CN115677723B - 5-HT2A receptor antagonists and their use for treating central nervous system disorders - Google Patents

5-HT2A receptor antagonists and their use for treating central nervous system disorders Download PDF

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CN115677723B
CN115677723B CN202211178292.9A CN202211178292A CN115677723B CN 115677723 B CN115677723 B CN 115677723B CN 202211178292 A CN202211178292 A CN 202211178292A CN 115677723 B CN115677723 B CN 115677723B
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methyl
benzyl
fluorobenzyl
methylpyrrolidin
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邢洪涛
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Huihan Medical Technology Co ltd
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Hanyuan Pharmaceutical Co ltd
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Abstract

The invention provides a compound with a structure of formula I, which has 5-HT2A receptor antagonist or inverse agonist activity, has high selectivity to 5-HT2A receptor, low cardiac toxicity and good metabolic stability, and can be used for treating certain mental diseases (such as depression, anxiety, psychosis, schizophrenia, insomnia and autism) and mental disorder symptoms related to or complicated with central nervous system degenerative diseases (such as Alzheimer's disease, parkinson's disease, huntington disease and Lewy body dementia).

Description

5-HT2A receptor antagonists and their use for treating central nervous system disorders
The application is a divisional application of Chinese patent application 202010076067.9, which is filed on 1 month 21 in 2020 and is named as a 5-HT2A receptor antagonist and application thereof for treating central nervous system diseases.
Technical Field
The invention belongs to the technical field of medicines, and relates to a 5-HT2A receptor antagonist or inverse agonist with a central nervous system disease treatment effect and application thereof. The compounds are useful for the treatment of certain psychotic disorders (e.g., depression, anxiety, psychosis, schizophrenia, insomnia, autism), psychotic disorder symptoms associated with or complicated with degenerative disorders of the central nervous system (e.g., alzheimer's disease, parkinson's disease, huntington's disease, lewy body dementia).
Background
Serotonin or 5-hydroxytryptamine (5-HT) plays an extremely important role in human physiological functions. In the central nervous system, 5-HT is an important neurotransmitter and neuromodulator, playing an extremely important role in regulating a variety of behaviors such as sleep, diet, activity, learning and memory, body temperature, blood pressure, and pathological states such as anxiety, mania, schizophrenia, obesity, drug addiction, migraine and hypertension through its receptors (Alenina N,et al.,(2009)ProcNatl Acad Sci USA,106,10332-10337;Filip M,et al.,(2005)Pharmacol Rep,57,685-700;Greek AR,(2006)Br J Pharmacol,147,Suppl 1：S145-S152).5-HT, classifying 5-HT receptors into 7 families (5-HT 1-5-HT 7) and at least 15 different subtypes (Barnes NM,et al.,(1999)Neuropharmacology,38,1083-1152;Hannon J,et al.,(2008)Behav Brain Res,195,198-213;Hoyer D,et al.,(2002)Pharmacol Biochem Behav,71,533-554;Pauwels PJ.(2003)Tocris Reviews,No.25). different subtype receptors are distributed, ligand preferences and related functions are different according to structural (amino acid sequence), biochemical (post-receptor mechanism of signal transduction) and pharmacological differences.
The 5-HT2A subtype receptors are expressed extensively and discretely in the central nervous system, with highest expression in the cerebral cortex, limbus, hippocampus, hypothalamus and basal ganglia involved in the regulation of advanced cognitive and affective functions. The 5-HT2A receptor is expressed on dopamine, GABA, glutamate and Ach neurons and acts as a dendritic heterogeneous receptor (Buhot MC,(1997)Curr Opin Neurobiol,7,243-254;Leysen JE,(2004)Curr Drug Targets CNS Neuro Disord,3,11-26). as most 5-HT receptors, the 5-HT2A receptor is a G-protein coupled receptor that accomplishes signal transduction by activating guanine nucleotide binding proteins (G proteins), resulting in an elevated or reduced level of second messenger molecules such as cyclic adenosine monophosphate (cAMP), inositol phosphates (inositol phosphates) and diacylglycerol (diacylglycerol). These second messenger molecules regulate the functions of a variety of intracellular enzymes (e.g., kinases and ion channels), ultimately affecting cellular excitability and cellular function.
Abnormal 5-HT transmission is associated with pathogenesis of various mental diseases, such as mental diseases (depression, panic attacks, schizophrenia, suicidal tendencies and the like), and in recent years research on nervous system degenerative diseases (Alzheimer's disease, huntington's chorea, parkinson's disease and the like )(Fioravanti et al.,(1992)Brain Cogn.18,116-124;Sinopoli VM,et al.,(2017)Neurosci Biobehav Rev,80：372-381). has found that 5-HT2A receptors are closely related to pathological states of the neuropsychiatric diseases, and that 5-HT2A receptors are involved in molecular action mechanisms (Gonzalez-Maeso J,et al.,(2009)Trends Neurosci,32：225-232;Fribourg M,et al.,(2011)Cell,147：1011-1023;Kurita M,et al.,(2012)Nat Neurosci,15：1245-1254);5-HT2A receptor antagonists of atypical antipsychotics such as clozapine, olanzapine and risperidone are very important (Blier P,et al.,(2005)J Clin Psychiatry 66,Suppl 8,30-40;Richtand NM,et al.,(2008)Prog Brain Res,172,141-153;Meltzer,H.Y.(2013)Annu Rev Med 64,393-406); for treating negative symptoms of schizophrenia (such as affective disorder, language hypofunction and the like), and research has demonstrated that 5-HT2A receptor modulation pathways of cortical cone neurons are important for mediating signal transduction and behavioral responses induced by hallucinogens (Gonzalez-Maeso J, et al., (Trends Neurosci, 32:225-232), suggesting the role of 5-HT2A receptors in treating various neurodegenerative hallucinations.
Drugs for the treatment of mental diseases, namely antipsychotics, fall into two main categories. "typical" antipsychotics or the previous generation drugs have been rarely used in clinic due to the side effects of motor functions on the human body (extrapyramidal side effects, parkinsonian-like symptoms, etc.), and more attention has been paid to "atypical" antipsychotics (Prim Cre Companion J Clin psychrory (2007) 9 (6): 444-54). However, the second generation antipsychotics all have a broad spectrum of receptor activity, and these compounds act as agonists, competitive antagonists or inverse agonists to modulate various monoaminergic receptors such as 5-HT, dopaminergic, adrenergic, muscarinic or histamine receptors, and this broad spectrum of modulation is likely to be responsible for side effects such as sedation, motor dysfunction, type II diabetes and the like. Most antipsychotics have dopamine D2 receptor antagonism, (Strange PG.(2001)Pharmacol Rev,53(1)：119-33;Tuppurainen H,et al.,(2010)Nord J Psychiatry,64(4)：233-8;Sykes DA,et al.,(2017)Nat Commun,8(1)：763). has been shown to be associated with extrapyramidal side effects and thus more 5-HT2A receptor antagonists or inverse agonists, especially with high selectivity and/or no dopamine D2 receptor binding activity, have been developed, which are of great importance for driving the development of antipsychotics, and for the treatment of diseases while avoiding many side effects due to non-selective receptor interactions.
The invention comprises the following steps:
The present invention provides a compound having 5-HT2A receptor antagonistic activity, and a pharmaceutical composition for the treatment of central nervous system diseases comprising the same, and further provides a method for the treatment of central nervous system diseases.
Specifically, the present invention provides a compound having the structure of formula I, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Wherein,
N is selected from integers from 0 to 4, defining the number of alkylene units of the alkylene chain;
A ring A group selected from 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl, or a fused ring group formed by fusing the above rings with 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, 4-8 membered aryl, or 4-8 membered heteroaryl, said ring A group being substituted with 1 or more H, halogen, hydroxy, C 1-6 alkyl, or C 1-6 alkoxy, or C 1-6 alkylene hydroxy; preferably, ring a is azetidinyl, pyrrolidinyl, piperidinyl, imidazolyl, C 4-7 cycloalkyl, quinolizinyl, pyridooxazinyl, said ring a group being substituted with 1 or more H, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylene hydroxy groups;
When n=0, the ring carbon atom on ring a is attached to the host N atom, and when N is selected from 1-4, the ring carbon atom or ring nitrogen atom on ring a is attached to the host N atom through a (CH 2) N group;
Z is connected at any substituted position of the ring and is selected from-O-, -N-, -S-, -SO 2 -, -CO-or-CH (OH) -groups;
R 1 is 1 or more substituents independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, substituted with a substituent selected from H, halogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy;
R 2 is 1 or more substituents, optionally substituted in the ring, R 2 are independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, hydroxy or NO 2; by substituted is meant that the group is further substituted with C 1-6 alkyl, halogen, hydroxy or amino;
R 3 is 1 or more substituents, located at any substituted position of the ring, independently of each other, selected from halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, hydroxy or NO 2; by substituted is meant that the group is further substituted with a C 1-6 alkyl, halogen, hydroxy or amino group.
In addition, the present invention provides a compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein n is selected from 1,2, or 3;
Ring X is the ring in which X is- (CH 2) m-, m is 0,1,2 or 3, whereby X, nitrogen and the other ring carbon atoms form a 4,5,6 or 7 membered nitrogen heterocycle, the X ring being linked to the alkylene chain of the host structure through a ring nitrogen atom or a ring carbon atom;
Z is connected at any substituted position of the ring and is selected from-O-, -N-, -S-, -SO 2 -, -CO-or-CH (OH) -groups;
R 1 is 1 or more substituents independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, substituted with a substituent selected from H, halogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy;
R 2 is 1 or more substituents, optionally substituted in the ring, R 2 are independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy or NO 2;
R 3 is 1 or more substituents, located at any substituted position of the ring, independently of each other selected from halogen, hydroxy or NO 2, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C 1-6 alkoxy; by "substituted" is meant that the group is further substituted with a C 1-6 alkyl or halogen.
Further preferred is:
n is 0,1 or 2;
Ring X is a 4-6 membered nitrogen-containing heterocycle;
Z is-O-, -S-, -CO-, or-SO 2 -group;
R 1 is 1 or more substituents independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, substituted with a substituent selected from H, halogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy, preferably R 1 is methyl, isobutyl, cyclobutane, oxolane, trifluoroethyl, or 2-hydroxyisobutyl;
R 2 is 1 or more substituents, located at any substituted position of the ring, independently of each other selected from H, halogen, hydroxy or NO 2; preferably R 2 is halogen, particularly preferably fluorine;
R 3 is 1 or more substituents, located at any substituted position of the ring, independently of each other selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, 3-6 membered cycloalkyl, halogenated 3-6 membered cycloalkyl, hydroxy or NO 2; c 1-6 alkyl, halogen, fluoro C 1-6 alkyl, 3-6 membered cycloalkyl are preferred.
Particularly preferably, n is selected from 1;
Ring X is a 4-6 membered nitrogen-containing heterocycle;
Z is-O-, -S-, -CO-, or-SO 2 -group;
R 1 is 1 or more substituents independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, substituted with a substituent selected from H, halogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy, preferably R 1 is methyl, isobutyl, cyclobutane, oxolane, trifluoroethyl, or 2-hydroxyisobutyl;
R 2 is 1 or more substituents, located at any substituted position of the ring, independently of each other selected from H, halogen, hydroxy or NO 2; preferably R 2 is halogen, particularly preferably fluorine;
R 3 is 1 or more substituents, located at any substituted position of the ring, independently of each other selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, 3-6 membered cycloalkyl, hydroxy or NO 2; c 1-6 alkyl, halogen, fluoro C 1-6 alkyl, 3-6 membered cycloalkyl are preferred.
The present invention also provides a compound of formula IB, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Wherein, in the ring X where X is located, X is- (CH 2) m-, where m is 0,1,2 or 3, thereby X, N forms a 4,5,6 or 7 membered nitrogen heterocycle with the other ring carbon atoms, the heterocycle being attached to the host structure N atom through a ring C atom;
ring B is fused to the X ring, and ring B is a 4-7 membered cycloalkyl or 4-7 membered heterocycloalkyl;
Z is connected at any substituted position of the ring and is selected from-O-, -N-, -S-, -SO 2 -, -CO-or-CH (OH) -groups;
R 1 is 1 or more substituents independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, substituted with a substituent selected from H, halogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy;
R 2 is 1 or more substituents, optionally substituted in the ring, R 2 are independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy or NO 2;
R 3 is 1 or more substituents, located at any substituted position of the ring, independently of each other selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, 3-6 membered cycloalkyl, hydroxy or NO 2; preferably C 1-6 alkyl, halogen, fluoro C 1-6 alkyl, 3-6 membered cycloalkyl;
Further, it is preferred that the fused ring of ring X and ring B is selected from the group consisting of:
Reference to "being substituted with a substituent selected from H" in this patent means that the substituent is H, meaning that the group is essentially unsubstituted with other substituents.
