CN115819319B - A kind of amide compound, preparation method and application thereof - Google Patents
A kind of amide compound, preparation method and application thereof Download PDFInfo
- Publication number
- CN115819319B CN115819319B CN202211140563.1A CN202211140563A CN115819319B CN 115819319 B CN115819319 B CN 115819319B CN 202211140563 A CN202211140563 A CN 202211140563A CN 115819319 B CN115819319 B CN 115819319B
- Authority
- CN
- China
- Prior art keywords
- alkyl
- compound
- halogens
- substituted
- pharmaceutically acceptable
- 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.)
- Active
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses an amide compound, a preparation method and application thereof. The structure of the amide compound is shown as a formula I-2. The compound has a good inhibition effect on soluble cyclooxygenase.
Description
Technical Field
The invention relates to an amide compound, a preparation method and application thereof.
Background
Epoxide hydrolases (EH, EC 3.3.2.3) catalyze the hydrolysis of epoxides or aromatic oxides to their corresponding diols (see Oesch, F. Et al, xenobiological, 1973,3,305-340). Some EHs play a vital role in the metabolism of a variety of compounds, including hormones, chemotherapeutics, carcinogens, environmental pollutants, mycotoxins and other harmful foreign compounds.
Microsomal epoxide hydrolase (mEH) and soluble epoxide hydrolase (sEH) are two well-studied EHs. In recent years, 1, 3-disubstituted ureas, carbamates and amides have been reported to be effective and stable novel inhibitors of sEH. Chinese patent CN101084216a reports urea containing a trifluoromethylphenyl substitution. There is still a need to develop more compounds with similar or improved activity.
Disclosure of Invention
The invention aims to solve the technical problem that the structure of the existing medicine for inhibiting the soluble cyclooxygenase is single, and therefore, the invention provides an amide compound, a preparation method and application thereof. The compound has a good inhibition effect on soluble cyclooxygenase.
The invention also provides a compound shown as the formula I-2 or pharmaceutically acceptable salt thereof,
Wherein ring A is a3 to 6 membered cycloalkane and n is 0, 1, 2 or 3;
R3 is independently "C 1-C6 alkyl substituted with 1 or more halogens", "C 1-C6 alkoxy substituted with 1 or more halogens", halogen or sulfur pentafluoride;
R 2 is hydrogen, C 1-C6 alkyl, Phenyl or "phenyl substituted by 1 or more carboxyl groups"; R 2-1 is hydrogen,C 3-C6 cycloalkyl or C 1-C6 alkyl, R 2-1-1 is C 1-C6 alkyl.
In one embodiment, in the compound of formula I-2 or a pharmaceutically acceptable salt thereof, certain groups may be defined as described in any one of the embodiments above (hereinafter referred to as "one embodiment"), wherein ring A is a 3-or 5-membered cycloalkane, n is 1 or 2;R 3 is independently "C 1-C6 alkyl substituted with 3 halogens", "C 1-C6 alkoxy substituted with 3 halogens", halogen or sulfur pentafluoride ", and R 2 is hydrogen or sulfur pentafluorideR 2-1 isC 3-C6 cycloalkyl or C 1-C6 alkyl, R 2-1-1 is C 1-C6 alkyl.
In one embodiment, ring a is a3 or 5 membered cycloalkane.
In one embodiment, n is 1 or 2.
In one embodiment, R 3 is independently "C 1-C6 alkyl substituted with 3 halogens", "C 1-C6 alkoxy substituted with 3 halogens", halogen or sulfur pentafluoride.
In one embodiment, R 2 is hydrogen or
In one embodiment, R 2-1 isC 3-C6 cycloalkyl or C 1-C6 alkyl.
In one embodiment, R 2-1 isOr isopropyl, R 2-1-1 is methyl.
In one embodiment, when R 3 is "C 1-C6 alkyl substituted with 3 halogens", R 2 isR 2-1 is isopropyl.
In one embodiment, when R 3 is sulfur pentafluoride, R 2 isR 2-1 isR 2-1-1 is methyl.
In one embodiment, the compound of formula I-2 is a compound of formula I-2-1
Wherein n is 1 or 2;R 3 is independently "C 1-C6 alkyl substituted with 3 halogens", "C 1-C6 alkoxy substituted with 3 halogens" or halogen; R 2 isR 2-1 isC 3-C6 cycloalkyl or C 1-C6 alkyl, R 2-1-1 is C 1-C6 alkyl.
In one embodiment, the compound of formula I-2 is a compound of formula I-2-1
Wherein n is 1 or 2;R 3 is independently "C 1-C6 alkyl substituted with 3 halogens", "C 1-C6 alkoxy substituted with 3 halogens", halogen or sulfur pentafluoride; R 2 isR 2-1 isC 3-C6 cycloalkyl or C 1-C6 alkyl, R 2-1-1 is C 1-C6 alkyl.
In one embodiment, the compound of formula I-2 is a compound of formula I-2-2
Wherein n is 1 or 2;R 3 is independently "C 1-C6 alkyl substituted with 1 or more fluoro", "C 1-C6 alkoxy substituted with 1 or more halogen" or halogen, R 2 is hydrogen orR 2-1 is C 3-C6 cycloalkyl or C 1-C6 alkyl.
In one embodiment, the compound of formula I-2 is a compound of formula I-2-2
Wherein n is 1 or 2;R 3 is independently "C 1-C6 alkyl substituted with 1 or more fluoro", "C 1-C6 alkoxy substituted with 1 or more halogen", halogen or sulfur pentafluoride, R 2 is hydrogen orR 2-1 is C 3-C6 cycloalkyl or C 1-C6 alkyl.
In one embodiment, the compound of formula I-2 is a compound of formula I-2-3
Wherein n is 1 or 2;R 2 isR 2-1 isOr C 1-C6 alkyl, R 2-1-1 is C 1-C6 alkyl, preferably sulfur pentafluoride is meta and/or para to the amide nitrogen.
In one scheme, in the compound shown as the formula I-2, n is 1 or 2;R 3 is sulfur pentafluoride, and R 2 isR 2-1 isOr C 1-C6 alkyl, R 2-1-1 is C 1-C6 alkyl, preferably sulfur pentafluoride is meta and/or para to the amide nitrogen.
In one embodiment, the compound of formula I-2 is a compound of formula I-2-4
N is 1 or 2;R 3 is independently "C 1-C6 alkyl substituted by 3 halogens" or sulfur pentafluoride, R 2 isR 2-1 isOr C 1-C6 alkyl, R 2-1-1 is C 1-C6 alkyl.
In one embodiment, R 3 is independently "C 1-C6 alkyl substituted with 3 halogens" or sulfur pentafluoride.
In one embodiment, R 3 is independently "C 1-C6 alkyl substituted with 1 or more fluoro", "C 1-C6 alkoxy substituted with 1 or more halogen", halogen or sulfur pentafluoride.
In one embodiment, R 2 is
In one embodiment, R 2-1 isOr C 1-C6 alkyl.
In one embodiment, R 2-1 is C 3-C6 cycloalkyl or C 1-C6 alkyl.
In one embodiment, the sulfur pentafluoride is located meta and/or para to the amide nitrogen.
In one embodiment, in R3, the C 1-C6 alkyl in the "C 1-C6 alkyl substituted by 1 or more halogens" may be C 1-C4 alkyl, the C 1-C4 alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, the C 1-C4 alkyl is also preferably methyl, and more preferably the "C 1-C6 alkyl substituted by 1 or more halogens" is C 1-C4 alkyl substituted by trifluoro, such as trifluoromethyl.
In one embodiment, in R 3, the C 1-C6 alkoxy group in the "C 1-C6 alkoxy group substituted with 1 or more halogens" may be a C 1-C4 alkoxy group, the C 1-C4 alkoxy group is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, the C 1-C4 alkoxy group is also preferably methyloxy, and more preferably the "C 1-C6 alkoxy group substituted with 1 or more halogens" is a trifluoro-substituted C 1-C4 alkoxy group, such as trifluoromethoxy.
In a certain scheme, in R 3, the halogen can be fluorine, chlorine, bromine or iodine, and also can be fluorine.
In one embodiment, R 2 is C 1-C6 alkyl which may be C 1-C4 alkyl, or methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
In one embodiment, R 2-1 is C 1-C6 alkyl which may be C 1-C4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, or isobutylOr isopropyl.
In one embodiment, R 2-1 is a C 3-C6 cycloalkyl group which may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and may be cyclopropyl.
In one embodiment, R 2-1-1 is C 1-C6 alkyl which may be C 1-C4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, or tert-butyl.
In one embodiment, R 2 may be Boc,
In one embodiment, R 3 may be fluoro, trifluoromethyl, trifluoromethoxy, or sulfur pentafluoride.
In one aspect of the present invention,Can be used forAnd can also be
In one aspect of the present invention,R 3 in the meta and/or para position to the amide nitrogen.
In one embodiment, the compound of formula I-2 is selected from any one of the following compounds:
The invention also provides a compound shown as a formula I-3 or a salt thereof,
Wherein, ring A, n and R 3 are as described previously.
In one embodiment, the salt is a salt of a mineral acid and a compound of formula I-3, which is conventional in the art, for example, the salt is a salt of a compound of formula I-3 and hydrochloric acid, and for example, the salt is a salt of a compound of formula I-3 and hydrochloric acid in a molar ratio of 1:1.
In one embodiment, the compound of formula I-3 is selected from any one of the following:
The invention also provides a preparation method of the compound shown as the formula I-2, wherein the preparation method is scheme 1 or scheme 2,
The scheme 1 comprises the following steps of carrying out condensation reaction of a compound shown as a formula II and an amine compound in the presence of alkali in a solvent, wherein the definition of a ring A, a ring n, a ring R 2 and a ring R 3 is as described above;
The scheme 2 comprises the following steps of carrying out amidation reaction of a compound shown as a formula I-3 or salt thereof and a compound shown as a formula I-4 in a solvent in the presence of a base, wherein R 2 is R 2-1, ring A, n and R 3 are as defined above;
In the condensation reaction, the solvent may be a solvent conventional in the art. The solvent may be selected from one or more of an ether solvent, a chlorinated alkane and an aromatic solvent. The ether solvent is preferably diethyl ether, tetrahydrofuran or methyl tert-butyl ether. The chlorinated alkane is preferably dichloromethane. The aromatic solvent is preferably toluene or benzene.
In the condensation reaction, the solvent is used in an amount conventional in the art, and the volume molar ratio of the solvent to the compound represented by formula II may be 1 to 10mL/mmol, for example, 7mL/mmol or 8mL/mmol.
In the condensation reaction, the molar ratio of the compound shown in the formula II to the amine compound can be 1:1.5 or 1:1.7, for example, in the range of 1:1-3.
In the condensation reaction, the base may be an organic base conventional in the art, and the base may be a nitrogen-containing organic base, such as triethylamine.
In the condensation reaction, the base may be used in an amount conventional in the art, and the molar ratio of the compound of formula II to the base may be 1:1 (1-3), for example 1:1.5 or 1:1.8.
In the condensation reaction, the reaction temperature of the condensation reaction is a reaction temperature conventional in the art, preferably 0 to 40 ℃, for example 0 ℃, 15 ℃, or 25 ℃.
In the scheme 2, the amidation reaction may be performed in the presence of an acid anhydride. The anhydride is a conventional anhydride in the art, preferably the anhydride is selected from one or more of propylphosphoric anhydride, HATU (2- (7-azabenzotriazol) -N, N' -tetramethylurea hexafluorophosphate), EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) and HOBt (1-hydroxybenzotriazole), for example propylphosphoric anhydride. The adding mode of the propyl phosphoric anhydride is preferably ethyl acetate solution with the mass fraction of the propyl phosphoric anhydride of 50 percent.
In the amidation reaction, the salt is a salt conventional in the art, preferably hydrochloride.
In scheme 2, the anhydride is used in an amount conventional in the art, and the molar ratio of the anhydride to the compound of formula I-3 may be 4:1 to 10, for example 3:1, 4:1 or 5:1.
In the amidation reaction, the molar ratio of the compound shown in the formula II to the compound shown in the formula I-4 can be 1:1.3, for example 1:1.3, 1:1.5 or 1:1.7.
In the amidation reaction, the solvent may be a solvent conventional in the art. The solvent may be a chlorinated alkane solvent and/or an amide solvent. The chlorinated alkane solvent is preferably DCM. The amide solvent is preferably DMF.
In the amidation reaction, the solvent is used in an amount conventional in the art, and the volume molar ratio of the solvent to the compound represented by formula II may be 1 to 20mL/mmol, for example 11mL/mmol or 12mL/mmol.
In the amidation reaction, the base may be an organic base conventional in the art, and the base may be a nitrogen-containing organic base, such as triethylamine.
In the amidation reaction, the base may be used in an amount conventional in the art, and the molar ratio of the compound of formula II to the base may be 1:1-10, for example 1:3, 1:4 or 1:5.
In the amidation reaction, the reaction temperature of the condensation reaction is a reaction temperature conventional in the art, preferably 0 to 40 ℃, for example 0 ℃, 15 ℃, or 25 ℃.
The invention also provides application of the substance Z in preparing a medicament for treating and/or preventing diseases related to soluble cyclooxygenase, wherein the substance Z is a compound shown in the formula I-2 or pharmaceutically acceptable salt thereof.
Preferably, the disease is hypertension, pain, cardiomyopathy, inflammation, adult respiratory distress syndrome, diabetic complications, kidney disease, raynaud's syndrome or arthritis.
The pain is preferably neuropathic pain and/or inflammatory pain.
The kidney disease is preferably end stage kidney disease.
The hypertension is preferably renal hypertension, liver hypertension or pulmonary hypertension.
The inflammation is preferably kidney inflammation, vascular inflammation or lung inflammation.
The invention also provides application of the substance Z in preparing the soluble cyclooxygenase inhibitor, wherein the substance Z is a compound shown in the formula I-2 or pharmaceutically acceptable salt thereof.
The invention also provides a pharmaceutical composition which comprises a substance Z and pharmaceutical excipients, wherein the substance Z is a compound shown as the formula I-2 or pharmaceutically acceptable salt thereof.
In the pharmaceutical composition, the substance Z may be a therapeutically effective amount of substance Z.
Definition of terms
Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C 1-C6 alkyl refers to an alkyl group as defined below having a total of 1,2, 3, 4, 5 or 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.
The term "room temperature" generally refers to 25-30 ℃.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "plurality" refers to 2, 3, 4, or 5.
The term "pharmaceutically acceptable salt" refers to salts formed from suitable non-toxic organic acids, inorganic acids, organic bases or inorganic bases with compounds of formula I-1 which retain the biological activity of the compounds of formula I-1.
The term "pharmaceutical excipients" refers to excipients and additives used in the manufacture of medicaments and formulation of prescriptions, and is all matter contained in the pharmaceutical formulation except for the active ingredient. See the pharmacopoeia of the people's republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe,2009 sibth Edition).
The term "treatment" refers to therapeutic therapy. Treatment, where a particular disorder is involved, refers to (1) alleviation of a disease or one or more biological manifestations of a disorder, (2) interference with (a) one or more points in a biological cascade leading to or causing a disorder or (b) one or more biological manifestations of a disorder, (3) amelioration of one or more symptoms, effects or side effects associated with a disorder, or one or more symptoms, effects or side effects associated with a disorder or treatment thereof, or (4) alleviation of progression of a disorder or one or more biological manifestations of a disorder.
The term "preventing" refers to a reduced risk of acquiring or developing a disease or disorder.
The term "therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat a disease or disorder described herein when administered to a patient. The "therapeutically effective amount" will vary depending on the compound, the condition and severity thereof, and the age of the patient to be treated, but can be adjusted as desired by one of ordinary skill in the art.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The positive progress effect of the invention is that the compound has better inhibition effect on soluble cyclooxygenase or good metabolic property (such as half-life, exposure dose AUC and maximum blood concentration Cmax).
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Preparation of chromatographic conditions for isolation (purification):
separation conditions:
mobile phase A water (0.225% formic acid) mobile phase B acetonitrile
Chromatographic column Phenomenexluna C18150 mm 15 μm
Gradient elution of 37-67% mobile phase B
Gradient elution time 10min
Detection wavelength of 254nm
The flow rate (mL/min) was 60mL/min.
Example 1 Synthesis of BX20-6-I06
The synthetic route is shown in the following formula:
Compound XR02-S1 (0.27 g,1.46 mmol), compound Int-1 (0.30 g,1.33 mmol) and TEA (triethylamine) (0.27 g,2.66 mmol) were added sequentially to DCM (10.0 mL) and the reaction mixture was reacted at 15℃for 12h. After the completion of the reaction, the reaction mixture was directly concentrated at 40℃under reduced pressure, and the residue was purified by column chromatography (PE/EA=2/1~0/1, V/V) to give Compound BX20-6-I06 (0.27 g, yield 49%) as a pale yellow solid.
1H NMR(400MHz,CDCl3)δ＝7.51-7.43(m,4H),7.22(s,1H),5.18(s,1H),4.28(q,J＝7.2Hz,1H),3.56-3.51(m,2H),3.15-3.12(m,2H),2.73(s,2H),1.89-1.67(m,4H),1.45(s,9H);MS(ESI,m/z)358.1[M-t-Bu+H]+.
EXAMPLE 2 Synthesis of BX20-6-I07
First step XR020009-I01 Synthesis
The synthetic route is shown in the following formula:
Compound XR02-S4 (2.00 g,8.90 mmol) was dissolved in DCM (30 mL), the reaction was cooled to below 0deg.C, bnNH (0.95 g,8.90 mmol) acetic acid (0.53 g,8.90 mmol) was added, the reaction was placed under ice-bath, stirred for 30min, naBH (OAc) 3 (3.76 g,17.8 mmol) in DCM (30 mL) was added and stirred for 12h at 25deg.C. After the reaction was completed, the reaction mixture was directly concentrated at 40℃under reduced pressure, and the residue was purified by column chromatography (PE/EA/MeOH=1/1/0~0/5/1, V/V) to give compound XR020009-I01 (2.30 g, yield 82.1%) as a pale yellow oil. MS (ESI, m/z) 317.2[ M+H ] +.
Second step, XR020009-I02 Synthesis
The synthetic route is shown in the following formula:
Compound XR020009-I01 (2.30 g,7.00 mmol), pd (OH) 2/C (2.07 g), after H2 displacement, the reaction mixture was reacted at 25℃for 12H under H2 (15 psi). After completion of the reaction, the reaction mixture was directly filtered, and the filtrate was collected and concentrated under reduced pressure at 40℃to give XR020009-I02 (1.70 g, crude product) as a colorless oily compound, which was directly used in the next reaction, m/z=227.17 [ M+H ] +.
Third step, synthesis of Compound BX20-6-I07
The synthetic route is shown in the following formula:
Compound XR020009-I02 (1.00 g,4.40 mmol), XR02-S1 (0.90 g,4.84 mmol), TEA (0.90 g,8.80 mmol) were added sequentially to DCM (30 mL) and the reaction mixture reacted at 25℃for 4h. After the reaction, the reaction mixture was concentrated directly at 40℃under reduced pressure, and the residue was purified by column chromatography (PE/EA=20/1 to 1/1, V/V) to give Compound BX20-6-I07 (1.50 g, yield 83.0%) as a white powder.
1H NMR(400MHz,CDCl3)δ＝7.58(s,1H),7.28-7.26(m,3H),5.61(d,J＝7.6Hz,1H),4.03-3.94(m,1H),3.25-3.22(m,2H),3.13-3.10(m,2H),2.43-2.41(m,2H),2.21-2.14(m,2H),1.28(s,9H),0.95-0.91(m,2H);MS(ESI,m/z)414.19[M+H]+.
Example 3 Synthesis of BX20-6-008
First step, synthesis of BX20-6-I06
By proceeding as in example 1, compound BX20-6-I06 was obtained as a pale yellow solid.
Second step Synthesis of Compound XR020008-I02
The synthetic route is shown in the following formula:
Compound BX20-6-I06 (0.20 g,0.48 mmol) was dissolved in dry methanol (5.0 mL) and a 2MHCl/EA solution (2.4 mL,4.80 mmol) was added. The reaction mixture was reacted at 10℃for 5h. After completion of the reaction, concentration under reduced pressure at 40 ℃ gave compound XR020008-I02 (0.16 g, hydrochloride, crude) as a white solid, which was used directly in the next reaction.
Third step, the synthesis of the compound BX20-6-008
The synthetic route is shown in the following formula:
Compound XR020008-I02 (0.16 g,0.46 mmol), compound isobutyric acid (52.0 mg,0.59 mmol), TEA (0.23 g,2.30 mmol) and T3P (propylphosphoric anhydride) (1.17 g, 50% strength by mass ethyl acetate solution of T3P, 1.84 mmol) were added sequentially to DCM (5.0 mL) and the reaction mixture was reacted at 15℃for 6h. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure at 40℃to give a residue, which was purified by preparative separation (formic acid system) and lyophilized to give compound BX20-6-008 (23 mg, yield 13%) as a white powder.
1H NMR(400MHz,DMSO-d6)δ＝8.74(s,1H),7.59-7.51(m,4H),6.41(d,J＝7.6Hz,1H),4.08(q,J＝7.2Hz,1H),3.65(t,J＝7.2Hz,1H),3.50-3.45(m,1H),3.28-3.25(m,1H),3.14(dd,J＝8.8,4.0Hz,1H),2.82-2.76(m,1H),2.70-2.60(m,2H),1.80-1.64(m,4H),1.00-0.95(m,6H);MS(ESI,m/z)384.2[M+H]+.
Example 4 Synthesis of BX20-6-009
First step, synthesis of BX20-6-I07
By proceeding according to example 2, compound BX20-6-I07 is obtained as a white powder.
Second step, XR020009-I04 Synthesis
The synthetic route is shown in the following formula:
Compound BX20-6-I07 (1.20 g,2.90 mmol) was dissolved in MeOH (10 mL), HCl (5 mL, 1M) was added and the reaction mixture was reacted at 25℃for 12h. After completion of the reaction, the reaction mixture was concentrated directly at 40℃under reduced pressure to give compound XR020009-I04 (1.00 g, crude product, hydrochloride) as a white powder, the crude product was used directly in the next step. MS (ESI, m/z) 314.14[ M+H ] +.
Third step, synthesis of BX20-6-009
The synthetic route is shown in the following formula:
Compound XR020009-I04 (0.60 g,1.71 mmol), isobutyric acid (0.18 g,2.06 mmol), TEA (0.87 g,8.58 mmol) and T3P (5.40 g,8.58 mmol) were added sequentially to DCM (20 mL) and the reaction mixture reacted at 25℃for 12h. After the reaction, the reaction mixture was concentrated directly at 40℃under reduced pressure to give a residue, which was purified by preparative separation (formic acid system) and lyophilized to give Compound BX20-6-009 (147 mg, yield 22.5%) as a white powder.
1H NMR(400MHz,DMSO-d6)δ＝8.72(s,1H),7.57-7.51(m,4H),6.46(d,J＝7.2Hz,1H),4.01-3.94(m,1H),3.61-3.56(m,1H),3.42-3.37(m,2H),2.66-2.61(m,2H),2.53-2.50(m,2H),2.21-2.16(m,2H),1.24-1.14(m,2H),1.00-0.95(m,6H);MS(ESI,m/z)384.1[M+H]+.
Example 5 Synthesis of BX20-6-011
First step, S2-011 synthesis
The synthetic route is shown in the following formula:
A solution of compound S1-011 (0.15 g,0.66 mmol) in DCM (3.0 mL) was slowly added dropwise to a solution of compound Int-1 (0.15 g,0.75 mmol) and TEA (0.10 g,1.00 mmol) in DCM (5.0 mL) at-78deg.C, and the reaction mixture was warmed to 20deg.C and reacted for 0.5h. After the completion of the reaction, the reaction mixture was directly concentrated under reduced pressure at 40℃and the residue was purified by column chromatography (PE/EA=3/1 to 1/1, V/V) to give compound S2-011 (160 mg, yield 49.7%) as a white solid, m/z=430.2 [ M+H ] +.
Second step, S3-011 synthesis
The synthetic route is shown in the following formula:
Compound S2-011 (160 mg,0.37 mmol) was dissolved in MeOH (5.0 mL) and HCl/EA (2M, 5 mL) was added and the reaction stirred at 20℃for 5h. After the reaction, it was directly concentrated at 40℃under reduced pressure to give compound S3-011 (136 mg, crude product, hydrochloride) as a yellow solid, m/z=330.3 [ M+H ] +.
Third step, BX20-6-011 synthesis
The synthetic route is shown in the following formula:
Compound S3-011 (136 mg, crude product, hydrochloride), (S) - (+) -2-methylbutanoic acid (46 mg,0.45 mmol), T3P (50% ethyl acetate solution, 0.76g,1.11 mmol) and TEA (187 mg,1.85 mmol) were added sequentially to DMF (2 mL) and the reaction mixture stirred at room temperature for 16h. After the reaction, water (20 mL) was added, ethyl acetate (5 mL. Times.3) was extracted, and the organic phase was dried, concentrated under reduced pressure at 40℃and purified by preparative separation (formic acid system), and after lyophilization, the compound BX20-6-011 (25 mg, yield 16.3%) was obtained as a white powder.
1H NMR(400MHz,DMSO-d6)δ＝8.60(s,1H),7.46(d,J＝7.6Hz,2H),7.20(d,J＝7.6Hz,2H),6.37(d,J＝8.0Hz,1H),4.11-4.08(m,1H),3.69-3.66(m,1H),3.52-3.49(m,1H),3.31-3.28(m,1H),3.20-3.17(m,1H),2.86-2.65(m,2H),2.49-2.46(m,1H),1.80-1.65(m,4H),1.58-1.53(m,1H),1.31-1.23(m,1H),1.00-0.95(m,3H),0.83-0.78(m,3H).
Example 6 Synthesis of BX20-6-012
First step, S2-012 synthesis
The synthetic route is shown in the following formula:
A solution of compound S1-011 (500 mg,2.46 mmol) in DCM (5.0 mL) was slowly added dropwise to a solution of compound Int-2 (528 mg,2.34 mmol) and TEA (28.0 mg,2.77 mmol) in DCM at-78℃and the reaction mixture was reacted at 0℃for 3h. After the completion of the reaction, the reaction mixture was directly concentrated under reduced pressure at 40℃and the residue was purified by column chromatography (PE/EA=3/1 to 1/1, V/V) to give Compound S2-012 (750 mg, yield 71.0%) as a white solid, m/z=430.2 [ M+H ] +.
Second step S3-012 synthesis
The synthetic route is shown in the following formula:
Compound S2-012 (750 mg,1.74 mmol) was dissolved in MeOH (10.0 mL) and HCl/EA (2M, 20 mL) was added and the reaction stirred at room temperature for 3 hours. After the reaction, it was directly concentrated at 40 ℃ under reduced pressure to give compound S3-012 (700 mg, crude product, hydrochloride) as a yellow solid, m/z=330.3 [ m+h ] +.
Third step, synthesis of BX20-6-012
The synthetic route is shown in the following formula:
Compound S3-012 (700 mg, crude product, hydrochloride), (S) - (+) -2-methylbutanoic acid (250 mg,2.46 mmol), T3P (50% ethyl acetate solution, 3.90g,6.20 mmol) and TEA (626 mg,6.20 mmol) were added sequentially to DMF (10 mL), and the reaction mixture was stirred at room temperature for 16h. After the reaction, water (80 mL) was added, ethyl acetate (35 mL. Times.3) was extracted, and the organic phase was dried, concentrated under reduced pressure at 40℃and purified by preparative separation (formic acid system), and after lyophilization, compound BX20-6-012 (110 mg, yield 15.3%) was obtained as a white powder. m/z=414.3 [ m+h ] +.
1H NMR(400MHz,DMSO-d6)δ＝8.46(s,1H),7.44(d,J＝8.8Hz,2H),7.18(d,J＝8.4Hz,2H),6.32(d,J＝7.6Hz,1H),4.01-3.90(m,1H),3.60-3.55(m,1H),3.42-3.36(m,2H),3.33-3.31(m,1H),2.63-2.58(m,1H),2.53-2.50(m,1H),2.49-2.44(m,1H),2.22-2.13(m,2H),1.56-1.48(m,1H),1.31-1.11(m,3H),0.98-0.93(m,3H),0.83-0.76(m,3H).
Example 7 Synthesis of BX20-6-013
First step, XR020008-I02 Synthesis
According to example 3, compound XR020008-I02 was synthesized.
Third step, BX20-6-013 synthesis
The synthetic route is shown in the following formula:
The compound XR020008-I02 (135 mg, crude product, hydrochloride), (S) - (+) -2-methylbutanoic acid (46 mg,0.45 mmol), T3P (50% ethyl acetate solution, 0.76g,1.11 mmol) and TEA (187 mg,1.85 mmol) were added sequentially to DMF (2 mL) and the reaction mixture stirred at room temperature for 12h. After completion of the reaction, water (20 mL) was added, ethyl acetate (5 mL. Times.3) was extracted, and the organic phase was dried, concentrated under reduced pressure at 40℃and purified by preparative separation (formic acid system), and after lyophilization, compound BX20-6-013 (55 mg, yield 33.7%) was obtained as a white powder.
1H NMR(400MHz,DMSO-d6)δ＝8.74(s,1H),7.58-7.53(m,4H),6.41(s,1H),4.11-4.09(m,1H),3.69-3.64(m,1H),3.51-3.49(m,1H),3.33-3.30(m,1H),3.21-3.16(mm,1H),2.83-2.70(m,2H),2.49-2.45(m,1H),1.79-1.68(m,4H),1.58-1.48(m,1H),1.31-1.24(m,1H),1.00-0.95(m,3H),0.85-0.80(m,3H).
Example 8 Synthesis of BX20-6-014
First step XR020009-I04 Synthesis
The second step was performed according to example 4, and compound XR020009-I04 was obtained.
Second step Synthesis of BX20-6-014
The synthetic route is shown in the following formula:
Compound XR020009-I04 (0.35 g,1.00 mmol), compound (S) - (+) -2-methylbutanoic acid (0.13 g,1.2 mmol) and TEA (0.30 g,3.00 mmol) were added sequentially to DMF (5.0 mL) and the reaction mixture reacted at 50℃for 12h. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure at 40℃to give a residue, which was purified by preparative separation (formic acid system) and lyophilized to give compound BX20-6-014 (59.4 mg, yield 15%) as a white powder.
1H NMR(400MHz,DMSO-d6)＝8.75(s,1H),7.54(t,J＝8.0Hz,4H),6.50(d,J＝7.6Hz,1H),3.98-3.96(m,1H),3.60-3.56(m,1H),3.42-3.40(m,3H),2.64-2.61(m,1H),2.57-2.51(m,2H),2.21-2.16(m,2H),1.65-1.47(m,1H),1.21-1.16(m,3H),0.99-0.94(m,3H),0.83-0.78(m,3H).
Example 9 Synthesis of BX20-6-015
First step, XR020008-I02 Synthesis
According to example 3, compound XR020008-I02 was synthesized.
Third step, synthesis of BX20-6-015
The synthetic route is shown in the following formula:
Compound XR020008-I02 (130 mg, crude product, hydrochloride), cyclopropanecarboxylic acid (70 mg,0.80 mmol), T3P (50% ethyl acetate solution, 1.27g,2.00 mmol) and TEA (160 mg,1.60 mmol) were added sequentially to DMF (3 mL) and the reaction mixture stirred at room temperature for 16h. After the reaction, water (40 mL) was added, ethyl acetate (25 mL. Times.3) was extracted, and the organic phase was dried, concentrated under reduced pressure at 40℃and purified by preparative separation (formic acid system), and after lyophilization, compound BX20-6-015 (55 mg, yield 36.9%) was obtained as a white powder. m/z=382.3 [ m+h ] +.
1H NMR(400MHz,DMSO-d6)δ＝8.73(s,1H),7.58-7.53(m,4H),6.42(d,J＝7.2Hz,1H),4.16-4.08(m,1H),3.81(t,J＝10.8Hz,1H),3.54-3.42(m,2H),3.17(dd,J＝12.0Hz,4.8Hz,1H),2.87-2.82(m,1H),2.74-2.67(m,1H),1.84-1.64(m,5H),0.73-0.68(m,4H).
Example 10 Synthesis of BX20-6-016
First step, XR020009-I04 Synthesis
The second step was performed according to example 4, and compound XR020009-I04 was obtained.
Second step, synthesis of BX20-6-016
The synthetic route is shown in the following formula:
Compound XR020009-I04 (667 mg,1.9mmol, crude product), cyclopropanecarboxylic acid (197mg, 2.30 mmol), T3P (50% ethyl acetate solution, 3.60g,5.70 mmol) and TEA (580 mg,5.70 mmol) were added sequentially to DMF (8 mL) at 0deg.C and the reaction mixture stirred at room temperature for 16h. After completion of the reaction, water (30 mL) was added and extracted with ethyl acetate (50 mL x 3), the organic phase was dried and concentrated under reduced pressure at 40 ℃, and the residue was purified by chromatography (PE/EA/meoh=1/1/0~0/20/1, 1% aqueous ammonia) to give compound BX20-6-016 as a white powder (320 mg, yield 43.9%). m/z=382.2 [ m+h ] +.
1H NMR(400MHz,Methanol-d4)δ＝7.54-7.49(m,4H),4.15-4.13(m,1H),3.88-3.84(m,1H),3.68-3.62(m,1H),3.58-3.55(m,1H),3.46-3.41(m,1H),2.82-2.66(m,2H),2.43-2.32(m,2H),1.84-1.77(m,1H),1.40-1.28(m,2H),0.89-0.80(m,4H).
Example 11 Synthesis of BX20-6-017
Step one, S2-017 synthesis
The synthetic route is shown in the following formula:
Triphosgene (59 mg,0.20 mmol) was dissolved in DCM (5 mL), after N2 substitution, cooled to-78℃and a reaction mixture of compound S1-017 (86.2 mg,0.44 mmol) dissolved in DCM (5 mL) was added dropwise to the reaction system, and after the dropwise addition, the temperature was raised naturally to 20℃and stirred for 1h. After the reaction, the reaction solution was directly used for the next reaction.
Step two, S3-017 synthesis
The synthetic route is shown in the following formula:
the reaction solution in example 1 was cooled to-78 ℃, int-1 (150 mg,0.66 mmol), TEA (134 mg,1.33 mmol) was dissolved in DCM (2 mL), the reaction mixture was slowly added dropwise to the reaction solution in example 1 and maintained at-78 ℃, after the dropwise addition, the reaction was stirred after naturally warming to room temperature for 3h. After the reaction, the reaction mixture was concentrated directly at 40℃under reduced pressure, and the residue was purified by column chromatography (PE/EA=3/1 to 2/1, V/V) to give Compound S3-017 (0.14 g, 73%) as a colorless oil. MS (ESI, m/z) 448.18[ M+H ] +.
Third step, S4-017 synthesis
The synthetic route is shown in the following formula:
Compound S3-017 (0.14 g,0.32 mmol) was dissolved in MeOH (10 mL) and the reaction mixture stirred at 25℃for 3h. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure at 40℃to give Compound S4-017 (0.10 g, crude product) as a colorless oil. MS (ESI, m/z) 348.13[ M+H ] +.
Fourth step, synthesizing BX20-6-017
The synthetic route is shown in the following formula:
Compound S4-017 (0.10 g,0.26 mmol), (S) - (+) -2-methylbutanoic acid (0.10 g,0.94 mmol), T3P (1.2 g,1.88 mmol), TEA (0.16 g,1.57 mmol) were added sequentially to DMF (3 mL) and the reaction mixture stirred at 25℃for 12h. After the reaction, the reaction mixture was concentrated directly at 40℃under reduced pressure to give a residue, which was purified by preparative separation (formic acid system) and lyophilized to give Compound BX20-6-017 (12 mg, 16%) as a white powder. MS (ESI, m/z) 432.18[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ＝8.72(s,1H),7.66-7.62(m,1H),7.36(t,J＝8.0Hz,1H),7.08(d,J＝7.6Hz,1H),6.43-6.42(m,1H),4.08-4.06(m,1H),3.64(t,J＝＝11.6Hz,1H),3.48(t,J＝8.0Hz,1H),3.18-2.17(m,1H),3.15-3.14(m,1H),2.79-2.76(m,1H),2.71-2.66(m,1H),2.46-2.43(m,1H),1.77-1.67(m,4H),1.54-1.46(m,1H),1.27-1.23(m,1H),0.98-0.93(m,3H),0.83-0.78(m,3H).
Example 12 Synthesis of BX20-6-018
First step, S1-018 synthesis
The synthetic route is shown in the following formula:
Triphosgene (345 mg,1.20 mmol) was added to anhydrous DCM (5.0 mL), nitrogen was replaced, and the reaction was cooled to-78 ℃. S1-017 (517 mg,2.60 mmol), TEA (400 mg,4.00 mmol) was dissolved in anhydrous DCM (5.0 mL) and added dropwise to the reaction, and the system was warmed to 0℃and stirred for 1 hour. The reaction was cooled again to-78 ℃, int-2 (500 mg,2.20 mmol), TEA (400 mg,4.00 mmol) was dissolved in anhydrous DCM (5.0 mL) to prepare solution B and added dropwise to the reaction, slowly brought to room temperature and stirring continued for 3 hours. After completion of the reaction, quenched with water (30 mL), extracted with DCM (50 mL x 3), the organic phase dried and concentrated under reduced pressure at 40 ℃, and the residue purified by chromatography (PE: ea=4:1 to 1:1) to give a white solid s1-018 (600 mg, yield 50.7%), m/z=448.2 [ m+h ] +.
Second step S2-018 synthesis
The synthetic route is shown in the following formula:
S1-018 (600 mg,1.30 mmol) was dissolved in MeOH (3.0 mL) and HCl/EA (2M, 6.0 mL) was added and the reaction stirred at 25℃for 2 h. After the reaction, the reaction mixture was directly concentrated at 40℃under reduced pressure to give Compound S2-018 (465 mg, crude product, hydrochloride) as a white solid, m/z=348.1 [ M+H ] +.
Third step, synthesis of BX20-6-018
The synthetic route is shown in the following formula:
Compound S2-018 (460 mg,1.20mmol, crude product), (S) - (+) -2-methylbutanoic acid (207 mg,2.0 mmol), T3P (50% ethyl acetate solution, 2.56g,4.00 mmol) and TEA (407 mg,4.00 mmol) were added sequentially to DMF (6.0 mL) and the reaction mixture stirred at 25℃for 16h. After the reaction, water (30 mL) was added and ethyl acetate (50 mL) was extracted to obtain an organic phase, which was dried and concentrated under reduced pressure at 40 ℃, the residue was purified by chromatography (PE: ea=1:1 to EA: meoh=20:1, 1% aqueous ammonia) and the crude product was isolated by preparative separation to give the compound BX20-6-018 as a white powder (62 mg, yield 13.5%). m/z=432.2 [ m+h ] +.
1H NMR(400MHz,Methanol-d4)＝7.56(d,J＝12.0Hz,1H),7.25(t,J＝7.6Hz,1H),7.04(d,＝12.0Hz,1H),4.15-4.06(m,1H),3.75-3.69(m,1H),3.60-3.52(m,2H),3.49-3.45(m,1H),2.79-2.58(m,3H),2.41-2.32(m,2H),1.69-1.61(m,1H),1.45-1.37(m,1H),1.34-1.26(m,2H),1.10-1.06(m,3H),0.93-0.86(m,3H).
EXAMPLE 13 Synthesis of BX20-6-019
First step, S3-011 synthesis
According to example 8, S3-011 is synthesized.
Second step, synthesis of BX20-6-019
The synthetic route is shown in the following formula:
Compounds S3-011 (62 mg,0.20mmol, crude product), cyclopropanecarboxylic acid (32 mg,4.00 mmol), T3P (50% ethyl acetate solution, 700mg,1.20 mmol) and TEA (76.0 mg,0.80 mmol) were added sequentially to DMF (1.0 mL) at 0deg.C and the reaction mixture was stirred for 12h at 20deg.C. After the reaction, water (5.0 mL) was added and extracted with ethyl acetate (20.0 mL x 3), the organic phase was dried and concentrated at 40 ℃ under reduced pressure, and the residue was isolated by preparative separation to give compound BX20-6-019 (10 mg, yield 14.9%) as a white powder. m/z=398.2 [ m+h ] +.
1H NMR(400MHz,DMSO-d6)＝8.48(s,1H),7.44(d,J＝7.6Hz,2H),7.19(d,J＝7.6Hz,2H),6.28(d,J＝4.0Hz,1H),4.12-4.08(m,1H),3.79(t,J＝8.0Hz,1H),3.50-3.40(m,2H),3.16-3.12(m,1H),2.82-2.78(m,1H),2.71-2.66(m,1H),1.78-1.65(m,5H),0.71-0.61(m,4H).
EXAMPLE 14 Synthesis of BX20-6-020
First step, S3-012 synthesis
Compound S3-012 was synthesized according to the first and second steps of example 9.
Second step, synthesizing BX20-6-020
The synthetic route is shown in the following formula:
Compound S3-012 (0.45 g, crude product, hydrochloride), cyclopropanecarboxylic acid (0.21 g,2.46 mmol), T3P (50% ethyl acetate solution, 3.90g,6.20 mmol) and TEA (626 mg,6.20 mmol) were added sequentially to DMF (10 mL) and the reaction mixture stirred at 40 ℃ for 5h. After the reaction, water (80 mL) was added, ethyl acetate (35 mL. Times.3) was extracted, and the organic phase was dried, concentrated under reduced pressure at 40℃and purified by preparative separation (formic acid system), and after lyophilization, compound BX20-6-020 (180 mg, yield 36.8%) was obtained as a white powder.
1H NMR(400MHz,DMSO-d6)＝8.50(s,1H),7.47(d,J＝7.6Hz,2H),7.20(d,J＝7.6Hz,2H),6.37(d,J＝4.0Hz,1H),4.03-3.99(m,1H),3.74(t,J＝8.8Hz,1H),3.57-3.55(m,1H),3.46-3.44(m,1H),2.67-2.53(m,2H),2.23-2.18(m,2H),1.78-1.78(m,1H),1.30-1.20(m,2H),0.71-0.61(m,4H).
EXAMPLE 15 Synthesis of BX20-6-021
First step, S3-021 synthesis
The synthetic route is shown in the following formula:
MeMgCl (3M, 10.4mL,31.2 mmol) was slowly added dropwise to a solution of S1-021 (4.37 g,25.8 mmol) and Ti (OiPr) 4 (9.20 mL,30.9 mmol) in THF (70 mL) at 0deg.C, and after stirring for 15 min, a solution of S2-021 (6.98 g,30.9 mmol) in THF (25 mL) was added. Finally, cyMgBr (2M, 25.8mL,51.6 mmol) was slowly added dropwise at 0 ℃. After the completion of the dropwise addition, the reaction was refluxed for 15 minutes, and H 2 O (18 mL) was added after cooling, followed by stirring at room temperature for 1 hour. After filtration through celite and drying of the filtrate, concentration under reduced pressure at 40℃was carried out, and the residue was purified by column chromatography (PE/EA=10/1 to 5/1, V/V) to give Compound S3-021 (2.00 g, yield 20.5%) as a pale yellow oil, m/z=379.3 [ M+H ] +.
Second step, S4-021 synthesis
The synthetic route is shown in the following formula:
s3-021 (2.00 g,5.20 mmol) was dissolved in MeOH (25 mL) at room temperature, pd/C (10%, 600 mg) was added, the reaction system was replaced with hydrogen, stirred under hydrogen atmosphere for 48 hours, the reaction was completed, the reaction solution was filtered, and the crude product of pale yellow oily compound S4-021 (1.20 g) was directly concentrated under reduced pressure at 40℃to give m/z=199.2 [ M+H ] +.
Third step, synthesizing intermediate S6-021
The synthetic route is shown in the following formula:
A solution of compound S1-011 (700 mg,3.45 mmol) in DCM (5.0 mL) was slowly added dropwise to a solution of compound S4-021 (500 mg, crude product), TEA (300 mg,2.96 mmol) in DCM at-78℃and the reaction mixture was reacted at 0℃for 3h. After the reaction was completed, the reaction system was quenched with 2 drops of water, and the reaction mixture was concentrated directly at 40℃under reduced pressure, and the residue was purified by column chromatography (PE/EA=3/1 to 1/1, V/V) to give Compound S6-021 (525 mg, yield 52.0%) as a white solid, m/z=402.3 [ M+H ] +.
Fourth step, S7-021 synthesis
The synthetic route is shown in the following formula:
compound S6-021 (500 mg,1.24 mmol) was dissolved in MeOH (10.0 mL) and HCl/1, 4-dioxane (1, 4-dioxane) (4M, 2.00 mL) was added and stirred at room temperature for 3 hours. After the reaction, the mixture was concentrated directly at 40℃under reduced pressure to give compound S7-021 (400 mg, crude hydrochloride) as a white solid, m/z=302.3 [ M+H ] +.
Fifth step, synthesis of BX20-6-021
The synthetic route is shown in the following formula:
Compounds S7-021 (400 mg, crude hydrochloride), S8-021 (250 mg,2.50 mmol), T3P (50% strength by mass in ethyl acetate T3P, 2.40g,4.00 mmol) and TEA (505 mg,5.00 mmol) were added sequentially to DMF (10 mL) at 0deg.C and the reaction mixture stirred at room temperature for 16h. After the reaction, water (80 mL) was added, ethyl acetate (35 mL. Times.3) was extracted, and the organic phase was dried, concentrated under reduced pressure at 40℃and purified by preparative separation (hydrochloric acid system), and after lyophilization, the white powdery compound BX20-6-021 (133 mg, yield 29.2%) was obtained. m/z=386.2 [ m+h ] +.
1H NMR(400MHz,DMSO-d6)δ＝8.59(d,J＝3.6Hz,1H),7.50(dd,J＝9.2Hz,2.0Hz,2H),7.22(d,J＝8.8Hz,2H),6.51(s,1H),3.75-3.58(m,3H),3.33-3.28(m,1H),2.45-2.38(m,1H),2.23-2.20(m,1H),1.78-1.75(m,1H),1.70-1.66(m,1H),1.56-1.45(m,1H),1.31-1.21(m,1H),0.95(dd,J＝6.8Hz,2.4Hz,3H),0.80(q,J＝7.2Hz,3H).
EXAMPLE 16 Synthesis of BX20-6-022
First step, S3-022 synthesis
The synthetic route is shown in the following formula:
S1-0110226 mg,1.10 mmol) was dissolved in anhydrous DCM (1.5 mL), nitrogen was replaced and the solution was cooled to-78 ℃. S2-022 (200 mg,1.00 mmol), TEA (204 mg,2.00 mmol) was dissolved in anhydrous DCM (1.5 mL) to prepare solution A, the solution A was added dropwise to the reaction solution, the reaction solution was slowly returned to room temperature after the dropwise addition, and stirring was continued for 4 hours. After completion of the reaction, quenched with water (30.0 mL), extracted with DCM (50.0 mL x 2) to give an organic phase which, after drying, is concentrated under reduced pressure at 40 ℃, the residue is purified by chromatography (PE/ea=5/1 to 2/1, V/V) to give compound S3-022 (250 mg, yield 61.7%) as a white solid, m/z=402.2 [ m+h ] +.
Second step S4-022 synthesis
The synthetic route is shown in the following formula:
S3-022 (250 mg,0.60 mmol) was dissolved in MeOH (2.0 mL) at room temperature, HCl/EA (2M, 3.0 mL) was added and stirred for 2 hours. After the reaction, the reaction mixture was directly concentrated at 40℃under reduced pressure to give compound S4-022 (188 mg, crude product, hydrochloride) as a white solid, m/z=302.1 [ M+H ] +.
Third step, synthesis of BX20-6-022
The synthetic route is shown in the following formula:
Compounds S4-022 (188 mg,0.60mmol, crude product), (S) - (+) -2-methylbutanoic acid (128 mg,1.20 mmol), T3P (50% strength by mass in ethyl acetate solution of T3P, 2.40g,3.60 mmol) and TEA (252 mg,2.4. Mmol) were added sequentially to DMF (4.0 mL) at 0deg.C and the reaction mixture stirred for 16h at 20deg.C. After completion of the reaction, water (30.0 mL) was added and extracted with ethyl acetate (10.0 mL of x 3), the organic phase was dried and concentrated at 40 ℃ under reduced pressure, and the residue was isolated by preparative separation to give compound BX20-6-022 (103 mg, yield 42.9%) as a white powder, m/z=386.2 [ m+h ] +.
1H NMR(400MHz,DMSO-d6)＝8.68(s,1H),7.48(d,J＝8.0Hz,1H),7.19(d,J＝12.0Hz,1H),6.60(s,1H),3.73-3.59(m,3H),3.28-3.26(m,1H),2.43-2.36(m,1H),2.19(d,J＝1.6Hz,1H),1.75-1.72(m,1H),1.67-1.64(m,1H),1.52-1.45(m,1H),1.26-1.22(m,1H),0.93(dd,J＝4.0Hz,3H),0.80-0.74(m,3H).
EXAMPLE 17 Synthesis of BX20-6-030
The synthetic route is shown in the following formula:
Triphosgene (365 mg,1.24 mmol) was added to the three-necked flask, nitrogen was replaced, anhydrous DCM (20 mL) was added, cooled to-78℃and then a solution of XR02-S4 (605 mg,2.76 mmol) and TEA (1 mL) in DCM (5.0 mL) was slowly added dropwise. After the reaction solution was naturally warmed to-10 ℃, stirring was continued under ice bath for 1 hour to obtain a solution of intermediate XR 020007-I01. Cooled to-78 ℃, int-1 (600 mg,2.30 mmol) and TEA (1.3 mL) in DCM (5 mL) were added dropwise to intermediate XR020007-I01 in DCM. After the completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour, quenched with water, concentrated at 40℃under reduced pressure, and the residue was purified by column chromatography (PE/EA=3/1 to 1/1, V/V) to give a crude product (620 mg, yield 51.5%, purity 90%). 150mg of crude product was purified by preparative separation (formic acid system) and lyophilized to give compound BX20-6-030 (60 mg, yield 22.0%) as a white powder. m/z=472.2 [ m+h ] +.
1H NMR(400MHz,DMSO-d6)δ＝8.97(s,1H),7.72(d,J＝9.2Hz,2H),7.55(d,J＝8.8Hz,2H),6.56(d,J＝7.2Hz,1H),4.12-4.07(m,1H),3.47-3.42(m,2H),3.04(dd,J＝11.6、3.6Hz,2H),2.72(s,2H),1.76-1.65(m,4H),1.34(s,9H).
Example 18 Synthesis of BX20-6-031
The synthetic route is shown in the following formula:
The compound triphosgene (0.49 g,1.64 mmol) was dissolved in anhydrous DCM (10 mL) as mixture A, replaced with N 2 for protection, cooled to-78℃and then XR02-S4 (0.80 g,3.65 mmol) was dissolved in anhydrous DCM (10 mL) as mixture B. The mixed solution B is taken by a syringe and slowly added into the mixed solution A at the temperature of minus 78 ℃, and after the dripping, the mixed solution is heated to 0 ℃ for reaction for 1h. Int-2 (0.73 g,3.29 mmol) was taken, TEA (1.5 mL) was dissolved in anhydrous DCM (15 mL), and the solution was added dropwise to the reaction solution AB at-78℃and stirred for 2h. After the reaction, the reaction solution was directly concentrated under reduced pressure at 40 ℃, and the obtained residue was purified by silica gel column chromatography (PE: ea=3:1 to 1:3) to obtain 620mg of the objective product, wherein 110mg was lyophilized to obtain white powdery compound BX20-6-031 (90 mg, 38.7%). m/z=472.1 [ m+h ] +.
1H NMR(400MHz,DMSO-d6)δ＝8.80(s,1H),7.71-7.69(m,2H),7.54-7.52(m,2H),6.47-6.45(m,1H),3.97-3.95(m,1H),3.36-3.43(m,2H),3.17-3.14(m,2H),2.52(s,2H),2.19-2.13(m,2H),1.38(s,9H),1.23-1.20(m,2H).
Example 19 Synthesis of BX20-6-028
First step, synthesis of BX20-6-030
According to example 16, compound BX20-6-030 was synthesized.
Second step, XR020028-I01 Synthesis
The synthetic route is shown in the following formula:
Compound BX20-6-030 (470 mg,0.86 mmol) was dissolved in MeOH (10.0 mL) and HCl/EA (2M, 2.5 mL) was added and the reaction stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated directly at 40℃under reduced pressure to give XR020028-I01 (450 mg, crude, hydrochloride) as a yellow solid, m/z=372.1 [ M+H ] +.
Third step, synthesis of BX20-6-028
The synthetic route is shown in the following formula:
The compound (R) -2-methylbutanoic acid (60 mg,0.59mmo 1), HATU (220 mg,0.58 mmol) and TEA (157 mg,1.55 mmol) were added to DMF (3 mL) and after stirring at room temperature for 10 min XR020028-I01 (200 mg,0.49mmol, crude, hydrochloride) was added and the reaction mixture stirred at room temperature for 2h. After the reaction, water (30 mL) was added, ethyl acetate (25 ml×3) was extracted to obtain an organic phase, which was dried, concentrated under reduced pressure at 40 ℃, and the residue was purified by column chromatography (PE/ea=1/1 to 1/3, V/V) to obtain a crude product, which was purified by preparative separation (formic acid system), and lyophilized to obtain compound BX20-6-028 (50 mg, yield 33.0%) as a white powder. m/z=456.2 [ m+h ] +.
1H NMR(400MHz,DMSO-d6)δ＝8.88(s,1H),7.74-7.70(m,2H),7.54(d,J＝8.8Hz,2H),6.49(d,J＝6.8Hz,1H),4.13-4.07(m,1H),3.69-3.64(m,1H),3.52-3.47(m,1H),3.32-3.27(m,1H),3.19(dd,J＝12.8、4.8Hz,1H),2.82-2.77(m,1H),2.73-2.67(m,1H),1.81-1.66(m,4H),1.57-1.49(m,1H),1.32-1.23(m,2H),0.97(q,J＝6.8Hz,3H),0.85-0.78(m,3H).
Example 20 Synthesis of BX20-6-029
First step, synthesis of BX20-6-031
Compound BX20-6-031 was synthesized according to example 17.
Second step, XR020029-I01 Synthesis
The synthetic route is shown in the following formula:
Compound BX20-6-031 (0.51 g,1.08 mmol) was dissolved in MeOH (10 mL), HCl/dioxane (2.5 mL, 4M) was added dropwise, and the reaction mixture was stirred at room temperature for 3h. After the reaction, the reaction mixture was concentrated directly at 40℃under reduced pressure to give a yellow solid compound XR020029-I01 (0.44 g, crude). m/z=408.09 [ m+h ] +.
Third step, synthesis of BX20-6-029
The synthetic route is shown in the following formula:
The compound (S) - (+) -2-methylbutanoic acid (0.13 g,1.27 mmol), HATU (0.49 g,1.30 mmol), TEA (0.40 g,3.90 mmol) were added sequentially to DMF (5 mL) as a mixture A, and the reaction mixture A was stirred at room temperature for 10min. After the reaction, XR020029-I01 (0.44 g,1.08 mmol) and TEA (0.40 g,3.90 mmol) were added to DMF (5 mL) and the mixture was stirred for 5min, and then the mixture was added dropwise to the mixture A via syringe, and the reaction was stirred overnight for 12h. After the reaction, the reaction mixture was concentrated directly at 40℃under reduced pressure to give a residue, which was purified by preparative separation (formic acid system) and lyophilized to give compound BX20-6-029 (270 mg, yield 55%) as a white powder. m/z=456.17 [ m+h ] +.
1H NMR(400MHz,DMSO-d6)δ＝8.87-8.86(m,1H),7.73-7.71(m,2H),7.56-7.54(m,2H),6.56-6.54(m,1H),4.00-3.98(m,1H),3.62-3.57(m,1H),3.44-3.39(m,2H),2.66-2.62(m,1H),2.58-2.53(m,2H),2.25-2.16(m,2H),1.58-1.50(m,1H),1.38-1.12(m,4H),1.00-0.96(dd,J＝12.0,4.0Hz,3H),0.85-0.78(m,3H).
Example 21 Synthesis of BX20-6-039
First step, S3 synthesis
The synthetic route is shown in the following formula:
Di (trichloromethyl) carbonate (178 mg,0.6 mmol) was added to a three-necked flask, nitrogen was replaced, anhydrous DCM (10 mL) was added, the temperature was reduced to-78℃and a solution of S1 (2910 mg,1.33 mmol) and TEA (403 mg,3.99 mmol) in DCM (5.0 mL) was slowly added dropwise. After the reaction solution was naturally warmed to-10 ℃, stirring was continued under ice bath for 1 hour to obtain a solution of intermediate S2. A solution of Int-1 (300 mg,1.33 mmol) and TEA (403 mg,3.99 mmol) in DCM (5 mL) was added dropwise to a solution of intermediate S2 in DCM, cooled to-78 ℃. After the completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour. After the reaction, the organic phase was concentrated under reduced pressure after water quenching and ethyl acetate extraction, and the residue was purified by column chromatography (PE/ea=3/1 to 2/1, V/V) to give the product S3 (498 mg, yield 79.6%) as a pale yellow solid. MS (ESI, m/z) 472.2[ M+H ] +.
Second step, the synthesis of intermediate S4
The synthetic route is shown in the following formula:
The procedure is to dissolve compound S3 (498 mg,1.05 mmol) in MeOH (10.0 mL) and then add HCl/1,4-dioxane (4M, 2.5mL,10.0 mmol) and stir at room temperature for 3 hours. After the reaction, the mixture was concentrated directly under reduced pressure to give S4 (400 mg, eude) as a yellow solid. MS (ESI, m/z) 372.2[ M+H ] +.
Third step, synthesis of BX20-6-039
The synthetic route is shown in the following formula:
Method Compound S4 (400 mg, crop), dimethyl pyrocarbonate (147 mg,1.1 mmol), TEA (320 mg,3.2 mmol) were added to DCM (10 mL) at 0deg.C and the reaction mixture stirred at room temperature for 12h. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and purified by preparation (formic acid system) to give Compound BX20-6-039 (295 mg, yield 62.5%) as a white powder. MS (ESI, m/z) 430.1[ M+H ] +.
1H NMR(400MHz,METHANOL-d4)δ 7.68-7.64(m,2H),7.50(d,J＝8.8Hz,2H),4.26-4.19(m,1H),3.67(s,3H),3.60-3.56(m,2H),3.25-3.22(m,2H),2.84(brs,2H),1.91-1.75(m,4H).
Example 22 Synthesis of BX 20-6-040:
first step, S3' synthesis
The synthetic route is shown in the following formula:
Di (trichloromethyl) carbonate (178 mg,0.6 mmol) was added to a three-necked flask, nitrogen was replaced, anhydrous DCM (10 mL) was added, the temperature was reduced to-78℃and a solution of S1 (2910 mg,1.33 mmol) and TEA (403 mg,3.99 mmol) in DCM (5.0 mL) was slowly added dropwise. After the reaction solution was naturally warmed to-10 ℃, stirring was continued under ice bath for 1 hour to obtain a solution of intermediate S2. Cooling to-78 ℃, int-1' (300 mg,1.33 mmol) and TEA (403 mg,3.99 mmol) in DCM (5 mL) were added dropwise to intermediate S2 in DCM. After the completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour. After the reaction, the organic phase was concentrated under reduced pressure after water quenching and ethyl acetate extraction, and the residue was purified by column chromatography (PE/ea=3/1 to 2/1, V/V) to give the product S3' (500 mg, yield 79.8%) as a pale yellow solid. MS (ESI, m/z) 472.2[ M+H ] +.
Second step, synthesizing intermediate S4
The synthetic route is shown in the following formula:
The procedure is to dissolve compound S3' (500 mg,1.06 mmol) in MeOH (10.0 mL) and then add HCl/1,4-dioxane (4M, 2.5mL,10.0 mmol) and stir at room temperature for 3 hours. After the reaction, the mixture was concentrated under reduced pressure to give S4' (400 mg, crude product) as a yellow solid. MS (ESI, m/z) 372.2[ M+H ] +.
Third step, synthesizing BX20-6-040
The synthetic route is shown in the following formula:
Method Compound S4' (400 mg, crude) dimethyl pyrocarbonate (147 mg,1.1 mmol), TEA (320 mg,3.2 mmol) was added to DCM (10 mL) at 0deg.C and the reaction mixture stirred at room temperature for 12h. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and purified by preparation (formic acid system) to give Compound BX20-6-040 (323 mg, yield 68.4%) as a white powder. MS (ESI, m/z) 430.2[ M+H ] +.
1H NMR(400MHz,DMSO-d4)δ 8.88(s,1H),7.74-7.70(m,2H),7.56(d,J＝8.8Hz,2H),6.51(d,J＝7.6Hz,1H),4.03-3.93(m,1H),3.58(s,3H),3.42(dd,J＝10.8Hz,J＝7.6Hz,2H),3.23(dd,J＝10.8Hz,J＝2.8Hz,2H),2.57(brs,2H),2.22-2.15(m,2H),1.27-1.19(m,2H).
Biological test evaluation
The invention is explained below in further detail in connection with test examples
Test example 1 test of the inhibitory Activity of the Compounds of the invention against human soluble cyclooxygenase (IC 50)
1. Purpose of experiment
The IC 50 values of the compounds of the invention for human recombinant soluble cyclooxygenase (sEH) inhibitory activity were determined using a sensitive fluorescence-based assay.
2. Laboratory instrument and reagent
2.1 Experimental sample
The embodiment of the invention and the reference compound are self-made.
2.2 Laboratory apparatus
Multifunctional enzyme label instrument (Tecan Spark 20M)
Microplate incubator (Thermo; PST-60 HL-4)
384 Kong Baiban (Cisbio 66PL 384025)
2.3 Experimental reagents
3-Phenyl-cyano (6-methoxy-2-naphthyl) methyl ester-2-oxiraneacetic acid (PHOME) (Cayman)
AUDA (Positive compound) (Cayman)
Tris Buffer (Tris-hydroxy methyl aminomethane hydrochloride) (pH 7.0,25mM, sigma)
Human soluble cyclooxygenase (hsEH) (Cayman)
3. Experimental procedure
Determination of IC50 values using sensitive fluorescence-based assays
1) HsEH formulated with Tris Buffer (Tris hydrochloride Buffer) at 2. Mu.g/mL was added to 384 blackboard at 8. Mu.L/well (final concentration 1. Mu.g/mL).
2) The formulated compound and positive control were then added to the plate at 4 μl/well. After mixing, the mixture was centrifuged at 1000rpm for 1min. Incubate at 30 ℃ for 5min. Positive (no compound added) and negative control wells (no sEH added) were set simultaneously.
3) The formulated fluorogenic substrate PHOME was then added to the plate at 4 μl/well ([ S ] = 1 μΜ). After mixing, the mixture was centrifuged at 1000rpm for 1min. Incubate at 30 ℃ for 15min.
4) The detection of the machine is carried out, wherein the excitation wavelength is 330nm, and the emission wavelength is 465nm.
4. Data analysis
Using GRAPHPAD PRISM analysis of the data, IC 50 values for the compounds were calculated by fitting the percent inhibition and ten point concentration data to a parametric nonlinear logic formula.
5. Experimental results
The results of the test of the human soluble cyclooxygenase inhibiting activity of the compounds of the present invention are shown in Table 1.
TABLE 1
6. Conclusion of the experiment
According to the scheme, the compound disclosed by the invention has a good inhibition effect on recombinant human soluble cyclooxygenase.
Test example 2 in vivo pharmacokinetic assay of Compounds of the invention in SD rats
1. Purpose of test
The pharmacokinetic behavior of plasma in rats orally administered at a dose of 6mg/kg was studied in the compound example using SD rats as test animals.
2. Test method
2.1. Test drug
The embodiment of the invention and the reference compound are self-made.
2.2. Test animals
Male SPF-grade SD rats, body weight (200+ -20) g, st Bei Fu (Beijing) Biotechnology Co., ltd., animal production license number SCXK (Beijing) 2019-0010.
2.3. Preparation of test drug
The medicine is prepared, the concentration of the prepared medicine is 0.3mg/mL or 0.6mg/mL, and the prepared solution is 0.5 percent CMC solution.
The preparation is carried out by weighing 4.5mg or 9mg of each drug by a precise balance of one part per million, and uniformly suspending in 15mL of 0.5% CMC solution. Care is taken to prevent the drug from adhering to the stirring rod or tube wall during the drug formulation process.
2.4. Administration:
Male SPF SD rats were fed with the drug for 3-4 days, and then were fed by gastric lavage with a dose of 6mg/kg and a drug delivery volume of 10mL/kg.
2.5. Sample collection
Before (0 h) and after administration, rats are subjected to blood sampling at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h and 24h, the rats are subjected to fundus puncture blood sampling, the blood sampling amount is about 0.5mL, the rats are placed in an EDTA-K2 anticoagulation test tube with a labeled, the blood sampling tube is immediately and lightly reversed for 3 times to be uniformly mixed with the anticoagulation agent, the rats are immediately and uniformly placed in an ice-water bath at 4500rpm under the condition of 4 ℃, the rats are centrifuged for 10min, and after the centrifugation operation is finished, blood plasma is taken and timely packaged in an EP tube with the labeled corresponding label, and the blood plasma is stored in a refrigerator at-80 ℃.
2.6. Sample detection
The concentration of example X and example Y in plasma after administration was determined in this experiment using a simplified validated HPLC-MS/MS method.
2.6.1. Sample treatment, namely taking 2 mu L of blank plasma in a 96 deep hole plate, adding 400 mu L of precipitator methanol, swirling for 10min, centrifuging for 15min at 4000rpm, taking 250 mu L of supernatant in the 96 deep hole plate, and carrying out HPLC-MS/MS analysis, wherein the sample injection volume is 5 mu L.
2.6.2. Liquid analysis:
1) Liquid phase conditions
Waters XSelect CHS C18, 2.150 mm,1.8 μm, 154;
pre-column, namely a Waters online filter;
mobile phase A0.1% formic acid &5mM ammonium acetate in water;
mobile phase B is 0.1% acetonitrile formate solution;
flow Rate (Flow Rate) 0.6mL/min;
column temperature (Column Temperature) 40 ℃;
autoinjector Temperature (SAMPLE TRAY Temperature): 4 ℃;
sample Volume (Injection Volume) 5.0 μl;
An automatic sample injection cleaning mode (Rinse Mode) before sample injection and after sample injection (Before and after aspiration);
The needle washing volume (Rinsing Volume) of the automatic injector is 500.0 mu L;
Soaking time (RINSE DIP TIME) of the automatic injector during cleaning of the sample injection needle is 5sec;
An automatic injector sample needle cleaning method (Rinse Method) Rinse Port Only;
the cleaning time RINSE TIME of the sample injection needle of the automatic sample injector is 2sec
The autosampler cleaning solution (Rinse Pump and Port Wash Solution) is a 50% acetonitrile in water.
Elution mode gradient elution
2) Mass spectrometry conditions:
Ion source Electrospray Ionization (ESI);
Ionization mode (Ionization) Positive ion mode (Positive);
Detection Mode (Mode) multiple reaction detection (MRM);
collision cell gas (CAD): 8psi;
Curtain Gas (CurtainGas Type) 40psi;
atomizing gas (GS 1) 50psi;
auxiliary gas (GS 2) of 50 to 60psi;
The electrospray voltage (Ion Spray Voltage) is 4500V;
the vortex ion spraying temperature (Turbo Ion Spray Temperature) is 600-650 ℃;
Mass spectrum resolution: unit;
3. Test results and analysis
The main pharmacokinetic parameters were calculated using WinNonlin 7.0 and the rat pharmacokinetic results are shown in table 2 below.
TABLE 2 rat drug substitution test results (6 mg/kg dose)
4. Conclusion of the experiment
From the results of the rat drug generation test in the table, the examples of the present invention show better metabolic properties than the reference compounds.
Claims (25)
1. A compound shown as a formula I-2 or pharmaceutically acceptable salt thereof is characterized in that,
Wherein ring A is a 5-membered cycloalkane, n is 0, 1,2 or 3;
R 3 is independently "C 1-C6 alkyl substituted with 1 or more halogens", "C 1-C6 alkoxy substituted with 1 or more halogens", halogen or sulfur pentafluoride;
R 2 is hydrogen, C 1-C6 alkyl, Phenyl or "phenyl substituted by 1 or more carboxyl groups"; R 2-1 is hydrogen,C 3-C6 cycloalkyl or C 1-C6 alkyl, R 2-1-1 is C 1-C6 alkyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein in R 3, the C 1-C6 alkyl in the "C 1-C6 alkyl substituted with 1 or more halogens" is C 1-C4 alkyl;
Or, in R 3, the C 1-C6 alkoxy group in the "C 1-C6 alkoxy group substituted with 1 or more halogens" is a C 1-C4 alkoxy group;
or, in R 3, the halogen is fluorine, chlorine, bromine, or iodine;
or, in R 2, the C 1-C6 alkyl is C 1-C4 alkyl;
Or, in R 2-1, the C 1-C6 alkyl is C 1-C4 alkyl;
Or, in R 2-1, the C 3-C6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
Or, in R 2-1-1, the C 1-C6 alkyl is C 1-C4 alkyl;
alternatively, sulfur pentafluoride is located meta and/or para to the amide nitrogen.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein in R 3, the C 1-C6 alkyl in the "C 1-C6 alkyl substituted with 1 or more halogens" is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl;
Or, in R 3, the C 1-C6 alkoxy group in the "C 1-C6 alkoxy group substituted with 1 or more halogens" is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy;
Or, in R 3, the halogen is fluorine;
Or, in R 2, the C 1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl;
or, in R 2-1, the C 1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl;
or, in R 2-1, said C 3-C6 cycloalkyl is cyclopropyl;
Or, in R 2-1-1, the C 1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein in R 3, the C 1-C6 alkyl in the "C 1-C6 alkyl substituted with 1 or more halogens" is methyl;
Or, in R 3, C 1-C6 alkoxy in the "C 1-C6 alkoxy substituted by 1 or more halogens" is C 1-C4 alkoxy, and the C 1-C4 alkoxy is methyl oxygen;
or, in R 2-1, the C 1-C6 alkyl is isobutyl or isopropyl;
Or, in R 2-1-1, the C 1-C6 alkyl is tert-butyl.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein in R 3, the "C 1-C6 alkyl substituted with 1 or more halogens" is a trifluoro-substituted C 1-C4 alkyl;
Or, in R 3, the "C 1-C6 alkoxy substituted with 1 or more halogens" is a trifluoro-substituted C 1-C4 alkoxy.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein in R 3, the "C 1-C6 alkyl substituted with 1 or more halogens" is trifluoromethyl;
Or, in R 3, the "C 1-C6 alkoxy substituted with 1 or more halogens" is trifluoromethoxy.
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2;
Or, R 3 is independently "C 1-C6 alkyl substituted with 3 halogens", "C 1-C6 alkoxy substituted with 3 halogens", halogen or sulfur pentafluoride;
Or R 2 is hydrogen or
Or R 2-1 isC 3-C6 cycloalkyl or C 1-C6 alkyl;
or, R 2-1-1 is methyl.
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 is independently "C 1-C6 alkyl substituted with 3 halogens" or sulfur pentafluoride, or R 3 is independently "C 1-C6 alkyl substituted with 1 or more fluorine", "C 1-C6 alkoxy substituted with 1 or more halogens", halogen or sulfur pentafluoride;
or R 2 is
Or R 2-1 isOr C 1-C6 alkyl, or R 2-1 is C 3-C6 cycloalkyl or C 1-C6 alkyl.
9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2-1 isOr isopropyl.
10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein when R 3 is "C 1-C6 alkyl substituted with 3 halogens", R 2 isR 2-1 is isopropyl, and/or R 2 is when R 3 is sulfur pentafluorideR 2-1 isR 2-1-1 is methyl.
11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I-2 is defined by scheme 1, scheme 2, scheme 3, scheme 4, or scheme 5:
Scheme 1,
Ring A is a 5-membered cycloalkane, n is 1 or 2;R 3 is independently "C 1-C6 alkyl substituted with 3 halogens", "C 1-C6 alkoxy substituted with 3 halogens", halogen or sulfur pentafluoride ", R 2 is hydrogen orR 2-1 isC 3-C6 cycloalkyl or C 1-C6 alkyl, R 2-1-1 is C 1-C6 alkyl;
scheme 2,
The compound shown in the formula I-2 is shown in the formula I-2-1Wherein n is 1 or 2;R 3 is independently "C 1-C6 alkyl substituted with 3 halogens", "C 1-C6 alkoxy substituted with 3 halogens", halogen or sulfur pentafluoride; R 2 isR 2-1 isC 3-C6 cycloalkyl or C 1-C6 alkyl, R 2-1-1 is C 1-C6 alkyl;
Scheme 3,
The compound shown in the formula I-2 is shown in the formula I-2-2Wherein n is 1 or 2;R 3 is independently "C 1-C6 alkyl substituted with 1 or more fluoro", "C 1-C6 alkoxy substituted with 1 or more halogen", halogen or sulfur pentafluoride; R 2 isR 2-1 is C 3-C6 cycloalkyl or C 1-C6 alkyl;
Scheme 4,
N is 1 or 2;R 3 is sulfur pentafluoride, R 2 isR 2-1 isOr C 1-C6 alkyl, R 2-1-1 is C 1-C6 alkyl;
scheme 5,
N is 1 or 2;R 3 is independently "C 1-C6 alkyl substituted by 3 halogens" or sulfur pentafluoride, R 2 isR 2-1 isOr C 1-C6 alkyl, R 2-1-1 is C 1-C6 alkyl.
12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2;R 3 is sulfur pentafluoride, R 2 isR 2-1 isOr C 1-C6 alkyl, R 2-1-1 is C 1-C6 alkyl, sulfur pentafluoride is positioned at the meta position and/or the para position of amide nitrogen.
13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, boc,
Or, R 3 is fluoro, trifluoromethyl, trifluoromethoxy, or sulfur pentafluoride;
Or alternatively, the first and second heat exchangers may be, Is that
Or alternatively, the first and second heat exchangers may be,R 3 in the meta and/or para position to the amide nitrogen.
14. A compound or pharmaceutically acceptable salt thereof according to any one of claim 1 to 11,Is that
15. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I-2 is selected from any one of the following:
16. A compound shown as a formula I-3 or a salt thereof is characterized in that,
Wherein the ring A, n and R 3 are as defined in any one of claims 1 to 15.
17. A compound or salt thereof according to claim 16 wherein the salt is a salt of a compound as shown in I-3 with hydrochloric acid.
18. A compound or salt thereof according to claim 16, wherein the salt is a salt of a compound represented by I-3 with hydrochloric acid in a molar ratio of 1:1.
19. The compound or salt thereof according to claim 16, wherein the compound of formula I-3 is selected from any one of the following:
20. a preparation method of a compound shown as a formula I-2 is characterized in that the preparation method is scheme 1 or scheme 2,
The scheme 1 comprises the steps of carrying out condensation reaction of a compound shown as a formula II and an amine compound in a solvent in the presence of alkali, wherein the definition of a ring A, a ring n, a ring R 2 and a ring R 3 is as defined in any one of claims 1-15;
The scheme 2 comprises the following steps of carrying out amidation reaction of a compound shown as a formula I-3 or salt thereof and a compound shown as a formula I-4 in a solvent in the presence of a base, wherein R 2 is R 2-1, ring A, n and R 3 are as defined in any one of claims 1 to 15;
21. use of a substance Z for the preparation of a medicament for the treatment and/or prophylaxis of diseases which are associated with soluble cyclooxygenase, characterized in that the substance Z is a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.
22. The use according to claim 21, wherein the disease is hypertension, pain, cardiomyopathy, inflammation, adult respiratory distress syndrome, diabetic complications, kidney disease or raynaud's syndrome.
23. The use according to claim 22, wherein the pain is neuropathic pain and/or inflammatory pain;
the kidney disease is end stage kidney disease;
the hypertension is renal hypertension, liver hypertension or pulmonary hypertension;
The inflammation is arthritis, kidney inflammation, vascular inflammation or lung inflammation.
24. Use of a substance Z for the preparation of a soluble cyclooxygenase inhibitor, wherein said substance Z is a compound according to any one of claims 1-15 or a pharmaceutically acceptable salt thereof.
25. A pharmaceutical composition comprising a substance Z and a pharmaceutically acceptable adjuvant, wherein the substance Z is a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2021110965307 | 2021-09-16 | ||
| CN202111096530 | 2021-09-16 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115819319A CN115819319A (en) | 2023-03-21 |
| CN115819319B true CN115819319B (en) | 2025-02-28 |
Family
ID=85523725
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211140563.1A Active CN115819319B (en) | 2021-09-16 | 2022-09-16 | A kind of amide compound, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115819319B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115819326B (en) * | 2021-09-16 | 2025-04-08 | 武汉熙瑞医药科技有限公司 | Amide compound, preparation method and application thereof |
| WO2024105225A1 (en) | 2022-11-18 | 2024-05-23 | Universitat De Barcelona | Synergistic combinations of a sigma receptor 1 (s1r) antagonist and a soluble epoxide hydrolase inhibitor (sehi) and their use in the treatment of pain |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009086426A2 (en) * | 2007-12-28 | 2009-07-09 | Arete Therapeutics, Inc. | Soluble epoxide hydrolase inhibitors for the treatment of endothelial dysfunction |
| WO2010053829A1 (en) * | 2008-11-04 | 2010-05-14 | Arete Therapeutics, Inc. | Soluble epoxide hydrolase inhibitors for treatment of metabolic syndrome and related disorders |
| JP2018020989A (en) * | 2016-08-05 | 2018-02-08 | 宇部興産株式会社 | Urea compounds |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008517072A (en) * | 2004-10-20 | 2008-05-22 | ザ レジェンツ オブ ザ ユニバーシティー オブ カリフォルニア | Improved inhibitors of soluble epoxide hydrolase |
-
2022
- 2022-09-16 CN CN202211140563.1A patent/CN115819319B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009086426A2 (en) * | 2007-12-28 | 2009-07-09 | Arete Therapeutics, Inc. | Soluble epoxide hydrolase inhibitors for the treatment of endothelial dysfunction |
| WO2010053829A1 (en) * | 2008-11-04 | 2010-05-14 | Arete Therapeutics, Inc. | Soluble epoxide hydrolase inhibitors for treatment of metabolic syndrome and related disorders |
| JP2018020989A (en) * | 2016-08-05 | 2018-02-08 | 宇部興産株式会社 | Urea compounds |
Non-Patent Citations (1)
| Title |
|---|
| RN号1550480-26-6等;STN;《STN-REG》;20180314;3-57 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115819319A (en) | 2023-03-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN115819319B (en) | A kind of amide compound, preparation method and application thereof | |
| JP4102022B2 (en) | Substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors | |
| JP6078601B2 (en) | Aryl dihydropyridinones and piperidinones as MGAT2 inhibitors | |
| JP2024529839A (en) | NLRP3 Modulators | |
| FR2926554A1 (en) | New azabicyclic carboxamide compounds are transient receptor potential vanilloid type 1 receptor modulators, useful to treat e.g. pain, inflammation, metabolic disorders, depression, gynecological disorders, psoriasis and pruritus | |
| CN107108640A (en) | The synthesis of bruton's tyrosine kinase inhibitor | |
| CN102232069A (en) | N-acetylneuraminic acid compound, its pharmaceutical composition and its preparation method and application | |
| CN112592331A (en) | Oseltamivir PROTAC compound, preparation method thereof and application thereof in anti-influenza virus drugs | |
| EP0732334A1 (en) | Piperidine derivatives, process for their preparation and their therapeutic application | |
| US6191277B1 (en) | Hydroxypropylamide peptidomimetics as inhibitors of aspartyl proteases | |
| EP3983387B1 (en) | Sulfonylurea derivatives and uses thereof | |
| US20140051867A1 (en) | Synthesis of an antiviral compound | |
| CN110343088B (en) | A kind of derivative based on PARP inhibitor Niraparib and its preparation method and application | |
| WO2020192129A1 (en) | Method for preparing 2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl-1-ol and use thereof | |
| US7189852B2 (en) | Synthesis | |
| AU2011336217B2 (en) | KAT II inhibitors | |
| FR2903106A1 (en) | USES OF 2-BENZOYL IMIDAZOPYRIDINES IN THERAPEUTICS | |
| CA3104342A1 (en) | Polycyclic compounds as soluble epoxide hydrolase inhibitors | |
| WO2011065420A1 (en) | Method for manufacturing a 6-substituted-1-methyl-1h-benzimidazole derivative, and manufacturing intermediate from said method | |
| CN115819326B (en) | Amide compound, preparation method and application thereof | |
| CN115003300A (en) | JAK inhibitors | |
| TW202140457A (en) | Process for preparing a phthalazinone derivative and intermediates thereof | |
| TWI386395B (en) | Stereoselective synthesis of piperidine derivatives | |
| WO2015189862A1 (en) | Chiral amines, a process for preparation and use thereof | |
| WO2012157504A1 (en) | β-LACTAM COMPOUND AND METHOD FOR PRODUCING SAME |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |