CN116396284A - Benzo-seven-membered nitrogen-oxygen heterocyclic indole-2-carboxamide derivative, preparation method and application thereof - Google Patents
Benzo-seven-membered nitrogen-oxygen heterocyclic indole-2-carboxamide derivative, preparation method and application thereof Download PDFInfo
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- -1 nitrogen-oxygen heterocyclic indole-2-carboxamide derivative Chemical class 0.000 title claims abstract description 117
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
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- 101001109145 Homo sapiens Receptor-interacting serine/threonine-protein kinase 1 Proteins 0.000 claims abstract description 21
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- 230000035484 reaction time Effects 0.000 claims description 9
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The benzoheptamembered azacyclic indole-2-carboxamide derivative has a structure shown in the following formula (I):
wherein R is selected from the group consisting of-H, -F, -CH 3 ，‑CF 3 ，‑OCH 3 One of the groups Ph. The invention also provides a preparation method of the benzo-seven-membered nitrogen-oxygen heterocyclic indole-2-carboxamide derivative. The invention also provides the use of a benzoheptamembered azacyclic indole-2-carboxamide derivative as an RIPK1 inhibitor. The invention also provides a benzo seven-membered azacyclo indole-2-formylUse of amine derivatives in the preparation of a medicament for the treatment of multiple sclerosis. The benzo-seven-membered azacyclo-indole-2-carboxamide derivative can inhibit the activity of RIPK1, reduce inflammatory injury and can be used as a medicament for treating multiple sclerosis.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a benzo-seven-membered nitrogen-oxygen heterocyclic indole-2-carboxamide derivative, and a preparation method and application thereof.
Background
Multiple sclerosis (multiple sclerosis, MS) is a degenerative disease of the central nervous system (central nervous system, CNS) that results in focal inflammatory demyelination in the brain and spinal white matter, leading to motor and cognitive dysfunction.
MS is good for young and young people, has the average age of onset of disease of 30 years, has the characteristics of high recurrence rate and high disability rate, and is a main cause of dysfunction of nervous system and loss of labor force in young and young people. At present, more than 280 ten thousand people are ill in the global scope, about 4 ten thousand people in China suffer from the disease, the disease trend is in an increasing mode year by year, and the disease age tends to be low. MS is listed in the first rare disease catalogue of China in 2018, and the current first-push treatment method of MS gold at home and abroad is Disease Modification Treatment (DMT), only 10% of patients clinically receiving DMT treatment are still in a non-drug available state due to various reasons such as side effects and relapse caused by intermittent medication. Thus, there is an urgent need for new therapeutic approaches and strategies.
The receptor interacting protein 1 (RIP 1) kinase is a serine/threonine protein kinase, abbreviated as RIPK1, capable of participating in apoptosis and non-apoptotic cell death: necrotic apoptosis. RIPK1 kinase activity was originally thought to induce inflammation by controlling a highly inflammatory cell death form known as apoptosis, but later studies have shown that activated RIPK1 can also directly regulate inflammatory cytokine production and some forms of apoptosis. In addition, RIPK1 has been shown to be a key driver of inflammation downstream of other various pathways (FasL, TRAIL, TLR and TLR 4), in addition to acting downstream of TNF receptor 1 (TNFR 1). Studies have found that activation of RIPK1 kinase exists in pathological samples of neurodegenerative diseases such as MS and ALS. Inhibition of RIPK1 kinase activity may reduce necrotic apoptosis caused by TNF, etc., thereby exerting anti-inflammatory effects. Thus, the development of RIPK1 small molecule inhibitors may have broad therapeutic potential for neurodegenerative diseases such as multiple sclerosis.
Currently, there are many studies on RIPK1 inhibitors worldwide. Wherein, the RIPK1 inhibitor jointly developed by the Sainophenanthrene and the Denali Therapeutics and DNL747 is a small molecular inhibitor capable of penetrating the blood brain barrier (brain penetration) and is used for treating nerve diseases such as Multiple Sclerosis (MS), amyotrophic Lateral Sclerosis (ALS) and the like, and is currently in phase II clinical study. As another example, application No. 202180029050.0, title of the invention is ecliptionb for the treatment of a condition involving systemic excessive inflammatory response, the proposed RIPK1 inhibitor regimen is a RIPK1 inhibitor comprising administering to a subject in need thereof an agent comprising (S) -5-benzyl-N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydropyrido [3,2-b ] [1,4] oxazepin-3-yl) -4H-1,2, 4-triazole-3-carboxamide and/or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof.
Disclosure of Invention
Aiming at the wide therapeutic potential of RIPK1 small molecule inhibitors, the invention provides a benzo-seven-membered nitrogen oxygen heterocyclic indole-2-carboxamide derivative which is different from the existing RIPK1 inhibitors, a preparation method thereof and application thereof.
In order to achieve the above object, the present invention provides the following technical solutions:
the benzoheptamembered azacyclic indole-2-carboxamide derivative of the invention specifically comprises: n- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7-phenyl-1H-indole-2-carboxamide derivative having the structure shown in formula (I):
wherein R is selected from the group consisting of-H, -F, -CH 3 ，-CF 3 ，-OCH 3 One of the groups Ph.
Preferably, the-F group comprises:
a single substituent: 2-F,3-F, 4-F;
or a di-substituent: 2-CH 3 ，3-CH 3 ；2-CH 3 ，4-CH 3 ；2-CH 3 ，5-CH 3 ；2-CH 3 ，6-CH 3 ；3-CH 3 ，4-CH 3 One of the above combinations;
the-CH 3 A group comprising:
a single substituent: 2-CH 3 ，3-CH 3 ，4-CH 3 One of them;
or a di-substituent: 2-CH 3 ，3-CH 3 ；2-CH 3 ，4-CH 3 ；2-CH 3 ，5-CH 3 ；2-CH 3 ，6-CH 3 ；3-CH 3 ，4-CH 3 One of the above combinations;
the-OCH 3 A group comprising: 2-OCH 3 ，3-OCH 3 ，4-OCH 3 One of them;
the-Ph group comprises: one of 2-Ph,3-Ph, 4-Ph.
Further preferably, the N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7-phenyl-1H-indole-2-carboxamide derivative of the present invention is selected from:
compound one: (S) -7- (4-fluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound two: (S) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7-phenyl-1H-indole-2-carboxamide having the structural formula:
or compound three: (S) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7- (p-tolyl) -1H-indole-2-carboxamide;
or compound four: (S) -7- (2-fluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound five: (S) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7- (m-tolyl) -1H-indole-2-carboxamide having the structural formula:
or compound six: (S) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-3-yl) -7- (2- (trifluoromethyl) phenyl) -1H-indole-2-carboxamide having the formula;
or compound seven: (S) -7- (2-methoxyphenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound eight: (S) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-3-yl) -7- (4- (trifluoromethyl) phenyl) -1H-indole-2-carboxamide having the formula:
or compound nine: (S) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-3-yl) -7- (3- (trifluoromethyl) phenyl) -1H-indole-2-carboxamide having the formula:
or compound ten: (S) -7- (4-methoxyphenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound eleven: (S) -7- (3-methoxyphenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound twelve: (S) -7- (3-fluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound thirteen: (S) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7- (o-tolyl) -1H-indole-2-carboxamide having the structural formula:
or compound fourteen: (S) -7- ([ 1,1' -biphenyl ] -4-yl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound pentadec: (S) -7- ([ 1,1' -biphenyl ] -2-yl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound sixteen: (S) -7- ([ 1,1' -biphenyl ] -3-yl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound seventeen: (S) -7- (2, 3-dimethylphenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or the compound eighteen: (S) -7- (2, 6-dimethylphenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or nineteen compounds: (S) -7- (2, 4-dimethylphenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound twenty: (S) -7- (2, 5-dimethylphenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound twenty-one: (S) -7- (3, 4-dimethylphenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or the compound twenty-two: (S) -7- (2, 3-difluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or the compound twenty-three: (S) -7- (2, 4-difluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound twenty four: (S) -7- (2, 5-difluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound twenty-five: (S) -7- (2, 6-difluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound twenty-six: (S) -7- (3, 4-difluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
one of the above compounds.
The N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7-phenyl-1H-indole-2-carboxamide derivative is prepared by the following reaction:
the method comprises the following specific steps:
step S1: in an organic solvent, the compound of the formula (III) is taken as a raw material, and the compound is mixed with substituted phenylboronic acid, pd (Ph) 3 ) 4 And Cs 2 CO 3 Carrying out Suzuki coupling reaction to obtain a compound of the formula (IV):
step S2: the compound of the formula (IV) undergoes hydrolysis reaction with sodium hydroxide in a mixed solvent of water and ethanol to obtain a compound of the formula (V);
step S3: the compound of formula (V) is subjected to condensation reaction with HATU and DIPEA of formula (II) in an organic solvent to obtain the compound of formula (VI).
In step (1), the organic solvent is selected from DMF or dioxane, H 2 O; preferably, the organic solvent is dioxane, H 2 O，dioxane:H 2 The volume ratio of O is 4:1;
in the step (1), the reaction temperature is 25-100 ℃; the reaction temperature is preferably 100 ℃.
In the step (1), the reaction time is 1h-5h; the reaction time is preferably 3h.
In step (1), the compound of formula (II) is reacted with Pd (PPh) 3 ) 4 The amount of the substance ranges from 1:0.05 to 0.2; the preferred amount of material is 1:0.1.
in step (1), the compound of formula (II) is combined with Cs 2 CO 3 The amount of the substance ranges from 1:1.0 to 2.5; the preferred amount of material is 1:2.0.
in step (2), the organic solvent is selected from MeOH or EtOH, H 2 O; preferably, the organic solvent is selected from EtOH, H 2 O，EtOH：H 2 The volume ratio of O is 1:1.
In the step (2), the reaction temperature is 0-100 ℃; the preferred reaction temperature is 95 ℃.
In the step (2), the reaction time is 1-5h; the preferred reaction time is 2h.
In the step (3), the organic solvent is selected from DMF and DMSO; the preferred organic solvent is DMF.
In the step (3), the reaction temperature is 0-60 ℃; the preferred reaction temperature is 25 ℃.
In the step (3), the reaction time is 1h-5h; the preferred reaction time is 3h.
In step (3), the amount of the compound of formula (VII) and the substance of formula (II) ranges from 1:1.0 to 1.5; the preferred amount of material is 1:1.0.
in step (3), the amount of the compound of formula (IV) and HATU ranges from 1:1.0 to 1.5; the preferred amount of material is 1:1.0.
in step (3), the amount of the compound of formula (IV) and DIPEA is in the range of 1:1.0 to 3.0; the preferred amount of material is 1:2.5.
the invention also provides application of the benzo-seven-membered azacyclo-indole-2-carboxamide derivatives as RIPK1 inhibitors.
The invention also provides application of the benzo-seven-membered azacyclo-indole-2-carboxamide derivatives in preparing medicaments for treating multiple sclerosis.
The beneficial effects are that: the benzo-seven-membered azacyclo-indole-2-carboxamide derivative can inhibit the activity of RIPK1, reduce inflammatory injury and can be used as a medicament for treating multiple sclerosis.
Drawings
FIG. 1 is a graph showing the effect of example 1 on the expression of inflammatory cytokine IL-6.
Detailed Description
The present invention will be further described in detail with reference to the following specific examples. The procedures, conditions, experimental methods, etc. for carrying out the present invention are common knowledge and common knowledge in the art, except for the following specific references, and the present invention is not particularly limited.
The starting materials used in the examples below were all commercially available analytical pure chemicals.
The invention is further illustrated in connection with the figures and examples, and is not intended to be limiting in any way.
Example 1: preparation of (S) -7- (4-fluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide, compound one;
first, 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid ethyl ester (hereinafter referred to as 1 a) was prepared:
to each of the three bottles, 2 (100 mg,0.37 mmol), 4-fluorobenzeneboronic acid (62.4 mg,0.45 mmol) and Cs were added 2 CO 3 (242.0mg，0.74mmol)，Pd(PPh 3 ) 4 (43.8 mg,0.038 mmol) and 4mL of dioxane H under nitrogen are added 2 O (4:1), and heating to 100 ℃ for reaction for 3h. The reaction mixture was cooled to room temperature, 15mL of water was then added to extract with ethyl acetate (3×20 mL), and the organic phases were combined and washed with saturated brine (3×20 mL), and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude product. Purification by silica gel chromatography (petroleum ether/ethyl acetate=10:1) afforded 1a as a white solid 122mg (71%).
Secondly, 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid (hereinafter referred to as 1 b) is prepared:
1a (314 mg,1.08 mmol) was dissolved in 5ml EtOH:H 2 O (1:1) solution, magneticNaOH (10.8 mg,2.69 mmol) was added with vigorous stirring and the reaction mixture was stirred at 95℃for 2 hours. The reaction mixture was cooled to room temperature, 15mL of 5% hydrochloric acid was then added, ethyl acetate (3×20 mL) was added for extraction, and the organic phases were combined and washed with saturated brine (3×20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 274mg of crude product, which was directly used for the next reaction.
Preparation of (S) -7- (4-fluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide (hereinafter abbreviated as 1 c):
1b (274 g,1.08 mmol) and (S) -3-amino-5-methyl-2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5H) -one (224 mg,1.08 mmol) were dissolved in 5mL DMF and DIPEA (139.1 mg,2.69 mmol) and HATU (410 mg,1.08 mmol) were added with magnetic stirring and the reaction mixture stirred at room temperature for 3 hours. 10mL of water was added, followed by extraction with ethyl acetate (3X 20 mL), and the organic phases were combined, washed with saturated brine (3X 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. Purification by silica gel chromatography (petroleum ether/ethyl acetate=12:1) afforded 1c as a white solid 324mg (70%).
1b (274 g,1.08 mmol) and (S) -3-amino-5-methyl-2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5H) -one (224 mg,1.08 mmol) were dissolved in 5mL DMF and DIPEA (139.1 mg,2.69 mmol) and HATU (410 mg,1.08 mmol) were added with magnetic stirring and the reaction mixture stirred at room temperature for 3 hours. 10mL of water was added, followed by extraction with ethyl acetate (3X 20 mL), and the organic phases were combined, washed with saturated brine (3X 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. Purification by silica gel chromatography (petroleum ether/ethyl acetate=12:1) afforded 1c as a white solid 324mg (70%). The molecular formula of 1c is:
1 H NMR(400MHz,CDCl 3 )δ9.13(s,1H),8.01(d,J＝8.0Hz,1H),7.66–7.64(m,1H),7.39–7.36(m,2H),7.34–7.07(m,9H),5.20–5.13(m,1H),4.73–4.69(m,1H),4.41(t,J＝12.0Hz,1H)。
example 2, preparation of compound two. Compound II was prepared in substantially the same manner as in example 1 except that 7-phenyl-1H-indole-2-carboxylic acid (100 mg,0.42 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid, to give compound II as a white solid (125 mg, 72%). 1 H NMR(400MHz,CDCl 3 )δ9.11(s,1H),7.67(d,J＝8.0Hz,1H),7.62–7.56(m,2H),7.54–7.46(m,2H),7.44–7.24(m,8H),7.09–7.07(m,1H),5.12–4.99(m,1H),4.85–4.72(m,1H),4.28(t,J＝10.0Hz,1H),3.46(s,3H)。
Example 3 the procedure used for the preparation of compound three was substantially the same as in example 1, except that 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid (100 mg,0.40 mmol) was used instead of 7- (p-tolyl) -1H-indole-2-carboxylic acid, to give compound three as a white solid (121 mg, 70%). 1 H NMR(400MHz,CDCl 3 )δ9.12(s,1H),7.64(d,J＝8.0Hz,1H),7.47–7.42(m,3H),7.33–7.18(m,8H),7.08(d,J＝4.0Hz,1H),5.09–5.02(m,1H),4.80–4.75(m,1H),4.29(t,J＝12.0Hz,1H),3.45(s,3H),2.42(s,3H)。
Example 4 the procedure used for the preparation of compound four was substantially the same as in example 1, except that 7- (2-fluorophenyl) -1H-indole-2-carboxylic acid (100 mg,0.39 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give compound four as a white solid (113 mg, 67%). Delta 9.25 (s, 1H), 7.73-7.62 (m, 2H), 7.43-7.30 (m, 2H), 7.29-7.20 (m, 6H), 7.18-7.07 (m, 3H), 5.11-4.98 (m, 1H), 4.76-4.65 (m, 1H), 4.28 (t, j=10.0 hz, 1H), 3.39 (s, 3H).
Example 5 the procedure used for the preparation of compound five was substantially the same as in example 1, except that 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid (100 mg,0.40 mmol) was used instead of 7- (m-tolyl) -1H-indole-2-carboxylic acid, to give compound five as a white solid (118 mg, 68%). 1 H NMR(400MHz,CDCl 3 )δ9.09(s,1H),7.81(d,J＝8.0Hz,1H),7.62(d,J＝8.0Hz,1H),7.36–7.28(m,1H),7.28–7.12(m,9H),7.08(d,J＝1.9Hz,1H),5.16–5.09(m,1H),4.73–4.69(m,1H),4.36(t,J＝12.0Hz,1H),3.43(s,3H),2.39(s,3H)。
Example 6 the said compoundThe preparation of Compound six was identical to example 1, except that 7- (2- (trifluoromethyl) phenyl) -1H-indole-2-carboxylic acid (100 mg,0.33 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give Compound six as a white solid (102 mg, 65%). 1 H NMR(400MHz,CDCl 3 )δ9.16–9.05(m,1H),7.81–7.54(m,3H),7.52–7.29(m,3H),7.22–7.00(m,7H),5.02–4.90(m,1H),4.73–4.60(m,1H),4.34–4.17(m,1H),3.44–3.43(m,3H)。
Example 7 the procedure used for the preparation of compound seven was substantially the same as in example 1, except that 7- (2-methoxyphenyl) -1H-indole-2-carboxylic acid (100 mg,0.37 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give compound seven as a white solid (93 mg, 56%). 1 H NMR(400MHz,CDCl 3 )δ9.20(s,1H),7.66(d,J＝8.0Hz,1H),7.49(d,J＝8.0Hz,1H),7.37–7.33(m,2H),7.28–7.15(m,6H),7.09(d,J＝4.0Hz,1H),7.05–6.94(m,2H),5.07–5.01(m,1H),4.74–4.70(m,1H),4.25(t,J＝10.0Hz,1H),3.68(s,3H),3.38(s,3H)。
Example 8 the procedure used for the preparation of compound eight was substantially the same as in example 1, except that 7- (4- (trifluoromethyl) phenyl) -1H-indole-2-carboxylic acid (100 mg,0.33 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give compound eight as a white solid (99 mg, 63%).
1 H NMR(400MHz,CDCl 3 )δ9.15(s,1H),7.98(d,J＝8.0Hz,1H),7.68–7.64(m,3H),7.49(d,J＝8.0Hz,2H),7.26–7.19(m,6H),7.08(d,J＝1.7Hz,1H),5.14–5.07(m,1H),4.68–4.63(m,1H),4.38(t,J＝10.0Hz,1H),3.44(s,3H)。
Example 9 the procedure used for the preparation of compound nine was substantially the same as example 1 except that 7- (3- (trifluoromethyl) phenyl) -1H-indole-2-carboxylic acid (100 mg,0.33 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give compound nine as a white solid (86 mg, 55%).
1 H NMR(400MHz,CDCl 3 )δ9.02(s,1H),7.96(d,J＝8.0Hz,1H),7.72–7.60(m,3H),7.57–7.48(m,2H),7.28–7.21(m,4H),7.20–7.17(m,2H),7.09(d,J＝1.8Hz,1H),5.18–5.11(m,1H),4.71–4.66(m,1H),4.39(t,J＝12.0Hz,1H),3.43(s,3H)
Example 10 the procedure used for the preparation of compound deca was substantially the same as in example 1, except that 7- (4-methoxyphenyl) -1H-indole-2-carboxylic acid (100 mg,0.37 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give compound deca as a white solid (106 mg, 64%).
1 H NMR(400MHz,CDCl 3 )δ9.25(s,1H),7.71(d,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.46(d,J＝4.0Hz,2H),7.32–7.19(m,6H),7.11(s,1H),7.01(d,J＝4.0Hz,2H),5.17–5.07(m,1H),4.77–4.73(m,1H),4.34(t,J＝10.0Hz,1H),3.87(s,3H),3.44(s,3H)。
Example 11 the procedure used for the preparation of compound eleven was substantially the same as in example 1 except 7- (3-methoxyphenyl) -1H-indole-2-carboxylic acid (100 mg,0.37 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give compound eleven as a white solid (62%). 1 H NMR(400MHz,CDCl 3 )δ9.28(s,1H),7.81(d,J＝4.0Hz,1H),7.66(d,J＝8.0Hz,1H),7.42–7.33(m,1H),7.31–7.18(m,7H),7.15–7.11(m,1H),7.10–7.05(m,2H),6.98–6.90(m,1H),5.20–5.10(m,1H),4.78–4.71(m,1H),4.37(t,J＝12.0Hz,1H),3.84(s,3H),3.44(s,3H)。
Example 12 the procedure used for the preparation of compound twelve was substantially the same as in example 1, except that 7- (3-fluorophenyl) -1H-indole-2-carboxylic acid (100 mg,0.48 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give compound twelve as a white solid (111 mg, 66%). 1 H NMR(400MHz,CDCl 3 )δ9.16(s,1H),8.07(d,J＝4.0Hz,1H),7.69–7.58(m,1H),7.37–7.29(m,1H),7.25–6.97(m,9H),5.20–5.07(m,1H),4.73–4.61(m,1H),4.40(t,J＝10.0Hz,1H),3.43(s,3H)。
Example 13 the procedure used for the preparation of compound thirteen was essentially the same as in example 1 except that 7- (o-tolyl) -1H-indole-2-carboxylic acid (100 mg,0.40 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give compound thirteen as a white solid 119mg (70%). 1 H NMR(400MHz,CDCl 3 )δ8.95(s,1H),7.69(d,J＝8.0Hz,1H),7.36–7.20(m,10H),7.19–7.09(m,2H),5.08–4.96(m,1H),4.79–4.74(m,1H),4.27(t,J＝10.0Hz,1H),3.46(s,3H),2.09(s,3H)。
Example 14 the preparation of compound fourteen was essentially the same as in example 1 except 7- ([ 1,1' -biphenyl ] -4-yl) -1H-indole-2-carboxylic acid (100 mg,0.32 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give compound fourteen as a white solid 104mg (67%).
1 H NMR(400MHz,CDCl 3 )δ9.46(s,1H),8.10(d,J＝8.0Hz,1H),7.71–7.69(m,5H),7.58–7.49(m,4H),7.46–7.39(m,1H),7.35–7.10(m,7H),5.26–5.16(m,1H),4.76–4.68(m,1H),4.42(t,J＝12.0Hz,1H),3.39(s,3H).
Example 15 the procedure used for the preparation of pentadecade was substantially the same as in example 1, except that 7- ([ 1,1' -biphenyl ] -2-yl) -1H-indole-2-carboxylic acid (100 mg,0.32 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give pentadecade as a white solid (109 mg, 70%).
1 H NMR(400MHz,CDCl 3 )δ8.87(s,1H),7.60–7.53(m,1H),7.51–7.35(m,4H),7.29(d,J＝4.0Hz,1H),7.25–7.18(m,4H),7.14–7.01(m,7H),6.94(d,J＝4.0Hz,1H),5.02–4.95(m,1H),4.73(dd,J＝10.0,6.0Hz,1H),4.23(t,J＝10.0Hz,1H),3.43(s,3H)。
Example 16 the procedure used for the preparation of compound sixteen was substantially the same as in example 1, except that 7- ([ 1,1' -biphenyl ] -3-yl) -1H-indole-2-carboxylic acid (100 mg,0.32 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give compound sixteen as a white solid 107mg (69%).
1 H NMR(400MHz,CDCl 3 )δ9.29(s,1H),7.82–7.81(m,1H),7.76–7.65(m,5H),7.62–7.47(m,4H),7.45–7.36(m,2H),7.32–7.26(m,5H),7.17(d,J＝4.0Hz,1H),5.19–5.12(m,1H),4.81(dd,J＝1.0,8.5Hz,1H),4.42–4.37(m,1H),3.51(s,3H)。
Example 17 the procedure used for the preparation of seventeen compounds was substantially the same as in example 1, except that 7- (2, 3-dimethylphenyl) -1H-indole-2-carboxylic acid (100 mg,0.32 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give seventeen compounds as 114mg (69%) of a white solid. 1 H NMR(400MHz,CDCl 3 )δ9.22–8.88(m,1H),7.68(d,J＝8.0Hz,1H),7.61–7.46(m,1H),7.33–7.05(m,10H),5.12–4.94(m,1H),4.75(dd,J＝16.0,8.0Hz,1H),4.35–4.25(m,1H),3.49–3.44(m,3H),2.34(s,3H),2.02–1.89(m,3H)。
Example 18 the procedure used for the preparation of the compound eighteen was substantially the same as in example 1 except that 7- (2, 6-dimethylphenyl) -1H-indole-2-carboxylic acid (100 mg,0.32 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give the compound eighteen as a white solid 66mg (40%). 1 H NMR(600MHz,CDCl 3 )δ9.45(s,1H),7.55(d,J＝6.0Hz,1H),7.29(d,J＝6.0Hz,1H),7.25–7.14(m,3H),7.14–7.06(m,2H),7.02–6.94(m,3H),6.87–6.83(m,2H),4.79–4.75(m,1H),4.60(dd,J＝9.8,7.6Hz,1H),4.11(t,J＝12.0Hz,1H),3.38(s,3H),1.70(s,3H),1.55(s,3H)。
Example 19 the procedure used for the preparation of the compound nineteen was substantially the same as in example 1 except that 7- (2, 4-dimethylphenyl) -1H-indole-2-carboxylic acid (100 mg,0.32 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give the compound nineteen as a white solid 109mg (66%). 1 H NMR(400MHz,CDCl 3 )δ9.05(s,1H),7.64(d,J＝8.0Hz,1H),7.54–7.45(m,1H),7.29–6.99(m,10H),5.07–4.95(m,1H),4.72(d,J＝1.8Hz,1H),4.24(t,J＝12.0Hz,1H),3.39(s,3H),2.34(s,3H),2.02(s,3H)。
Example 20 the procedure used for the preparation of compound twenty was substantially the same as in example 1, except that 7- (2, 5-dimethylphenyl) -1H-indole-2-carboxylic acid (100 mg,0.32 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid, to give compound twenty as a white solid (99 mg, 60%). 1 H NMR(600MHz,CDCl 3 )δ8.80–8.62(m,1H),7.58(d,J＝12.0Hz,1H),7.33–7.21(m,1H),7.21–7.09(m,6H),7.08–6.98(m,4H),4.97–4.93(m,1H),4.74–4.65(m,1H),4.19(t,J＝9.0Hz,1H),3.37(s,3H),2.26(s,3H),1.98(s,3H)。
EXAMPLE 21 the compound twenty-one was prepared essentially the same as in example 1, except that 7- (3, 4-dimethylphenyl) -1H-indole-2-carboxylic acid (100 mg,0.32 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give compound twentyOnce, 97mg (59%) of a white solid. 1 H NMR(400MHz,CDCl 3 )δ9.18(s,1H),7.82(d,J＝8.0Hz,1H),7.61(d,J＝8.0Hz,1H),7.27–7.14(m,9H),7.09(d,J＝1.9Hz,1H),5.15–5.18(m,1H),4.70(dd,J＝10.0,6.0Hz,1H),4.35(t,J＝10.0Hz,1H),3.41(s,3H),2.29–2.28(m,6H)。
Example 22 the compound twenty-two was prepared essentially the same as in example 1, except that 7- (2, 3-difluorophenyl) -1H-indole-2-carboxylic acid (100 mg,0.37 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give compound twenty-two as a white solid (68%). 1 H NMR(400MHz,CDCl 3 )δ9.28(s,1H),7.76(d,J＝8.0Hz,1H),7.68(d,J＝8.0Hz,1H),7.28–7.13(m,7H),7.09–7.06(m,5H),5.08–5.02(m,1H),4.74–4.63(m,1H),4.31(t,J＝10.0Hz,1H),3.42(s,3H)。
Example 23 the procedure used for the preparation of the compound twenty-third was substantially the same as in example 1, except that 2, 6-dimethoxybenzoic acid (100 mg,0.37 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give compound twenty-three as a white solid (106 mg, 65%). 1 H NMR(600MHz,CDCl 3 )δ8.88(s,1H),7.63(d,J＝6.0Hz,1H),7.38–7.31(m,1H),7.21–7.13(m,7H),7.00(s,1H),6.94–6.85(m,2H),4.99–4.94(m,1H),4.73–4.67(m,1H),4.21(t,J＝12.0Hz,1H),3.38(s,3H)。
Example 24 the compound twenty-four was prepared essentially the same as in example 1 except that 7- (2, 5-difluorophenyl) -1H-indole-2-carboxylic acid (100 mg,0.37 mmol) was used in place of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give compound twenty-four as a light yellow solid, 99mg (61%).
1 H NMR(400MHz,CDCl 3 )δ9.22(s,1H),7.71–7.65(m,2H),7.28–7.17(m,6H),7.13–7.00(m,4H),5.10–4.99(m,1H),4.71(dd,J＝9.7,7.6Hz,1H),4.30(t,J＝10.0Hz,1H),3.42(s,3H)。
EXAMPLE 25 the compound twenty-five was prepared essentially the same as in example 1, except that 2,7- (2, 6-difluorophenyl) -1H-indole-2-carboxylic acid (100 mg,0.37 mmol) was used instead of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give the compound twenty-five, yellow solidBody 49mg (30%). 1 H NMR(600MHz,CDCl 3 )δ8.95(s,1H),7.64–7.53(m,1H),7.50(d,J＝6.0Hz,1H),7.34(d,J＝12.0Hz,1H),7.22–7.14(m,5H),6.95–6.92(m,2H),5.06(d,J＝5.3Hz,1H),4.70(t,J＝8.6Hz,1H),4.27(dd,J＝14.3,6.4Hz,1H),3.42(d,J＝6.3Hz,3H)。
Example 26 the compound twenty-six was prepared essentially the same as in example 1, except that 7- (3, 4-difluorophenyl) -1H-indole-2-carboxylic acid (100 mg,0.37 mmol) was used in place of 7- (4-fluorophenyl) -1H-indole-2-carboxylic acid to give compound twenty-six as a yellow solid (106 mg, 65%). 1 H NMR(400MHz,CDCl 3 )δ9.06(s,1H),8.24(d,J＝4.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.34–7.28(m,3H),7.27–7.22(m,1H),7.21–7.10(m,4H),7.09–7.01(m,2H),5.23–5.17(m,1H),4.68(dd,J＝9.7,7.8Hz,1H),4.53–4.39(m,1H),3.48(s,3H)。
The above is a method for preparing the compounds of the present invention, and the following procedure is as in example 27, for verifying whether each compound is effective or not by a programmed cell necrosis RIPK1 inhibition assay:
example 27
1. Reagent(s)
Dulbecco's Modified Eagle's Medium (DMEM), fetal Bovine Serum (FBS), penicillin-streptomycin liquid (100), phosphate Buffered Saline (PBS). Recombinant mouse/human TNF-alpha was purchased from Novoprotein (Shanghai, china). Z-VAD-fmk (T6013) was purchased from Targetmol (U.S. Targetmol). Smac mimetic (HY-15989) was purchased from MedChemexpress (Monmouth Junction, NJ, USA).
2. Cell culture
HT-29 (NCI-DTP Cat#HT-29) and U937 cells were cultured in DMEM containing 10% FBS (v/v) RPM I-1640, 1% L-glutamine and 100U/mL penicillin/streptomycin (v/v). U937 (ProcelC L-0239) is described by Procell Life Science&Technical company. Cells were incubated at 37℃with 5% CO 2 Grown in humidified atmosphere and obtained from exponentially growing cultures in all experiments.
3. Necrosis induction and cell viability assay
Necrosis was induced by pretreatment with z-VAD-fmk (30. Mu.M) and Smac mimetic (15 nM) or cyclohexylamine (350. Mu.M) for 30 min, followed by TNF- α (20 ng/mL) for 12 or 16 hours (TSZ). TNF- α (20 ng/mL) induced apoptosis for 24 hours with cycloheximide (2 mM). The compounds were incubated with cells exposed to one of the above combinations for 16 hours or 24 hours at the indicated concentrations. Cell viability was then calculated by detecting chemiluminescent values using the CellTiter-Glo luminescent cell viability assay kit test, thereby yielding the biological activity of the compound to inhibit apoptosis.
Measured at 10nM<EC 50 <10. Mu.M, as shown in the following Table, 10nM<EC 50 <100nM(+++)，100nM<EC 50 <1μM(++)，1μM<EC 50 <10μM(+)。
TABLE 1 data on RIPK1 inhibitory Activity of Compounds
| Numbering device | EC 50 |
| Example 1 | ++ |
| Example 2 | +++ |
| Example 3 | + |
| Example 4 | +++ |
| Example 5 | ++ |
| Example 6 | ++ |
| Example 7 | ++ |
| Example 8 | + |
| Example 9 | + |
| Example 10 | + |
| Example 11 | ++ |
| Example 12 | +++ |
| Example 13 | +++ |
| Example 14 | ++ |
| Example 15 | ND |
| Example 16 | ND |
| Example 17 | ++ |
| Example 18 | + |
| Example 19 | + |
| Example 20 | + |
| Example 21 | + |
| Example 22 | ++ |
| Example 23 | ++ |
| Example 24 | +++ |
| Example 25 | + |
| Example 26 | ++ |
Results and evaluation: as can be seen from Table 1, N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] prepared according to the present invention][1,4]Oxazin-3-yl) -7-phenyl-1H-indole-2-carboxamide derivatives exhibit high inhibitory activity against RIPK 1. Wherein, the inhibitory activity EC of example 2 50 The value was less than 100nM.
Example 28: tnfα -induced inflammatory cytokine IL-6 assay.
To measure TNF- α -induced IL-6 levels in serum, mice were sacrificed 2 hours after TNF- α injection and serum was collected using a mouse IL-6ELISA kit (Multisciences, like) to analyze IL-6. As shown in fig. 1, the example 1 treated group significantly reduced the level of IL-6 (P < 0.01) compared to the non-treated group.
In summary, the invention provides N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7-phenyl-1H-indole-2-carboxamide derivatives with good activity and novel structure as RIPK1 small molecule inhibitors, which can reduce TNF-alpha induced necrotic apoptosis, thereby playing an anti-inflammatory role and being used for preparing medicaments for treating inflammation related diseases such as multiple sclerosis.
The foregoing disclosure is illustrative of the preferred embodiments of the present invention, and is not to be construed as limiting the scope of the invention, as it is understood by those skilled in the art that all or part of the above-described embodiments may be practiced with equivalents thereof, which fall within the scope of the invention as defined by the appended claims.
Claims (9)
1. An N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7-phenyl-1H-indole-2-carboxamide derivative characterized in that: the structure of the compound is shown as the following formula (I):
wherein R is selected from the group consisting of-H, -F, -CH 3 ，-CF 3 ，-OCH 3 One of the groups Ph.
2. The N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7-phenyl-1H-indole-2-carboxamide derivative according to claim 1, characterized in that:
the-F group includes:
a single substituent: 2-F,3-F, 4-F;
or a di-substituent: 2-CH 3 ，3-CH 3 ；2-CH 3 ，4-CH 3 ；2-CH 3 ，5-CH 3 ；2-CH 3 ，6-CH 3 ；3-CH 3 ，4-CH 3 One of the above combinations;
the-CH 3 A group comprising:
a single substituent: 2-CH 3 ，3-CH 3 ，4-CH 3 One of them;
or a di-substituent: 2-CH 3 ，3-CH 3 ；2-CH 3 ，4-CH 3 ；2-CH 3 ，5-CH 3 ；2-CH 3 ，6-CH 3 ；3-CH 3 ，4-CH 3 One of the above combinations;
the-OCH 3 A group comprising: 2-OCH 3 ，3-OCH 3 ，4-OCH 3 One of them;
the-Ph group comprises: one of 2-Ph,3-Ph, 4-Ph.
3. The N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7-phenyl-1H-indole-2-carboxamide derivative according to claim 1, characterized in that: selected from the group consisting of
Compound one: (S) -7- (4-fluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound two: (S) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7-phenyl-1H-indole-2-carboxamide having the structural formula:
or compound three: (S) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7- (p-tolyl) -1H-indole-2-carboxamide;
or compound four: (S) -7- (2-fluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound five: (S) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7- (m-tolyl) -1H-indole-2-carboxamide having the structural formula:
or compound six: (S) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-3-yl) -7- (2- (trifluoromethyl) phenyl) -1H-indole-2-carboxamide having the formula;
or compound seven: (S) -7- (2-methoxyphenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound eight: (S) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-3-yl) -7- (4- (trifluoromethyl) phenyl) -1H-indole-2-carboxamide having the formula:
or compound nine: (S) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-3-yl) -7- (3- (trifluoromethyl) phenyl) -1H-indole-2-carboxamide having the formula:
or compound ten: (S) -7- (4-methoxyphenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound eleven: (S) -7- (3-methoxyphenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound twelve: (S) -7- (3-fluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound thirteen: (S) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7- (o-tolyl) -1H-indole-2-carboxamide having the structural formula:
or compound fourteen: (S) -7- ([ 1,1' -biphenyl ] -4-yl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound pentadec: (S) -7- ([ 1,1' -biphenyl ] -2-yl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound sixteen: (S) -7- ([ 1,1' -biphenyl ] -3-yl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound seventeen: (S) -7- (2, 3-dimethylphenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or the compound eighteen: (S) -7- (2, 6-dimethylphenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or nineteen compounds: (S) -7- (2, 4-dimethylphenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound twenty: (S) -7- (2, 5-dimethylphenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound twenty-one: (S) -7- (3, 4-dimethylphenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or the compound twenty-two: (S) -7- (2, 3-difluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or the compound twenty-three: (S) -7- (2, 4-difluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound twenty four: (S) -7- (2, 5-difluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound twenty-five: (S) -7- (2, 6-difluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
or compound twenty-six: (S) -7- (3, 4-difluorophenyl) -N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -1H-indole-2-carboxamide having the structural formula:
one of the above compounds.
The preparation method of the N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7-phenyl-1H-indole-2-carboxamide derivative comprises the following steps:
step S1: in an organic solvent, the compound of the formula (III) is taken as a raw material, and the compound is mixed with substituted phenylboronic acid, pd (Ph) 3 ) 4 And Cs 2 CO 3 Carrying out Suzuki coupling reaction to obtain a compound of the formula (IV):
step S2: the compound of the formula (IV) undergoes hydrolysis reaction with sodium hydroxide in a mixed solvent of water and ethanol to obtain a compound of the formula (V);
step S3: the compound of formula (V) is subjected to condensation reaction with HATU and DIPEA of formula (II) in an organic solvent to obtain the compound of formula (VI).
5. The N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] according to claim 4][1,4]A process for the preparation of oxazin-3-yl) -7-phenyl-1H-indole-2-carboxamide derivatives, characterised in that: in step (1), the organic solvent is selected from DMF or dioxane, H 2 O；dioxane:H 2 The volume ratio of O is 4:1; the Suzuki coupling reaction temperature is 25-100 ℃ and the reaction time is 1-5h, the compound of the formula (II) and Pd (PPh) 3 ) 4 Is a matter of (2)The mass range is 1:0.05 to 0.2, wherein the compound of formula (II) and Cs 2 CO 3 The amount of the substance ranges from 1:1.0 to 2.5.
6. The N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] according to claim 4][1,4]A process for the preparation of oxazin-3-yl) -7-phenyl-1H-indole-2-carboxamide derivatives, characterised in that: in step (2), the organic solvent is selected from MeOH or EtOH, H 2 O；EtOH：H 2 The volume ratio of O is 1:1, the hydrolysis reaction temperature is 0-100 ℃, and the reaction time is 1-5h.
7. The process for the preparation of N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7-phenyl-1H-indole-2-carboxamide derivatives according to claim 4, characterized in that: in the step (3), the organic solvent is selected from DMF or DMSO, the condensation reaction temperature is 0-60 ℃, the reaction time is 1-5h, and the amount of the compound of the formula (VII) and the substance of the formula (II) ranges from 1:1.0 to 1.5, the amount of the compound of formula (IV) and HATU ranges from 1:1.0 to 1.5, the amount of the compound of formula (IV) and DIPEA being in the range 1:1.0 to 3.0.
8. Use of an N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7-phenyl-1H-indole-2-carboxamide derivative according to any one of claims 1 to 3 as RIPK1 inhibitor.
9. Use of an N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazin-3-yl) -7-phenyl-1H-indole-2-carboxamide derivative according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of multiple sclerosis.
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