The term "halogen" refers to F, cl, br or I.
The term "alkyl" refers to saturated hydrocarbon groups, including straight chain alkyl groups, branched chain alkyl groups.
The term "alkylene" refers to a divalent alkyl group. The "alkylene chain" is polymethylene, i.e., - (CH 2) x-, where x is a positive integer.
The term "cycloalkyl" refers to a monocyclic hydrocarbon group that is saturated or contains one or more unsaturated units but is not aromatic, the ring being a 3-20 membered ring having a single point of attachment to the remainder of the compound.
The term "heterocycloalkyl" is a monocyclic group containing 1 to 5 heteroatoms independently selected from N, S, O, etc., and can be a saturated or unsaturated ring, which is a 3-20 membered ring, including piperidine, pyrrolidine, tetrahydrofuran, etc.
The term "aryl", "aromatic ring" or "aromatic ring" refers to a single ring, the system having a total of 5 to 10 (preferably 5, 6 or 9) ring members, the ring members being ring carbon atoms; (4n+2) pi electrons (where n is a positive integer) are shared in the ring system to meet the shock rule.
The terms "heteroaryl" and "heteroaryl ring radical" refer to a radical having 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms; (4n+2) pi electrons (where n is a positive integer) to meet the rule of shock; and has 1 to 5 heteroatoms in addition to carbon atoms, selected from nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen, such as pyridine, imidazole groups, and the like.
The term "independent of each other" means in the present application that the substitutions are independent of each other and are not related to each other.
The term "optionally substituted position of the ring" means that the substituent is located at any position in the ring that can be substituted, including the substitution sites of ring carbon atoms, ring nitrogen, ring sulfur atoms, and the like. Examples are: when the ring is a benzene ring, the substitution position is ortho, meta and/or para with respect to the substitution position of the main chain, or the 2,3,4,5 or 6 position (with respect to the position of the benzene ring attached to the main chain); when the ring is a nitrogen-containing 5-or 6-membered ring, the substitution position may be a ring nitrogen position, or an ortho, meta, or para position of the ring nitrogen position, or a2, 3,4, or 5 position, or the like.
The term "pharmaceutically acceptable salts" includes those salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids and the like, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic or malonic acid and the like, or by using other methods in the art such as ion exchange and the like. Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonic acid salts, benzoic acid salts, bisulfate salts, boric acid salts, butyric acid salts, camphoric acid salts, citric acid salts, cyclopentapropionic acid salts, gluconic acid salts, dodecylsulfuric acid salts, ethanesulfonic acid salts, formic acid salts, fumaric acid salts, glucoheptonate salts, glycerophosphate, gluconic acid salts, hemisulfate salts, heptanoic acid salts, hydroiodic acid salts, 2-hydroxyethanesulfonic acid salts, lactic acid salts, lauric acid salts, lauryl sulfate salts, malic acid salts, maleic acid salts, malonic acid salts, methanesulfonic acid salts, 2-naphthalenesulfonic acid salts, nicotinic acid salts, nitrate, oleic acid salts, oxalic acid salts, palmitic acid salts, pamoic acid salts, pectic acid salts, persulfates, 3-phenylpropionic acid salts, phosphoric acid salts, pivalic acid salts, propionic acid salts, stearic acid salts, succinic acid salts, sulfuric acid salts, p-toluenesulfonic acid salts, undecanoic acid salts, valeric acid salts, and the like.
Preferably, the present invention protects the following specific compounds, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof:
1- (4-fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (9-methyl-3-oxa-9-aza-bicyclo [3.3.1] non-7-yl) -urea,
1- (3- (Azetidin-1-yl) -propyl) -1- (4-fluoro-benzyl) -3- (4-isobutoxy-benzyl) -urea,
1- (4-Fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (1-methyl-pyrrolidin-3-ylmethyl) -urea,
1- (4-Fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (1-methyl-azetidin-3-ylmethyl) -urea,
1- (4-Fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (octahydro-quinolizin-2-yl) -urea,
1- (4-Fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (octahydro-pyrido [2,1-c ] [1,4] oxazin-8-yl) -urea,
1- (4-Fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (2- (pyrrolidin-1-yl) -ethyl) -urea,
3- (4-Isobutoxy-benzyl) -1- (4-fluoro-benzyl) -1- [2- (1-methyl-1H-imidazol-4-yl) -ethyl ] -urea,
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- (2- (piperidin-1-yl) ethyl) urea,
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea,
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-3-yl) methyl) urea,
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1- (2-fluoroethyl) pyrrolidin-3-yl) methyl) urea,
3- (4-Cyclobutoxybenzyl) -1- ((1-ethylpyrrolidin-3-yl) methyl) -1- (4-fluorobenzyl) urea,
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-2-yl) methyl) urea,
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- (2- (pyrrolidin-1-yl) ethyl) urea,
3- (4-Cyclobutoxybenzyl) -1- ((1-cyclopropylpyrrolidin-3-yl) methyl) -1- (4-fluorobenzyl) urea,
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- (2- (1-methylpyrrolidin-2-yl) ethyl) urea,
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- (2- (1-methylpiperidin-2-yl) ethyl) urea,
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylazetidin-3-yl) methyl) urea,
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea,
(S) -3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea,
(R) -3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea,
3- (4-Cyclobutoxy-3-fluorobenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea,
(S) -3- (4-cyclobutoxy-3-fluorobenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea,
(R) -3- (4-cyclobutoxy-3-fluorobenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea,
1- (4-Fluorobenzyl) -1- ((1-methylazetidin-3-yl) methyl) -3- (4- (3-methylbutanoyl) benzyl) urea,
(S) -1- (4-fluorobenzyl) -3- (4- (3-methylbutyryl) benzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea,
(R) -1- (4-fluorobenzyl) -3- (4- (3-methylbutyryl) benzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea,
(S) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea,
(R) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea,
(S) -1- (4-fluorobenzyl) -3- (4-isobutoxybenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea,
(R) -1- (4-fluorobenzyl) -3- (4-isobutoxybenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea,
1- (4-Fluorobenzyl) -3- (4-isobutoxybenzyl) -1- ((1-methylazetidin-3-yl) methyl) urea,
1- (4-Fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) -3- (4-isobutoxybenzyl) urea,
1- (4-Fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea,
3- (4-Cyclobutoxy-3-fluorobenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea,
3- (3-Fluoro-4-methoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea,
(R) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4-isobutoxybenzyl) urea,
(S) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4-isobutoxybenzyl) urea,
(R) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea,
(S) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea,
3- (3-Fluoro-4-methoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea,
3- (4-Cyclobutoxy-3-fluorobenzyl) -1- (2, 4-difluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea,
1- (2, 4-Difluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea,
3- (Chroman-6-ylmethyl) -1- (2, 4-difluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea,
1- (2, 4-Difluorobenzyl) -3- (4- (3-methylbutanoyl) benzyl) -1- (1-methylpiperidin-4-yl) urea,
(R) -1- (2, 4-difluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea,
(S) -1- (2, 4-difluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea,
(R) -1- (2, 4-difluorobenzyl) -3- (3-fluoro-4-methoxybenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
(R) -3- (3-fluoro-4-methoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
(S) -3- (3-fluoro-4-methoxybenzyl) -1- (4-fluorobenzyl) -1- ((l-methylpyrrolidin-3-yl) methyl) urea,
3- (3-Fluoro-4-isobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea,
(S) -1- (2, 4-difluorobenzyl) -3- (3-fluoro-4-methoxybenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
3- (3-Fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea,
1- (2, 4-Difluorobenzyl) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea,
(R) -1- (2, 4-difluorobenzyl) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
(S) -1- (2, 4-difluorobenzyl) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
(S) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
(R) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
3- (4- (2-Hydroxy-2-methylpropyloxy) benzyl) -1- (2, 4-difluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea,
3- (4- (2-Hydroxy-2-methylpropyloxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea,
(R) -3- (4- (2-hydroxy-2-methylpropyloxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
3- (4- ((Tetrahydrofuran-3-yl) -oxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea,
(R) -3- (4- ((tetrahydrofuran-3-yl) -oxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
(S) -3- (4- (tetrahydrofuran-3-yl) -oxy) benzyl) -1- (2, 4-difluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
(S) -3- (4- ((tetrahydrofuran-3-yl) -oxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
1- (2- (Azetidin-1-yl) -ethyl) -1- (4-fluoro-benzyl) -3- (4-isobutoxy-benzyl) -urea.
The invention provides a method for preparing a compound of formula I, which is characterized in that:
Step 1, reacting an isocyanic acid compound with a structure shown in a formula A with an amino compound shown in a formula B according to the following reaction formula to obtain a compound shown in a formula I through synthesis,
And 2, if necessary, carrying out functional group modification on the compound shown in the formula I according to the requirement of a target product, and converting the compound into the target product with the structure shown in the formula I, or converting the compound into pharmaceutically acceptable salt or precursor compound of the compound.
The preparation method is also applicable to the preparation of the compounds of the formula IA and the compounds of the formula IB.
The compounds of formula I, formula IA, formula IB, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof of the present invention have 5HT2A receptor inhibitory or inverse agonistic activity and are useful in the treatment of conditions mediated by 5HT2A receptor activity.
The inhibitory activity of the compounds of the present invention against 5HT2A was tested by IP-One experiments using Flp-In-CHO-5HT2A stable cell lines. The IP-One experiment was based on competitive immunoassay with HTRF (homogeneous time resolved fluorescence) using terbium cryptate-labeled anti-IP 1 mab and d 2-labeled IP1. If the compound exhibits EC 50.ltoreq.1. Mu.M, the compound tested in the above assay is considered to have inhibitory activity of 5HT 2A. Preferred compounds of the invention have EC 50.ltoreq.150 nM, more preferred compounds have EC 50.ltoreq.50 nM, and most preferred compounds have EC 50.ltoreq.20 nM.
The compounds of formula I, IA, IB, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof of the present invention possess good antagonistic activity at the 5HT2A receptor. Further, the compounds of the invention have good selectivity, in particular for 5HT2B and/or 5HT2C, reduced cardiotoxicity, and/or improved metabolic stability.
The present invention provides the use of a compound of formula I, a compound of formula IA, a compound of formula IB, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of a disease associated with 5HT2A receptor activity mediated by such compounds.
Such 5HT2A receptor activity mediated related disorders include, but are not limited to, disorders of the central nervous system.
Such central nervous system disorders include, but are not limited to: mental disorders, degenerative disorders of the central nervous system, symptoms of mental disorders associated with or concurrent with degenerative disorders of the central nervous system, and negative symptoms of mental disorders.
The mental disorders include, but are not limited to: depression, anxiety, mania, schizophrenia, schizoaffective disorder, bipolar disorder, insomnia, autism, etc.
Such degenerative diseases of the central nervous system include, but are not limited to: alzheimer's disease, parkinson's disease, huntington's disease, lewy body dementia, and the like.
Symptoms of the central nervous system degenerative disease-related or concurrent psychotic disorder, negative symptoms of the psychotic disease, include, but are not limited to: affective disorders, language hypofunction, hallucinations, lack of interest, and the like.
The invention provides a pharmaceutical composition, which is characterized by comprising a compound of formula I, a compound of formula IA, a compound of formula IB or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
The pharmaceutical compositions may be used to treat diseases associated with 5HT2A receptor activity. The definition of the related diseases mediated by 5HT2A receptor activity is as described above.
The pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
The pharmaceutically acceptable carrier is a variety of excipients commonly used or known in the pharmaceutical arts, including but not limited to: diluents, binders, antioxidants, pH adjusters, preservatives, lubricants, disintegrants, and the like.
Such as for example: lactose, starch, cellulose derivatives, inorganic calcium salts, sorbitol, etc. The binder is for example: starch, gelatin, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and the like. Such as: vitamin E, sodium bisulphite, sodium sulfite, butylated hydroxyanisole, etc. The pH adjuster is, for example: hydrochloric acid, sodium hydroxide, citric acid, tartaric acid, tris, acetic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, and the like. Such as: methyl parahydroxybenzoate, ethyl parahydroxybenzoate, m-cresol, benzalkonium chloride, and the like. The lubricant is for example: magnesium stearate, silica gel micropowder, talc, etc. Such as: starch, methylcellulose, xanthan gum, croscarmellose sodium, and the like.
The pharmaceutical composition contains the compound of formula I, the compound of formula IA, the compound of formula IB, or pharmaceutically acceptable salts, solvates or stereoisomers thereof in an amount of 0.1 to 1000mg, preferably 1 to 500mg, more preferably 5 to 100mg.
The compound of formula I, the compound of formula IA, the compound of formula IB, or pharmaceutically acceptable salts, solvates or stereoisomers thereof account for 10-90%, preferably 20-80%, more preferably 30-70% of the mass of the pharmaceutical composition.
The dosage form of the pharmaceutical composition may be in the form of an oral dosage form, such as a tablet, capsule, pill, powder, granule, suspension, syrup, etc.; it may also be in the form of an injectable administration, such as an injectable solution, powder injection, etc., by intravenous, intraperitoneal, subcutaneous or intramuscular route. All dosage forms used are well known to those of ordinary skill in the pharmaceutical arts.
Routes of administration of the pharmaceutical composition include, but are not limited to: oral administration; is taken orally; sublingual, sublingual; transdermal; lung; rectal; parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous; by implantation into a reservoir or reservoir.
The dosage of the compound of formula I, the compound of formula IA, the compound of formula IB, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, will depend upon the age, health and weight of the recipient, the type of combination drug, the frequency of treatment, the route of administration, and the like. The drug may be administered in a single daily dose, once daily, once every two days, once every three days, once every four days, or the total daily dose may be administered in divided doses of two, three or four times per day. The dose may be administered one or more times and the administration time may be from a single day to several months or longer. The compound of formula I, formula IA, formula IB or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered in an amount of 0.01-100 mg/kg/day, preferably 0.1-10 mg/kg/day, e.g. 0.5 mg/kg/day, 1 mg/kg/day, 2 mg/kg/day, 5 mg/kg/day, etc.
The pharmaceutical composition can be used in combination with other drugs for treating related diseases mediated by 5HT2A receptor activity.
The pharmaceutical composition may further comprise a second therapeutic agent that is another agent for the treatment of a related disorder mediated by 5HT2A receptor activity.
The present invention provides a method of treating a disease associated with 5HT2A receptor activity, characterized by administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, a compound of formula IA, a compound of formula IB, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
The routes of administration of the compound of formula I, the compound of formula IA, the compound of formula IB, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof include, but are not limited to: oral administration; is taken orally; sublingual, sublingual; transdermal; lung; rectal; parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial; by implantation into a reservoir or reservoir.
The method further comprises administering to a patient in need thereof an additional agent for treating a disease associated with 5HT2A receptor activity.
Other drugs for treating diseases mediated by 5HT2A receptor activity include, but are not limited to: mental disease therapeutic drugs, central nervous system degenerative disease therapeutic drugs, etc.
The psychotropic drugs include, but are not limited to: benzodiazepinesClass (e.g.: methyltriazepam, clozapine/>)Clonazepam, diazepam, sulbactam, fluoazepam, midazolam, etc.); barbiturates (e.g., phenobarbital, pentobarbital, etc.); hydrating chloral; buspirone; phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, etc.); thioxanthenes (e.g., thioxanthenes); butyrylbenzenes (e.g., haloperidol); clozapine; risperidone; tricyclic antidepressants (e.g., imipramine, doxepin, nortriptyline, amitriptyline, etc.); heterocyclic antidepressants (e.g., amoxapine, maprotiline, trazodone, bupropion, venlafaxine, etc.); selective 5-HT reuptake inhibitors (e.g., fluoxetine, paroxetine, sertraline, citalopram, fluvoxamine, etc.); monoamine oxidase inhibitors (e.g., phenelzine, moclobemide, etc.); ketamine; mirtazapine, and the like.
Such central nervous system degenerative disease treatment drugs include, but are not limited to: levodopa, bromocriptine, thiopropion, propynylamphetamine, amantadine, reserpine, and the like.
Detailed description of the preferred embodiments
The chemical reagents used in the examples were all commercially available compounds, wherein:
DMF: n, N-dimethylformamide;
DIEA: n, N-diisopropylethylamine;
Et3N: triethylamine and process for preparing same
DCM: dichloromethane (dichloromethane)
THF: tetrahydrofuran (THF)
Acetone: acetone (acetone)
Pyridine: pyridine compound
Pd (PPh 3)4: tetrakis (triphenylphosphine) palladium)
TFA: trifluoroacetic acid
TFE:2, 2-trifluoroethanol
Triphosgene: triphosgene
Et: ethyl, ac: an acetyl group; for example, etOAc is ethyl acetate or ethyl acetate and EtOH is ethanol.
Example 1: synthesis of 1- (4-fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (9-methyl-3-oxa-9-aza-bicyclo [3.3.1] non-7-yl) -urea (Compound # 1), ER10048
(4-Fluoro-benzyl) - (9-methyl-3-oxa-9-za-bicyclo [3, 1] non-7-yl) amine (1-1): to a solution of 9-methyl-3-oxa-9-aza-bicyclo [3, 1] nonan-7-one (125 mg, 0.805 mmol) in 5.0mL of methylene chloride was added 4-fluorobenzylamine (151 mg,1.21 mmol) at room temperature, followed by sodium triacetoxy borohydride (3411 mg,1.61 mmol) and 0.1mL of acetic acid in portions. The mixture was stirred at room temperature overnight. Ice water (10 ml) was added, and the mixture was extracted with 10% (v/v) isopropanol/chloroform (30 ml. Times.2). The organic phase Na 2SO4 was dried, filtered and concentrated under vacuum to give intermediate (1-1) as a colourless oil (181 mg, 85% yield). LCMS: [ M+1] + 265.2.
4-Isobutoxybenzonitrile (1-2): potassium carbonate (58.0 g,420 mmol) was added to a mixture of 4-hydroxybenzonitrile (25.0 g,210 mmol) and 1-bromo-2-methylpropane (34.5 g,252 mmol) in acetone (150 mL). Stirred at 60℃for 3 days. The solid was filtered off and washed with acetone (50 mL). After removal of the solvent under vacuum, saturated NaHCO 3 solution (100 ml) was added and the mixture was extracted with EtOAc (50 ml×3). The organic phase was washed with brine (30 ml), dried over Na 2SO4 and concentrated in vacuo to afford intermediate (1-2) (29.3 g, 80% yield). LCMS: [ M+1] + 176.2.
(4-Isobutoxyphenyl) methylamine (1-3): lithium aluminum hydride (3.25 g,86 mmol) was added to anhydrous THF (200 ml) under argon and cooled to 0deg.C in an ice bath. A solution of 4-isobutoxy-benzonitrile (10.0 g,57 mmol) in THF (20 mL) was then slowly added dropwise. The mixture was stirred overnight at room temperature, the resulting mixture was cooled to 0 ℃, and then a saturated aqueous Na 2SO4 solution of 2N NaOH was added dropwise to form a white suspension. The white solid was filtered off and washed with THF (30 ml). The filtrate Na 2SO4 was dried, filtered and concentrated in vacuo to give a colorless oil (10.1 g, 98% yield). LCMS: [ M+1] + 180.2.2.
1-Isobutoxy-4- (isocyanatomethyl) benzene (1-4): a solution of triphosgene (3.3 g,11.2 mmol) in DCM (10 mL) was slowly added to a solution of (4-isobutoxyphenyl) methylamine (2.0 g,11.2 mmol) in DCM (10 mL) at 0deg.C. The mixture was stirred at room temperature for 1 hour. Ice water (20 ml) was added and the mixture extracted with DCM (50 ml×2). The organic phase was washed with brine, dried over Na 2SO4, filtered and concentrated under vacuum to give the product (1-4) as an oil (2.20 g,98% yield). LCMS: [ M+1] + 206.2.
1- (4-Fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (9-methyl-3-oxa-9-aza-bicyclo [3.3.1] non-7-yl) -urea (compound # 1): a solution of (4-fluoro-benzyl) - (9-methyl-3-oxa-9-aza-bicyclo [3, 1] non-7-yl) amine (1) in anhydrous THF (5 mL) was slowly added to a solution of 1-isobutoxy-4- (isocyanatomethyl) benzene in DCM (5.0 mL) at 0deg.C. The resulting mixture was heated at 40℃for about 10 minutes. The solvent was removed under vacuum. The crude product was purified by high performance liquid chromatography. Compound #1 (149 mg, 89% yield) was obtained as a white solid .1H NMR(300MHz,CDCl3)：δ7.26-7.23(d,J＝9.0Hz,2H),7.15-6.95(m,4H),6.82(d,J＝8.5Hz,2H),4.71-4.85(m,2H),4.50(s,2H),4.35(d,J＝5.5Hz,2H),3.90(d,J＝11.2Hz),3.71(d,J＝6.5Hz,2H),3.27(d,J＝11.2Hz,2H),2.83(d,J＝10.8Hz,2H),2.57(s,2H),2.34-2.01(m,2H),1.62-1.75(m,4H),1.04(d,J＝6.6hz,6H).LCMS：[M+1]+470.21.
Example 2: synthesis of 1- (3- (azetidin-1-yl) -propyl) -1- (4-fluoro-benzyl) -3- (4-isobutoxy-benzyl) -urea (Compound # 12), ER10053
(3- (Azetidin-1) -yl-propyl) - (4-fluoro-benzyl) -amine (12-1): the synthesis is similar to intermediate (1-1). Using 0.88mmol of 3- (azetidin-1-yl) -propylamine and 4-fluorobenzaldehyde, compound (12-1) was obtained as a brown oil (155 mg,80% yield). LCMS: [ M+1] + 223.3.
1- (3- (Azetidin-1-yl) -propyl) -1- (4-fluoro-benzyl) -3- (4-isobutoxy-benzyl) -urea (Compound # 12) was synthesized in a similar manner to Compound #1. Reaction of 1-isobutoxy-4- (isocyanatomethyl) benzene (1-4) with 0.70mmol (3- (azetidin-1) -yl-propyl) - (4-fluoro-benzyl) -amine (12-1) gave compound #12 (100 mg.33% yield) as a white solid ).1H NMR(300MHz,CDCl3)：δ7.31(d,J＝6.4Hz,4H),7.01(t,J＝8.7Hz,2H),6.93-6.84(m,2H),4.48(s,2H),4.41(s,2H),3.73(d,J＝6.5Hz,2H),3.245(s,2Hz),3.02-2.91(m,4H),2.36(d,J＝5.9Hz,2H),2.09(dp,J＝12.4,6.1Hz,2H),1.74(p,J＝7.2Hz,2H),1.50-1.40(m,2H),1.03(d,J＝6.6Hz,6H),LCMS：[M+1]+428.3.
Example 3: synthesis of 1- (4-fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (1-methyl-pyrrolidin-3-ylmethyl) -urea (Compound # 10), ER10054
(4-Fluoro-benzyl) - (1-methyl-pyrrolidin-3-ylmethyl) -amine (10-1): the synthesis is similar to intermediate (1-1). Reaction of 4-fluorobenzaldehyde with (1-methyl-pyrrolidin-3-yl) -methylamine (100 mg,0.87 mmol) gave product (10-1) as a yellow oil (155 mg,80% yield). LCMS: [ M+1] + 223.4.4.
The synthesis of 1- (4-fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (1-methyl-pyrrolidin-3-ylmethyl) -urea (compound # 10) was similar to compound #1. Reaction of 1-isobutoxy-4- (isocyanatomethyl) benzene (1-4) with 0.69mmol of (4-fluoro-benzyl) - (1-methyl-pyrrolidin-3-ylmethyl) -amine (10-1) gave compound #10 (140 mg,47% yield) as yellow solid ).1H NMR(300MHz,CDCl3)：δ7.29-7.17(m,4H),7.02(dd,J＝9.8,7.5Hz,2H),6.86(dd,J＝9.1,2.4Hz,2H),6.37(s,1H),4.70-4.58(m,2H),4.44-4.32(m,2H),3.80(s,2H),3.72(d,J＝6.4Hz,2H),3.31(dd,J＝15.2,10.6Hz,2H),3.08-2.89(m,2H),2.67(d,J＝9.8Hz,2H),2.14(s,2H),2.15-2.01(m,2H),2.06-1.83(m,1H),1.44(d,J＝9.0Hz,2H),1.04(d,J＝6.7Hz,6H).LCMS：[M+1]+428.3.
Example 4: synthesis of 1- (4-fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- ((1-methyl-azetidin) -3-ylmethyl) -urea (Compound # 11), ER10057
(4-Fluoro-benzyl) - ((1-methyl-azetidin) -3-ylmethyl) -amine (11-1): the synthesis is similar to intermediate (1-1). Reaction of 4-fluorobenzaldehyde with 0.5mmol (1-methyl-azetidin-3-yl) -methylamine gave intermediate (11-1) as a brown oil (88 mg,85% yield). LCMS: [ M+1] + 209.3.
1- (4-Fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (1-methyl-azetidin-3-ylmethyl) -urea (Compound # 11) was synthesized similarly to Compound #1. Reaction of 1-isobutoxy-4- (isocyanatomethyl) benzene (1-4) with 0.42mmol of (4-fluoro-benzyl) - ((1-methyl-azetidin) -3-ylmethyl) -amine (11-1) gave compound #11 (23 mg,14% yield) as a yellow solid. LCMS: [ M+1] + 414.5.
Example 5: synthesis of 1- (4-fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (octahydro-quinolizin-2-yl) -urea (Compound # 5), ER10063
2- (1- (3-Ethyl propionate) -piperidin) -2-yl) -acetic acid ethyl ester (5/6-1): a mixture of ethyl 2- (piperidin-2-yl) acetate (500 mg,3.0 mmol), ethyl acrylate (901 mg,9.0 mmol), triethylamine (180 mg,18 mmol) in ethanol was stirred at room temperature under argon for 4 days and the solvent and excess reagent were removed under vacuum. The crude intermediate compound (5/6-1) (600 mg, 76% yield) was obtained and used directly in the next step.
2-Carbonyl-octahydro-quinolizine-1-carboxylic acid ethyl ester (5-2): 2- (1- (3-Ethyl propionate) -piperidin) -2-yl) -acetic acid ethyl ester (5-1) (720 mg,3.0 mmol) was dissolved in 6 ml anhydrous THF under argon. A solution of 1.3M LiHDMS (6.0 mmol) in THF was slowly added dropwise at-78deg.C. Then stirred at-78℃for 2 hours, 1 ml of 6NHCl was added. After warming to room temperature, 30 ml of water were added. The mixture was extracted with 30 ml of diethyl ether. The aqueous layer was extracted with saturated Na 2CO3 aqueous solution ph=8.0-9.0 diethyl ether. The organic phase was washed with brine and dried over Na 2SO4. Concentration under reduced pressure gave 900 mg of crude product (5/6-2). Is used directly in the next reaction.
Octahydro-quinolizin-2-one (5-3): 900mg of ethyl 2-carbonyl-octahydro-quinolizine-1-carboxylate (5-2) were refluxed in 10ml of 6N HCl for 20 hours. The reaction mixture was neutralized with solid Na 2CO3, extracted with 3×30ml of diethyl ether, the organic phase was washed with brine and dried over Na 2SO4, and the solvent was evaporated to give 300mg of crude product (49% yield).
(4-Fluoro-benzyl) - (octahydro-quinolizin-2-yl) -amine (5-4): the synthesis method is similar to (1-1). Using 0.97mmol of octahydro-quinolizin-2-one (5/6-3) gives the product (5/6-4) as a colourless oil (215 mg, yield 85%). LCMS: [ M+1] + 263.21.
1- (4-Fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (octahydro-quinolizin-2-yl) -urea (Compound # 5): the synthesis method is similar to that of compound #1. Reaction of 1-isobutoxy-4- (isocyanatomethyl) benzene (1-4) with 0.83mmol (4-fluoro-benzyl) - (octahydro-quinolizin-2-yl) -amine (5/6-4) gave compound #5 (280 mg,73% yield) as a white solid ).1H NMR(300MHz,CDCl3)：δ7.19(dd,J＝6.6Hz,2H),7.03(d,J＝8.5Hz,4H),6.80(d,J＝8.6Hz,2H),4.45-4.6(m,2H),4.43(s,,2H),4.39-4.25(m,4H),3.70(d,J＝6.6Hz,2H),3.14(d,J＝13.4Hz,2H),2.55(s,1H),2.08(dt,J＝13.40Hz,1H),2.04-2.06(m,4H),1.88(d,J＝13.2Hz,,4H),1.34(s,2H),1.31-1.16(m,2H),1.03(d,J＝6.7Hz,6H),LCMS：[M+1]+468.10.
Example 6: synthesis of 1- (4-fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (octahydro-pyrido [2,1-c ] [1,4] oxazin-8-yl) -urea (Compound # 7), ER10065
3- ((3-Ethoxycarbonylmethyl) -morpholin-4-yl) propanoic acid ethyl ester (7/8-1): the synthesis method was similar to (5-1). Using 2- (morpholin-3-yl) -acetic acid ethyl ester (1.0 g,5.8 mmol) gave the crude product (1.3 g,87% yield) which was used directly in the next reaction.
8-Carbonyl-octahydro-pyrido [2,1-c ] [1,4] oxazine-9-carboxylic acid ethyl ester (7-2): the synthesis method was similar to (5-2). Ethyl 3- ((3-ethoxycarbonylmethyl) -morpholin-4-yl) propionate (7-1) (1.3 g,3.9 mmol) gave the crude product (900 mg,100% yield) which was used directly in the next reaction.
Hexahydro-pyrido [2,1-c ] [1,4] oxazin-8-one (7-3): the synthesis method is similar to (5/6-3). Ethyl 8-carbonyl-octahydro-pyrido [2,1-c ] [1,4] oxazine-9-carboxylate (7-2) (900 mg,4.0 mmol) was used to give the crude product (300 mg,48% yield) which was used directly in the next reaction.
(4-Fluoro-benzyl) - (hexahydro-pyrido [1,2-c ] [1,4] oxazin-6-yl) -amine (7-4): the synthesis method is similar to (1-1). Using hexahydro-pyrido [2,1-c ] [1,4] oxazin-8-one (7-3) (150 mg,0.97 mmol) and 4-fluorophenyl methylamine gave the crude product (166 mg,65% yield) which was used directly in the next reaction. LCMS: [ M+1] + 265.21.
1- (4-Fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (octahydro-pyrido [2,1-c ] [1,4] oxazin-8-yl) -urea (Compound # 7): the synthesis method is similar to that of compound #1. Reaction of 1-isobutoxy-4- (isocyanatomethyl) benzene (1-4) with 0.63mmol (4-fluoro-benzyl) - (hexahydro-pyrido [1,2-c ] [1,4] oxazin-6-yl) -amine (7/8-4) gave #7 as a white solid (150 mg,58% yield ).1H NMR(300MHz,CDCl3)：δ7.19(dt,J＝8.7Hz,4.8Hz,2H),7.04(dd,J＝8.4Hz,4H),6.8(s,2H),4.52(s,2H),4.38-4.25(m,3H),3.91-3.73(m,2H),3.72(s,2Hz),3.67(d,J＝12.2Hz,2H),3.58-3.48(m,2H),3.04(dd,J＝11.3.4.8Hz,2H),2.91-2.61(m,1H),2.52-2.20(m,1H),2.08(dt,J＝13.4,6.6Hz,1H),1.80(td,J＝14.6,14.0,6.4Hz,2H),1.31-1.16(m,2H),1.03(d,J＝6.8Hz,6H),LCMS：[M+1]+470.11.
Example 7: synthesis of 1- (4-fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (2- (pyrrolidin-1-yl) -ethyl) -urea (Compound # 53), ER10066
(4-Fluoro-benzyl) - (2- (pyrrolidin-1-yl) -ethyl) -amine (53-1): the synthesis method is similar to (1-1). Using 1.3 mmole of 2- (pyrrolidin-1-yl) -ethylamine gives (53-1) as brown oil (213 mg,73% yield). LCMS: [ M+1] + 223.35
1- (4-Fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- (2- (pyrrolidin-1-yl) -ethyl) -urea (Compound # 53) was synthesized in a similar manner to Compound #1. Reaction of 1-isobutoxy-4- (isocyanatomethyl) benzene (1-4) with 0.95mmol (4-fluoro-benzyl) - (2-pyrrolidin-1-yl-ethyl) -amine (53-1) gave compound #53 (210 mg,51% yield). LCMS: [ M+1] + 428.18.
Example 8: synthesis of 3- (4-isobutoxy-benzyl) -1- (4-fluoro-benzyl) -1- [2- (1-methyl-1H-imidazol-4-yl) -ethyl ] -urea (Compound # 55), ER10117
The synthesis of (4-fluoro-benzyl) - [2- (1-methyl-1H-imidazol-4-yl) -ethyl ] -amine (55-1) is similar to (1-1). Using 2- (1-methyl-1H-imidazol-4-yl) -ethylamine (250 mg,1.26 mmol) gave (55-1) as a colorless oil (176 mg,60% yield). LCMS: [ M+1] + 234.31.
1- (4-Fluoro-benzyl) -3- (4-isobutoxy-benzyl) -1- [2- (1-methyl-1H-imidazol-4-yl) -ethyl ] -urea (composition # 55) was synthesized in a similar manner to composition #1. Reaction of 1-isobutoxy-4- (isocyanatomethyl) benzene (1-4) with 0.76mmol of (4-fluoro-benzyl) - [2- (1-methyl-1H-imidazol-4-yl) -ethyl ] -amine (55-1) gave compound #55 (75 mg,23% yield as a yellow solid ).1H NMR(300MHz,CDCl3)：δ7.56(s,2H),7.30(s,2H),7.30-7.14(m,1H),7.12-6.85(m,4H),4.25(d,J＝11.4Hz,2H),3.77-3.60(m,2H),3.16(q,J＝6.7Hz,2H),2.61-2.50(m,1Hz),2.41(m,4H),2.26(m,2H),1.89(p,J＝7.1Hz,2H),1.38(m,2H),1.04(s,3H),1.08-0.94(m,6H),LCMS：[M+1]+440.08.
Example 9: synthesis of 3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- (2- (piperidin-1-yl) ethyl) urea (H001-017, ER 10173)
N- (4-Fluorobenzyl) -2- (piperidin-1-yl) ethan-1-amine (H001-003) was synthesized in a similar manner to (1-1). Using 0.9mmol of 2-piperidin-1-yl-ethylamine gives brown intermediate (H001-003) (104 mg,44% yield). LCMS: [ M+1] + 237.3.3.
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- (2- (piperidin-1-yl) ethyl) urea (H001-017, ER 10173) was synthesized in a similar manner to compound #1. Reaction of the above intermediate with 0.76mmol of 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) gave compound ER10173 as a white solid (58.6 mg,18% yield) ).1H NMR(400MHz,CDCl3)：δ7.26-7.23(m,4H),7.02-6.97(m,2H),6.72(d,J＝8.5Hz,2H),5.40(bs,1H),4.62-4.59(m,1H),4.42(s,2H),4.28(s,2H),3.70(m,2Hz),3.61(d,J＝6.5Hz,2H),3.12(m,2H),2.62(m,2H),2.45-2.38(m,6H),2.16-2.12(m,2H),1.94-1.71(m,2H),1.68-1.65(m,1H),1.39(m 1H).LCMS：[M+1]+440.3.
Example 10: synthesis of 3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (H001-018) ER10174
N- (4-Fluorobenzyl) -1- (1-methylpiperidin-4-yl) methylamine (H001-004) was synthesized in a similar manner to (1-1). Starting with 0.9mmol of 2-piperidin-1-yl-ethylamine, brown intermediate (H001-004) was obtained (82 mg,35% yield). LCMS: [ M+1] + 237.3.3.
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (H001-018) ER10174
Synthesis method analogous to Compound #1 Using 0.76 mmole of 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) as a starting material, was reacted with H001-004 compound to give Compound # H001-018 as a white solid (26.2 mg,8% yield ).1H NMR(400MHz,CDCl3)：δ7.19-7.09(m,2H),7.04-6.93(m,4H),6.72(d,J＝8.5Hz,2H),4.80(bs,1H),4.42(m,4H),4.28(s,2H),3.60(m,2Hz),3.24(d,J＝6.5Hz,2H),2.77(s,3H),2.62(m,2H),2.45-2.38(m,2H),2.16-1.94(m,4H),1.85-1.60(m,4H).LCMS：[M+1]+440.3.
Example 11: synthesis of 3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-3-yl) methyl) urea (H001-019) ER10175
N- (4-Fluorobenzyl) -1- (1-methylpiperidin-3-yl) methylamine (H001-007) the synthesis was similar to (1-1) reacting 7.2mmol (1-methylpiperidin-3-yl) methylamine with 4-fluorobenzaldehyde to give intermediate (H001-007) as a brown oil (560 mg,33% yield). LCMS: [ M+1] +237.3
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-3-yl) methyl) urea (H001-019) ER10175
Synthesis method analogous to Compound #1 using 0.76mmol of 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) gave Compound # H001-019 (24.7 mg,7% yield) as a white solid ).1H NMR(400MHz,CDCl3)：δ7.19-7.09(m,2H),7.04-6.93(m,4H),6.72(d,J＝8.5Hz,2H),4.80(bs,1H),4.57(m,1H),4.48-4.43(d,J＝8.5Hz,1H),4.32-4.17(m,3H),3.77(m,5H),3.54(m,2Hz),2.94(m,1H),2.76(s,3H),2.54(m,2H),2.45-2.36(m,3H),2.16-2.04(m,2H),2.05-1.60(m,2H).LCMS：[M+1]+440.3.
Example 12: synthesis of 3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1- (2-fluoroethyl) pyrrolidin-3-yl) methyl) urea (H001-024, ER 10176)
Tert-butyl 3- (((4-fluorobenzyl) amino) methyl) pyrrolidine-1-carboxylate (H001-009) was synthesized in analogy to (1-1) to react with 4-fluorobenzaldehyde using tert-butyl 3- (aminomethyl) pyrrolidine-1-carboxylate (390 mg,1.29 mmol) to give the product as a colourless oil (290 mg,73% yield). LCMS: [ M+1] + 209.2.2.
Tert-butyl 3- ((3- (4-cyclobutoxy-benzyl) -1- (4-fluorobenzyl) ureido) methyl) pyrrolidine-1-carboxylate (H001-020) was synthesized in analogy to (1-1) using 3mmol of tert-butyl 3- (((4-fluorobenzyl) amino) methyl) pyrrolidine-1-carboxylate (H001-009) and 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) to give intermediate (H001-020) (600 mg,39% yield): LCMS: [ M+1] + 512.2.
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- (pyrrolidin-3-ylmethyl) urea (H001-022) was synthesized in analogy to (9-1). 1mmol of tert-butyl 3- ((3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) ureido) methyl) pyrrolidine-1-carboxylate (H01-020) was stirred in a mixed solution of dichloromethane and TFA (2:1) for 1 hour and desolventized at low pressure to give a white solid (H001-022) (250 mg,61% yield). LCMS: [ M+1] + 412.3
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1- (2-fluoroethyl) pyrrolidin-3-yl) methyl) urea (H001-024, ER 10176)
To 3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- (pyrrolidin-3-ylmethyl) urea (0.39 mmol) in anhydrous DMF (2 mL) was added 1-fluoro-2-iodoethane (0.39 mmol) and cesium carbonate (0.39 mmol). The reaction mixture was stirred at 60 ℃ overnight, the solvent was removed and purification was performed by high performance liquid chromatography. Obtained as a white solid (120 mg,67% yield ).1H NMR(400MHz,CDCl3)：δ7.19-7.09(m,3H),7.04-6.93(m,3H),6.72(d,J＝8.5Hz,2H),4.84(bs,1H),4.70(m,1H),4.62-4.53(m,2H),4.42-4.19(m,5H),3.86(m,2H),3.50(m,3Hz),3.25(m,2H),3.03(m,1H),2.80(m,2H),2.44(m,2H),2.28-2.05(m,3H),1.875-1.63(m,3H).LCMS：[M+1]+458.1
Example 13: synthesis of 3- (4-Cyclobutoxybenzyl) -1- ((1-ethylpyrrolidin-3-yl) methyl) -1- (4-fluorobenzyl) urea (H001-026) ER10177
1- (1-Ethylpyrrolidin-3-yl) -N- (4-fluorobenzyl) methylamine (H001-006) the synthesis was similar to (1-1) reacting 10mmol (1-ethylpyrrolidin-3-yl) methylamine with 4-fluorobenzaldehyde to give intermediate (H001-006) (300 mg,13% yield). LCMS: [ M+1] + 237.3
3- (4-Cyclobutoxybenzyl) -1- ((1-ethylpyrrolidin-3-yl) methyl) -1- (4-fluorobenzyl) urea (H001-026) ER10177
Synthesis method of the product was analogous to Compound #1. 1.0mmol of 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) was reacted with 1- (1-ethylpyrrolidin-3-yl) -N- (4-fluorobenzyl) methylamine to give Compound # H001-026 (80 mg,18% yield) ).1H NMR(400MHz,CDCl3)：δ7.19-7.09(m,3H),7.04-6.93(m,3H),6.72(d,J＝8.5Hz,2H),4.67(bs,1H),4.58(m,1H),4.41-4.32(m,2H),4.27-4.17(m,2H),3.80(m,2H),3.75(m,2H),3.62-3.47(m,2H),3.31-3.12(m,2H),2.99-2.65(m,2H),2.41(m,2H),2.24-2.05(m,4H),1.89-1.63(m,1H),1.35(m,3H).LCMS：[M+1]+440.2
Example 14: synthesis of 3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-2-yl) methyl) urea (H001-028) ER10179
N- (4-Fluorobenzyl) -1- (1-methylpiperidin-2-yl) methylamine (H001-021) was synthesized in a similar manner to (1-1). Using 3mmol of (1-methylpiperidin-2-yl) methylamine gives intermediate (H001-021) (457 mg,64% yield). LCMS: [ M+1] + 237.3.3.
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-2-yl) methyl) urea (H001-028) ER10179, the synthesis was similar to that of compound #1. Reaction of 1.0mmol of 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) with N- (4-fluorobenzyl) -1- (1-methylpiperidin-2-yl) methylamine (H001-021) gave the product compound #H2-028 (60 mg,14% yield) ).1H NMR(400MHz,CDCl3)：δ7.12(m,2H),7.07-6.97(m,4H),6.70(d,J＝6.7Hz,2H),5.24(bs,1H),4.46(s,1H),4.35-4.18(m,3H),4.15-3.99(m,1H),3.59(m,1H),3.76(m,2H),3.55(m,2H),3.45-3.15(m,2H),2.90-2.72(m,4H),2.47-2.30(m,3H),2.20-2.09(m,1H),1.99-1.78(m,2H),1.65(m,3H).LCMS：[M+1]+440.2
Example 15: synthesis of 3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- (2- (pyrrolidin-1-yl) ethyl) urea (H001-029) ER10180
N- (4-Fluorobenzyl) -2- (pyrrolidin-1-yl) ethane-1-amine (H001-025) was synthesized in a similar manner to (1-1). Reaction of 4-fluorobenzaldehyde with 5mmol of 2- (pyrrolidin-1-yl) ethane-1-amine gave intermediate (H001-025) (618 mg,51% yield). LCMS: [ M+1] + 223.3.
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- (2- (pyrrolidin-1-yl) ethyl) urea (H001-029) ER10180 was synthesized in a similar manner to compound #1. Reaction of 1.0mmol of 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) with N- (4-fluorobenzyl) -2- (pyrrolidin-1-yl) ethane-1-amine (H001-025) gave product H001-029 (80 mg,18% yield) ).1H NMR(400MHz,CDCl3)：δ7.14-7.10(m,2H),7.08-6.99(m,4H),6.70(d,J＝8.8Hz,2H),5.32(bs,1H),4.64-4.56(m,1H),4.43(s,2H),4.28(s,2H),3.90-3.69(m,5H),3.31-3.25(m,2H),2.47-2.38(m,2H),2.19-2.04(m,6H),1.88-1.80(m,2H),1.73-1.61(m,1H).LCMS：[M+1]+426.3.
Example 16: synthesis of 3- (4-Cyclobutoxybenzyl) -1- ((1-cyclopropylpyrrolidin-3-yl) methyl) -1- (4-fluorobenzyl) urea (H001-030) ER10181
3- (4-Cyclobutoxybenzyl) -1- ((1-cyclopropylpyrrolidin-3-yl) methyl) -1- (4-fluorobenzyl) urea (H001-030) ER10181, (1-ethoxycyclopropyloxy) trimethylsilane (79 μl) and TFE (5.0 mL) were mixed and stirred at 40deg.C for 5 min. 3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- (pyrrolidin-3-ylmethyl) urea (161 mg) was then added. After the mixture was stirred for 5 minutes, naBH 4 (340.5 mg) was added and then stirred at room temperature overnight. All solvents were rotary evaporated and purified by high performance liquid chromatography. White solid compound #H2-030 (85 mg, yield) 48％).1H NMR(400MHz,CDCl3)：δ7.18-6.94(m,6H),6.70(d,J＝8.8Hz,2H),6.32(bs,1H),4.59(s,2H),4.43-4.13(m,3H),3.90-3.76(m,2H),3.28-3.08(m,2H),3.07-2.69(m,4H),2.564-2.35(m,3H),2.24-2.04(m,3H),1.88-1.60(m,2H),1.31-1.12(m,2H),0.90-0.71(m,2H).LCMS：[M+1]+452.2.
Example 17: synthesis of 3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- (2- (1-methylpyrrolidin-2-yl) ethyl) urea (H001-033) ER10182
N- (4-fluorobenzyl) -2- (1-methylpyrrolidin-2-yl) ethane-1-amine (H001-031): the synthesis method is similar to (1-1).
Using 10mmol of 2- (1-methylpyrrolidin-2-yl) ethane-1-amine gives intermediate (H001-031) as a brown oil (4816 mg,21% yield). LCMS: [ M+1] + 237.3.3.
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- (2- (1-methylpyrrolidin-2-yl) ethyl) urea (H001-033) ER10182, the synthesis was similar to that of compound #1. Reaction of N- (4-fluorobenzyl) -2- (1-methylpyrrolidin-2-yl) ethane-1-amine (H001-031) with 0.5mmol of 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) gave compound #H001-033 (190 mg,86% yield) ).1H NMR(400MHz,CDCl3)：δ7.17-7.10(m,2H),7.08-6.99(m,4H),6.70(d,J＝8.8Hz,2H),5.01(bs,1H),4.64-4.56(m,1H),4.45-4.24(m,4H),3.90-3.69(m,3H),3.38-3.09(m,4H),2.47-2.26(m,3H),2.19-1.94(m,6H),1.92-1.80(m,2H),1.73-1.61(m,2H).LCMS：[M+1]+440.3.
Example 18: synthesis of 3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- (2- (1-methylpiperidin-2-yl) ethyl) urea (H001-034) ER10183
N- (4-Fluorobenzyl) -2- (1-methylpiperidin-2-yl) ethan-1-amine (H001-032) was synthesized in a similar manner to (1-1). Using 6.3mmol of 2- (1-methylpiperidin-2-yl) ethane-1-amine gives intermediate (H001-032) as a brown oil (292 mg,13% yield). LCMS: [ M+1] + 251.3.
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- (2- (1-methylpiperidin-2-yl) ethyl) urea (H001-034) ER10183, the synthesis was similar to that of compound #1. Reaction with 0.5mmol of 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) gave compound #H2-034 (120 mg,47% yield) as a white solid ).1H NMR(400MHz,CDCl3)：δ7.32-7.21(m,4H),7.04-6.97(m,2H),6.70(d,J＝8.8Hz,2H),4.64-4.56(m,2H),4.51-4.45(m,1H),4.33-4.21(m,2H),4.06-3.99(m,1H),3.18-3.09(m,1H),2.88-2.78(m,1H),2.65-2.56(m,2H),2.47-2.30(m,3H),2.20-2.01(m,4H),1.92-1.60(m,6H),1.32-1.12(m,4H),0.90-0.79(m,1H).LCMS：[M+1]+454.3.
Example 19: synthesis of 3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylazetidin-3-yl) methyl) urea (H001-061) ER10188
N- (4-fluorobenzyl) -1- (1-methylazetidin-3-yl) methylamine (H001-057) was synthesized in a similar manner to (1-1). Using 5.5mmol (1-methylazetidin-3-yl) methylamine gives intermediate (H001-057) as a brown oil (500 mg,44% yield). LCMS: [ M+1] + 209.2.2.
3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylazetidin-3-yl) methyl) urea (H001-061) ER10188, the synthesis procedure was similar to that of compound #1. Reaction of N- (4-fluorobenzyl) -1- (1-methylazetidin-3-yl) methylamine (H001-057) with 0.2mmol of 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) gave compound #H001-061 (15 mg,15% yield) as a white solid. LCMS: [ M+1] + 412.3.
Example 20: synthesis of (S) -3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea (H001-062) ER10189
(S) -N- (4-fluorobenzyl) -1- (1-methylpyrrolidin-2-yl) methylamine (H001-058) was synthesized in a similar manner to (1-1). Using 8.5mmol (S) - (1-methylpyrrolidin-2-yl) methylamine gives intermediate (H001-058) as a brown oil (720 mg,38% yield). LCMS: [ M+1] + 223.2.2.
(S) -3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea (H001-062) ER10189 was synthesized in a similar manner to compound #1. Reaction of (S) -N- (4-fluorobenzyl) -1- (1-methylpyrrolidin-2-yl) methylamine (H001-058) with 0.5mmol of 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) gave compound #H001-062 (52 mg,26% yield) as a white solid. LCMS: [ M+1] + 426.3.3.
Example 21: synthesis of (R) -3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea (H001-063) ER10190
(R) -N- (4-fluorobenzyl) -1- (1-methylpyrrolidin-2-yl) methylamine (H001-059) was synthesized in a similar manner to (1-1). Using 8.5mmol of (R) - (1-methylpyrrolidin-2-yl) methylamine gives intermediate (H001-059) as a brown oil (750 mg,40% yield). LCMS: [ M+1] + 223.2.2.
(R) -3- (4-Cyclobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea (H001-063) ER10190 was synthesized in a similar manner to compound #1. Reaction of (R) -N- (4-fluorobenzyl) -1- (1-methylpyrrolidin-2-yl) methylamine (H001-059) with 0.2mmol of 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) gave compound #H001-063 as a white solid (55 mg,28% yield). LCMS: [ M+1] + 426.3.3.
Example 22: synthesis of (S) -3- (4-cyclobutoxy-3-fluorobenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea (H001-067) ER10194
4-Cyclobutoxy-3-fluorobenzonitrile (H001-037) was synthesized in a similar manner to (37-1). Reaction of 1-bromocyclobutane with 15mmol of 3-fluoro-4-hydroxybenzonitrile gave intermediate (H001-037) (1.8 g,65% yield). LCMS: [ M+1] + 192.2.
The synthesis of (4-cyclobutoxy-3-fluorophenyl) methylamine (H002-039) was similar to (1-3). Reduction with 5mmol of 4-cyclobutoxy-3-fluorobenzonitrile (H001-037) gives intermediate (H002-039) (900 mg,89% yield). LCMS: [ M+1] + 196.2.2.
1-Cyclobutoxy-2-fluoro-4- (isocyanatomethyl) benzene (H001-067-1) was synthesized in a similar manner to (37-3). Reaction of Triphogene with 0.15mmol (4-cyclobutoxy-3-fluorophenyl) methylamine (H002-039) gives intermediate (H001-067-1) (30 mg,89% yield). LCMS: [ M+1] + 222.2.2.
(S) -3- (4-Cyclobutoxy-3-fluorobenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea (H001-067) ER10194, the synthesis process was similar to that of compound #1. Reaction with 0.5mmol of 1-cyclobutoxy-2-fluoro-4-isocyanatomethylbenzene (H001-067-1) gave compound #H001-067 (130 mg,59% yield) as a white solid. LCMS: [ M+1] + 444.3.
Example 23: synthesis of (R) -3- (4-cyclobutoxy-3-fluorobenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea (H001-068) ER10195
(R) -3- (4-Cyclobutoxy-3-fluorobenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea (H001-068) ER10195 was synthesized similarly to compound #1. Using 0.5mmol of 1-cyclobutoxy-2-fluoro-4- (isocyanatomethyl) benzene (H002-067-1) gives compound #H2-068 as a white solid (120 mg,54% yield). LCMS: [ M+1] + 444.3.
Example 24: synthesis of 1- (4-fluorobenzyl) -1- ((1-methylazetidin-3-yl) methyl) -3- (4- (3-methylbutyryl) benzyl) urea (H001-069) ER10196
1- (4-Fluorobenzyl) -1- ((1-methylazetidin-3-yl) methyl) -3- (4- (3-methylbutyryl) benzyl) urea (H001-069) ER10196, synthesis method was similar to that of compound #1. Using 0.05mmol of 1- (3-methylbutyryl) - (4-isocyanatomethyl) phenyl (39-5) gave compound H001-069 as a white solid (7.1 mg,33% yield). LCMS: [ M+1] + 426.3.3.
Example 25: synthesis of (S) -1- (4-fluorobenzyl) -3- (4- (3-methylbutyryl) benzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea (H001-070) ER10197
(S) -1- (4-fluorobenzyl) -3- (4- (3-methylbutyryl) benzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea (H001-070) ER10197 was synthesized in analogy to compound #1, using 0.5mmol of 1- (3-methylbutyryl) - (4-isocyanatomethyl) phenyl (39-5) to give a white solid compound H001-070 (70 mg,32% yield). LCMS: [ M+1] + 440.3.
Example 26: synthesis of (R) -1- (4-fluorobenzyl) -3- (4- (3-methylbutyryl) benzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea (H001-071) ER10198
(R) -1- (4-fluorobenzyl) -3- (4- (3-methylbutyryl) benzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea (H001-071) ER10198 the synthesis was similar to that of compoud #1, using 0.3mmol 1- (3-methylbutyryl) - (4-isocyanatomethyl) phenyl (39-5) to give compoud H001-071 as a white solid (60 mg,45% yield). LCMS: [ M+1] + 440.3.
Example 27: synthesis of (S) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea (H002-027) ER10199
4- (2, 2-Trifluoroethoxy) benzonitrile (H002-009), the synthesis was similar to (37-1). Using 6mmol of 4-hydroxybenzonitrile gave intermediate (H002-009) (960 mg,78% yield). LCMS: [ M+1] + 202.2.
The synthesis of (4- (2, 2-trifluoroethoxy) phenyl) methylamine (H002-012) was similar to that of (1-3), and 5mmol of 4- (2, 2-trifluoroethoxy) benzonitrile was used to give (H002-012) (700 mg,71% yield). LCMS: [ M+1] + 206.2.
1- (Isocyanatomethyl) -4- (2, 2-trifluoroethoxy) benzene (H002-027-1), the synthesis was similar to (37-3). Using 0.15mmol (4- (2, 2-trifluoroethoxy) phenyl) methylamine (H002-027-1) gives intermediate (H002-027-1) (30 mg,89% yield). LCMS: [ M+1] + 232.2.2.
(S) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea (H002-027) ER10199 was synthesized similarly to compound #1. Using 0.15mmol of 1- (isocyanatomethyl) -4- (2, 2-trifluoroethoxy) benzene (H002-027-1) gave compound H002-027 as a white solid (50 mg,75% yield). LCMS: [ M+1] + 455.2.
Example 28: synthesis of (R) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea (H002-028) ER10200
(R) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea (H002-028) ER10200 was synthesized similarly to compound #1. Using 0.15mmol of 1- (isocyanatomethyl) -4- (2, 2-trifluoroethoxy) benzene (H002-027-1) gave compound H002-028 as a white solid (40 mg,53% yield). LCMS: [ M+1] + 455.2.
Example 29: synthesis of (S) -1- (4-fluorobenzyl) -3- (4-isobutoxybenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea (H002-035) ER10201
(S) -1- (4-fluorobenzyl) -3- (4-isobutoxybenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea (H002-035) ER10201 was synthesized in analogy to compound #1, using 0.15mmol of 1-isobutoxy-4-isocyanatomethyl-benzene (1-4) to give H002-035 (50 mg,70% yield) as a white solid. LCMS: [ M+1] + 429.3.3.
Example 30: synthesis of (R) -1- (4-fluorobenzyl) -3- (4-isobutoxybenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea (H002-036) ER10202
(R) -1- (4-fluorobenzyl) -3- (4-isobutoxybenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) urea (H002-036) ER10202 was synthesized similarly to compound #1. Using 0.15mmol of 1-isobutoxy-4-isocyanatomethyl-benzene (1-4) gave compound H002-036 (50 mg,70% yield) as a white solid.
Example 31: synthesis of 1- (4-fluorobenzyl) -3- (4-isobutoxybenzyl) -1- ((1-methylazetidin-3-yl) methyl) urea (H002-037) ER10203
1- (4-Fluorobenzyl) -3- (4-isobutoxybenzyl) -1- ((1-methylazetidin-3-yl) methyl) urea (H002-037) ER10203 was synthesized in analogy to compound #1, using 0.15mmol of 1-isobutoxy-4-isocyanatomethyl-benzene (1-4) to give compound H002-037 as a white solid (20 mg,29% yield).
Example 32: synthesis of 1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) -3- (4-isobutoxybenzyl) urea (H001-080) ER10204
1- (4-Fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) -3- (4-isobutoxybenz-me thyl) urea (H001-080) ER10204 was synthesized in analogy to compound #1, using 0.15mmol of 1-isobutoxy-4-isocyanatomethyl-benzene (1-4) to give compound H001-080 as a white solid (50 mg,40% yield). LCMS: [ M+1] + 442.3.
Example 33: synthesis of 1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea (H001-081) ER10205
1- (4-Fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea (H001-081) ER10205 was synthesized in analogy to compound #1, using 0.15mmol of 1- (isocyanatomethyl) -4- (2, 2-trifluoroethoxy) benzene (H002-027-1) to give a white solid compound H001-081 (8 mg,11% yield). LCMS: [ M+1] + 468.2.
Example 34: synthesis of 3- (4-cyclobutoxy-3-fluorobenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (H001-082) ER10206
3- (4-Cyclobutoxy-3-fluorobenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (H001-082) ER10206 was synthesized in a similar manner to compound #1 using 0.15mmol of 1-cyclobutoxy-2-fluoro-4- (isocyanatomethyl) benzene (H001-067-1) to give white solid compound # H001-082 (30 mg,44% yield). LCMS: [ M+1] + 458.3.3.
Example 35: synthesis of 3- (3-fluoro-4-methoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (H001-084) ER10207
The synthesis of 2-fluoro-4- (isocyanatomethyl) -1-methoxybenzene (H001-084-1) is similar to (H002-012). Using 13mmol of 3-fluoro-4-methoxybenzonitrile, intermediate (H001-084-1) was obtained (1.8 g,88% yield). LCMS: [ M+1] + 182.2.
3- (3-Fluoro-4-methoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (H001-084) ER10207 was synthesized in a similar manner to compound #1 using 0.2mmol of 2-fluoro-4- (isocyanatomethyl) -1-methoxybenzene (H001-084-1) to give a white solid compound # H001-084 (9 mg,11% yield). LCMS: [ M+1] + 418.2.
Example 36: synthesis of (R) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4-isobutoxybenz-me thyl) urea (H001-088) ER10209
(R) -1- (4-Fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4-isobutoxybenz-me thyl) urea (H001-088) ER10209 was synthesized in analogy to compound #1, using 0.28mmol of 1-isobutoxy-4-isocyanatomethyl-benzene (1-4) to give compound H001-088 as a white solid (25 mg,21% yield). LCMS: [ M+1] + 428.3.
Example 37: synthesis of (S) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4-isobutoxybenz-nyl) urea (H001-089) ER10210
(S) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4-isobutoxybenz-me thyl) urea (H001-089) ER10210 was synthesized similarly to compound #1. Using 0.28mmol of 1-isobutoxy-4-isocyanatomethyl-benzene (1-4) gives compound H001-089 (26 mg,22% yield) as a white solid. LCMS: [ M+1] + 428.3.
Example 38: synthesis of (R) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea (H001-090) ER10211
(R) -1- (4-Fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea (H001-090) ER10211 was synthesized in analogy to compound #1, using 0.24mmol of 1- (isocyanatomethyl) -4- (2, 2-trifluoroethoxy) benzene (H002-027-1) to give a white solid compound H001-090 (23 mg,21% yield). LCMS: [ M+1] + 454.2.2.
Example 39: synthesis of (S) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea (H001-091) ER10212
(S) -1- (4-Fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea (H001-091) ER10212 was synthesized in analogy to compound #1, using 0.24mmol of 1- (isocyanatomethyl) -4- (2, 2-trifluoroethoxy) benzene (H002-027-1) to give a white solid compound H001-091 (22 mg,20% yield). LCMS: [ M+1] + 454.2.2.
Example 40: synthesis of 3- (3-fluoro-4-methoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (H002-071) ER10213
N- (2, 4-difluorobenzyl) -1- (1-methylpiperidin-4-yl) methylamine (H002-070) was synthesized in a similar manner to (1-1). Using 8.8mmol (1-methylpiperidin-4-yl) methylamine gives intermediate (H002-070) as a brown oil (1.5 g,75% yield). LCMS: [ M+1] + 255.3.
3- (3-Fluoro-4-methoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (H002-071) ER10213 was synthesized in a similar manner to compound #1. Using 0.2mmol of 2-fluoro-4- (isocyanatomethyl) -1-methoxybenzene (H001-084-1) gives compound #H2-071 as a white solid (46 mg,55% yield). LCMS: [ M+1] + 436.2.
Example 41: synthesis of 3- (4-cyclobutoxy-3-fluorobenzyl) -1- (2, 4-difluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (H002-072) ER10214
3- (4-Cyclobutoxy-3-fluorobenzyl) -1- (2, 4-difluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (H002-072) ER10214 was synthesized in a similar manner to compound #1. Using 0.15mmol of 1-cyclobutoxy-2-fluoro-4- (isocyanatomethyl) benzene (H001-067-1) gives compound #H2-072 (25 mg,34% yield) as a white solid. LCMS: [ M+1] + 476.3.
Example 42: synthesis of 1- (2, 4-difluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea (H002-073) ER10215
1- (2, 4-Difluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea (H002-073) ER10215 was synthesized in a similar manner to that of compound #1. Using 0.15mmol of 1- (isocyanatomethyl) -4- (2, 2-trifluoroethoxy) benzene (H002-027-1) gave compound #H2-073 as a white solid (7.5 mg,11% yield). LCMS: [ M+1] + 486.2.
Example 44: synthesis of 1- (2, 4-difluorobenzyl) -3- (4- (3-methylbutanoyl) benzyl) -1- (1-methylpiperidin-4-yl) urea (H002-079) ER10219
1- (2, 4-Difluorobenzyl) -3- (4- (3-methylbutanoyl) benzyl) -1- (1-methylpiperidin-4-yl) urea (H002-079) ER10219 was synthesized in a similar manner to compound #1. Using 0.16 mmole of 1- (4-isocyanatomethyl-phenyl) -3-methyl-butan-1-one (39-5) gave compound #H2-079 (36 mg,50% yield) as a white solid. LCMS: [ M+1] + 458.3.3.
Example 45: synthesis of (R) -1- (2, 4-difluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea (H002-081) ER10221
(R) -1- (2, 4-difluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea (H002-081) ER10221 was synthesized in a similar manner to that of compound #1. Using 0.15mmol of 1- (isocyanatomethyl) -4- (2, 2-trifluoroethoxy) benzene (H002-027-1) gave compound #H2-081 (10 mg,15% yield) as a white solid. LCMS: [ M+1] + 472.2.2.
Example 46: synthesis of (S) -1- (2, 4-difluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea (H002-082) ER10222
(R) -N- (2, 4-difluorobenzyl) -1- (1-methylpyrrolidin-3-yl) methylamine (H002-077) was synthesized in a similar manner to (1-1). Using 4mmol (R) - (1-methylpyrrolidin-3-yl) methylamine gives intermediate (H002-077) as a brown oil (0.3 g,29% yield). LCMS: [ M+1] + 241.3.
(S) -1- (2, 4-difluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea (H002-082) ER10222 was synthesized in a similar manner to that of compound #1. Using 0.15mmol of 1- (isocyanatomethyl) -4- (2, 2-trifluoroethoxy) benzene (H002-027-1) gave compound #H2-082 (18 mg,26% yield) as a white solid. LCMS: [ M+1] + 472.2.2.
Example 47: synthesis of (R) -1- (2, 4-difluorobenzyl) -3- (3-fluoro-4-methoxybenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (H002-088) ER10224
(R) -1- (2, 4-difluorobenzyl) -3- (3-fluoro-4-methoxybenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (H002-088) ER10224 was synthesized in a similar manner to compound #1. Using 0.26mmol of 2-fluoro-4- (isocyanatomethyl) -1-methoxybenzene (H001-084-1) gives compound #H2-088 as a white solid (35 mg,32% yield). LCMS: [ M+1] + 422.8.
Example 48: synthesis of (R) -3- (3-fluoro-4-methoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (H002-089) ER10225
(R) -3- (3-fluoro-4-methoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (H002-089) ER10225 was synthesized in a similar manner to compound #1. Using 0.26mmol of 2-fluoro-4- (isocyanatomethyl) -1-methoxybenzene (H001-084-1) gives compound #H2-089 as a white solid (35 mg,34% yield). LCMS: [ M+1] + 404.9.
Example 49: synthesis of (S) -3- (3-fluoro-4-methoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (H002-090) ER10226
(S) -3- (3-fluoro-4-methoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (H002-090) ER10226 was synthesized in a similar manner to compound #1. Using 0.32mmol of 2-fluoro-4- (isocyanatomethyl) -1-methoxybenzene (H001-084-1) gives compound #H2-090 as a white solid (57 mg,44% yield). LCMS: [ M+1] + 403.8.
Example 50: synthesis of 3- (3-fluoro-4-isobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (H002-093) ER10227
The synthesis of 2-fluoro-1-isobutoxy-4- (isocyanatomethyl) benzene (H002-093-1) was similar to (37-3) using 0.13mmol (3-fluoro-4-isobutoxyphenyl) methylamine to give intermediate (H002-093-1) (28 mg,99% yield). LCMS: [ M+1] + 224.3.3.
3- (3-Fluoro-4-isobutoxybenzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (H002-093) ER10227 was synthesized in analogy to compound #1, using 0.13mmol of 2-fluoro-1-isobutoxy-4- (isocyanatomethyl) benzene (H002-093-1) to give a white solid compound H002-093 (22 mg,37% yield). LCMS: [ M+1] + 460.8.
Example 51: synthesis of (S) -1- (2, 4-difluorobenzyl) -3- (3-fluoro-4-methoxybenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (H002-094) ER10228
(S) -1- (2, 4-difluorobenzyl) -3- (3-fluoro-4-methoxybenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (H002-094) ER10228, synthesized in analogy to compound #1, using 0.19mmol of 2-fluoro-4- (isocyanatomethyl) -1-methoxybenzene (H001-084-1) gave compound # H002-094 as a white solid (29 mg,36% yield). LCMS: [ M+1] + 422.8.
Example 52: synthesis of 3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (H002-096) ER10229
The synthesis of 2-fluoro-4- (isocyanatomethyl) -1- (2, 2-trifluoroethoxy) benzene (H002-096-1) was similar to (37-3), using 0.22mmol (3-fluoro-4- (2, 2-trifluoroethoxy) phenyl) methylamine to give intermediate (H002-096-1) (55 mg,98% yield). LCMS: [ M+1] + 249.2.
Synthesis of 3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (H002-096) ER10229 was performed in analogy to compound #1 using 0.22mmol of 2-fluoro-4- (isocyanatomethyl) -1- (2, 2-trifluoroethoxy) benzene (H002-096-1) to give compound H002-096 as a white solid (60 mg,55% yield). LCMS: [ M+1] + 486.7.
Example 53: synthesis of 1- (2, 4-difluorobenzyl) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (H002-097) ER10230
1- (2, 4-Difluorobenzyl) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- ((1-methylpiperidin-4-yl) methyl) ER10230 was synthesized in analogy to compound #1 using 0.22mmol of 2-fluoro-4- (isocyanatomethyl) -1- (2, 2-trifluoroethoxy) benzene (H002-096-1) to give a white solid compound H002-097 (45 mg,40% yield). LCMS: [ M+1] + 504.7.
Example 54: synthesis of (R) -1- (2, 4-difluorobenzyl) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (H002-098) ER10231
(R) -1- (2, 4-difluorobenzyl) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (H002-098) ER10231 was synthesized in a similar manner to that of compound #1. Using 0.13mmol of 2-fluoro-4- (isocyanatomethyl) -1- (2, 2-trifluoroethoxy) benzene (H002-096-1) gave compound #H2-098 as a white solid (40 mg,61% yield). LCMS: [ M+1] + 490.7.
Example 55: synthesis of (S) -1- (2, 4-difluorobenzyl) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (H002-099) ER10232
(S) -1- (2, 4-difluorobenzyl) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (H002-099) ER10232 was synthesized in a similar manner to that of compound #1. Using 0.13mmol of 2-fluoro-4- (isocyanatomethyl) -1- (2, 2-trifluoroethoxy) benzene (H002-096-1) gives a white solid compound #H2-099 (31 mg,47% yield). LCMS: [ M+1] + 490.7.
Example 56: synthesis of (S) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (H002-100) ER10233
(S) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (H002-100) ER10233 was synthesized in a similar manner to compound #1 using 0.13mmol of 2-fluoro-4- (isocyanatomethyl) -1- (2, 2-trifluoroethoxy) benzene (H002-096-1) to give a white solid compound # H2002-100 (12 mg,19% yield). LCMS: [ M+1] + 472.7.
Example 57: synthesis of (R) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (H003-001) ER10234
(R) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (H003-001) ER10234 was synthesized in a similar manner to that of compound #1. Using 0.13mmol of 2-fluoro-4- (isocyanatomethyl) -1- (2, 2-trifluoroethoxy) benzene (H002-096-1) gives a white solid compound #H003-001 (49 mg,77% yield). LCMS: [ M+1] + 472.7.
Example 58: synthesis of 3- (4- (2-hydroxy-2-methylpropyloxy) benzyl) -1- (2, 4-difluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea ER10248
The compound of the example was prepared and purified by placing a mixture comprising 1- (2, 4-difluorobenzyl) -3- (4-hydroxybenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (50 mg,0.124 mmol), cesium carbonate (121 mg,0.37 mmol), 2-dimethyloxirane (89 mg,1.24 mmol) and DMF (1.0 mL) in a sealed tube and heating overnight at 100 ℃. The resulting mixture was purified by HPLC to give the desired product (13 mg,22% yield). LCMS: [ M+1] + 476.8.
Example 59: synthesis of 3- (4- (2-hydroxy-2-methylpropyloxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea ER10241
The compound of this example was prepared and purified using a method similar to that of example 58 using 1- (4-fluorobenzyl) -3- (4-hydroxybenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (30 mg,0.078 mmol) as starting material to give 3- (4- (2-hydroxy 2-methylpropyloxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (36 mg, 18%). LCMS: [ M+1] + 458.8.
Example 60: synthesis of (R) -3- (4- (2-hydroxy-2-methylpropyloxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea ER10247
The compound of this example was prepared and purified using a method similar to example 58 using (R) -1- (4-fluorobenzyl) -3- (4-hydroxybenzyl) -1- ((1-methylpiperidin-4-yl) methyl) urea (50 mg,0.135 mmol) as starting material to give (R) -3- (4- (2-hydroxy 2-methylpropyloxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea (60 mg, 12%). LCMS: [ M+1] + 444.8.
Examples 61 to 64: using a similar procedure, the following compounds were synthesized:
biological Activity assay
In the following biological activity assays, ER10152 was used as a positive control, having the structural formula:
Commercially available or synthetically prepared according to the methods described in US7601740B 2.
1. Screening assay for 5-HT2A receptor antagonist Activity
To demonstrate the antagonistic activity of the compounds of the present invention on 5-HT2A receptors, an IP-One assay was selected to complete the assay. The following experiments were performed using Flp-In-CHO-5HT2A stable cell lines. The IP-One experiment was based on competitive immunoassay with HTRF (homogeneous time resolved fluorescence) using terbium cryptate-labeled anti-IP 1 mab and d 2-labeled IP1. IP1 produced by cells and IP1 marked with d2 provided by the kit compete for the antigen binding site of the anti-IP 1 antibody, when terbium marked anti-IP 1 antibody is combined with the IP1 marked with d2, energy resonance transfer occurs, so that signals are generated, the free IP1 is combined with the antibody and the signals are gradually reduced along with the increase of the intracellular IP1 production.
Materials and methods:
according to the user manual, the chinese ground mouse ovarian cell transformed line (Flp-In TM -CHO cell line) (purchased from invitrogen, R75007) was generated by transfecting CHO cells with pFRT// acZeo2 and selecting Zeocin TM resistant clones. Flp-In TM -CHO cell lines were cultured In Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Hyclone) +1× PENICILIN-Streptomycin (15140-122, gibco) followed by stable transfection with the Human HTR2A gene (Human HTR2A, geneBank, NM-000621) to give Flp-In-CHO-5HT2A cells. The stably transfected cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Hyclone) +1X PENICILIN-Streptomycin +800 μg/ml Hygromycin B (ant-hg-5, invivogen). To verify compound activity, flp-In-CHO-5HT2A stable cell lines were cultured (7.5K) In 384 well plates at 37℃under 5% CO 2 for 20 hours. The compounds were diluted to different concentrations in Ham's F-12K medium, the medium was replaced with 100 μl/well overnight with fresh medium, the cells were treated with the compounds for 30 minutes and then incubated with 5-HT at 37℃for 45 minutes, after which lysis detection buffer, IP1-d2 and IP1-Ab were added sequentially and incubated for 1 hour at room temperature and then read on an Envision plate (HTRF module) and the inhibition of 5-HT2A receptors by the compounds was calculated.
According to the results shown, the 5HT2A receptor activity of Flp-In-CHO-5HT2A stable cell lines was inhibited by compounds which were suggested to have 5HT2A receptor antagonistic activity.
2. Screening assay for 5-HT2B/2C VGV receptor antagonist Activity
To demonstrate the antagonistic activity of the compounds of the present invention on the 5-HT2B/2C VGV receptor, an IP-One assay was selected to complete the assay. The following experiments were performed using Flp-In-CHO-5HT2B/2C VGV stable cell lines. The IP-One experiment was based on competitive immunoassay with HTRF (homogeneous time resolved fluorescence) using terbium cryptate-labeled anti-IP 1 mab and d 2-labeled IP1. IP1 produced by cells and IP1 marked with d2 provided by the kit compete for the antigen binding site of the anti-IP 1 antibody, when terbium marked anti-IP 1 antibody is combined with the IP1 marked with d2, energy resonance transfer occurs, so that signals are generated, the free IP1 is combined with the antibody and the signals are gradually reduced along with the increase of the intracellular IP1 production.
Materials and methods:
According to the user manual, the chinese ground mouse ovarian cell transformed cell line (Flp-In TM -CHOcell line) (purchased from invitrogen, R7587) was generated by transfecting CHO cells with pFRT// acZeo2 and selecting Zeocin TM resistant clones. Flp-In TM -CHO cell lines were cultured In Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Gibco) +1× PENICILIN-Streptomycin (15140122, gibco), followed by the addition of Human HTR2B/2C VGV gene (Human HTR2B, geneBank, NM 000867; stable transfection of Human HTR2C (5-HT 2C VGV), geneBank, NM 000868) gave Flp-In-CHO-5HT2B/2C VGV cells. The stably transfected cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Gibco) +1X PENICILIN-Streptomycin +800 μg/ml Hygromycin B (ant-hg-5, invivogen). To verify compound activity, flp-In-CHO-5HT2B/2C VGV stable cell lines were cultured (5K, 7.5K) In 384 well plates at 37℃under 5% CO 2 for 20 hours. The compounds were diluted to different concentrations in Ham's F-12K medium, the medium was replaced with 100 μl/well overnight with fresh medium, the cells were treated with the compounds for 30 min and then incubated with 5-HT at 37℃for 45 min, after which lysis detection buffer, IP1-d2 and IP1-Ab were added sequentially and incubated for 1 hour at room temperature and then plates were read on Envision (HTRF module) and the inhibition of 5-HT2B/2C VGV receptors by the compounds was calculated.
The EC50 value for each compound for 5-HT2B or 5-HT2C divided by its EC50 value for 5-HT2A, the fold ratio of the selectivity of each compound for 5-HT2B or 5-HT2C over 5-HT2A was calculated:
test compounds and their inhibition values
Numbering of compounds Selectivity to 2B (multiple) Selectivity to 2C (multiple)
ER10152 86 4
ER10200 222 18
ER10204 192 7
ER10205 280 15
ER10206 58 14
ER10207 138 68
ER10211 126 16
ER10212 103 16
ER10241 231 57
ER10247 97 45
ER10248 1000 52
ER10254 84 69
3. HERG Membrane protein specific binding assay
To test the toxicity of the compounds of the invention to the heart, hERG membrane protein specific binding assays were selected to complete the assay. The experiment was performed using HEK293 cell lines stably expressing hERG (human Ether-a-go-go RELATED GENE) encoding potassium channels. In the myocardium, hERG-encoded potassium channels mediate a delayed rectifier potassium current (IKr), ikr inhibition being the most important mechanism for drug-induced QT interval prolongation. hERG, due to its specific molecular structure, either loss of function or drug inhibition affects the cardiac action potential repolarization process and causes prolongation of QT interval, while potentially inducing torsades de pointes, leading to cardiac arrhythmias.
In this experiment, hERG membrane protein, detection compound and a fixed concentration of radioligand are mixed, detection compound and radioligand are competitively bound to hERG membrane protein, after incubation for a certain time to reach equilibrium, radioligand not bound to membrane protein is filtered off with vacuum, the filter plate is dried, scintillation fluid is added, and isotope signal (CPM) is detected on Microbeta. Higher signals represent weaker binding of the test compound to hERG membrane protein.
Materials and methods:
Compounds, diluted hERG membrane protein, and diluted H3-Duofilite ligand (NET 1144100UC, perkinelmer) were added sequentially to 96-well plates (3631, corning), membrane plates were closed, incubated for 1 hour at room temperature with shaking, the incubated hERG membrane protein was transferred to GF/B plates (600517, perkinelmer) using a Perkinelmer cell harvester, and washed 5 times (4 ℃ C., 0.4mL each time) using wash buffer (20 mmol/L HEPES (pH 7.4) (Sigma-H3375); 10mmol/L potassium chloride (Sigma-P9333); 1mmol/L magnesium chloride (Sigma-449172)). The GF/B plates were then baked in an oven at 50 ℃ for 30min, after which the GF/B plates were thoroughly dried, the bottom plate was closed with a bottom plate cover (6005199, perkinelmer), 50 μl of scintillation fluid 20 (603621, perkinelmer) was added to each well of the plates, the plates were sealed with a top plate cover (6005250, perkinelmer), and the radioactive signals were detected on Microbeta plates.
Compounds and their binding rate values were tested.
4. Human liver microsome metabolism stability experiment
The liver is the major organ of endogenous matrix and exogenous drug metabolism. There are several in vitro tools that can help researchers study the metabolism of candidate drugs, including isolated fresh or cryopreserved hepatocytes, liver slices, and subcellular components of liver particles and S9 components. These subcellular components are prepared from the liver by a series of homogenization and ultracentrifugation.
The S9 fraction produced by the initial low speed centrifugation of 10,000g of liver homogenate is the fraction in the supernatant obtained by this centrifugation. The S9 fraction contained all phase I and phase II enzymes, and the S9 fraction was further centrifuged at 100,000g to obtain endoplasmic reticulum-derived microparticles. Microsomes are rich in cytochrome P450 (CYP) and Flavin Monooxygenase (FMO). In addition, some phase II enzymes (such as certain glucuronide transferase UGT subtypes and cyclooxygenase EH) are also present in microsomes. Microsomes can be used to study UGT activity, however, microsomal membranes limit UGT matrix and/or cofactor entry. Optimal UGT activity can be achieved by adding MgCl 2 and pore-forming antibiotics (e.g., procyanidins). These components enable efficient transport of glucuronic acid products and cofactors UDPGA in the microsomal network. Individual or combined donor liver microsomes may be used to conduct metabolic-related studies. The combined donors may represent the average level of the population or the limiting capacity of a particular study factor, such as age, BMI or a particular CYP subtype. The aim of this study was to assess the metabolic stability of the compounds in human liver microsomes.
Materials and methods
Human liver microsomes used in this test system were purchased from Corning (Cat No. 452117) and stored in a refrigerator below-60℃prior to use. The coenzymes are NADPH (Chem-impex international, cat. No. 00616) and UDPGA (Sigma, cat. No. U6751) cofactors. The weighed NADPH powder and UDPGA powder were dissolved in MgCl 2 solution to prepare 25mM of NADPH working solution mM UGPDA and 10mM of NADPH working solution. Eight 96-well plates (T0, T5, T10, T20, T30, T60, NFC60, blast) were prepared, 10 μl of compound working fluid (T0, T5, T10, T20, T30, T60, NFC 60) was added to each well using an Apricot automated liquid station (PP-550 ds, usa), cold acetonitrile stop was added to the T0 plate, followed by 80 μl/well of human liver microsomes, pre-incubation at 37 degrees for 10 minutes. NCF60 plates were incubated in a 37℃water bath with 10. Mu.L/well of 100mM potassium phosphate buffer for 1 hour. Other plates were incubated at the end of incubation with 10 μl/well nadph+ UDPGA cofactor combination at different times per plate setting. After the incubation was completed, the reaction was stopped by adding 300. Mu.L/well cold acetonitrile, shaking the plate for 10 minutes, and centrifuging at 4000rpm for 20 minutes at 4 ℃. 100. Mu.L/well of the supernatant was added to a new plate to which 300. Mu.L/well of HPLC water had been added, and mixed well to deliver LC-MS/MS bioassay.
Calculating the area ratio of the compound to the internal standard peak to be converted into the residual percentage to obtain in-vitro elimination rate constants ke of the test and control compounds: % remaining = peak area ratio of control to internal standard at any time point/peak area ratio of control to internal standard at 0min x 100%.
CL int(mic)＝0.693/T1/2/microsomal protein content (microsomal protein concentration mg/mL during incubation)
CL int(liver)＝CLint(mic) x microsomal protein amount in liver (mg/g) x liver weight to weight ratio
According to the well-stirred model (well still model), the intrinsic liver clearance and liver clearance can be scaled by:
CL(Liver)＝(CLint(liver)×Qh)/(GLint(liver)+Qh)
Hepatic microsomal clearance of compounds:

Claims (7)

1. A compound of formula IA or a pharmaceutically acceptable salt or stereoisomer thereof:
Wherein n is 1;
x is-CH 2 -; whereby X, nitrogen and other ring carbon atoms form a5 membered nitrogen heterocycle, the X ring being linked to the alkylene chain of the host structure through a ring carbon atom;
the para position of the ring where the Z connection is positioned is-O-;
r 1 is oxolane, trifluoroethyl, or 2-hydroxyisobutyl;
R 2 is 1 or more substituents, and is positioned at any substituted position of the ring, R 2 is independently selected from H and halogen;
R 3 is 1 substituent, is positioned on the ring nitrogen atom of the ring and is C 1-6 alkyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is fluoro.
3. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from the group consisting of:
(S) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea,
(R) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-2-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea,
(R) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea,
(S) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea,
(R) -1- (2, 4-difluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea,
(S) -1- (2, 4-difluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) -3- (4- (2, 2-trifluoroethoxy) benzyl) urea,
(R) -1- (2, 4-difluorobenzyl) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
(S) -1- (2, 4-difluorobenzyl) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
(S) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
(R) -3- (3-fluoro-4- (2, 2-trifluoroethoxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
(R) -3- (4- (2-hydroxy-2-methylpropyloxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
(R) -3- (4- ((tetrahydrofuran-3-yl) -oxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
(S) -3- (4- (tetrahydrofuran-3-yl) -oxy) benzyl) -1- (2, 4-difluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea,
(S) -3- (4- ((tetrahydrofuran-3-yl) -oxy) benzyl) -1- (4-fluorobenzyl) -1- ((1-methylpyrrolidin-3-yl) methyl) urea.
4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt or stereoisomer thereof.
5. Use of a compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or stereoisomer thereof, for the manufacture of a medicament for the treatment of a disorder related to 5HT2A receptor activity, said disorder being a psychotic disorder, a central nervous system degenerative disorder, a symptom of a psychotic disorder related to or concurrent with a central nervous system degenerative disorder, a symptom of a psychotic disorder, wherein the symptom of a psychotic disorder related to or concurrent with a central nervous system degenerative disorder, the symptom of a psychotic disorder is an affective disorder, a language decline, hallucinations, a lack of interest.
6. The use according to claim 5, wherein the psychotic disorder is depression, anxiety, mania, schizophrenia, schizoaffective disorder, bipolar disorder, insomnia, autism.
7. The use according to claim 5, wherein the degenerative disorder of the central nervous system is alzheimer's disease, parkinson's disease, huntington's disease, lewy body dementia.
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