CN105461693A - Crth2 antagonist compound and use thereof - Google Patents

Crth2 antagonist compound and use thereof Download PDF

Info

Publication number
CN105461693A
CN105461693A CN201510621564.1A CN201510621564A CN105461693A CN 105461693 A CN105461693 A CN 105461693A CN 201510621564 A CN201510621564 A CN 201510621564A CN 105461693 A CN105461693 A CN 105461693A
Authority
CN
China
Prior art keywords
compound
independently
radical
methyl
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201510621564.1A
Other languages
Chinese (zh)
Other versions
CN105461693B (en
Inventor
余天柱
刘兵
张英俊
张翔宇
张仕国
郑常春
张健存
雷健华
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong HEC Pharmaceutical
Original Assignee
Guangdong HEC Pharmaceutical
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangdong HEC Pharmaceutical filed Critical Guangdong HEC Pharmaceutical
Priority to CN201510621564.1A priority Critical patent/CN105461693B/en
Publication of CN105461693A publication Critical patent/CN105461693A/en
Application granted granted Critical
Publication of CN105461693B publication Critical patent/CN105461693B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention concretely relates to a compound (with a structure represented by formula (I)) as a CRTH2 receptor antagonist, or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof. The invention also relates to a use of the CRTH2 antagonist compound in treatment and prevention of asthma, allergic rhinitis, atopic dermatitis and other diseases mediated by prostaglandin D2 (PGD2) acting on a cell CRTH2 receptor.

Description

CRTH2 antagonist compounds and uses thereof
Technical Field
The invention relates in particular to compounds which are CRTH2 receptor antagonists and their use in the treatment and prevention of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis and other prostaglandins D2 (PGD) acting at the cellular CRTH2 receptor2) Use in a mediated inflammatory disease, wherein said cells comprise eosinophils, basophils and Th2 lymphocytes.
Background
CRTH2 is a G-protein-coupled chemoattractant receptor expressed on Th2 cells, eosinophils. Th 2-polarization has been observed in allergic diseases such as asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis. Th2 cells regulate allergic diseases by producing Th2 cytokines such as IL-4, IL-5 and IL-3. In allergic diseases, these Th2 cytokines induce migration, activation, triggering and prolonged survival of effector cells, such as eosinophils and basophils, directly or indirectly.
PGD2(prostaglandin D2), the ligand of CRTH2, is produced by mast cells and other important effector cells in allergic diseases. In human cells, PGD2Migration and activation of Th2 cells, eosinophils and basophils was induced by CRTH 2. Thus, antagonism of PGD at the CRTH2 receptor2Is an attractive approach for the treatment of Th 2-dependent allergic diseases such as asthma, allergic rhinitis and atopic dermatitis. CRTH2 receptor antagonists have also been reported to be useful for the treatment of other eosinophil-related diseases, such as Churg-Strauss syndrome and sinusitis.
As CRTH2 inhibitors, indolylacetic acid derivatives (see WO2005/019171), phenoxyacetic acid derivatives (see WO2005/115382), pyrimidinylacetic acid derivatives (see WO2004/096777), bicyclic ring derivatives (see CN103373996), isoquinoline derivatives (WO2010/074244), and the like have been reported.
The invention provides a series of indole derivatives with indole nitrogen substituted by alkyl carboxylate, which are PGD on CRTH2 receptor2And can be used to treat PGD at the CRTH2 receptor2Mediated diseases and conditions.
Disclosure of Invention
The invention provides a series of indole derivatives with indole nitrogen substituted by alkyl carboxylate, which are PGD on CRTH2 receptor2And can be used to treat PGD at the CRTH2 receptor2Mediated diseases and conditions. The compounds of the present invention have good activity and are useful for treating PGD at the CRTH2 receptor2Mediated diseases and conditions.
In one aspect, the present invention provides a compound which is a structure represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof,
wherein, A, E, h, w, L1、L2And L3Have the meaning as described in the present invention.
In some embodiments, a is arylene, heteroarylene, heterocyclylene, or cycloalkylene; a is optionally substituted by 1,2,3 or 4 independently selected from R2Substituted with the substituent(s); wherein R is2Have the meaning as described in the present invention.
In some embodiments, the compounds of the present invention wherein A is C6-12Arylene radical, C1-9Heteroarylene radical, C2-10Heterocyclylene or C3-12A cycloalkylene group; a is optionally substituted by 1,2,3 or 4 independently selected from R2Substituted with the substituent(s); wherein R is2Have the meaning as described in the present invention.
In some embodiments, the compounds of the present invention, wherein a is of the following subformula:
the sub-structural formula represented by A is optionally selected from 1,2,3 or 4 independently selected from R2Substituted with the substituent(s);
wherein,when the carbon atom is a single bond,is composed of
In the case of a double bond, the double bond,is composed of
Each X1，X2And X3Independently is- (CR)3R3a)b-，-O-，-N(R4) -or-S (═ O)t1-；
Each X4，X5，X6，X7X and X8Independently is-C (R)3) -or-N-;
each b is independently 0, 1,2,3 or 4;
each of q, m, f1, p and r is independently 0, 1,2,3 or 4;
each t1 is independently 0, 1 or 2;
wherein R is2、R4、R3aAnd R3Have the meaning as described in the present invention.
In some embodiments, the compounds of the present invention, wherein,
a is
Wherein, the sub-structural formula represented by A is optionally selected from 1,2,3 or 4 independently selected from R2Substituted with the substituent(s); wherein R is2Have the meaning as described in the present invention.
In some embodiments, E is heterocyclyl, cycloalkyl, fused heterobicyclic, bridged heterobicyclic, spiroheterobicyclic, aryl, or heteroaryl; e is optionally substituted with 1,2,3 or 4 independently selected from R2cSubstituted with the substituent(s); wherein R is2cHave the meaning as described in the present invention.
In some embodiments, the compounds of the present invention wherein E is C2-10Heterocyclic radical, C5-12Spiro heterobicyclic radical, C5-12Condensed hetero bicyclic group, C5-12Bridged bicyclic radical, C3-12Cycloalkyl radical, C6-12Aryl or C1-12A heteroaryl group; e is optionally substituted with 1,2,3 or 4 independently selected from R2cSubstituted with the substituent(s); wherein R is2cHave the meaning as described in the present invention.
In some embodiments, wherein E is the following subformula:
wherein, Y1，Y2，Y3，Y4，Y5And Y6Each independently is N or CH;
T1，T2，T3and T is each independently-O-, -S-, -NH-or-CH2-；
Each e and f is independently 0, 1,2,3 or 4;
the sub-structural formula represented by E is optionally selected from 1,2,3 or 4 independently selected from R2cSubstituted with the substituent(s); wherein R is2cHave the meaning as described in the present invention.
In some embodiments, the compounds of the present invention, wherein E is of the subformula:
the sub-structural formula represented by E is optionally selected from 1,2,3 or 4 independently selected from R2cSubstituted with the substituent(s); wherein R is2cHave the meaning as described in the present invention.
In some embodiments, L3is-O-, -S-, -S (═ O)t-，-C(OH)H-，-N(R1) -or-C (═ O) -; wherein R is1Have the meaning as described in the present invention.
In some embodiments, each L is independently-O-, -S (═ O)t-，-S-，-N(R1)-，-CH2-，-C(＝O)-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R1)-，-C(＝S)-N(R1) -or- (CH)2)n-C (═ O) -; wherein t, n and R1Have the meaning as described in the present invention.
In some embodiments, -L3-(L)h-is-O-, -S-, -S (═ O)t-, - (C (oh) H-, -NH-C (═ O) -, -C (═ O) -NH-, -C (═ O) -or-C (═ O) -.
In some embodiments, L1is-O-, -S (═ O)t-，-S-，-N(R1a)-，-CH2-，-C(＝O)-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R1a)-，-C(＝S)-N(R1a) -or- (CH)2)n-C (═ O) -; wherein t, n and R1aHave the meaning as described in the present invention.
In some embodiments, each L2Independently a bond, -O-, -S (═ O)t-，-S-，-N(R1a)-，-CH2-，-C(＝O)-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R1a)-，-C(＝S)-N(R1a) -or- (CH)2)n-C (═ O) -; wherein t, n and R1aHave the meaning as described in the present invention.
In some embodiments, -L1-(L2)w-is-NH-C (═ O) -, -S (═ O)2-，-NH-S(＝O)2-，-C(＝O)-NH-CH2-or-C (═ O) -NH-.
In some embodiments, h is 0, 1,2,3, or 4.
In some embodiments, w is 0, 1,2,3, or 4.
In some embodiments, each n is independently 0, 1,2,3, or 4.
In some embodiments, each t is independently 0, 1, or 2.
In some embodiments, each R1aIndependently of one another is hydrogen, C1-4Alkyl, halo C1-4Alkyl radical, C1-4An alkyl acyl group or a hydroxyl group.
In some embodiments, each R1Independently of one another is hydrogen, C1-4Alkyl, halo C1-4Alkyl radical, C1-4An alkyl acyl group or a hydroxyl group.
In some embodiments, each R2Independently hydrogen, alkyl, haloalkyl, hydroxy, nitro, cyano, halogen, carboxy, alkoxy, alkylamino, alkylthio, alkanoyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aminoalkyl, amino, hydroxyalkyl, sulfonic acid, aminosulfonyl or aminoacyl.
In some embodiments, each R2Independently of one another is hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, hydroxy, nitro, amino, cyano, halogen, carboxy, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Alkylthio radical, C1-4Alkyl acyl radical, C3-12Cycloalkyl radical, C3-9Heterocyclic radical, C6-12Aryl radical, C1-9Heteroaryl, amino C1-4Alkyl, hydroxy C1-4Alkyl, sulfonic, aminosulfonyl or aminoacyl.
In some embodiments, each R2Independently hydrogen, methyl, ethyl, propyl, butyl, trifluoromethyl, hydroxy, nitro, amino, cyano, fluoro, chloro, bromo, carboxy, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, methylacyl, aminomethyl, hydroxymethyl, sulfonic acid, aminosulfonyl or aminoacyl.
In some embodiments, each R2cIndependently hydrogen, alkyl, haloalkyl, hydroxy, nitro, cyano, halogen, carboxy, alkoxy, alkylamino, alkylthio, alkanoyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aminoalkyl, amino, hydroxyalkyl, sulfonic acid, aminosulfonyl or aminoacyl.
In some embodiments, each R2cIndependently of one another is hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, hydroxy, nitro, amino, cyano, halogen, carboxy, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Alkylthio radical, C1-4Alkyl acyl radical, C3-12Cycloalkyl radical, C3-9Heterocyclic radical, C6-12Aryl radical, C1-9Heteroaryl, amino C1-4Alkyl, hydroxy C1-4Alkyl, sulfonic, aminosulfonyl or aminoacyl.
In some embodiments, each R2cIndependently hydrogen, methyl, ethyl, propyl, butyl, trifluoromethyl, hydroxy, nitro, amino, cyano, fluoro, chloro, bromo, carboxy, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, methylacyl, aminomethyl, hydroxymethyl, sulfonic acid, aminosulfonyl or aminoacyl.
In some embodiments, the compounds of the present invention are stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof of the structure of formula (II) or of the structure of formula (II),
wherein,when the carbon atom is a single bond,is composed of
In the case of a double bond, the double bond,is composed of
Each X1，X2And X3Independently is- (CR)3R3a)b-，-O-，-N(R4) -or-S (═ O)t-；
X4is-C (R)3) -or-N-;
each b is independently 0, 1,2,3 or 4;
wherein, E, h, w, L1、L2、L3、R3、R3a、R4And t has the meaning as described in the present invention.
In some embodiments, each R3aAnd R3Independently of one another is hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, hydroxy, nitro, cyano, halogen, amino, carboxy, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Alkylthio radical, C1-4Alkyl acyl radical, C3-12Cycloalkyl radical, C3-9Heterocyclic radical, C6-12Aryl radical, C1-9Heteroaryl, amino C1-4Alkyl, hydroxy C1-4Alkyl, sulfonic, aminosulfonyl or aminoacyl.
In some embodiments, each R4Independently of one another is hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, hydroxy, C3-12Cycloalkyl radical, C3-9Heterocyclic radical, C6-12Aryl radical, C1-9Heteroaryl, amino C1-4Alkyl or hydroxy C1-4An alkyl group.
In some embodiments, each R3aAnd R3Independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, hydroxyl, nitro, cyano, fluorine, chlorine, bromine, carboxyl, methoxy, ethoxy, amino, trifluoromethyl, amino C1-4Alkyl, hydroxy C1-4Alkyl, sulfonic, aminosulfonyl or aminoacyl.
In some embodiments, each R4Independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butylAlkyl, tert-butyl, trifluoromethyl, hydroxy, amino C1-4Alkyl or hydroxy C1-4An alkyl group.
In some embodiments, the compounds of the present invention are stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof of the structure of formula (III) or of the structure of formula (III),
X5and X are each independently-CH-or-N-;
wherein p and f1 are each independently 0, 1,2,3, or 4;
wherein L is1，L2W and E have the meanings given in the description of the invention.
In some embodiments, the pharmaceutically acceptable salt of the compound of the present invention is a salt of the compound of formulae (I) - (III) with an inorganic acid, an organic acid, an inorganic base, a metal base, or an organic base.
In some embodiments, the compound of the invention, wherein the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acetate, propionate, butyrate, lactate, methanesulfonate, p-toluenesulfonate, maleate, benzoate, succinate, tartrate, citrate, oxalate, fumarate, taurate, sodium salt, potassium salt or ammonium salt.
In one aspect, the invention provides a pharmaceutical composition comprising any of the compounds according to the invention.
In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.
In some embodiments, the pharmaceutical compositions of the invention further comprise one or more agents useful for treating PGD at the CRTH2 receptor2Other active agents of the mediated disease.
In still other embodiments, the pharmaceutical composition of the invention, wherein the additional active agent is a TNF- α inhibitor, a COX-1/COX-2 inhibitor, a glucocorticoid, an inactivated antibody to interleukin, a chemokine receptor modulator, a histamine H1 receptor antagonist/antihistamine, a leukotriene D4 receptor antagonist, a LTD4 antagonist, a VLA-4 antagonist, a corticosteroid analog, theophylline, a leukotriene biosynthesis inhibitor, a cyclooxygenase-2 inhibitor, an opioid analgesic, an anticoagulant, a β -blocker, a β -adrenergic agonist, an angiotensin converting enzyme inhibitor, an HMG-CoA reductase inhibitor, a β 2 agonist, a corticosteroid, an antihistamine, a leukotriene antagonist, an anti-IgE antibody therapeutic, an anti-infective agent, an antifungal agent, an immunosuppressive agent, other PGD acting on other receptors2Antagonists, inhibitors of phosphodiesterase type 4, agents modulating cytokine production, agents modulating the activity of the Th2 cytokines IL-4 and IL-5, 5-lipoxygenase inhibitors.
In still other embodiments, the active agent is salmeterol, fluticasone, loratadine, montelukast, omalizumab, fusidic acid, clotrimazole, tacrolimus, pimecrolimus, DP antagonists, cilomilast, TNF-alpha converting enzyme (TACE) inhibitors, blocking monoclonal antibodies or soluble receptors for IL-4 or IL-5, and zileuton.
In one aspect, the present invention provides a method of using any one of the compounds of the present invention or any one of the pharmaceutical compositions of the present invention for the preparation of a medicament for protecting, treating or ameliorating PGD at the CRTH2 receptor in a patient2Use of a pharmaceutical product for a mediated disease.
In some embodiments, the present inventionThe use of the compounds, wherein the PGD is at the CRTH2 receptor2The mediated disease is asthma, allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity, conjunctivitis, eosinophilic bronchitis, food allergy, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and crohn's disease, mastocytosis, autoimmune disease, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriatic arthritis or osteoarthritis.
In still other embodiments, the use of the invention, wherein the autoimmune disease is psoriasis, multiple sclerosis, allograft rejection, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus and osteoarthritis.
In a further aspect, the invention provides a combination pharmaceutical preparation comprising a compound according to any one of the preceding claims and one or more agents according to any one of the preceding claims as a combined preparation for simultaneous, separate or sequential use in the prevention, treatment or alleviation of PGD at the CRTH2 receptor2Use of the mediated disease.
In yet another aspect, the invention provides a method of protecting, managing, treating or ameliorating PGD at the CRTH2 receptor in a patient2A method of treating a mediated disease or condition, the method comprising administering to a patient having the infectious disease a therapeutically effective amount of a compound according to any of the present invention or a pharmaceutical composition according to any of the present invention.
In yet another aspect, a compound according to any one of the invention or a pharmaceutical composition according to any one of the invention for use in protecting, treating or reducing PGD at the CRTH2 receptor in a patient2Mediated diseases and conditions.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied, unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of organic chemistry can be referred to as described in "organic chemistry", ThomasSorrell, university science Books, Sausaltito: 1999, and "March's sAdvanceorganics" by Michael B.Smith JerreryMarch, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated to be employed or used in an implementation of the described embodiments.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-HillDictionaryof chemical terms (1984) McGraw-HillBook company, New York; andEliel, E.andWilen, S., "Stereochemistry of organic Compounds", John Wiley & Sons, Inc., New York, 1994.
Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers may be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemases and solutions (wiley inter science, new york, 1981); principlisof asymmetricsynthesis (2nd ed. roberte. gawley, jeffreyaaub, Elsevier, Oxford, UK, 2012); eliel, e.l. stereoshemistry of carbon compounds (McGraw-Hill, NY, 1962); wilen, s.h. tablet of resining agentsand optical resolution sp.268(e.l. eliel, ed., univ. of notredam press, notredam, IN 1972); ChiralSeparationoTechniques: APractalcaproach (Subramanian, G.Ed., Wiley-VCHVerlag GmbH & Co. KGaA, Weinheim, Germany, 2007).
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (lowenergy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valentetatomers) include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
"cis-trans isomer" refers to a factor in the molecule that restricts the free rotation of carbon atoms, such as double bonds (e.g., oximes, azos, alkenes, etc.) or rings (e.g., alicyclic rings); and atoms which cannot rotate freely are respectively connected with two different atoms or atom groups. Cis-trans isomers belong to configurational isomers, and two isomers which differ from each other are produced, which are called cis (cis) and trans (trans) isomers, respectively. The presence of an alicyclic ring prevents the free rotation of the carbon atoms constituting the ring, and cis-trans isomerism is possible when at least 2 carbon atoms in the ring are each bound to 2 different atoms or groups of atoms. In a cyclic compound, if two identical substituents are located on the same side of the ring plane, the compound is said to be cis; if two identical substituents are located on opposite sides of the ring plane, the compound is said to be trans. Although different cis-trans isomers have the same functional groups, they have different physical properties (e.g., melting point, boiling point, dipole moment, etc.), chemical properties, and biological activities. Unless otherwise indicated, all cis-trans isomeric forms of the compounds of the present invention are within the scope of the present invention.
As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as compounds of the general formula above or as specifically exemplified, sub-classes, and classes of compounds encompassed by the present invention within the examples. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Substitutions contemplated by the present invention include only substitutions that form stable compounds. In some embodiments, certain suitable optional substituents 1 may be further substituted with corresponding suitable optional substituents 2. In other embodiments, the corresponding suitable optional substituent 2 is not further substituted. Wherein said substituent may be, but is not limited to: hydrogen, alkyl, haloalkyl, hydroxyl, nitro, cyano, halogen, carboxyl, alkoxy, alkylamino, alkylthio, alkanoyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aminoalkyl, amino, hydroxyalkyl, sulfonic acid, sulfonamide or aminoacyl.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3, 3-dimethyl-2-butyl, n-heptyl, n-octyl, and the like.
The terms "halogen", "halogen atom" or "halogen atom" as used herein include fluorine, chlorine, bromine, iodine.
The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).
The term "alkoxy", as used herein, relates to an alkyl group, as defined herein, attached to the main carbon chain through an oxygen atom. In some of these examples, alkoxy is a lower C1-3Alkoxy, some examples include, but are not limited to, methoxy, ethoxy, propoxy, and the like.
The term "haloalkyl" or "haloalkoxy" denotes a situation where an alkyl or alkoxy group may be substituted by one or more of the same or different halogen atoms. Wherein alkyl and alkoxy groups have the meaning as described herein, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.
The term "alkylthio" includes C1-10A linear or branched alkyl group is attached to a divalent sulfur atom, wherein the alkyl group has the meaning as described herein. In some of these embodiments, the alkylthio group is a lower C1-3Alkylthio groups, and such examples include, but are not limited to, methylthio (CH)3S-), ethylthio, and the like.
The term "alkanoyl" includes C1-10A straight or branched alkyl group is attached to-C (═ O) -, where the alkyl group has the meaning as described in the present invention. In some of these examples, the alkanoyl group is a lower C1-3And alkanoyl, and such examples include, but are not limited to, acetyl, propionyl, and the like.
The term "aminoacyl" refers to-C (═ O) NH2。
The term "aminosulfonyl" refers to-S (═ O)2NH2。
The term "amino" refers to a compound having the formula-NH2。
The term "aminoalkyl" refers to a group having the formula R 'R "N-alkyl, wherein R' and R" are each independently hydrogen, alkyl, or haloalkyl. Alkyl has the meaning as described in the present invention. In some of these examples, aminoalkyl is a lower amino C1-4Alkyl groups, some examples of which are, but not limited to, aminoethyl, aminomethyl, aminopropyl and the like.
The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups, wherein the alkyl groups have the meaning as described herein. In some of these embodiments, the alkylamino group is one or two C1-6Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In other embodiments, the alkyl groupAmino being C1-3Lower alkylamino groups of (a). Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.
The term "hydroxyalkyl" or "hydroxyalkoxy" refers to the situation where an alkyl or alkoxy group may be substituted with one or more hydroxyl groups. Wherein the alkyl and alkoxy groups have the meaning as described in the present invention, wherein in some embodiments the hydroxyalkyl group is a lower hydroxy C1-4Examples of such alkyl groups include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, hydroxypropyl, 1, 2-dihydroxypropyl, hydroxymethoxy, 1-hydroxyethoxy, and the like.
The term "aryl" may be used alone or as a large part of an "aralkyl", "aralkoxy", or "aryloxyalkyl", and may be a monocyclic, bicyclic, and tricyclic carbocyclic ring system, and may be used in place of an arylene group in certain embodiments of the invention. Wherein at least one ring system of the aryl group is aromatic, wherein each ring system comprises 3 to 7 atoms. The term "aryl" may be used interchangeably with the term "aromatic ring", e.g., aromatic rings may include phenyl, naphthyl, and anthracene. Depending on the structure, the aryl group can be a monovalent group or a divalent group (i.e., arylene). One or more of the ring hydrogen atoms are independently optionally substituted with one or more substituents described herein.
The terms "heteroaryl", "heteroaryl ring" are used interchangeably herein and may be used alone or as part of a "heteroarylalkyl" or "heteroarylalkoxy", and may be used in place of a heteroarylene group in certain embodiments of the invention. All refer to monocyclic, bicyclic, tricyclic or tetracyclic ring systems, wherein the bicyclic, tricyclic or tetracyclic heteroaromatic ring system forms a ring in fused form. Wherein the heteroaromatic ring system is aromatic and one or more of the atoms in the ring is independently optionally substituted by a heteroatom (heteroatom selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give a compound like SO, SO2，PO，PO2The group of (1). The heteroaryl system may be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable compound. The heteroaryl group may be a monocyclic ring of 3 to 7 atoms or a bicyclic ring of 7 to 10 atoms or a tricyclic ring of 10 to 15 atoms. The bicyclic ring having 7 to 10 atoms may be bicyclo [4,5]]，[5,5]，[5,6]Or [6,6]]The tricyclic ring having 10 to 15 atoms may be a tricyclic [5,5, 6]]，[5,6,6]Or [6,5, 6]]And (4) preparing the system. Depending on the structure, heteroaryl groups can be monovalent or divalent (i.e., heteroarylene). One or more of the ring hydrogen atoms are independently optionally substituted with one or more substituents described herein.
In other embodiments, heteroaryl systems (including heteroaryl, heteroaryl rings) include, but are not limited to, the following examples: 2-furyl group, 3-furyl group, N-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 4-methylisoxazol-5-yl group, N-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, pyrimidin-5-yl group, pyridazinyl group (e.g., 3-pyridazinyl group) group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, tetrazolyl group (e.g., 5-tetrazolyl group), triazolyl group (e.g., 2-triazolyl group and 5-triazolyl group), 2-thienyl, 3-thienyl, pyrazolyl (e.g. 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3, 5-triazinyl, benzo [ d ] thiazol-2-yl, imidazo [1,5-a ] pyridin-6-yl, benzimidazolyl, benzoxazolyl, quinoxalinyl, 1, 8-diazanaphthalyl, benzofuranyl, benzothienyl, benzothiazolyl, indolyl (e.g. 2-indolyl) group, purinyl group, quinolyl group (e.g. 2-quinolyl, 3-quinolyl, 4-quinoline), isoquinolyl group (e.g. 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), tetrahydronaphthyl, benzopyrazolyl, acridinyl, benzimidazolyl, benzindolyl, benzisoxazinyl, benzothiopyranyl, benzoxazolyl, benzothiazolyl, beta-carbolinyl, carbazolyl, phthalazinyl, dibenzofuranyl, imidazopyridyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isobenzothianyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolidinyl, oxazolopyridyl, oxazolyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyridopyridyl, quinazolinyl, quinoxalinyl, thiophenyl, triazinyl, 2H-pyrrolo [3,4-c ] pyridyl, pyrazolo [2',1':2,3] oxazolo [4,5-c ] pyridyl, imidazo [2',1':2,3] thiazolo [4,5-b ] pyrazinyl, imidazo [2',1':2,3] thiazolo [5,4-b ] pyridyl, imidazo [2',1':2,3] thiazolo [4,5-c ] pyridyl and the like.
The terms "carbocyclyl" or "cyclic aliphatic", "carbocycle", "cycloalkyl" refer to a mono-or polyvalent, non-aromatic, saturated or partially unsaturated ring, and contain no heteroatoms, including monocyclic rings of 3 to 12 carbon atoms or bicyclic or tricyclic rings of 7 to 12 carbon atoms. The carbocycle having 7 to 12 atoms may be a bicyclo [4,5], [5,5], [5,6] or [6,6] system, while the carbocycle having 9 or 10 atoms may be a bicyclo [5,6] or [6,6] system. Depending on the structure, "carbocyclyl" or "cyclic aliphatic", "carbocycle", "cycloalkyl" may be monovalent or divalent, i.e., in certain embodiments of the invention, may be used in place of or as a carbocyclylene, cycloalkylene. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of cyclic aliphatic groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, and the like. One or more of the ring hydrogen atoms are independently optionally substituted with one or more substituents described herein.
The term "cycloalkylene" refers to a divalent non-aromatic, saturated or partially unsaturated ring, and contains no heteroatoms, including monocyclic rings of 3-12 carbon atoms or bicyclic or tricyclic rings of 7-12 carbon atoms. The bicyclic system may be a [4,5], [5,5], [5,6] or [6,6] system. In some embodiments, cycloalkylene is a saturated monocyclic or partially unsaturated monocyclic ring of 4-7 carbon atoms, and in still other embodiments, cycloalkylene is a saturated monocyclic or monocyclic ring containing one unsaturation of 6 carbon atoms. Examples of cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, 1-cyclopentylene-1-enyl, 1-cyclopentylene-2-enyl, 1-cyclopentylene-3-enyl, cyclohexylene, 1-cyclohexylene-1-enyl, 1-cyclohexylene-2-enyl, 1-cyclohexylene-3-enyl, cyclohexadienylene, cycloheptylene, cyclooctylene, cyclononylene, cyclodecylene, cycloundecylene, cyclododecylene, adamantylene, and the like. One or more of the ring hydrogen atoms are independently optionally substituted with one or more substituents described herein.
The terms "heterocyclyl", "heterocycle", "heteroalicyclic" or "heterocyclic" are used interchangeably herein and all refer to monocyclic, bicyclic, tricyclic or tetracyclic ring systems in which one or more atoms in the ring are independently optionally replaced by a heteroatom, the ring being fully saturated or containing one or more degrees of unsaturation, but in no way aromatic. Depending on the structure, "heterocyclyl", "heterocycle", "heteroalicyclic" may be a monovalent group or a divalent group, i.e., in certain embodiments of the invention, may be used in place of or as a heterocyclylene group. The heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable compound. One or more of the ring hydrogen atoms are independently optionally substituted with one or more substituents described herein. Some examples of these are "heterocyclyl", "heterocycle", "heterocyclylene", "heteroalicyclic" or "heterocyclic" groups which are monocyclic (1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S; when the ring is a three-membered ring, there is only one heteroatom) or bicyclic (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S) of 7 to 10 atoms with a 3 to 7-membered ring.
"heterocyclyl" may be a carbon or heteroatom radical. "Heterocyclyl" also includes heterocyclic groups fused to saturated or partially unsaturated rings or heterocycles. Examples of heterocycles include, but are not limited to, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl, azepinyl, oxepinyl, thiepinyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, homopiperazinyl, oxazepinyl, diazepinyl, thiazepinyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxolyl, dithianyl, Dihydrothienyl, 1,2,3, 4-tetrahydroisoquinolinyl, hexahydro-2H- [1,4] dioxin [2,3-c ] pyrrolyl, 2,3,3a,7 a-tetrahydro-1H-isoindolyl, 1,2,3, 4-tetrahydroquinolinyl, dioxolanyl, 3, 7-diazabicyclo [3.3.0] octanyl, 2, 6-diazabicyclo [3.3.0] octanyl, 2, 7-diazabicyclo [3.3.0] octanyl, 2, 8-diazabicyclo [4.3.0] nonanyl, 3-oxo-8-azabicyclo [4.3.0] nonanyl, 2, 8-diaza-5-oxabicyclo [4.3.0] nonanyl, 4, 9-diazabicyclo [4.3.0] nonanyl, 2, 9-diazabicyclo [4.3.0] nonanyl, 3, 8-diazabicyclo [4.3.0] nonanyl, 3, 7-diazabicyclo [4.3.0] nonanyl, 3, 9-diazabicyclo [4.3.0] nonanyl, 3-oxo-8-azabicyclo [4.3.0] nonanyl, 3-thio-8-azabicyclo [4.3.0] nonanyl, 5, 6-dihydro-4H-pyrrolo [3,4-c ] isoxazolyl, [1,2,4] triazolo [4,3-a ] piperidyl, isoxazolo [4,3-c ] piperidyl, 4,5,6, 7-tetrahydroisooxazolo [3,4-c ] pyridyl, [1,2,4] triazolo [4,3-a ] piperazinyl, 2-oxo-7-azabicyclo [4.4.0] decanyl, 1, 5-dioxo-9-azabicyclo [4.4.0] decyl, 3-azabicyclo [4.4.0] decyl, 5-benzyl-2-oxo-5, 8-diazabicyclo [4.3.0] nonanyl, 2, 7-diazanahydronaphthyl, 2-oxo-8-azabicyclo [4.4.0] decyl, 2-oxo-5-azabicyclo [2.2.1] heptanyl, 2-thio-5-azabicyclo [2.2.1] heptanyl, 2-oxo-5-azabicyclo [2.2.1] heptanyl, 2, 5-diazabicyclo [2.2.1] heptanyl, 4-azaspiro [2.4] heptanyl, 4-oxaspiro [2.4] heptanyl, 5-azaspiro [2.4] heptanyl, 2-azaspiro [4.5] decanyl, 2-azaspiro [3.3] heptanyl, 2-azaspiro [4.4] nonanyl, 3-azaspiro [5.4] decanyl, 2-oxo-6-azaspiro [3.3] heptanyl, 2, 6-diazaspiro [3.3] heptanyl, 2-thio-6-azaspiro [3.3] heptanyl 2-monoxide, 2-thio-6-azaspiro [3.3] heptanyl 2, 2-dioxide and the like.
The term "heterocyclylene" refers to a monocyclic, bicyclic, tricyclic, or tetracyclic ring system wherein one or more atoms of the ring are independently optionally substituted with heteroatoms, the ring being fully saturated or containing one or more degrees of unsaturation, but in no way aromatic. Heterocyclylene is a divalent radical and the heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable compound. One or more of the ring hydrogen atoms are independently optionally substituted with one or more substituents described herein. Some of these examples are "heterocyclylene" groups which are 3-7 membered rings monocyclic (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give the same SO, SO2，PO，PO2A group of (a); when the ring is a three-membered ring, in which there is only one heteroatom) or a bicyclic ring of 7 to 10 atoms (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give a ring such as SO, SO2，PO，PO2The group of (1). In some embodiments, heterocyclylene is a 4-7 atom saturated monocyclic or partially unsaturated monocyclic ring, and in still other embodiments, heterocyclylene is a 6 atom saturated monocyclic or monocyclic ring containing one degree of unsaturation.
"Heterocyclylene" may be carbon-based or heteroatom-based. "Heterocyclylene" likewise includes heterocyclic groups which are formed by the union of a saturated or partially unsaturated ring or heterocycle. Examples of heterocyclylene groups include, but are not limited to, 1,2,3, 6-tetrahydropyridinylene, piperidylene, piperazinyl, pyrrolidinylene, tetrahydrofurylene, dihydrofuranylene, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, azetidinylene, oxetanyl, thietanyl, homopiperidinylene, epoxypropyl, azepinyl, oxepinyl, thietanyl, N-morpholinylene, 2-morpholinylene, 3-morpholinylene, thiomorpholinylene, homopiperazinylene, 4-methoxy-piperidin-1-ylene, oxazepinyl, diazepinyl, thiazepinyl, pyrrolin-1-ylene, 2-pyrrolinyl, 3-pyrrolinyl, thiiranyl, oxazepinyl, pyrrolin-1-yl, and oxazepinyl, Dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexylidene, 1, 3-dioxolanyl, dithianyl, dithienoalkyl, dihydrothienyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2, 6-thiadiazinane 1, 1-dioxo-2-yl, hexahydro-2H- [1,4] dioxol [2,3-c ] pyrrolyl, dihydropyridinyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, 1, 4-dithianyl, morpholinyl, decahydroindolyl, 2-oxo-8-azabicyclo [4.3.0] nonanyl, 2, 8-diaza-5-oxabicyclo [4.3.0] nonanyl, 4, 9-diazabicyclo [4.3.0] nonanyl, oxabicyclo [4.3.0] nonanyl, oxa-1, 2-thiadiazolyl, 3.0] nonanyl, and mixtures thereof, 2, 9-diazabicyclo [4.3.0] nonane, 3-oxo-2, 4, 8-triazabicyclo [4.3.0] nonane, 3-oxo-4-oxo-2, 8-diazabicyclo [4.3.0] nonane, 3, 7-diazabicyclo [4.3.0] nonane, 3, 9-diazabicyclo [4.3.0] nonane, 3-oxo-8-azabicyclo [4.3.0] nonane, 3-thio-8-azabicyclo [4.3.0] nonane, 5, 6-dihydro-4H-pyrrolo [3,4-c ] isoxazole, sub [1,2,4] triazolo [4,3-a ] piperidyl, isoxazolo [4,3-c ] piperidyl, 4,5,6, 7-tetrahydroisooxazolo [3,4-c ] pyridyl, 1,2,4] triazolo [4,3-a ] piperazinyl, 2-oxo-3-oxo-8-azabicyclo [4.3.0] nonanyl, 2-oxo-7-azabicyclo [4.4.0] decanyl, 1, 5-dioxo-9-azabicyclo [4.4.0] decanyl, 3-azabicyclo [4.4.0] decanyl, 2, 7-diazanaphthyl, 2-oxo-8-azabicyclo [4.4.0] decanyl, 2-oxo-5-azabicyclo [2.2.1] heptanyl, 5-azaspiro [2.4] heptanyl, 2.4] heptanyl, 2-azaspiro [4.5] decylene, 2-azaspiro [3.3] heptylene, 2-azaspiro [4.4] nonanylene, 3-azaspiro [5.4] decylene, 2-oxo-6-azaspiro [3.3] heptanylene, 2, 6-diazaspiro [3.3] heptanylene, 2-thio-6-azaspiro [3.3] heptanylene 2-monoxide, 2-thio-6-azaspiro [3.3] heptanylene 2, 2-dioxide and the like.
The terms "fused bicyclic", "fused ring", "fused bicyclic group" or "fused ring group" mean a fused ring system, saturated or unsaturated, and refers to a non-aromatic bicyclic ring system, at least one of the rings being non-aromatic. Depending on the structure, a "fused bicyclic ring", "fused bicyclic group" or "fused ring group" may be a monovalent or divalent group, i.e., in certain embodiments of the present invention, a fused bicyclic group may be used in place of or as a subfused bicyclic group. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). Each ring in the fused bicyclic ring can be either a carbocyclic or a heteroalicyclic, and examples include, but are not limited to, hexahydro-furan [3,2-b ] furanyl, 2,3,3a,4,7,7 a-hexahydro-1H-indenyl, 7-azabicyclo [2.2.1] heptanyl, fused bicyclo [3.3.0] octanyl, fused bicyclo [3.1.0] hexanyl, 1,2,3,4,4a,5,8,8 a-octahydronaphthyl, all of which are included in the fused bicyclic ring system. One or more of the ring hydrogen atoms are independently optionally substituted with one or more substituents described herein.
The term "fused heterobicyclic group" refers to a saturated or unsaturated fused ring system, involving a non-aromatic bicyclic ring system, at least one of the rings being non-aromatic. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). Depending on the structure, a "fused heterobicyclic group" may be a monovalent or divalent group, i.e., in certain embodiments of the invention, may be used in place of or as a subfenzenated heterobicyclic group. And at leastOne ring system containing one or more hetero atoms, wherein each ring system contains a ring of 3-7 atoms, i.e. 1-6 carbon atoms and 1-3 hetero atoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give compounds like SO, SO2，PO，PO2In addition, the carbon atom may also be oxo-C (═ O) -; examples include, but are not limited to, hexahydro-2H- [1,4]Dioxin [2,3-c ]]Pyrrolyl, 3-azabicyclo [3.3.0]Octyl 3-methyl-3, 7-diazabicyclo [3.3.0]Octyl, 8-azabicyclo [4.3.0] groups]Nonanyl, 8-azabicyclo [4.3.0]Nonane 3-yl, 3-azabicyclo [4.3.0]Nonan-3-yl, 1, 5-dioxo-8-azabicyclo [4.3.0]Nonyl, (1R,6S) -2, 5-dioxo-8-azabicyclo [4.3.0]Nonyl, (1R,6R) -2, 5-dioxo-8-azabicyclo [4.3.0]Nonanyl, isoindolinyl, 1,2,3, 4-tetrahydroquinolinyl, (1S,5S) -1-hydroxy-3-azabicyclo [3.1.0]Hexane radical, (1R,5S) -1-hydroxy-3-azabicyclo [3.1.0]Hexane radical, (1R,5S) -1-N, N-dimethylamino-3-azabicyclo [3.1.0]Hexane radical, (1S,5R,6R) -1-methyl-6-ol-3-azabicyclo [3.2.0]Heptenyl, 3-nitrogen-7-oxabicyclo [3.3.0]Octyl 3, 7-diazabicyclo [3.3.0]]Octyl, 2, 6-diazabicyclo [3.3.0]]Octyl, 2, 7-diazabicyclo [3.3.0]]Octyl, 2, 8-diazabicyclo [4.3.0]]Nonanyl, 3-oxo-8-azabicyclo [4.3.0]Nonanyl, 2-oxo-8-azabicyclo [4.3.0]Nonanyl, 2, 8-diaza-5-oxabicyclo [4.3.0]Nonanyl, 2, 7-diazanaphthyl or 2-oxo-8-azabicyclo [4.4.0]Decyl, and the like. One or more of the ring hydrogen atoms are independently optionally substituted with one or more substituents described herein.
The term "bridged bicyclic group" denotes a saturated or unsaturated bridged ring system, involving a bicyclic system that is not aromatic. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). Wherein each ring system contains 3 to 7 atoms, examples include, but are not limited to, bicyclo [2.2.1] heptanyl, 2-methyl-heterobicyclo [2.2.1] heptanyl, and the like. One or more of the ring hydrogen atoms are independently optionally substituted with one or more substituents described herein.
The term "bridged heterobicyclic group" denotes a saturated or unsaturated bridged ring system, involving a bicyclic system that is not aromatic. Depending on the structure, a "bridged heterobicyclic group" may be a monovalent group or a divalent group, i.e., may be used in place of or as a bridged heterobicyclic group in certain embodiments of the invention. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises 3 to 7 atoms, i.e. 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, whereby S or P is optionally substituted by one or more oxygen atoms to give compounds like SO, SO2，PO，PO2In addition, the carbon atom may also be oxo-C (═ O) -; examples include, but are not limited to, 2-oxo-5-azabicyclo [2.2.1]Heptylalkyl, 2-thio-5-azabicyclo [2.2.1]]Heptylalkyl, 2-oxo-5-azabicyclo [2.2.1]Heptylalkyl, 2, 5-diazabicyclo [2.2.1]Heptylalkyl, 2-methyl-2, 5-diazabicyclo [2.2.1]Heptalkyl, and the like. One or more of the ring hydrogen atoms are independently optionally substituted with one or more substituents described herein.
The terms "spirocyclic", "spiro", "spirobicyclic group", "spirobicyclic ring" indicate that one ring originates from a particular cyclic carbon on the other ring. For example, as described below, a saturated bridged ring system (rings B and B ') is referred to as a "fused bicyclic ring", whereas rings a' and B share a carbon atom in two saturated ring systems, is referred to as a "spiro ring". Each ring within the spiro ring is either a carbocyclic or a heteroalicyclic. Examples of such include, but are not limited to, 4-azaspiro [2.4] heptan-5-yl, 4-oxaspiro [2.4] heptan-5-yl, 5-azaspiro [2.4] heptan-5-yl, spiro [2.4] heptanyl, spiro [4.4] nonanyl, 7-hydroxy-5-azaspiro [2.4] heptan-5-yl, and the like. One or more of the ring hydrogen atoms are independently optionally substituted with one or more substituents described herein.
The term "spiroheterobicyclic group" means that one ring originates from a specific cyclic carbon on the other ring. For example, as described above, a saturated bridged ring system (rings B and B ') is referred to as a "fused bicyclic ring", whereas rings a' and B share a carbon atom in two saturated ring systems, is referred to as a "spiro ring". And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises 3 to 7 atoms, i.e. 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, whereby S or P is optionally substituted by one or more oxygen atoms to give compounds like SO, SO2，PO，PO2Examples of such include, but are not limited to, 4-azaspiro [2.4]]Heptalkyl, 4-oxaspiro [2.4]]Heptylalkyl, 5-azaspiro [2.4]Heptylalkyl, 2-azaspiro [4.5]Decyl, 2-azaspiro [3.3]Heptylalkyl, 2-azaspiro [4.4]Nonanyl, 3-azaspiro [5.4]]Decyl, 2-methyl-2-azaspiro [3.3]Heptylalkyl, 2-oxo-6-azaspiro [3.3]Heptylalkyl, 2, 6-diazaspiro [3.3]Heptylalkyl, 2-thio-6-azaspiro [3.3]Heptylalkyl 2-monoxides, 2-thio-6-azaspiro [3.3]Heptalkyl 2, 2-dioxide, and the like. One or more of the ring hydrogen atoms are independently optionally substituted with one or more substituents described herein.
The ring system formed by the ring with the substituent R bonded to the center, as described herein, represents that the substituent R may be substituted at any substitutable or any reasonable position on the ring. For example, formula a represents the A' ring or any possible substituted position on the B ring may be substituted with R, as shown in formula B, formula c, formula d, formula e, formula f, formula g, and formula h.
As described herein, substituent (R)nBy a keyThe ring system formed on the ring attached to the center represents that the n substituents R may be substituted at any substitutable position on the ring. For example, formula i represents that any possible substituted position on the A 'or B' ring may be substituted by n R.
As described herein, there are two attachment points on ring C that can be attached to the rest of the molecule, for example, as shown in formula j, meaning that either the E "or E' end is attached to the rest of the molecule, i.e., the attachment of the two ends can be interchanged.
The attachment point may be attached to the rest of the molecule at any point on the ring that is attachable, as described herein. For example, formula k represents the point of attachment at any possible attachment position on the A 'ring or the B' ring.
As described herein, the attachment point can be attached to the rest of the molecule at any point on the ring that is attachable, while the two ends of the attachment can be interchanged. For example, the formula m represents that any possible connection position on the ring can be used as a connection point, and the two ends of the connection point can be interchanged. The dotted line in the formula indicates the presence or absence.
As described in the present invention, "- (L) is present in the general formula (I)2)w- "indicates that, when w takes different values, there are different numbers of L2And each L2Independently represent the same or different groups. For example, when w is 3, then L2Having three identical or different radicals, e.g. L2May optionally represent-NH-, -C (═ O) -and-CH2-. In this case, - (L)2)w-is-C (═ O) -NH-CH2-，-CH2of-C (═ O) -NH-or of the other three groupsAnd (4) combining.
In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other. For example, formula i represents that any possible substituted position on the a 'or B' ring may be substituted by n R, wherein each R is independently selected from the same or different groups. As another example, in the formula (I), each L2The same or different groups may be used.
The "hydrate" of the present invention refers to the compound or salt thereof provided by the present invention, which further comprises water bonded by non-covalent intermolecular forces in a chemical amount or in a non-chemical equivalent amount, and may be said to be an association of solvent molecules with water.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.
By "ester" herein is meant that the compounds of formulae (I) - (III) containing a hydroxyl group can form an in vivo hydrolysable ester. Such esters are, for example, pharmaceutically acceptable esters which are hydrolysed in the human or animal body to yield the parent alcohol. The group of the in vivo hydrolysable ester of the compounds of formulae (I) - (III) containing a hydroxy group include, but are not limited to, phosphate, acetoxymethoxy, 2, 2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, benzoylacetyl, alkoxycarbonyl, dialkylcarbamoyl and N- (dialkylaminoethyl) -N-alkylcarbamoyl and the like.
"nitroxide" in the context of the present invention means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acids), to form the N-oxide (see advanced organic chemistry, wiley interscience, 4 th edition, JerryMarch, pages). In particular, the N-oxide may be prepared by the method of L.W.Deady (Syn.Comm.1977,7,509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as methylene chloride.
The compounds may exist in a variety of different geometric isomers and tautomers and the compounds of formulae (I) - (III) include all such forms. For the avoidance of doubt, when a compound exists as one of several geometric isomers or tautomers and only one is specifically described or shown, it is apparent that all other forms are encompassed in formulas (I) - (III).
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I) - (III). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchiand V.Stella, Pro-drugs NovelDelivery systems, Vol.14soft A.C.S.Symphosium series, Edward dB.Roche, ed., Bioversicolor Crierrie DrugDesign, American pharmaceutical Association PergammonPress, 1987, J.Rautooral, Prodraugs Designa and Clevelocpplications,NatureReviewDrugDiscovery,2008,7,255-270,andS.J.Heckeretal,ProdrugsofPhosphatesandPhosphonates,JournalofMedicinalChemistry,2008,51，2328-2345。
Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
Various pharmaceutically acceptable salt forms of the compounds of the present invention are useful. The term "pharmaceutically acceptable salts" means those salt forms that are readily apparent to the pharmaceutical chemist as being substantially non-toxic and providing the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. Other factors, more practical in nature, are also important for selection, these are: cost of raw materials, ease of crystallization, yield, stability, hygroscopicity and, as a result, flowability of the drug substance. Briefly, the pharmaceutical composition can be prepared by combining the active ingredient with a pharmaceutically acceptable carrier.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: bergeet, descriptive bepharmaceuticalliferalbales indinavilin J.PExamples of the compounds are described in pharmaceutical sciences,66:1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulphates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, malates, 2-hydroxypropionates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, caproates, hydroiodiates, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurylsulfates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates and aromatic sulfonates. Amine salts such as, but not limited to, N' -dibenzylethylenediamine, chloroprocaine, choline, ammonia, isopropylamine, benzathine (benzathine), choline salts (cholinate), lysine, dextranMethylamine (meglumine), piperazine, tromethamine, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methyl reduced glucamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1' -ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris (hydroxymethyl) aminomethane; alkaline earth metal salts such as, but not limited to, barium, calcium and magnesium; a transition metal salt such as, but not limited to, zinc.
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
As used herein, "inflammatory disease" refers to any disease, disorder or condition of excessive inflammatory symptoms, host tissue damage or loss of tissue function due to excessive or uncontrolled inflammatory response. "inflammatory disease" also refers to a pathological condition mediated by leukocyte influx and/or neutrophil chemotaxis.
As used herein, "inflammation" refers to a local protective response caused by tissue damage or destruction that serves to destroy, dilute, or separate (sequester) harmful substances from damaged tissue. Inflammation is significantly linked to leukocyte influx and/or neutrophil chemotaxis. Inflammation can result from infection by pathogenic organisms and viruses, as well as from non-infectious means, such as trauma or reperfusion following myocardial infarction or stroke, immune and autoimmune responses to foreign antigens. Thus, inflammatory diseases that may be treated with the disclosed compounds include: diseases associated with specific defense system reactions as well as non-specific defense system reactions.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.) or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In e.g. "Remington's pharmaceutical sciences", 20 th edition, MackPublishing company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (handbook of pharmaceutical salts: Properties, Selection, and use) ", StahlandWermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable salts.
In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms.
Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H，3H，11C，13C，14C，15N，17O，18O，18F，31P，32P，35S，36Cl and125I。
in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present3H，14C and18those compounds of F or in which a non-radioactive isotope is present, e.g.2H and13C. the isotopically enriched compounds can be used for metabolic studies (use)14C) Reaction kinetics study (using, for example2H or3H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution assays or in radiotherapy of a patient.18F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.
In addition, heavier isotopes are, in particular, deuterium (i.e.,2substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is considered as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has, for each designated deuterium atom, at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation), at leastIncorporation) of the isotopic enrichment factor. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D2O, acetone-d6、DMSO-d6Those solvates of (a).
"combination" means a fixed combination or a kit of parts for combined administration in the form of a single dosage unit, wherein a compound disclosed herein and a combination partner may be administered separately at the same time or may be administered separately within certain time intervals, in particular such that the combination partners show a cooperative, e.g. synergistic, effect. The terms "co-administration" or "co-administration" and the like as used herein are intended to encompass the administration of the selected combination partners to a single individual in need thereof (e.g., a patient), and are intended to encompass treatment regimens in which the substances are not necessarily administered by the same route of administration or simultaneously. The term "pharmaceutical combination product" as used herein denotes a product obtained by mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, such as the disclosed compounds and combination partners, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, such as the compounds of the disclosed compounds and the combination partners, are both administered to a patient as separate entities simultaneously, jointly or sequentially with no specific time limits, wherein the administration provides therapeutically effective levels of both compounds in the patient. The latter is also applicable to cocktail therapy, e.g. administering 3 or more active ingredients.
Description of the Compounds of the invention
The present invention provides a series of indole derivatives wherein the indole nitrogen is substituted with a carboxylic acid moiety which is the PGD at the CRTH2 receptor2And can be used to treat PGD at the CRTH2 receptor2Mediated diseases and conditions.
The present invention provides a compound of one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof:
in one aspect, the invention provides a pharmaceutical composition comprising any of the compounds according to the invention.
In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.
In some embodiments, the pharmaceutical compositions of the invention further comprise one or more agents useful for treating PGD at the CRTH2 receptor2Other active agents of the mediated disease.
In still other embodiments, the pharmaceutical compositions of the invention, wherein the additional active agent is a TNF- α inhibitor, a COX-1/COX-2 inhibitor, a glucocorticoid, an inactivated antibody to interleukin, a chemokine receptor modulator, a histamine H1 receptor antagonist/antihistamine, a leukotriene D4 receptor antagonist, a LTD4 antagonist, a VLA-4 antagonist, a corticoid 4 antagonistSteroid analogues, theophylline, leukotriene biosynthesis inhibitors, cyclooxygenase-2 inhibitors, opioid analgesics, anticoagulants, β -blockers, β -adrenergic agonists, angiotensin converting enzyme inhibitors, HMG-CoA reductase inhibitors, β 2 agonists, corticosteroids, antihistamines, leukotriene antagonists, anti-IgE antibody therapeutics, anti-infective agents, antifungal agents, immunosuppressive agents, other PGD's acting on other receptors2Antagonists, inhibitors of phosphodiesterase type 4, agents modulating cytokine production, agents modulating the activity of the Th2 cytokines IL-4 and IL-5, 5-lipoxygenase inhibitors.
In still other embodiments, the active agent is salmeterol, fluticasone, loratadine, montelukast, omalizumab, fusidic acid, clotrimazole, tacrolimus, pimecrolimus, DP antagonists, cilomilast, TNF-alpha converting enzyme (TACE) inhibitors, blocking monoclonal antibodies or soluble receptors for IL-4 or IL-5, and zileuton.
In one aspect, the present invention provides a method of using any one of the compounds of the present invention or any one of the pharmaceutical compositions of the present invention for the preparation of a medicament for protecting, treating or ameliorating PGD at the CRTH2 receptor in a patient2Use of a pharmaceutical product for a mediated disease.
In some embodiments, the use of the invention, wherein the PGD at the CRTH2 receptor is administered2The mediated disease is asthma, allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity, conjunctivitis, eosinophilic bronchitis, food allergy, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and crohn's disease, mastocytosis, autoimmune disease, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriatic arthritis or osteoarthritis.
In still other embodiments, the use of the invention, wherein the autoimmune disease is psoriasis, multiple sclerosis, allograft rejection, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus and osteoarthritis.
In a further aspect, the invention provides a combination pharmaceutical preparation comprising a compound according to any one of the preceding claims and one or more agents according to any one of the preceding claims as a combined preparation for simultaneous, separate or sequential use in the prevention, treatment or alleviation of PGD at the CRTH2 receptor2Use of the mediated disease.
In yet another aspect, the invention provides a method of protecting, managing, treating or ameliorating PGD at the CRTH2 receptor in a patient2A method of treating a mediated disease or condition, the method comprising administering to a patient having the infectious disease a therapeutically effective amount of a compound according to any of the present invention or a pharmaceutical composition according to any of the present invention.
In yet another aspect, a compound according to any one of the invention or a pharmaceutical composition according to any one of the invention for use in protecting, treating or reducing PGD at the CRTH2 receptor in a patient2Mediated diseases and conditions.
Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the present invention. In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes materials or compositions which must be compatible chemically or toxicologically, with the other components comprising the formulation, and with the mammal being treated. Salts of the compounds of the present invention also include, but are not necessarily pharmaceutically acceptable salts of intermediates used in the preparation or purification of the compounds of formulae (I) - (III) or isolated enantiomers of the compounds of formulae (I) - (III).
If the compounds of the invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Or using organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, 2-hydroxypropionic acid, citric acid, oxalic acid, glycolic acid and salicylic acid; pyranonic acids, such as glucuronic acid and galacturonic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids, such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, and the like or combinations thereof.
If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali metal hydroxides, ammonium, N+(R14)4Salts and alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary, N+(R14)4Salts, e.g. R14Is H, C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl, etc., and cyclic amines, such as piperidine, morpholine, piperazine, etc., and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. Also included are suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, e.g. halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates and aromatic sulfonates.
Uses, formulations and compositions of the compounds of the invention
The compounds of the present invention are useful in the treatment of PGD at the CRTH2 receptor2A method of mediating diseases and conditions, the method comprising administering to a patient in need of treatment an amount of a compound of formula (I) - (III).
In another aspect of the present invention, there is provided novel compounds represented by the general formulae (I) to (III)For medical use, in particular for the treatment or prophylaxis of PGD at the CRTH2 receptor2Mediated diseases and conditions.
As mentioned above, such diseases and conditions include allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis), conjunctivitis, especially allergic conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and other PGD' s2Mediated diseases, for example autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematosus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease, and rheumatoid arthritis, psoriatic arthritis and osteoarthritis.
The compounds of formula (I) must be formulated in an appropriate manner according to the disease or condition to be treated.
Accordingly, in another aspect of the present invention, there is provided a pharmaceutical composition comprising the novel compounds of formulae (I) - (III) and a pharmaceutical excipient or carrier. Other active substances which are considered suitable or suitable for the treatment or prevention of the above-mentioned diseases or conditions may also be included. The carrier, or each carrier if more than one is present, must be acceptably compatible with the other components of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, rectal, nasal, bronchial (inhalation), topical (including eye drops, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration and may be prepared by any method well known in the art of pharmacy.
The route of administration depends on the disease to be treated, but it is preferred to prepare the composition as a preparation for oral, nasal, bronchial or topical administration.
The compositions may be prepared by mixing the active agents described above with a carrier. Generally, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or a mixture of both, and then, if necessary, shaping the product. The present invention provides a process for the preparation of a pharmaceutical composition comprising combining or combining a novel compound of formula (I) - (III) with a pharmaceutically or veterinarily acceptable carrier or vehicle.
The oral formulation of the present invention may be presented as: discrete units, such as capsules, sachets or tablets, each containing a predetermined amount of active agent; a powder or granules; solutions or suspensions of the active agent in aqueous or non-aqueous liquids; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; or bolus etc.
For oral compositions (e.g., tablets and capsules), the term "acceptable carrier" includes excipients such as commonly used excipients, for example, binding agents, such as syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, such as corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, stearic acid, glyceryl stearate, silicone fluids, talc waxes, oils and colloidal silica. Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring, and the like may also be used. If desired, colorants may also be added to make the dosage form easily identifiable. Tablets may also be coated by methods well known in the art.
Tablets may optionally be prepared by compression or molding with one or more accessory ingredients. The process for preparing compressed tablets comprises compressing in a suitable machine the active pharmaceutical agent, which is, for example, in the form of a powder or granules, in free-flowing form, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. The process for making the molded tablets involves molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained or controlled release of the active agent.
Other formulations suitable for oral administration include lozenges of the active agent in a flavored basis, usually sucrose and acacia or tragacanth; pastilles of the active agent in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes of the active agent in a suitable liquid carrier.
For topical application to the skin, the compounds of formulae (I) - (III) may be formulated as creams, ointments, jellies, solutions or suspensions, etc. Cream or ointment formulations which may be used as medicaments are conventional formulations well known in the art, for example as described in standard textbooks of pharmacy, for example the british pharmacopoeia.
The compounds of the general formulae (I) to (III) can be administered nasally, bronchially or buccally for the treatment of respiratory diseases, for example as aerosols or sprays, which disperse the pharmaceutically active ingredients in powder form or in the form of droplets of solutions or suspensions. Pharmaceutical compositions having powder-dispersing properties usually comprise, in addition to the active ingredient, a liquid propellant having a boiling point below room temperature and, if desired, additives, such as liquid or solid nonionic or anionic surfactants and/or diluents. Pharmaceutical compositions of the pharmaceutically active component in solution comprise, in addition to the solution and the pharmaceutically active component, a suitable propellant and, if desired, further solvents and/or stabilizers. It is also possible to replace the propellant with a compressed gas, which can be prepared by suitable compression and expansion means, if desired.
Parenteral formulations are generally sterile.
Typically, the dose of the compound is about 0.01 to 100 mg/kg; the dose is sufficient to maintain the concentration of the drug in the plasma at a level effective to inhibit PGD at the CRTH2 receptor2Is rich inAnd (4) degree. The precise therapeutically effective amount of the compounds of formulae (I) - (III) and the optimal route of administration of these compounds can be determined by one of ordinary skill in the art by comparing the blood concentration of the formulation to the concentration required to have a therapeutic effect.
Typically a therapeutically effective amount should result in a serum concentration of the active ingredient of about 0.1ng/ml to about 50-100 micrograms/ml. The pharmaceutical composition should typically provide a dose of from about 0.001mg to about 2000mg of the compound per day per kilogram of body weight. The pharmaceutical dosage unit forms may be prepared to provide from about 1mg to about 1000mg, and in certain embodiments, from about 10mg to about 500mg, from about 20mg to about 250mg, or from about 25mg to about 100mg of the essential active ingredient or combination of essential ingredients per dosage unit form. In certain embodiments, the pharmaceutical dosage unit form may be prepared to provide about 1mg, 20mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg of the essential active ingredient. In certain embodiments, the pharmaceutical dosage unit form is prepared to provide about 50mg of the essential active ingredient.
The active ingredient of the active compound in the pharmaceutical composition can be administered once or divided into several smaller doses to be administered at certain time intervals. It will be understood that the precise dose and duration of treatment is a function of the condition to be treated and may be determined empirically using known experimental methods or extrapolated from experimental data in vivo or in vitro. It should be noted that concentrations and dosage values may also vary with the degree of severity of the symptoms to be alleviated. It is further to be understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
The "effective amount" or "effective dose" of the present invention means: an amount effective to treat or ameliorate one or more of the foregoing disorders. Any effective amount and any effective route of administration can be used to treat or reduce the severity of the disorder or disease according to the compounds or compositions disclosed herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, severity of infection, particular formulation, mode of administration, and the like. The compound or composition may also be administered with one or more other drugs, as described above.
The compounds of formulae (I) - (III) may be used in combination with one or more active agents for the treatment of the diseases and conditions listed above, although these active agents are not necessarily PGDs at the CRTH2 receptor2The inhibitor of (1). Thus, the pharmaceutical compositions described above may also comprise one or more such active agents.
The invention also provides the use of a compound of formulae (I) - (III) for the preparation of a medicament for the treatment of PGD at the CRTH2 receptor2These other active agents, which may have completely different modes of action, include existing therapeutics for allergic and other inflammatory diseases, including β 2 agonists such as salmeterol, corticosteroids such as fluticasone, antihistamines such as loratadine, leukotriene antagonists such as montelukast, anti-IgE antibody therapeutics such as omalizumab, anti-infectives such as fusidic acid (particularly for the treatment of atopic dermatitis), antifungals such as clotrimazole (particularly for the treatment of atopic dermatitis), immunosuppressants such as tacrolimus and pimecrolimus selected particularly in inflammatory skin diseases.
The CRTH2 antagonist may also be used in combination with a therapeutic agent for the treatment of the development of an inflammatory indication, wherein the therapeutic agent comprises: other PGDs acting on other receptors2Antagonists, e.g. DP antagonists, inhibitors of phosphodiesterase type 4, e.g. cilonilast, agents modulating cytokine production, e.g. TNF α invertase (TACE) inhibitors, agents modulating the activity of Th2 cytokines IL-4 and IL-5, e.g. blocking monoclonal antibodies and soluble receptors, PPAR-gamma agonists, e.g. RoglieA ketone; 5-lipoxygenase inhibitors, such as zileuton.
In another aspect of the invention, there is provided a product comprising a novel compound of formulae (I) to (III) and one or more of the agents described above as a combined preparation for simultaneous, separate or sequential use in the treatment of PGD at the CRTH2 receptor2Diseases and conditions mediated by the action.
The invention also provides pharmaceutical compositions comprising a compound of the general formulae (I) - (III), pharmaceutically acceptable salts thereof and stereoisomers thereof and one or more therapeutically active agents selected from TNF-alpha inhibitors, COX-1/COX-2 inhibitors, glucocorticoids, inactivated antibodies to interleukins, chemokine receptor modulators, histamine H1 receptor antagonists/antihistamines, leukotriene D4 receptor antagonists, leukotriene antagonists, LTD4 antagonists, VLA-4 antagonists, corticosteroids, corticosteroid analogs, beta 2-agonists, theophylline, leukotriene biosynthesis inhibitors, cyclooxygenase-2 inhibitors, phosphodiesterase type IV inhibitors, opioid analgesics, anticoagulants, beta-blockers, pharmaceutically acceptable salts thereof, and stereoisomers thereof, Beta-adrenergic agonists, angiotensin converting enzyme inhibitors or HMG-CoA reductase inhibitors.
The term "composition" as used herein, is intended to include any product which comprises the active ingredient and which constitutes a carrier, either by inert complexation or polymerization or resulting from decomposition of one or more of the ingredients or from other types of reactions or interactions of one or more of the ingredients, in a pharmaceutical composition, and thus includes any composition prepared by admixing a compound of formulae (I) - (III) with one or more pharmaceutically acceptable excipients.
The pharmaceutical carriers used may be: solid, liquid or gas. Examples of solid carriers include: lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Examples of liquid carriers include: syrup, peanut oil, olive oil, water, etc. Examples of gaseous carriers include: carbon dioxide and/or nitrogen. Likewise, the carrier or diluent may include a time delay material disclosed in the literature, such as glyceryl monostearate or glyceryl stearate, alone or in combination with a wax.
On the other hand, substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; alumina; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate; salts such as sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylate esters; a wax; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphoric acid buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants.
General synthetic methods
In general, the compounds of the invention can be prepared by the methods described herein, wherein the substituents are defined as shown in formulas (I) - (III), unless further indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein or by some conventional modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich chemical company, Arco chemical company and Alfa chemical company, and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. Nuclear magnetic resonance spectroscopy with CDC13,d6-DMSO,CD3OD or d6Acetone as solvent (reported in ppm) with TMS (0ppm) or chloroform (7.25ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet )) M (multiplet ), br (broad), dd (doubletoflubelets, quartet), dt (doublettoftriplets, double triplet). Coupling constants are expressed in hertz (Hz).
Low resolution Mass Spectral (MS) data were determined by Agilent6320 series LC-MS spectrometer equipped with a G1312A binary pump and an aG1316ATCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315BDAD detector were used for analysis, and an ESI source was used for LC-MS spectrometer.
Low resolution Mass Spectral (MS) data were determined by Agilent6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316ATCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315DDAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.
Both spectrometers were equipped with an Agilent ZorbaxSB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:
TABLE 1
Compound purification was assessed by Agilent1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, 2.1X 30mm, 4 μm, 10min, flow rate 0.6mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.
The following acronyms are used throughout the invention:
boc tert-butyloxycarbonyl group
CHCl3Chloroform
CDC13Deuterated chloroform
CD3OD deuterated methanol
d6-DMSO deuterated dimethyl sulfoxide
DMFN, N-dimethylformamide
DMAP 4-dimethylaminopyridine
DIPEAN, N-diisopropylethylamine
DMSO dimethyl sulfoxide
H2Hydrogen gas
HCl hydrogen chloride, hydrochloric acid
MeOH,CH3OH methanol
mL, mL
N2Nitrogen gas
Pd/C Palladium/carbon
RTrt Room temperature
Rt Retention time
LiOH·H2Lithium O-hydroxide hydrate
NaH sodium hydride
H2O water
Synthesis scheme 1
Compound (8) can be prepared according to the method of FIG. 1. Wherein A and E have the meanings as described in the invention. 5-fluoro-2-methyl-1H-indole with DMF in POCl3In the presence of a catalyst to obtain a compound (1). Reacting the compound (1) with methyl bromoacetate under alkaline conditions (the alkali can be sodium hydride, sodium hydroxide, organic alkali and the like) to obtain a compound (2). Compound (2) in potassium permanganateTo obtain a compound (3). The compound (3) and the compound (9) are subjected to condensation reaction to obtain a compound (4), then the compound (4) is subjected to deprotection to obtain a compound (5), and then the compound (5) and the compound (6) are subjected to condensation to obtain a compound (7), and the compound (7) is subjected to deprotection under the alkaline condition (alkali can be lithium hydroxide, sodium hydroxide, aluminum hydroxide and the like) and is subjected to post-treatment under the acidic condition to obtain a target product (8).
Synthesis scheme 2
Compound (14) can be prepared according to the method of FIG. 2. Wherein A and E have the meanings as described in the invention. The compound (3) was obtained according to the relevant synthetic procedures of synthetic scheme 1. Compound (3) and compound (10) undergo condensation reaction under basic conditions (the base may be DIPEA but not limited to) to obtain compound (11), and undergo deprotection under acidic conditions (the acid may be HCl but not limited to) to obtain compound (12). Then the compound (12) and the compound (6) are condensed to obtain a compound (13), and the compound (13) is deprotected under alkaline conditions (alkali can be lithium hydroxide, sodium hydroxide, aluminum hydroxide and the like) and is post-treated under acidic conditions to obtain a target product (14).
Synthesis scheme 3
Compound (22) can be prepared according to the procedure of FIG. 3. Wherein L is1，L2M, A and E have the meanings given in the description. The compound (3) was obtained according to the relevant synthetic procedures of synthetic scheme 1. The compound (3) and the compound (20) are condensed to obtain a compound (21), and then the compound (21) is deprotected under the condition of alkalinity (alkali can be lithium hydroxide, sodium hydroxide, aluminum hydroxide and the like) and is post-processed under the acidic condition to obtain a target product (22).
Synthesis scheme 4
Compound (25) can be prepared according to the procedure of FIG. 4. Wherein A and E have the meanings as described in the invention. Compound (5) was obtained according to the relevant synthetic procedures of FIG. 1. The compound (5) is condensed with the compound (23) to obtain a compound (24), and then the compound (24) is deprotected under the alkaline condition (alkali can be lithium hydroxide, sodium hydroxide, aluminum hydroxide and the like) and is post-processed under the acidic condition to obtain a target product (25).
Synthesis scheme 5
Compound (29) can be prepared according to the procedure of FIG. 5. Wherein A and E have the meanings as described in the invention. Compound (12) was obtained according to the relevant synthetic procedures of FIG. 2. The compound (12) is condensed with the compound (23) to obtain a compound (28), and then the compound (28) is deprotected under alkaline conditions (alkali can be lithium hydroxide, sodium hydroxide, aluminum hydroxide and the like) and is post-treated under acidic conditions to obtain the target product (29).
The following examples may further illustrate the present invention, however, these examples should not be construed as limiting the scope of the present invention.
Examples
EXAMPLE 1 Synthesis of the Compound 2- (5-fluoro-2-methyl-3- (4- (quinoline-5-carbonyl) piperazine-1-carbonyl) -1H-indol-1-yl) acetic acid hydrochloride
Step 1: synthesis of compound 5-fluoro-2-methyl-1H-indole-3-carbaldehyde
Under the ice bath condition, anhydrous DMF (2.6mL,33.5mmol) is dropwise added into phosphorus oxychloride (3.7mL,40.2mmol) protected by nitrogen, the mixture reacts for 5min at the temperature of 0 ℃, a solution (10mL) of 5-fluoro-2-methyl-1H-indole (2g,13.4mmol) in the anhydrous DMF is dropwise added, the mixture is stirred for 1.5H at room temperature, the system is poured into ice water (20mL), sodium hydroxide is added to adjust the mixture to be alkaline, solid is precipitated and filtered, and after a filter cake is dried, 1.97g of off-white solid is obtained, and the yield is 82%.
1HNMR(400MHz,CD3OD):ppm10.0(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/z178.1[M+H]+.
Step 2: synthesis of compound methyl 2- (5-fluoro-3-formyl-2-methyl-1H-indol-1-yl) acetate
Methyl bromoacetate (1.2mL,12.5mmol) was added dropwise to a solution of the compound 5-fluoro-2-methyl-1H-indole-3-carbaldehyde (1.11g,6.26mmol) and sodium hydride (451mg,18.8mmol) in N, N-dimethylformamide (14mL), stirred at room temperature for 14 hours, washed with 20mL of water after removal of the solvent, extracted with ethyl acetate (15mL × 2), combined organic phases were dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (V (petroleum ether)/V (ethyl acetate) ═ 2/1) to obtain 1.32g of a pale yellow solid in 84% yield.
1HNMR(400MHz,CDCl3):ppm10.2(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]+.
And step 3: synthesis of compound 5-fluoro-1- (2-methoxy-2-oxoethyl) -2-methyl-1H-indole-3-carboxylic acid
To a solution of methyl 2- (5-fluoro-3-formyl-2-methyl-1H-indol-1-yl) acetate (1.32g,5.30mmol) in acetone (12mL) was added an aqueous solution (6mL) of potassium permanganate (837mg,5.30mmol) under ice-bath conditions, stirred at room temperature for 3.5H, filtered through celite, the filtrate was acidified with concentrated hydrochloric acid, stirred, extracted with ethyl acetate, the organic phase was dried, and concentrated to give 1.10g of a gray solid with a yield of 78%.
1HNMR(600MHz,d6-DMSO):ppm7.66(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/z266.0[M+H]+
And 4, step 4: synthesis of Compound 4- (5-fluoro-1- (2-methoxy-2-oxoethyl) -2-methyl-1H-indole-3-carbonyl) piperazine-1-acetic acid tert-butyl ester
The compound 5-fluoro-1- (2-methoxy-2-oxoethyl) -2-methyl-1H-indole-3-carboxylic acid (460mg,1.74mmol), N-Boc piperazine (388mg,2.08mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (498mg,2.60mmol) and N-hydroxy-7-azabenzotriazole (590mg,4.34mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (1.2mL,6.94mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 17H, washed with water (10mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (V (petroleum ether)/V (ethyl acetate) ═ 1/1), 608mg of white solid are obtained, yield: 80 percent.
1HNMR(400MHz,CDCl3):ppm7.14(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/z434.3[M+H]+.
And 5: synthesis of compound methyl 2- (5-fluoro-2-methyl-3- (piperazine-1-carbonyl) -1H-indol-1-yl) acetate hydrochloride
The compound tert-butyl 4- (5-fluoro-1- (2-methoxy-2-oxoethyl) -2-methyl-1H-indole-3-carbonyl) piperazine-1-acetate (595mg,1.37mmol) was dissolved in dichloromethane (6mL), a 4mol/LHCl solution in ethyl acetate (6mL) was added, and the reaction was stopped after stirring at room temperature for 1.5H. Removal of the solvent gave 507mg of an off-white solid as a white solid in 99% yield.
1HNMR(400MHz,CD3OD):ppm7.40(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/z334.3[M+H-HCl]+.
Step 6: synthesis of the Compound methyl 2- (5-fluoro-2-methyl-3- (4- (quinoline-5-carbonyl) piperazine-1-carbonyl) -1H-indol-1-yl) acetate
The compound methyl 2- (5-fluoro-2-methyl-3- (piperazine-1-carbonyl) -1H-indol-1-yl) acetate hydrochloride (155mg,0.42mmol), quinoline-5-carboxylic acid (87mg,0.50mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (121mg,0.63mmol) and N-hydroxy-7-azabenzotriazole (143mg,1.05mmol) were dissolved in dichloromethane (12mL), N-diisopropylethylamine (0.29mL,1.68mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 18H, water washed (10mL × 2) was added, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (V (dichloromethane)/V (methanol) ═ 30/1), 124mg of white solid are obtained, yield: 60 percent.
1HNMR(600MHz,CDCl3):ppm8.97(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/z489.0[M+H]+.
And 7: synthesis of Compound 2- (5-fluoro-2-methyl-3- (4- (quinoline-5-carbonyl) piperazine-1-carbonyl) -1H-indol-1-yl) acetic acid hydrochloride
To a mixed solution of the compound methyl 2- (5-fluoro-2-methyl-3- (4- (quinoline-5-carbonyl) piperazine-1-carbonyl) -1H-indol-1-yl) acetate (120mg,0.25mmol) in tetrahydrofuran (8mL) and water (4mL) was added lithium hydroxide monohydrate (52mg,1.23mmol), reacted at 45 ℃ for 2 hours, added 1mol/L hydrochloric acid to adjust the pH to about 1, the organic solvent was removed, filtered, and the filter cake was dissolved in methanol and then drained to give 69mg of a yellow solid with a yield of 55%.
1HNMR(400MHz,d6-DMSO):ppm8.99(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)；
13CNMR(100MHz,d6-DMSO):ppm170.3,167.5,166.4,157.2,151.2,147.4,141.2,134.9,133.1,130.0,129.7,125.1,125.0,122.8,111.5,109.8,45.1,11.6；
MS-ESI:m/z475.0[M+H-HCl]+.
EXAMPLE 2 Synthesis of the Compound 2- (5-fluoro-3- (4- (5-fluoro-1-naphthamide) piperidine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetic acid
Step 1: synthesis of the compound methyl 2- (3- (4- ((tert-butoxycarbonyl) amino) piperidine-1-carbonyl) -5-fluoro-2-methyl-1H-indol-1-yl) acetate
Dissolving compound 5-fluoro-1- (2-methoxy-2-oxoethyl) -2-methyl-1H-indole-3-carboxylic acid (320mg,1.2mmol), compound 4-N-Boc piperidine (290mg,1.4mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (460mg,2.4mmol) and N-hydroxy-7-azabenzotriazole (250mg,1.8mmol) in dichloromethane (10mL), adding N, N-diisopropylethylamine (0.65mL,3.6mmol) dropwise to the solution at 0 ℃, stirring at room temperature for 10H, washing with water (10mL × 3), drying the organic phase with anhydrous sodium sulfate, removing the solvent, subjecting the concentrate to column separation (V (petroleum ether)/V (ethyl acetate) ═ 1/1), 500mg of white solid are obtained, yield: 93 percent.
1HNMR(400MHz,CDCl3):ppm7.17–7.19(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/z448.10[M+H]+.
Step 2: synthesis of compound methyl 2- (3- (4-aminopiperidine-1-carbonyl) -5-fluoro-2-methyl-1H-indol-1-yl) acetate hydrochloride
The compound methyl 2- (3- (4- ((tert-butoxycarbonyl) amino) piperidine-1-carbonyl) -5-fluoro-2-methyl-1H-indol-1-yl) acetate (500mg,1.1mmol) was dissolved in dichloromethane (4mL), a 4mol/LHCl solution in ethyl acetate (6mL) was added, and the reaction was stopped after stirring at room temperature for 2H. The solvent was removed to give 420mg of a white solid in 99% yield.
1HNMR(400MHz,CD3OD):ppm7.28–7.31(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/z348.10[M+H-HCl]+.
And step 3: synthesis of compound methyl 2- (5-fluoro-3- (4- (5-fluoro-1-naphthamide) piperidine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetate
The compound methyl 2- (3- (4-aminopiperidine-1-carbonyl) -5-fluoro-2-methyl-1H-indol-1-yl) acetate hydrochloride (210mg,0.55mmol), 5-fluoro-1-naphthoic acid (125mg,0.66mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (157mg,0.82mmol) and N-hydroxy-7-azabenzotriazole (186mg,1.37mmol) were dissolved in dichloromethane (15mL), to this solution was added dropwise N, N-diisopropylethylamine (0.38mL,2.19mmol) at 0 ℃, stirred at room temperature for 16H, washed with water (10mL × 2), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (V (dichloromethane)/V (methanol) ═ 30/1), 270mg of white solid are obtained, yield: 94 percent.
1HNMR(400MHz,CDCl3):ppm8.19(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/z520.3[M+H]+.
And 4, step 4: synthesis of Compound 2- (5-fluoro-3- (4- (5-fluoro-1-naphthamide) piperidine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetic acid
To a mixed solution of methyl 2- (5-fluoro-3- (4- (5-fluoro-1-naphthamide) piperidine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetate (260mg,0.50mmol) in tetrahydrofuran (10mL) and water (5mL) was added lithium hydroxide monohydrate (105mg,2.50mmol), reacted at 45 ℃ for 2.5 hours, added 1mol/L hydrochloric acid to adjust pH to about 1, extracted with ethyl acetate (10mL × 2), and the solvent was removed to give 210mg of a white solid in 83% yield.
1HNMR(600MHz,d6-DMSO):ppm8.61–8.58(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)；
13CNMR(150MHz,d6-DMSO):ppm172.5,170.4,167.9,159.2,157.6,139.7,135.5,131.6,127.3,126.7,126.3,123.5,122.1,121.9,111.5,110.5,110.4,109.7,109.5,108.9,67.5,46.9,45.1,30.9,11.5；
MS-ESI:m/z506.2[M+H]+.
EXAMPLE 3 Synthesis of the Compound 2- (5-fluoro-2-methyl-3- (4- (quinoline-2-carboxamide) piperidine-1-carbonyl) -1H-indol-1-yl) acetic acid hydrochloride
Step 1: synthesis of compound methyl 2- (5-fluoro-2-methyl-3- (4- (quinoline-2-carboxamide) piperidine-1-carbonyl) -1H-indol-1-yl) acetate
The compound methyl 2- (3- (4-aminopiperidine-1-carbonyl) -5-fluoro-2-methyl-1H-indol-1-yl) acetate hydrochloride (210mg,0.55mmol), quinoline-2-carboxylic acid (114mg,0.66mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (157mg,0.82mmol) and N-hydroxy-7-azabenzotriazole (186mg,1.37mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.38mL,2.19mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 20H, water (10mL × 2) was added, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (V (petroleum ether)/V (ethyl acetate) ═ 1/3), 105mg of a pale yellow solid are obtained, yield: 38 percent.
1HNMR(600MHz,CDCl3):ppm8.32–8.29(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/z503.3[M+H]+.
Step 2: synthesis of Compound 2- (5-fluoro-2-methyl-3- (4- (quinoline-2-carboxamide) piperidine-1-carbonyl) -1H-indol-1-yl) acetic acid hydrochloride
To a mixed solution of the compound methyl 2- (5-fluoro-2-methyl-3- (4- (quinoline-2-carboxamide) piperidine-1-carbonyl) -1H-indol-1-yl) acetate (100mg,0.20mmol) in tetrahydrofuran (8mL) and water (4mL) was added lithium hydroxide monohydrate (42mg,1.00mmol), reacted at 45 ℃ for 2.5H, added 1mol/L hydrochloric acid to adjust the pH to about 1, extracted with ethyl acetate (10 mL. times.2), and the solvent was removed to give 85mg of a yellow solid, yield 81.4%
1HNMR(600MHz,CD3OD):ppm8.38–8.36(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)；
13CNMR(150MHz,CD3OD):ppm174.1,170.0,167.8,159.5,158.0,149.2,139.6,137.8,132.7,130.3,129.4,128.1,127.7,118.5,110.0,108.4,47.0,44.6,11.0；
MS-ESI:m/z489.0[M+H-HCl]+.
EXAMPLE 4 Synthesis of the Compound 2- (5-fluoro-2-methyl-3- (4- (quinoline-2-carbonyl) piperazine-1-carbonyl) -1H-indol-1-yl) acetic acid hydrochloride
Step 1: synthesis of the Compound methyl 2- (5-fluoro-2-methyl-3- (4- (quinoline-2-carbonyl) piperazine-1-carbonyl) -1H-indol-1-yl) acetate
The compound methyl 2- (5-fluoro-2-methyl-3- (piperazine-1-carbonyl) -1H-indol-1-yl) acetate hydrochloride (200mg,0.54mmol), quinoline-2-carboxylic acid (112mg,0.65mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (156mg,0.81mmol) and N-hydroxy-7-azabenzotriazole (184mg,1.35mmol) were dissolved in dichloromethane (20mL), N-diisopropylethylamine (0.38mL,2.16mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 3.5H, water (10mL × 2) was added, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (V (dichloromethane)/V (methanol) ═ 40/1), 225mg of white solid are obtained, yield: 85 percent.
1HNMR(400MHz,CDCl3):ppm8.28(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/z489.4[M+H]+.
Step 2: synthesis of Compound 2- (5-fluoro-2-methyl-3- (4- (quinoline-2-carbonyl) piperazine-1-carbonyl) -1H-indol-1-yl) acetic acid hydrochloride
To a mixed solution of the compound methyl 2- (5-fluoro-2-methyl-3- (4- (quinoline-2-carbonyl) piperazine-1-carbonyl) -1H-indol-1-yl) acetate (216mg,0.44mmol) in tetrahydrofuran (10mL) and water (5mL) was added lithium hydroxide monohydrate (93mg,2.21mmol), reacted at 45 ℃ for 5H, added 1mol/L hydrochloric acid to adjust the pH to about 1, extracted with ethyl acetate (10mL × 2), and the solvent was removed to give 73mg of a yellow solid, yield 32.3%, purity 65%, purification by preparative chromatography, which gave 27mg of a pale yellow solid after workup, yield 11.9%.
1HNMR(600MHz,CD3OD):ppm8.48(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)；
13CNMR(150MHz,CD3OD):ppm170.4,168.3,168.1,159.6,158.0,153.1,138.0,133.0,130.4,129.7,128.6,127.8,124.9,119.9,110.2,109.8,64.5,10.2；
MS-ESI:m/z475.3[M+H-HCl]+.
EXAMPLE 5 Synthesis of the Compound 2- (5-fluoro-2-methyl-3- (4- (quinolin-2-ylcarbamoyl) piperidine-1-carbonyl) -1H-indol-1-yl) acetic acid hydrochloride
Step 1: synthesis of compound N- (quinolin-2-yl) piperidine-4-carboxamide dihydrochloride
Dissolving N-Boc-4-piperidinecarboxylic acid (200mg,0.87mmol), 2-aminoquinoline (151mg,1.05mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (251mg,1.31mmol) and N-hydroxy-7-azabenzotriazole (297mg,2.18mmol) in dichloromethane (15mL), to this solution was added dropwise N, N-diisopropylethylamine (0.61mL,3.49mmol) at 0 ℃, stirred at room temperature for 16h, washed with water (10mL × 2) was added, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (V (petroleum ether)/V (ethyl acetate) ═ 3/1) to give compound 4- (quinolin-2-ylcarbamoyl) piperidine-1-carboxylic acid tert-butyl ester: 290mg yellow oil, yield: 93 percent.
1HNMR(400MHz,CDCl3):ppm8.42(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/z356.3[M+H]+.
Compound 4- (quinolin-2-ylcarbamoyl) piperidine-1-carboxylic acid tert-butyl ester (295mg,0.83mmol) was dissolved in dichloromethane (3mL), a 4mol/LHCl solution in ethyl acetate (3mL) was added, and the reaction was stirred at room temperature for 2h and then stopped. The solvent was removed to give the compound N- (quinolin-2-yl) piperidine-4-carboxamide dihydrochloride 242mg as a white solid in 99% yield.
1HNMR(400MHz,CD3OD):ppm8.97(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/z256.2[M+H-2HCl]+.
Step 2: synthesis of the Compound methyl 2- (5-fluoro-2-methyl-3- (4- (quinolin-2-ylcarbamoyl) piperidine-1-carbonyl) -1H-indol-1-yl) acetate
The compound 5-fluoro-1- (2-methoxy-2-oxoethyl) -2-methyl-1H-indole-3-carboxylic acid (261mg,0.99mmol), the compound N- (quinolin-2-yl) piperidine-4-carboxamide hydrochloride (240mg,0.82mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (237mg,1.23mmol) and N-hydroxy-7-azabenzotriazole (280mg,2.06mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.57mL,3.29mmol) was added dropwise to this solution at 0 deg.C, stirred at room temperature for 15H, washed with water (10 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, the concentrated solution was subjected to column separation (V (dichloromethane)/V (methanol) ═ 40/1), to give 163mg of a pale yellow solid, yield: 39 percent.
1HNMR(400MHz,CDCl3):ppm8.47–8.41(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/z503.2[M+H]+.
And step 3: synthesis of the Compound 2- (5-fluoro-2-methyl-3- (4- (quinolin-2-ylcarbamoyl) piperidine-1-carbonyl) -1H-indol-1-yl) acetic acid hydrochloride
To a mixed solution of the compound methyl 2- (5-fluoro-2-methyl-3- (4- (quinolin-2-ylcarbamoyl) piperidine-1-carbonyl) -1H-indol-1-yl) acetate (161mg,0.32mmol) in tetrahydrofuran (8mL) and water (4mL) was added lithium hydroxide monohydrate (67mg,1.60mmol), reacted at 45 ℃ for 2H, added 1mol/L hydrochloric acid to adjust the pH to about 1, extracted with ethyl acetate (10mL × 2), and the solvent was removed to give a crude yellow solid 93mg, yield 55.3%, which was subjected to preparative chromatographic purification to give a pale red solid 5mg, yield 3%.
1HNMR(400MHz,CD3OD):ppm8.47(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/z489.3[M+H-HCl]+.
EXAMPLE 6 Synthesis of the Compound 2- (5-fluoro-3- (4- (5-fluoro-1H-indole-2-carboxamido) piperidine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetic acid hydrochloride
Step 1: synthesis of the compound methyl 2- (3- (4- ((tert-butoxycarbonyl) amino) piperidine-1-carbonyl) -5-fluoro-2-methyl-1H-indol-1-yl) acetate
The compound 5-fluoro-1- (2-methoxy-2-oxoethyl) -2-methyl-1H-indole-3-carboxylic acid (320mg,1.2mmol), the compound piperidine-4-carbamic acid tert-butyl ester (290mg,1.4mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (460mg,2.4mmol) and N-hydroxy-7-azabenzotriazole (250mg,1.8mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.65mL,3.6mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 10H, washed with water (10mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, the concentrate was subjected to column separation (V (petroleum ether)/V (ethyl acetate) ═ 1/1) to give 500mg of a white solid, yield: 93 percent.
1HNMR(400MHz,CDCl3):ppm7.09-7.20(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/z448.10[M+H]+.
Step 2: synthesis of compound methyl 2- (3- (4-aminopiperidine-1-carbonyl) -5-fluoro-2-methyl-1H-indol-1-yl) acetate hydrochloride
The compound methyl 2- (3- (4- ((tert-butoxycarbonyl) amino) piperidine-1-carbonyl) -5-fluoro-2-methyl-1H-indol-1-yl) acetate (500mg,1.1mmol) was dissolved in dichloromethane (4mL), a 4mol/LHCl solution in ethyl acetate (6mL) was added, and the reaction was stopped after stirring at room temperature for 2H. The solvent was removed to give 420mg of a white solid in 99% yield.
1HNMR(400MHz,CD3OD):ppm7.29-7.31(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/z348.10[M+H-HCl]+.
And step 3: synthesis of compound methyl 2- (5-fluoro-3- (4- (5-fluoro-1H-indole-2-carboxamido) piperidine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetate
Dissolving compound methyl 2- (3- (4-aminopiperidine-1-carbonyl) -5-fluoro-2-methyl-1H-indol-1-yl) acetate hydrochloride (210mg,0.5mmol), compound 5-fluoro-2-carboxylic acid-1H-indole (100mg,0.5mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (210mg,1.1mmol) and N-hydroxy-7-azabenzotriazole (110mg,0.8mmol) in dichloromethane (10mL), adding N, N-diisopropylethylamine (0.5mL,2.2mmol) dropwise to the solution at 0 deg.C, stirring at room temperature for 10H, adding water (10 mL. times.3), drying the organic phase with anhydrous sodium sulfate, removing the solvent, the concentrated solution was subjected to column separation (V (petroleum ether)/V (ethyl acetate) ═ 1/1) ═ 1/3) to obtain 70mg of a white solid, yield: 25 percent.
1HNMR(400MHz,CDCl3):ppm11.65(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/z509.00[M+H]+.
And 4, step 4: synthesis of compound 2- (5-fluoro-3- (4- (5-fluoro-1H-indole-2-carboxamido) piperidine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetic acid hydrochloride
The compound methyl 2- (5-fluoro-3- (4- (5-fluoro-1H-indole-2-carboxamido) piperidine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetate (70mg,0.14mmol) was reacted with LiOH. H2O (42mg,1.0mmol) was dissolved in a mixed solvent of tetrahydrofuran (5mL) and water (3mL), reacted at 45 ℃ for 1h, pH 1 was adjusted by addition of 1.0mol/L hydrochloric acid, extracted with ethyl acetate (10mL × 3), the organic phases were combined and dried over sodium sulfate, and the solvent was removed to give 60mg of a white solid in 82.2% yield.
1HNMR(600MHz,d6-DMSO):ppm11.64(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/z493.30[M-H-HCl]-.
EXAMPLE 7 Synthesis of the Compound 2- (5-fluoro-3- (4- ((4-fluorophenyl) sulfonyl) piperazine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetic acid
Step 1: synthesis of the compound methyl 2- (5-fluoro-3- (4- ((4-fluorophenyl) sulfonyl) piperazine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetate
Dissolving 4-fluorobenzenesulfonic acid (110mg,0.61mmol) in dichloromethane (5mL), adding thionyl chloride (120mg,0.93mmol) at room temperature, adding DMF (1mL) after 10min, reacting at room temperature for 1H, then spin-drying the solvent, adding to a solution of methyl 2- (5-fluoro-2-methyl-3- (piperazine-1-carbonyl) -1H-indol-1-yl) acetate hydrochloride (150mg,0.41mmol) and triethylamine (250mg,2.43mmol) in DMF (5mL) at 0 ℃, stirring at room temperature for 3H, spin-out the solvent, washing with water (15mL), extracting with ethyl acetate (10mL × 3), drying the organic phase with anhydrous sodium sulfate, removing the solvent, subjecting the concentrate to column separation (V (petroleum ether)/V (ethyl acetate) ═ 1/1) to obtain 95mg of a white solid, yield: and 47 percent.
1HNMR(400MHz,CDCl3):ppm7.75-7.79(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/z492.95[M+H]+.
Step 2: synthesis of the compound 2- (5-fluoro-3- (4- ((4-fluorophenyl) sulfonyl) piperazine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetic acid
To a mixed solution of the compound methyl 2- (5-fluoro-3- (4- ((4-fluorophenyl) sulfonyl) piperazine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetate (90mg,0.18mmol) in tetrahydrofuran (5mL) and water (3mL) was added lithium hydroxide monohydrate (40mg,0.92mmol), reacted at 45 ℃ for 1H, 1.0mol/L hydrochloric acid was added to adjust pH 1, ethyl acetate was extracted (5mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 70mg of a pale yellow solid in 80% yield.
1HNMR(600MHz,d6-DMSO):ppm7.81-7.84(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/z478.90[M+H]+.
EXAMPLE 8 Synthesis of the Compound (R) -2- (5-fluoro-3- (4- ((4-fluorophenyl) sulfonyl) -2-methylpiperazine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetic acid
Step 1: synthesis of Compound (R) -4- (5-fluoro-1- (2-methoxy-2-oxoethyl) -2-methyl-1H-indole-3-carbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester
The compounds 5-fluoro-1- (2-methoxy-2-oxoethyl) -2-methyl-1H-indole-3-carboxylic acid (450mg,1.70mmol), (R) -4-tert-butoxycarbonyl-2-methylpiperazine (400mg,2.03mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (650mg,3.39mmol) and N-hydroxy-7-azabenzotriazole (350mg,2.55mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.9mL,5.09mmol) was added dropwise to the solution at 0 ℃, stirred at room temperature for 17H, washed with water (10mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (V (petroleum ether)/V (ethyl acetate) ═ 1/1) to give 330mg of a white solid Body, yield: and 43 percent.
1HNMR(400MHz,CDCl3):ppm7.08-7.20(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/z448.10[M+H]+.
Step 2: synthesis of compound (R) -methyl 2- (5-fluoro-2-methyl-3- (2-methylpiperazine-1-carbonyl) -1H-indol-1-yl) acetate hydrochloride
The compound (R) -tert-butyl 4- (5-fluoro-1- (2-methoxy-2-oxoethyl) -2-methyl-1H-indole-3-carbonyl) -3-methylpiperazine-1-carboxylate (320mg,0.71mmol) was dissolved in dichloromethane (3mL), a 4mol/LHCl solution in ethyl acetate (4mL) was added, and the reaction was stopped after stirring at room temperature for 1.5H. The solvent was removed to give 270mg of a white solid with a yield of 98%.
1HNMR(400MHz,CD3OD):ppm7.38(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/z348.10[M+H-HCl]+.
And step 3: synthesis of the compound (R) -methyl 2- (5-fluoro-3- (4- ((4-fluorophenyl) sulfonyl) -2-methylpiperazine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetate
4-fluorobenzenesulfonic acid (185mg,1.06mmol) was added to dichloromethane (5mL), thionyl chloride (192mg,1.62mmol) was added at room temperature, DMF (1mL) was added after 10min, the solvent was spun off after 1H reaction at room temperature, added to a solution of (R) -2- (5-fluoro-2-methyl-3- (2-methylpiperazine-1-carbonyl) -1H-indol-1-yl) acetic acid methyl ester hydrochloride (270mg,0.7mmol) and triethylamine (430mg,4.22mmol) in DMF (5mL) at 0 ℃, stirred at room temperature for 3H, the solvent was spun off, washed with water (15mL), extracted with ethyl acetate (10mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (V (petroleum ether)/V (ethyl acetate) ═ 2/1) to give 130mg of a white solid, yield: 37 percent.
1HNMR(400MHz,CDCl3):ppm7.73-7.79(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/z506.30[M+H]+.
And 4, step 4: synthesis of the compound (R) -2- (5-fluoro-3- (4- ((4-fluorophenyl) sulfonyl) -2-methylpiperazine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetic acid
To a mixed solution of the compound methyl (R) -2- (5-fluoro-3- (4- ((4-fluorophenyl) sulfonyl) -2-methylpiperazine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetate (130mg,0.26mmol) in tetrahydrofuran (5mL) and water (3mL) was added lithium hydroxide monohydrate (60mg,1.29mmol), reacted at 45 ℃ for 1H, added 1.0mol/L hydrochloric acid to adjust the pH to 1, extracted with ethyl acetate (5mL × 3), and the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 120mg of a pale yellow solid with a yield of 94%.
1HNMR(400MHz,CD3OD):ppm7.81-7.88(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/z492.95[M+H]+.
EXAMPLE 9 Synthesis of the Compound 2- (5-fluoro-3- (4- (4-fluorophenylsulphonamido) piperidine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetic acid
Step 1: synthesis of compound methyl 2- (5-fluoro-3- (4- (4-fluorophenylsulfonylamino) piperidine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetate
4-fluorobenzenesulfonic acid (140mg,0.78mmol) was added to dichloromethane (5mL), thionyl chloride (150mg,1.19mmol) was added at room temperature, DMF (1mL) was added after 10min, the solvent was spun off after 1H reaction at room temperature, added to a solution of the compound methyl 2- (3- (4-aminopiperidine-1-carbonyl) -5-fluoro-2-methyl-1H-indol-1-yl) acetate hydrochloride (200mg,0.52mmol) and triethylamine (400mg,3.13mmol) in DMF (5mL) at 0 deg.C, stirred at room temperature for 3H, the solvent was spun off, washed with water (15mL), extracted with ethyl acetate (10 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (V (petroleum ether)/V (ethyl acetate) ═ 2/1) to give 168mg of a white solid, yield: and 64 percent.
1HNMR(400MHz,CDCl3):ppm7.87(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/z506.10[M+H]+.
Step 2: synthesis of compound 2- (5-fluoro-3- (4- (4-fluorophenylsulfonylamino) piperidine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetic acid
The compound methyl 2- (5-fluoro-3- (4- (4-fluorophenylsulfonylamino) piperidine-1-carbonyl) -2-methyl-1H-indol-1-yl) acetate (160mg,0.32mmol) was reacted with LiOH. H2O (710mg,1.58mmol) was dissolved in a mixed solvent of tetrahydrofuran (5mL) and water (3mL), reacted at 45 ℃ for 1h, adjusted to pH 1 with 1.0mol/L hydrochloric acid, extracted with ethyl acetate (10mL × 3) and provided withThe combined phases were dried over sodium sulfate and the solvent was removed to yield 150mg of a white solid in 96% yield.
1HNMR(400MHz,CD3OD):ppm7.94(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/z492.10[M+H]+.
EXAMPLE 10 Synthesis of the Compound 2- (5-fluoro-2-methyl-3- (4- (quinoline-5-carboxamido) piperidine-1-carbonyl) -1H-indol-1-yl) acetic acid hydrochloride
Step 1: synthesis of Compound methyl 2- (5-fluoro-2-methyl-3- (4- (quinoline-5-carboxamido) piperidine-1-carbonyl) -1H-indol-1-yl) acetate
The compound methyl 2- (3- (4-aminopiperidine-1-carbonyl) -5-fluoro-2-methyl-1H-indol-1-yl) acetate hydrochloride (200mg,0.52mmol), quinoline 5-carboxylate (108mg,0.63mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (200mg,1.05mmol) and N-hydroxy-7-azabenzotriazole (106mg,0.78mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.4mL,2.09mmol) was added dropwise to the solution at 0 ℃, stirred at room temperature for 10 hours, washed with water (10mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (V (petroleum ether)/V (ethyl acetate) ═ 1/1) to give 210mg of a pale yellow solid Body, yield: 80 percent.
1HNMR(400MHz,CDCl3):ppm8.93(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/z503.00[M+H]+.
Step 2: synthesis of Compound 2- (5-fluoro-2-methyl-3- (4- (quinoline-5-carboxamido) piperidine-1-carbonyl) -1H-indol-1-yl) acetic acid hydrochloride
The compound methyl 2- (5-fluoro-2-methyl-3- (4- (quinoline-5-carboxamido) piperidine-1-carbonyl) -1H-indol-1-yl) acetate (200mg,0.4mmol) was reacted with LiOH. H2O (83mg,2.0mmol) was dissolved in a mixed solvent of tetrahydrofuran (5mL) and water (3mL), reacted at 45 ℃ for 1h, pH 1 was adjusted with 1.0mol/L hydrochloric acid, extracted with ethyl acetate (10mL × 3), the organic phases were combined and dried over sodium sulfate, and the solvent was removed to give 160mg of a pale yellow solid with a yield of 76.6%.
1HNMR(600MHz,CD3OD):ppm8.99-9.04(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/z489.20[M+H-HCl]+.
EXAMPLE 11 Synthesis of the Compound 2- (5-fluoro-2-methyl-3- (4- ((quinoline-2-methylene) carbamoyl) piperidine-1-carbonyl) -1H-indol-1-yl) acetic acid hydrochloride
Step 1: synthesis of Compound 1- (tert-Butoxycarbonyl) piperidine-4-carboxylic acid
The compound tert-butyl 4-methoxycarbonylpiperidine-1-carboxylate (1.0g,4.1mmol) was reacted with LiOH. H2O (860mg,21mmol) was dissolved in a mixed solvent of tetrahydrofuran (10mL) and water (5mL), reacted at 45 ℃ for 1h, adjusted to pH 1 with 1.0mol/L hydrochloric acid, extracted with ethyl acetate (10mL × 3), the organic phases were combined and dried over sodium sulfate, and the solvent was removed to give 860mg of a white solid, 91% yield.
1HNMR(400MHz,CD3OD):ppm3.97-4.02(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/z174.20[M-55]+.
Step 2: synthesis of Compound 4- ((quinoline-2-methylene) carbamoyl) piperidine-1-carboxylic acid tert-butyl ester
The compound 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (200mg,0.87mmol), the compound quinoline-2-methylamine (165mg,1.05mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (334mg,1.74mmol) and N-hydroxy-7-azabenzotriazole (180mg,1.31mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.45mL,2.62mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 10h, washed with water (10mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (V (petroleum ether)/V (ethyl acetate) ═ 1/1) to give 285mg of a white solid, yield: 88 percent.
1HNMR(400MHz,CDCl3):ppm8.14(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/z370.20[M+H]+.
And step 3: synthesis of compound N- (quinoline-2-methylene) piperidine-4-carboxamide hydrochloride
Compound 4- ((quinoline-2-methylene) carbamoyl) piperidine-1-carboxylic acid tert-butyl ester (280mg,0.76mmol) was dissolved in dichloromethane (4mL), a 4mol/LHCl solution in ethyl acetate (4mL) was added, and the reaction was stopped after stirring at room temperature for 2 h. The solvent was removed to give 230mg of a white solid in 99% yield.
1HNMR(400MHz,CD3OD):ppm9.17(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/z270.20[M+H-HCl]+.
And 4, step 4: synthesis of the compound methyl 2- (5-fluoro-2-methyl-3- (4- ((quinoline-2-methylene) carbamoyl) piperidine-1-carbonyl) -1H-indol-1-yl) acetate
The compound N- (quinoline-2-methylene) piperidine-4-carboxamide hydrochloride (200mg,0.75mmol), the compound N- (quinoline-2-methylene) piperidine-4-carboxamide hydrochloride (230mg,0.75mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (290mg,1.51mmol) and N-hydroxy-7-azabenzotriazole (154mg,1.13mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.65mL,3.77mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 10h, washed with water (10mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, the concentrate was subjected to column separation (V (dichloromethane)/V (methanol) ═ 30/1) to give 194mg of a white solid, yield: 49 percent.
1HNMR(400MHz,CDCl3):ppm8.14(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/z517.30[M+H]+.
And 5: synthesis of the compound 2- (5-fluoro-2-methyl-3- (4- ((quinoline-2-methylene) carbamoyl) piperidine-1-carbonyl) -1H-indol-1-yl) acetic acid hydrochloride
The compound methyl 2- (5-fluoro-2-methyl-3- (4- ((quinoline-2-methylene) carbamoyl) piperidine-1-carbonyl) -1H-indol-1-yl) acetate (190mg,0.37mmol) was reacted with LiOH. H2O (77mg,1.84mmol) was dissolved in a mixed solvent of tetrahydrofuran (5mL) and water (3mL), reacted at 45 ℃ for 1h, adjusted to pH 1 with 1mol/L hydrochloric acid, extracted with ethyl acetate (10mL × 3), the organic phases were combined and dried over sodium sulfate, and the solvent was removed to give 134mg of a white solid in 67.7% yield.
1HNMR(400MHz,d6-DMSO):ppm8.60-8.64(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/z503.20[M+H-HCl]+.
EXAMPLE 12 Synthesis of the Compound (R) -2- (5-fluoro-2-methyl-3- (3-methyl-4- (quinoline-2-carbonyl) piperazine-1-carbonyl) -1H-indol-1-yl) acetic acid hydrochloride
Step 1: synthesis of Compound (R) -3-methyl-4- (quinoline-2-carbonyl) piperazine-1-carboxylic acid tert-butyl ester
The compound (R) -tert-butyl 3-methylpiperazine-1-carboxylate (530mg,2.6mmol), the compound quinoline-2-carboxylic acid (450mg,2.6mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (996mg,5.2mmol) and N-hydroxy-7-azabenzotriazole (530mg,3.9mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (1.3mL,7.8mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 10h, washed with water (10mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (V (petroleum ether)/V (ethyl acetate) ═ 1/1) to give 820mg of a white solid, yield: 88 percent.
1HNMR(400MHz,CDCl3):ppm8.26(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/z356.20[M+H]+.
Step 2: synthesis of Compound (R) - (2-methylpiperazin-1-yl) (quinolin-2-yl) methanone hydrochloride
Compound (R) -3-methyl-4- (quinoline-2-carbonyl) piperazine-1-carboxylic acid tert-butyl ester (250mg,0.7mmol) was dissolved in dichloromethane (4mL), a 4mol/LHCl solution in ethyl acetate (4mL) was added, and the reaction was stopped after stirring at room temperature for 2 h. The solvent was removed to give 230mg of a white solid in 99% yield.
MS-ESI:m/z256.25[M+H-HCl]+.
And step 3: synthesis of compound (R) -methyl 2- (5-fluoro-2-methyl-3- (3-methyl-4- (quinoline-2-carbonyl) piperazine-1-carbonyl) -1H-indol-1-yl) acetate
The compound 5-fluoro-1- (2-methoxy-2-oxoethyl) -2-methyl-1H-indole-3-carboxylic acid (200mg,0.75mmol), the compound (R) - (2-methylpiperazin-1-yl) (quinolin-2-yl) methanone hydrochloride (192mg,0.75mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (290mg,1.51mmol) and N-hydroxy-7-azabenzotriazole (154mg,1.13mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.65mL,3.77mmol) was added dropwise to the solution at 0 ℃, stirred at room temperature for 10H, washed with water (10 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column separation (V (ethyl acetate)/V (methanol) ═ 120/1) to obtain 150mg of a white solid, yield: 39 percent.
MS-ESI:m/z503.25[M+H]+.
And 4, step 4: synthesis of compound (R) -2- (5-fluoro-2-methyl-3- (3-methyl-4- (quinoline-2-carbonyl) piperazine-1-carbonyl) -1H-indol-1-yl) acetic acid hydrochloride
The compound methyl (R) -2- (5-fluoro-2-methyl-3- (3-methyl-4- (quinoline-2-carbonyl) piperazine-1-carbonyl) -1H-indol-1-yl) acetate (150mg,0.3mmol) was reacted with LiOH. H2O (63mg,1.5mmol) was dissolved in a mixed solvent of tetrahydrofuran (5mL) and water (3mL), reacted at 45 ℃ for 1h, pH 1 was adjusted with 1.0mol/L hydrochloric acid, extracted with ethyl acetate (10mL × 3), the organic phases were combined and dried over sodium sulfate, and the solvent was removed to give 110mg of a pale yellow solid with a yield of 70.3%.
1HNMR(400MHz,CD3OD):ppm8.64-8.70(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/z489.30[M+H-HCl]+.
EXAMPLE 13 Synthesis of the Compound 2- (5-fluoro-3- (8- ((4-fluorophenyl) sulfonyl) -2, 8-diazaspiro [4.5] decane-2-carbonyl) -2-methyl-1H-indol-1-yl) acetic acid
Step 1: synthesis of the Compound tert-butyl 2- (5-fluoro-1- (2-methoxy-2-oxoethyl) -2-methyl-1H-indole-3-carbonyl) -2, 8-diazaspiro [4.5] decane-8-carboxylate
The compounds 5-fluoro-1- (2-methoxy-2-oxoethyl) -2-methyl-1H-indole-3-carboxylic acid (170mg,0.64mmol), tert-butyl 2, 8-diazaspiro [4.5] decane-8-carboxylate (155mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (184mg,0.96mmol) and N-hydroxy-7-azabenzotriazole (130mg,0.96mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.35mL,1.92mmol) was added dropwise to the solution at 0 ℃, the solution was stirred at room temperature for 10 hours, water was added (10mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (V (petroleum ether)/V (ethyl acetate) ═ 1/1) to give 163mg of white Solid, yield: 52 percent.
1HNMR(400MHz,CDCl3):ppm7.11–7.14(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: synthesis of methyl 2- (5-fluoro-2-methyl-3- (2, 8-diazaspiro [4.5] decane-2-carbonyl) -1H-indol-1-yl) acetate hydrochloride, a compound
The compound tert-butyl 2- (5-fluoro-1- (2-methoxy-2-oxoethyl) -2-methyl-1H-indole-3-carbonyl) -2, 8-diazaspiro [4.5] decane-8-carboxylate (160mg,0.33mmol) was dissolved in dichloromethane (4mL), a 4mol/LHCl solution in ethyl acetate (2mL) was added, and the mixture was stirred at room temperature for 50min, and the solvent was removed to give 121mg of a pale yellow liquid in 95% yield.
1HNMR(400MHz,CD3OD):ppm7.31–7.37(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/z388.30[M+H-HCl]+.
And step 3: synthesis of the compound methyl 2- (5-fluoro-3- (8- ((4-fluorophenyl) sulfonyl) -2, 8-diazaspiro [4.5] decane-2-carbonyl) -2-methyl-1H-indol-1-yl) acetate
Adding 4-fluorobenzenesulfonic acid (91mg,0.52mmol) to dichloromethane (10mL), adding thionyl chloride (92mg,0.78mmol) at room temperature, adding DMF (1mL) after 10min, reacting for 1H at room temperature, drying the solvent after adding it to a solution of the compound 2- (5-fluoro-2-methyl-3- (2, 8-diazaspiro [4.5] decane-2-carbonyl) -1H-indol-1-yl) acetic acid methyl ester hydrochloride (110mg,0.26mmol) and triethylamine (0.36mL,2.59mmol) in DMF (5mL) at 0 ℃, stirring for 3H at room temperature, removing the solvent, washing with water (10mL), extracting with ethyl acetate (10mL × 3), drying the organic phase with anhydrous sodium sulfate, removing the solvent, column-separating the concentrate (V (petroleum ether)/V (ethyl acetate) ═ 1/3) to give 104mg of a white solid, yield: 73 percent.
1HNMR(400MHz,CDCl3):ppm7.74–7.79(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/z546.80[M+H]+.
And 4, step 4: synthesis of the compound 2- (5-fluoro-3- (8- ((4-fluorophenyl) sulfonyl) -2, 8-diazaspiro [4.5] decane-2-carbonyl) -2-methyl-1H-indol-1-yl) acetic acid
The compound methyl 2- (5-fluoro-3- (8- ((4-fluorophenyl) sulfonyl) -2, 8-diazaspiro [4.5] decane-2-carbonyl) -2-methyl-1H-indol-1-yl) acetate (95mg,0.18mmol) and LiOH · H2O (36mg,0.87mmol) were dissolved in a mixed solvent of tetrahydrofuran (5mL) and water (3mL), reacted at 45 ℃ for 30min, pH adjusted to 1 with 1N hydrochloric acid, extracted with dichloromethane (10mL × 3), the organic phases were combined and dried over sodium sulfate to remove the solvent, and 85mg of a white solid was obtained in 92% yield.
1HNMR(600MHz,d6-DMSO):ppm7.74–7.83(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)ppm170.4,166.1,164.1,158.9,157.3,139.9,133.1,132.4,130.9,125.6,117.1,116.9,111.3,110.4,109.5,55.3,45.0,43.8,11.6；
MS-ESI:m/z532.30[M+H]+.
Example 14 synthesis of the compound 2- (5-fluoro-2-methyl-3- (3- (quinoline-2-carboxamido) azetidine-1-carbonyl) -indol-1-yl) acetic acid hydrochloride:
step 1: synthesis of compound N- (azetidin-3-yl) quinoline-2-carboxamide hydrochloride
Dissolving the compound 1-Boc-3-aminocyclobutylamine oxalate (500mg,1.91mmol), quinoline-2-carboxylic acid (396mg,2.29mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (658mg,3.43mmol) and N-hydroxy-7-azabenzotriazole (778mg,5.72mmol) in dichloromethane (15mL), adding N, N-diisopropylethylamine (1.3mL,7.63mmol) dropwise to the solution at 0 deg.C, stirring at room temperature for 16h, adding water (10 mL. times.2), drying the organic phase over anhydrous sodium sulfate, removing the solvent, subjecting the concentrate to column separation (V (petroleum ether)/V (ethyl acetate) ═ 4/1) to obtain 454mg of colorless liquid 3- (quinoline-2-carboxamido) azetidine-1-carboxylic acid tert-butyl ester, yield: 72 percent.
1HNMR(600MHz,CDCl3):ppm8.31(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 a solution of the compound tert-butyl 3- (quinoline-2-carboxamido) azetidine-1-carboxylate (440mg,1.34mmol) in dichloromethane (4mL) was added a solution of hydrogen chloride in ethyl acetate (4N,4mL), stirred at room temperature for 1h, and the solvent was removed to give 350mg of a white solid in 98% yield.
1HNMR(400MHz,d6-DMSO):ppm8.58(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/z228.0[M+H-HCl]+.
Step 2: synthesis of compound methyl 2- (5-fluoro-2-methyl-3- (3- (quinoline-2-carboxamido) azetidine-1-carbonyl) -indol-1-yl) acetate
The compound 5-fluoro-1- (2-methoxy-2-oxoethyl) -2-methyl-indole-3-carboxylic acid (170mg,0.64mmol), N- (azetidin-3-yl) quinoline-2-carboxamide hydrochloride (254mg,0.96mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (184mg,0.96mmol) and N-hydroxy-7-azabenzotriazole (218mg,1.60mmol) were dissolved in dichloromethane (16mL), N-diisopropylethylamine (0.45mL,2.56mmol) was added dropwise to this solution at 0 ℃ and stirred at room temperature for 16h, water (10 mL. times.2) was added, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (ethyl acetate), 207mg of a pale yellow solid are obtained, yield: 68 percent.
1HNMR(400MHz,CDCl3):ppm8.32(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/z475.2[M+H]+.
And step 3: synthesis of compound 2- (5-fluoro-2-methyl-3- (3- (quinoline-2-carboxamido) azetidine-1-carbonyl) -indol-1-yl) acetic acid hydrochloride
To a mixed solution of the compound methyl 2- (5-fluoro-2-methyl-3- (3- (quinoline-2-carboxamido) azetidine-1-carbonyl) -indol-1-yl) acetate (202mg,0.43mmol) in tetrahydrofuran (8mL) and water (4mL) was added lithium hydroxide monohydrate (89mg,1.00mmol), reacted at 45 ℃ for 2h, adjusted to pH 1 by the addition of 1N hydrochloric acid, extracted with ethyl acetate (10 mL. times.2), and the solvent was removed to give 184mg of a yellow solid in 87% yield.
1HNMR(600MHz,CDCl3):ppm8.74(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/z461.9[M+H-HCl]+.
Examples 15 to 29
The preparation method adopts corresponding raw materials and is similar to the synthesis method of the embodiment of the invention and the synthesis method described in the invention to obtain:
biological Activity assay
Example 1 detection of the inhibitory Effect of Compounds on the CRTH2 receptor by Using intracellular calcium ion fluorescence technology
1. Solution preparation:
accurately weighing the compound to be detected, dissolving the compound in a proper amount of DMSO (dimethyl sulfoxide) to prepare 10mM stock solution, clarifying and transparent the solution, subpackaging, and freezing at-20 ℃ for later use. Before detection, the test compound was diluted with a balanced salt buffer solution (HBSSbuffer, containing 20mM hydroxyethylpiperazine ethanesulfonic acid) to prepare a solution five times the detection concentration.
FLIPR detection (real-time fluorescence imaging analysis)
CHO-K1/G stably expressing CRTH2 receptor is prepared into five times of cells with detection concentration and inoculated into 384 micro-well plates, and then placed at 37 ℃/5% CO2And continuing culturing in the incubator. After 18 hours, the cells were removed, 20. mu.L of dye was added, 10. mu.L of the prepared test compound solution was added, and the cell plates were placed at 37 ℃/5% CO2The incubator was incubated for 1 hour and finally allowed to equilibrate at room temperature for 15 minutes. To each well of the cell plate 12.5. mu.L of 5xEC was added80RFU (fluorescence intensity) values of the test compounds are measured after a positive agonist concentration (PGD 2).
3. Data analysis
After raw data was obtained by ScreenWorks (version3.1), the data was collected and analyzed using Excel and GraphPadprism6 software programs to calculate IC50The value is obtained.
TABLE 2CRTH2 inhibitory Activity
In conclusion, as can be seen from the data in table 2, most of the compounds of the present invention have better CRTH2 inhibitory activity.
Biological example 2 in vivo pharmacodynamic Activity assay
Purpose of the experiment: test compounds were evaluated for efficacy in an OVA (ovalbumin) -induced rat asthma model.
The experimental method comprises the following steps:
1. sensitization process
Animals were randomly divided into control, model and dosing groups. On days 1,2, and 3, control mice were injected intraperitoneally with 1ml of PBS (phosphate buffered saline); rats of the model group and the administration group were intraperitoneally injected with a sensitizing solution (prepared by mixing 6ml of a 1% OVA solution (a solution of 1% OVA phosphate buffer) and 54 ml of an alum solution at a ratio of 1: 9) to conduct sensitization (1 ml/mouse).
2. Administration and challenge procedures
Administering a dose of the test compound to the gavage of rats of the administration group once a day for three consecutive days starting on day 19; the rats of the control group and the model group are correspondingly given the corresponding dose of the menstruum by intragastric administration. After 1 hour of each administration, rats were challenged with the challenge solution for 20 minutes; wherein the challenge solution of the model group and the administration group is 1% OVA solution, and the challenge solution of the control group is PBS.
3. Index detection and sample collection:
on day 23, animals were anesthetized by intraperitoneal injection of 1% sodium pentobarbital (60 mg/kg). Blood was collected from the abdominal aorta under pentobarbital anesthesia and collected in EDTA-K2 tubes. Animals were intubated with the trachea and the lungs were first lavaged with 3ml PBS (1% FBS in PBS); the lavage was then repeated at least twice with 5ml PBS (1% FBS in PBS); the lavage solutions were combined and adjusted to a total volume of 15ml with PBS. The total number of cells in the lavage fluid was counted by a hemocytometer and trypan blue staining experiments, and the white blood cells in the lavage fluid were counted by differential counting.
4. The results show that the compound of the invention can show certain inhibition effect on the total number of leucocytes and eosinophils, and plays a role in
Reducing inflammation degree and relieving diseases.
Biological example 3LC/MS/MS measurement method
The 4000QTRAPP series LC/MS/MS mass spectrometer is provided with an Agilent 1200 binary injection pump, a 1290 automatic sampler and a column incubator; ESI source, negative ion MRM mode detection. A waters xbridge c18 column was used during the analysis; mobile phase (a) was 2mM ammonium formate + 0.1% aqueous ammonia; mobile phase (B) was 2mM ammonium formate + 0.1% ammonia in methanol; the flow rate is 0.4 mL/min; the column temperature is 40 ℃; the sample size was 3. mu.L.
Biological example 4 testing of liver microsome stability
The compounds were incubated in human, canine and rat liver microsomes at 37 ℃ and pH 7.4, sample concentrations were determined by LC/MS (method described for biological example 3) for different incubation times, rate constants were plotted as "Log [ drug concentration ]" versus "incubation time" in graphpadprism5.01, drug half-life and intrinsic clearance were calculated, and drug stability in liver microsomes was evaluated as drug half-life and intrinsic clearance.
Biological example 5PK Experimental method
Male Beagle dogs or rats were administered the compound of the present invention intravenously (0.4mg/Kg) and gavage (1mg/Kg), respectively, and blood was collected at time points of 0.083, 0.25, 0.5, 1,2,4, 6, 8, 10, 24 and 36h and centrifuged to prepare plasma. The concentration of the compound of the present invention in plasma at each time point was measured by LC/MS/MS (method described in biological example 3), the main pharmacokinetic parameters were calculated, and the PK parameters of the compound of the present invention in Beagle dogs or rats were examined. The specific results are as follows:
the results show that the compounds of the invention have a higher exposure.
Biological example 6 Experimental study on DK-PGD2 Induction of Wistar rat airway eosinophilia
Purpose of the experiment: evaluation of inhibitory Effect of Compounds on DK-PGD2 Induction of increase in Total airway leukocytes and eosinophils in rats
The experimental system is as follows: the experimental system is used for observing the curative effect of the medicament for preventive administration, and comprises the following specific operations: after 0.5h of preventive administration, the administration group and the model group of rats are sprayed and injected with 100uLDK-PGD2 to induce the increase of airway eosinophils, and the normal group is sprayed and injected with normal saline with corresponding dose; 24 hours after injection molding, the rats were sacrificed by abdominal aorta exsanguination, the trachea and the thoracic cavity were exposed, the trachea was cannulated, bronchoalveolar lavage was performed 2 times with 8mL of 4 ℃ PBS + 1% BSA solution, bronchoalveolar lavage fluid (BALF) was collected and placed in an ice bath until the cell smears were counted by classification. The concentration of the DK-PGD2 mother liquor is 10mg/ml, and the concentration is 2mg/ml after 5-time dilution.
The results show that the compound has good inhibition effect on the increase of the total number of leukocytes and the number of eosinophils of rat airways induced by DK-PGD2, and has strong inhibition effect on the total number of the leukocytes and the number of the eosinophils.

Claims (14)

1. A compound which is a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof of the structure shown in formula (I),
wherein,
a is C6-12Arylene radical, C1-9Heteroarylene radical, C2-10Heterocyclylene or C3-12A cycloalkylene group; a is optionally substituted by 1,2,3 or 4 identical or different R2Substituted;
e is C2-10Heterocyclic radical, C5-12Spiro heterobicyclic radical, C5-12Condensed hetero bicyclic group, C5-12Bridged bicyclic radical, C3-12Cycloalkyl radical, C6-12Aryl or C1-12A heteroaryl group; e is optionally substituted by 1,2,3 or 4 identical or different R2cSubstituted;
L3is-O-, -S-, -S (═ O)t-，-C(OH)H-，-N(R1) -or-C (═ O) -;
each L is independently-O-, -S (═ O)t-，-S-，-N(R1)-，-CH2-，-C(＝O)-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R1)-，-C(＝S)-N(R1) -or- (CH)2)n-C(＝O)-；
L1is-O-, -S (═ O)t-，-S-，-N(R1a)-，-CH2-，-C(＝O)-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R1a)-，-C(＝S)-N(R1a) -or- (CH)2)n-C(＝O)-；
Each L2Independently a bond, -O-, -S (═ O)t-，-S-，-N(R1a)-，-CH2-，-C(＝O)-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R1a)-，-C(＝S)-N(R1a) -or- (CH)2)n-C(＝O)-；
h is 0, 1,2,3 or 4;
w is 0, 1,2,3 or 4;
each n is independently 0, 1,2,3 or 4;
each t is independently 0, 1 or 2;
each R1aAnd R1Independently of one another is hydrogen, C1-4Alkyl, halo C1-4Alkyl radical, C1-4An alkyl acyl group or a hydroxyl group;
each R2cAnd R2Independently of one another is hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, hydroxy, nitro, amino, cyano, halogen, carboxy, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Alkylthio radical, C1-4Alkyl acyl radical, C3-12Cycloalkyl radical, C3-9Heterocyclic radical, C6-12Aryl radical, C1-9Heteroaryl, amino C1-4Alkyl, hydroxy C1-4Alkyl, sulfonic, aminosulfonyl or aminoacyl.
2. The compound of claim 1, wherein,
a is the following subformula:
the sub-formulae represented by A are optionally substituted by 1,2,3 or 4 identical or different R2Substituted;
wherein,when the carbon atom is a single bond,is composed of
In the case of a double bond, the double bond,is composed of
Each X1，X2And X3Independently is- (CR)3R3a)b-，-O-，-N(R4) -or-S (═ O)t1-；
Each X4，X5，X6，X7X and X8Independently is-C (R)3) -or-N-;
each b is independently 0, 1,2,3 or 4;
each of q, m, f1, p and r is independently 0, 1,2,3 or 4;
each t1 is independently 0, 1 or 2;
each R3aAnd R3Independently of one another is hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, hydroxy, nitro, cyano, halogen, amino, carboxy, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Alkylthio radical, C1-4Alkyl acyl radical, C3-12Cycloalkyl radical, C3-9Heterocyclic radical, C6-12Aryl radical, C1-9Heteroaryl, amino C1-4Alkyl, hydroxy C1-4Alkyl, sulfonic, aminosulfonyl or aminoacyl;
each R4Independently of one another is hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, hydroxy, C3-12Cycloalkyl radical, C3-9Heterocyclic radical, C6-12Aryl radical, C1-9Heteroaryl, amino C1-4Alkyl or hydroxy C1-4An alkyl group.
3. The compound of claim 1, wherein,
a is
A is optionally substituted by 1,2,3 or 4 independently selected from R2Substituted with the substituent(s).
4. The compound of claim 1, wherein,
e is the following subformula:
wherein, Y1，Y2，Y3，Y4，Y5And Y6Each independently is N or CH;
T1，T2，T3and T is each independently-O-, -S-, -NH-or-CH2-；
Each e and f is independently 0, 1,2,3 or 4;
the sub-formulae represented by E are optionally substituted by 1,2,3 or 4 identical or different R2cAnd (4) substituting.
5. The compound of claim 1, wherein each R2cAnd R2Independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, hydroxy, nitro, amino, cyano, fluoro, chloro, bromo, carboxy, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, methylacyl, aminomethyl, hydroxymethyl, sulfonic acid, aminosulfonyl or aminoacyl.
6. The compound of claim 1, which is a structure of formula (II), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof,
wherein,when the carbon atom is a single bond,is composed of
In the case of a double bond, the double bond,is composed of
Each X1，X2And X3Independently is- (CR)3R3a)b-，-O-，-N(R4) -or-S (═ O)t-；
X4is-C (R)3) -or-N-;
each b is independently 0, 1,2,3 or 4;
each R3aAnd R3Independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, hydroxyl, nitro, cyano, fluorine, chlorine, bromine, carboxyl, methoxy, ethoxy, amino, trifluoromethyl, amino C1-4Alkyl, hydroxy C1-4Alkyl, sulfonic, aminosulfonyl or aminoacyl;
each R4Independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, hydroxy, amino C1-4Alkyl or hydroxy C1-4An alkyl group.
7. The compound of claim 1, which is a structure of formula (III), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof,
wherein each X5And X is independently-CH-or-N-;
p and f1 are each independently 0, 1,2,3 or 4.
8. The compound of claim 1, 6 or 7, wherein,
e is the following subformula:
the sub-formulae represented by E are optionally substituted by 1,2,3 or 4 identical or different R2cAnd (4) substituting.
9. The compound of claim 1, wherein said pharmaceutically acceptable salt is a hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acetate, propionate, butyrate, lactate, methanesulfonate, p-toluenesulfonate, maleate, benzoate, succinate, tartrate, citrate, oxalate, fumarate, taurate, sodium, potassium or ammonium salt.
10. The compound of claim 1, which is one of the following structures:
or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof of said compound.
11. A pharmaceutical composition comprising a compound of any one of claims 1-10, further comprising at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle.
12. The pharmaceutical composition of claim 11, further comprising one or more agents useful for treating PGD at the CRTH2 receptor2Other active agents of the mediated disease;
the other active agents are TNF- α inhibitors, COX-1/COX-2 inhibitors, glucocorticoids, inactivated antibodies to interleukins, chemokine receptor modulators, histamine H1 receptor antagonists/antihistamines, leukotriene D4 receptor antagonists, LTD4 antagonists, VLA-4 antagonists, corticosteroid analogs, theophylline, leukotriene biosynthesis inhibitors, cyclooxygenase-2 inhibitors, opioid analgesics, anticoagulantsβ -blockers, β -adrenergic agonists, angiotensin converting enzyme inhibitors, HMG-CoA reductase inhibitors, β 2 agonists, corticosteroids, antihistamines, leukotriene antagonists, anti-IgE antibody therapeutics, anti-infectives, antifungals, immunosuppressants, other PGDs that act on other receptors2Antagonists, inhibitors of phosphodiesterase type 4, agents that modulate cytokine production, agents that modulate the activity of the Th2 cytokines IL-4 and IL-5, 5-lipoxygenase inhibitors;
further preferred wherein the additional active agent is salmeterol, fluticasone, loratadine, montelukast, omalizumab, fusidic acid, clotrimazole, tacrolimus, pimecrolimus, DP antagonists, cilomilast, TNF-alpha converting enzyme (TACE) inhibitors, blocking monoclonal antibodies or soluble receptors for IL-4 or IL-5 and zileuton.
13. Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to any one of claims 11 to 12 for the preparation of a medicament for the prevention, treatment or alleviation of PGD at the CRTH2 receptor in a patient2Use of a pharmaceutical product for a mediated disease.
14. The use according to claim 13, wherein the PGD at the CRTH2 receptor is released2The mediated disease is asthma, allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity, conjunctivitis, eosinophilic bronchitis, food allergy, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and crohn's disease, mastocytosis, autoimmune disease, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriatic arthritis or osteoarthritis.
CN201510621564.1A 2014-09-26 2015-09-25 CRTH2 agonist compounds and application thereof Active CN105461693B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510621564.1A CN105461693B (en) 2014-09-26 2015-09-25 CRTH2 agonist compounds and application thereof

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN201410503514 2014-09-26
CN2014105035149 2014-09-26
CN201510621564.1A CN105461693B (en) 2014-09-26 2015-09-25 CRTH2 agonist compounds and application thereof

Publications (2)

Publication Number Publication Date
CN105461693A true CN105461693A (en) 2016-04-06
CN105461693B CN105461693B (en) 2019-10-25

Family

ID=55599908

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510621564.1A Active CN105461693B (en) 2014-09-26 2015-09-25 CRTH2 agonist compounds and application thereof

Country Status (1)

Country Link
CN (1) CN105461693B (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018151678A1 (en) * 2017-02-15 2018-08-23 Agency For Science, Technology And Research Compounds for treatment of cancer and epigenetics
CN113292570A (en) * 2021-05-27 2021-08-24 山东大学 Compound containing 2, 4-thiazole ring and preparation method and application thereof
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
US12053459B2 (en) 2021-06-26 2024-08-06 Cedilla Therapeutics, Inc. CDK2 inhibitors and methods of using the same
US12065445B2 (en) 2021-01-29 2024-08-20 Cedilla Therapeutics, Inc. CDK2 inhibitors and methods of using the same

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007045867A1 (en) * 2005-10-19 2007-04-26 Argenta Discovery Limited 3 -aminoindole compounds as crth2 receptor ligands
US20090030014A1 (en) * 2005-07-22 2009-01-29 Akira Kugimiya Indole Derivative Having Pgd2 Receptor Antagonist Activity
CN102558021A (en) * 2006-05-26 2012-07-11 阿斯利康(瑞典)有限公司 Bi-aryl or aryl-heteroaryl substituted indoles

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090030014A1 (en) * 2005-07-22 2009-01-29 Akira Kugimiya Indole Derivative Having Pgd2 Receptor Antagonist Activity
WO2007045867A1 (en) * 2005-10-19 2007-04-26 Argenta Discovery Limited 3 -aminoindole compounds as crth2 receptor ligands
CN102558021A (en) * 2006-05-26 2012-07-11 阿斯利康(瑞典)有限公司 Bi-aryl or aryl-heteroaryl substituted indoles

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018151678A1 (en) * 2017-02-15 2018-08-23 Agency For Science, Technology And Research Compounds for treatment of cancer and epigenetics
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
US12065445B2 (en) 2021-01-29 2024-08-20 Cedilla Therapeutics, Inc. CDK2 inhibitors and methods of using the same
CN113292570A (en) * 2021-05-27 2021-08-24 山东大学 Compound containing 2, 4-thiazole ring and preparation method and application thereof
US12053459B2 (en) 2021-06-26 2024-08-06 Cedilla Therapeutics, Inc. CDK2 inhibitors and methods of using the same

Also Published As

Publication number Publication date
CN105461693B (en) 2019-10-25

Similar Documents

Publication Publication Date Title
CN105461693B (en) CRTH2 agonist compounds and application thereof
US9994546B2 (en) Cyclopropylamines as LSD1 inhibitors
TWI672301B (en) 1h-pyrrolo[2,3-c]pyridin-7(6h)-ones and pyrazolo[3,4-c]pyridin-7(6h)-ones as inhibitors of bet proteins
CN112312904A (en) Spiro compounds
CN105764900B (en) CRTH2 agonist compounds and application thereof
EP3080107A1 (en) Benzotriazole derivatives as modulators of tnf activity
MX2012003476A (en) Methods for preparing pyrimidine derivatives useful as protein kinase inhibitors.
EP3303337A1 (en) Fused tricyclic imidazo pyrazines as modulators of tnf activity
JP2020510684A (en) Fused pentacyclic imidazole derivatives as modulators of TNF activity
CN105153154A (en) BTK (bruton tyrosine kinase) inhibitor and purpose of BTK inhibitor
CN106188027B (en) Aromatic heterocyclic derivative and application thereof in medicine
WO2017156177A1 (en) 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
WO2017167996A1 (en) Fused pentacyclic imidazole derivatives as modulators of tnf activity
CN105524053B (en) Tetrahydrobenzothiophene compounds
CN105367472B (en) Indoline derivative and application thereof in medicine
CN116075515A (en) Benzodiazepine derivatives useful for the treatment of respiratory syncytial virus infection
CN105367473B (en) Indoline derivative and application thereof in medicine
WO2024099225A1 (en) Ulk inhibitors
CN117659023A (en) Pyridine acetamide derivative, pharmaceutical composition containing same and medical application of pyridine acetamide derivative

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
TA01 Transfer of patent application right
TA01 Transfer of patent application right

Effective date of registration: 20180612

Address after: 523808 No. 1 Industrial North Road, Hubei Industrial Park, Songshan, Dongguan, Guangdong

Applicant after: SUNSHINE LAKE PHARMA Co.,Ltd.

Applicant after: Ruyuan Yongxing Technical Service Co.,Ltd.

Address before: 523808 No. 1 Industrial North Road, Hubei Industrial Park, Songshan, Dongguan, Guangdong

Applicant before: SUNSHINE LAKE PHARMA Co.,Ltd.

GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20200429

Address after: 523808 Guangdong city of Dongguan province Hubei Songshan Industrial Park Industrial Road No. 1

Patentee after: SUNSHINE LAKE PHARMA Co.,Ltd.

Address before: 523808 Guangdong city of Dongguan province Hubei Songshan Industrial Park Industrial Road No. 1

Co-patentee before: Ruyuan Yongxing Technical Service Co.,Ltd.

Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd.

CP03 Change of name, title or address
CP03 Change of name, title or address

Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province

Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd.

Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei

Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd.