample collection:
At the 23rd day, 1% yellow Jackets (60 mgs/kg) anesthetized animal was injected intraperitoneally in animal.In amobarbital Under anesthesia, the blood sampling of abdominal aorta, blood collection is into EDTA-K2 pipe.The trachea cannula of animal, with 3 milliliters of PBS (including in PBS 1%FBS (fetal calf serum)) carries out first time lavation to lung；It (include later 1% in PBS with 5 milliliters of PBS FBS), lavation is repeated at least twice；Irrigating solution is merged and is adjusted with PBS to 15 milliliters of total volume.By haemocytometer and Trypan Blue experiment counts the total cell number in irrigating solution, and to the Arneth's count in irrigating solution.
4. the results show that the compounds of this invention can show certain suppression to total white blood cells and eosinophil number Effect processed, is played
The effect for reducing degree of inflammation, alleviating disease.
Biological Examples 3LC/MS/MS measuring method
4000QTRAPP series LC/MS/MS mass spectrograph be equipped with 1200 binary syringe pump of Agilent, 1290 automatic samplers and Column oven；The source ESI, anion MRM mode detection.Waters Xbridge C18 chromatographic column is used during analysis；Mobile phase It (A) is+0.1% ammonia aqueous solution of 2mM ammonium formate；Mobile phase (B) is+0.1% ammonium hydroxide methanol solution of 2mM ammonium formate；Flow velocity is 0.4mL/min；40 DEG C of column temperature；3 μ L of sample volume.
The test of 4 hepatomicrosome stability of biological Examples
Compound is incubated for jointly under conditions of 37 DEG C, pH=7.4 in people, dog and rat liver microsomes, passes through LC/ The sample concentration of the different incubation times of MS/MS measurement (method is the record of biological Examples 3), in GraphPad Prism5.01 It is mapped with " Log [drug concentration] " to " incubation time " and obtains rate constant, asked and calculate drug half-life and inherent clearance rate, with Drug half-life evaluates stability of the drug in hepatomicrosome with inherent clearance rate value.
Biological Examples 5PK experimental method
Male Beagle dog or rat chemical combination of the present invention are given by vein (0.4mg/Kg) and stomach-filling (1mg/Kg) respectively Object, acquires the blood at 0.083,0.25,0.5,1,2,4,6,8,10,24 and 36h time point, and centrifugation prepares blood plasma.Pass through LC/ The concentration of the compounds of this invention, it is main to calculate it in MS/MS measurement (method is the record of biological Examples 3) its each time point blood plasma Pharmacokinetic parameter, investigate the compounds of this invention in Beagle dog or the intracorporal PK parameter of rat etc..Concrete outcome is as follows:
The results show that the compounds of this invention exposed amount with higher.
Biological Examples 6 induce Wistar rat airway eosinophilia's experimental study to DK-PGD2
Experiment purpose: evaluation compound increases DK-PGD2 induced rat air flue total white blood cells and eosinophil Inhibiting effect
Experimental system: this experimental system is that preventive administration observes curative effect of medication, concrete operations: preventive administration 0.5h Afterwards, administration group and model group rats air flue are injected 100uL DK-PGD2 inducing airway eosinophil by spraying and are increased, and normal group The physiological saline of corresponding dosage is injected by spraying；After injection modeling 24 hours, abdominal aorta sacrificed by exsanguination rat exposes tracheae and chest Chamber, trachea cannula carry out bronchoalveolar lavage with 4 DEG C of 8mL of PBS+1%BSA solution point 2 times, collect bronchoalveolar lavage Washing lotion (BALF) is placed in ice bath, to cell smear differential counting.DK-PGD2 mother liquid concentration 10mg/ml, 5 times of dilutions, concentration are 2mg/ml。
The results show that the compounds of this invention increases DK-PGD2 induced rat air flue total white blood cells, eosinophil number Add with good inhibiting effect, and strong to the inhibiting effect of total white blood cells and eosinophil number.

Claims (10)

1. a kind of compound, is the stereoisomer of the structure as shown in formula (I) or the structure as shown in formula (I), geometry is different Structure body, tautomer or pharmaceutically acceptable salt,
Wherein,
A is
A is optionally independently selected from R by 1,2,3 or 42Substituent group replaced；
E is following subformula:
Wherein, Y, Y1, Y2, Y3, Y4And Y5It is each independently N or CH；
T is-NH-；
The subformula that the E is represented is optionally by 1,2,3 or 4 identical or different R2cIt is replaced；
L3For-C (=O)-；
Each L independently is-O- ,-S (=O)t,-S- ,-N (R1)-,-CH2,-C (=O)-,-OC (=O)-,-C (=S)-,-C (=O)-N (R1)-or-C (=S)-N (R1)-；
L1For-S (=O)t,-N (R1a)-,-C (=O)-or-C (=O)-N (R1a)-；
Each L2It independently is a key ,-S (=O)t,-N (R1a)-,-CH2Or-C (=O)-；
H is 0；
W is 0 or 1；
Each t independently is 2；
Each R1aAnd R1It independently is hydrogen；
Each R2cAnd R2It independently is hydrogen, C1-4Alkyl or halogen.
2. compound according to claim 1, wherein each R2cAnd R2It independently is hydrogen, methyl, ethyl, n-propyl, isopropyl Base, normal-butyl, tert-butyl, fluorine, chlorine or bromine.
3. compound according to claim 1, wherein
E is following subformula:
The subformula that the E is represented is optionally by 1,2,3 or 4 identical or different R2cIt is replaced.
4. compound according to claim 1, wherein the pharmaceutically acceptable salt be hydrochloride, hydrobromate, Hydriodate, nitrate, sulfate, disulfate, phosphate, acetate, propionate, butyrate, lactate, mesylate, Tosilate, maleate, benzoate, succinate, tartrate, citrate, oxalates, fumarate, ox Sulfonate, sodium salt, sylvite or ammonium salt.
5. compound according to claim 1, for such as one of flowering structure:
Or the stereoisomer of the compound, geometric isomer mutually make a variation Structure body or pharmaceutically acceptable salt.
6. pharmaceutical composition includes the described in any item compounds of claim 1-5, further includes pharmaceutically acceptable load At least one of body, excipient, diluent, adjuvant and medium.
7. pharmaceutical composition according to claim 6, further comprising one or more for treating by CRTH2 receptor On PGD2Other active agents of the disease mediated；
Other described active agents be TNF-α inhibitor, COX-1/COX-2 inhibitor, cox 2 inhibitor, glucocorticoid, The inactivation antibody of interleukin, chemokine receptor modulators, histamine H 1 receptor antagonist/antihistaminic, leukotriene D receptor are short of money Anti-agent, LTD4 antagonist, VLA-4 antagonist, corticosteroid is similar to object, theophylline, inhibitors of leukotriene biosynthesis, epoxy - 2 inhibitor of enzyme, opium kind analgesics, anticoagulant, beta blocker, beta-adrenergic agonist, angiotensin converting enzyme Inhibitor, HMG-CoA reductase inhibitor, β2agonists, corticosteroid, antihistaminic, leukotriene antagonist are anti-IgE anti- Body therapeutic agent, anti-infectious agent, antifungal, immunosuppressor act on other PGD of other receptors2Antagonist, 4 type phosphoric acid The inhibitor of diesterase adjusts the drug that cell factor generates, and adjusts the active drug of Th2 cell factor IL-4 and IL-5,5- Lipoxidase inhibitor.
8. pharmaceutical composition according to claim 6, further include it is one or more for treat by CRTH2 by PGD on body2Other active agents of the disease mediated；Wherein other described active agents are salmeterol, and fluorine is for card Pine, Loratadine, montelukast, omalizumab, Fusidic Acid, clotrimazole, tacrolimus, Elidel, DP antagonist, west The blocking monoclonal antibody or soluble recepter of Luo Site, TNF-α invertase (TACE) inhibitor, IL-4 or IL-5 are stayed together It is logical.
9. being come using the described in any item compounds of claim 1-5 or the described in any item pharmaceutical compositions of claim 6-8 Preparation is for protecting, handling, treat or mitigating patient by PGD on CRTH2 receptor2The purposes of the drug of the disease mediated.
10. purposes according to claim 9, wherein by PGD on CRTH2 receptor2The disease mediated is asthma, perennially Allergic rhinitis, pollinosis, atopic dermatitis, contact hypersensitivity, conjunctivitis, eosinophil driven's bronchus Inflammation, food hypersenstivity, eosinophilic gastroenteritis, inflammatory bowel disease, mastocytosis, autoimmune disease, psoriasis, Cuo Sore, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease, rheumatoid arthritis, Arthritic psoriasis or osteoarthritis.
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