CN116354923A - Nitrogen-containing heterocyclic compound and application thereof - Google Patents
Nitrogen-containing heterocyclic compound and application thereof Download PDFInfo
- Publication number
- CN116354923A CN116354923A CN202211661648.4A CN202211661648A CN116354923A CN 116354923 A CN116354923 A CN 116354923A CN 202211661648 A CN202211661648 A CN 202211661648A CN 116354923 A CN116354923 A CN 116354923A
- Authority
- CN
- China
- Prior art keywords
- isobutoxybenzyl
- diazaspiro
- octan
- methylpiperidin
- formula
- 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.)
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- -1 Nitrogen-containing heterocyclic compound Chemical class 0.000 title claims abstract description 208
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 239000003814 drug Substances 0.000 claims abstract description 16
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 14
- 208000028017 Psychotic disease Diseases 0.000 claims abstract description 8
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 5
- 206010012289 Dementia Diseases 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 55
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- RHLVCLIPMVJYKS-UHFFFAOYSA-N 3-octanone Chemical compound CCCCCC(=O)CC RHLVCLIPMVJYKS-UHFFFAOYSA-N 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 10
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
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- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
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- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- TVEXGJYMHHTVKP-UHFFFAOYSA-N 6-oxabicyclo[3.2.1]oct-3-en-7-one Chemical compound C1C2C(=O)OC1C=CC2 TVEXGJYMHHTVKP-UHFFFAOYSA-N 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
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- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 4
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
Abstract
The invention relates to the field of chemical medicine, in particular to a nitrogenous heterocyclic compound and application thereof, and the nitrogenous heterocyclic compound provided by the invention is shown as a formula I and acts on 5-HT 2A 、5‑HT 2C Receptors for 5-HT 2A Is superior or similar to pimavanserin in selectivity. Can be used for treating behavior disorder and psychosis associated with schizophrenia or Parkinson's disease and dementia. The antipsychotic activity of the compounds of the present application is comparable to pimecroline, sedating side effects, and cardiotoxicity less than pimecroline.
Description
Technical Field
The invention relates to the field of chemical medicines, in particular to a nitrogen-containing heterocyclic compound and application thereof.
Background
The Schizophrenia (Schizophrenia) has hidden incidence, low cure rate and higher incidence rate in life. About 0.3-0.7% of the world population is currently affected by schizophrenia during its lifetime, with a global estimated over 2100 tens of thousands of schizophrenic patients in 2016; the existing anti-schizophrenia drugs mainly comprise typical anti-schizophrenia drugs and atypical anti-schizophrenia drugs, but the current anti-schizophrenia therapeutic drugs block dopamine receptors strongly, so that adverse reactions such as extrapyramidal reaction (EPS), tardive dyskinesia, increase of prolactin and the like are caused. In the medical field, although various types of active compounds acting on different targets are available for the treatment of Sleep disorders (Sleep disorders), adverse reactions such as addiction, drug resistance and sequelae remain unsolved.
Traditionally, it is customary to block dopamine D by 2 Antipsychotics whose receptors exert pharmacological effects are known as first-generation antipsychotics, i.e. "typical" antipsychotics (e.g. haloperidol), which are breakthrough in the treatment of positive symptoms of schizophrenia but fail to treat negative symptoms and cognitive disorders. Typical antipsychotics generally have severe EPS side effects and are ineffective in one third of schizophrenic patients.
After the 60 s of the 20 th century, a series of new generation antipsychotics including Ziprasidone, risperidone and the like, which are called second generation antipsychotics, i.e., novel antipsychotics, which have common pharmacological characteristics, i.e., 5-hydroxytryptamine (5-HT) receptor (5-HT), although their respective pharmacological actions are not completely consistent, have been developed 1A、2A、2C ) And Norepinephrine (NA) receptor (alpha) 1 、α 2 ) Far aligned with D 2 The receptor is high. Compared with the first-generation antipsychotics, the clinical effect of the traditional Chinese medicine composition has more advantages, is effective on positive symptoms and traditional antipsychotics, is effective on negative symptoms and cognition deficiency symptoms, has a wider action spectrum, and has adverse reactions such as QT interval prolongation, hyperprolactinemia, weight gain and the like. Thus, finding drugs that are effective against positive, negative symptoms and cognitive impairment of schizophrenia with small side effects is a hotspot of current research.
The 5-hydroxytryptamine system plays an important role in the function of the regulated prefrontal cortex (PFC), including mood control, cognitive behavior and working memory. Pyramidal neurons of PFC and GABA mid-godThe menstrual cell contains several 5-HT receptor subtypes with a particularly high density 1A And 5-HT 2A . PFC and NMDA receptor channels have recently been demonstrated to be 5-HT 1A The targets of R, these two receptors regulate cortical excitatory neurons, affecting cognitive function. Indeed, various preclinical data indicate 5-HT 1A R may be a new target for the development of antipsychotic drugs. Atypical antipsychotics (such as olanzapine, aripiprazole, etc.) against 5-HT 1A The high affinity of R and its low EPS side effects both indicate that the 5-hydroxytryptamine system plays an important role in the function of the regulated prefrontal cortex (PFC), including mood control, cognitive behavior and working memory. Pyramidal neurons of PFC and GABA interneurons comprise several 5-HT with a particularly high density of 5-hydroxytryptamine receptor subtypes 1A And 5-HT 2A . Recent studies have shown 5-HT 1A Agonists are associated with atypical antipsychotic therapy and improve negative symptoms and cognitive dysfunction. In the treatment of schizophrenia with the atypical antipsychotic drug clozapine, 5-HT has been found 2A Play an important role in this context, involving various aspects of perception, mood regulation and motor control. Blocking 5-HT 2A The receptor can normalize dopamine release and act as an antipsychotic. In addition, 5-HT 2C The receptors are closely related to weight gain.
Pimavanserin is a p-5-HT 2A Inverse agonists with high affinity, 5-HT 2C Antagonists, shown by in vitro experiments, against 5-HT 2A Affinity of receptor [ inhibition constant (Ki) of 0.4nm]Compared with 5-HT 2C High (ki=16 nm), for 5-HT 2B Receptors, dopamine receptors (including D 2 None of the receptors, adrenergic receptors, muscarinic receptors or calcium channel receptors have significant affinity (Ki)>300 nm). The medicine was approved by the U.S. food and drug administration for 4 months in 2016 to be marketed under the trade name Nuplazid TM The Chinese medicinal composition is mainly used for treating parkinsonism symptoms such as illusion and illusion.
Therefore, there is a need to find a composition that is effective against both positive and negative symptoms, improves cognitive impairment and prevents extrapyramidal side effects, including tardive dyskinesia, parkinson's disease; and can reduce weight gain.
The invention comprises the following steps:
the present invention aims to solve at least one of the technical problems existing in the prior art, and therefore, an object of the present invention is to provide a nitrogen-containing heterocyclic compound, as shown in formula I:
Wherein N7 is 0, 1 or 2, A is C, O or N;
n3, n6 are each independently selected from integers of 0, 1,2, 3, and n3, n6 are not simultaneously 0;
n2 is an integer of 1,2 or 3;
w is O or S;
z, Q, Y are each independently selected from C, N and Z, Q are not simultaneously C;
R 2 selected from hydrogen, substituted or unsubstituted C 1 -C 5 Straight-chain or branched alkyl, substituted or unsubstituted C 3 -C 5 Cycloalkyl of (C), said substituents being selected from methyl, ethyl, propyl, butyl, fluoro, C 3 -C 5 Cycloalkyl of (c);
R 3 、R 4 selected from H, halogen, C 1- C 5 Straight-chain or branched alkyl, phenyl, or R 3 And R is R 4 Formation of C 3-6 Cycloalkyl of (c);
R 5 hydrogen or halogen;
R 1 selected from the structures of formula II, III, IV:
in the formula III, n5 is an integer of 0-4, R 8 、R 9 Are independently selected from C 1-3 Or R is an alkyl group of 8 、R 9 A 4-6 membered heterocyclic ring substituted or unsubstituted with N, said substituents being selected from methyl, ethyl, propylGroup, butyl, fluorine, chlorine;
in the formula II, n4 is an integer of 1-4;
R 7 selected from methyl, ethyl, isopropyl, isobutyl, benzyl, phenyl, halogenated C 1 -C 5 Straight or branched alkyl of (a);
R 6 halogen, methyl or hydrogen.
In one embodiment, when R 3 And R is R 4 Formation of C 3 -C 6 The cycloalkyl group of formula I is as shown in formula I-1:
wherein n1 is an integer of 1,2 or 3.
In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
In another aspect, the invention provides application of a compound shown in formula I and a pharmaceutical composition thereof in preparing medicines for treating mental diseases. The mental disease is schizophrenia. The mental diseases are Parkinson's disease, dementia related behavioral disorder and psychosis.
Compounds of formula I
Wherein N7 is 0, 1 or 2, A is C, O or N;
n3, n6 are each independently selected from integers of 0, 1, 2, 3, and n3, n6 are not simultaneously 0;
n2 is an integer of 1, 2 or 3;
w is O or S;
z, Q, Y are each independently selected from C, N and Z, Q are not simultaneously C;
R 2 selected from hydrogen, substituted or unsubstituted C 1 -C 5 Straight chain or branch of (2)Chain alkyl, substituted or unsubstituted C 3 -C 5 Cycloalkyl of (C), said substituents being selected from methyl, ethyl, propyl, butyl, fluoro, C 3 -C 5 Cycloalkyl of (c);
R 3 、R 4 selected from H, halogen, C 1- C 5 Straight-chain or branched alkyl, phenyl, or R 3 And R is R 4 Formation of C 3-6 Cycloalkyl of (c);
R 5 hydrogen or halogen;
R 1 selected from the structures of formula II, III, IV:
in the formula III, n5 is an integer of 0-4, R 8 、R 9 Are independently selected from C 1-3 Alkyl or R of (2) 8 、R 9 A substituted or unsubstituted 4-6 membered heterocyclic ring with N, said substituents selected from methyl, ethyl, propyl, butyl, fluoro, chloro;
in the formula II, n4 is an integer of 1-4;
R 7 selected from methyl, ethyl, isopropyl, isobutyl, benzyl, phenyl, halogenated C 1 -C 5 Straight or branched alkyl of (a);
R 6 halogen, methyl or hydrogen.
In one embodiment, when R 3 And R is R 4 Formation of C 3 -C 6 The cycloalkyl group of formula I is as shown in formula I-1:
wherein n1 is an integer of 1,2 or 3.
In one embodiment, the compound of formula I is as shown in formula V:
in yet another embodiment, when R 3 And R is R 4 Formation of C 3 -C 6 The cycloalkyl group of formula I is as shown in formula V-1:
wherein n1 is an integer of 1,2 or 3.
In the above formula V-1 compound, when R1 is a structure of formula II, the formula V-1 compound is a structure of formula V-2:
in one embodiment, the compound of formula I is as shown in formula VI:
in yet another embodiment, when R 3 And R is R 4 Formation of C 3 -C 6 The compound shown in the formula I is shown as a formula VI-1:
wherein n1 is an integer of 1,2 or 3.
In the compound of the formula VI-1, when R1 is a structure of the formula II, the compound of the formula VI-1 is a structure of the formula VI-2:
Wherein n4 is an integer of 1, 2 or 3.
In one embodiment, the halogen is selected from fluorine, chlorine, bromine, iodine; the C is 1 -C 5 Is selected from methyl, ethyl, propyl, isopropyl, isobutyl, neopentyl; the C is 3 -C 5 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl; substituted C 3 -C 5 Cycloalkyl of (2) is selected from methylcyclopropyl, ethylcyclopropyl; the halogeno in the halogenoalkyl is selected from fluoroalkyl, chloroalkyl, bromoalkyl and iodoalkyl; the C is 1 -C 3 The straight or branched alkyl of (a) is methyl, ethyl or propyl.
In one embodiment, the 4-6 membered heterocycle is selected from the group consisting of azetidine, piperazine, pyrrolidine.
In one embodiment, n2 is an integer of 1, 2, or 3. In a preferred embodiment, n2 is 1 or 2. In a particularly preferred embodiment, n2 is 1.
In one embodiment, n3, n6 are each independently selected from integers of 0, 1, 2, 3, and n3 and n6 are not both 0. In a preferred embodiment, n3, n6 are each independently selected from integers of 0, 1, 2, and n3 and n6 are not both 0.
In one embodiment, n7 is 0, 1 or 2. In a preferred embodiment, n7 is 0 or 1. In a specific embodiment, n7 is 0. In another specific embodiment, n7 is 1.
In one embodiment, n4 is selected from integers from 1 to 4. In a preferred embodiment, n4 is 1,2 or 3. In a specific embodiment, n4 is 1. In another specific embodiment, n4 is 2. In yet another specific embodiment, n4 is 3.
In one embodiment, n5 is selected from integers from 0 to 4. In a preferred embodiment, n5 is 0, 1,2 or 3. In a specific embodiment, n5 is 0. In another specific embodiment, n5 is 1.
In one embodiment, n1 is an integer of 1,2 or 3. In a preferred embodiment, n1 is 1 or 2. In a specific embodiment, n1 is 1. In another specific embodiment, n1 is 2.
In one embodiment, a is C, N or O. In a preferred embodiment, a is N or O.
In one embodiment, R 2 Selected from hydrogen, substituted or unsubstituted C 1 -C 5 Straight-chain or branched alkyl, substituted or unsubstituted C 3 -C 5 Cycloalkyl of (C), said substituents being selected from methyl, ethyl, propyl, butyl, fluoro, C 3 -C 5 Cycloalkyl groups of (a). In a preferred embodiment, R 2 Selected from hydrogen, substituted or unsubstituted C 1 -C 5 Straight or branched alkyl of (a); substituted or unsubstituted C 3 -C 5 Is selected from methyl, ethyl, fluoro, cyclopropyl. In a more preferred embodiment, R 2 Selected from hydrogen, methyl, isopropyl, isobutyl, cyclopropyl, cyclopropylmethyl, neopentyl.
A compound of formula I as described above, selected from any one of the following: 5- (4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (3-fluoro-1-methylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (4-isobutoxybenzyl) -7- (1-methylpyrrolidin-3-yl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (2- (dimethylamino) ethyl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (4-methoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (4-cyclopropoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (4- (cyclopropylmethoxy) benzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (1-benzylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (1- (2, 2-difluoroethyl) piperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (4-isobutoxybenzyl) -7- (2-methyl-2-azaspiro [3.3] heptan-6-yl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (1-methylpiperidin-4-yl) -7- (4- (neopentyloxy) benzyl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (4-isobutoxybenzyl) -7- (1-isobutylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (4-isobutoxybenzyl) -7- (1-isopropylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one; 6- (4-isobutoxybenzyl) -8- (1-methylpiperidin-4-yl) -6, 8-diazaspiro [3.5] non-7-one; 5- (4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-thione; 5- (4-hydroxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
7- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.6] non-6-one; 5- (4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.6] non-6-one; 7- [ (dimethylamino) methyl ] -5- (4-isobutoxybenzyl) -5-azaspiro [2.5] octan-6-one;
7- (dimethylamino) -5- (4-isobutoxybenzyl) -5-azaspiro [2.5] octan-6-one;
7- (azetidin-1-yl) -5- (4-isobutoxybenzyl) -5-azaspiro [2.5] octan-6-one;
1- (4-isobutoxybenzyl) -5-methyl-3- (1-methylpiperidin-4-yl) -5-phenyltetrahydropyrimidin-2 (1H) -one; 5, 5-difluoro-1- (4-isobutoxybenzyl) -3- (1-methylpiperidin-4-yl) tetrahydropyrimidin-2 (1H) -one;
1- (4-isobutoxybenzyl) -5-methyl-3- (1-methylpiperidin-4-yl) tetrahydropyrimidin-2 (1H) -one;
5- (4-isobutoxybenzyl) -7- (4-methylpiperazin-1-yl) -5-azaspiro [2.5] octan-6-one;
7- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) -5-azaspiro [2.5] octan-6-one;
5- ((6-isobutoxypyridin-3-yl) methyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (2-fluoro-4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (3-fluoro-4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (4-isobutoxybenzyl) -7- (1-methylazo-4-yl) -5-7-diazaoxazol [2.5] octan-6-one; 5- ((2R) -1, 2-dimethylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one; 5- ((2S) -1, 2-dimethylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (2-chloro-4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (3-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
4- (4-isobutoxybenzyl) -6- (1-methylpiperidin-4-yl) -4, 6-diazaspiro [2.4] heptane-5-one;
6- (4-isobutoxybenzyl) -4- (1-methylpiperidin-4-yl) -4, 6-diazaspiro [2.4] heptane-5-one;
5- (1-ethylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (4-isopentylbenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (4- (isobutylamino) benzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (4- (isopropoxymethyl) benzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one.
Term interpretation:
the term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects. It should be understood that the term "comprising" may cover the closed meaning, i.e. "consisting of …".
As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above or as specified in the examples, subclasses, and examples. It is to be understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. An optionally substituted group may be substituted at each substitutable position of the group, unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.
In addition, unless explicitly stated otherwise, the description as used in this application is to be construed broadly as meaning that the terms "independently of each other" and "independently of each other" may refer to the fact that, in different groups, specific terms expressed between the same symbols do not affect each other, or may mean that, in the same groups, specific terms expressed between the same symbols do not affect each other.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C 1 -C 5 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 An alkyl group. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ) Ethyl (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) Etc.
Ranges recited herein (e.g., numerical ranges) can encompass each and every subrange within the range as well as each subrange formed by each value. Thus, for example, the expression "n 2 Is 0 to 3Any integer therebetween "includes, for example, any integer from 0 to 2, any integer from 2 to 3, etc., such as 1, 2, 3.
The expression "one or more" may denote 1, 2, 3, 4, 5, 6 or more.
The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of carbon and hydrogen atoms, preferably containing 1 or 2 rings. The cycloalkyl group may be a monocyclic, fused polycyclic, bridged or spiro ring structure. Cycloalkyl groups can have 3 to 6 carbon atoms, i.e. "C 3 -C 6 Cycloalkyl ", e.g. C 6 Cycloalkyl, C 5 Cycloalkyl, C 4 Cycloalkyl, C 3 Cycloalkyl groups. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term also covers the case where the C atom may be substituted by oxo (=o).
The terms "heterocycle" and "heterocyclyl" are used interchangeably to denote a monovalent or polyvalent, monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms in which one or more atoms in the ring are independently replaced by heteroatoms having the meaning as described herein, and the ring may be fully saturated or contain one or more unsaturations, but none of the aromatic rings. Unless otherwise indicated, a heterocyclic group may be a carbon or nitrogen group, and-CH 2 The group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and the like. In heterocyclic groups-CH 2 Examples of substitution of the-group by-C (=o) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl and pyrimidinedionyl. Examples of sulfur atoms in the heterocyclic group that are oxidized include, but are not limited to, sulfolane, 1-dioxothiomorpholino. The heterocyclyl group may be optionally substituted with one or more substituents described herein.
The term "hydrogen (H)" means a single hydrogen atom. Such radicals may be attached to other groups, such as to an oxygen atom, to form a hydroxyl group.
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term "pharmaceutically acceptable salt" refers to an inorganic or organic salt of a compound of the invention.
The beneficial technical effects of the invention are as follows:
the compounds provided herein act on 5-HT2A, 5-HT2C receptors with selectivity for 5-HT2A over or similar to pimavanserin. Can be used for treating behavior disorder and psychosis associated with schizophrenia or Parkinson's disease and dementia. The antipsychotic activity of the compounds of the present application is comparable to pimecroline, sedative side effects are less than pimecroline, and cardiotoxicity is less than pimecroline.
Detailed description of the preferred embodiments
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. Those skilled in the art will appreciate that various changes and modifications can be made to the invention without departing from the spirit and scope thereof.
TABLE 1 Structure of Compounds and names of Compounds
Detailed description of the preferred embodiments
The following examples are for illustrative purposes only and are not intended to be limiting of the invention.
Examples of synthetic aspects
Example 1.5- (4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (1)
Reaction 1
1.1 preparation of methyl 1- ([ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamoyl) cyclopropane-1-carboxylate
1- [4- (2-methylpropyloxy) phenyl ] methylamine (800.00 mg,4.463 mmol), 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid (643.19 mg,4.463 mmol), HATU (2036.23 mg,5.355 mmol) and DIEA (1153.55 mg,8.925 mmol) were dissolved in 20ml DMF and stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The solvent was distilled off, and the column chromatography was performed (PE: ea=4:1) to give methyl 1- ([ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamoyl) cyclopropane-1-carboxylate 1100mg, yield: 80.72%.
1.2 preparation of [1- [ ([ [4- (2-methylpropyloxy) phenyl ] methyl ] amino) methyl ] cyclopropyl ] methanol
1- ([ [4- (2-methylpropyloxy) phenyl ]]Methyl group]Carbamoyl) cyclopropane-1-carboxylic acid methyl ester (1.10 g,3.602 mmol) and BH 3 THF (10.00 mL,104.490 mmol) was dissolved with 10mL THF and heated at reflux overnight. After the reaction, cooling to room temperature, quenching the reaction by adding 2N HCl solution, stirring at room temperature for 1 hour, washing the aqueous phase with ethyl acetate, adjusting the pH of the aqueous phase to 10 with 4N NaOH solution, extracting with dichloromethane, and evaporating the solvent to obtain [1- [ ([ [4- (2-methylpropyloxy) phenyl) ]Methyl group]Amino) methyl group]Cyclopropyl group]800mg of crude methanol. 1.3 benzyl N- [ [1- (hydroxymethyl) cyclopropyl ]]Methyl group]-N- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]Preparation of carbamates
Taking [1- [ ([ [4- (2-methylpropyloxy) phenyl)]Methyl group]Amino) methyl group]Cyclopropyl group]Methanol (800.00 mg,3.037 mmol) and CbzCl (777.25 mg,4.556 mmol) were added to 10ml NaHCO 3 And 10ml of THF, and stirred at room temperature for 2 hours. After the completion of the reaction, water was added thereto, followed by extraction with ethyl acetate. Removing the solvent, and separating and purifying by column chromatography (PE: EA=1:1) to obtain N- [ [1- (hydroxymethyl) cyclopropyl)]Methyl group]-N- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]800mg of carbamate and 66.26% yield.
1.4 preparation of benzyl N- [ (1-formylcyclopropyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamate
N- [ [1- (hydroxymethyl) cyclopropyl ] methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamate (700.00 mg,1.761 mmol) and PCC (759.16 mg,3.522 mmol) were dissolved with 20ml dichloromethane, stirred at room temperature for 2 hours, and filtered to give a solution. Removal of the solvent afforded benzyl N- [ (1-formylcyclopropyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamate 500mg in 71.79% yield.
1.5 preparation of benzyl N- [ (1- [ (1-methylpiperidin-4-yl) amino ] methyl ] cyclopropyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamate
Benzyl N- [ (1-formyl cyclopropyl) methyl]-N- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]Carbamic acid ester (500.00 mg,1.264 mmol), 1-methyl-4-piperidinamine (216.55 mg,1.896 mmol), naBH 3 CN (158.89 mg,2.528 mmol) was added to a mixed solution of 10ml ethanol and 1ml acetic acid, and stirred overnight at room temperature. After the reaction, the reaction solution is poured into saturated NaHCO 3 The solution was extracted with ethyl acetate. The solvent was removed and purified by column chromatography (DCM: meoh=10:1) to give benzyl N- [ (1- [ (1-methylpiperidin-4-yl) amino)]Methyl group]Cyclopropyl) methyl group]-N- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]350mg of carbamate is obtained in a yield of 56.08%.
1.6 Preparation of 1-methyl-N- ([ 1- [ ([ [4- (2-methylpropyloxy) phenyl ] methyl ] amino) methyl ] cyclopropyl ] methyl) piperidin-4-amine
Benzyl N- [ (1-methylpiperidin-4-yl) amino)]Methyl group]Cyclopropyl) methyl group]-N- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]Carbamate (100.00 mg,0.203 mmol) and Pd (OH) 2 10ml of CF are added to the mixture/C (20.00 mg) 3 CH 2 To the OH solution, hydrogen was introduced and stirred overnight at room temperature. After the reaction, filtering to obtain filtrate, and removing solvent to obtain 1-methyl-N- ([ 1- [ ([ [4- (2-methylpropyloxy) phenyl) ]Methyl group]Amino) methyl group]Cyclopropyl group]Methyl) piperidin-4-amine 50mg, yield 68.65%.
1.7 Preparation of 5- (1-methylpiperidin-4-yl) -7- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -5, 7-diazaspiro [2.5] octan-6-one
1-methyl-N- ([ 1- [ ([ [4- (2-methylpropyloxy) phenyl)]Methyl group]Amino) methyl group]Cyclopropyl group]Methyl) piperidin-4-amine (50.00 mg,0.139 mmol) was dissolved in 5ml THF, triphosgene (50.00 mg,0.139 mmol) was added to the solution and stirred at room temperature for 2 hours. After the reaction, the reaction solution is poured into saturated NaHCO 3 Extraction with ethyl acetate, removal of solvent, column chromatography separation and purification (DCM: meoh=20:1) gave 5- (1-methylpiperidin-4-yl)-7- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-5, 7-diazaspiro [2.5]]17mg of octan-6-one with a yield of 31.7%. 1 H-NMR(400MHz,Methanol-d 4 ):δ7.21–7.09(m,2H),6.98–6.83(m,2H),4.47(s,2H),3.73(d,J＝6.5Hz,2H),3.59(d,J＝12.5Hz,2H),3.17(dt,J＝16.5,5.3Hz,2H),3.02(d,J＝12.2Hz,4H),2.90(s,3H),2.07(dq,J＝13.3,6.7Hz,1H),1.96(t,J＝11.7Hz,3H),1.04(d,J＝6.7Hz,6H),0.59(d,J＝4.6Hz,2H),0.52(d,J＝4.7Hz,2H).LCMS(ES,m/z):386[M+H] + 。
Example 2.5- (3-fluoro-1-methylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one (2)
The title compound was prepared as in example 1 by substituting 3-fluoro-1-methylpiperidin-4-amine for 1-methylpiperidin-4-amine, and the structural formula is shown in Table 1 under number (2). 1 H NMR(400MHz,Methanol-d 4 )δ7.18(dq,J＝8.7,2.3,1.6Hz,2H),6.95–6.81(m,2H),4.67–4.39(m,3H),3.73(dd,J＝6.5,1.1Hz,2H),3.46(ddt,J＝13.3,10.4,3.1Hz,1H),3.13–2.87(m,3H),2.85–2.66(m,1H),2.60(s,3H),2.32–2.18(m,1H),2.06(hept,J＝6.7Hz,1H),1.81–1.70(m,1H),1.04(d,J＝6.6Hz,6H),0.68–0.44(m,4H).LCMS(ES,m/z):404[M+H] + 。
Example 3.5- (4-isobutoxybenzyl) -7- (1-methylpyrrolidin-3-yl) -5, 7-diazaspiro [2.5] octane-6-one (3)
The title compound was prepared as in example 1 by substituting 1-methylpiperidin-4-amine for 1-methylpyrrolidine-3-amine, and the structural formula is shown in Table 1 under number (3). 1 H NMR(400MHz,DMSO-d 6 )δ7.17–7.05(m,2H),6.93–6.81(m,2H),4.98(qd,J＝9.5,9.0,5.8Hz,1H),4.41–4.29(m,2H),3.70(d,J＝6.5Hz,2H),3.12–3.01(m,2H),2.91(d,J＝2.4Hz,2H),2.85(td,J＝8.3,3.4Hz,1H),2.68(dd,J＝10.3,4.9Hz,1H),2.60(dd,J＝10.3,8.5Hz,1H),2.40(q,J＝8.3Hz,1H),2.34(s,3H),2.12–1.90(m,2H),1.69(dt,J＝13.6,7.3Hz,1H),0.97(d,J＝6.7Hz,6H),0.54(q,J＝3.5Hz,2H),0.42(q,J＝3.5Hz,2H).LCMS(ES,m/z):298[M+H] + 。
Example 4.5- (2- (dimethylamino) ethyl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octane-6-one (4)
The title compound was prepared as in example 1 by substituting N, N-dimethylethane-1, 2-diamine for 1-methylpiperidin-4-amine, and the structural formula is shown in Table 1 under number (4). 1 H NMR(400MHz,DMSO-d 6 )δ7.17–7.11(m,2H),6.90–6.84(m,2H),4.36(s,2H),3.71(d,J＝6.4Hz,2H),3.62(s,1H),3.27–3.11(m,5H),2.94(s,2H),2.80(d,J＝4.9Hz,6H),1.99(tt,J＝12.8,6.1Hz,1H),0.97(d,J＝6.7Hz,7H),0.57(t,J＝2.8Hz,2H),0.46–0.38(m,2H).LCMS(ES,m/z):360[M+H] + 。
Example 5.5- (4-methoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (5)
The reaction material 1- [4- (2-methylpropyloxy) phenyl]The title compound was prepared as in example 1 by substituting 4-methoxybenzylamine for methylamine and has the structural formula shown in Table 1 under number (5). 1 H NMR(400MHz,DMSO-d 6 )δ7.14(d,J＝8.2Hz,2H),6.88(d,J＝8.3Hz,2H),4.37(s,3H),3.73(s,3H),3.13(m,2H),3.00(m,2H),2.92(s,4H),2.71(d,J＝4.9Hz,3H),2.00–1.85(m,2H),1.69(d,J＝13.3Hz,2H),0.52(d,J＝5.5Hz,4H).LCMS(ES,m/z):344[M+H] + 。
Example 6.5- (4-Cyclopropoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (6)
The reaction material 1- [4- (2-methylpropyloxy) phenyl]The title compound was prepared as in example 1 by substituting (4-cyclopropoxyphenyl) methylamine for methylamine and has the structural formula shown in Table 1 under number (6). 1 H NMR(400MHz,DMSO-d 6 )δ7.17–7.10(m,1H),7.02–6.95(m,1H),4.37(s,1H),3.80(tt,J＝6.1,3.0Hz,1H),3.16–3.11(m,1H),2.93(d,J＝3.4Hz,2H),2.60(s,1H),2.49(s,2H),1.81–1.70(m,1H),1.58(d,J＝12.5Hz,1H),1.27–1.22(m,2H),0.81–0.69(m,1H),0.67–0.58(m,1H),0.52(t,J＝2.7Hz,1H),0.50–0.40(m,1H).LCMS(ES,m/z):370[M+H] + 。
Example 7.5- (4- (cyclopropylmethoxy) benzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (7)
The reaction material 1- [4- (2-methylpropyloxy) phenyl]The methylamine is replaced with (4- (cyclopropane)The title compound was prepared as in example 1, having the structural formula shown in table 1 under number (7). 1 HNMR(400MHz,DMSO-d 6 )δ7.11(d,J＝8.3Hz,2H),6.90–6.82(m,2H),4.34(s,2H),4.12(tt,J＝12.2,4.2Hz,1H),3.77(d,J＝6.9Hz,2H),2.90(d,J＝15.5Hz,4H),2.79(d,J＝11.1Hz,2H),2.14(s,3H),1.90(td,J＝11.7,2.5Hz,2H),1.56(qd,J＝12.2,4.0Hz,2H),1.47–1.38(m,2H),1.21(ddt,J＝12.3,7.8,3.8Hz,1H),0.62–0.47(m,4H),0.39(q,J＝4.2Hz,2H),0.34–0.26(m,2H).LCMS(ES,m/z):384[M+H] + 。
Example 8.5- (1-Benzylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one (8)
The title compound was prepared as in example 1 by substituting 1-methylpiperidin-4-amine for 1-benzylpiperidin-4-amine, and the structural formula is shown in Table 1 under number (8). 1 H NMR(400MHz,DMSO-d 6 )δ7.66–7.55(m,2H),7.52–7.42(m,3H),7.16–7.07(m,2H),6.91–6.82(m,2H),4.50–4.35(m,1H),4.35(s,2H),4.26(d,J＝5.2Hz,2H),3.70(d,J＝6.5Hz,2H),3.09(d,J＝11.2Hz,2H),3.03(d,J＝11.7Hz,2H),2.90(s,4H),1.99(ddd,J＝13.3,7.6,5.2Hz,3H),1.69(d,J＝12.2Hz,2H),0.96(d,J＝6.7Hz,6H),0.52–0.39(m,4H).LCMS(ES,m/z):462[M+H] + 。
Example 9.5- (1- (2, 2-difluoroethyl) piperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one (9)
The title compound was prepared as in example 1 by substituting 1- (difluoromethyl) piperidin-4-amine for 1-methylpiperidin-4-amine, and the structural formula was shown in Table 1 under number (9). 1 H NMR(400MHz,DMSO-d 6 )δ7.15–7.08(m,1H),6.90–6.83(m,1H),4.35(s,1H),3.71(d,J＝6.5Hz,1H),2.92(d,J＝19.2Hz,3H),2.73(d,J＝14.6Hz,1H),2.22(t,J＝11.4Hz,1H),2.00(dt,J＝13.2,6.6Hz,0H),1.57(d,J＝13.0Hz,1H),1.44(d,J＝11.8Hz,1H),0.97(d,J＝6.7Hz,3H),0.51(s,1H),0.40(s,1H).LCMS(ES,m/z):436[M+H] + 。
Example 10.5- (4-isobutoxybenzyl) -7- (2-methyl-2-azaspiro [3.3] heptan-6-yl) -5, 7-diazaspiro [2.5] octan-6-one (10)
1-methylpiperidin-4-amine as reaction material is replaced by 2-methyl-2-aza spiro [3.3]]Heptane-6-amine the title compound was prepared as in example 1, having the structural formula shown in table 1 under number (10). 1 H NMR(400MHz,DMSO-d 6 )δ7.10(d,J＝8.3Hz,2H),6.86(d,J＝8.5Hz,2H),4.71(q,J＝8.8Hz,1H),4.32(s,2H),3.70(d,J＝6.5Hz,2H),3.42(s,2H),3.26(s,2H),2.99(s,2H),2.89(s,2H),2.32(s,3H),2.15(d,J＝8.9Hz,3H),1.98(dq,J＝13.3,6.6Hz,1H),1.36(s,1H),0.97(d,J＝6.7Hz,6H),0.52(d,J＝4.5Hz,2H),0.40(s,2H).LCMS(ES,m/z):398[M+H] + 。
Example 11.5- (1-methylpiperidin-4-yl) -7- (4- (neopentyloxy) benzyl) -5, 7-diazaspiro [2.5] octan-6-one (11)
The reaction material 1- [4- (2-methylpropyloxy) phenyl]The title compound was prepared as in example 1 by substituting (4- (neopentyloxy) phenyl) methylamine and the structural formula is shown in table 1 under number (11). 1 H NMR(400MHz,Methanol-d 4 )δ7.21–7.14(m,2H),6.92–6.84(m,2H),4.59–4.41(m,3H),3.63–3.55(m,4H),3.17(td,J＝12.9,3.3Hz,2H),3.06(s,2H),3.00(s,2H),2.89(s,3H),2.03(qd,J＝13.1,3.9Hz,2H),1.96–1.87(m,2H),1.05(s,9H),0.68–0.56(m,2H),0.50(t,J＝3.0Hz,2H).LCMS(ES,m/z):427[M+H] + 。
EXAMPLE 12.5- (4-isobutoxybenzyl) -7- (1-isobutylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (12)
The title compound was prepared as in example 1, with the replacement of 1-methylpiperidin-4-amine for 1-isobutylpiperidin-4-amine as the starting material, and the structural formula was shown as number (12) in Table 1. 1 H NMR(400MHz,DMSO-d 6 )δ7.15–7.07(m,2H),6.91–6.83(m,2H),4.35(s,2H),4.20–4.03(m,1H),3.71(d,J＝6.5Hz,2H),2.94(s,2H),2.87(d,J＝12.2Hz,4H),2.07–1.87(m,5H),1.74(dq,J＝13.6,6.9Hz,1H),1.63–1.50(m,2H),1.45(d,J＝11.5Hz,2H),0.97(d,J＝6.7Hz,6H),0.84(d,J＝6.5Hz,6H),0.52(q,J＝4.1Hz,2H),0.39(q,J＝4.1Hz,2H).LCMS(ES,m/z):428[M+H] + 。
Example 13.5- (4-isobutoxybenzyl) -7- (1-isopropylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (13)
The title compound was prepared as in example 1, with the replacement of 1-methylpiperidin-4-amine for 1-isopropylpiperidin-4-amine, and the structural formula was shown as number (13) in Table 1. 1 H NMR(400MHz,DMSO-d 6 )δ7.15–7.08(m,2H),6.90–6.83(m,2H),4.35(s,2H),4.15(dt,J＝11.2,6.0Hz,1H),3.71(d,J＝6.5Hz,2H),2.91(d,J＝16.9Hz,4H),2.85(s,2H),2.81–2.70(m,1H),2.23(t,J＝11.0Hz,2H),2.06–1.91(m,1H),1.51(s,5H),0.97(dd,J＝6.6,2.1Hz,12H),0.50(d,J＝4.4Hz,2H),0.43–0.36(m,2H).LCMS(ES,m/z):414[M+H] + 。
EXAMPLE 14.6- (4-isobutoxybenzyl) -8- (1-methylpiperidin-4-yl) -6, 8-diazaspiro [3.5] non-7-one (14)
The title compound was prepared by the method of example 1 by substituting 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid for 1- (ethoxycarbonyl) cyclobutane-1-carboxylic acid, and the structural formula is shown in Table 1 under number (14). 1 H NMR(400MHz,DMSO-d 6 )δ7.14(d,J＝8.1Hz,2H),6.87(d,J＝8.2Hz,2H),4.35(s,3H),3.71(d,J＝6.5Hz,2H),3.42(d,J＝11.9Hz,2H),3.15–3.05(m,6H),2.72(d,J＝4.8Hz,3H),2.00(td,J＝13.3,11.8,4.8Hz,3H),1.90–1.81(m,2H),1.68(d,J＝11.5Hz,6H),0.97(d,J＝6.7Hz,6H).LCMS(ES,m/z):400[M+H] + 。
EXAMPLE 15.5- (4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-thione (15)
The target compound was prepared as in example 1 by replacing the reaction raw material triphosgene with thiophosgene, and the structural formula is shown as number (15) in table 1. 1 H NMR(400MHz,DMSO-d 6 )δ7.23(d,J＝8.3Hz,2H),6.88(d,J＝8.4Hz,2H),5.65(tt,J＝11.4,4.7Hz,1H),5.11(s,2H),3.71(d,J＝6.5Hz,2H),3.41(d,4H),3.11(d,J＝11.3Hz,1H),3.06(d,J＝10.2Hz,4H),2.73(t,J＝5.7Hz,3H),1.99(qd,J＝12.7,12.0,5.8Hz,1H),1.88(s,3H),0.97(d,J＝6.7Hz,6H),0.53(s,2H),0.45(s,2H).LCMS(ES,m/z):402[M+H] + 。
EXAMPLE 16.5- (4-hydroxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (16) reaction scheme 2
Taking 5- (4-methoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5]]Octane-6-one (100 mg,0.0291 mmol) (prepared as in example 5) and 20ml of dichloromethane were mixed, cooled in an ice-water bath, and purged with nitrogen, boron tribromide (7.5 mg,0.0300 mmol) dissolved in dichloromethane was slowly added dropwise thereto, and the mixture was left to react at room temperature after the completion of the dropwise addition. After the reaction, water is added dropwise to perform a hair-quenching reaction, the organic phase is washed by saturated sodium bicarbonate solution, the solvent is removed, and the mixture is separated and purified by column chromatography (DCM: meOH=20:1) to obtain 5- (4-hydroxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5]]67mg of octan-6-one and 70.0% of yield. 1 HNMR(400MHz,DMSO-d 6 )δ9.26(s,1H),7.04–6.97(m,2H),6.72–6.65(m,2H),4.30(s,3H),2.90(d,J＝17.3Hz,4H),2.79(d,J＝11.1Hz,2H),2.14(s,3H),1.90(t,J＝11.1Hz,2H),1.56(td,J＝13.1,9.3Hz,2H),1.42(d,J＝11.6Hz,2H),0.54–0.47(m,2H),0.40(t,J＝2.9Hz,2H).LCMS(ES,m/z):330[M+H] + 。
EXAMPLE 17.7- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.6] nonan-6-one (17)
Reaction 3
17.1 Preparation of 2- (1-formylcyclopropyl) acetonitrile
2- [1- (hydroxymethyl) cyclopropyl ] acetonitrile (2.50 g,22.493 mmol) and silica gel (2.50 g,41.608 mmol) were added to 25.00 dichloromethane, nitrogen blanketed, cooled to 0deg.C, PCC (7.27 g,33.727 mmol) was added, stirred for 2 hours, filtered, the filter cake was washed with dichloromethane, and the solvent was removed under pressure to give 3g of 2- (1-formylcyclopropyl) acetonitrile in 122.22% yield as a tan oil.
17.2 Preparation of 2- [1- [ (1-methylpiperidin-4-yl) amino ] methyl ] cyclopropylacetonitrile
2- (1-formyl cyclopropyl) ethylNitrile (2.80 g, 25.618 mmol) and acetic acid (7.70 g,128.222 mmol) were added to 30.00mL of dichloromethane, nitrogen blanketed, 1-methylpiperidin-4-amine (3.21 g,28.210 mmol) was added, stirred for 30 min, STAB (8.16 g,38.501 mmol) was added, and the temperature was reduced to 0℃for reaction. After the reaction, 30ml of water was added dropwise at room temperature to quench the reaction. Extraction with dichloromethane (3X 10 ml), washing the organic phase with saturated brine, anhydrous Na 2 SO 4 And (5) drying. The filtrate was filtered and concentrated to dryness and the next reaction was carried out directly without purification.
17.3 preparation of benzyl (1- (cyanomethyl) cyclopropyl) methyl) (1-methylpiperidin-4-yl) carbamate
2- [1- [ (1-methylpiperidin-4-yl) amino ] amino]Methyl group]Cyclopropylacetonitrile (3.03 g, 14.65mmol) and Na 2 CO 3 (4.66 g,43.967 mmol) to 50ml THF/H 2 In the mixed solution of O, the temperature is reduced to 0 ℃ under the protection of nitrogen, benzyl chloroformate (2.75 g,16.121 mmol) is slowly added dropwise, and the temperature is raised to room temperature for reaction after the dropwise addition. After the reaction, 20ml of water was added at room temperature to quench the reaction. Extraction with ethyl acetate (3X 10 ml), washing of the organic phase with saturated brine, washing with anhydrous Na 2 SO 4 The organic phase was dried. Filtration, concentration of the filtrate to dryness, column chromatography separation and purification (n-hexane/ea=5:1) gave benzyl (1- (cyanomethyl) cyclopropyl) methyl) (1-methylpiperidin-4-yl) carbamate 1.9g, yield 38.1%, yellow oil.
17.4 preparation of benzyl [ [1- (2-aminoethyl) cyclopropyl ] methyl ] (1-methylpiperidin-4-yl) carbamate
Benzyl (1- (cyanomethyl) cyclopropyl) methyl) (1-methylpiperidin-4-yl) carbamate (1.52 g,4.444 mmol) and Raney-Ni (200.00 mg,2.334 mmol) were added to a solution of 20.00ml of methanolic amine, hydrogen gas was introduced and stirred at room temperature. After the reaction is finished, filtering, washing a filter cake with methanol, concentrating the filtrate under reduced pressure, and directly carrying out the next reaction without purifying the obtained product.
17.5 preparation of benzyl [ [1- [2- [ (4-isobutoxybenzyl) amino ] ethyl ] cyclopropyl ] methyl ] (1-methylpiperidin-4-yl) carbamate
Benzyl [ [1- (2-aminoethyl) cyclopropyl ]]Methyl group](1-methylpiperidin-4-yl) aminoFormate (1.92 g,5.561 mmol) and MgSO 4 (2.68 g,22.265 mmol) was added to 25.00ml of ethanol under nitrogen, and 4-isobutoxybenzaldehyde (1.09 g,6.116 mmol) was added portionwise. Cooling to 0deg.C, adding NaBH 4 (0.53 g,14.009 mmol) and after the addition was completed, the reaction was carried out at room temperature. After completion of the reaction, the temperature was lowered to 0℃and the reaction was quenched by adding 20ml of water, extracted with ethyl acetate (3X 10 ml), the organic phase was washed with saturated sodium chloride solution and with anhydrous Na 2 SO 4 And (5) drying. Filtering, concentrating the filtrate under reduced pressure to obtain benzyl [ [1- [2- [ (4-isobutoxybenzyl) amino ] amino group]Ethyl group]Cyclopropyl group]Methyl group](1-methylpiperidin-4-yl) carbamate 1.4g, yield 49.6%, yellow oil.
Preparation of 6N- [ [1- [2- [ (4-isobutoxybenzyl) amino ] ethyl ] cyclopropyl ] methyl ] -1-methylpiperidin-4-amine
Benzyl [ [1- [2- [ (4-isobutoxybenzyl) amino ] ethyl ] cyclopropyl ] methyl ] (1-methylpiperidin-4-yl) carbamate (1.40 g,2.358 mmol) was added to 15.00ml of tetrahydrofuran, pd/C (200.00 mg,1.879 mmol) was added thereto in portions, and the reaction was put under a hydrogen atmosphere to react at room temperature. After the reaction, the mixture was filtered and the cake was washed with tetrahydrofuran. The filtrate is concentrated to dryness under reduced pressure, and the obtained product is directly subjected to the next reaction without purification.
17.7 Preparation of 7- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.6] non-6-one
N- [ [1- [2- [ (4-isobutoxybenzyl) amino ] amino group]Ethyl group]Cyclopropyl group]Methyl group]1-methylpiperidin-4-amine (0.65 g,1.740 mmol) and triethanolamine (0.70 g,6.909 mmol) were added to 10.00ml tetrahydrofuran, cooled to-78℃and nitrogen protected, and triphosgene (0.21 g, 0.514 mmol) was slowly added. After the reaction, 4ml of saturated NaHCO was added at room temperature 3 The reaction was quenched with solution. The aqueous phase was extracted with ethyl acetate (3X 10 ml), the organic phase was washed with saturated sodium chloride solution, and dried over anhydrous Na 2 SO 4 And (5) drying. Filtration, concentration of the filtrate under reduced pressure, and purification by column chromatography (DCM: meoh=20:1) afforded 7- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [ 2.6)]0.12g of nonyl-6-ketone with the yield of 17.4 percent. 1 H NMR(400MHz,DMSO-d 6 )δ7.24(d,J＝8.0Hz,2H),6.87(d,J＝8.1Hz,2H),4.28(s,2H),3.87(s,2H),3.71(s,2H),3.39(d,J＝11.1Hz,5H),2.85(s,2H),2.68(s,3H),2.03–1.95(m,3H),1.79(d,J＝12.9Hz,2H),1.39–1.33(m,2H),0.97(d,J＝6.7Hz,6H),0.37(d,J＝11.5Hz,4H).LCMS(ES,m/z):400[M+H] + 。
EXAMPLE 18.5- (4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.6] non-6-one (18)
The title compound was prepared as in example 17, substituting 1-methylpiperidin-4-amine for (4-isobutoxyphenyl) methylamine and substituting 1-methyl-4-piperidone for 4-isobutoxybenzaldehyde, and the structural formula was shown as number (18) in Table 1. 1 H NMR(400MHz,DMSO-d 6 )δ7.24–7.18(m,2H),6.90–6.82(m,2H),4.20(s,2H),3.92(s,1H),3.71(d,J＝6.6Hz,2H),3.13(s,2H),3.06(d,J＝12.0Hz,2H),2.81(s,2H),2.75(d,J＝4.9Hz,3H),2.56(m,2H),2.05(m,2H),1.92(m,1H),1.88(s,2H),1.40(s,2H),0.97(d,J＝6.7Hz,6H),0.26(d,J＝4.5Hz,2H),0.17(d,J＝4.4Hz,2H).LCMS(ES,m/z):400[M+H] + 。
EXAMPLE 19.7- [ (dimethylamino) methyl ] -5- (4-isobutoxybenzyl) -5-azaspiro [2.5] octan-6-one (19) reaction scheme 4
19.1 Preparation of 5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -6-oxo-5-azaspiro [2.5] octane-7-carbaldehyde
5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -5-azaspiro [2.5] octan-6-one (1.00 g,3.479 mmol) and LiHMDS (5.00 ml) were added to a 5.00ml tetrahydrofuran solution, the temperature was lowered to-78℃under nitrogen protection, and the reaction mixture was allowed to react for 1 hour, DMF (508.65 mg,6.959 mmol) was slowly added dropwise thereto, and the reaction mixture was allowed to react at-78℃for 1 hour. After the completion of the reaction, 10ml of water was added to quench the reaction, the reaction mixture was extracted with ethyl acetate (3X 10 ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give 600mg of 5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -6-oxo-5-azaspiro [2.5] octane-7-carbaldehyde in a yield of 54.7%. A light brown oil.
19.2 Preparation of 7- (hydroxymethyl) -5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -5-azaspiro [2.5] octan-6-one
5- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-6-oxo-5-azaspiro [2.5]]Octane-7-carbaldehyde (600.00 mg,1.902 mmol) and 5.00mL methanol were added to a 25mL round bottom flask, nitrogen was purged, the temperature was lowered to 0℃and NaBH was added 4 (215.91 mg,5.707 mmol) and allowed to react at room temperature for 30 minutes. After completion of the reaction, the reaction was quenched by adding 10ml of water, extracted with ethyl acetate (3X 10 ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give 7- (hydroxymethyl) -5- [ [4- (2-methylpropyloxy) phenyl)]Methyl group]-5-azaspiro [2.5]]600mg of octan-6-one with 99.36 percent of yield.
19.3 (5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -6-oxo-5-azaspiro [2.5] oct-7-yl) methyl methanesulfonate
7- (hydroxymethyl) -5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -5-azaspiro [2.5] octan-6-one (150.00 mg,0.473 mmol), 2.00mL tetrahydrofuran and triethylamine (95.64 mg,0.945 mmol) were added to an 8mL sealed tube, the temperature was reduced to 0℃under nitrogen protection, msCl (81.20 mg,0.709 mmol) was added, and the reaction was allowed to proceed at room temperature for 30 minutes after the completion of the addition. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate (3X 10 ml), and the organic phase was dried over anhydrous sodium sulfate, and the dried filtrate was concentrated under reduced pressure. 110mg of (5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -6-oxo-5-azaspiro [2.5] oct-7-yl) methylsulfonate was obtained in a yield of 58.86% as a light brown oil.
19.4 Preparation of 7- [ (dimethylamino) methyl ] -5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -5-azaspiro [2.5] octan-6-one
(5- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-6-oxo-5-azaspiro [2.5]]Octane-7-yl) methyl methanesulfonate (110.00 mg,0.278 mmol), dimethylamine hydrochloride (45.36 mg, 0.554 mmol) and DIEA (107.84 mg,0.834 mmol) were added to 3.00ml ethylene glycol and reacted at 80℃for 3 hours. The organic phase was dried over anhydrous sodium sulfate, extracted with ethyl acetate (3×10 ml) and the filtrate concentrated under reduced pressure. Column chromatography separation and purification (DCM: meoh=20:1)To obtain 7- [ (dimethylamino) methyl]-5- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-5-azaspiro [2.5]]37.7mg of octan-6-one with a yield of 39.35%. 1 H NMR(400MHz,Methanol-d 4 )δ7.28–7.14(m,2H),6.94–6.82(m,2H),4.76(d,J＝14.4Hz,1H),4.32(d,J＝14.4Hz,1H),3.74(d,J＝6.5Hz,2H),3.60(d,J＝12.5Hz,1H),3.49(t,J＝13.0Hz,1H),3.10(d,J＝10.0Hz,1H),2.99(d,J＝13.5Hz,6H),2.59(dd,J＝12.5,1.7Hz,1H),2.12–1.91(m,2H),1.30(dd,J＝13.1,5.5Hz,1H),1.04(d,J＝6.7Hz,6H),0.63–0.35(m,4H).LCMS(ES,m/z):345[M+H] + 。
EXAMPLE 20.7- (dimethylamino) -5- (4-isobutoxybenzyl) -5-azaspiro [2.5] octane-6-one (20)
Reaction 5
Dimethylamine (21.82 mg, 0.284 mmol), DMF (5.00 mL) and DIEA (125.08 mg,0.968 mmol) were added to a 25mL round bottom flask, stirred for 0.5 h, and 7-iodo-5- [ [4- (2-methylpropyloxy) phenyl ] was added]Methyl group]-5-azaspiro [2.5]]Octan-6-one (100.00 mg,0.242 mmol), warmed to 60℃and reacted overnight. After the reaction was completed, ethyl acetate was extracted (2×20 ml), the organic phase was washed with water (2×20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under pressure to dryness. Column chromatography purification (DCM: meoh=20:1) afforded 7- (dimethylamino) -5- (4-isobutoxybenzyl) -5-azaspiro [ 2.5) ]63.6mg of octan-6-one, yield 69.82%. 1 H NMR(400MHz,DMSO-d 6 ):δ7.17–7.04(m,2H),6.94–6.80(m,2H),4.54–4.32(m,2H),3.71(d,J＝6.5Hz,2H),3.57–3.39(m,2H),2.42(s,6H),2.35(dd,J＝12.0,2.0Hz,1H),2.16(t,J＝12.2Hz,1H),2.00(hept,J＝6.6Hz,1H),1.25(ddd,J＝13.0,6.4,2.0Hz,1H),0.97(d,J＝6.7Hz,6H),0.50–0.37(m,3H),0.34–0.24(m,1H).LCMS(ES,m/z):331[M+H] + 。
Example 21.7- (azetidin-1-yl) -5- (4-isobutoxybenzyl) -5-azaspiro [2.5] octan-6-one (21)
The reaction starting material dimethylamine was replaced by heteroalicyclobutane as in the examples20, and the structural formula of the target compound is shown as a number (21) in table 1. 1 H NMR(400MHz,DMSO-d 6 ):δ7.17–7.04(m,2H),6.94–6.80(m,2H),4.54–4.32(m,2H),3.71(d,J＝6.5Hz,2H),3.57–3.39(m,2H),3.21–3.24(m，4H),2.35(dd,J＝12.0,2.0Hz,1H),2.21–2.23(m,2H),2.16(t,J＝12.2Hz,1H),2.00(hept,J＝6.6Hz,1H),1.25(ddd,J＝13.0,6.4,2.0Hz,1H),0.97(d,J＝6.7Hz,6H),0.50–0.37(m,3H),0.34–0.24(m,1H).LCMS(ES,m/z):343[M+H] + 。
EXAMPLE 22.1- (4-isobutoxybenzyl) -5-methyl-3- (1-methylpiperidin-4-yl) -5-phenyltetrahydropyrimidin-2 (1H) -one (22)
The title compound was prepared by the method of example 1, substituting 3-ethoxy-2-methyl-3-oxo-2-phenylpropionic acid for 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid, and the structural formula is shown in table 1 under number (22). 1 HNMR(400MHz,Methanol-d 4 )δ7.24(dtd,J＝11.1,8.0,4.0Hz,7H),6.89(d,J＝8.5Hz,2H),4.52(s,2H),4.50–4.37(m,1H),3.75(dd,J＝6.5,1.2Hz,2H),3.53(dd,J＝24.8,11.9Hz,4H),3.35(s,1H),3.27(d,J＝12.1Hz,1H),3.11(dt,J＝24.3,13.1Hz,2H),2.92–2.79(m,3H),2.22–1.95(m,3H),1.88(d,J＝13.7Hz,1H),1.47(d,J＝13.8Hz,1H),1.28(d,J＝1.5Hz,3H),1.05(dd,J＝6.7,1.2Hz,6H).LCMS(ES,m/z):450[M+H] + 。
Example 23.5,5-difluoro-1- (4-isobutoxybenzyl) -3- (1-methylpiperidin-4-yl) tetrahydropyrimidin-2 (1H) -one (23)
The title compound was prepared by the method of example 1 by substituting 3-ethoxy-2, 2-difluoro-3-oxopropanoic acid for 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid, and the structural formula is shown in Table 1 under number (23). 1 H NMR(400MHz,Methanol-d 4 )δ7.21(d,J＝8.4Hz,2H),6.95–6.83(m,2H),4.50(s,3H),3.74(d,J＝6.4Hz,2H),3.58(dt,J＝42.1,12.5Hz,6H),3.34(s,2H),3.20(td,J＝13.1,3.0Hz,2H),2.90(s,3H),2.21–2.00(m,3H),2.00–1.90(m,2H),1.04(d,J＝6.7Hz,6H).LCMS(ES,m/z):396[M+H] + 。
Example 24.5,5-difluoro-1- (4-isobutoxybenzyl) -3- (1-methylpiperidin-4-yl) tetrahydropyrimidin-2 (1H) -one (24)
By reacting the raw materialsThe title compound was prepared by the method of example 1 by substituting 3-ethoxy-2-methyl-3-oxopropionic acid for 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid, and the structural formula is shown in Table 1 under number (24). 1 H NMR(400MHz,Methanol-d 4 )δ7.19(d,J＝8.5Hz,2H),6.90–6.85(m,2H),4.47(s,3H),3.74(d,J＝6.4Hz,2H),3.68–3.54(m,2H),3.30–3.26(m,1H),3.26–3.13(m,3H),2.89(d,J＝9.6Hz,5H),2.07(td,J＝13.0,6.2Hz,4H),1.92(t,J＝12.8Hz,2H),1.04(d,J＝6.7Hz,6H),0.99(d,J＝6.7Hz,3H).LCMS:(ES,m/z):374[M+H] + 。
Example 25 5- (-isobutoxybenzyl) 7- (-methylpiperazin-1-yl) 5-azaspiro [2.5] octan-6-one (25)
The title compound was prepared by the method of example 20 by substituting N-methylpiperazine for dimethylamine as the reaction material, and the structural formula of the title compound is shown in Table 1 under the number (25). 1 H NMR(400MHz,DMSO-d 6 )δ11.90(s,1H),7.17(dd,J＝9.0,2.5Hz,2H),6.89(dd,J＝9.2,2.6Hz,2H),4.59(d,J＝14.6Hz,1H),4.48–4.43(m,2H),4.36(d,J＝14.6Hz,1H),3.89(d,J＝11.7Hz,1H),3.70(t,J＝10.3Hz,5H),3.63–3.33(m,5H),2.82(s,3H),2.48(d,J＝9.9Hz,2H),2.00(hept,J＝6.6Hz,1H),1.62(dd,J＝11.9,5.9Hz,1H),0.97(d,J＝6.7Hz,6H),0.61(d,J＝2.6Hz,2H),0.59–0.49(m,1H),0.38(d,J＝9.3Hz,1H).LCMS(ES,m/z):386[M+H] + 。
EXAMPLE 26 5- (-isobutoxybenzyl) 7- (-methylpiperazin-1-yl) 5-azaspiro [2.5] octan-6-one (26)
The reaction raw material 7-iodo-5- [ [4- (2-methylpropyloxy) phenyl ]]Methyl group]-5-azaspiro [2.5]]Replacement of octan-6-one with 7-iodo-5- (1-methylpiperidin-4-yl) -5-azaspiro [2.5]]The title compound was prepared by the method of example 20, replacing octane-6-one with 4-isobutoxybenzaldehyde, and the structural formula of the title compound was shown in the number (26) of Table 1. 1 H NMR(400MHz,Methanol-d 4 )δ7.16–7.00(m,2H),6.88–6.75(m,2H),4.41(tt,J＝12.1,4.3Hz,1H),3.71(d,J＝6.4Hz,2H),3.29(d,J＝12.4Hz,1H),3.17(dd,J＝12.8,3.3Hz,1H),3.02–2.88(m,2H),2.84–2.61(m,3H),2.31(s,3H),2.17(tdd,J＝12.1,7.1,2.7Hz,2H),2.10–1.97(m,J＝6.7Hz,1H),1.82–1.66(m,2H),1.65–1.54(m,2H),1.16(ddd,J＝13.3,6.5,1.9Hz,1H),1.04(d,J＝6.7Hz,6H),0.50(dddd,J＝34.8,19.0,9.7,5.1Hz,3H),0.35(dt,J＝9.7,4.9Hz,1H).LC MS(ES,m/z):385[M+H] + 。
EXAMPLE 27 5- [ (6-Isobutoxypyridin-3-yl) methyl ] -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-one (27)
The reaction material 1- [4- (2-methylpropyloxy) phenyl]The title compound was prepared by the method of example 1 by substituting methyl amine with (6-isobutylpyridin-3-yl) methyl amine and the structural formula is shown in Table 1 under number (27). 1 HNMR(400MHz,Methanol-d 4 )δ8.43(dd,J＝9.1,2.3Hz,1H),8.25(d,J＝2.3Hz,1H),7.61(d,J＝9.1Hz,1H),4.59(s,2H),4.47(tt,J＝12.3,4.1Hz,1H),4.28(d,J＝6.5Hz,2H),3.68–3.54(m,2H),3.19(s,3H),3.15(dd,J＝12.8,2.8Hz,2H),3.11(s,2H),2.89(s,3H),2.23(hept,J＝6.7Hz,1H),2.06(qd,J＝13.3,4.0Hz,2H),1.94–1.82(m,2H),1.12(d,J＝6.7Hz,6H),0.76–0.56(m,4H).LC MS(ES,m/z):387[M+H] + 。
Example 28 5- (2-fluoro-4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-one (28)
The reaction material 1- [4- (2-methylpropyloxy) phenyl]The title compound was prepared by the method of example 1 by substituting (2-fluoro-4-isobutoxyphenyl) methylamine for methylamine and the structural formula is shown in Table 1 as number (28). 1 HNMR(400MHz,Methanol-d 4 )δ7.22(t,J＝8.7Hz,1H),6.73(dd,J＝8.5,2.5Hz,1H),6.66(dd,J＝12.1,2.5Hz,1H),4.52(s,2H),4.28(tt,J＝11.7,4.7Hz,1H),3.74(d,J＝6.5Hz,2H),3.03(s,4H),2.96(dq,J＝11.6,2.8,2.0Hz,2H),2.31(s,3H),2.16(td,J＝11.8,3.3Hz,2H),2.05(dh,J＝13.4,6.7Hz,1H),1.76–1.58(m,4H),1.04(d,J＝6.7Hz,6H),0.64–0.56(m,2H),0.53(d,J＝4.6Hz,2H).LC MS:(ES,m/z):404[M+H] + 。
Example 29 5- (3-fluoro-4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (29)
The reaction material 1- [4- (2-methylpropyloxy) phenyl]The title compound was prepared by the method of example 1 by substituting (3-fluoro-4-isobutoxyphenyl) methylamine for methylamine and has the structural formula shown in Table 1And number (29). 1 HNMR(400MHz,DMSO-d6)δ7.09(t,J＝8.6Hz,1H),7.02(dd,J＝12.3,2.0Hz,1H),6.95(dd,J＝8.5,2.1Hz,1H),4.34(s,2H),4.11(tt,J＝12.1,4.1Hz,1H),3.79(d,J＝6.5Hz,2H),2.93(d,J＝7.2Hz,4H),2.83–2.75(m,2H),2.14(s,3H),2.03(dh,J＝13.4,6.7,6.3Hz,1H),1.90(td,J＝11.8,2.5Hz,2H),1.57(qd,J＝12.1,3.9Hz,2H),1.47–1.38(m,2H),0.97(d,J＝6.7Hz,6H),0.52(q,J＝4.2Hz,2H),0.42(t,J＝2.8Hz,2H).LCMS(ES,m/z):404[M+H] + 。
Example 30 5- (4-isobutoxybenzyl) -7- (1-methylazo-4-yl) -5-7-diazaoxazol [2.5] octan-6-one (30)
The title compound was prepared as in example 1, with the replacement of 1-methylazepan-4-amine by 1-methyl-4-piperidylamine as the starting material, and the structural formula is shown in Table 1 under the number (30). 1 H-NMR(400MHz,Methanol-d 4 ):δ7.17(d,J＝8.3Hz,2H),6.87(d,J＝8.2Hz,2H),4.52–4.40(m,3H),3.73(d,J＝6.4Hz,2H),3.58–3.42(m,2H),3.50(s,4H),3.25(dt,J＝14.5,11.0Hz,1H),3.22–2.97(m,4H),2.95(d,J＝22.1Hz,1H),2.91(s,2H),2.38–1.66(m,4H),1.04(d,J＝6.7Hz,6H),0.63(d,J＝3.7Hz,2H),0.48(d,J＝3.2Hz,2H).LCMS(ES,m/z):400[M+H] + 。
Example 31- ((2R) -1, 2-dimethylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octane-6-one (31)
The title compound was prepared as in example 1 by substituting (2R) -1, 2-dimethylpiperidin-4-amine for 1-methyl-4-piperidinamine as the starting material, and the structural formula was shown as number (31) in Table 1. 1 H NMR(400MHz,Methanol-d 4 )δ7.18(d,J＝8.3Hz,2H),6.87(d,J＝8.4Hz,2H),4.57(tq,J＝11.9,4.4Hz,1H),4.47(s,2H),3.73(d,J＝6.4Hz,2H),3.59(ddd,J＝12.7,4.2,2.3Hz,1H),3.26–3.13(m,1H),3.08(s,2H),3.00(d,J＝2.1Hz,2H),2.89(s,3H),2.09(dtd,J＝26.6,13.3,5.5Hz,2H),2.00–1.81(m,2H),1.46(d,J＝6.3Hz,3H),1.04(d,J＝6.7Hz,6H),0.63(q,J＝4.7Hz,2H),0.50(d,J＝4.8Hz,2H).LCMS(ES,m/z):400[M+H] + 。
Example 32 5- ((2S) -1, 2-dimethylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one (32)
The title compound was prepared as in example 1, with the replacement of 1-methyl-4-piperidylamine with (2S) -1, 2-dimethylpiperidin-4-amine, having the structural formula shown in Table 1 under number (32). 1 H NMR(400MHz,Methanol-d 4 )δ7.18(d,J＝8.2Hz,2H),6.87(d,J＝8.4Hz,2H),4.75(ddt,J＝12.6,7.7,3.8Hz,1H),4.47(s,2H),3.90–3.79(m,1H),3.73(d,J＝6.5Hz,2H),3.36(p,J＝4.6,3.7Hz,1H),3.08–2.96(m,4H),2.82(s,2H),2.23(td,J＝13.2,5.0Hz,1H),2.06(p,J＝6.8Hz,1H),1.93–1.76(m,2H),1.58(d,J＝7.0Hz,1H),1.49(d,J＝6.0Hz,2H),1.04(d,J＝6.7Hz,6H),0.62(q,J＝5.5,4.8Hz,2H),0.50(d,J＝4.6Hz,2H).LCMS(ES,m/z):400[M+H] + 。
Example 33 5- (2-chloro-4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (33)
The reaction material 1- [4- (2-methylpropyloxy) phenyl]The title compound was prepared by the method of example 1 by substituting (2-chloro-4-isobutoxyphenyl) methylamine for methylamine and the structural formula is shown in Table 1 as number (33). 1 HNMR(400MHz,Methanol-d 4 )δ7.21(d,J＝8.5Hz,1H),6.96(d,J＝2.4Hz,1H),6.88(dd,J＝8.6,2.5Hz,1H),4.59(s,2H),4.56–4.45(m,1H),3.74(d,J＝6.4Hz,2H),3.64–3.52(m,2H),3.26–3.14(m,2H),3.12(s,2H),3.04(s,2H),2.88(s,3H),2.09(dtd,J＝29.7,13.1,5.1Hz,3H),1.90(d,J＝13.5Hz,2H),1.03(d,J＝6.7Hz,6H),0.67(d,J＝4.8Hz,2H),0.57(d,J＝4.8Hz,2H).LCMS(ES,m/z):420[M+H] + 。
Example 34 5- (3-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-one (34)
The reaction material 1- [4- (2-methylpropyloxy) phenyl]Substitution of methylamine for 1- [3- (2-methylpropyloxy) phenyl]The target compound was prepared as in example 1, and the structural formula is shown in table 1 under number (33). 1 H NMR(400MHz,Methanol-d 4 )δ7.27–7.18(m,1H),6.81(d,J＝8.3Hz,3H),4.51(s,2H),4.31(tt,J＝11.6,4.7Hz,1H),3.74(d,J＝6.5Hz,2H),3.05(s,2H),3.03–2.89(m,4H),2.31(s,3H),2.16(td,J＝11.8,3.4Hz,2H),2.06(dp,J＝13.2,6.6Hz,1H),1.78–1.60(m,4H),1.04(d,J＝6.7Hz,6H),0.64–0.53(m,2H),0.53–0.40(m,2H).LCMS(ES,m/z):386[M+H] + 。
Example 35 4- (4-isobutoxybenzyl) -6- (1-methylpiperidin-4-yl) -4, 6-diazaspiro [2.4] heptane-5-one (35)
Replacement of the starting 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid with 1- [ (tert-butoxycarbonyl) amino group]Cyclopropane-1-carboxylic acid, 1- [4- (2-methylpropyloxy) phenyl ]]The title compound was prepared as in example 1 by substituting 1-methyl-4-piperidylamine and substituting 4- (2-methylpropyloxy) benzaldehyde by 1-methyl-4-piperidylamine, and the structural formula is shown in Table 1 under the number (35). 1 H NMR(400MHz,Methanol-d 4 )δ7.10(d,J＝8.2Hz,2H),6.87(d,J＝8.2Hz,2H),6.33(s,1H),4.83(s,2H),4.02(tt,J＝10.8,5.9Hz,1H),3.73(d,J＝6.5Hz,2H),3.02(d,J＝11.9Hz,2H),2.34(d,J＝12.5Hz,5H),2.22(td,J＝11.4,4.3Hz,2H),2.05(hept,J＝6.6Hz,1H),1.88(td,J＝11.6,10.5,3.6Hz,4H),1.12(t,J＝7.4Hz,3H),1.03(d,J＝6.7Hz,6H).LCMS(ES,m/z):372[M+H] + 。
Example 36 6- (4-isobutoxybenzyl) -4- (1-methylpiperidin-4-yl) -4, 6-diazaspiro [2.4] heptane-5-one (36)
Replacement of the starting 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid with 1- [ (tert-butoxycarbonyl) amino group]Cyclopropane-1-carboxylic acid, 1-methyl-4-piperidinamine was replaced with 1-methylpiperidine-4-carbaldehyde, and the title compound was prepared as described in example 1, with the structural formula shown in Table 1 under the number (36). 1 H NMR(400MHz,Methanol-d 4 )δ7.22–7.14(m,2H),6.93–6.85(m,2H),4.29(s,2H),3.74(d,J＝6.5Hz,2H),3.22(s,2H),3.04–2.89(m,2H),2.57–2.41(m,3H),2.27(s,3H),2.13–1.99(m,3H),1.57(dt,J＝9.5,2.8Hz,2H),1.07–0.97(m,8H),0.62–0.55(m,2H).LCMS(ES,m/z):372[M+H] + 。
Example 37 5- (1-ethylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one (37)
The title compound was prepared as in example 1, with the replacement of 1-methyl-4-piperidylamine with 1-ethyl-4-piperidylamine, the structural formula of which is shown in Table 1 as number (37). 1 H NMR(400MHz,Methanol-d 4 )δ7.23–7.11(m,2H),6.95–6.81(m,2H),4.47(s,2H),4.32(tt,J＝10.8,5.7Hz,1H),3.73(d,J＝6.4Hz,2H),3.33(p,J＝1.6Hz,4H),3.12–3.05(m,2H),3.05–2.96(m,4H),2.48(q,J＝7.2Hz,2H),2.17–1.99(m,3H),1.74–1.61(m,4H),1.13(t,J＝7.2Hz,3H),1.04(d,J＝6.7Hz,6H),0.58(t,J＝3.0Hz,2H),0.50–0.45(m,2H).LCMS(ES,m/z):400[M+H] + 。
Example 38 5- (4-Isopentylbenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (38)
The reaction material 1- [4- (2-methylpropyloxy) phenyl]The title compound was prepared as in example 1 by substituting (4-isopentylphenyl) methylamine for methylamine and has the structural formula shown in Table 1 under number (38). 1 H NMR(400MHz,Methanol-d 4 ):δ7.16(s,4H),4.51(s,2H),4.49–4.41(m,1H),3.59(dq,J＝10.6,2.3Hz,2H),3.17(td,J＝12.8,3.3Hz,2H),3.05(d,J＝16.6Hz,4H),2.90(s,3H),2.69–2.57(m,2H),2.12–1.86(m,4H),1.71–1.43(m,3H),0.95(d,J＝6.5Hz,6H),0.68–0.58(m,2H),0.58–0.47(m,2H).LCMS(ES,m/z):384[M+H] + 。
Example 39 5- (4- (isobutylamino) benzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-one (39)
The reaction material 1- [4- (2-methylpropyloxy) phenyl ]The title compound was prepared as described in example 1, with the structural formula shown in Table 1 as number (39), substituting methyl amine for 4- (aminomethyl) -N-isobutylaniline. 1 H NMR(400MHz,Methanol-d 4 )δ7.57–7.45(m,4H),4.61(s,2H),4.57–4.44(m,1H),3.68–3.53(m,2H),3.28(d,J＝7.2Hz,2H),3.23–3.13(m,2H),3.13–3.07(m,4H),2.89(d,J＝1.8Hz,3H),2.19–2.01(m,3H),1.92(d,J＝13.8Hz,2H),1.11(d,J＝6.6Hz,6H),0.66(d,J＝5.0Hz,2H),0.56(d,J＝4.6Hz,2H).LCMS(ES,m/z):505[M+H] + 。
Example 40 5- (4- (isobutylamino) benzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-one (40)
The reaction material 1- [4- (2-methylpropyloxy) phenyl]Substitution of methylamine with [4- (methyl isopropoxy) phenyl ]]The target compound was prepared as in example 1, and the structural formula is shown in table 1, number (40). 1 HNMR(400MHz,Methanol-d 4 )δ7.32(d,J＝8.2Hz,2H),7.25(d,J＝8.0Hz,2H),4.53(d,J＝10.9Hz,4H),4.30(td,J＝11.5,5.3Hz,1H),3.73(p,J＝6.2Hz,1H),3.05(s,2H),2.98(d,J＝18.0Hz,4H),2.32(s,3H),2.17(td,J＝11.7,3.4Hz,2H),1.70(ddt,J＝24.2,12.9,6.4Hz,4H),1.21(d,J＝6.1Hz,6H),0.64–0.56(m,2H),0.49(t,J＝3.0Hz,2H).LCMS(ES,m/z):386[M+H] + 。
Pharmacological examples:
in vitro receptor binding assay
1. Experimental method
1.1 preparation of solutions required for experiments
A: (for the preparation of 5-HT 2C Receptor membrane): 50mM Tris-HCl buffer: 96.8g Tris was dissolved in double distilled water to a total volume of 4000ml, pH 7.5 was adjusted with HCl, diluted to 16000mL, pH=7.4
B: (for the preparation of 5-HT 2A Receptor membrane): weighing 11.7mg EDTA,380.84mg MgCl 2 The total volume of 50mM Tris-HCl buffer was 400mL and pH=7.4 was adjusted. So that the final concentration is EDTA0.1mM and MgCl respectively 2 10mM。
C: (for preparing a Dopamine receptor film): weighing 2.978g HEPES,1.17g NaCl,0.119g MgCl 2 36.5mg EDTA was added to a total volume of 250ml of purified water to adjust pH=7.4. To final concentrations of 50mM HEPES,50mM NaCl,5mM MgCl respectively 2 ,0.5mM EDTA,pH 7.4。
1.2 preparation of receptor membranes
1)CHO-5-HT 2A Preparation of acceptor membranes
CHO-5-HT 2A The cells were removed from the freezer at-80℃and naturally thawed and centrifuged at 2000g for 15 minutes at 4 ℃. Taking the precipitate, and discarding the supernatant. Adding solution B into the sediment. The cells were mixed for 20-30 seconds and then centrifuged at 50000g for 25min at 4 ℃. Carefully discarding the supernatant, adding the solution B again, mixing well, centrifuging at 4 ℃ for 25min and 50000 g. The precipitate was stored at-80 ℃.
2)5-HT 2C Preparation of the film
Taking out rat cortex at-80deg.C, naturally thawing, adding solution A, homogenizing for 4 times at 4 th gear for 3-4s, centrifuging at-80deg.C for 25min, discarding supernatant, adding solution A, mixing with vortex mixer, centrifuging at-80deg.C for 25min, repeating the centrifugation twice, discarding supernatant, and storing at-80deg.C.
3)CHO-D 2 Preparation of acceptor membranes
Cell CHO-D 2 Naturally thawing after taking out by a refrigerator at-80 ℃, centrifuging 2000g for 15min, adding the precipitate into homogenate C, uniformly mixing by a vortex mixer, centrifuging at 50000g and 4 ℃ for 25min, discarding the supernatant, taking the precipitate, adding the buffer solution C again for washing, resuspending and centrifuging, discarding the supernatant after centrifuging, and storing the precipitate at-80 ℃ for later use.
1.3 receptor competitive binding assay
1)5-HT 2A Receptor competitive binding assay
The first step: the prepared membrane is prepared into suspension of 10mg/mL membrane by homogenate B for standby.
And a second step of: each reaction tube was charged with 100. Mu.L of the membrane preparation.
And a third step of: total binding Tube (TB) was filled with 100. Mu. L B solution, non-specific binding tube (NB) was filled with methyl 100. Mu.L (final concentration 1.0X10) -5 M) 100. Mu.L of test compound was added to each test compound tube (CB).
Fourth step: the radioligand is added into each reaction tube 3 H-Ketanserin 10. Mu.L, final concentration 2.98nM.
Fifth step: incubating each reaction tube at 37 ℃ for 25min, after the reaction, quickly filtering the Whatman test paper GF/C plate under reduced pressure to soak the combined ligand with 0.5% PEI for more than 1h, drying the filter membrane at 60 ℃ after filtering, adding 40 mu L of scintillation liquid after attaching a bottom membrane, sealing the upper membrane, and standing.
Sixth step: the scintillation cup is placed into a liquid scintillation counter for counting.
2)5-HT 2C Receptor competitive binding assay
The first step: the prepared membrane is prepared into suspension of 210mg/mL membrane by homogenate B for standby.
And a second step of: each reaction tube was charged with 100. Mu.L of the membrane preparation.
And a third step of: total binding Tube (TB) was filled with 100. Mu. L B solution, nonspecific binding tube (NB) was filled with Ketansert (final concentration 1.0X10) -5 M) 100. Mu.L of each subjectTest compound tube (CB) 100. Mu.L of test compound is added.
Fourth step: the radioligand is added into each reaction tube 3 H-Mesulergine 10. Mu.L, final concentration 3nM.
Fifth step: after the reaction tube was incubated at 37℃for 25min, the bound ligands were rapidly filtered under reduced pressure, whatman paper GF/C was saturated with 0.5% PEI solution 1h ahead, washed well with ice-cold Tris buffer, the filter was removed and placed in a 4mL scintillation cup, 1mL toluene scintillation solution was added and mixed well.
Sixth step: the scintillation cup is placed into a liquid scintillation counter for counting.
3)CHO-D 2 Receptor competitive binding assay
The first step: the prepared membrane is prepared into 8mg/mL membrane suspension by homogenate C for standby.
And a second step of: each reaction tube was charged with 100. Mu.L of the membrane preparation.
And a third step of: total binding Tube (TB) was filled with 100. Mu. L C solution and non-specific binding tube (NB) was filled with 100. Mu.L Haloposteridol (final concentration 1.0X10) -5 M) 100. Mu.L of test compound was added to each test compound-binding tube (CB).
Fourth step: the radioligand is added into each reaction tube 3 H-Spiponone 10. Mu.L, final concentration 1.176nM.
Fifth step: incubating each reaction tube at 37 ℃ for 25min, after the reaction, quickly filtering the Whatman test paper GF/B plate by decompression, soaking the combined ligand in 0.5% PEI for more than 1h, filtering, drying the filter membrane at 60 ℃, attaching a bottom membrane, adding 40 mu L of scintillation liquid, sealing the upper membrane, and standing.
Sixth step: and (5) putting the filter plate into a liquid flash counter for counting.
2. Experimental results
Pimavanserin and 5-HT 2A 、5-HT 2C The receptor Ki values were 0.036, 2.94nM, compound 1 and 5-HT, respectively 2A 、5-HT 2C Receptor Ki values of 0.0002 and 3.54nM, respectively, are superior to pimavanserin. The details are given in the following table:
table 2 in vitro receptor binding Activity (Ki value, nM) of the compounds
| Numbering of compounds | 5-HT 2A (Ki value, nM) | 5-HT 2C (Ki value, nM) | 2C/2A |
| Pimavanserin | 0.036 | 2.94 | 81.667 |
| 1 | 0.0002 | 3.54 | 17700.00 |
| 8 | 0.07 | >1000 | >14285.71 |
| 15 | 0.015 | 458.50 | 31435.87 |
| 27 | 17.9499 | 1807.00 | 100.67 |
| 28 | 0.5700 | 543.60 | 953.68 |
| 32 | 0.89 | 106.80 | 120.10 |
| 33 | 0.19 | 330.60 | 1740.00 |
In vitro hERG assay
Cells were seeded onto slides with cell densities below 50% and cultured overnight. The experimental cells were transferred to a bath of about 1ml embedded in an inverted microscope platform, and the extracellular fluid was perfused at a perfusion rate of 2.7 ml/min. After 5 minutes of stabilization, the experiment was started. Membrane current was recorded using a HEKA EPC-10 patch clamp amplifier and PATCHMASTER acquisition system (HEKA Instruments inc. D-67466lambrecht, pfalz, germany). All experiments were performed at room temperature (22-24 ℃).
A P-97 microelectrode drawing instrument (Sutter Instrument Company, one Digital Drive, novat, calif. 94949) was used in the experiment to straighten the electrode (BF 150-110-10). The inner diameter of the electrode is 1-1.5mm, and the water inlet resistance after being filled with the internal liquid is 2-4MΩ.
The electrophysiological stimulation scheme of hERG potassium channel is that first, the membrane voltage is clamped at-80 mV, the cell is stimulated for 2s, +20mV voltage, the hERG potassium channel is activated, and then repolarized to-50 mV for 5s, so as to generate outward tail current, and the stimulation frequency is once every 15 s. The current value is the peak value of the tail current.
The channel current was recorded using a whole cell recording mode in the experiment. Extracellular fluid (approximately 2 ml per minute) was first perfused and recorded continuously, and current stabilization was awaited (current decay (Run-Down) less than 5% in 5 minutes), at which point the tail current peak was the control current value. And then, the extracellular fluid containing the drug to be detected is perfused and continuously recorded until the inhibition effect of the drug on hERG current reaches a stable state, and at the moment, the tail current peak value is the current value after drug addition. The steady state criteria is determined by whether the nearest 3 consecutive current traces overlap. After reaching the steady state, if hERG current reverts to or approaches the magnitude prior to drug administration after rinsing with extracellular fluid perfusion, then perfusion testing may continue for other concentrations or drugs.
Experimental results
Pimavanserin hERG experiment IC 50 Compound 1, compound 15, compound 24, compound 28, compound 31, compound 33 have a cardiotoxicity of less than pimavanserin at 208 nM. The results are shown in the following table.
Table 3 in vitro hERG test results of compounds
| Numbering of compounds | hERG(nM) |
| Pimavanserin | 208 |
| 1 | 2252 |
| 15 | 2045 |
| 24 | 3655 |
| 28 | 1298 |
| 31 | 1809 |
| 33 | 1235 |
Animal experiment
1. Test method
1.1 experiment of influence on MPTP+MK-801 Parkinson's psychosis mouse model (anti-PDP drug efficacy model)
Animals received intraperitoneal injections at each morning to administer different doses of MPTP, and were continuously administered for 5 days, after the interval of 1.5h after the MPTP injection on the 5 th morning, pimaline or NS was intraperitoneally injected, after the interval of 0.5h, MK-801 was intraperitoneally injected for 0.3mg/kg (or NS), after the interval of 0.25h, the mice were placed in an autonomous incubator (a black polyethylene incubator with the specification of 29cm×29cm×30 cm) for video recording for 20min, and video analysis was performed after video recording was completed to evaluate the activity of the mice.
1.2 influence on MPTP+APO-induced climbing behavior in Male mice (DA motor deterioration model)
Animals received intraperitoneal injections at each morning to administer different doses of MPTP for 5 days, after the injection of MPTP at 5 morning, pimapine, clozapine, quetiapine or NS were intraperitoneally injected at 1.5h intervals, 1mg/kg of APO (administration volume 0.1ml/10g body weight) was injected subcutaneously at 0.5h intervals, and immediately after the subcutaneous injection, the animals were placed in climbing cages (climbing cages made of stainless steel wire mesh with a diameter of about 0.1cm, semi-transparent polyethylene plates at the bottom, stainless steel cage covers) and the behaviors of 10-11, 20-21, 30-31 minutes after APO injection were observed and scored.
The scoring criteria were: the score of the four feet on the floor is 0; the scores of the two forefeet on the net cage are 1; the four feet scored 2 on the netpen.
1.3 study of sedative side Effect (anti-sedative model)
Qualified SPF grade C57BL/6j mice are randomly divided into 13 groups, and 8 mice in each group: blank, pimavanserin 1, 3, 10, 30mg/kg group, compound 1: 1.3, 10, 30mg/kg group. Solutions with different concentrations are prepared according to different dosages of each group for intraperitoneal injection administration, and the final administration volume is 10ml/kg.
All groups were tested for autonomous activity 45min after administration of pimavanserin and the like, video recorded for 0-20min movement, and Top Scan3.00 software analyzed for 20min movement path. The inhibition rate of each group was calculated relative to the blank group after administration, and the sedation of the compound was comprehensively evaluated in combination with the statistical conclusion.
2. Test results
Experiments show that the drug effect of pimavanserin PDP, the sedative and exercise deterioration ED50 are respectively 0.37, 6.79 and more than 30mg/kg, the sedative/PDP drug effect ratio is 18.35, and the exercise deterioration/PDP drug effect ratio is more than 81.08; the PDP efficacy and the sedated ED50 of Compound 1 were 0.261 and 21.34mg/kg, respectively, and the sedated/PDP efficacy ratio was 81.76. Compound 1 was found to have better efficacy and higher safety than pimavanserin.
TABLE 4 Table 4
Claims (14)
1. A compound of formula I:
wherein n7 is 0, 1 or 2; a is C, O or N;
n3, n6 are each independently selected from integers of 0, 1, 2, 3, and n3, n6 are not simultaneously 0;
n2 is an integer of 1, 2 or 3;
w is O or S;
z, Q, Y are each independently selected from C, N and Z, Q are not simultaneously C;
R 2 selected from hydrogen, substituted or unsubstituted C 1 -C 5 Straight-chain or branched alkyl, substituted or unsubstituted C 3 -C 5 Cycloalkyl of (C), said substituents being selected from methyl, ethyl, propyl, butyl, fluoro, C 3 -C 5 Cycloalkyl of (c);
R 3 、R 4 are independently selected from H, halogen, C 1- C 5 Straight-chain or branched alkyl, phenyl, or R 3 And R is R 4 Formation of C 3-6 Cycloalkyl of (c);
R 5 hydrogen or halogen;
R 1 selected from the structures of formula II, III, IV:
in the formula III, n5 is an integer of 0-4, R 8 、R 9 Are independently selected from C 1-3 Or R is an alkyl group of 8 、R 9 A 4-6 membered heterocyclic ring substituted or unsubstituted with N, said substituents selected from methyl, ethyl, propyl, butyl, fluoro, chloro;
in the formula II, n4 is selected from integers of 1-4;
R 7 selected from methyl, ethyl, isopropyl, isobutyl, benzyl, phenyl, halogenated C 1-5 Straight or branched alkyl of (a);
R 6 halogen, methyl or hydrogen;
when R is 3 And R is R 4 Formation of C 3 -C 6 The structure of the cycloalkyl is as shown in formula I-1:
wherein n1 is an integer of 1,2 or 3.
2. A compound of formula i according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula i is of formula v:
when R is 3 And R is R 4 Formation of C 3 -C 6 When cycloalkyl, the structure is as shown in formula V-1:
wherein n1 is an integer of 1,2 or 3.
3. The compound of formula i or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula i is of formula vi:
when R is 3 And R is R 4 Formation of C 3 -C 6 The structure of the cycloalkyl is shown as a formula VI-1:
wherein n1 is an integer of 1, 2 or 3.
4. A compound of formula i or a pharmaceutically acceptable salt thereof according to claim 1 or 3, wherein when R 1 In the structure of formula II, the compound of formula I is in the structure of formula VI-2:
wherein n4 is an integer of 1, 2 or 3.
5. A compound of formula i or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein when R 1 In the case of the structure of formula II, the compound has the structure of formula V-2:
6. a compound of formula I according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the halogen is fluoro, chloro, bromo or iodo.
7. A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein C 1 -C 5 Is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl; the unsubstituted C 3 -C 5 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl; substituted C 3 -C 5 Cycloalkyl of (2) is selected from methylcyclopropyl, ethylcyclopropyl; the halogeno in the halogenoalkyl is selected from fluoroalkyl, chloroalkyl, bromoalkyl and iodoalkyl; the C is 1 -C 3 Is selected from methyl, ethyl, propyl, isopropyl; and/or
The 4-6 membered heterocycle is selected from azetidinyl, piperazine, pyrrolidine.
8. A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5,
wherein n1, n2, n4 are independently selected from integers of 1, 2, 3;
R 2 selected from hydrogen, methyl, isopropyl, isobutyl, cyclopropyl, cyclopropylmethyl, neopentyl;
R 5 selected from hydrogen, fluorine, chlorine, bromine, iodine;
R 7 selected from methyl, ethyl, isopropylButyl, phenyl, benzyl, difluoroethyl;
R 6 selected from fluorine, chlorine, bromine, iodine, hydrogen, methyl.
9. A compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5, wherein,
R 1 selected from the structures of formula II, III, IV:
in the formula III, n5 is an integer of 0-4, R 8 、R 9 Independently selected from methyl, ethyl, propyl, or R 8 、R 9 A substituted or unsubstituted azetidinyl group, a substituted or unsubstituted piperazine group, and N, wherein the substituent is selected from methyl, ethyl, and propyl;
in the formula II, n4 is an integer of 1-4;
R 7 selected from methyl, ethyl, isopropyl, isobutyl, phenyl, benzyl, difluoroethyl;
R 6 Selected from fluorine, chlorine, bromine, iodine, hydrogen, methyl.
10. A compound of formula I as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from any one of the following:
5- (4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (3-fluoro-1-methylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (4-isobutoxybenzyl) -7- (1-methylpyrrolidin-3-yl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (2- (dimethylamino) ethyl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (4-methoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (4-cyclopropoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (4- (cyclopropylmethoxy) benzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (1-benzylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (1- (2, 2-difluoroethyl) piperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (4-isobutoxybenzyl) -7- (2-methyl-2-azaspiro [3.3] heptan-6-yl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (1-methylpiperidin-4-yl) -7- (4- (neopentyloxy) benzyl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (4-isobutoxybenzyl) -7- (1-isobutylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (4-isobutoxybenzyl) -7- (1-isopropylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
6- (4-isobutoxybenzyl) -8- (1-methylpiperidin-4-yl) -6, 8-diazaspiro [3.5] non-7-one;
5- (4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-thione;
5- (4-hydroxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
7- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.6] non-6-one;
5- (4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.6] non-6-one; 7- [ (dimethylamino) methyl ] -5- (4-isobutoxybenzyl) -5-azaspiro [2.5] octan-6-one;
7- (dimethylamino) -5- (4-isobutoxybenzyl) -5-azaspiro [2.5] octan-6-one;
7- (azetidin-1-yl) -5- (4-isobutoxybenzyl) -5-azaspiro [2.5] octan-6-one;
1- (4-isobutoxybenzyl) -5-methyl-3- (1-methylpiperidin-4-yl) -5-phenyltetrahydropyrimidin-2 (1H) -one;
5, 5-difluoro-1- (4-isobutoxybenzyl) -3- (1-methylpiperidin-4-yl) tetrahydropyrimidin-2 (1H) -one;
1- (4-isobutoxybenzyl) -5-methyl-3- (1-methylpiperidin-4-yl) tetrahydropyrimidin-2 (1H) -one;
5- (4-isobutoxybenzyl) -7- (4-methylpiperazin-1-yl) -5-azaspiro [2.5] octan-6-one;
7- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) -5-azaspiro [2.5] octan-6-one;
5- ((6-isobutoxypyridin-3-yl) methyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (2-fluoro-4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (3-fluoro-4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (4-isobutoxybenzyl) -7- (1-methylazo-4-yl) -5-7-diazaoxazol [2.5] octan-6-one;
5- ((2R) -1, 2-dimethylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one; 5- ((2S) -1, 2-dimethylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one; 5- (2-chloro-4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (3-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
4- (4-isobutoxybenzyl) -6- (1-methylpiperidin-4-yl) -4, 6-diazaspiro [2.4] heptane-5-one;
6- (4-isobutoxybenzyl) -4- (1-methylpiperidin-4-yl) -4, 6-diazaspiro [2.4] heptane-5-one;
5- (1-ethylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (4-isopentylbenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (4- (isobutylamino) benzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (4- (isopropoxymethyl) benzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one.
11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.
12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 11 in the manufacture of a medicament for the treatment of psychotic disorders.
13. The use according to claim 12, wherein the psychotic disorder is schizophrenia.
14. The use according to claim 12, wherein the psychotic disorder is parkinson's disease, dementia-related behavioral disorders and psychoses.
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| CN2021116187342 | 2021-12-27 | ||
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