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CN109232362B - Aromatic heterocyclic derivative and application thereof in medicines - Google Patents

Aromatic heterocyclic derivative and application thereof in medicines Download PDF

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CN109232362B
CN109232362B CN201810699359.0A CN201810699359A CN109232362B CN 109232362 B CN109232362 B CN 109232362B CN 201810699359 A CN201810699359 A CN 201810699359A CN 109232362 B CN109232362 B CN 109232362B
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金传飞
钟文和
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Abstract

The invention discloses aromatic heterocyclic derivatives and application thereof in medicaments, and particularly relates to novel aromatic heterocyclic derivatives and a pharmaceutical composition containing the same. The invention also relates to processes for the preparation of such compounds and pharmaceutical compositions, and their use in the preparation of a medicament for the treatment of 5-HT 6 Receptor-related diseases, in particular Alzheimer's disease.

Description

Aromatic heterocyclic derivative and application thereof in medicines
Technical Field
The invention belongs to the field of medicines, and particularly relates to a compound for treating Alzheimer's disease, a pharmaceutical composition containing the compound, and application and a using method of the compound. In particular, the compounds of the present invention are useful as 5-HT 6 Heteroaromatic derivatives of receptor antagonists.
Background
Various Central Nervous System (CNS) disorders such as anxiety, depression, and the like are associated with disorders in the neurotransmitter 5-hydroxytryptamine (5-HT). 5-hydroxytryptamine (5-HT), a major regulatory neurotransmitter in the brain, functions mediated through a number of receptor families, including 5-HT 1 ，5-HT 2 ，5-HT 3 ，5-HT 4 ，5-HT 5 ，5-HT 6 And 5-HT 7 . Based on high levels of 5-HT in the brain 6 Receptor and its study, 5-HT has been proposed 6 Receptors may play a role in the pathology and treatment of central nervous system disorders. In particular, 5-HT has been identified 6 Selective ligands have potential therapeutic utility in certain Central Nervous System (CNS) disorders, such as Parkinson's disease, huntington's chorea, anxiety, depression, manic depression, psychosis, epilepsy, obsessive compulsive disorder, migraine, alzheimer's disease, sleep disorders, eating disorders (such as anorexia and bulimia), panic attacks, attention Deficit Hyperactivity Disorder (ADHD), attention Deficit Disorder (ADD), drugs of abuse (such as cocaine, ethanol, nicotine, and benzodiazepines)
Figure BDA0001713906860000011
Class) of the brain, schizophrenia, and conditions associated with spinal trauma or head injury (e.g., hydrocephalus). The 5-HT is expected 6 Selective ligands may also be used in the treatment of certain gastrointestinal diseases (such as functional bowel disorders) (see, e.g., roth, b.l. Et al, j.pharmacol. Exp. Ther.,268, 1403-14120 (1994), sibley, d.r. Et al, mol, pharmacol.,43, 320-327 (1993), a.j.sleight et al, neurosransisition, 11,1-5 (1995) and Sleight, a.j. Et al, serotonin ID Research Alert,1997,2 (3), 115-8).
It was found that 5-HT is involved in memory and cognition 6 Selective antagonists can significantly increase glutamate and aspartate levels in the frontal cortex without increasing norepinephrine, dopamine, or 5-HT 6 The level of (c). This increased selectivity for specific neurochemicals strongly suggests 5-HT 6 Role of ligands in cognition (Dawson, L.A.; nguyen, H.Q.; li, P., british Journal of Pharmacology,2000, 130 (1), 23-26). Furthermore, one uses selective 5-HT 6 Antagonists have been studied for memory and learning in animals and have produced positive effects (Rogers, D.C.; hascher, P.D.; hagan, J.J., society of Neuro)science, abstracts,2000, 26, 680). Furthermore, 5-HT 6 Antagonists increase the activity of the nigrostriatal dopamine pathway (Ernst, M; zametkin, A.J.; matochik, J.H.; journal, P.A.; cohen, R.M., journal of Neuroscience,1998, 18 (5), 5901-5907), and thus 5-HT 6 The ligands have potential therapeutic use in attention deficit disorders in children and adults. In addition, 5-HT 6 Antagonists may also be potentially useful compounds for the treatment of obesity (see, e.g., bentley et al, br.j.pharmac.1999, supplement 126, bentley et al, j.psychopharmacol.1997, supplement a64:255, wooley et al, neuropharmacology 2001, 41.
Disclosure of Invention
The invention provides a compound with 5-HT 6 The aromatic heterocyclic derivatives with receptor antagonistic activity have better clinical application prospect. Compared with the existing similar compounds, the compound of the invention is used for treating 5-HT 6 The receptors have a high affinity and show high selectivity and antagonistic properties towards this receptor, while having better pharmacodynamic, pharmacokinetic and/or toxicological properties, such as a good brain/plasma ratio (brain plasma ratio), a good bioavailability, a good metabolic stability or a reduced inhibition of mitochondrial respiration.
The excellent characteristics of some parameters of the compound of the invention, such as half-life period, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility and the like, can promote the reduction of side effects, the expansion of therapeutic index or the improvement of tolerance and the like.
The present invention relates to novel heteroaromatic derivatives for the treatment of alzheimer's disease and methods for the treatment of alzheimer's disease. The compounds of the invention and pharmaceutical compositions comprising said compounds are active against 5-HT 6 The receptor has better affinity function, and particularly has better treatment effect on the Alzheimer disease.
In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I),
Figure BDA0001713906860000021
wherein:
y is
Figure BDA0001713906860000022
Or
Figure BDA0001713906860000023
n is 1,2,3 or 4;
q is CH or N;
m is-NR 8 -、-CR 8a R 8b -, -C (= O) -or-O-;
each R 1 Independently H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NH 2 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl or C 1-9 Heteroaryl, or two adjacent R 1 And the carbon atoms to which they are attached form a 5-7 atom carbocycle, heterocycle, aryl ring or heteroaryl ring, wherein said 5-7 atom carbocycle, heterocycle, aryl ring and heteroaryl ring are optionally independently substituted with one or more substituents independently selected from D, F, cl, br, I, -CN, -NO 2 、-OH、-NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl and C 1-9 Heteroaryl or a substituted heteroaryl;
R 2 、R 2a 、R 3 and R 3a Independently H, D, F, cl, Br、I、-CN、-NO 2 、-OH、-NH 2 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl or C 1-9 A heteroaryl group;
each R 4 And R 5 Independently H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、-S(＝O) 2 NR a R b 、-S(＝O) p R c 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl group, C 6-10 Aryloxy or C 1-9 A heteroaryloxy group;
each R 6 Independently H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkyl, halo C 1-6 Alkoxy, hydroxy-substituted halogeno C 1-6 Alkyl, (C) 1-6 Alkoxy) - (C 1-6 Alkylene) -, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, (C) 6-10 Aryl group) - (C 1-6 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-6 Alkylene) -;
each R 7 Independently H, D, -C (= O) R c 、-C(＝O)OR d 、C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 3-8 Cycloalkyl, C 2-10 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, (C) 6-10 Aryl group) - (C 1-6 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-6 Alkylene) -;
R 8 is H, D, -CN, -NO 2 、-OH、-NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, (C) 6-10 Aryl group) - (C 1-6 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-6 Alkylene) -;
R 8a and R 8b Each independently of the other is H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, (C) 6-10 Aryl) - (C 1-6 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-6 Alkylene) -;
each R a And R b Independently H, D, -C (= O) R c 、-S(＝O) 2 -C 1-6 Alkyl radical, C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, (C) 6-10 Aryl) - (C 1-6 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-6 Alkylene) -;
each R c And R d Independently H, D, C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, (C) 6-10 Aryl) - (C 1-6 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-6 Alkylene) -; and
p is 0, 1 or 2.
In one embodiment, each R is 1 Independently H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NH 2 、C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-4 Alkyl, halo C 1-4 Alkoxy radical, C 3-6 Cycloalkyl or C 3-8 Heterocyclyl, or two adjacent R 1 And the carbon atoms to which they are attached form an aromatic or heteroaromatic ring of 5 to 6 atoms, wherein the aromatic and heteroaromatic ring of 5 to 6 atoms are optionally independently substituted by one or more substituents independently selected from D, F, cl, br, I, -CN, -NO 2 、-OH、-NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-4 Alkyl and halo C 1-4 Substituted by a substituent of alkoxy; wherein each R a 、R b 、R c And R d Have the meaning as described in the present invention.
In one embodiment, each R is 4 And R 5 Independently H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-4 Alkyl, halo C 1-4 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-8 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, C 6-10 Aryloxy or C 1-9 A heteroaryloxy group; wherein each R a 、R b 、R c And R d Have the meaning as described in the present invention.
In one embodiment, each R is 7 Independently H, D, -C (= O) R c 、-C(＝O)OR d 、C 1-4 Alkyl, halo C 1-4 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-8 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, (C) 6-10 Aryl) - (C 1-4 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-4 Alkylene) -; wherein each R c And R d Have the meaning as described in the present invention.
In one embodiment, each R is 1 Independently H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NH 2 Methyl, ethyl, n-propyl, isopropyl, -CHF 2 、-CF 3 、-CH 2 CF 3 、-CF 2 CHF 2 、-CHFCF 3 、-CF 2 CF 3 、-CH 2 CF 2 CF 3 、-CH 2 CF 2 CHF 2 Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 、-OCF 3 、-OCH 2 CF 3 、-OCF 2 CHF 2 、-OCHFCF 3 、-OCF 2 CF 3 、-OCF 2 CH 2 CH 3 、-OCF 2 CH 2 CF 3 、-OCF 2 CH 2 CHF 2 、-OCH 2 CHFCH 3 、-OCH 2 CF 2 CH 3 、-OCH 2 CF 2 CF 3 or-OCH 2 CF 2 CHF 2 Or two adjacent R 1 And the carbon atoms to which they are attached form a phenyl ring, wherein said phenyl ring is optionally substituted by one or more groups independently selected from D, F, cl, br, I, -CN, -NO 2 、-OH、C 1-4 Alkyl radical, C 1-4 Alkoxy, halo C 1-4 Alkyl and halo C 1-4 Substituted by a substituent of alkoxy.
In one embodiment, each R is 4 And R 5 Independently is H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NH 2 Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CHF 2 、-CF 3 、-CH 2 CF 3 、-CF 2 CHF 2 、-CHFCF 3 、-CF 2 CF 3 、-CH 2 CF 2 CF 3 or-CH 2 CF 2 CHF 2 。
In one embodiment, each R is 6 Independently is H, D, F, cl, br, I, -CN, -C (= O) CH 3 、-C(＝O)CH 2 CH 3 、-C(＝O)CH 2 CH 2 CH 3 Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CHF 2 、-CF 3 、-CH 2 CF 3 、-CF 2 CHF 2 、-CHFCF 3 、-CF 2 CF 3 、-CH 2 CF 2 CF 3 、-CH 2 CF 2 CHF 2 、-CH(OH)CF 3 、-CH(OH)CHF 2 、-CH 2 CH(OH)CF 3 、-CH 2 CH(OH)CHF 2 、-CH(OH)CH 2 CHF 2 、-CH(OH)CH 2 CF 3 、-CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 or-CH 2 CH 2 OCH 2 CH 2 CH 3 。
In one embodiment, each R is 7 Independently H, D, methyl, ethyl, n-propyl, isopropyl, -CHF 2 、-CF 3 、-CH 2 CF 3 、-CF 2 CHF 2 、-CHFCF 3 、-CF 2 CF 3 、-CH 2 CF 2 CF 3 、-CH 2 CF 2 CHF 2 Cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl or tetrahydrofuranyl.
In one embodiment, R 8 Is H, D, methyl, ethyl, n-propyl, isopropyl, -CH 2 CH 2 CH(CH 3 ) 2 、-CH 2 C(CH 3 ) 3 Cyclopropyl, cyclobutylA group selected from cyclopentyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, or tetrahydrofuranyl;
R 8a and R 8b Each independently is H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, -CH 2 CH 2 CH(CH 3 ) 2 、-CH 2 C(CH 3 ) 3 Methoxy, ethoxy, n-propyloxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, or tetrahydrofuranyl;
each R a And R b Independently H, D, methyl, ethyl, n-propyl or isopropyl; and
each R c And R d Independently H, D, methyl, ethyl, n-propyl, isopropyl, cyclohexyl or morpholinyl.
In one embodiment, the present invention relates to a compound that is a structure of formula (III) or formula (IV), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a structure of formula (III) or formula (IV),
Figure BDA0001713906860000041
Figure BDA0001713906860000042
each R 1 、R 4 、R 5 、R 6 、R 7 And R 8 Have the meaning as described in the present invention.
In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention.
In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.
In another embodiment, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent that is a drug for treating alzheimer's disease, a drug for treating a neurological disorder, or a combination thereof.
In another embodiment, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent which is donepezil (donepezil), nalmefene (nalmefene), risperidone (risperidone), vitamin E (Vitamin E), SAM-760, AVN-211, AVN-101, RP-5063, tozaden, PRX-3140, PRX-8066, SB-742457, naluzaton, lu-AE58054, tacrine (tacrine), rivastigmine (rivastigmine), galantamine (galantamine), memantine (memantine), mirtazapine (Mirtazapine), venlafaxine (venlafaxine), despramine (desipramine), nortriptyline (nortriptyline), zolpidem (zolpidem), zonecline (zopiclone), theobromine (piperacillin), or a combination thereof.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention for the preparation of a medicament for the prevention, treatment or amelioration of 5-HT 6 A receptor associated disease.
In one embodiment, the invention relates to the treatment of 5-HT 6 The receptor associated disease is a CNS disorder.
In one embodiment, the invention relates to the treatment of 5-HT 6 The receptor-associated CNS disorder is attention deficit hyperactivity disorder, anxiety, a stress-related disorder, schizophrenia, obsessive compulsive disorder, manic depression, a neurological disorder, a memory disorder, an attention deficit disorder, parkinson's disease, amyotrophic lateral sclerosis, alzheimer's disease or huntington's chorea.
In another embodiment, the invention relates to the treatment of 5-HT 6 The receptor-associated disease is a gastrointestinal disorder.
In another embodiment, the invention relates to the treatment of 5-HT 6 The receptor-associated disease is obesity.
Another aspect of the invention relates to methods for the preparation, isolation and purification of compounds of formula (I), formula (III) or formula (IV).
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.
The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below. All references in this specification are incorporated herein by reference in their entirety.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", thomas Sorrell, university Science Books, sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, john Wiley & Sons, new York:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
The term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.
The term "chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
The term "enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.
The term "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers lacking optical activity.
The term "diastereomer" refers to a stereoisomer that has two or more chiral neutrals and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, E.and Wilen, S, "Stereochemistry of Organic Compounds", john Wiley & Sons, inc, new York,1994. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by a compound, where (-) or l indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A 50.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configurations.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
The racemates of any resulting final products or intermediates can be resolved into the optical enantiomers by known methods, by methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, enantiomers, racemates and solutions (Wiley Interscience, new York, 1981); principles of Asymmetric Synthesis (2) nd Ed.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (value tautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
The term "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optional bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds.
The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.
The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. One is optional unless otherwise indicatedThe substituent group(s) of (a) may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein the substituent may be, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, azido, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo (= O), carboxyl, haloalkyl, haloalkoxy, hydroxyl-substituted alkyl, hydroxyl-substituted haloalkyl, hydroxyl-substituted alkoxy, alkoxy-C (= O) -, alkyl-C (= O) -, amino-C (= O) -, alkyl-S (= O) 2 -, amino-S (= O) 2 -, hydroxy-substituted alkyl-S (= O) 2 -, carboxyalkoxy, (alkoxy) - (alkylene) -, (aryl) - (alkylene) -, (heteroaryl) - (alkylene) -, and the like.
In addition, unless otherwise explicitly indicated, the descriptions of "… is independently" and "… is independently" and "… is independently" used in the present invention are interchangeable and should be understood in a broad sense, which means that specific options expressed between the same symbols do not affect each other in different groups, or that specific options expressed between the same symbols do not affect each other in the same groups.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C 1-6 Alkyl "means in particular independently disclosed methyl, ethyl, C 3 Alkyl radical, C 4 Alkyl radical, C 5 Alkyl and C 6 An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "alkyl" or "alkyl group" as used herein, means a saturated straight or branched chain monovalent hydrocarbon radical containing 1 to 20 carbon atoms, wherein said alkyl radical may be optionally substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH) 3 ) Ethyl group (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl group (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH)) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2,3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3,3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like.
The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms; in another embodiment, the alkylene group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 3 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 2 carbon atoms. Examples of this include methylene (-CH) 2 -, ethylene (-CH) 2 CH 2 -, isopropylidene (-CH (CH) 3 )CH 2 -) and the like. The alkylene group is optionally substituted with one or more substituents described herein.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp 2 A double bond, wherein the alkenyl group is optionally substituted with one or more substituents described herein, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, an alkenyl group contains 2 to 4 carbon atoms. Alkenyl radicalsExamples of (c) include, but are not limited to, vinyl (-CH = CH) 2 ) Allyl (-CH) 2 CH＝CH 2 ) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp triple bond, wherein said alkynyl radical is optionally substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-8 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C ≡ CH), propargyl (-CH) 2 C.ident.CH), 1-propynyl (-C.ident.C-CH) 3 ) And so on.
The term "carboxy", whether used alone or in combination with other terms such as "carboxyalkyl", denotes-CO 2 H; the term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl" or "acyloxy", denotes- (C = O) -.
The term "H" represents a single hydrogen atom. Such radicals may be attached to other groups, such as oxygen atoms, to form hydroxyl groups.
The term "heteroatom" denotes one or more of oxygen (O), sulfur (S), nitrogen (N), phosphorus (P) or silicon (Si), including nitrogen (N), sulfur (S) and phosphorus (P) in any oxidation state; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, e.g., N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).
The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" mean alkyl, alkenyl or alkoxy groups substituted with one or more halogen atoms, wherein the alkyl, alkenyl or alkoxy group has the meaning described herein, examples of which include, but are not limited to, difluoromethyl, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,3,3-tetrafluoropropoxy, and the like. The haloalkyl, haloalkenyl, or haloalkoxy group is optionally substituted with one or more substituents described herein.
The term "hydroxy-substituted haloalkyl" means that the haloalkyl group is substituted with one or more hydroxy groups, wherein the haloalkyl group has the meaning described herein. Examples include, but are not limited to, 1-hydroxy-2,2,2-trifluoroethyl, 1-hydroxy-2,2-difluoroethyl, and the like. The hydroxy-substituted haloalkyl group is optionally substituted with one or more substituents described herein.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group is optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) 1-pentyloxy (n-pentyloxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyloxy (-OCH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyloxy (-OCH (CH)) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH)) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-l-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-l-butoxy (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) And so on.
The term "alkoxyalkyl" denotes an alkyl group substituted with one or more alkoxy groups, wherein alkyl and alkoxy groups have the meaning described herein. Examples include, but are not limited to, methoxymethyl, ethoxymethyl, and the like. The alkoxyalkyl group is optionally substituted with one or more substituents described herein.
The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups, wherein the alkyl groups have the meaning as described herein. In one embodiment, alkylamino is one or two C 1-6 Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In another embodiment, alkylamino is C 1-3 Lower alkylamino groups of (a). Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like. The alkylamino group is optionally substituted with one or more substituents described herein.
The term "n-atomic" where n is an integer typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, piperidinyl is a6 atom heterocyclic group, while 1,2,3,4-tetrahydronaphthalene is a 10 atom aromatic ring.
The term "carbocyclyl" or "carbocycle" denotes a monovalent or multivalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Carbobicyclic groups include spirocarbocyclic and fused carbocyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. The carbocyclyl group is optionally substituted with one or more substituents described herein.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. Bicyclic or tricyclic ring systems may include fused, bridged and spiro rings. In one embodiment, cycloalkyl groups contain 3 to 10 carbon atoms; in another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl group is optionally substituted with one or more substituents described herein.
The terms "heterocyclyl" or "heterocycle" are used interchangeably herein and all refer to monocyclic, bicyclic, or tricyclic ring systems containing 3 to 12 ring atoms in which one or more atoms in the ring are independently replaced by a heteroatom having the meaning described herein, which ring may be fully saturated or contain one or more unsaturations, but none of the aromatic rings. In one embodiment, the heterocyclyl group is a 3-8 membered ring monocyclic (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give a ring like SO, SO 2 ，PO，PO 2 When said ring is a three-membered ring, in which there is only one heteroatom), or 7-12 membered bicyclic rings (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give the group like SO, SO 2 ，PO，PO 2 The group of (1). The heterocyclyl group is optionally substituted with one or more substituents described herein.
The ring atoms of the heterocyclic group may be carbon-based or heteroatom-based. Wherein, is cyclic-CH 2 The group is optionally replaced by-C (= O) -the sulphur atom of the ring is optionally oxidised to S-oxide and the nitrogen atom of the ring is optionally oxidised to N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl, oxazepanyl, oxazepinyl, thiazepinyl, and the like
Figure BDA0001713906860000101
Radical, diaza
Figure BDA0001713906860000102
Radical, S-N-aza
Figure BDA0001713906860000103
Aryl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, and the like. In heterocyclic radicals-CH 2 Examples of-groups substituted with-C (= O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl, 3,5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like. The heterocyclyl group is optionally substituted with one or more substituents described herein.
The term "aryl" or "aromatic ring" means a monocyclic, bicyclic, and tricyclic carbon ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms. The aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of the aryl group may include phenyl, naphthyl, and anthracene. The aryl group is optionally substituted with one or more substituents described herein.
The term "aralkyl" or "arylalkyl" refers to an aryl-substituted alkyl group. In one embodiment, an aralkyl group refers to a "lower aralkyl" group, i.e., the aryl group is attached to C 1-6 On the alkyl group of (a). In another embodiment, aralkyl refers to a group containing C 1-4 The "phenylalkylene" of an alkyl group of (a). Specific examples thereof include benzyl, diphenylmethyl, phenethyl, and the like. The aralkyl group is optionally substituted with one or more substituents described herein.
The term "aryloxy" denotes an optionally substituted aryl group, as defined herein, attached to an oxygen atom and linked to the rest of the molecule by an oxygen atom, wherein the aryl group has the meaning as described herein, examples of which include, but are not limited to, phenoxy, tolyloxy, ethylbenzene oxy, and the like. The aryloxy group is optionally substituted with one or more substituents described herein.
The term "heteroaryl" or "heteroaromatic ring" means monocyclic, bicyclic, and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms. The heteroaryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring", "aromatic heterocycle" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a 5-10 atom heteroaryl group comprises 1,2,3 or 4 heteroatoms independently selected from O, S and N.
Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 3835 zxft 35-oxadiazolyl, 1,2,4-oxadiazolyl, 3534-triazolyl, 3534-zft 5248, thioxft 57525725, thiooxazolyl, 345732-triazolyl, 3457525732, thioxft-345732; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyridyl, pyrazolo [1,5-a ] pyrimidyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.
As described herein, the ring system formed by the substituent R on the ring with a bond to the center (as shown in the following figures) represents that the substituent R is limited to any substitutable or any reasonable position on the A ring. For example, formula f represents any possible substituted position on the A ring, such as formula f 1 -f 4 Shown in the figure:
Figure BDA0001713906860000111
as described herein, the substituent (R) x ) n The ring system formed by a ring bound to the center represents n substituents R x Substitutions may be made at any substitutable position on the ring. For example, formula a represents a phenyl ring substituted by n R x And (4) substitution.
Figure BDA0001713906860000121
The term "heteroaryloxy" or "heteroaryloxy" means an optionally substituted heteroaryl group, as defined herein, attached to an oxygen atom and linked to the rest of the molecule by an oxygen atom, wherein the heteroaryl group has the meaning as set forth herein, examples of which include, but are not limited to, pyridyloxy, pyrimidyloxy, and the like. The heteroaryloxy group is optionally substituted with one or more substituents described herein.
The term "heteroarylalkyl" means an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl groups have the meaning described herein, and examples include, but are not limited to, imidazole-2-methyl, furan-2-ethyl, indole-3-methyl, and the like. The heteroarylalkyl group is optionally substituted with one or more substituents described herein.
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I) to (IV). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C) 1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: higuchi et al, pro-drugs as Novel Delivery Systems, vol.14, a.c.s.symposium Series; roche et al, ed., bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press,1987; rautio et al, primers, design and Clinical Applications, nature Reviews Drug Discovery,2008,7,255-270, and Hecker et al, primers of pharmaceuticals and Phosphonates, j.med.chem.,2008,51,2328-2345, each of which is incorporated herein by reference.
The term "metabolite" as used herein refers to a product obtained by the metabolism of a particular compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with a mammal for a sufficient period of time.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: s.m.berge et al, j.pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable salts include salts of the compounds with acids including, but not limited to, salts of inorganic acids (e.g., hydrochloride, hydrobromide, phosphate, sulfate, nitrate, perchlorate) and salts of organic acids (e.g., acetate, glycolate, oxalate, maleate, tartrate, citrate, succinate, fumarate, mandelate, sulfosalicylate), or obtained by other methods described in the literature, such as ion exchange. Further pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, oleates,palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts also include salts of the compounds with bases, including, but not limited to, inorganic base salts (e.g., alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 Alkyl radical) 4 Salts), alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulphonates and aromatic sulphonates. Salts of organic amines (e.g., primary, secondary and tertiary amine salts, substituted amines (including naturally occurring substituted amines, cyclic amines, basic ion exchange resins) salts), some of which include, for example, isopropylamine, benzathine, choline (cholinate), diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate, and in yet another embodiment, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.
The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality of a substituent of a hydroxy group to block or protect the hydroxy group, and suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene et al, protective Groups in Organic Synthesis, john Wiley&Sons,New York,1991and Kocienski et al.,Protecting Groups,Thieme,Stuttgart,2005。
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
The term "prevent" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., arresting the development of at least one clinical symptom of a disease in a subject that may be facing or predisposed to facing such a disease, but who has not yet experienced or exhibited symptoms of the disease).
The term "CNS" is an abbreviation for Central nervous system, meaning the Central nervous system. CNS disorders refer to central nervous system disorders. The central nervous system is composed of the brain and spinal cord (which are the central parts of the various reflex arcs) and is the most major part of the human nervous system.
The term "ADHD" is an abbreviation for Attention-deficiency disorder, a mental disorder that is very common in childhood. According to the world health organization's handbook of Classification of Universal diseases in the world (ICD-10, WHO, 1992), the disease is called "hyperactive Disorder" (Hyperkinetic Disorder), and the classification number is F90, which is commonly called "hyperactive infant".
The term "schizophrenia" refers to schizophrenia, schizophreniform disorder, schizoaffective disorder and psychotic disorder, wherein the term "psychosis" refers to delusions, manifest hallucinations, disorganized speech or disorganized or catatonic behavior. See the diagnostic Statistical Manual of Mental Disporder, fourth edition, american Psychiatric Association, washington, D.C.
Pharmaceutically acceptable acid addition salts can be formed by reacting a compound of the present invention with an inorganic or organic acid, and pharmaceutically acceptable base addition salts can be formed by reacting a compound of the present invention with an inorganic or organic base. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., na, ca, mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, selection and application (Handbook of pharmaceutical Salts: properties, selection, and Use) ", stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002), may find a list of additional suitable Salts.
In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The present invention discloses that compounds may form solvates, either inherently or by design, with pharmaceutically acceptable solvents (including water); thus, the present invention is intended to include both solvated and unsolvated forms.
Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H， 3 H， 11 C， 13 C， 14 C， 15 N， 17 O， 18 O， 18 F， 31 P， 32 P， 35 S， 36 Cl and 125 I。
in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present 3 H， 14 C and 18 those of F, or in which a non-radioactive isotope is present, e.g. 2 H and 13 C. the isotopically enriched compounds can be used for metabolic studies (use) 14 C) Reaction kinetics study (using, for example 2 H or 3 H) Detection or imaging techniques, e.g. Positron Emission Tomography (PET) or single photon emission computing involving measurement of tissue distribution of drugs or substratesComputed Tomography (SPECT), or may be used in radiotherapy of a patient. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formulae (I) to (IV) can be prepared by conventional techniques known to those skilled in the art or by using a suitable isotopically labelled reagent in place of the original used unlabelled reagent as described in the examples and preparations of this invention.
In addition, heavier isotopes are particularly preferred for deuterium (i.e., 2 substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is considered as a substituent for the compounds of formulae (I) to (IV). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D 2 O, acetone-d 6 、DMSO-d 6 Those solvates of (a).
Description of the Compounds of the invention
The invention relates to aromatic heterocyclic derivatives, pharmaceutically acceptable salts thereof, pharmaceutical preparations thereof and pharmaceutical compositions thereof, which have 5-HT 6 Receptor antagonism, in particular for the treatment of Alzheimer's disease.
In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I),
Figure BDA0001713906860000151
wherein each R is 1 、R 2 、R 2a 、R 3 、R 3a Y, Q, M and n have the meaning as described herein.
In one embodiment, Y is
Figure BDA0001713906860000152
Or
Figure BDA0001713906860000153
In one embodiment, n is 1,2,3 or 4.
In one embodiment, Q is CH or N.
In one embodiment, M is-NR 8 -、-CR 8a R 8b -, -C (= O) -or-O-; wherein each R 8 、R 8a And R 8b Have the meaning as described in the present invention.
In one embodiment, each R is 1 Independently H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NH 2 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl or C 1-9 Heteroaryl, or two adjacent R 1 And the carbon atoms to which they are attached form a 5-7 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein said 5-7 membered carbocyclic, heterocyclic, aromatic and heteroaromatic ring are optionally independently substituted with one or more substituents selected from the group consisting of D, F, cl, br, I, -CN, -NO 2 、-OH、-NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 3-8 Cycloalkyl, C 2-10 Heterocyclic group, C 6-10 Aryl and C 1-9 Heteroaryl or a substituted heteroaryl; wherein each R a 、R b 、R c And R d Have the meaning as described in the present invention.
In one embodiment, R 2 、R 2a 、R 3 And R 3a Independently H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NH 2 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl or C 1-9 A heteroaryl group.
In one embodiment, each R is 4 And R 5 Independently H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、-S(＝O) 2 NR a R b 、-S(＝O) p R c 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl group, C 6-10 Aryloxy or C 1-9 A heteroaryloxy group; wherein each of p and R a 、R b 、R c And R d Have the meaning as described in the present invention.
In one embodiment, each R is 6 Independently H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、C 1-6 Alkyl radical, C 1-6 Alkoxy radicalHalogen substituted C 1-6 Alkyl, halo C 1-6 Alkoxy, hydroxy-substituted halogeno C 1-6 Alkyl, (C) 1-6 Alkoxy) - (C 1-6 Alkylene) -, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, (C) 6-10 Aryl group) - (C 1-6 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-6 Alkylene) -; wherein each R a 、R b 、R c And R d Have the meaning as described in the present invention.
In one embodiment, each R is 7 Independently H, D, -C (= O) R c 、-C(＝O)OR d 、C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, (C) 6-10 Aryl group) - (C 1-6 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-6 Alkylene) -; wherein each R c And R d Have the meaning as described in the present invention.
In one embodiment, R 8 Is H, D, -CN, -NO 2 、-OH、-NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, (C) 6-10 Aryl) - (C 1-6 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-6 Alkylene) -; wherein each R a 、R b 、R c And R d Have the meaning as described in the present invention.
In one embodiment, R 8a And R 8b Each independently is H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, (C) 6-10 Aryl group) - (C 1-6 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-6 Alkylene) -; wherein each R a 、R b 、R c And R d Have the meaning as described in the present invention.
In one embodiment, each R is a And R b Independently H, D, -C (= O) R c 、-S(＝O) 2 -C 1-6 Alkyl radical, C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-10 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, (C) 6-10 Aryl group) - (C 1-6 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-6 Alkylene) -; wherein each R c Have the meaning as described in the present invention.
In one embodiment, each R is c And R d Independently H, D, C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 3-8 Cycloalkyl, C 2-10 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, (C) 6-10 Aryl group) - (C 1-6 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-6 Alkylene) -.
In one embodiment, p is 0, 1 or 2.
In one embodiment, each R is 1 Independently H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NH 2 、C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-4 Alkyl, halo C 1-4 Alkoxy radical, C 3-6 Cycloalkyl or C 3-8 Heterocyclyl, or two adjacent R 1 And the carbon atoms to which they are attached form an aromatic or heteroaromatic ring of 5 to 6 atoms, wherein the aromatic and heteroaromatic ring of 5 to 6 atoms are optionally independently substituted with one or more substituents independently selected from the group consisting of D, F, cl, br, I, -CN, -NO 2 、-OH、-NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-4 Alkyl and halo C 1-4 Substituted with a substituent of alkoxy; wherein each R a 、R b 、R c And R d Have the meaning as described in the present invention.
In one embodiment, R 2 、R 2a 、R 3 And R 3a Independently H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NH 2 、C 1-4 Alkyl radical, C 1-4 Alkoxy, halo C 1-4 Alkyl, halo C 1-4 Alkoxy radical, C 3-6 Cycloalkyl or C 3-8 A heterocyclic group.
In one embodiment, each R is 4 And R 5 Independently H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-4 Alkyl, halo C 1-4 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-8 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl group, C 6-10 Aryloxy or C 1-9 A heteroaryloxy group; wherein each R a 、R b 、R c And R d Have the meaning as described in the present invention.
In one embodiment, each R is 6 Independently H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、C 1-4 Alkyl radical, C 1-4 Alkoxy, halo C 1-4 Alkyl, halo C 1-4 Alkoxy, hydroxy-substituted halogeno C 1-4 Alkyl, (C) 1-4 Alkoxy group) - (C 1-4 Alkylene) -, C 3-6 Cycloalkyl radical, C 3-8 Heterocyclic group, C 6-10 Aryl radicals、C 1-9 Heteroaryl, (C) 6-10 Aryl group) - (C 1-4 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-4 Alkylene) -; wherein each R a 、R b 、R c And R d Have the meaning as described in the present invention.
In one embodiment, each R is 7 Independently H, D, -C (= O) R c 、-C(＝O)OR d 、C 1-4 Alkyl, halo C 1-4 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-8 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, (C) 6-10 Aryl group) - (C 1-4 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-4 Alkylene) -; wherein each R c And R d Have the meaning as described in the present invention.
In one embodiment, R 8 Is H, D, -CN, -NO 2 、-OH、-NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、C 1-6 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-4 Alkyl, halo C 1-4 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-8 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, (C) 6-10 Aryl group) - (C 1-4 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-4 Alkylene) -; wherein each R a 、R b 、R c And R d Have the meaning as described in the present invention.
In one embodiment, R 8a And R 8b Each independently of the other is H, D, F, cl, br, I, -CN, -NO 2 、-OH、NR a R b 、-C(＝O)NR a R b 、-C(＝O)R c 、-C(＝O)OR d 、C 1-6 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-4 Alkyl, halo C 1-4 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-8 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, (C) 6-10 Aryl group) - (C 1-4 Alkylene) -or (C) 1-9 Heteroaryl) - (C) 1-4 Alkylene) -; wherein each R a 、R b 、R c And R d Have the meaning as described in the present invention.
In one embodiment, each R is a And R b Independently H, C 1-4 Alkyl or halo C 1-4 An alkyl group.
In one embodiment, each R is c And R d Independently H, C 1-4 Alkyl, halo C 1-4 Alkyl radical, C 3-6 Cycloalkyl or C 3-8 A heterocyclic group.
In one embodiment, the compound of the present invention is a structure of formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a structure of formula (II),
Figure BDA0001713906860000171
each R 1 、R 8 Y and n have the meanings given in the description.
In another embodiment, the compound of the present invention is a structure of formula (III) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a structure of formula (III),
Figure BDA0001713906860000181
each R 1 、R 4 、R 5 、R 6 、R 7 And R 8 Have the meaning as described in the present invention.
In another embodiment, the compound of the present invention is a structure of formula (IV) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a structure of formula (IV),
Figure BDA0001713906860000182
each R 1 、R 4 、R 5 、R 6 、R 7 And R 8 Have the meaning as described in the present invention.
In one embodiment, each R is 1 Independently H, D, F, cl, br, I, -CN, -NO 2 、-OH、-NH 2 Methyl, ethyl, n-propyl, isopropyl, -CHF 2 、-CF 3 、-CH 2 CF 3 、-CF 2 CHF 2 、-CHFCF 3 、-CF 2 CF 3 、-CH 2 CF 2 CF 3 、-CH 2 CF 2 CHF 2 Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 、-OCF 3 、-OCH 2 CF 3 、-OCF 2 CHF 2 、-OCHFCF 3 、-OCF 2 CF 3 、-OCF 2 CH 2 CH 3 、-OCF 2 CH 2 CF 3 、-OCF 2 CH 2 CHF 2 、-OCH 2 CHFCH 3 、-OCH 2 CF 2 CH 3 、-OCH 2 CF 2 CF 3 or-OCH 2 CF 2 CHF 2 Or two adjacent R 1 And the carbon atoms to which they are attached form a benzene ring, wherein the benzene ring is optionally substituted with one or more substituents independently selected from D, F, cl, br, I, -CN, -NO 2 、-OH、C 1-4 Alkyl radical, C 1-4 Alkoxy, halo C 1-4 Alkyl and halo C 1-4 Substituted by a substituent of alkoxy.
In one embodiment, R 2 、R 2a 、R 3 And R 3a Independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl.
In one embodiment, each R is 4 And R 5 Independently H, D, F, cl, br, I,-CN、-NO 2 、-OH、-NH 2 Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CHF 2 、-CF 3 、-CH 2 CF 3 、-CF 2 CHF 2 、-CHFCF 3 、-CF 2 CF 3 、-CH 2 CF 2 CF 3 or-CH 2 CF 2 CHF 2 。
In one embodiment, each R is 6 Independently is H, D, F, cl, br, I, -CN, -C (= O) CH 3 、-C(＝O)CH 2 CH 3 、-C(＝O)CH 2 CH 2 CH 3 Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CHF 2 、-CF 3 、-CH 2 CF 3 、-CF 2 CHF 2 、-CHFCF 3 、-CF 2 CF 3 、-CH 2 CF 2 CF 3 、-CH 2 CF 2 CHF 2 、-CH(OH)CF 3 、-CH(OH)CHF 2 、-CH 2 CH(OH)CF 3 、-CH 2 CH(OH)CHF 2 、-CH(OH)CH 2 CHF 2 、-CH(OH)CH 2 CF 3 、-CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 or-CH 2 CH 2 OCH 2 CH 2 CH 3 。
In one embodiment, each R is 7 Independently H, D, methyl, ethyl, n-propyl, isopropyl, -CHF 2 、-CF 3 、-CH 2 CF 3 、-CF 2 CHF 2 、-CHFCF 3 、-CF 2 CF 3 、-CH 2 CF 2 CF 3 、-CH 2 CF 2 CHF 2 Cyclopropyl, cyclobutyl, cyclopentyl, nitrogenA heterocycloalkyl, oxetane, thietanyl, pyrrolidinyl or tetrahydrofuranyl group.
In one embodiment, R 8 Is H, D, methyl, ethyl, n-propyl, isopropyl, -CH 2 CH 2 CH(CH 3 ) 2 、-CH 2 C(CH 3 ) 3 Cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, or tetrahydrofuranyl.
In one embodiment, R 8a And R 8b Each independently is H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, -CH 2 CH 2 CH(CH 3 ) 2 、-CH 2 C(CH 3 ) 3 Methoxy, ethoxy, n-propyloxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl or tetrahydrofuranyl.
In one embodiment, each R is a And R b Independently H, D, methyl, ethyl, n-propyl or isopropyl.
In one embodiment, each R is c And R d Independently H, D, methyl, ethyl, n-propyl, isopropyl, cyclohexyl or morpholinyl.
In one embodiment, the compound of the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound having one of the following structures:
Figure BDA0001713906860000191
Figure BDA0001713906860000201
Figure BDA0001713906860000211
Figure BDA0001713906860000221
Figure BDA0001713906860000231
Figure BDA0001713906860000241
the invention also comprises the use of the compounds of the invention and their pharmaceutically acceptable salts for the manufacture of a pharmaceutical product for the treatment of alzheimer's disease, as well as those disorders described herein. The compounds of the invention are also useful in the manufacture of a medicament for the alleviation, prevention, control or treatment of 5-HT mediated disorders, particularly Alzheimer's disease. The present invention encompasses pharmaceutical compositions comprising therapeutically effective amounts of the compounds represented by formulae (I) to (IV) in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent.
Unless otherwise indicated, all suitable isotopic variations, stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are within the scope of the present invention.
Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): such as the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformers) thereof are within the scope of the present invention.
Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.
The compounds of the present disclosure may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention contemplates that all stereoisomeric forms of the compounds of formulae (I) to (IV), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, as well as mixtures thereof, such as racemic mixtures, are integral to the present invention.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.
Nitroxides of the compounds of the present invention are also included within the scope of the present invention. The nitroxides of the compounds of the present invention may be prepared by oxidation of the corresponding nitrogen-containing basic species using a common oxidizing agent (e.g. hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperature, or by reaction with a peracid in a suitable solvent, for example peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
In another aspect, the invention relates to intermediates for the preparation of compounds of formulae (I) to (IV).
In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formulae (I) to (IV).
The compounds of formulae (I) to (IV) may be present in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.
If the compounds of the invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Or using organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranonic acids, such as glucuronic and galacturonic acids; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, and the like.
If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali or alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
Compounds of the invention and pharmaceutical compositions, formulations and administrations thereof
When useful in therapy, therapeutically effective amounts of the compounds of formulae (I) to (IV) and pharmaceutically acceptable salts thereof may be administered as raw chemicals and may also be provided as active ingredients of pharmaceutical compositions. Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of formulae (I) to (IV) or individual stereoisomers, racemic or non-racemic mixtures of isomers or pharmaceutically acceptable salts or solvates thereof. In one embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant, or vehicle, and optionally, other therapeutic and/or prophylactic ingredients.
Suitable carriers, adjuvants and excipient agents are well known to those skilled in the art and are described in detail, for example, in Ansel h.c.et al, ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, williams & Wilkins, philidelphia; gennaro a.r.et al, remington: the Science and Practice of Pharmacy (2000) Lippincott, williams & Wilkins, philadelphia; and Rowe R.C., handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, chicago.
A method of treatment comprising administering a compound or pharmaceutical composition of the invention, further comprising administering to the patient an additional anti-Alzheimer's disease agent (combination therapy), wherein the additional anti-Alzheimer's disease agent is donepezil, nalmefene, risperidone, vitamin E, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, lu-AE58054, tacrine, rivastigmine, galantamine, memantine, mitazapine, venlafaxine, descumidine, nortriptyline, zolpidem, zopiclone, nicergoline, piracetam, selegiline, pentoxifylline or a combination thereof.
The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to show meaningful patient benefit. When the active ingredient alone is used for separate administration, the term refers only to that ingredient. When used in combination, the term refers to the combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, sequentially or simultaneously. The compounds represented by the formulae (I) to (IV) and pharmaceutically acceptable salts thereof are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to another aspect of the present disclosure, there is also provided a process for preparing a pharmaceutical formulation, which comprises mixing a compound represented by formulae (I) to (IV) or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
In general, the compounds of the present invention are administered in therapeutically effective amounts by any conventional means of administration for substances that exert similar effects. Suitable dosage ranges are typically from 1 to 500mg per day, preferably from 1 to 100mg per day, most preferably from 1 to 30mg per day, depending on a variety of factors such as the severity of the disease being treated, the age and relative health of the subject to be administered, the potency of the compound used, the route and form of administration, the indication for which administration is being made, and the preferences and experience of the relevant medical practitioner. A therapeutically effective amount of a compound of the invention for a given disease can be determined by one of ordinary skill in the art of treating such diseases without undue experimentation, relying on personal knowledge and the disclosure of this application.
Typically, the compounds of the invention are administered in the form of pharmaceutical formulations including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or for administration by inhalation or insufflation. The preferred mode of administration is generally oral, and may be adjusted to the level of pain using a suitable daily dosage regimen.
One or more compounds of the present invention may be presented in pharmaceutical compositions and unit dosage forms together with one or more conventional adjuvants, carriers or diluents. The pharmaceutical compositions and unit dosage forms can contain conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and the unit dosage forms can contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be applied in the form of solids such as tablets or filled capsules, semisolids, powders, sustained release formulations or liquids such as solutions, suspensions, emulsions, elixirs or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of a sterile injectable solution for parenteral use. Thus, formulations containing about 1mg of active ingredient per tablet or, more broadly, from about 0.01 to about 100mg of active ingredient are suitable representative unit dosage forms.
The compounds of the present invention may be formulated in a variety of orally administered dosage forms. Pharmaceutical compositions and dosage forms may comprise one or more compounds of the invention or a pharmaceutically acceptable salt thereof as an active ingredient. Pharmaceutically acceptable carriers can be either solid or liquid. Formulations in solid form include: powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is typically a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is usually mixed with a carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain from about 1% to about 70% of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like. The term "formulation" is intended to include preparations of the active compound that contain the encapsulating material as a carrier to provide a capsule in which the active ingredient, with or without a carrier, is surrounded by the carrier in association therewith. Similarly, cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges are solid forms suitable for oral administration.
Other forms suitable for oral administration include liquid form preparations (including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions) or solid form preparations which are intended to be converted into a liquid form preparation immediately prior to use. Emulsions may be prepared in solutions such as aqueous propylene glycol or may contain emulsifying agents such as lecithin, sorbitan monooleate or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions may be formulated by dispersing the finely divided active ingredient in water with viscous material, for example, natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents. Liquid form preparations include solutions, suspensions, and emulsions, which may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The compounds of the invention may be formulated for parenteral administration (e.g., by injection, such as bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil) and injectable organic esters (e.g. ethyl oleate), and may contain formulatory agents such as preservatives, wetting agents, emulsifying or suspending agents, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic packaging of a sterile solid or by lyophilisation of a solution for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
The compounds of the invention may be formulated for topical application to the epidermis in the form of an ointment, cream or lotion or in the form of a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; lozenges comprising the active ingredient in an inert base such as gelatin and glycerol or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
The compounds of the present invention may be formulated for administration in the form of suppositories. The low melting wax, such as a fatty acid glyceride mixture or cocoa butter, can be melted first and the active ingredient dispersed homogeneously, for example by stirring. The molten homogeneous mixture is then poured into a suitably sized mold, allowed to cool and solidify.
The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions can be applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or nebulizer. The formulations may be in single or multiple dose form. For a dropper or pipette multi-dose form, this may be achieved by the patient administering an appropriate, predetermined volume of solution or suspension. For a nebulizer, this can be achieved, for example, by a metered atomizing spray pump.
The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compounds typically have small particle sizes, for example, on the order of 5 microns or less. The particle size may be obtained by methods well known in the art, for example by micronization. The active ingredient is provided in pressurized packs containing a suitable propellant, such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may also suitably contain a surfactant such as lecithin. The dose of medicament may be controlled by a metering valve. Alternatively, the active ingredient may be provided in dry powder form, e.g. as a powder mixture of the compound in a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone. The powder carrier will form a gel in the nasal cavity. The powder compositions may be presented in unit dosage form, for example in gelatin capsules or cartridges or blister packs, and the powder may be administered by means of an inhaler.
If desired, the formulations may be prepared with enteric coatings suitable for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention may be formulated as transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with the treatment regimen is critical. The compounds in transdermal delivery systems are often attached to a skin-adherent solid carrier. The compounds of interest may also be used in combination with a penetration enhancer, such as laurocapram (1-dodecyl azepan-2-one). The sustained release delivery system may be inserted subcutaneously into the subcutaneous layer by surgery or injection. Subcutaneous implants encapsulate the compound in a liquid soluble film such as silicone rubber or a biodegradable polymer such as polylactic acid.
The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as tablets, capsules, and powders or ampoules in vials. In addition, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in a packaged form.
Other suitable pharmaceutical carriers and their formulations are described in Remington: the Science and Practice of Pharmacy 1995Martin, edited by E.W., mack Publishing Company, 19 th edition, easton, pennsylvania.
Use of the Compounds and pharmaceutical compositions of the invention
The compound and the pharmaceutical composition provided by the invention can be used for preparing medicines for preventing, treating or reducing Alzheimer's disease and can also be used for preparing medicines for preventing, treating or reducing Alzheimer's disease and 5-HT 6 A pharmaceutical product for treating a disease associated with a receptor.
The pharmaceutical composition of the present invention is characterized by comprising the compounds represented by formulas (I) to (IV) or the compounds listed in the present invention, and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of compound in the pharmaceutical composition of the present invention is effective to detectably antagonize 5-HT 6 Receptor for the treatment of obesity, gastrointestinal disordersCNS disorders, wherein said CNS disorder is ADHD, anxiety, stress-related diseases, schizophrenia, obsessive-compulsive disorders, manic-depressive disorders, neurological disorders, memory disorders, attention deficit disorder, parkinson's disease, amyotrophic lateral sclerosis, alzheimer's disease and huntington's chorea, and the like.
An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the invention refers to an amount effective to treat or reduce the severity of one or more of the conditions mentioned herein. The compounds and compositions according to the methods of the present invention can be administered in any amount and by any route effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient's condition, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein.
In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.
General Synthesis of Compounds of the invention
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these examples, but is provided only to practice the invention.
In general, the compounds of the invention can be prepared by the methods described herein, wherein the substituents are as defined in formulae (I) to (IV), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents than those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Ling Kai medicine, aldrich Chemical Company, inc., arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou West Long chemical plant, guangdong Guanghua chemical plant, guangzhou chemical plant, tianjin HaoYu Chemicals Co., ltd, qingdao Tenglong chemical reagent Co., and Qingdao maritime chemical plant.
The anhydrous tetrahydrofuran is obtained by refluxing and drying the metallic sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, N, N-dimethylacetamide and petroleum ether were used dried over anhydrous sodium sulfate in advance.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao oceanic plants. Nuclear magnetic resonance spectroscopy with CDC1 3 、DMSO-d 6 、CD 3 OD or acetone-d 6 As solvent (reported in ppm) TMS (0 ppm) or chloroform (7.25 ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton, singlet), d (doublet ), t (triplet, triplet), q (quatet, quartet), m (multiplet ), br (broad, broad), br (broad singleton), dd (doublet of doublet), dd (triplet, doublet, triplet), and combinations thereofts, doublet), ddd (doublet of doublet), dt (doublet of triplet ), td (triplet of doublet, triplet), tt (triplet of triplet, triplet). Coupling constant J, expressed in Hertz (Hz).
Low resolution Mass Spectral (MS) data were determined by Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and G1315B DAD detector applied for analysis, and an ESI source applied to the LC-MS spectrometer.
Low resolution Mass Spectral (MS) data were measured by Agilent6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.
Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, with a format of 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:
TABLE 1
Time (min) Phase A (CH) 3 CN，0.1％HCOOH) Phase B (H) 2 O，0.1％HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
Compound purification was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm on a Zorbax SB-C18 column, 2.1X 30mm, 4 μm,10 min, flow rate 0.6mL/min,5-95% (0.1% formic acid in acetonitrile) in 0.1% formic acid in water, the column temperature was maintained at 40 ℃.
The following acronyms are used throughout the invention:
CH 2 Cl 2 DCM dichloromethane HCl hydrochloric acid
CH 3 I methyl iodide HCl in EtOAc hydrochloric acid ethyl acetate solution
CH 3 CH 2 I Iodothane EDTA ethylenediaminetetraacetic acid
CH 2 ClCH 2 Cl, DCE 1,2-dichloroethane g
CDC1 3 Deuterated chloroform for h
DMSO-d 6 Deuterated dimethyl sulfoxide NaHCO 3 Sodium bicarbonate
DMF N, N-dimethylformamide Na 2 SO 4 Sodium sulfate
EtOAc, EA ethyl acetate KOH potassium hydroxide
THF tetrahydrofuran NH 4 Cl ammonium chloride
CH 3 OH methanol MgCl 2 Magnesium chloride
CH 3 CH 2 OH ethanol (CH) 3 COO) 2 Cu copper acetate
Et 3 N-Triethylamine CuI cuprous iodide
I 2 Iodine NaBH 3 CN Cyanoborohydride sodium salt
Fe iron powder mL, mL
NaH sodium hydride PE Petroleum ether (60-90 ℃ C.)
Acetone Acetone RT, RT, r.t. Room temperature
H 2 O-PEI (polyethyleneimine) hydrate
(Boc) 2 Di-tert-butyl O-dicarbonate Pargyline Pargyline
Tris-HCl Tris (hydroxymethyl) aminomethane-hydrochloric acid
The following synthetic schemes describe the steps for preparing the compounds disclosed herein. Unless otherwise stated, each R 4 、R 5 、R 6 、R 7 Having the definitions as described in the present invention.
Synthesis scheme 1
Figure BDA0001713906860000311
Formula (A), (B) and10) The compound shown can be prepared by the following processes: formula (A), (B) and1) Reacting the compound with hydrazine hydrate to obtain a compound of the formula (A)2) A compound shown in the specification; then the formula (A), (B) and2) A compound of the formula (I) and3) Reacting the compound shown in the formula (A) to obtain a compound shown in the formula (B)4) The compounds shown. Formula (A), (B) and4) Oxidation of the compound shownTo obtain the formula (A)5) A compound shown in the specification; then the formula (A), (B) and5) The nitro group of the compound is reduced to obtain a compound of the formula (A)6) The compounds shown. Formula (A), (B) and6) The compound shown in the formula (I) is synthesized into a piperazine ring to obtain a compound shown in the formula (I)7) The compounds shown. Formula (A), (B) and7) The protecting group on the compound shown is obtained by the formula (I)8) A compound shown in the specification; formula (A), (B) and8) The indole nitrogen atom of the compound shown is introduced with a substituent to obtain a compound shown as a formula (A)9) The compounds shown. Formula (A), (B) and9) Removing the protecting group of the compound to obtain a compound of the formula (I)10) The target compound shown.
Synthesis scheme 2
Figure BDA0001713906860000321
Formula (A), (B) and17) The compound shown can be prepared by the following processes: formula (A), (B) and11) A compound of the formula3) Reacting the compound shown in the formula (A) to obtain a compound shown in the formula (B)12) The compounds shown. Formula (A), (B) and12) The compound shown in the formula (I) is synthesized into a piperazine ring to obtain a compound shown in the formula (I)13) A compound of (I) shown; then formula (A), (B)13) The protecting group on the compound shown is obtained by the formula (I)14) The compounds shown. Formula (A), (B) and14) The compound shown in the formula is oxidized to obtain a compound shown in the formula (A)15) The compounds shown. Formula (A), (B) and15) The indole nitrogen atom of the compound is introduced with a substituent to obtain a formula (I)16) The compounds shown. Formula (A), (B) and16) Removing the protecting group of the compound to obtain a compound of the formula (I)17) The target compound shown.
Synthesis scheme 3
Figure BDA0001713906860000331
Formula (A), (B) and26) The compound shown can be prepared by the following steps: formula (A), (B)18) Reacting the compound with hydrazine hydrate to obtain a compound of the formula (A)19) A compound shown in the specification; then formula (A), (B)19) A compound of the formula3) Reacting the compound shown in the formula (A) to obtain a compound shown in the formula (B)20) The compounds shown. Formula (A), (B) and20) The compound shown is oxidized to obtain a compound shown in the formula (A)21) The compounds shown(ii) a Then formula (A), (B)21) Reduction of the compound to give a compound of the formula22) The compounds shown. Formula (A), (B) and22) Removing the protecting group of the compound to obtain a compound of the formula (I)23) The compounds shown. Formula (A), (B)23) Protecting groups on the compounds shown in the formula (A) to obtain24) A compound shown in the specification; formula (A), (B) and24) The indole nitrogen atom of the compound is introduced with a substituent to obtain a formula (I)25) The compounds shown. Formula (A), (B) and25) Removing the protecting group of the compound to obtain a compound of the formula (I)26) The target compound shown.
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated in the following examples.
Examples
Example 1 Synthesis of 5-fluoro-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000341
Step 1) Synthesis of 3-Nitrobenzene sulfonyl hydrazide
Hydrazine hydrate (5.6 mL) and tetrahydrofuran (20 mL) were charged into a 100mL single-neck round-bottom flask, and after cooling in a 0 ℃ low temperature bath, 3-nitrobenzenesulfonyl chloride (5.0 g,22.5 mmol) was added in portions and transferred to reaction at 25 ℃ at reaction time 12. The reaction was stopped, spin-dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale yellow solid (3.9g, 80%).
MS(ESI,pos.ion)m/z:218.1[M+H] + .
Step 2) Synthesis of 5-fluoro-3- ((3-nitrophenyl) thio) -1H-indole
3-Nitrobenzenesulfonylhydrazide (2.46g, 11.3mmol), 5-fluoroindole (2.5g, 18.5mmol), iodine (0.234g, 0.92mmol) and ethanol (20 mL) were charged into a 100mL single-necked round-bottomed flask and reacted at 90 ℃ for 5 hours. The reaction was stopped, cooled, spun-dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 10/1) to give the title compound as a white solid (2.78g, 85%).
MS(ESI,neg.ion)m/z:286.9[M-H] - ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.92(ddd,J＝8.0,2.1,1.1Hz,1H),7.90(t,J＝1.9Hz,1H),7.62(d,J＝2.7Hz,1H),7.43(dd,J＝8.9,4.2Hz,1H),7.41-7.38(m,1H),7.35(t,J＝7.9Hz,1H),7.22(dd,J＝9.0,2.5Hz,1H),7.07(td,J＝9.0,2.5Hz,1H).
Step 3) Synthesis of 5-fluoro-3- ((3-nitrophenyl) sulfonyl) -1H-indole
5-fluoro-3- ((3-nitrophenyl) thio) -1H-indole (2.78g, 9.64mmol), potassium peroxymonosulfonate (17.8g, 27.5 mmol), acetone (20 mL), and water (10 mL) were charged at 25 ℃ to a 100mL single-neck round-bottom flask, followed by the addition of sodium bicarbonate solid (2.52g, 30.0 mmol) in portions, and the reaction was allowed to stir for an additional 24 hours. The reaction was stopped, water (40 mL) was added, and the mixture was extracted with ethyl acetate (50 mL), and after separation, the organic phase was dried over anhydrous sodium sulfate (5 g). Filtration, spin-drying of the filtrate under reduced pressure, and purification by column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) gave the title compound as a brown solid (2.03g, 65.7%).
MS(ESI,pos.ion)m/z:321.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.64(t,J＝1.9Hz,1H),8.49-8.40(m,3H),7.88(t,J＝8.0Hz,1H),7.55(dd,J＝8.8,4.4Hz,2H),7.14(td,J＝9.2,2.5Hz,1H).
Step 4) Synthesis of 3- ((5-fluoro-1H-indol-3-yl) sulfonyl) aniline
5-fluoro-3- ((3-nitrophenyl) sulfonyl) -1H-indole (2.0g, 6.2mmol), ammonium chloride (0.66g, 12.3mmol), tetrahydrofuran (10 mL), ethanol (10 mL), and water (2 mL) were charged into a 100mL single-neck round-bottom flask, followed by addition of iron powder (1.4g, 25.0mmol), and reacted at 90 ℃ for 3 hours. The reaction was stopped, cooled, filtered, the filtrate was spin-dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) = 50/1) to give the title compound as a tan solid (1.5g, 83%).
MS(ESI,pos.ion)m/z:291.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.16(s,1H),7.53(dd,J＝8.9,4.5Hz,1H),7.43(dd,J＝9.6,2.4Hz,1H),7.21-7.08(m,3H),7.05(d,J＝7.8Hz,1H),6.71(dd,J＝8.0,1.5Hz,1H),5.59(s,2H).
Step 5) Synthesis of 5-fluoro-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
3- ((5-fluoro-1H-indol-3-yl) sulfonyl) aniline (1.45g, 4.98mmol), bis (2-chloroethyl) amine hydrochloride (0.9g, 5.0 mmol), chlorobenzene (20 mL) were added to a 100mL single neck round bottom flask and reacted in an oil bath at 140 ℃ for 30 hours. The reaction was stopped, cooled, and added to a saturated sodium bicarbonate solution (40 mL) to precipitate a solid, which was filtered to give a crude solid, which was purified by column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale yellow solid (1.7g, 95%).
MS(ESI,pos.ion)m/z:360.3[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.25(s,1H),7.53(dd,J＝8.9,4.5Hz,1H),7.48(dd,J＝9.5,2.4Hz,1H),7.41(s,1H),7.38-7.32(m,2H),7.12-7.09(m,2H),3.10(brs,4H),2.83(brs,4H).
Example 2 Synthesis of 5-fluoro-1-methyl-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000351
Step 1) Synthesis of tert-butyl 4- (3- ((5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate
5-fluoro-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole (1.7 g, 4.73mmol), montmorillonite (1.0 g) and dichloromethane (15 mL) were added to a 50mL single neck round bottom flask followed by di-tert-butyl dicarbonate (1.55g, 7.1 mmol) and reaction at 25 ℃ for 2 hours. The reaction was stopped, spin-dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a colorless oil (1.2g, 55%).
MS(ESI,pos.ion)m/z:404.3[M+H-56] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)10.31(s,1H),7.94-7.82(m,1H),7.55(d,J＝9.2Hz,1H),7.51(s,1H),7.44(d,J＝7.7Hz,1H),7.40-7.25(m,2H),7.04-6.90(m,2H),3.57(brs,4H),3.17(brs,4H),1.50(s,9H).
Step 2) tert-butyl 4- (3- ((5-fluoro-1-methyl-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate Synthesis of (2)
Tert-butyl 4- (3- ((5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (500mg, 1.09mmol), N-dimethylformamide (5 mL) were added to a 50mL single-neck round-bottom flask, followed by sodium hydride (60%, 65mg, 1.62mmol). After cooling in a low temperature bath at 0 deg.C, methyl iodide (170. Mu.L, 2.72 mmol) was added and the reaction was transferred to 25 deg.C for 6 hours. After quenching with water (30 mL), followed by extraction with dichloromethane (20 mL), liquid separation, collection of the organic phase, drying over anhydrous sodium sulfate (3 g), filtration, spin-drying of the filtrate under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) = 100/1) the title compound was obtained as a pale yellow solid (480mg, 93%).
MS(ESI,pos.ion)m/z:417.9[M+H-56] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.78(s,1H),7.62(dd,J＝9.2,2.4Hz,1H),7.55(d,J＝1.9Hz,1H),7.46(d,J＝7.8Hz,1H),7.35(t,J＝8.0Hz,1H),7.31-7.27(m,1H),7.08(td,J＝9.0,2.5Hz,1H),7.02(dd,J＝8.2,2.2Hz,1H),3.85(s,3H),3.65-3.51(m,4H),3.24-3.15(m,4H),1.50(s,9H).
Step 3) Synthesis of 5-fluoro-1-methyl-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Tert-butyl 4- (3- ((5-fluoro-1-methyl-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (480mg, 1.01mmol), dichloromethane (10 mL) were added to a 50mL single-neck round-bottom flask at 25 ℃, followed by addition of a hydrogen chloride ethyl acetate solution (2M, 2mL), and the reaction was stirred for an additional 2 hours. The reaction was stopped, spin-dried under reduced pressure, saturated sodium bicarbonate solution (20 mL) was added, followed by extraction with ethyl acetate (20 mL), the layers were separated, and the organic phase was dried over anhydrous sodium sulfate (5 g). Filtration, spin-drying of the filtrate under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) = 20/1) gave the title compound as a pale yellow solid (307mg, 81%).
MS(ESI,pos.ion)m/z:374.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.76(s,1H),7.61(dd,J＝9.2,2.4Hz,1H),7.55-7.52(m,1H),7.41(dd,J＝7.8,0.7Hz,1H),7.31(t,J＝8.0Hz,1H),7.25(dd,J＝9.0,4.1Hz,1H),7.04(td,J＝9.0,2.5Hz,1H),7.00(dd,J＝8.3,2.0Hz,1H),3.81(s,3H),3.20-3.18(m,4H),3.03-3.01(m,4H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)159.3(d,J＝237.6Hz),151.9,144.0,134.7,133.8,129.8,124.9(d,J＝11.1Hz),119.3,117.0,115.3,112.9,112.2(d,J＝26.4Hz),111.4(d,J＝9.8Hz),105.2(d,J＝25.2Hz),49.5,45.8,33.9.
Example 3 Synthesis of 1- (difluoromethyl) -5-fluoro-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000361
Step 1) tert-butyl 4- (3- ((1- (difluoromethyl) -5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1- Synthesis of carboxylic acid esters
Tert-butyl 4- (3- ((5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (230mg, 0.5 mmol), sodium difluorochloroacetate (200mg, 1.3 mmol), sodium hydride (60%, 24mg,0.6 mmol), and N, N-dimethylformamide (5 mL) were added to a 50mL single-neck round bottom flask and reacted at 110 ℃ for 40 minutes in an oil bath. The reaction was stopped, cooled to room temperature, quenched with water (30 mL), extracted with ethyl acetate (30 mL), the organic phase after separation was dried over anhydrous sodium sulfate (5 g), filtered, the filtrate was spin-dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 10/1) to give the title compound as a colorless viscous substance (103mg, 40%).
MS(ESI,pos.ion)m/z:454.1[M+H-56]+；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.03(s,1H),7.63(dd,J＝8.7,2.4Hz,1H),7.58-7.52(m,2H),7.47(d,J＝7.8Hz,1H),7.40(d,J＝8.4Hz,1H),7.27(t,J＝43.2Hz,1H),7.16(td,J＝9.0,2.5Hz,1H),7.08(dd,J＝8.2,2.1Hz,1H),3.66-3.51(m,4H),3.29-3.17(m,4H),1.51(s,9H).
Step 2) Synthesis of 1- (difluoromethyl) -5-fluoro-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Tert-butyl 4- (3- ((1- (difluoromethyl) -5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (230mg, 0.45mmol), dichloromethane (10 mL) were added to a 50mL single neck round bottom flask at 25 ℃, followed by addition of a solution of ethyl hydrogen chloride in ethyl acetate (2m, 2ml) and stirring of the reaction continued for 1.5 hours. The reaction was stopped, spin-dried under reduced pressure, saturated sodium bicarbonate solution (20 mL) was added, followed by extraction with ethyl acetate (20 mL), the layers were separated, and the organic phase was dried over anhydrous sodium sulfate (5 g). Filtration, spin-drying of the filtrate under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) = 30/1) gave the title compound as a pale yellow solid (163mg, 88%).
MS(ESI,pos.ion)m/z:410.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.05(s,1H),7.62(dd,J＝8.8,2.5Hz,1H),7.57-7.52(m,2H),7.45-7.41(m,1H),7.37(dd,J＝10.8,5.2Hz,1H),7.28(t,J＝60.0Hz,1H),7.14(td,J＝9.0,2.5Hz,1H),7.07(dd,J＝8.3,2.0Hz,1H),3.22-3.20(m,4H),3.05-3.03(m,4H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)159.8(d,J＝240.6Hz),152.1,142.5,130.5,130.1,129.6,125.5(d,J＝10.8Hz),120.8,119.9,117.2,114.0(d,J＝26.1Hz),113.1,113.0,109.8(t,J＝249.9Hz),106.3,106.1(d,J＝25.5Hz),49.4,45.8.
Example 4 Synthesis of 1-cyclopropyl-5-fluoro-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000371
Step 1) tert-butyl 4- (3- ((1-cyclopropyl-5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylic acid Synthesis of esters
Tert-butyl 4- (3- ((5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (222mg, 0.48mmol), cyclopropylboronic acid (86mg, 0.95mmol) and 1,2-dichloroethane (4 mL) were charged to a 50mL single neck round bottom flask, followed by copper acetate (88mg, 0.47mmol) and 2,2' -bipyridine (75mg, 0.47mmol), and reacted for 7 hours in a 90 ℃ oil bath. The reaction was stopped, spin-dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a white solid (183mg, 75.8%).
MS(ESI,pos.ion)m/z:443.8[M+H-56] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.84(s,1H),7.59(dd,J＝9.2,2.4Hz,1H),7.57-7.50(m,2H),7.45(d,J＝7.8Hz,1H),7.36(t,J＝8.0Hz,1H),7.08(td,J＝9.1,2.5Hz,1H),7.05-7.01(m,1H),3.63-3.55(m,4H),3.46-3.37(m,1H),3.23-3.16(m,4H),1.51(s,9H),1.18(q,J＝7.0Hz,2H),1.09-1.04(m,2H).
Step 2) Synthesis of 1-cyclopropyl-5-fluoro-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Tert-butyl 4- (3- ((1-cyclopropyl-5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (183mg, 0.37mmol) and dichloromethane (10 mL) were added to a 50mL single-neck round-bottom flask at 25 ℃, a solution of ethyl hydrogen chloride in ethyl acetate (2m, 2ml) was added, and the reaction was stirred for an additional 1.5 hours. The reaction was stopped, spin-dried under reduced pressure, saturated sodium bicarbonate solution (20 mL) was added, followed by extraction with ethyl acetate (20 mL), the layers were separated, and the organic phase was dried over anhydrous sodium sulfate (5 g). Filtration, spin-drying of the filtrate under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) = 30/1) gave the title compound as a white solid (126mg, 85%).
MS(ESI,pos.ion)m/z:400.3[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.27(s,1H),7.69(dd,J＝9.0,4.4Hz,1H),7.52(dd,J＝9.4,2.5Hz,1H),7.43(s,1H),7.36(d,J＝5.1Hz,2H),7.20(td,J＝9.2,2.5Hz,1H),7.14-7.08(m,1H),3.60-3.56(m,1H),3.11-3.07(m,4H),2.83-2.79(m,4H),1.09-1.06(m,4H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm)159.1(d,J＝235.2Hz),152.3,144.2,135.6,134.7,130.5,124.6(d,J＝10.9Hz),119.4,116.3,114.8(d,J＝4.3Hz),113.9(d,J＝9.8Hz),112.2(d,J＝25.9Hz),111.9,104.5(d,J＝25.1Hz),49.1,45.8,28.6,6.5.
Example 5 Synthesis of 1-ethyl-5-fluoro-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000372
Step 1) tert-butyl 4- (3- ((1-ethyl-5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate Synthesis of (2)
Tert-butyl 4- (3- ((5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (500mg, 1.09mmol), N-dimethylformamide (10 mL) were added to a 50mL single-neck round-bottom flask at 25 ℃, sodium hydride (60%, 80mg, 2.0mmol) was added, iodoethane (265mg, 1.70mmol) was then added, and the reaction was continued for 8.5 hours. The reaction was stopped, quenched by addition of water (30 mL), extracted with dichloromethane (30 mL), and the organic phase was dried over anhydrous sodium sulfate (5 g) after separation. Filtration, spin-drying of the filtrate under reduced pressure, and purification by column chromatography (petroleum ether/ethyl acetate (v/v) = 5/1) gave the title compound as a white solid (250mg, 47%).
MS(ESI,pos.ion)m/z:431.9[M+H-56] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.03(s,1H),7.61(dd,J＝9.2,2.4Hz,1H),7.55(s,1H),7.45(d,J＝7.8Hz,1H),7.39-7.29(m,2H),7.11-6.96(m,2H),4.20(q,J＝7.3Hz,2H),3.63-3.54(m,4H),3.24-3.15(m,4H),1.54(t,J＝7.3Hz,3H),1.50(s,9H).
Step 2) Synthesis of 1-ethyl-5-fluoro-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Tert-butyl 4- (3- ((1-ethyl-5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (200mg, 0.41mmol), methylene chloride (5 mL) were added to a 50mL single-neck round bottom flask at 25 ℃, ethyl hydrogen chloride in ethyl acetate (2m, 2ml) was added, and the reaction was stirred for an additional 4 hours. The reaction was stopped, dried under reduced pressure, saturated sodium bicarbonate solution (20 mL) was added, followed by extraction with ethyl acetate (20 mL), liquid separation, and the organic phase was dried over anhydrous sodium sulfate (4 g). Filtration, spin-drying of the filtrate under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) = 30/1) gave the title compound as a white solid (146mg, 91.8%).
MS(ESI,pos.ion)m/z:387.9[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.85(s,1H),7.63(dd,J＝9.1,2.2Hz,1H),7.57(s,1H),7.42(d,J＝7.7Hz,1H),7.37-7.29(m,2H),7.10-6.99(m,2H),4.20(q,J＝7.3Hz,2H),3.24-3.16(m,4H),3.08-2.98(m,4H),1.54(t,J＝7.3Hz,3H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)159.2(d,J＝239.0Hz),152.0,144.0,133.0,132.9,129.8,125.1(d,J＝11.1Hz),119.3,117.0,115.4(d,J＝4.6Hz),113.0,112.2(d,J＝26.5Hz),111.3(d,J＝9.8Hz),105.4(d,J＝25.4Hz),49.7,45.9,42.2,15.0.
Example 6 Synthesis of 5-fluoro-1-isopropyl-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000381
Step 1) tert-butyl 4- (3- ((1-isopropyl-5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylic acid Synthesis of esters
Tert-butyl 4- (3- ((5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (500mg, 1.09mmol), N-dimethylformamide (10 mL) were added to a 50mL single-neck round-bottom flask at 25 deg.C, sodium hydride (60%, 80mg,2.0 mmol) was added, followed by 2-iodopropane (290mg, 1.71mmol), and the reaction was continued for 3 hours. The reaction was stopped, quenched by addition of water (30 mL), extracted with dichloromethane (30 mL), and the organic phase was dried over anhydrous sodium sulfate (3 g) after separation. Filtration, spin-drying of the filtrate under reduced pressure, and purification by column chromatography (petroleum ether/ethyl acetate (v/v) = 10/1) gave the title compound as a yellow oil (270mg, 49.5%).
MS(ESI,pos.ion)m/z:445.9[M+H-56] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.93(s,1H),7.60(dd,J＝9.1,2.4Hz,1H),7.57(s,1H),7.45(d,J＝7.8Hz,1H),7.40-7.31(m,2H),7.12-6.96(m,2H),4.74-4.56(m,1H),3.62-3.56(m,4H),3.25-3.17(m,4H),1.58(d,J＝6.7Hz,6H),1.51(s,9H).
Step 2) Synthesis of 5-fluoro-1-isopropyl-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Tert-butyl 4- (3- ((1-isopropyl-5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (255mg, 0.51mmol) and dichloromethane (5 mL) were added to a 50mL single-neck round-bottom flask at 25 ℃, a solution of ethyl acetate hydrochloride (2m, 2ml) was added, and the reaction was stirred for an additional 4 hours. The reaction was stopped, spin-dried under reduced pressure, saturated sodium bicarbonate solution (20 mL) was added, followed by extraction with ethyl acetate (20 mL), the layers were separated, and the organic phase was dried over anhydrous sodium sulfate (3 g). Filtration, spin-drying of the filtrate under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) = 40/1) gave the title compound as a white solid (195mg, 95.5%).
MS(ESI,pos.ion)m/z:402.3[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.93(s,1H),7.62(dd,J＝9.2,2.4Hz,1H),7.57(s,1H),7.42(d,J＝7.7Hz,1H),7.37-7.32(m,2H),7.09-7.00(m,2H),4.71-4.60(m,1H),3.26-3.18(m,4H),3.06-3.01(m,4H),1.58(d,J＝6.7Hz,6H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)159.1(d,J＝239.1Hz),152.0,143.9,132.8,130.2,129.8,125.1(d,J＝11.0Hz),119.3,117.1,115.3(d,J＝4.6Hz),113.0,112.0(d,J＝26.4Hz),111.5(d,J＝9.7Hz),105.3(d,J＝25.3Hz).49.7,48.6,45.9,22.6.
Example 7 Synthesis of 5-chloro-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000391
Step 1) Synthesis of 5-chloro-3- ((3-nitrophenyl) thio) -1H-indole
The title compound was prepared as described in example 1, step 2 by reacting 5-chloroindole (3.5g, 23mmol), 3-nitrobenzenesulfonylhydrazide (2.5g, 12mmol), iodine (0.28g, 1.09mmol) in ethanol (30 mL), and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 20/1), concentrated and dried to give the title compound as a yellow solid (2.4g, 68%).
MS(ESI,neg.ion)m/z:302.8[M-H] - ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.92(dd,J＝7.5,1.7Hz,1H),7.89(s,1H),7.60(d,J＝2.7Hz,1H),7.55(d,J＝1.5Hz,1H),7.45-7.32(m,3H),7.28-7.24(m,1H).
Step 2) Synthesis of 5-chloro-3- ((3-nitrophenyl) sulfonyl) -1H-indole
The title compound was prepared as described in example 1, step 3 by reacting 5-chloro-3- ((3-nitrophenyl) thio) -1H-indole (2.4 g, 7.9mmol), potassium peroxymonosulfonate (14.5 g,22.4 mmol), sodium bicarbonate (2.0g, 24mmol) in acetone (35 mL) and water (15 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a yellow solid (2.45g, 92%).
MS(ESI,pos.ion)m/z:336.8[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.64(t,J＝1.9Hz,1H),8.49-8.41(m,3H),7.89(t,J＝8.0Hz,1H),7.81(d,J＝1.8Hz,1H),7.56(d,J＝8.7Hz,1H),7.30(dd,J＝8.7,2.0Hz,1H).
Step 3) Synthesis of 3- ((5-chloro-1H-indol-3-yl) sulfonyl) aniline
The title compound of this step was prepared by the method described in example 1, step 4, i.e. 5-chloro-3- ((3-nitrophenyl) sulfonyl) -1H-indole (2.4 g, 7.1mmol), ammonium chloride (0.76g, 14.2mmol), iron powder (1.99g, 35.5 mmol) were reacted in tetrahydrofuran (20 mL), ethanol (10 mL) and water (2 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a yellow solid (1.59g, 73%).
MS(ESI,pos.ion)m/z:307.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.19(s,1H),7.71(d,J＝2.0Hz,1H),7.54(d,J＝8.7Hz,1H),7.27(dd,J＝8.7,2.0Hz,1H),7.22-7.12(m,2H),7.04(d,J＝7.7Hz,1H),6.72(dd,J＝8.0,1.6Hz,1H),5.61(s,2H).
Step 4) Synthesis of 5-chloro-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound was prepared as described in example 1, step 5 by reacting 3- ((5-chloro-1H-indol-3-yl) sulfonyl) aniline (3.3g, 11mmol), bis (2-chloroethyl) amine hydrochloride (2.3g, 13mmol) in chlorobenzene (30 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a yellow solid (3.3g, 82%).
MS(ESI,pos.ion)m/z:375.9[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.27(s,1H),7.76(s,1H),7.55(d,J＝8.6Hz,1H),7.49(s,1H),7.44-7.36(m,2H),7.26(d,J＝8.2Hz,1H),7.19(d,J＝7.1Hz,1H),3.43-3.37(m,4H),3.15-3.09(m,4H).
Example 8 Synthesis of 5-chloro-1-methyl-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000401
Step 1) Synthesis of tert-butyl 4- (3- ((5-chloro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate
The title compound of this step was prepared as described in example 2, step 1, by reacting 5-chloro-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole (3.8g, 10mmol), montmorillonite (0.6 g), and di-tert-butyl dicarbonate (2.6g, 12mmol) in dichloromethane (30 mL), and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a pale yellow solid (2.74g, 57%).
MS(ESI,pos.ion)m/z:419.8[M+H-56] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.92(d,J＝1.7Hz,1H),7.89(d,J＝3.0Hz,1H),7.54(s,1H),7.45(d,J＝7.8Hz,1H),7.36(dd,J＝8.4,5.8Hz,2H),7.24(dd,J＝8.7,1.9Hz,1H),7.03(dd,J＝8.2,2.2Hz,1H),3.63-3.54(m,4H),3.27-3.15(m,4H),1.51(s,9H).
Step 2) tert-butyl 4- (3- ((5-chloro-1-methyl-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate Synthesis of (2)
The title compound of this step was prepared by the method described in example 2, step 2, i.e. tert-butyl 4- (3- ((5-chloro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (0.3g, 0.63mmol), sodium hydride (38mg, 0.95mmol) and iodomethane (98 μ L,1.57 mmol) were reacted in N, N-dimethylformamide (5 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a white solid (180mg, 58%).
MS(ESI,pos.ion)m/z:434.2[M+H-56] + ；
1 HNMR(400MHz,CDCl 3 )δ(ppm)7.95(s,1H),7.76(s,1H),7.56(s,1H),7.45(d,J＝7.8Hz,1H),7.35(t,J＝8.0Hz,1H),7.28-7.27(m,2H),7.03(dd,J＝8.2,2.2Hz,1H),3.84(s,3H),3.63-3.56(m,4H),3.25-3.17(m,4H),1.50(s,9H).
Step 3) Synthesis of 5-chloro-1-methyl-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (3- ((5-chloro-1-methyl-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (157mg, 0.32mmol), ethyl hydrogen chloride acetate solution (2m, 4 mL) was reacted in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a pale yellow solid (116mg, 93%).
MS(ESI,pos.ion)m/z:390.2[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.30(s,1H),7.77(d,J＝2.0Hz,1H),7.60(d,J＝8.8Hz,1H),7.41-7.39(m,1H),7.37(t,J＝8.0Hz,1H),7.32(dd,J＝8.8,2.0Hz,1H),7.30(d,J＝7.8Hz,1H),7.12(dd,J＝8.3,2.1Hz,1H),3.86(s,3H),3.12-3.06(m,4H),2.83-2.76(m,4H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm)152.2,144.3,136.8,136.0,130.5,127.4,124.9,123.7,119.5,118.3,116.0,113.9,113.8,111.7,49.1,45.7,34.0.
Example 9 Synthesis of 5-chloro-1- (difluoromethyl) -3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000411
Step 1) tert-butyl 4- (3- ((5-chloro-1- (difluoromethyl) -1H-indol-3-yl) sulfonyl) phenyl) piperazine-1- Synthesis of carboxylic acid esters
The title compound of this step was prepared by the method described in reference to example 3, step 1, namely tert-butyl 4- (3- ((5-chloro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (600mg, 1.26mmol), sodium difluorochloroacetate (383 mg, 2.49mmol) and sodium hydride (60%, 66mg, 1.65mmol) were reacted in N, N-dimethylformamide (5 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a pale yellow solid (470mg, 71%).
MS(ESI,pos.ion)m/z:469.7[M+H-56] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.01(s,1H),7.96(d,J＝1.8Hz,1H),7.54(dd,J＝7.9,5.5Hz,2H),7.47(d,J＝7.8Hz,1H),7.43-7.34(m,2H),7.27(t,J＝60.0Hz,1H),7.08(dd,J＝8.1,2.0Hz,1H),3.66-3.55(m,4H),3.29-3.17(m,4H),1.50(s,9H).
Step 2) Synthesis of 5-chloro-1- (difluoromethyl) -3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound of this step was prepared by the method described in step 3 of example 2, i.e., tert-butyl 4- (3- ((5-chloro-1- (difluoromethyl) -1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (470mg, 0.89mmol), ethyl hydrogen chloride solution (2m, 4 mL) was reacted in dichloromethane (10 mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a pale yellow solid (181mg, 47.5%).
MS(ESI,pos.ion)m/z:425.8[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.65(s,1H),8.02(t,J＝58.6Hz,1H),7.86(d,J＝2.0Hz,1H),7.79(d,J＝8.8Hz,1H),7.48(dd,J＝8.8,2.1Hz,1H),7.46-7.44(m,1H),7.42(t,J＝7.9Hz,1H),7.38(d,J＝7.9Hz,1H),7.18(dd,J＝8.2,1.8Hz,1H),3.15-3.08(m,4H),2.86-2.78(m,4H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm)152.4,142.8,132.9,132.4,130.8,129.2,125.9,125.5,120.1,119.3,119.2,116.4,114.9,112.1,110.9(t,J＝246.9Hz),49.0,45.7.
Example 10 Synthesis of 5-chloro-1-cyclopropyl-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000421
Step 1) tert-butyl 4- (3- ((1-cyclopropyl-5-chloro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylic acid Synthesis of esters
The title compound of this step was prepared by the method described in step 1 of example 4, i.e. tert-butyl 4- (3- ((5-chloro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (400mg, 0.84mmol), cyclopropylboronic acid (145mg, 1.60mmol), copper acetate (153mg, 0.82mmol) and 2,2' -bipyridine (131mg, 0.82mmol) were reacted in 1,2-dichloroethane (5 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a white solid (316mg, 72.8%).
MS(ESI,pos.ion)m/z:460.2[M+H-56] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.92(d,J＝1.8Hz,1H),7.82(s,1H),7.56(d,J＝1.9Hz,1H),7.51(d,J＝8.8Hz,1H),7.45(d,J＝7.8Hz,1H),7.36(t,J＝8.0Hz,1H),7.28(dd,J＝8.7,2.0Hz,1H),7.03(dd,J＝8.2,1.9Hz,1H),3.62-3.55(m,4H),3.41(tt,J＝7.1,3.8Hz,1H),3.24-3.16(m,4H),1.51(s,9H),1.18(q,J＝7.1Hz,2H),1.08-1.03(m,2H).
Step 2) Synthesis of 5-chloro-1-cyclopropyl-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (3- ((1-cyclopropyl-5-chloro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (292mg, 0.56mmol), ethyl hydrogen chloride acetate solution (2m, 4 mL) was reacted in dichloromethane (10 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (206mg, 87.5%).
MS(ESI,pos.ion)m/z:416.2[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.29(s,1H),7.78(d,J＝1.8Hz,1H),7.69(d,J＝8.8Hz,1H),7.43(s,1H),7.37(t,J＝8.0Hz,1H),7.33-7.29(m,2H),7.12(dd,J＝8.0,1.3Hz,1H),3.62-3.53(m,1H),3.14-3.05(m,4H),2.86-2.77(m,4H),1.09-1.07(m,4H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm)152.2,144.1,136.6,135.6,130.5,127.7,125.1,124.0,119.5,118.5,116.2,114.5,114.1,111.9,49.0,45.8,28.5,6.5.
Example 11 Synthesis of 5-chloro-1-ethyl-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000431
Step 1) tert-butyl 4- (3- ((1-ethyl-5-chloro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate Synthesis of (2)
The title compound of this step was prepared by the method described in reference to example 5, step 1, namely tert-butyl 4- (3- ((5-chloro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (350mg, 0.73mmol), iodoethane (0.23ml, 2.8mmol) and sodium hydride (60%, 30mg, 1.19mmol) were reacted in N, N-dimethylformamide (5 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a white solid (357mg, 97%).
MS(ESI,pos.ion)m/z:447.8[M+H-56] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.95(d,J＝1.2Hz,1H),7.83(s,1H),7.57(s,1H),7.44(d,J＝7.8Hz,1H),7.35(t,J＝8.0Hz,1H),7.30(d,J＝8.8Hz,1H),7.26(dd,J＝8.9,1.7Hz,1H),7.03(dd,J＝8.2,2.1Hz,1H),4.19(q,J＝7.3Hz,2H),3.62-3.56(m,4H),3.25-3.18(m,4H),1.53(t,J＝7.4Hz,3H),1.51(s,9H).
Step 2) Synthesis of 5-chloro-1-ethyl-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (3- ((1-ethyl-5-chloro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (350mg, 0.69mmol), ethyl hydrogen chloride solution (2m, 4 mL) was reacted in dichloromethane (10 mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a pale yellow solid (261mg, 94%).
MS(ESI,pos.ion)m/z:404.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.94(d,J＝1.2Hz,1H),7.85(s,1H),7.57(s,1H),7.51(d,J＝7.7Hz,1H),7.38(t,J＝8.0Hz,1H),7.31(d,J＝8.8Hz,1H),7.27(dd,J＝9.0,1.5Hz,1H),7.04(dd,J＝8.1,1.7Hz,1H),4.20(q,J＝7.3Hz,2H),3.42-3.30(m,4H),3.28-3.26(m,4H),1.53(t,J＝7.3Hz,3H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)151.7,144.0,134.9,132.8,130.0,128.4,125.4,124.1,119.6,117.4,115.2,113.3,111.5,49.1,45.5,42.2,15.0.
Example 12 Synthesis of 5-chloro-1-isopropyl-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000432
Step 1) tert-butyl 4-(3- ((1-isopropyl-5-chloro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylic acid Synthesis of esters
This step titled compound was prepared by the procedure described in example 6, step 1, i.e., tert-butyl 4- (3- ((5-chloro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (350mg, 0.73mmol), 2-iodopropane (0.23ml, 2.8mmol) and sodium hydride (60%, 30mg, 1.19mmol) were reacted in N, N-dimethylformamide (5 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the titled compound as a white solid (298mg, 79%).
MS(ESI,pos.ion)m/z:462.2[M+H-56] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.94(d,J＝1.8Hz,1H),7.92(s,1H),7.58(d,J＝1.8Hz,1H),7.44(d,J＝7.9Hz,1H),7.38-7.32(m,2H),7.26(dd,J＝8.8,1.9Hz,1H),7.03(dd,J＝8.1,2.0Hz,1H),4.70-4.60(m,1H),3.62-3.57(m,4H),3.24-3.19(m,4H),1.57(d,J＝6.7Hz,6H),1.50(s,9H).
Step 2) Synthesis of 5-chloro-1-isopropyl-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (3- ((1-isopropyl-5-chloro-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (290mg, 0.56mmol), ethyl hydrogen chloride acetate solution (2m, 4 mL) was reacted in dichloromethane (10 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a pale yellow solid (222mg, 95%).
MS(ESI,pos.ion)m/z:418.9[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.95(d,J＝1.6Hz,1H),7.91(s,1H),7.58(s,1H),7.41(d,J＝7.7Hz,1H),7.36-7.31(m,2H),7.26(dd,J＝8.8,1.7Hz,1H),7.03(dd,J＝8.2,2.3Hz,1H),4.69-4.61(m,1H),3.24-3.19(m,4H),3.07-3.01(m,4H),1.57(d,J＝6.7Hz,6H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)152.0,143.9,134.7,130.0,129.9,128.3,125.4,123.9,119.6,119.4,117.0,115.2,113.0,111.6,49.7,48.6,45.9,22.6.
Example 13 Synthesis of 5-bromo-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000441
Step 1) Synthesis of 5-bromo-3- ((3-nitrophenyl) thio) -1H-indole
The title compound was prepared as described in example 1, step 2, by reacting 5-bromoindole (4.1g, 20.9mmol), 3-nitrophenylsulfonyl hydrazide (3.0 g, 13.8mmol), iodine (0.35g, 1.4mmol) in ethanol (30 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 20/1) to give the title compound as a yellow solid (4.8g, 99.5%).
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.70(s,1H),7.94-7.91(m,1H),7.89(d,J＝1.9Hz,1H),7.71(s,1H),7.58(d,J＝2.7Hz,1H),7.40-7.35(m,4H).
Step 2) Synthesis of 5-bromo-3- ((3-nitrophenyl) sulfonyl) -1H-indole
The title compound was prepared as described in example 1, step 3, by reacting 5-bromo-3- ((3-nitrophenyl) thio) -1H-indole (4.8g, 13.7mmol), potassium peroxymonosulfonate (25.4g, 40.5mmol), sodium bicarbonate (3.5g, 42mmol) in acetone (40 mL) and water (20 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a tan solid (4.93g, 94.1%).
MS(ESI,pos.ion)m/z:381.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)12.66(s,1H),8.63(t,J＝1.9Hz,1H),8.46-8.42(m,3H),7.95(d,J＝1.7Hz,1H),7.89(t,J＝8.0Hz,1H),7.51(d,J＝8.7Hz,1H),7.43-7.40(m,1H).
Step 3) Synthesis of 3- ((5-bromo-1H-indol-3-yl) sulfonyl) aniline
The title compound of this step was prepared as described in example 1, step 4, by reacting 5-bromo-3- ((3-nitrophenyl) sulfonyl) -1H-indole (4.93g, 12.9mmol), ammonium chloride (1.38g, 25.8mmol), iron powder (2.89g, 51.7mmol) in tetrahydrofuran (20 mL), ethanol (20 mL), and water (5 mL), and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a yellow solid (3.6g, 79.3%).
MS(ESI,pos.ion)m/z:350.8[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)12.41(s,1H),8.17(s,1H),7.85(s,1H),7.49(d,J＝8.6Hz,1H),7.38(d,J＝8.6Hz,1H),7.20-7.13(m,2H),7.03(d,J＝7.3Hz,1H),6.72(d,J＝7.6Hz,1H).
Step 4) Synthesis of 5-bromo-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound was prepared as described in example 1, step 5, by reacting 3- ((5-bromo-1H-indol-3-yl) sulfonyl) aniline (3.6 g,10.0 mmol), bis (2-chloroethyl) amine hydrochloride (2.2 g,12.0 mmol) in chlorobenzene (30 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a brown solid (4.2g, 97.5%).
MS(ESI,pos.ion)m/z:419.8[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.25(s,1H),7.77(s,1H),7.54(d,J＝8.2Hz,1H),7.48(s,1H),7.43-7.37(m,2H),7.25(d,J＝8.4Hz,1H),7.18(d,J＝7.2Hz,1H),3.45-3.35(m,4H),3.15-3.07(m,4H).
Example 14 Synthesis of 5-bromo-1-methyl-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000451
Step 1) Synthesis of tert-butyl 4- (3- ((5-bromo-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate
The title compound of this step was prepared as described in example 2, step 1, by reacting 5-bromo-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole (4.2g, 9.99mmol), montmorillonite (0.6 g) and di-tert-butyl dicarbonate (3.3g, 15.0 mmol) in dichloromethane (30 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a pale yellow solid (3.43g, 66%).
MS(ESI,pos.ion)m/z:464.1[M+H-56] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.42(s,1H),8.09(d,J＝1.2Hz,1H),7.88(d,J＝3.0Hz,1H),7.55(s,1H),7.45(d,J＝7.8Hz,1H),7.39-7.34(m,2H),7.31(d,J＝8.7Hz,1H),7.05-7.02(m,1H),3.61-3.58(m,4H),3.22-3.20(m,4H),1.51(s,9H).
Step 2) tert-butyl 4- (3- ((5-bromo-1-methyl-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate Synthesis of (2)
The title compound was prepared as described in example 2, step 2, by reacting tert-butyl 4- (3- ((5-bromo-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (0.4g, 0.77mmol), sodium hydride (38mg, 0.95mmol) and iodomethane (218mg, 1.53mmol) in N, N-dimethylformamide (5 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a yellow sticky (372mg, 90.5%).
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.12(d,J＝1.7Hz,1H),7.74(s,1H),7.57(s,1H),7.45-7.41(m,2H),7.35(t,J＝8.0Hz,1H),7.22(d,J＝8.8Hz,1H),7.04-7.01(m,1H),3.84(s,3H),3.61-3.58(m,4H),3.23-3.20(m,4H),1.50(s,9H).
Step 3) Synthesis of 5-bromo-1-methyl-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound was prepared by reacting tert-butyl 4- (3- ((5-bromo-1-methyl-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (372mg, 0.70mmol), ethyl hydrogen chloride solution (2m, 4 mL) in dichloromethane (5 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) as a pale yellow solid (220mg, 72.7%) as described in step 3 of example 2.
MS(ESI,pos.ion)m/z:434.1[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.12(d,J＝1.7Hz,1H),7.73(s,1H),7.56-7.5(m,1H),7.42-7.38(m,2H),7.33(t,J＝8.0Hz,1H),7.20(d,J＝8.7Hz,1H),7.03-7.01(m,1H),3.81(s,3H),3.23-3.22(m,4H),3.07-3.05(m,4H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)151.9,143.9,136.0,134.3,129.9,126.7,125.8,122.5,119.5,117.1,116.0,115.1,113.1,111.8,49.4,45.7,33.8.
Example 15 Synthesis of 5-bromo-1- (difluoromethyl) -3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000461
Step 1) tert-butyl 4- (3- ((1- (difluoromethyl) -5-bromo-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1- Synthesis of carboxylic acid esters
The title compound of this step was prepared by the method described in example 3, step 1, i.e. tert-butyl 4- (3- ((5-bromo-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (600mg, 1.15mmol), sodium difluorochloroacetate (352mg, 2.29mmol) and sodium hydride (60%, 57mg, 1.43mmol) were reacted in N, N-dimethylformamide (5 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a pale yellow solid (513mg, 78%).
MS(ESI,pos.ion)m/z:514.2[M+H-56] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.13(d,J＝1.3Hz,1H),7.98(s,1H),7.56(s,1H),7.53-7.45(m,3H),7.41(d,J＝8.1Hz,1H),7.25(t,J＝52.0Hz,1H),7.09-7.07(m,1H),3.62-3.59(m,4H),3.25-3.22(m,4H),1.50(s,9H).
Step 2) 5-bromo-1- (difluoromethyl) -3- ((3- (piperazin-1-yl) benzeneYl) Synthesis of sulfonyl) -1H-indoles
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (3- ((1- (difluoromethyl) -5-bromo-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (513mg, 0.90mmol), ethyl hydrogen chloride solution (2m, 4 mL) was reacted in dichloromethane (10 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a pale yellow solid (309mg, 73.1%).
MS(ESI,pos.ion)m/z:469.7[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.14(d,J＝1.5Hz,1H),7.99(s,1H),7.56-7.55(m,1H),7.51-7.46(m,2H),7.43-7.42(m,1H),7.39(d,J＝8.1Hz,1H),7.26(t,J＝63.0Hz,1H),7.08-7.07(m,1H),3.24-3.22(m,4H),3.05-3.04(m,4H).
Example 16 Synthesis of 5-bromo-1-cyclopropyl-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000471
Step 1) tert-butyl 4- (3- ((1-cyclopropyl-5-bromo-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylic acid Synthesis of esters
The title compound of this step was prepared by the method described in example 4, step 1, i.e. tert-butyl 4- (3- ((5-bromo-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (500mg, 0.96mmol), cyclopropylboronic acid (165mg, 1.82mmol), copper acetate (175mg, 0.96mmol) and 2,2' -bipyridine (150mg, 0.94mmol) were reacted in 1,2-dichloroethane (5 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a pale yellow solid (351mg, 65%).
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.07(d,J＝1.2Hz,1H),7.77(s,1H),7.55(s,1H),7.46-7.38(m,3H),7.34(t,J＝8.0Hz,1H),7.02-7.00(m,1H),3.59-3.56(m,4H),3.41-3.36(m,1H),3.21-3.19(m,4H),1.48(s,9H),1.19-1.14(m,2H),1.05-1.01(m,2H).
Step 2) Synthesis of 5-bromo-1-cyclopropyl-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (3- ((1-cyclopropyl-5-bromo-1H-indol-3-yl) sulfonyl) phenyl) piperazine-1-carboxylate (351mg, 0.63mmol), ethyl hydrogen chloride acetate solution (2m, 4 mL) was reacted in dichloromethane (10 mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (210mg, 72.8%).
MS(ESI,pos.ion)m/z:460.0[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.10(d,J＝1.5Hz,1H),7.79(s,1H),7.57(s,1H),7.46(d,J＝8.7Hz,1H),7.41-7.39(m,2H),7.34(t,J＝8.0Hz,1H),7.04-7.02(m,1H),3.41-3.38(m,1H),3.23-3.22(m,4H),3.06-3.04(m,4H),1.19-1.15(m,2H),1.05-1.03(m,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)152.0,143.7,136.8,133.7,129.9,126.8,125.8,122.6,119.4,117.1,116.3,115.3,113.1,112.8,49.5,45.8,28.0,6.4.
Example 17 Synthesis of 6-fluoro-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000472
Step 1) Synthesis of 6-fluoro-3- ((3-nitrophenyl) thio) -1H-indole
The title compound was prepared as described in example 1, step 2, by reacting 6-fluoroindole (2.49g, 18.4 mmol), 3-nitrophenylsulfonyl hydrazide (2.0 g, 9.2mmol), iodine (0.23g, 0.92mmol) in ethanol (30 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 20/1) to give the title compound as a yellow solid (2.12g, 97.2%). MS (ESI, neg.ion) m/z:287.0[ M-H ]] - ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.23-8.15(m,2H),7.84(s,1H),7.74(dd,J＝8.8,5.2Hz,1H),7.70-7.59(m,2H),7.52-7.46(m,1H),7.25-7.17(m,1H).
Step 2) Synthesis of 6-fluoro-3- ((3-nitrophenyl) sulfonyl) -1H-indole
The title compound was prepared as described in example 1, step 3, by reacting 6-fluoro-3- ((3-nitrophenyl) thio) -1H-indole (2.0g, 6.94mmol), potassium peroxymonosulfonate (12.8g, 20.8mmol), sodium bicarbonate (1.75g, 20.8mmol) in acetone (30 mL) and water (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a yellow solid (2.05g, 92.2%).
MS(ESI,pos.ion)m/z:321.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.62(s,1H),8.41-8.34(m,3H),7.92-7.82(m,1H),7.80(s,1H),7.33(d,J＝8.4Hz,1H),7.11(d,J＝7.8Hz,1H).
Step 3) Synthesis of 3- ((6-fluoro-1H-indol-3-yl) sulfonyl) aniline
The title compound of this step was prepared as described in example 1, step 4, by reacting 6-fluoro-3- ((3-nitrophenyl) sulfonyl) -1H-indole (2.0 g, 6.24mmol), ammonium chloride (0.76g, 14.2mmol), iron powder (1.74g, 31.2mmol) in tetrahydrofuran (20 mL), ethanol (10 mL), and water (2 mL), and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a yellow solid (1.32g, 72.9%).
MS(ESI,pos.ion)m/z:291.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.10(s,1H),7.73(dd,J＝8.4,5.4Hz,1H),7.32(d,J＝9.4Hz,1H),7.20-7.13(m,2H),7.11-7.02(m,2H),6.72(d,J＝7.8Hz,1H),5.57(s,2H).
Step 4) Synthesis of 6-fluoro-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound was prepared as described in example 1, step 5 by reacting 3- ((6-fluoro-1H-indol-3-yl) sulfonyl) aniline (1.12g, 3.86mmol), bis (2-chloroethyl) amine hydrochloride (1.03g, 5.79mmol) in chlorobenzene (15 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a yellow solid (815mg, 58.7%).
MS(ESI,pos.ion)m/z:360.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.16(s,1H),7.77(dd,J＝9.0,5.4Hz,1H),7.40(s,1H),7.36(d,J＝7.8Hz,1H),7.31(dd,J＝14.2,4.8Hz,2H),7.15-7.11(m,1H),7.08(d,J＝1.2Hz,1H),3.15-3.12(m,4H),2.90-2.86(m,4H).
Example 18 Synthesis of 6-chloro-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000481
Step 1) Synthesis of 6-chloro-3- ((3-nitrophenyl) thio) -1H-indole
The title compound was prepared as described in example 1, step 2, by reacting 6-chloroindole (2.1g, 14.0 mmol), 3-nitrophenylsulfonyl hydrazide (2.0 g, 9.2mmol), iodine (0.23g, 0.92mmol) in ethanol (30 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 20/1) to give the title compound as a yellow solid (2.8g, 99.8%).
MS(ESI,neg.ion)m/z:303.0[M-H] - ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.65(s,1H),7.93-7.91(m,2H),7.57(d,J＝2.6Hz,1H),7.50-7.46(m,2H),7.39-7.32(m,2H),7.19-7.16(m,1H).
Step 2) Synthesis of 6-chloro-3- ((3-nitrophenyl) sulfonyl) -1H-indole
This step was performed as described in example 1, step 3, using 6-chloro-3- ((3-nitrophenyl) thio) -1H-indole (2.8g, 9.2mmol), potassium peroxomonosulfonate (16.9g, 26.9mmol), sodium bicarbonate (2.3g, 27mmol) in acetone (30 mL) and water (10 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1), concentrated and dried to give the title compound as a yellow solid (2.7g, 87.3%).
MS(ESI,pos.ion)m/z:337.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.63-8.62(m,1H),8.44-8.39(m,3H),7.87(t,J＝8.0Hz,1H),7.82(d,J＝8.6Hz,1H),7.58(d,J＝1.7Hz,1H),7.29-7.27(m,1H).
Step 3) Synthesis of 3- ((6-chloro-1H-indol-3-yl) sulfonyl) aniline
The title compound of this step was prepared as described in example 1, step 4, by reacting 6-chloro-3- ((3-nitrophenyl) sulfonyl) -1H-indole (2.7g, 6.76mmol), ammonium chloride (0.76g, 14.2mmol), iron powder (1.34g, 24.0 mmol) in tetrahydrofuran (20 mL), ethanol (10 mL) and water (2 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a yellow solid (668mg, 27.2%).
MS(ESI,pos.ion)m/z:307.0[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.13(s,1H),7.73(d,J＝8.6Hz,1H),7.56(d,J＝1.8Hz,1H),7.25-7.22(m,1H),7.16(t,J＝7.9Hz,1H),7.12(t,J＝1.9Hz,1H),7.03(d,J＝7.9Hz,1H),6.72-6.70(m,1H),5.58(s,2H).
Step 4) Synthesis of 6-chloro-3- ((3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound was prepared as described in example 1, step 5, by reacting 3- ((6-chloro-1H-indol-3-yl) sulfonyl) aniline (300mg, 0.98mmol), bis (2-chloroethyl) amine hydrochloride (209mg, 1.15mmol) in chlorobenzene (5 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a tan solid (138mg, 37.5%).
MS(ESI,pos.ion)m/z:376.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.20(s,1H),7.79(d,J＝8.6Hz,1H),7.56(d,J＝1.7Hz,1H),7.41-7.40(m,1H),7.36(t,J＝8.0Hz,1H),7.32-7.31(m,1H),7.25-7.23(m,1H),7.13-7.12(m,1H),3.13-3.11(m,4H),2.87-2.85(m,4H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm)152.1,144.3,137.2,132.9,130.5,128.4,122.7,122.4,120.5,119.5,116.4,115.8,113.0,112.0,48.5,45.3.
Example 19 Synthesis of 5-chloro-1-methyl-3- ((4-methyl-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000501
Step 1) Synthesis of 5- ((5-chloro-1H-indol-3-yl) thio) -2-methylaniline
The title compound was prepared as described in example 1, step 2 by reacting 5-chloroindole (2.45g, 16.2mmol), 2,2,2-trifluoro-N- (5- (sulfonyl hydrazide) -2-methylphenyl) acetamide (3.0g, 10.1mmol), iodine (0.27g, 1.1mmol) in ethanol (30 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a yellow solid (1.80g, 62%).
MS(ESI,pos.ion)m/z:289.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.36(s,1H),7.66(d,J＝1.7Hz,1H),7.46(d,J＝2.5Hz,1H),7.32(d,J＝8.6Hz,1H),7.19(dd,J＝8.6,1.9Hz,1H),7.02(d,J＝1.3Hz,1H),6.95(dd,J＝8.2,1.9Hz,1H),6.55(d,J＝8.2Hz,1H),2.10(s,3H).
Step 2) Synthesis of 5-chloro-3- ((4-methyl-3- (piperazin-1-yl) phenyl) thio) -1H-indole
The title compound was prepared as described in example 1, step 5, by reacting 5- ((5-chloro-1H-indol-3-yl) thio) -2-methylaniline (1.5 g,5.2 mmol), bis (2-chloroethyl) amine hydrochloride (1.1g, 6.2 mmol) in chlorobenzene (15 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a red brown solid (780mg, 42%).
MS(ESI,pos.ion)m/z:358.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.62(s,1H),7.64(d,J＝1.8Hz,1H),7.50(s,1H),7.36(d,J＝8.6Hz,1H),7.22(dd,J＝8.6,1.9Hz,1H),7.02(d,J＝1.9Hz,1H),6.91(dd,J＝8.5,2.1Hz,1H),6.85(d,J＝8.4Hz,1H),3.02-2.99(m,4H),2.84-2.80(m,4H),2.22(s,3H).
Step 3) preparation of tert-butyl 4- (5- ((5-chloro-1H-indol-3-yl) thio) -2-methylphenyl) piperazine-1-carboxylate Synthesis of
The title compound of this step was prepared as described in example 2, step 1, by reacting 5-chloro-3- ((4-methyl-3- (piperazin-1-yl) phenyl) thio) -1H-indole (0.61g, 1.7mmol), montmorillonite (0.31 g) and di-tert-butyl dicarbonate (0.66g, 3.0mmol) in dichloromethane (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 5/1) to give the title compound as a pale yellow solid (357mg, 46%).
MS(ESI,pos.ion)m/z:458.3[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.72(s,1H),7.63(d,J＝1.2Hz,1H),7.50(d,J＝2.5Hz,1H),7.36(d,J＝8.6Hz,1H),7.22(dd,J＝8.6,1.8Hz,1H),7.02(d,J＝1.5Hz,1H),6.89(dd,J＝8.3,1.8Hz,1H),6.82(d,J＝8.4Hz,1H),3.57-3.53(m,4H),2.80-2.76(m,4H),2.22(s,3H),1.50(s,9H).
Step 4) tert-butyl 4- (5- ((5-chloro-1H-indol-3-yl) sulfonyl) -2-methylphenyl) piperazine-1-carboxylate Synthesis of (2)
The title compound of this step was prepared as described in example 1, step 3, by reacting tert-butyl 4- (5- ((5-chloro-1H-indol-3-yl) thio) -2-methylphenyl) piperazine-1-carboxylate (0.36g, 0.79mmol), potassium peroxymonosulfonate (2.0g, 3.2mmol), sodium bicarbonate (0.3g, 3.6 mmol) in acetone (10 mL) and water (3 mL), and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a red solid (333mg, 86%).
MS(ESI,pos.ion)m/z:490.3[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)9.58(s,1H),7.88(d,J＝1.4Hz,1H),7.87(d,J＝2.9Hz,1H),7.81-7.76(m,2H),7.34(d,J＝8.7Hz,1H),7.21(dd,J＝8.7,1.8Hz,1H),7.00(d,J＝8.4Hz,1H),3.58-3.55(m,4H),2.89-2.86(m,4H),2.32(s,3H),1.50(s,9H).
Step 5) tert-butyl 4- (5- ((5-chloro-1-methyl-1H-indol-3-yl) sulfonyl) -2-methylphenyl) piperazine- Synthesis of 1-carboxylic acid esters
The title compound of this step was prepared by the method described in example 2, step 2, i.e. tert-butyl 4- (5- ((5-chloro-1H-indol-3-yl) sulfonyl) -2-methylphenyl) piperazine-1-carboxylate (0.13g, 0.27mmol), sodium hydride (24mg, 0.6mmol) and iodomethane (200mg, 1.4mmol) were reacted in N, N-dimethylformamide (5 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a yellow sticky substance (112mg, 82%).
MS(ESI,pos.ion)m/z:504.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.95-7.93(m,1H),7.84-7.79(m,2H),7.76(s,1H),7.28-7.27(m,2H),7.01(d,J＝8.3Hz,1H),3.84(s,3H),3.59-3.55(m,4H),2.90-2.86(m,4H),2.34(s,3H),1.49(s,9H).
Step 6) Synthesis of 5-chloro-1-methyl-3- ((4-methyl-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (5- ((5-chloro-1-methyl-1H-indol-3-yl) sulfonyl) -2-methylphenyl) piperazine-1-carboxylate (110mg, 0.22mmol), ethyl hydrogen chloride acetate solution (2m, 4 mL) was reacted in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a pale yellow solid (88mg, 99%).
MS(ESI,pos.ion)m/z:404.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.93(s,1H),7.80(dd,J＝8.4,2.0Hz,1H),7.77(d,J＝1.7Hz,1H),7.74(s,1H),7.26-7.22(m,2H),7.01(d,J＝8.5Hz,1H),3.82(s,3H),3.03-2.99(m,4H),2.91-2.87(m,4H),2.32(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)155.9,136.2,135.6,134.2,132.9,129.5,128.3,125.6,125.1,124.0,119.4118.9,115.7,111.4,52.5,46.3,33.8,18.5.
EXAMPLE 20 Synthesis of 5-chloro-1- (difluoromethyl) -3- ((4-methyl-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000511
Step 1) tert-butyl 4- (5- ((5-chloro-1- (difluoromethyl) -1H-indol-3-yl) sulfonyl) -2-methylphenyl) Synthesis of piperazine-1-carboxylic acid esters
The title compound of this step was prepared by the method described in step 1 of example 3, i.e. tert-butyl 4- (5- ((5-chloro-1H-indol-3-yl) sulfonyl) -2-methylphenyl) piperazine-1-carboxylate (150mg, 0.31mmol), sodium difluorochloroacetate (130mg, 0.84mmol) and sodium hydride (24mg, 0.6 mmol) were reacted in N, N-dimethylformamide (5 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give the title compound as a pink solid (112mg, 67%).
MS(ESI,pos.ion)m/z:540.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.00(s,1H),7.95(d,J＝1.8Hz,1H),7.85(dd,J＝8.4,2.2Hz,1H),7.81(d,J＝1.9Hz,1H),7.52(d,J＝8.9Hz,1H),7.37(dd,J＝8.8,1.9Hz,1H),7.26(t,J＝60.2Hz,1H),7.05(d,J＝8.4Hz,1H),3.59-3.56(m,4H),2.93-2.88(m,4H),2.35(s,3H),1.50(s,9H).
Step 2) 5-chloro-1- (difluoromethyl) -3- ((4-methyl-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of (2)
The title compound was prepared by reaction of tert-butyl 4- (5- ((5-chloro-1- (difluoromethyl) -1H-indol-3-yl) sulfonyl) -2-methylphenyl) piperazine-1-carboxylate (112mg, 0.21mmol), ethyl hydrogen chloride in ethyl acetate (2m, 4 mL) in dichloromethane (5 mL) and purification of the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) according to the procedure described in example 2, step 3 to give the title compound as a pale yellow solid (91mg, 99%).
MS(ESI,pos.ion)m/z:440.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.00(s,1H),7.95(s,1H),7.84(d,J＝8.0Hz,1H),7.79(s,1H),7.52(d,J＝8.7Hz,1H),7.36(d,J＝8.8Hz,1H),7.27(t,J＝60.1Hz,1H),7.05(d,J＝8.4Hz,1H),3.04-3.00(m,4H),2.95-2.91(m,4H),2.34(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)156.6,134.5,133.0,132.5,130.2,129.9,128.9,126.1,125.8,125.7,121.2,120.2,119.0,112.9,109.8(t,J＝251.6Hz),52.5,46.2,18.7.
Example 21 Synthesis of 5-methoxy-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000521
Step 1) synthesis of 4-methoxy-3- (4- (2,2,2-trichloroacetyl) piperazine-1-yl) benzenesulfonyl hydrazide
4-methoxy-3- [4- (2,2,2-trichloroacetyl) piperazin-1-yl ] benzenesulfonyl chloride (11g, 25.2mmol) and tetrahydrofuran (20 mL) were added to a 100mL single-neck round bottom flask at 0 deg.C, hydrazine hydrate (6.5mL, 130mmol) was added, and the mixture was transferred to 25 deg.C for 2 hours. Water (200 mL) was added and filtered to give a solid which was dried to give the title compound as a white solid (10 g, 92%).
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.47(dd,J＝8.5,2.0Hz,1H),7.29(d,J＝2.0Hz,1H),7.16(d,J＝8.6Hz,1H),3.89(brs,7H),3.13(brs,4H).
Step 2) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-methoxy-1H-indol-3-yl) thio) phenyl) Synthesis of piperazin-1-yl) acetyl
The title compound was prepared as described in example 1, step 2 by reacting 5-methoxyindole (0.5g, 3.4 mmol), 4-methoxy-3- (4- (2,2,2-trichloroacetyl) piperazin-1-yl) benzenesulfonylhydrazide (1.76g, 4.1mmol), iodine (86mg, 0.34mmol) in ethanol (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a white solid (851mg, 49%).
MS(ESI,pos.ion)m/z:514.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.48(s,1H),7.42(d,J＝2.6Hz,1H),7.30(d,J＝8.8Hz,1H),7.04(d,J＝2.3Hz,1H),6.89(dd,J＝8.8,2.4Hz,1H),6.81(s,1H),6.80-6.76(m,1H),6.69(d,J＝8.5Hz,1H),4.00-3.79(m,7H),3.79(s,3H),3.04(brs,4H).
Step 3) 1- (2-methoxy-5- ((5-methoxy-1H-indol-3-yl) sulfonyl) phenyl) -4- (2,2,2-tris Synthesis of chloroacetyl) piperazine 1-oxideThe title compound of this step was prepared as described in example 1, step 3, by reacting 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-methoxy-1H-indol-3-yl) thio) phenyl) piperazin-1-yl) acetyl (0.85g, 1.66mmol), potassium peroxymonosulfonate (4.06g, 6.64mmol), sodium bicarbonate (0.56g, 6.64mmol) in acetone (15 mL) and water (5 mL), and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a white solid (840mg, 90%).
MS(ESI,pos.ion)m/z:562.1[M+H] + .
Step 4) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-methoxy-1H-indol-3-yl) sulfonyl) benzene Synthesis of yl) piperazin-1-yl) acetyl
1- (2-methoxy-5- ((5-methoxy-1H-indol-3-yl) sulfonyl) phenyl) -4- (2,2,2-trichloroacetyl) piperazine 1-oxide (0.5g, 0.89mmol) and tetrahydrofuran (10 mL) were charged at 25 ℃ into a 50mL single neck round bottom flask, triethylamine (0.12mL, 0.89mmol) and cuprous iodide (0.17g, 0.89mmol) were added, and the reaction was continued for 4.5 hours. The reaction was stopped, dried under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1), concentrated and dried to give the title compound as a pale yellow solid (178mg, 40%).
MS(ESI,pos.ion)m/z:546.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.12(s,1H),7.80(d,J＝3.0Hz,1H),7.72(dd,J＝8.5,2.1Hz,1H),7.50(d,J＝2.1Hz,1H),7.32(d,J＝2.3Hz,1H),7.29(d,J＝8.9Hz,1H),6.91(s,1H),6.89(s,1H),4.11-3.87(m,7H),3.83(s,3H),3.11(t,J＝4.5Hz,4H).
Step 5) Synthesis of 5-methoxy-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-methoxy-1H-indol-3-yl) sulfonyl) phenyl) piperazin-1-yl) acetyl (0.35g, 0.64mmol), tetrahydrofuran (10 mL) were added to a 50mL single neck round bottom flask at 25 deg.C, potassium hydroxide (0.11g, 1.92mmol, dissolved in 2mL water) was added and the reaction was continued for 24 hours. Most of the organic solvent was removed by spin-drying under reduced pressure, dichloromethane (20 mL) was added, the organic phase was separated, spin-dried under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1), concentrated and dried to give the title compound as a pale yellow solid (227mg, 88%).
MS(ESI,pos.ion)m/z:402.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.04(s,1H),7.57(dd,J＝8.5,1.6Hz,1H),7.40(s,1H),7.38(s,1H),7.20(d,J＝1.9Hz,1H),7.05(d,J＝8.6Hz,1H),6.87(dd,J＝8.8,2.0Hz,1H),3.79(s,3H),3.78(s,3H),2.89(brs,4H),2.85(brs,4H)；
13 C NMR(100MHz,DMSO-d 6 )δ(ppm)155.6,155.5,142.2,135.8,131.7,131.4,124.3,121.7,115.8,115.7,114.2,113.6,112.2,100.7,56.3,55.9,51.2,45.8.
Example Synthesis of 5-methoxy-3- ((4-methoxy-3- (4-methylpiperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000531
5-methoxy-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole (82mg, 0.2mmol) and methanol (5 mL) were charged to a 50mL single-neck round bottom flask at 25 deg.C, paraformaldehyde (18mg, 0.6mmol) was added, followed by sodium cyanoborohydride (32mg, 0.5 mmol), and the reaction was continued for 10 hours. The reaction was stopped, water (20 mL) was added, then dichloromethane (20 mL) was added for extraction, the phases were separated, the organic phase was spun dry under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1), concentrated and dried to give the title compound as a pale yellow solid (76mg, 90%).
MS(ESI,pos.ion)m/z:416.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.03(s,1H),7.56(dd,J＝8.6,2.1Hz,1H),7.39(d,J＝1.4Hz,1H),7.38(d,J＝5.0Hz,1H),7.19(d,J＝2.3Hz,1H),7.06(d,J＝8.6Hz,1H),6.87(dd,J＝8.9,2.4Hz,1H),3.80(s,3H),3.78(s,3H),2.95(brs,4H),2.43(brs,4H),2.20(s,3H)；
13 C NMR(100MHz,DMSO-d 6 )δ(ppm)155.5,155.4,141.7,135.8,131.7,131.4,124.2,121.6,115.8,115.7,114.2,113.6,112.2,100.7,56.3,55.9,55.1,50.1,46.2.
Example Synthesis of 5-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000541
Step 1) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-fluoro-1H-indol-3-yl) thio) phenyl) piperazine- Synthesis of 1-yl) acetyl
The title compound of this step was prepared as described in example 1, step 2, by reacting 5-fluoroindole (0.5g, 3.7mmol), 4-methoxy-3- (4- (2,2,2-trichloroacetyl) piperazin-1-yl) benzenesulfonylhydrazide (1.9g, 4.4mmol), iodine (94mg, 0.37mmol) in ethanol (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a white solid (1.42g, 76%).
MS(ESI,pos.ion)m/z:501.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.47(s,1H),7.31(dd,J＝8.8,4.2Hz,1H),7.19(dd,J＝9.3,2.4Hz,1H),6.93(td,J＝9.0,2.4Hz,1H),6.76-6.74(m,2H),6.69-6.65(m,1H),3.92-3.73(m,7H),3.00(brs,4H).
Step 2) 1- (2-methoxy-5- ((5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) -4- (2,2,2-trichloroethylene Synthesis of acyl) piperazine 1-oxides
The title compound of this step was prepared as described in example 1, step 3, by reacting 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-fluoro-1H-indol-3-yl) thio) phenyl) piperazin-1-yl) acetyl (1.42g, 2.82mmol), potassium peroxymonosulfonate (6.95g, 11.3 mmol), sodium bicarbonate (0.95g, 11.3 mmol) in acetone (15 mL) and water (5 mL), and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a white solid (1.43g, 92%).
MS(ESI,pos.ion)m/z:550.1[M+H] + .
Step 3) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piper ine Synthesis of oxazin-1-yl) acetyl
The title compound of this step was prepared by the method described in example 21, step 4, i.e. 1- (2-methoxy-5- ((5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) -4- (2,2,2-trichloroacetyl) piperazine 1-oxide (0.6g, 1.09mmol), cuprous iodide (0.21g, 1.09mmol), triethylamine (0.15ml, 1.09mmol) were reacted in tetrahydrofuran (10 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a white solid (0.23g, 39%).
MS(ESI,pos.ion)m/z:534.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.44(s,1H),7.88(d,J＝3.0Hz,1H),7.72(dd,J＝8.6,2.1Hz,1H),7.51(dd,J＝9.1,2.3Hz,1H),7.46(d,J＝2.1Hz,1H),7.35(dd,J＝8.9,4.2Hz,1H),7.00(td,J＝9.0,2.4Hz,1H),6.92(d,J＝8.6Hz,1H),4.06-3.86(m,7H),3.13(t,J＝4.4Hz,4H).
Step 4) Synthesis of 5-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound of this step was prepared by the method described in example 21, step 5, i.e. 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piperazin-1-yl) acetyl (0.23g, 0.43mmol), potassium hydroxide (72mg, 1.29mmol) were reacted in tetrahydrofuran (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a light yellow solid (0.111g, 66%).
MS(ESI,pos.ion)m/z:390.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.22(s,1H),7.60(dd,J＝8.6,2.1Hz,1H),7.51(dd,J＝8.9,4.5Hz,1H),7.45(dd,J＝9.5,2.4Hz,1H),7.35(d,J＝2.1Hz,1H),7.10(td,J＝9.2,2.4Hz,1H),7.06(d,J＝8.7Hz,1H),3.80(s,3H),2.90(brs,4H),2.85(brs,4H)；
13 C NMR(100MHz,DMSO-d 6 )δ(ppm)158.6(d,J＝236.6Hz),155.6,142.3,135.4,133.4,133.0,124.0(d,J＝11.0Hz),121.8,116.4(d,J＝4.5Hz),115.7,114.8(d,J＝9.8Hz),112.2,112.9(d,J＝26.1Hz),103.9(d,J＝25.3Hz),56.3,51.1,45.8.
Example Synthesis of 5-fluoro-3- ((4-methoxy-3- (4-methylpiperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000551
The title compound was prepared as described in example 22 for 5-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole (96mg, 0.25mmol), naBH 3 CN (39mg, 0.62mmol), paraformaldehyde (22mg, 0.75mmol) in methanol (5 mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as pale yellowA colored solid (93mg, 94%).
MS(ESI,pos.ion)m/z:404.1[M+H] + ；
1 HNMR(400MHz,DMSO-d 6 )δ(ppm)8.17(s,1H),7.58(dd,J＝8.5,2.1Hz,1H),7.50(dd,J＝8.9,4.5Hz,1H),7.44(dd,J＝9.6,2.4Hz,1H),7.36(d,J＝2.0Hz,1H),7.08-7.03(m,2H),3.80(s,3H),2.96(brs,4H),2.42(brs,4H),2.19(s,3H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm)158.5(d,J＝235.6Hz),155.5,141.8,135.7,134.5,134.0,124.4(d,J＝12.1Hz),121.7,115.8(d,J＝3.0Hz),115.6,115.2(d,J＝10.6Hz),112.1,111.5(d,J＝25.7Hz),103.8(d,J＝25.7Hz),56.3,55.1,50.1,46.2.
Example Synthesis of 5-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1-methyl-1H-indole
Figure BDA0001713906860000552
Step 1) 2,2,2-trichloro-1- (4- (5- ((5-fluoro-1-methyl-1H-indol-3-yl) sulfonyl) -2-methoxy Synthesis of phenylpiperazin-1-yl) acetyl
The title compound of this step was prepared by the method described in example 2, step 2, i.e. 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-fluoro-1H-indol-3-yl) sulfonyl) phenyl) piperazin-1-yl) acetyl (0.68g, 1.3 mmol), sodium hydride (73mg, 1.82mmol) and iodomethane (361mg, 2.53mmol) were reacted in N, N-dimethylformamide (5 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a white solid (292mg, 41.8%).
MS(ESI,pos.ion)m/z:547.6[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.77(s,1H),7.75-7.72(m,1H),7.59-7.57(m,1H),7.51(d,J＝2.1Hz,1H),7.30(d,J＝4.2Hz,1H),7.10-7.06(m,1H),6.94(d,J＝8.6Hz,1H),4.01(d,J＝13.7Hz,4H),3.92(s,3H),3.86(s,3H),3.18-3.15(m,4H).
Step 2) Synthesis of 5-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1-methyl-1H-indole Become into
The title compound of this step was prepared by the method described in example 21, step 5, i.e. 2,2,2-trichloro-1- (4- (5- ((5-fluoro-1-methyl-1H-indol-3-yl) sulfonyl) -2-methoxyphenylpiperazin-1-yl) acetyl (292mg, 0.53mmol), potassium hydroxide (90mg, 1.36mmol) were reacted in tetrahydrofuran (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a light yellow solid (0.15g, 70%).
MS(ESI,pos.ion)m/z:404.2[M+H] + ；
1 HNMR(600MHz,CDCl 3 )δ(ppm)7.76(s,1H),7.68-7.67(m,1H),7.60-7.58(m,1H),7.52(d,J＝2.2Hz,1H),7.28-7.26(m,1H),7.07-7.04(m,1H),6.89(d,J＝8.6Hz,1H),3.89(s,3H),3.84(s,3H),3.07(brs,4H),3.04(brs,4H).
Example 26 Synthesis of 1- (difluoromethyl) -5-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000561
Step 1) tert-butyl 4- (5- ((5-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylic acid Synthesis of esters
The title compound was prepared as described in example 2, step 1 by reacting 5-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole (0.7g, 1.8mmol), montmorillonite (0.5 g) and di-tert-butyl dicarbonate (588mg, 2.67mmol) in dichloromethane (10 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a pale yellow solid (647mg, 73.5%).
MS(ESI,pos.ion)m/z:489.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.49(s,1H),7.89(d,J＝3.0Hz,1H),7.73-7.71(m,1H),7.56-7.54(m,1H),7.49(d,J＝2.1Hz,1H),7.38-7.35(m,1H),7.05-7.00(m,1H),6.92(d,J＝8.6Hz,1H),3.91(s,3H),3.61-3.59(m,4H),3.02-2.99(m,4H),1.51(s,9H).
Step 2) tert-butyl 4- (5- ((1- (difluoromethyl) -5-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxybenzene Synthesis of 1-piperazinecarboxylate
This step title compound was prepared by the method described in reference to example 3, step 1, i.e. tert-butyl 4- (5- ((5-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (340mg, 0.88mmol), sodium difluorochloroacetate (267mg, 1.73mmol) and sodium hydride (60%, 43mg, 1.07mmol) were reacted in N, N-dimethylformamide (5 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give the title compound as a pink solid (256mg, 66.7%).
1 HNMR(400MHz,CDCl 3 )δ(ppm)8.00(s,1H),7.74-7.71(m,1H),7.61-7.58(m,1H),7.57-7.53(m,1H),7.51(d,J＝2.2Hz,1H),7.26(t,J＝60.0Hz,1H),7.18-7.12(m,1H),6.95(d,J＝8.6Hz,1H),3.93(s,3H),3.62-3.59(m,4H),3.04-3.02(m,4H),1.51(s,9H).
Step 3) 1- (difluoromethyl) -5-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of indole
The title compound was prepared by reacting tert-butyl 4- (5- ((1- (difluoromethyl) -5-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (256mg, 0.58mmol), ethyl hydrogen chloride in ethyl acetate (2m, 4ml) in dichloromethane (5 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) as a white solid (180mg, 70.1%) as described in step 3 of example 2.
MS(ESI,pos.ion)m/z:440.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.02(s,1H),7.71-7.69(m,1H),7.61-7.59(m,1H),7.56-7.54(m,1H),7.52(d,J＝2.2Hz,1H),7.28(t,J＝60.0Hz,1H),7.15-7.12(m,1H),6.93(d,J＝8.6Hz,1H),3.91(s,3H),3.07(brs,8H).
Example 27 Synthesis of 1-cyclopropyl-5-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000571
Step 1) tert-butyl 4- (5- ((1-cyclopropyl-5-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piper-ine Synthesis of oxazine-1-carboxylic acid esters
The title compound of this step was prepared by the method described in example 4, step 1, i.e. tert-butyl 4- (5- ((5-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (300mg, 0.77mmol), cyclopropylboronic acid (133mg, 1.47mmol), copper acetate (140mg, 0.77mmol) and 2,2' -bipyridine (121mg, 0.76mmol) were reacted in 1,2-dichloroethane (5 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a pale yellow solid (235mg, 71%).
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.82(s,1H),7.72-7.69(m,1H),7.57-7.51(m,3H),7.09-7.04(m,1H),6.92(d,J＝8.6Hz,1H),3.91(s,3H),3.62-3.59(m,4H),3.43-3.40(m,1H),3.03-3.01(m,4H),1.51(s,9H),1.20-1.16(m,2H),1.07-1.03(m,2H).
Step 2) preparation of 1-cyclopropyl-5-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of the Synthesis
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (5- ((1-cyclopropyl-5-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (235mg, 0.55mmol), ethyl hydrogen chloride in ethyl acetate (2m, 4 mL) was reacted in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (132mg, 56%).
MS(ESI,pos.ion)m/z:429.9[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.82(s,1H),7.70-7.68(m,1H),7.57-7.55(m,1H),7.53-7.51(m,2H),7.08-7.04(m,1H),6.90(d,J＝8.6Hz,1H),3.90(s,3H),3.43-3.39(m,1H),3.10(brs,4H),3.08(brs,4H),1.19-1.16(m,2H),1.06-1.04(m,2H).
Example 28 Synthesis of 1-ethyl-5-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000581
Step 1) tert-butyl 4- (5- ((1-ethyl-5-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piper-ine Synthesis of oxazine-1-carboxylic acid esters
The title compound of this step was prepared by the method described in reference to example 5, step 1, i.e. tert-butyl 4- (5- ((5-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (300mg, 0.61mmol), iodoethane (115mg, 0.73mmol) and sodium hydride (60%, 49mg, 1.94mmol) were reacted in N, N-dimethylformamide (5 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a pale yellow oil (230mg, 72.5%).
MS(ESI,pos.ion)m/z:517.8[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.83(s,1H),7.71(dd,J＝8.6,2.1Hz,1H),7.58(dd,J＝9.2,2.4Hz,1H),7.52(d,J＝2.1Hz,1H),7.31(dd,J＝9.1,4.2Hz,1H),7.08-7.04(m,1H),6.92(d,J＝8.6Hz,1H),4.20(q,J＝7.3Hz,2H),3.91(s,3H),3.61-3.59(m,4H),3.03-3.01(m,4H),1.54(t,J＝7.3Hz,3H),1.51(s,9H).
Step 2) Synthesis of 1-ethyl-5-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (5- ((1-ethyl-5-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (230mg, 0.44mmol), ethyl hydrogen chloride acetate solution (2m, 4 mL) was reacted in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (134mg, 72%).
MS(ESI,pos.ion)m/z:417.9[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.86(s,1H),7.73(dd,J＝8.6,1.9Hz,1H),7.57(dd,J＝9.1,2.3Hz,1H),7.50(d,J＝1.9Hz,1H),7.30(dd,J＝9.0,4.1Hz,1H),7.06-7.03(m,1H),6.91(d,J＝8.6Hz,1H),4.20(q,J＝7.3Hz,2H),3.89(s,3H),3.21(brs,4H),3.18(brs,4H),1.53(t,J＝7.3Hz,3H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)159.1(d,J＝237.0Hz),155.6,141.2,135.3,133.0,132.7,124.9(d,J＝12.0Hz),122.8,116.7,115.7(d,J＝4.5Hz),112.1(d,J＝27.0Hz),111.4(d,J＝10.5Hz),111.0,105.2(d,J＝25.5Hz),55.9,49.7,45.0,42.2,15.0.
Example 29 Synthesis of 1-isopropyl-5-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000582
Step 1) tert-butyl 4- (5- ((1-isopropyl-5-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) Synthesis of piperazine-1-carboxylic acid esters
This step title compound was prepared by the method described in example 6, step 1, i.e. tert-butyl 4- (5- ((5-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (300mg, 0.61mmol), 2-iodopropane (125mg, 0.73mmol) and sodium hydride (60%, 49mg, 1.94mmol) were reacted in N, N-dimethylformamide (5 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a light yellow oil (230mg, 70.6%).
MS(ESI,pos.ion)m/z:531.8[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.91(s,1H),7.70(dd,J＝8.6,2.2Hz,1H),7.57(dd,J＝9.2,2.4Hz,1H),7.53(d,J＝2.1Hz,1H),7.34(dd,J＝9.0,4.2Hz,1H),7.08-7.03(m,1H),6.92(d,J＝8.6Hz,1H),4.69-4.62(m,1H),3.91(s,3H),3.61-3.59(m,4H),3.03-3.01(m,4H),1.58(d,J＝6.7Hz,6H),1.51(s,9H).
Step 2) preparation of 1-isopropyl-5-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of the Synthesis
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (5- ((1-isopropyl-5-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (230mg, 0.43mmol), ethyl hydrogen chloride acetate solution (2m, 4 mL) was reacted in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (153mg, 81.9%).
MS(ESI,pos.ion)m/z:432.3[M+H] + ；
1 HNMR(600MHz,CDCl 3 )δ(ppm)7.92(s,1H),7.68(dd,J＝8.5,1.8Hz,1H),7.57(dd,J＝9.1,2.2Hz,1H),7.53(d,J＝1.8Hz,1H),7.33(dd,J＝9.0,4.1Hz,1H),7.06-7.03(m,1H),6.90(d,J＝8.6Hz,1H),4.67-4.63(m,1H),3.89(s,3H),3.07(brs,8H),1.57(d,J＝6.7Hz,6H).
Example Synthesis of 5-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000591
Step 1) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-chloro-1H-indol-3-yl) thio) phenyl) piperazine- Synthesis of 1-yl) acetyl
The title compound was prepared as described in example 1, step 2 by reacting 5-chloroindole (0.5g, 3.3mmol), 4-methoxy-3- (4- (2,2,2-trichloroacetyl) piperazin-1-yl) benzenesulfonylhydrazide (1.7g, 4.0mmol), iodine (84mg, 0.66mmol) in ethanol (10 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a white solid (1.14g, 67%).
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.68(s,1H),7.58(d,J＝1.7Hz,1H),7.48(d,J＝2.6Hz,1H),7.33(d,J＝8.6Hz,1H),7.18(dd,J＝8.6,1.9Hz,1H),6.79(s,1H),6.78-6.77(m,1H),6.70(d,J＝8.7Hz,1H),4.03-3.76(m,7H),3.04(brs,4H).
Step 2) 1- (2-methoxy-5- ((5-chloro-1H-indol-3-yl) sulfonyl) phenyl) -4- (2,2,2-trichloroethyl) Synthesis of acyl) piperazine 1-oxides
The title compound was prepared as described in example 1, step 3, by reacting 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-chloro-1H-indol-3-yl) thio) phenyl) piperazin-1-yl) acetyl (1.13g, 2.18mmol), potassium peroxymonosulfonate (5.4g, 8.74mmol), sodium bicarbonate (0.73g, 8.74mmol) in acetone (15 mL) and water (5 mL), and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a white solid (1.05g, 85%).
MS(ESI,pos.ion)m/z:565.9[M+H] + .
Step 3) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-chloro-1H-indol-3-yl) sulfonyl) phenyl) piperazine Synthesis of oxazin-1-yl) acetyl
The title compound was prepared as described in example 21, step 4 by reacting 1- (2-methoxy-5- ((5-chloro-1H-indol-3-yl) sulfonyl) phenyl) -4- (2,2,2-trichloroacetyl) piperazine 1-oxide (0.81g, 1.43mmol), cuprous iodide (0.27g, 1.43mmol), triethylamine (0.2ml, 1.43mmol) in tetrahydrofuran (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a white solid (0.4g, 51%).
MS(ESI,pos.ion)m/z:550.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.55(s,1H),7.86-7.85(m,2H),7.71(dd,J＝8.6,2.1Hz,1H),7.48(d,J＝2.0Hz,1H),7.33(d,J＝8.7Hz,1H),7.20(dd,J＝8.7,1.8Hz,1H),6.92(d,J＝8.6Hz,1H),4.09-3.85(m,7H),3.14(brs,4H).
Step 4) Synthesis of 5-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound of this step was prepared by the method described in example 21, step 5, i.e. 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-chloro-1H-indol-3-yl) sulfonyl) phenyl) piperazin-1-yl) acetyl (0.25g, 0.45mmol), potassium hydroxide (76mg, 1.37mmol) were reacted in tetrahydrofuran (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale yellow solid (0.13g, 71%).
MS(ESI,pos.ion)m/z:406.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.22(s,1H),7.73(d,J＝1.9Hz,1H),7.57(dd,J＝8.6,2.1Hz,1H),7.52(d,J＝8.7Hz,1H),7.35(d,J＝2.1Hz,1H),7.26(dd,J＝8.7,2.0Hz,1H),7.07(d,J＝8.6Hz,1H),3.80(s,3H),2.88-2.87(m,4H),2.82-2.81(m,4H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm)155.7,142.5,135.4,135.2,133.0,126.8,124.6,123.7,121.7,118.2,116.1,115.7,115.2,112.2,56.3,51.6,46.0.
Example Synthesis of 5-chloro-3- ((4-methoxy-3- (4-methylpiperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000601
The title compound was prepared as described in example 22 for 5-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole (94mg, 0.23mmol), naBH 3 CN (36mg, 0.57mmol), paraformaldehyde (21mg, 0.69mmol) in methanol (5 mL) was reacted, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale yellow solid (92mg, 95%).
MS(ESI,pos.ion)m/z:420.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.22(s,1H),7.74(s,1H),7.58(dd,J＝8.5,1.9Hz,1H),7.52(d,J＝8.7Hz,1H),7.38(d,J＝1.6Hz,1H),7.25(dd,J＝8.7,1.9Hz,1H),7.07(d,J＝8.6Hz,1H),3.80(s,3H),2.97(brs,4H),2.42(brs,4H),2.19(s,3H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm)155.6,141.9,135.4,135.2,133.0,126.8,124.6,123.7,121.8,118.2,116.3,115.7,115.1,112.2,56.3,55.1,50.1,46.2.
Example Synthesis of 5-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1-methyl-1H-indole
Figure BDA0001713906860000611
Step 1) 2,2,2-trichloro-1- (4- (5- ((5-chloro-1-methyl-1H-indol-3-yl) sulfonyl) -2-methoxy Synthesis of phenylpiperazin-1-yl) acetyl
The title compound of this step was prepared by the method described in example 2, step 2, i.e. 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-chloro-1H-indol-3-yl) sulfonyl) phenyl) piperazin-1-yl) acetyl (0.4g, 0.72mmol), sodium hydride (44mg, 1.1mmol) and iodomethane (113 μ L,1.8 mmol) were reacted in N, N-dimethylformamide (5 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a white solid (395mg, 96.3%).
MS(ESI,pos.ion)m/z:564.6[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.92(s,1H),7.76-7.71(m,2H),7.53(d,J＝2.2Hz,1H),7.28(s,2H),6.94(d,J＝8.6Hz,1H),3.92(br,7H),3.85(s,3H),3.21-3.13(m,4H).
Step 2) Synthesis of 5-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1-methyl-1H-indole Become into
The title compound was prepared as described in example 21, step 5 by reacting 2,2,2-trichloro-1- (4- (5- ((5-chloro-1-methyl-1H-indol-3-yl) sulfonyl) -2-methoxyphenylpiperazin-1-yl) acetyl (395mg, 0.70mmol), potassium hydroxide (117mg, 2.06mmol) in tetrahydrofuran (10 mL) and ethanol (5 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a white solid (202mg, 68.8%).
MS(ESI,pos.ion)m/z:420.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.84(s,1H),7.72(s,1H),7.62(d,J＝8.6Hz,1H),7.47(s,1H),7.25-7.19(m,2H),6.86(d,J＝8.6Hz,1H),3.84(s,3H),3.79(s,3H),2.99(brs,8H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)155.7,141.9,135.7,134.8,134.2,128.3,124.9,124.0,122.3,119.1,116.4,115.4,111.5,110.9,55.8,51.3,45.6,33.7.
Example Synthesis of 1- (difluoromethyl) -5-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000612
Step 1) tert-butyl 4- (5- ((5-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylic acid Synthesis of esters
The title compound of this step was prepared by the method described in example 2, step 1, i.e. 5-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole (0.97g, 2.4 mmol), montmorillonite (0.5 g) and di-tert-butyl dicarbonate (780mg, 3.5 mmol) were reacted in dichloromethane (10 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a pale yellow solid (1.09g, 90%).
MS(ESI,pos.ion)m/z:505.8[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.60(s,1H),7.87(dd,J＝5.1,2.4Hz,2H),7.71(dd,J＝8.6,2.1Hz,1H),7.50(d,J＝2.1Hz,1H),7.35(d,J＝8.7Hz,1H),7.22(dd,J＝8.7,1.9Hz,1H),6.92(d,J＝8.6Hz,1H),3.91(s,3H),3.65-3.55(m,4H),3.06-2.96(m,4H),1.51(s,9H).
Step 2) tert-butyl 4- (5- ((1- (difluoromethyl) -5-chloro-1H-indol-3-yl) sulfonyl) -2-methoxybenzene Synthesis of 1-piperazinecarboxylate
The title compound was prepared as described in example 3, step 1, i.e. tert-butyl 4- (5- ((5-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (427mg, 0.84mmol), sodium difluorochloroacetate (282mg, 1.83mmol) and sodium hydride (60%, 44mg,1.1 mmol) were reacted in N, N-dimethylformamide (5 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give the title compound as a white solid (301mg, 64%).
MS(ESI,pos.ion)m/z:555.8[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.98(s,1H),7.93(d,J＝1.9Hz,1H),7.72(dd,J＝8.6,2.2Hz,1H),7.52(dd,J＝5.5,3.2Hz,2H),7.36(dd,J＝8.8,1.9Hz,1H),7.19(t,J＝60.3Hz,1H),6.96(d,J＝8.6Hz,1H),3.93(s,3H),3.65-3.57(m,4H),3.08-3.00(m,4H),1.51(s,9H).
Step 3) 1- (difluoromethyl) -5-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of indole
The title compound was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (5- ((1- (difluoromethyl) -5-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (290mg, 0.52mmol), ethyl hydrogen chloride acetate solution (2m, 4 mL) was reacted in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a pale yellow solid (202mg, 84.9%).
MS(ESI,pos.ion)m/z:456.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.01(s,1H),7.93(d,J＝1.8Hz,1H),7.68(dd,J＝8.6,2.2Hz,1H),7.54(d,J＝2.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.34(dd,J＝8.8,1.9Hz,1H),7.29(t,J＝60.0Hz,1H),6.93(d,J＝8.6Hz,1H),3.91(s,3H),3.06(brs,8H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)156.2,142.4,133.4,132.5,130.1,128.8,125.8,125.6,122.7,121.2,120.1,116.7,113.0,111.1,109.8(d,J＝249.9Hz),55.9,51.7,46.0.
Example 34 Synthesis of 1-cyclopropyl-5-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000621
Step 1) tert-butyl 4- (5- ((1-cyclopropyl-5-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piper-ine Synthesis of oxazine-1-carboxylic acid esters
This step title compound was prepared by the method described in example 4, step 1, i.e., tert-butyl 4- (5- ((5-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (408mg, 0.81mmol), cyclopropylboronic acid (139mg, 1.54mmol), copper acetate (146mg, 0.79mmol), and 2,2' -bipyridine (126mg, 0.79mmol) were reacted in 1,2-dichloroethane (5 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a white solid (349mg, 79.2%).
MS(ESI,pos.ion)m/z:545.8[M+H] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.88(s,1H),7.78(s,1H),7.68(dd,J＝8.6,1.9Hz,1H),7.51(dd,J＝8.1,5.4Hz,2H),7.26(dd,J＝8.8,1.7Hz,1H),6.91(d,J＝8.6Hz,1H),3.90(s,3H),3.66-3.52(m,4H),3.40(tt,J＝7.2,3.7Hz,1H),3.09-2.95(m,4H),1.50(s,9H),1.17(q,J＝6.9Hz,2H),1.07-1.00(m,2H).
Step 2) preparation of 1-cyclopropyl-5-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of the Synthesis
The title compound was prepared by reaction of tert-butyl 4- (5- ((1-cyclopropyl-5-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (324mg, 0.59mmol), ethyl hydrogen chloride acetate solution (2m, 4ml) in dichloromethane (5 mL) according to the procedure described in example 2, step 3, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (253mg, 95.6%).
MS(ESI,pos.ion)m/z:445.8[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.89(d,J＝1.9Hz,1H),7.79(s,1H),7.66(dd,J＝8.6,2.2Hz,1H),7.54(d,J＝2.2Hz,1H),7.50(d,J＝8.7Hz,1H),7.26(dd,J＝8.7,1.9Hz,1H),6.89(d,J＝8.6Hz,1H),3.89(s,3H),3.39(tt,J＝7.1,3.8Hz,1H),3.05(brs,8H),1.16(q,J＝6.9Hz,2H),1.05-1.01(m,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)155.7,142.2,136.4,134.8,133.4,128.5,125.1,124.1,122.2,119.4,116.5,116.0,112.4,110.9,55.8,51.8,46.1,27.9,6.4.
Example Synthesis of 35-Ethyl-5-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000631
Step 1) tert-butyl 4- (5- ((1-ethyl-5-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piper-ine Synthesis of oxazine-1-carboxylic acid esters
The title compound of this step was prepared by the method described in step 1 of example 5, i.e. tert-butyl 4- (5- ((5-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (300mg, 0.59mmol), iodoethane (110mg, 0.71mmol) and sodium hydride (60%, 50mg, 1.25mmol) were reacted in N, N-dimethylformamide (5 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a white solid (310mg, 97.9%).
MS(ESI,pos.ion)m/z:533.8[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.89(d,J＝1.3Hz,1H),7.78(s,1H),7.67(dd,J＝8.6,2.2Hz,1H),7.51(d,J＝2.2Hz,1H),7.28-7.22(m,2H),6.90(d,J＝8.6Hz,1H),4.17(q,J＝7.3Hz,2H),3.88(s,3H),3.58(t,J＝4.8Hz,4H),3.00(t,J＝5.0Hz,4H),1.51(t,J＝7.3Hz,3H),1.48(s,9H).
Step 2) Synthesis of 1-ethyl-5-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (5- ((1-ethyl-5-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (243mg, 0.45mmol), ethyl hydrogen chloride in ethyl acetate (2m, 4 mL) was reacted in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (107mg, 54.2%).
MS(ESI,pos.ion)m/z:433.8[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.89(s,1H),7.78(s,1H),7.64(dd,J＝8.5,1.6Hz,1H),7.52(d,J＝1.6Hz,1H),7.25(s,1H),7.22(d,J＝8.7Hz,1H),6.87(d,J＝8.6Hz,1H),4.15(q,J＝7.3Hz,2H),3.86(s,3H),3.04(s,8H),1.49(t,J＝7.3Hz,3H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)155.6,142.0,135.0,134.8,132.3,128.1,125.2,123.8,122.2,119.4,116.5,115.8,111.4,110.8,55.8,51.5,46.0,42.0,14.9.
Example 361 Synthesis of isopropyl-5-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000641
Step 1) tert-butyl 4- (5- ((1-isopropyl-5-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) Synthesis of piperazine-1-carboxylic acid esters
This step title compound was prepared by reacting tert-butyl 4- (5- ((5-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (300mg, 0.59mmol), 2-iodopropane (0.065ml, 0.65mmol) and sodium hydride (60%, 49mg, 1.94mmol) in N, N-dimethylformamide (5 mL) as described in example 6, step 1, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a white solid (155mg, 47.7%).
MS(ESI,pos.ion)m/z:548.3[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.88(d,J＝1.9Hz,1H),7.87(s,1H),7.67(dd,J＝8.6,2.2Hz,1H),7.52(d,J＝2.2Hz,1H),7.30(d,J＝8.8Hz,1H),7.23(dd,J＝8.8,1.9Hz,1H),6.90(d,J＝8.6Hz,1H),4.70-4.57(m,1H),3.88(s,3H),3.58(t,J＝4.7Hz,4H),3.00(t,J＝4.9Hz,4H),1.56(brs,3H),1.54(brs,3H),1.48(s,9H).
Step 2) preparation of 1-isopropyl-5-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of the Synthesis
The title compound was prepared as described in example 2, step 3, i.e. tert-butyl 4- (5- ((1-isopropyl-5-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (360mg, 0.66mmol), ethyl hydrogen chloride acetate solution (2m, 4ml) was reacted in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (227mg, 77%).
MS(ESI,pos.ion)m/z:448.3[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.88(d,J＝1.8Hz,1H),7.87(s,1H),7.63(dd,J＝8.6,2.1Hz,1H),7.52(d,J＝2.1Hz,1H),7.28(d,J＝8.8Hz,1H),7.20(dd,J＝8.8,1.9Hz,1H),6.86(d,J＝8.6Hz,1H),4.62-4.58(m,1H),3.85(s,3H),3.01(s,8H),1.52(d,J＝6.7Hz,6H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)155.5,142.0,134.9,134.6129.5128.0,125.1,123.7122.0,119.3,116.4115.7,111.6110.8,55.7,51.6,48.546.0,22.5.
Example Synthesis of 5-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000651
Step 1) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-bromo-1H-indol-3-yl) thio) phenyl) piperazine- Synthesis of 1-yl) acetyl
The title compound of this step was prepared by the method described in example 1, step 2, i.e., 5-bromoindole (0.5g, 2.56mmol), 4-methoxy-3- (4- (2,2,2-trichloroacetyl) piperazin-1-yl) benzenesulfonylhydrazide (1.32g, 3.08mmol), iodine (65mg, 0.51mmol) were reacted in ethanol (10 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a white solid (1.13g, 78%).
MS(ESI,pos.ion)m/z:561.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.64(s,1H),7.74(s,1H),7.46(d,J＝2.6Hz,1H),7.32(dd,J＝8.6,1.6Hz,1H),7.29(d,J＝8.6Hz,1H),6.80(s,1H),6.78-6.77(m,1H),6.71(d,J＝8.3Hz,1H),4.04-3.78(m,7H),3.04(s,4H).
Step 2) 1- (2-methoxy-5- ((5-bromo-1H-indol-3-yl) sulfonyl) phenyl) -4- (2,2,2-trichloroethyl) Synthesis of acyl) piperazine 1-oxides
The title compound was prepared as described in example 1, step 3, by reacting 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-bromo-1H-indol-3-yl) thio) phenyl) piperazin-1-yl) acetyl (1.12g, 2.0mmol), potassium peroxymonosulfonate (4.9g, 8.0mmol), sodium bicarbonate (0.67g, 8.0mmol) in acetone (15 mL) and water (5 mL), and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a white solid (1.16g, 95%).
MS(ESI,pos.ion)m/z:609.9[M+H] + .
Step 3) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-bromo-1H-indol-3-yl) sulfonyl) phenyl) piperazine Oxazin-1-yl) acetylSynthesis of (2)
The title compound of this step was prepared by the method described in example 21, step 4, i.e. reacting 1- (2-methoxy-5- ((5-bromo-1H-indol-3-yl) sulfonyl) phenyl) -4- (2,2,2-trichloroacetyl) piperazine 1-oxide (1.15g, 1.89mmol), cuprous iodide (0.36g, 1.89mmol), triethylamine (0.26ml, 1.89mmol) in tetrahydrofuran (10 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a white solid (0.5g, 45%).
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.53(s,1H),8.03(s,1H),7.84(d,J＝1.9Hz,1H),7.72-7.68(m,1H),7.49(d,J＝2.1Hz,1H),7.34(dd,J＝8.7,1.4Hz,1H),7.28(d,J＝8.8Hz,1H),6.92(d,J＝8.6Hz,1H),3.97-3.90(m,7H),3.14(t,J＝4.4Hz,4H).
Step 4) Synthesis of 5-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound of this step was prepared by the method described in example 21, step 5, i.e. 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-bromo-1H-indol-3-yl) sulfonyl) phenyl) piperazin-1-yl) acetyl (224mg, 0.38mmol), potassium hydroxide (63mg, 1.13mmol) was reacted in tetrahydrofuran (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a light yellow solid (117mg, 69%).
MS(ESI,pos.ion)m/z:450.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.20(s,1H),7.88(d,J＝1.6Hz,1H),7.56(dd,J＝8.5,2.1Hz,1H),7.47(d,J＝8.7Hz,1H),7.38-7.35(m,2H),7.07(d,J＝8.6Hz,1H),3.80(s,3H),2.88-2.87(m,4H),2.81(brs,4H)；
13 C NMR(100MHz,DMSO-d 6 )δ(ppm)155.7,142.5,135.7,135.2,132.8,126.1,125.2,121.5,121.1,115.9,115.7,115.5,114.7,112.2,56.3,51.6,46.0.
Example 38 Synthesis of 5-bromo-3- ((4-methoxy-3- (4-methylpiperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000661
The title compound was prepared as described in example 22, i.e. 5-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole (76mg, 0.17mmol), naBH 3 CN (27mg, 0.42mmol), paraformaldehyde (15mg, 0.5mmol) were reacted in methanol (5 mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale yellow solid (70mg, 90%).
MS(ESI,pos.ion)m/z:464.0[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.20(s,1H),7.89(d,J＝1.6Hz,1H),7.56(dd,J＝8.5,2.0Hz,1H),7.47(d,J＝8.7Hz,1H),7.38-7.35(m,2H),7.07(d,J＝8.6Hz,1H),3.81(s,3H),2.97(brs,4H),2.43(brs,4H),2.20(s,3H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm)155.6,141.8,135.6,135.2,132.8,126.2,125.2,121.7,121.2,116.0,115.7,115.5,114.8,112.2,56.3,55.1,50.1,46.2.
Example 39 Synthesis of 5-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1-methyl-1H-indole
Figure BDA0001713906860000662
Step 1) tert-butyl 4- (5- ((5-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylic acid Synthesis of esters
The title compound was prepared as described in example 2, step 1, by reacting 5-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole (2.18g, 4.84mmol), montmorillonite (0.8 g) and di-tert-butyl dicarbonate (1.58g, 7.17mmol) in dichloromethane (10 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a white solid (2.62g, 98.3%).
MS(ESI,pos.ion)m/z:550.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.47(s,1H),8.06(d,J＝1.3Hz,1H),7.86(d,J＝3.0Hz,1H),7.71(dd,J＝8.6,2.1Hz,1H),7.52(d,J＝2.1Hz,1H),7.37(dd,J＝8.7,1.7Hz,1H),7.30(d,J＝8.7Hz,1H),3.91(s,3H),3.65-3.56(m,4H),3.08-2.96(m,4H),1.51(s,9H).
Step 2) tert-butyl 4- (5- ((5-bromo-1-methyl-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piper-ine Synthesis of oxazine-1-carboxylic acid esters
This title compound was prepared as described in example 2, step 2, by reacting tert-butyl 4- (5- ((5-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (0.3g, 0.54mmol), sodium hydride (33mg, 0.82mmol) and iodomethane (85 μ L,1.35 mmol) in N, N-dimethylformamide (5 mL), and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a white solid (202mg, 65.6%).
MS(ESI,pos.ion)m/z:563.7[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.09(d,J＝1.7Hz,1H),7.72(s,1H),7.69(dd,J＝8.6,2.2Hz,1H),7.54(d,J＝2.1Hz,1H),7.41(dd,J＝8.7,1.8Hz,1H),7.22(d,J＝8.8Hz,1H),6.92(d,J＝8.6Hz,1H),3.91(s,3H),3.84(s,3H),3.66-3.54(m,4H),3.07-2.99(m,4H),1.52(s,9H).
Step 3) Synthesis of 5-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1-methyl-1H-indole Become into
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (5- ((5-bromo-1-methyl-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (192mg, 0.34mmol), ethyl hydrogen chloride in ethyl acetate (2m, 4 mL) in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (125mg, 79%).
MS(ESI,pos.ion)m/z:464.2[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.25(s,1H),7.90(d,J＝1.4Hz,1H),7.56(dd,J＝12.2,5.4Hz,2H),7.45(dd,J＝8.7,1.5Hz,1H),7.36(d,J＝1.9Hz,1H),7.08(d,J＝8.6Hz,1H),3.85(s,3H),3.81(s,3H),2.89(brs,4H),2.82(brs,4H)；
13 C NMR(100MHz,DMSO-d 6 )δ(ppm)155.7,142.5,136.2,136.1,135.2,126.2,125.4,121.5,121.3,115.6,115.2,114.7,114.1,112.3,56.3,51.6,46.1,33.9.
EXAMPLE 40 Synthesis of 1- (difluoromethyl) -5-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000671
Step 1) tert-butyl 4- (5- ((1- (difluoromethyl) -5-bromo-1H-indol-3-yl) sulfonyl) -2-methoxybenzene Synthesis of 1-piperazinecarboxylate
The title compound was prepared by reaction of tert-butyl 4- (5- ((5-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (500mg, 0.91mmol), sodium difluorochloroacetate (282mg, 1.83mmol) and sodium hydride (60%, 47mg, 1.17mmol) in N, N-dimethylformamide (5 mL) and purification of the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) by the method described in step 1 of example 3 to give the title compound as a white solid (195mg, 35.7%).
MS(ESI,pos.ion)m/z:599.7[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.11(d,J＝1.4Hz,1H),7.95(s,1H),7.72(dd,J＝8.6,2.2Hz,1H),7.54(d,J＝2.2Hz,1H),7.51(dd,J＝8.8,1.7Hz,1H),7.47(d,J＝8.8Hz,1H),7.18(t,J＝60.3Hz,1H),6.96(d,J＝8.6Hz,1H),3.93(s,3H),3.66-3.56(m,4H),3.10-2.96(m,4H),1.51(s,9H).
Step 2) 1- (difluoromethyl) -5-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of indole
The title compound of this step was prepared by the method described in reference to example 2, step 3, i.e. tert-butyl 4- (5- ((1- (difluoromethyl) -5-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (185mg, 0.31mmol), ethyl hydrogen chloride in ethyl acetate (2m, 4 mL) was reacted in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (122mg, 79%).
MS(ESI,pos.ion)m/z:500.1[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.11(d,J＝0.5Hz,1H),7.98(s,1H),7.70(dd,J＝8.6,2.0Hz,1H),7.55(d,J＝2.0Hz,1H),7.51-7.45(m,2H),7.23(t,J＝60.2Hz,1H),6.94(d,J＝8.6Hz,1H),3.92(s,3H),3.10(brs,8H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)156.2,142.3,133.4,132.9,128.6,128.4,126.1,123.2,122.8,121.1,117.7,116.8,113.3,111.1,109.7(t,J＝250.2Hz),55.9,51.3,45.9.
Example 41 Synthesis of 1-cyclopropyl-5-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000681
Step 1) tert-butyl 4- (5- ((1-cyclopropyl-5-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piper-ine Synthesis of oxazine-1-carboxylic acid esters
The title compound of this step was prepared by the method described in example 4, step 1, i.e. tert-butyl 4- (5- ((5-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (400mg, 0.73mmol), cyclopropylboronic acid (139mg, 1.54mmol), copper acetate (146mg, 0.79mmol) and 2,2' -bipyridine (126mg, 0.79mmol) were reacted in 1,2-dichloroethane (5 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a white solid (320mg, 74.6%).
MS(ESI,pos.ion)m/z:590.7[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.06(d,J＝1.6Hz,1H),7.77(s,1H),7.69(dd,J＝8.6,2.2Hz,1H),7.54(d,J＝2.2Hz,1H),7.46(d,J＝8.7Hz,1H),7.41(dd,J＝8.7,1.7Hz,1H),6.92(d,J＝8.6Hz,1H),3.91(s,3H),3.64-3.55(m,4H),3.40(tt,J＝7.1,3.8Hz,1H),3.08-3.00(m,4H),1.51(s,9H),1.18(q,J＝7.0Hz,2H),1.07-1.02(m,2H).
Step 2) preparation of 1-cyclopropyl-5-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of the Synthesis
The title compound was prepared by reaction of tert-butyl 4- (5- ((1-cyclopropyl-5-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (170mg, 0.29mmol), ethyl hydrogen chloride acetate solution (2m, 4 mL) in dichloromethane (5 mL) and purification of the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) according to the procedure described in example 2, step 3 to give the title compound as a white solid (113mg, 80%).
MS(ESI,pos.ion)m/z:490.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.07(d,J＝1.4Hz,1H),7.77(s,1H),7.66(dd,J＝8.6,2.1Hz,1H),7.56(d,J＝2.1Hz,1H),7.45(d,J＝8.7Hz,1H),7.39(dd,J＝8.7,1.6Hz,1H),6.90(d,J＝8.6Hz,1H),3.89(s,3H),3.40(tt,J＝7.1,3.7Hz,1H),3.07(brs,8H),1.17(q,J＝6.8Hz,2H),1.03(q,J＝7.1Hz,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)155.7,142.2,136.7,134.8,133.2,126.7,125.7,122.5,122.2,116.6,116.2,116.0,112.7,110.9,55.9,51.7,46.1,27.9,6.4.
Example Synthesis of 1-ethyl-5-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000691
Step 1) tert-butyl 4- (5)- ((1-ethyl-5-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piper-ine Synthesis of oxazine-1-carboxylic acid esters
The title compound of this step was prepared by the method described in step 1 of example 5, i.e. tert-butyl 4- (5- ((5-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (300mg, 0.54mmol), iodoethane (127mg, 0.82mmol) and sodium hydride (60%, 43mg, 1.08mmol) were reacted in N, N-dimethylformamide (5 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a white solid (262mg, 83%).
MS(ESI,pos.ion)m/z:578.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.09(d,J＝1.6Hz,1H),7.80(s,1H),7.71(dd,J＝8.5,2.1Hz,1H),7.58(s,1H),7.41(dd,J＝8.8,1.8Hz,1H),7.25(d,J＝8.8Hz,1H),6.93(d,J＝8.6Hz,1H),4.20(q,J＝7.3Hz,2H),3.91(s,3H),3.66-3.58(m,4H),3.11-2.99(m,4H),1.55(t,J＝7.3Hz,3H),1.51(s,9H).
Step 2) Synthesis of 1-ethyl-5-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (5- ((1-ethyl-5-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (250mg, 0.43mmol), ethyl hydrogen chloride acetate solution (2m, 4 mL) was reacted in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (185mg, 89.5%).
MS(ESI,pos.ion)m/z:478.2[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.32(s,1H),7.90(d,J＝1.8Hz,1H),7.64(d,J＝8.8Hz,1H),7.56(dd,J＝8.6,2.2Hz,1H),7.44(dd,J＝8.8,1.9Hz,1H),7.36(d,J＝2.2Hz,1H),7.09(d,J＝8.7Hz,1H),4.28(q,J＝7.2Hz,2H),3.82(s,3H),2.89-2.86(m,4H),2.86-2.75(m,4H),1.37(t,J＝7.2Hz,3H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm)155.7,142.5,135.3,135.1,134.7,126.2,125.5,121.6,121.4,115.7,115.1,114.9,114.2,112.3,56.3,51.5,46.0,42.0,15.6.
EXAMPLE 43 Synthesis of 1-isopropyl-5-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000692
Step 1) tert-butyl 4- (5- ((1-isopropyl-5-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) Synthesis of piperazine-1-carboxylic acid esters
The title compound of this step was prepared by reacting tert-butyl 4- (5- ((5-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (300mg, 0.54mmol), 2-iodopropane (0.082ml, 0.82mmol) and sodium hydride (60%, 43mg, 1.08mmol) in N, N-dimethylformamide (5 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) by the method described in step 1 of example 6 to give the title compound as a white solid (320mg, 99%).
MS(ESI,pos.ion)m/z:592.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.07(d,J＝1.6Hz,1H),7.87(s,1H),7.68(dd,J＝8.6,2.2Hz,1H),7.55(d,J＝2.2Hz,1H),7.39(dd,J＝8.8,1.7Hz,1H),7.28(d,J＝1.8Hz,1H),6.92(d,J＝8.6Hz,1H),4.64(dt,J＝13.3,6.7Hz,1H),3.91(s,3H),3.65-3.54(m,4H),3.08-2.97(m,4H),1.57(d,J＝6.7Hz,6H),1.51(s,9H).
Step 2) preparation of 1-isopropyl-5-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of the Synthesis
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (5- ((1-isopropyl-5-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (310mg, 0.52mmol), ethyl hydrogen chloride in ethyl acetate (2m, 4 mL) in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (176mg, 68.3%).
MS(ESI,pos.ion)m/z:492.3[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)8.07(d,J＝1.7Hz,1H),7.87(s,1H),7.65(dd,J＝8.6,2.1Hz,1H),7.55(d,J＝2.2Hz,1H),7.37(dd,J＝8.8,1.8Hz,1H),7.26(d,J＝8.8Hz,1H),6.89(d,J＝8.6Hz,1H),4.63(dt,J＝13.3,6.7Hz,1H),3.88(s,3H),3.05(brs,8H),1.55(d,J＝6.7Hz,6H).
Example Synthesis of 6-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000701
Step 1) 2,2,2-trichloro-1- (4- (5- ((6-fluoro-1H-indol-3-yl) thio) -2-methoxyphenyl) piperazine- Synthesis of 1-yl) acetyl
The title compound was prepared as described in example 1, step 2 by reacting 6-fluoroindole (2.04g, 15.1 mmol), 4-methoxy-3- (4- (2,2,2-trichloroacetyl) piperazin-1-yl) benzenesulfonylhydrazide (4.34g, 10.1 mmol), iodine (195mg, 1.51mmol) in ethanol (20 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a pale yellow solid (3.76g, 74.4%).
MS(ESI,pos.ion)m/z:501.7[M+H] + ；
1 HNMR(400MHz,CDCl 3 )δ(ppm)8.65(s,1H),7.51(dd,J＝8.7,5.3Hz,1H),7.45(d,J＝2.5Hz,1H),7.11(dd,J＝9.3,2.1Hz,1H),6.92(td,J＝9.3,2.2Hz,1H),6.84-6.78(m,2H),6.74-6.70(m,1H),4.10-3.85(m,4H),3.82(s,3H),3.09-3.01(m,4H).
Step 2) 1- (5- ((6-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) -4- (2,2,2-trichloroethylene Synthesis of acyl) piperazine 1-oxides
The title compound of this step was prepared as described in example 1, step 3, i.e. 2,2,2-trichloro-1- (4- (5- ((6-fluoro-1H-indol-3-yl) thio) -2-methoxyphenyl) piperazin-1-yl) acetyl (3.6g, 7.16mmol), potassium peroxymonosulfonate (13g, 20.7mmol), sodium bicarbonate (1.8g, 21.4mmol) were reacted in acetone (20 mL) and water (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale pink solid (3.55g, 90%).
MS(ESI,pos.ion)m/z:551.6[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)12.40(s,1H),8.78(s,1H),8.26-8.19(m,2H),7.79(dd,J＝8.8,5.3Hz,1H),7.53(d,J＝8.9Hz,1H),7.33(dd,J＝9.5,2.2Hz,1H),7.11(td,J＝9.3,2.2Hz,1H),4.59-4.46(m,4H),4.00(s,3H),3.74-3.53(m,4H).
Step 3) 2,2,2-trichloro-1- (4- (5- ((6-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piper ine Synthesis of oxazin-1-yl) acetyl
The title compound was prepared as described in example 21, step 4, by reacting 1- (5- ((6-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) -4- (2,2,2-trichloroacetyl) piperazine 1-oxide (3.5g, 6.4mmol), cuprous iodide (1.3g, 6.8mmol), triethylamine (1.0ml, 7.1mmol) in tetrahydrofuran (10 mL), purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1), and concentrating and drying to give the title compound as a pale pink solid (2.7g, 79%).
MS(ESI,pos.ion)m/z:533.7[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)10.01-9.97(m,1H),7.89(d,J＝2.9Hz,1H),7.78(dd,J＝8.8,5.1Hz,1H),7.73(dd,J＝8.6,2.1Hz,1H),7.49(d,J＝1.8Hz,1H),7.12(dd,J＝9.0,2.0Hz,1H),6.98(td,J＝9.1,2.1Hz,1H),6.94(d,J＝8.7Hz,1H),4.12-3.88(m,7H),3.17-3.11(m,4H).
Step 4) Synthesis of 6-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound of this step was prepared as described in example 21, step 5, by reacting 2,2,2-trichloro-1- (4- (5- ((6-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazin-1-yl) acetyl (2.5g, 4.7mmol), potassium hydroxide (790mg, 14mmol) in tetrahydrofuran (15 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale yellow solid (1.3g, 71%).
MS(ESI,pos.ion)m/z:390.2[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)8.14(s,1H),7.76(dd,J＝8.8,5.3Hz,1H),7.57(dd,J＝8.6,2.2Hz,1H),7.36(d,J＝2.1Hz,1H),7.29(dd,J＝9.5,2.2Hz,1H),7.10-7.04(m,2H),3.81(s,3H),2.90-2.84(m,4H),2.84-2.80(m,4H).
Example Synthesis of 6-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1-methyl-1H-indole
Figure BDA0001713906860000711
Step 1) tert-butyl 4- (5- ((6-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylic acid Synthesis of esters
The title compound was prepared as described in example 2, step 1, by reacting 6-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole (1.0g, 2.57mmol), montmorillonite (0.5 g), and di-tert-butyl dicarbonate (0.88g, 4 mmol) in dichloromethane (10 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a white solid (1.06g, 84.3%).
MS(ESI,pos.ion)m/z:489.9[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)9.64(s,1H),7.85(d,J＝2.7Hz,1H),7.82(dd,J＝8.8,5.1Hz,1H),7.71(dd,J＝8.6,1.4Hz,1H),7.49(d,J＝1.6Hz,1H),7.11(dd,J＝8.9,1.7Hz,1H),7.01(td,J＝9.1,1.8Hz,1H),6.91(d,J＝8.6Hz,1H),3.90(s,3H),3.62-3.58(m,4H),3.02-2.98(m,4H),1.51(s,9H).
Step 2) tert-butyl 4- (5- ((6-fluoro-1-methyl-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piper-ine Synthesis of oxazine-1-carboxylic acid esters
The title compound of this step was prepared by the method described in example 2, step 2, i.e. tert-butyl 4- (5- ((6-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (0.3g, 0.61mmol), sodium hydride (40mg, 1.0mmol) and iodomethane (100 μ L,2.0 mmol) were reacted in N, N-dimethylformamide (5 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a pale yellow solid (270mg, 87%).
MS(ESI,pos.ion)m/z:504.3[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.86(dd,J＝8.5,5.1Hz,1H),7.72(s,1H),7.70(dd,J＝8.6,2.1Hz,1H),7.52(d,J＝2.0Hz,1H),7.06-7.02(m,2H),6.91(d,J＝8.6Hz,1H),3.90(s,3H),3.81(s,3H),3.62-3.58(m,4H),3.02-2.99(m,4H),1.51(s,9H).
Step 3) Synthesis of 6-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1-methyl-1H-indole Become into
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (5- ((6-fluoro-1-methyl-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (270mg, 0.54mmol), ethyl hydrogen chloride acetate solution (2m, 4 mL) was reacted in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a pale yellow solid (200mg, 92%).
MS(ESI,pos.ion)m/z:404.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.86(dd,J＝7.6,5.2Hz,1H),7.73(s,1H),7.68(d,J＝7.7Hz,1H),7.53(s,1H),7.07-7.00(m,2H),6.89(d,J＝8.5Hz,1H),3.89(s,3H),3.80(s,3H),3.13-3.03(m,8H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)160.5(d,J＝241.8Hz),155.6,141.9,137.5(d,J＝12.0Hz),135.2,133.6,122.4,120.9(d,J＝9.9Hz),120.6,116.6,116.4,111.2(d,J＝24.6Hz),110.9,96.9(d,J＝26.5Hz),55.9,51.2,45.8,33.8.
EXAMPLE 46 Synthesis of 1- (difluoromethyl) -6-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000721
Step 1) tert-butyl 4- (5- ((1- (difluoromethyl) -6-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxybenzene Synthesis of 1-piperazinecarboxylate
The title compound of this step was prepared by reacting tert-butyl 4- (5- ((6-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (350mg, 0.71mmol), sodium difluorochloroacetate (275mg, 1.79mmol) and sodium hydride (60%, 49mg,1.2 mmol) in N, N-dimethylformamide (5 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) by the method described in example 3, step 1 to give the title compound as a pale yellow solid (270mg, 70%).
MS(ESI,pos.ion)m/z:540.3[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.95(s,1H),7.88(dd,J＝8.6,5.1Hz,1H),7.72(d,J＝7.8Hz,1H),7.51(s,1H),7.30(d,J＝8.7Hz,1H),7.24(t,J＝60.24Hz,1H),7.14-7.11(m,1H),6.94(d,J＝8.6Hz,1H),3.92(s,3H),3.62-3.58(m,4H),3.04-3.00(m,4H),1.51(s,9H).
Step 2) 1- (difluoromethyl) -6-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of indole
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (5- ((1- (difluoromethyl) -6-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (270mg, 0.5 mmol), ethyl hydrogen chloride acetate solution (2m, 4 mL) was reacted in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a pale yellow solid (190mg, 86%).
MS(ESI,pos.ion)m/z:439.9[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.97(s,1H),7.88(dd,J＝8.7,5.1Hz,1H),7.70(dd,J＝8.5,1.8Hz,1H),7.53(d,J＝1.8Hz,1H),7.30(d,J＝8.7Hz,1H),7.26(t,J＝60.12Hz,1H),7.13(td,J＝9.0,1.8Hz,1H),6.93(d,J＝8.6Hz,1H),3.91(s,3H),3.13-3.04(m,8H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)161.0(d,J＝244.6Hz),156.2,142.2,134.4(d,J＝12.2Hz),133.6,128.2,122.9,121.7,121.6,120.9,116.8,113.0(d,J＝24.3Hz),111.1,109.8(t,J＝251.4Hz),99.1(d,J＝27.7Hz),55.9,51.3,45.9.
Example 47 Synthesis of 1-cyclopropyl-6-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000731
Step 1) tert-butyl 4- (5- ((1-cyclopropyl-6-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piper-ine Synthesis of oxazine-1-carboxylic acid esters
The title compound of this step was prepared by the method described in example 4, step 1, i.e. tert-butyl 4- (5- ((6-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (380mg, 0.78mmol), cyclopropylboronic acid (140mg, 1.55mmol), copper acetate (140mg, 0.77mmol) and 2,2' -bipyridine (124mg, 0.78mmol) were reacted in 1,2-dichloroethane (5 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a white solid (360mg, 88%).
MS(ESI,pos.ion)m/z:529.8[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.82(dd,J＝8.8,5.1Hz,1H),7.77(s,1H),7.69(dd,J＝8.6,2.1Hz,1H),7.52(d,J＝2.1Hz,1H),7.26(dd,J＝9.2,2.1Hz,1H),7.04(td,J＝9.1,2.1Hz,1H),6.91(d,J＝8.6Hz,1H),3.90(s,3H),3.62-3.58(m,4H),3.37(tt,J＝7.1,3.7Hz,1H),3.03-2.99(m,4H),1.51(s,9H),1.19-1.15(m,2H),1.07-1.03(m,2H).
Step 2) preparation of 1-cyclopropyl-6-fluoro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of the Synthesis
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (5- ((1-cyclopropyl-6-fluoro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (360mg, 0.68mmol), ethyl hydrogen chloride in ethyl acetate (2m, 4 mL) in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to yield the title compound as a pale yellow solid (270mg, 92%).
MS(ESI,pos.ion)m/z:429.9[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.82(dd,J＝8.7,5.1Hz,1H),7.78(s,1H),7.68(dd,J＝8.5,1.9Hz,1H),7.53(d,J＝1.8Hz,1H),7.26(dd,J＝9.1,1.8Hz,1H),7.03(td,J＝9.2,2.0Hz,1H),6.90(d,J＝8.6Hz,1H),3.89(s,3H),3.37(tt,J＝6.9,3.6Hz,1H),3.12-3.04(m,8H),1.19-1.14(m,2H),1.07-1.02(m,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)160.4(d,J＝241.3Hz),155.7,141.9,138.4(d,J＝12.1Hz),135.1,133.0(d,J＝2.9Hz),122.5,120.9(d,J＝9.9Hz),120.6,116.6,116.5,111.4(d,J＝24.5Hz),110.9,97.9(d,J＝26.5Hz),55.9,51.2,45.8,27.8,6.3.
Example Synthesis of 6-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000741
Step 1) 2,2,2-trichloro-1- (4- (5- ((6-chloro-1H-indol-3-yl) thio) -2-methoxyphenyl) piperazine- Synthesis of 1-yl) acetyl
The title compound was prepared as described in step 2 of example 1 by reacting 6-chloroindole (2.4g, 16.0mmol), 4-methoxy-3- (4- (2,2,2-trichloroacetyl) piperazin-1-yl) benzenesulfonylhydrazide (6.1g, 14.0mmol), iodine (400mg, 1.57mmol) in ethanol (20 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a light brown solid (3.6g, 49%).
MS(ESI,pos.ion)m/z:518.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.53(s,1H),7.47(d,J＝8.4Hz,1H),7.43(d,J＝2.4Hz,1H),7.39(d,J＝1.6Hz,1H),7.08(dd,J＝ 8.4,1.6 Hz,1H),6.78-6.73(m,2H),6.68(d,J＝8.4Hz,1H),3.96(brs,4H),3.78(s,3H),3.01(brs,4H).
Step 2) 1- (5- ((6-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) -4- (2,2,2-trichloroethyl Synthesis of acyl) piperazine 1-oxides
This title compound was prepared as described in example 1, step 3, by reacting 2,2,2-trichloro-1- (4- (5- ((6-chloro-1H-indol-3-yl) thio) -2-methoxyphenyl) piperazin-1-yl) acetyl (3.6 g, 6.9mmol), potassium peroxymonosulfonate (4.3 g, 6.9mmol), sodium bicarbonate (0.59g, 7.0mmol) in acetone (20 mL) and water (5 mL), and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale yellow solid (3.6 g, 92%).
MS(ESI,pos.ion)m/z:565.9[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)12.42(s,1H),9.35(d,J＝2.4Hz,1H),8.22(s,1H),8.10(dd,J＝8.4,2.4Hz,1H),7.76(d,J＝8.4Hz,1H),7.56(s,1H),7.39(d,J＝8.8Hz,1H),7.24(dd,J＝8.4,1.2Hz,1H),4.33(brs,4H),3.96(s,3H),3.73-3.55(m,4H).
Step 3) 2,2,2-trichloro-1- (4- (5- ((6-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piper ine Synthesis of oxazin-1-yl) acetyl
The title compound of this step was prepared as described in example 21, step 4, by reacting 1- (5- ((6-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) -4- (2,2,2-trichloroacetyl) piperazine 1-oxide (3.4 g, 6.0mmol), cuprous iodide (1.3g, 6.8mmol), triethylamine (1.0ml, 7.1mmol) in tetrahydrofuran (10 mL), and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a pale yellow solid (2.8g, 85%).
MS(ESI,pos.ion)m/z:550.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.54(s,1H),7.83(d,J＝3.2Hz,1H),7.76(d,J＝8.4Hz,1H),7.51(dd,J＝5.6,3.2Hz,1H),7.44(d,J＝2.0Hz,1H),7.37(d,J＝1.6Hz,1H),7.18(dd,J＝8.8,1.6Hz,1H),6.89(d,J＝8.8Hz,1H),3.99(brs,4H),3.87(s,3H),3.10(brs,4H).
Step 4) Synthesis of 6-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound of this step was prepared as described in example 21, step 5, by reacting 2,2,2-trichloro-1- (4- (5- ((6-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazin-1-yl) acetyl (2.8g, 5.1mmol), potassium hydroxide (855mg, 15.2mmol) in tetrahydrofuran (20 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale yellow solid (1.7g, 82%).
MS(ESI,pos.ion)m/z:406.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.82(s,1H),7.78(d,J＝8.8Hz,1H),7.65(dd,J＝8.8,2.4Hz,1H),7.46(d,J＝2.0Hz,1H),7.37(d,J＝1.6Hz,1H),7.18(dd,J＝8.8,1.6Hz,1H),6.85(d,J＝8.8Hz,1H),3.85(brs,4H),3.04(s,3H),3.01(brs,4H).
Example 49 Synthesis of 6-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1-methyl-1H-indole
Figure BDA0001713906860000751
Step 1) tert-butyl 4- (5- ((6-chloro-1)H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylic acid Synthesis of esters
The title compound of this step was prepared as described in example 2, step 1, by reacting 6-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole (1.7g, 4.2mmol), montmorillonite (0.5 g) and di-tert-butyl dicarbonate (1.21g, 5.5mmol) in dichloromethane (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a white solid (2.0g, 94%).
MS(ESI,pos.ion)m/z:506.3[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.27(s,1H),7.82(d,J＝2.8Hz,1H),7.78(d,J＝8.8Hz,1H),7.67(dd,J＝8.4,2.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.38(d,J＝1.6Hz,1H),7.19(dd,J＝8.8,1.6Hz,1H),6.87(d,J＝8.4Hz,1H),3.86(s,3H),3.59-3.53(m,4H),2.98-2.92(m,4H),1.47(s,9H).
Step 2) tert-butyl 4- (5- ((6-chloro-1-methyl-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piper-ine Synthesis of oxazine-1-carboxylic acid esters
The title compound of this step was prepared by the method described in example 2, step 2, i.e. tert-butyl 4- (5- ((6-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (0.5g, 0.99mmol), sodium hydride (60mg, 1.5mmol) and iodomethane (125 μ L,2.5 mmol) were reacted in N, N-dimethylformamide (5 mL), the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1), concentrated to dryness to give the title compound as a white solid (320mg, 62.3%).
MS(ESI,pos.ion)m/z:520.3[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.80(d,J＝8.4Hz,1H),7.68(s,1H),7.65(dd,J＝8.8,2.4Hz,1H),7.46(d,J＝2.4Hz,1H),7.32(d,J＝1.6Hz,1H),7.21(dd,J＝8.8,1.6Hz,1H),6.86(d,J＝8.8Hz,1H),3.86(s,3H),3.78(s,3H),3.58-3.52(m,4H),2.98-2.94(m,4H),1.47(s,9H).
Step 3) 6-chloro-3- ((4-methoxy-Synthesis of 3- (piperazin-1-yl) phenyl) sulfonyl) -1-methyl-1H-indole To become
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (5- ((6-chloro-1-methyl-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (320mg, 0.62mmol), ethyl hydrogen chloride acetate solution (2m, 4 mL) was reacted in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a pale yellow solid (250mg, 96.8%).
MS(ESI,pos.ion)m/z:420.8[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.81(d,J＝8.4Hz,1H),7.68(s,1H),7.62(dd,J＝8.4,1.8Hz,1H),7.49(d,J＝2.4Hz,1H),7.31(d,J＝1.2Hz,1H),7.20(dd,J＝8.4,1.2Hz,1H),6.84(d,J＝9.0Hz,1H),3.84(s,3H),3.77(s,3H),3.01(brs,4H),2.99(brs,4H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)155.8,142.4,137.9,135.3,133.8,130.0,123.2,122.9122.4,121.0,116.7,116.7,111.0,110.6,56.0,51.9,46.3,33.9.
Example 50 Synthesis of 1- (difluoromethyl) -6-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000761
Step 1) tert-butyl 4- (5- ((1- (difluoromethyl) -6-chloro-1H-indol-3-yl) sulfonyl) -2-methoxybenzene Synthesis of 1-piperazinecarboxylate
The title compound of this step was prepared by the method described in step 1 of example 3, i.e. tert-butyl 4- (5- ((6-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (500mg, 0.99mmol), sodium difluorochloroacetate (301mg, 2.0mmol) and sodium hydride (60%, 49mg, 1.2mmol) were reacted in N, N-dimethylformamide (5 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give the title compound as a white solid (501mg, 91%).
MS(ESI,pos.ion)m/z:556.7[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.95(s,1H),7.85(d,J＝8.4Hz,1H),7.71(dd,J＝8.4,2.0Hz,1H),7.61(s,1H),7.50(d,J＝2.0Hz,1H),7.34(dd,J＝8.4,1.6Hz,1H),7.27(t,J＝60.0Hz,1H),3.91(s,3H),3.62-3.54(m,4H),3.03-2.99(m,4H),1.50(s,9H).
Step 2) 1- (difluoromethyl) -6-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of indole
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (5- ((1- (difluoromethyl) -6-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (500mg, 0.9mmol), ethyl hydrogen chloride in ethyl acetate (2m, 4 mL) in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a pale yellow solid (190mg, 46.3%).
MS(ESI,pos.ion)m/z:456.2[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.91(s,1H),7.83(d,J＝8.4Hz,1H),7.66(dd,J＝9.0,2.4Hz,1H),7.57(s,1H),7.49(d,J＝1.8Hz,1H),7.31(d,J＝8.4Hz,1H),7.21(t,J＝60.0Hz,1H),6.89(d,J＝9.0Hz,1H),3.87(s,3H),3.05(brs,4H),3.04(brs,4H).
Example 51 Synthesis of 1-cyclopropyl-6-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000771
Step 1) tert-butyl 4- (5- ((1-cyclopropyl-6-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piper-ine Synthesis of oxazine-1-carboxylic acid esters
The title compound of this step was prepared by the method described in example 4, step 1, i.e. tert-butyl 4- (5- ((6-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (500mg, 0.99mmol), cyclopropylboronic acid (170mg, 1.88mmol), copper acetate (180mg, 0.99mmol) and 2,2' -bipyridine (157mg, 0.99mmol) were reacted in 1,2-dichloroethane (5 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a white solid (270mg, 49.4%).
MS(ESI,pos.ion)m/z:546.3[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.77(d,J＝8.8Hz,1H),7.73(s,1H),7.65(dd,J＝8.8,2.4Hz,1H),7.55(d,J＝1.6Hz,1H),7.47(d,J＝2.0Hz,1H),7.21(dd,J＝8.8,2.0Hz,1H),6.86(d,J＝8.8Hz,1H),3.86(s,3H),3.64-3.50(m,4H),3.34(tt,J＝7.0,3.7Hz,1H),3.00-2.93(m,4H),1.47(s,9H),1.25-1.22(m,2H),1.05-1.01(m,2H).
Step 2) preparation of 1-cyclopropyl-6-chloro-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of the Synthesis
The title compound was prepared by reaction of tert-butyl 4- (5- ((1-cyclopropyl-6-chloro-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (270mg, 0.49mmol), ethyl hydrogen chloride acetate solution (2m, 4 mL) in dichloromethane (5 mL) and purification of the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) by the method described in example 2, step 3 to give the title compound as a white solid (212mg, 97.1%).
MS(ESI,pos.ion)m/z:446.1[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.77(d,J＝8.4Hz,1H),7.73(s,1H),7.63(d,J＝9.0Hz,1H),7.54(s,1H),7.49(s,1H),7.20(d,J＝9.0Hz,1H),6.85(d,J＝8.4Hz,1H),3.85(s,3H),3.39-3.35(m,1H),3.02(brs,4H),3.01(brs,4H),1.17-1.13(m,2H),1.05-1.01(m,2H).
Example 52 Synthesis of 6-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000772
Step 1) 2,2,2-trichloro-1- (4- (5- ((6-bromo-1H-indol-3-yl) thio) -2-methoxyphenyl) piperazine- Synthesis of 1-yl) acetyl
This title compound was prepared as described in example 1, step 2, by reacting 6-bromoindole (4.2g, 21mmol), 4-methoxy-3- (4- (2,2,2-trichloroacetyl) piperazin-1-yl) benzenesulfonylhydrazide (6.0g, 13.9mmol), iodine (360mg, 1.4mmol) in ethanol (20 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a light brown solid (5.8g, 74%). MS (ESI, pos.ion) m/z:561.9[ M ] +H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.73(s,1H),7.57(d,J＝1.3Hz,1H),7.51-7.41(m,2H),7.25(dd,J＝8.5,1.5Hz,1H),6.85-6.75(m,2H),6.71(d,J＝8.3Hz,1H),3.99(brs,4H),3.82(s,3H),3.05(brs,4H).
Step 2) 1- (5- ((6-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) -4- (2,2,2-trichloroethylene Synthesis of acyl) piperazine 1-oxides
The title compound of this step was prepared as described in example 1, step 3, by reacting 2,2,2-trichloro-1- (4- (5- ((6-bromo-1H-indol-3-yl) thio) -2-methoxyphenyl) piperazin-1-yl) acetyl (5.8g, 10.2 mmol), potassium peroxymonosulfonate (17.0g, 27.1mmol), sodium bicarbonate (2.3g, 27mmol) in acetone (40 mL) and water (15 mL), and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale brown solid (5.7g, 91%).
MS(ESI,pos.ion)m/z:609.9[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)12.47(d,J＝2.0Hz,1H),8.87(s,1H),8.25(d,J＝3.0Hz,1H),8.19(dd,J＝8.7,2.2Hz,1H),7.79-7.64(m,2H),7.51(d,J＝8.9Hz,1H),7.36(dd,J＝8.5,1.6Hz,1H),4.64-4.35(m,4H),3.99(s,3H),3.52-3.49(m,4H).
Step 3) 2,2,2-trichloro-1- (4- (5- ((6-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piper-ine Synthesis of oxazin-1-yl) acetyl
The title compound was prepared as described in example 21, step 4, by reacting 1- (5- ((6-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) -4- (2,2,2-trichloroacetyl) piperazine 1-oxide (5.7g, 9.3mmol), cuprous iodide (1.9g, 10mmol), triethylamine (1.4mL, 9.9mmol) in tetrahydrofuran (30 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a pale yellow solid (3.5g, 63%).
MS(ESI,pos.ion)m/z:593.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.15(s,1H),7.86(d,J＝2.9Hz,1H),7.77(d,J＝8.6Hz,1H),7.74(dd,J＝8.6,2.2Hz,1H),7.59(d,J＝1.2Hz,1H),7.49(d,J＝2.1Hz,1H),7.37(dd,J＝8.6,1.5Hz,1H),6.94(d,J＝8.6Hz,1H),3.98(brs,4H),3.89(s,3H),3.17-3.12(m,4H).
Step 4) Synthesis of 6-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
The title compound of this step was prepared by the method described in example 21, step 5, i.e. 2,2,2-trichloro-1- (4- (5- ((6-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazin-1-yl) acetyl (3.5g, 5.9mmol), potassium hydroxide (1.0g, 18mmol) were reacted in tetrahydrofuran (20 mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a white solid (2.6g, 98%).
MS(ESI,pos.ion)m/z:450.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.16(s,1H),7.71(d,J＝8.6Hz,1H),7.68(d,J＝1.4Hz,1H),7.56(dd,J＝8.5,2.1Hz,1H),7.36-7.29(m,2H),7.05(d,J＝8.6Hz,1H),3.80(s,3H),2.85(d,J＝4.4Hz,4H),2.80(d,J＝4.2Hz,4H).
Example 53 Synthesis of 6-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1-methyl-1H-indole
Figure BDA0001713906860000781
Step 1) 1- (4- (5- ((6-bromo-1-methyl-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1- Synthesis of Yl) -2,2,2-trichloroacetyl
This step the title compound was prepared by the method described in example 2, step 2, i.e. 2,2,2-trichloro-1- (4- (5- ((6-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazin-1-yl) acetyl (0.75g, 1.26mmol), sodium hydride (76mg, 1.9mmol) and iodomethane (125 μ L,2.5 mmol) were reacted in N, N-dimethylformamide (5 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a white solid (250mg, 32.5%).
MS(ESI,pos.ion)m/z:607.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.03(s,1H),7.79(d,J＝8.6Hz,1H),7.74-7.66(m,2H),7.56-7.47(m,2H),7.38(dd,J＝8.6,1.4Hz,1H),6.92(d,J＝8.6Hz,1H),4.00(brs,4H),3.91(s,3H),3.23-3.08(m,4H).
Step 2) Synthesis of 6-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1-methyl-1H-indole Become into
The title compound of this step was prepared by the method described in example 21, step 5, i.e. 1- (4- (5- ((6-bromo-1-methyl-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazin-1-yl) -2,2,2-trichloroacetyl (200mg, 0.4 mmol), potassium hydroxide (67g, 1.2mmol) were reacted in tetrahydrofuran (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a white solid (150mg, 80.9%).
MS(ESI,pos.ion)m/z:464.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)8.16(s,1H),7.71(d,J＝8.6Hz,1H),7.68(d,J＝1.4Hz,1H),7.56(dd,J＝8.5,2.1Hz,1H),7.36-7.29(m,2H),7.05(d,J＝8.6Hz,1H),3.80(s,3H),2.85(d,J＝4.4Hz,4H),2.80(d,J＝4.2Hz,4H).
Example 54 Synthesis of 1- (difluoromethyl) -6-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000791
Step 1) tert-butyl 4- (5- ((6-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylic acid Synthesis of esters
The title compound of this step was prepared as described in example 2, step 1, by reacting 6-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole (2.6g, 5.8mmol), montmorillonite (0.5 g), and di-tert-butyl dicarbonate (2.0 g, 9.2mmol) in dichloromethane (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a white solid (2.1g, 66%).
MS(ESI,pos.ion)m/z:549.7[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.17(s,1H),7.85(d,J＝3.0Hz,1H),7.78(d,J＝8.6Hz,1H),7.71(dd,J＝8.6,2.2Hz,1H),7.59(d,J＝1.4Hz,1H),7.49(d,J＝2.2Hz,1H),7.37(dd,J＝8.6,1.6Hz,1H),6.91(d,J＝8.6Hz,1H),3.90(s,3H),3.63-3.55(m,4H),3.03-2.96(m,4H),1.51(s,9H).
Step 2) tert-butyl 4- (5- ((1- (difluoromethyl) -6-bromo-1H-indol-3-yl) sulfonyl) -2-methoxybenzene Synthesis of 1-piperazinecarboxylate
The title compound was prepared as described in example 3, step 1, i.e. tert-butyl 4- (5- ((6-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (500mg, 0.91mmol), sodium difluorochloroacetate (260mg, 1.7mmol) and sodium hydride (60%, 51mg,1.3 mmol) were reacted in N, N-dimethylformamide (5 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give the title compound as a white solid (250mg, 45.8%).
MS(ESI,pos.ion)m/z:599.7[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.92(s,1H),7.81(d,J＝8.6Hz,1H),7.77(s,1H),7.72(dd,J＝8.6,2.2Hz,1H),7.52-7.47(m,2H),7.24(t,J＝60.3Hz,1H),6.94(d,J＝8.6Hz,1H),3.92(s,3H),3.65-3.51(m,4H),3.06-3.00(m,4H),1.51(s,9H).
Step 3) 1- (difluoromethyl) -6-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of indole
The title compound of this step was prepared by the method described in example 2, step 3, i.e. tert-butyl 4- (5- ((1- (difluoromethyl) -6-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (200mg, 0.33mmol), ethyl hydrogen chloride in ethyl acetate (2m, 4 mL) in dichloromethane (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (166mg, 99.6%).
MS(ESI,pos.ion)m/z:500.1[M+H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.94(s,1H),7.81(d,J＝8.6Hz,1H),7.77(s,1H),7.69(dd,J＝8.6,2.0Hz,1H),7.52(d,J＝2.0Hz,1H),7.48(d,J＝8.6Hz,1H),7.25(t,J＝60.2Hz,1H),6.92(d,J＝8.6Hz,1H),3.91(s,3H),3.09-3.03(m,8H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)156.2,142.4,134.8,133.5,128.1,127.6,123.4,122.8,121.9,121.6,119.2,116.7,115.0,111.0,109.6(t,J＝251.7Hz),55.9,51.6,46.0.
Example 55 Synthesis of 1-cyclopropyl-6-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole
Figure BDA0001713906860000801
Step 1) tert-butyl 4- (5- ((1-cyclopropyl-6-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piper-ine Synthesis of oxazin-1-carboxylic acid estersBecome into
The title compound of this step was prepared by the method described in example 4, step 1, i.e. tert-butyl 4- (5- ((6-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (500mg, 0.91mmol), cyclopropylboronic acid (150mg, 1.75mmol), copper acetate (165mg, 0.91mmol) and 2,2' -bipyridine (145mg, 0.92mmol) were reacted in 1,2-dichloroethane (5 mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a white solid (310mg, 57.8%).
MS(ESI,pos.ion)m/z:590.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.79-7.72(m,3H),7.69(dd,J＝8.5,2.1Hz,1H),7.51(d,J＝2.1Hz,1H),7.39(dd,J＝8.5,1.5Hz,1H),6.91(d,J＝8.6Hz,1H),3.90(s,3H),3.68-3.52(m,4H),3.42-3.37(m,1H),3.05-2.96(m,4H),1.51(s,9H),1.23-1.14(m,2H),1.10-1.02(m,2H).
Step 2) preparation of 1-cyclopropyl-6-bromo-3- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -1H-indole Synthesis of the Synthesis
The title compound was prepared by reaction of tert-butyl 4- (5- ((1-cyclopropyl-6-bromo-1H-indol-3-yl) sulfonyl) -2-methoxyphenyl) piperazine-1-carboxylate (310mg, 0.52mmol), ethyl hydrogen chloride acetate solution (2m, 4 mL) in dichloromethane (5 mL) and purification of the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) by the method described in example 2, step 3 to give the title compound as a white solid (250mg, 97%). MS (ESI, pos.ion) m/z 489.8[ 2 ] M + H] + ；
1 H NMR(600MHz,CDCl 3 )δ(ppm)7.79-7.72(m,3H),7.65(dd,J＝8.5,2.1Hz,1H),7.52(d,J＝2.0Hz,1H),7.37(dd,J＝8.5,1.4Hz,1H),6.88(d,J＝8.6Hz,1H),3.88(s,3H),3.37(tt,J＝7.1,3.7Hz,1H),3.05(brs,4H),3.04(brs,4H),1.20-1.14(m,2H),1.04(t,J＝7.9Hz,2H)；
13 C NMR(150MHz,CDCl 3 )δ(ppm)155.7,142.2,138.8,134.9,132.9,125.9,123.1,122.3,121.1,117.4,116.5,114.4,110.9,51.6,46.1,30.9,27.8,6.4.
Example 565 the Synthesis of methoxy-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole
Figure BDA0001713906860000811
Step 1) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-methoxy-3-methyl-1H-indol-2-yl) thio) Synthesis of substituted) phenyl) piperazin-1-yl) acetyl
The title compound was prepared as described in example 1, step 2 by reacting 3-methyl-5-methoxyindole (0.5g, 3.1mmol), 4-methoxy-3- (4- (2,2,2-trichloroacetyl) piperazin-1-yl) benzenesulfonylhydrazide (1.6 g, 3.73mmol), iodine (80mg, 0.3 mmol) in ethanol (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a light brown solid (1.05g, 64%).
MS(ESI,pos.ion)m/z:528.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.96(s,1H),7.17(d,J＝8.8Hz,1H),6.99(d,J＝2.3Hz,1H),6.89(dd,J＝8.8,2.4Hz,1H),6.78-6.76(m,1H),6.74(d,J＝1.9Hz,1H),6.72(d,J＝8.5Hz,1H),4.04-3.85(m,7H),3.81(s,3H),3.08(t,J＝4.7Hz,4H),2.37(s,3H).
Step 2) 1- (2-methoxy-5- ((5-methoxy-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) -4- (2, synthesis of 2,2-trichloroacetyl) piperazine 1-oxide
The title compound of this step was prepared as described in example 1, step 3, by reacting 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-methoxy-3-methyl-1H-indol-2-yl) thio) phenyl) piperazin-1-yl) acetyl (1.0 g, 1.9mmol), potassium peroxymonosulfonate (4.8g, 7.6mmol), sodium bicarbonate (0.63g, 7.6mmol) in acetone (10 mL) and water (5 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to afford the title compound as a pale yellow solid (0.98g, 90%).
MS(ESI,pos.ion)m/z:576.1[M+H] + .
Step 3) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-methoxy-3-methyl-1H-indol-2-yl) sulfonyl) Synthesis of phenyl) piperazin-1-yl) acetyl
The title compound was prepared as described in example 21, step 4 by reacting 1- (2-methoxy-5- ((5-methoxy-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) -4- (2,2,2-trichloroacetyl) piperazine 1-oxide (0.98g, 1.7 mmol), cuprous iodide (323mg, 1.7 mmol), triethylamine (0.23ml, 1.7 mmol) in tetrahydrofuran (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a pale yellow solid (0.55g, 58%).
MS(ESI,pos.ion)m/z:560.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.07(s,1H),7.68(dd,J＝8.6,2.2Hz,1H),7.47(d,J＝2.2Hz,1H),7.28(s,1H),6.98(dd,J＝8.9,2.4Hz,1H),6.94-6.92(m,2H),4.01-3.91(m,7H),3.83(s,3H),3.08(t,J＝4.6Hz,,4H),2.50(s,3H).
Step 4) 5-methoxy-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole Synthesis of (2)
The title compound of this step was prepared by the method described in example 21, step 5, i.e. 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-methoxy-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) piperazin-1-yl) acetyl (0.54g, 0.96mmol), potassium hydroxide (0.16g, 2.88mmol) was reacted in tetrahydrofuran (10 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a white solid (0.31g, 78%).
MS(ESI,pos.ion)m/z:416.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)7.56(dd,J＝8.6,2.1Hz,1H),7.39(d,J＝2.0Hz,1H),7.30(d,J＝8.9Hz,1H),7.12(d,J＝8.7Hz,1H),7.04(d,J＝2.2Hz,1H),6.93(dd,J＝8.9,2.4Hz,1H),3.82(s,3H),3.75(s,3H),2.94(brs,4H),2.87(brs,4H),2.47(s,3H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm)156.2,154.4,142.5,134.1,131.9,130.9,128.0,122.1,117.4,116.0,115.7,114.0,112.5,101.0,56.4,55.8,51.0,45.7,9.3.
Example Synthesis of 5-methoxy-2- ((4-methoxy-3- (4-methylpiperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole
Figure BDA0001713906860000821
The title compound was prepared as described in example 22 for 5-methoxy-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole (130mg, 0.31mmol), naBH 3 CN (48mg, 0.77mmol), paraformaldehyde (28mg, 0.93mmol) in methanol (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale yellow solid (120mg, 92%).
MS(ESI,pos.ion)m/z:430.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)11.80(s,1H),7.55(d,J＝7.4Hz,1H),7.39(s,1H),7.29(d,J＝8.9Hz,1H),7.12(d,J＝8.5Hz,1H),7.03(s,1H),6.93(d,J＝8.7Hz,1H),3.82(s,3H),3.76(s,3H),2.98(brs,4H),2.46(brs,7H),2.20(s,3H).
Example Synthesis of 5-fluoro-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole
Figure BDA0001713906860000822
Step 1) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-fluoro-3-methyl-1H-indol-2-yl) thio) benzene Synthesis of yl) piperazin-1-yl) acetyl
The title compound was prepared as described in example 1, step 2 by reacting 3-methyl-5-fluoroindole (0.5g, 3.35mmol), 4-methoxy-3- (4- (2,2,2-trichloroacetyl) piperazin-1-yl) benzenesulfonylhydrazide (1.7g, 4.03mmol), iodine (85mg, 0.33mmol) in ethanol (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a pale yellow solid (1.15g, 67%).
MS(ESI,pos.ion)m/z:516.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.04(s,1H),7.21-7.15(m,2H),6.96(td,J＝9.1,2.5Hz,1H),6.79(s,1H),6.77(d,J＝2.0Hz,1H),6.74(d,J＝8.2Hz,1H),4.03-3.79(m,7H),3.08(t,J＝4.8Hz,4H),2.35(s,3H).
Step 2) 1- (2-methoxy-5- ((5-fluoro-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) -4- (2,2,2- Synthesis of trichloroacetyl) piperazine 1-oxideBecome into
The title compound was prepared as described in example 1, step 3, by reacting 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-fluoro-3-methyl-1H-indol-2-yl) thio) phenyl) piperazin-1-yl) acetyl (1.14g, 2.21mmol), potassium peroxymonosulfonate (5.4g, 8.84mmol), sodium bicarbonate (0.74g, 8.84mmol) in acetone (15 mL) and water (5 mL), and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale yellow solid (1.1g, 92%).
MS(ESI,pos.ion)m/z:564.0[M+H] + .
Step 3) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-fluoro-3-methyl-1H-indol-2-yl) sulfonyl) Synthesis of phenyl) piperazin-1-yl) acetyl
The title compound was prepared as described in example 21, step 4 by reacting 1- (2-methoxy-5- ((5-fluoro-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) -4- (2,2,2-trichloroacetyl) piperazine 1-oxide (0.5g, 0.89mmol), cuprous iodide (168mg, 0.89mmol), triethylamine (0.12ml, 0.89mmol) in tetrahydrofuran (5 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a pale yellow solid (338mg, 70%).
MS(ESI,pos.ion)m/z:548.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.25(s,1H),7.69(dd,J＝8.6,2.2Hz,1H),7.47(d,J＝2.2Hz,1H),7.32(dd,J＝9.0,4.2Hz,1H),7.21(dd,J＝9.0,2.3Hz,1H),7.07(td,J＝9.0,2.4Hz,1H),6.94(d,J＝8.7Hz,1H),3.91(s,7H),3.09(t,J＝4.7Hz,4H),2.48(s,3H).
Step 4) Synthesis of 5-fluoro-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole Become into
The title compound of this step was prepared as described in example 21, step 5, by reacting 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-fluoro-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) piperazin-1-yl) acetyl (0.33g, 0.6 mmol), potassium hydroxide (0.1g, 1.8mmol) in tetrahydrofuran (5 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a white solid (0.18g, 75%).
MS(ESI,pos.ion)m/z:404.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)7.58(dd,J＝8.6,2.1Hz,1H),7.42-7.41(m,1H),7.40-7.39(m,2H),7.16-7.13(m,2H),3.83(s,3H),2.94(brs,4H),2.88-2.87(m,4H),2.45(s,3H).
Example Synthesis of 5-fluoro-2- ((4-methoxy-3- (4-methylpiperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole
Figure BDA0001713906860000831
The title compound was prepared as described in example 22 for 5-fluoro-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole (73mg, 0.18mmol), naBH 3 CN (28mg, 0.45mmol), paraformaldehyde (1695g, 0.54mmol) were reacted in methanol (5 mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale yellow solid (72mg, 95%).
MS(ESI,pos.ion)m/z:418.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.57(dd,J＝8.6,2.1Hz,1H),7.43-7.36(m,3H),7.16-7.12(m,2H),3.83(s,3H),2.99(brs,4H),2.45(brs,7H),2.20(s,3H).
EXAMPLE 60 Synthesis of 5-chloro-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole
Figure BDA0001713906860000841
Step 1) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-chloro-3-methyl-1H-indol-2-yl) thio) benzene Synthesis of yl) piperazin-1-yl) acetyl
The title compound was prepared as described in example 1, step 2 by reacting 3-methyl-5-chloroindole (0.5g, 3.03mmol), 4-methoxy-3- (4- (2,2,2-trichloroacetyl) piperazin-1-yl) benzenesulfonylhydrazide (1.5g, 3.63mmol), iodine (76mg, 0.3 mmol) in ethanol (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a pale yellow solid (1.46g, 91%).
MS(ESI,pos.ion)m/z:532.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.10(s,1H),7.52(s,1H),7.19-7.13(m,2H),6.79(s,1H),6.76(d,J＝1.9Hz,1H),6.74(d,J＝8.3Hz,1H),4.02-3.74(m,7H),3.08(t,J＝4.8Hz,4H),2.36(s,3H).
Step 2) 1- (2-methoxy-5- ((5-chloro-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) -4- (2,2,2- Synthesis of trichloroacetyl) piperazine 1-oxideBecome into
The title compound was prepared as described in example 1, step 3, by reacting 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-chloro-3-methyl-1H-indol-2-yl) thio) phenyl) piperazin-1-yl) acetyl (1.43g, 2.69mmol), potassium peroxymonosulfonate (6.61g, 10.76mmol), sodium bicarbonate (0.9g, 10.76mmol) in acetone (15 mL) and water (5 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale yellow solid (1.4g, 90%).
MS(ESI,pos.ion)m/z:580.0[M+H] + .
Step 3) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-chloro-3-methyl-1H-indol-2-yl) sulfonyl) Synthesis of phenyl) piperazin-1-yl) acetyl
The title compound of this step was prepared as described in example 21, step 4, by reacting 1- (2-methoxy-5- ((5-chloro-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) -4- (2,2,2-trichloroacetyl) piperazine 1-oxide (0.7 g, 1.21mmol), cuprous iodide (230mg, 1.21mmol), triethylamine (0.17ml, 1.21mmol) in tetrahydrofuran (5 mL), and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to obtain the title compound as a pale yellow solid (458mg, 78%).
MS(ESI,pos.ion)m/z:564.0[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)12.17(s,1H),7.70(d,J＝1.4Hz,1H),7.63(dd,J＝8.6,2.1Hz,1H),7.44(d,J＝2.1Hz,1H),7.41(d,J＝8.8Hz,1H),7.27(dd,J＝8.8,2.0Hz,1H),7.19(d,J＝8.7Hz,1H),3.99-3.77(m,7H),3.12(brs,4H),2.47(s,3H).
Step 4) Synthesis of 5-chloro-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole Become into
The title compound of this step was prepared by the method described in example 21, step 5, i.e. 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-chloro-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) piperazin-1-yl) acetyl (0.46g, 0.82mmol), potassium hydroxide (0.14g, 2.5mmol) were reacted in tetrahydrofuran (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a white solid (281mg, 82%).
MS(ESI,pos.ion)m/z:420.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)7.70(d,J＝1.9Hz,1H),7.57(dd,J＝8.6,2.2Hz,1H),7.41(d,J＝8.8Hz,1H),7.38(d,J＝2.2Hz,1H),7.27(dd,J＝8.8,2.0Hz,1H),7.13(d,J＝8.7Hz,1H),3.83(s,3H),2.90-2.89(m,4H),2.84-2.83(m,4H),2.46(s,3H).
Example 61 Synthesis of 5-chloro-2- ((4-methoxy-3- (4-methylpiperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole
Figure BDA0001713906860000851
The title compound was prepared as described in example 22 for 5-chloro-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole (105mg, 0.24mmol), naBH 3 CN (38mg, 0.6 mmol), paraformaldehyde (22mg, 0.72mmol) were reacted in methanol (5 mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale yellow solid (100mg, 93%).
MS(ESI,pos.ion)m/z:434.0[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.69(d,J＝1.8Hz,1H),7.58(dd,J＝8.6,2.1Hz,1H),7.42-7.40(m,2H),7.27(dd,J＝8.8,2.0Hz,1H),7.13(d,J＝8.7Hz,1H),3.83(s,3H),2.99(brs,4H),2.47(s,3H),2.44(brs,4H),2.20(s,3H).
Example 62 Synthesis of 5-bromo-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole
Figure BDA0001713906860000852
Step 1) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-bromo-3-methyl-1H-indol-2-yl) thio) benzene Synthesis of yl) piperazin-1-yl) acetyl
The title compound was prepared as described in example 1, step 2 by reacting 3-methyl-5-bromoindole (0.533g, 2.55mmol), 4-methoxy-3- (4- (2,2,2-trichloroacetyl) piperazin-1-yl) benzenesulfonylhydrazide (1.3g, 3.06mmol), iodine (64mg, 0.25mmol) in ethanol (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a pale yellow solid (1.3g, 88%).
MS(ESI,pos.ion)m/z:576.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.07(s,1H),7.69(d,J＝1.2Hz,1H),7.28(dd,J＝8.7,1.8Hz,1H),7.13(d,J＝8.6Hz,1H),6.79(s,1H),6.77(d,J＝1.9Hz,1H),6.74(d,J＝8.8Hz,1H),4.02-3.79(m,7H),3.08(t,J＝4.8Hz,4H),2.35(s,3H).
Step 2) 1- (2-methoxy-5- ((5-bromo-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) -4- (2,2,2- Synthesis of trichloroacetyl) piperazine 1-oxide
The title compound of this step was prepared by the method described in example 1, step 3, i.e. 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-bromo-3-methyl-1H-indol-2-yl) thio) phenyl) piperazin-1-yl) acetyl (1.26g, 2.19mmol), potassium peroxymonosulfonate (5.37g, 8.76mmol), sodium bicarbonate (0.73g, 8.76mmol) were reacted in acetone (15 mL) and water (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a light yellow solid (1.24g, 91%).
MS(ESI,pos.ion)m/z:623.9[M+H] + .
Step 3) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-bromo-3-methyl-1H-indol-2-yl) sulfonyl) Synthesis of phenyl) piperazin-1-yl) acetyl
The title compound was prepared as described in example 21, step 4 by reacting 1- (2-methoxy-5- ((5-bromo-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) -4- (2,2,2-trichloroacetyl) piperazine 1-oxide (0.8g, 1.28mmol), cuprous iodide (240mg, 1.28mmol), triethylamine (0.17ml, 1.21mmol) in tetrahydrofuran (5 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a pale yellow solid (0.64g, 82%).
MS(ESI,pos.ion)m/z:608.0[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)12.17(s,1H),7.84(s,1H),7.63(dd,J＝8.6,2.1Hz,1H),7.43(d,J＝2.1Hz,1H),7.39(dd,J＝8.8,1.7Hz,1H),7.35(d,J＝8.7Hz,1H),7.19(d,J＝8.7Hz,1H),3.87(brs,7H),3.12(brs,4H),2.46(s,3H).
Step 4) Synthesis of 5-bromo-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole Become into
The title compound of this step was prepared by the method described in example 21, step 5, i.e. 2,2,2-trichloro-1- (4- (2-methoxy-5- ((5-bromo-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) piperazin-1-yl) acetyl (0.63g, 0.82mmol), potassium hydroxide (0.14g, 2.5mmol) were reacted in tetrahydrofuran (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a white solid (0.4g, 83%).
MS(ESI,pos.ion)m/z:464.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.84(s,1H),7.57(dd,J＝8.6,2.1Hz,1H),7.43-7.33(m,3H),7.12(d,J＝8.7Hz,1H),3.83(s,3H),2.89-2.88(m,4H),2.83-2.82(m,4H),2.46(s,3H)；
13 C NMR(150MHz,DMSO-d 6 )δ(ppm)156.4,142.8,135.1,133.5,132.1,129.4,128.4,123.3,122.2,116.0,115.8,115.1,112.9,112.5,56.4,51.6,46.1,9.0.
Example Synthesis of 5-bromo-2- ((4-methoxy-3- (4-methylpiperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole
Figure BDA0001713906860000861
The title compound was prepared as described in example 22 for 5-bromo-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole (100mg, 0.21mmol), naBH 3 CN (33mg, 0.52mmol), paraformaldehyde (19mg, 0.63mmol) in methanol (5 mL) and purification of the crude product by silica gel column chromatography (bisMethyl chloride/methanol (v/v) = 20/1), yielding the title compound as a light yellow solid (100mg, 97%).
MS(ESI,pos.ion)m/z:478.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.81(s,1H),7.57(dd,J＝8.6,2.1Hz,1H),7.39(d,J＝2.2Hz,1H),7.34(s,2H),7.12(d,J＝8.7Hz,1H),3.83(s,3H),2.98(brs,4H),2.46(s,3H),2.44(brs,4H),2.20(s,3H).
Example Synthesis of 64-fluoro-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole
Figure BDA0001713906860000862
Step 1) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((6-fluoro-3-methyl-1H-indol-2-yl) thio) benzene Synthesis of yl) piperazin-1-yl) acetyl
The title compound was prepared as described in example 1, step 2 by reacting 3-methyl-6-fluoroindole (0.5g, 3.35mmol), 4-methoxy-3- (4- (2,2,2-trichloroacetyl) piperazin-1-yl) benzenesulfonylhydrazide (1.8g, 4.26mmol), iodine (85mg, 0.33mmol) in ethanol (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a pale yellow solid (1.21g, 70%).
MS(ESI,pos.ion)m/z:516.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.03(s,1H),7.20-7.15(m,2H),7.01-6.94(m,1H),6.78(s,1H),6.78(d,J＝2.0Hz,1H),6.73(d,J＝8.0Hz,1H),4.04-3.79(m,7H),3.10(brs,4H),2.37(s,3H).
Step 2) 1- (2-methoxy-5- ((6-fluoro-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) -4- (2,2,2- Synthesis of trichloroacetyl) piperazine 1-oxide
The title compound was prepared as described in example 1, step 3, by reacting 2,2,2-trichloro-1- (4- (2-methoxy-5- ((6-fluoro-3-methyl-1H-indol-2-yl) thio) phenyl) piperazin-1-yl) acetyl (1.1lg, 2.25mmol), potassium peroxymonosulfonate (5.4g, 8.84mmol), sodium bicarbonate (0.74g, 8.84mmol) in acetone (15 mL) and water (5 mL), and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale yellow solid (0.98g, 81.9%).
MS(ESI,pos.ion)m/z:564.0[M+H] + .
Step 3) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((6-fluoro-3-methyl-1H-indol-2-yl) sulfonyl) Synthesis of phenyl) piperazin-1-yl) acetyl
The title compound was prepared as described in example 21, step 4 by reacting 1- (2-methoxy-5- ((6-fluoro-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) -4- (2,2,2-trichloroacetyl) piperazine 1-oxide (0.5g, 0.89mmol), cuprous iodide (168mg, 0.89mmol), triethylamine (0.12ml, 0.89mmol) in tetrahydrofuran (5 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a pale yellow solid (394mg, 81.6%).
MS(ESI,pos.ion)m/z:548.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.26(s,1H),7.68(dd,J＝8.4,2.2Hz,1H),7.47(d,J＝2.2Hz,1H),7.31(dd,J＝8.6,4.2Hz,1H),7.22(dd,J＝8.6,2.4Hz,1H),7.07(td,J＝9.0,2.4Hz,1H),6.95(d,J＝8.7Hz,1H),3.93(brs,7H),3.12-3.07(m,4H),2.49(s,3H).
Step 4) Synthesis of 6-fluoro-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole Become into
The title compound of this step was prepared by the method described in example 21, step 5, i.e. 2,2,2-trichloro-1- (4- (2-methoxy-5- ((6-fluoro-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) piperazin-1-yl) acetyl (0.3g, 0.55mmol), potassium hydroxide (90mg, 1.6 mmol) was reacted in tetrahydrofuran (5 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a white solid (0.16g, 66.7%).
MS(ESI,pos.ion)m/z:404.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)7.59-7.57(m,1H),7.42-7.40(m,1H),7.39-7.36(m,2H),7.16-7.13(m,2H),3.83(s,3H),2.94(brs,4H),2.88(brs,4H),2.45(s,3H).
Example 65 Synthesis of 6-chloro-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole
Figure BDA0001713906860000871
Step 1) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((6-chloro-3-methyl-1H-indol-2-yl) thio) benzene Synthesis of yl) piperazin-1-yl) acetyl
The title compound was prepared as described in example 1, step 2 by reacting 3-methyl-6-chloroindole (0.5g, 3.03mmol), 4-methoxy-3- (4- (2,2,2-trichloroacetyl) piperazin-1-yl) benzenesulfonylhydrazide (1.6 g, 3.87mmol), iodine (76mg, 0.3 mmol) in ethanol (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a pale yellow solid (1.35g, 84%).
MS(ESI,pos.ion)m/z:532.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.09(s,1H),7.51(s,1H),7.20-7.13(m,2H),6.78(s,1H),6.77(d,J＝2.0Hz,1H),6.74(d,J＝8.1Hz,1H),4.03-3.74(m,7H),3.09-3.07(m,4H),2.36(s,3H).
Step 2) 1- (2-methoxy-5- ((6-chloro-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) -4- (2,2,2- Synthesis of trichloroacetyl) piperazine 1-oxide
The title compound was prepared as described in example 1, step 3, by reacting 2,2,2-trichloro-1- (4- (2-methoxy-5- ((6-chloro-3-methyl-1H-indol-2-yl) thio) phenyl) piperazin-1-yl) acetyl (1.3g, 2.44mmol), potassium peroxymonosulfonate (5.83g, 9.5 mmol), sodium bicarbonate (0.8g, 9.5 mmol) in acetone (15 mL) and water (5 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale yellow solid (1.25g, 88.6%).
MS(ESI,pos.ion)m/z:580.0[M+H] + .
Step 3) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((6-chloro-3-methyl-1H-indol-2-yl) sulfonyl) Synthesis of phenyl) piperazin-1-yl) acetyl
The title compound was prepared as described in example 21, step 4 by reacting 1- (2-methoxy-5- ((6-chloro-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) -4- (2,2,2-trichloroacetyl) piperazine 1-oxide (0.7 g, 1.21mmol), cuprous iodide (230mg, 1.21mmol), triethylamine (0.17ml, 1.21mmol) in tetrahydrofuran (5 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a pale yellow solid (467mg, 79.5%).
MS(ESI,pos.ion)m/z:564.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.22(s,1H),7.71(dd,J＝8.4,2.4Hz,1H),7.52(d,J＝1.6Hz,1H),7.48-7.41(m,2H),7.27-7.22(m,1H),6.95(d,J＝8.4Hz,1H),3.92-3.81(m,7H),3.08(t,J＝4.4Hz,4H),2.51(s,3H).
Step 4) Synthesis of 6-chloro-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole Become into
The title compound was prepared as described in example 21, step 5, by reacting 2,2,2-trichloro-1- (4- (2-methoxy-5- ((6-chloro-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) piperazin-1-yl) acetyl (0.45g, 0.8mmol), potassium hydroxide (0.13g, 2.4mmol) in tetrahydrofuran (5 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a white solid (265mg, 79%).
MS(ESI,pos.ion)m/z:420.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.18(s,1H),7.63(dd,J＝8.6,2.4Hz,1H),7.55(d,J＝1.2Hz,1H),7.47(d,J＝2.4Hz,1H),7.44(d,J＝8.6Hz,1H),7.21(dd,J＝6.8,1.6Hz,1H),6.92(d,J＝8.8Hz,1H),3.90(s,3H),3.09(brs,4H),3.06(brs,4H),2.51(s,3H).
Example 66 Synthesis of 6-bromo-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole
Figure BDA0001713906860000881
Step 1) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((6-bromo-3-methyl-1H-indol-2-yl) thio) benzene Synthesis of yl) piperazin-1-yl) acetyl
The title compound of this step was prepared by the method described in example 1, step 2, i.e., 3-methyl-6-bromoindole (0.445g, 2.13mmol), 4-methoxy-3- (4- (2,2,2-trichloroacetyl) piperazin-1-yl) benzenesulfonylhydrazide (1.1g, 2.59mmol), iodine (54mg, 0.21mmol) were reacted in ethanol (10 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a pale yellow solid (727mg, 60%).
MS(ESI,pos.ion)m/z:575.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.02(s,1H),7.41-7.39(m,2H),7.22(dd,J＝8.8,1.6Hz,1H),6.78(d,J＝1.2Hz,1H),6.75-6.72(m,2H),3.97(brs,4H),3.82(s,3H),3.08(t,J＝4.8Hz,4H),2.38(s,3H).
Step 2) 1- (2-methoxy-5- ((6-bromo-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) -4- (2,2,2- Synthesis of trichloroacetyl) piperazine 1-oxide
The title compound of this step was prepared as described in example 1, step 3, by reacting 2,2,2-trichloro-1- (4- (2-methoxy-5- ((6-bromo-3-methyl-1H-indol-2-yl) thio) phenyl) piperazin-1-yl) acetyl (727mg, 1.26mmol), potassium peroxymonosulfonate (2.32g, 3.78mmol), sodium bicarbonate (318mg, 3.78mmol) in acetone (15 mL) and water (5 mL), and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a pale yellow solid (786mg, 99%).
MS(ESI,pos.ion)m/z:624.0[M+H] + .
Step 3) 2,2,2-trichloro-1- (4- (2-methoxy-5- ((6-bromo-3-methyl-1H-indol-2-yl) sulfonyl) Synthesis of phenyl) piperazin-1-yl) acetyl
The title compound of this step was prepared by the method described in example 21, step 4, i.e. 1- (2-methoxy-5- ((6-bromo-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) -4- (2,2,2-trichloroacetyl) piperazine 1-oxide (786 mg, 1.26mmol), cuprous iodide (240mg, 1.28mmol), triethylamine (0.17ml, 1.21mmol) were reacted in tetrahydrofuran (5 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/1) to give the title compound as a pale yellow solid (615mg, 80%).
MS(ESI,pos.ion)m/z:608.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.21(s,1H),7.69(dd,J＝8.8,2.4Hz,1H),7.52(d,J＝1.6Hz,1H),7.49-7.41(m,2H),7.26-7.22(m,1H),6.95(d,J＝8.4Hz,1H),3.92-3.78(m,7H),3.08(t,J＝4.4Hz,4H),2.51(s,3H).
Step 4) Synthesis of 6-bromo-2- ((4-methoxy-3- (piperazin-1-yl) phenyl) sulfonyl) -3-methyl-1H-indole To become
The title compound was prepared as described in example 21, step 5, by reacting 2,2,2-trichloro-1- (4- (2-methoxy-5- ((6-bromo-3-methyl-1H-indol-2-yl) sulfonyl) phenyl) piperazin-1-yl) acetyl (605mg, 0.79mmol), potassium hydroxide (134mg, 2.4 mmol) in tetrahydrofuran (5 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a white solid (383mg, 83%).
MS(ESI,pos.ion)m/z:464.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)9.16(s,1H),7.62(dd,J＝8.4,2.4Hz,1H),7.55(d,J＝1.2Hz,1H),7.48(d,J＝2.4Hz,1H),7.44(d,J＝8.8Hz,1H),7.22(dd,J＝6.8,1.6Hz,1H),6.90(d,J＝8.8Hz,1H),3.90(s,3H),3.09(brs,4H),3.06(brs,4H),2.50(s,3H).
Biological assay
The following experimental methods were used for the biological testing of the compounds of the invention:
EXAMPLE A radioligand binding assay to evaluate Compounds of the invention on human 5-HT expressed on CHO cells 6 Affinity of receptor
32 mu g of the prepared expression active human 5-HT 6 A CHO cell membrane protein of a receptor, 2nM radioactive label [2 ] 3 H]Uniformly mixing LSD, compounds with different test concentrations and test buffer solution, and then incubating the mixed solution at 37 ℃ for 120min; wherein, the components of the test buffer solution are as follows: 50mM Tris-HCl (pH 7.4), 10mM MgCl 2 0.5mM EDTA, 10. Mu.M pargyline and 20mg/l protease inhibitor.
Non-specific binding sites were removed by adding 100. Mu.M 5-HT. After the incubation, the mixture was filtered under vacuum through a glass filter (GF/B, packard), the filter membrane of which was pre-impregnated with 0.3% PEI prior to filtration. After filtration, the filters were washed several times with 50mM Tris-HCl. After the filters are dried, the radioactivity of the filters is counted in a scintillation counter (Topcount, packard) using scintillation cocktail. Wherein the standard reference compound is 5-HT, and multiple concentrations are tested in each experiment to obtain its competitive inhibition curve, and nonlinear regression analysis is performed via Hill equation curve to obtain IC 50 The value is calculated by the ChengPrusoff equation to obtain the Ki value.
The compound of the invention is used for treating human 5-HT expressed on CHO cells 6 The results of the receptor affinity assay are shown in table a.
Table a results of affinity assay of the compounds of the present invention
Example No. 2 Ki(nM) Example No. 2 Ki(nM)
Example 17 2.9 Example 58 4.5
Example 21 3.1 Example 60 2.0
Example 30 1.3 Example 64 3.9
Example 37 0.55 Example 65 4.6
As can be seen from Table A, the compounds of the present invention are shown to be in 5-HT 6 Higher activity is generally shown in affinity assays for receptors.
Example B pharmacokinetic evaluation of dogs and monkeys after intravenous or intragastric dosing of Compounds of the invention
1) Test animal
The tested animals are dogs and monkeys, and the specific information is shown in table 2:
table 2 information sheet of the subject animal of the present invention
Germling Grade Sex Body weight Age (age) Source
Beagle dog Cleaning stage Male(s) 8～10kg 6-7 weeks Hunan Slek laboratory animals Co., ltd
Macaca fascicularis SPF Male(s) 3～5kg 4 years old GUANGDONG LANDAU BIOTECHNOLOGY Co.,Ltd.
2) Analytical method
The LC/MS/MS system for analysis included an Agilent 1200 series vacuum degasser, a binary pump, an orifice plate autosampler, a thermostatted column oven, an Agilent G6430A triple quadrupole mass spectrometer with an electrospray ionization (ESI) source. The quantitative analysis was performed in MRM mode, where the parameters of the MRM transition are shown in table 3:
TABLE 3
Fragmentation voltage 30V
Capillary voltage 140V
Dryer temperature 350℃
Atomizer 40psi
Flow rate of dryer 9L/min
The analysis was performed using waters XBridge C18 (2.1x 50mm,3.5 μ M column, injected with 5 μ L sample) under the following conditions: the mobile phases were water +2mM ammonium formate +0.1% formic acid (mobile phase a) and methanol +2mM ammonium formate +0.1% formic acid (mobile phase B), the flow rate was 0.4mL/min, and the mobile phase gradient is shown in table 4:
TABLE 4
Time Gradient of mobile phase B
1.1min 5％
1.6min 95％
2.6min 95％
2.7min 5％
3.7min Terminate
3) Experimental methods
The compounds of the invention were evaluated for pharmacokinetics in dogs and monkeys by the following specific steps:
the experiment was divided into two groups, one group administered by intravenous injection and one group administered by intragastric gavage. The compounds of the invention are administered to the test animals as 5% DMSO +5% Kolliphor HS 15+2% (2% HCl) +88% Saline saline solution or 10% DMSO +10% aqueous physiological saline solution. For the group administered by intravenous injection, the dose was 1mg/kg, followed by intravenous blood (0.3 mL) at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration and centrifugation at 3,000 or 4,000rpm for 10 minutes, and the plasma solution was collected and stored at-20 ℃ or-70 ℃. For the gavage group, the dose was 2.5mg/kg or 5mg/kg, and then blood was taken intravenously (0.3 mL) at time points of 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after administration and centrifuged at 3,000 or 4,000rpm for 10 minutes, and the plasma solution was collected and stored at-20 ℃ or-70 ℃.
The plasma solutions collected from the above groups were analyzed by LC/MS/MS, and the analysis results show that the compounds of the present invention have better pharmacokinetic properties in dogs and monkeys.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an embodiment," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment, or example is included in at least one embodiment, or example of the invention. In this specification, a schematic representation of the above terms does not necessarily refer to the same embodiment, implementation, or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations, or examples. Furthermore, the various examples, embodiments, or examples described in this specification, as well as features of various examples, embodiments, or examples, may be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (12)

1. A compound of formula (III) or formula (IV), or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt of a compound of formula (III) or formula (IV),
Figure FDA0003865362900000011
wherein:
each R 1 Independently is methoxy;
each R 4 And R 5 Independently H, D, F, cl, br, I, C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkyl radicalOr halo C 1-6 An alkoxy group;
each R 6 Independently H, D, F, cl, br, I, C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group;
each R 7 Independently H, D, C 1-6 Alkyl, halo C 1-6 Alkyl or C 3-8 A cycloalkyl group;
R 8 is H, D or C 1-6 An alkyl group.
2. The compound of claim 1, wherein each R 4 And R 5 Independently H, D, F, cl, br, I, C 1-4 Alkyl radical, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group.
3. The compound of claim 1, wherein each R 7 Independently H, D, C 1-4 Alkyl, halo C 1-4 Alkyl or C 3-6 A cycloalkyl group.
4. The compound of claim 1, wherein each R 4 And R 5 Independently H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CHF 2 、-CF 3 、-CH 2 CF 3 、-CF 2 CHF 2 、-CHFCF 3 、-CF 2 CF 3 、-CH 2 CF 2 CF 3 or-CH 2 CF 2 CHF 2 。
5. The compound of claim 1, wherein each R 6 Independently H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CHF 2 、-CF 3 、-CH 2 CF 3 、-CF 2 CHF 2 、-CHFCF 3 、-CF 2 CF 3 、-CH 2 CF 2 CF 3 or-CH 2 CF 2 CHF 2 。
6. The compound of claim 1, wherein each R 7 Independently H, D, methyl, ethyl, n-propyl, isopropyl, -CHF 2 、-CF 3 、-CH 2 CF 3 、-CF 2 CHF 2 、-CHFCF 3 、-CF 2 CF 3 、-CH 2 CF 2 CF 3 、-CH 2 CF 2 CHF 2 Cyclopropyl, cyclobutyl or cyclopentyl.
7. The compound of claim 1, wherein R 8 Is H, D, methyl, ethyl, n-propyl, isopropyl, -CH 2 CH 2 CH(CH 3 ) 2 or-CH 2 C(CH 3 ) 3 。
8. The compound of claim 1, having the structure of one of:
Figure FDA0003865362900000021
Figure FDA0003865362900000031
Figure FDA0003865362900000041
Figure FDA0003865362900000051
Figure FDA0003865362900000052
or a solid thereofIsomers, geometric isomers, tautomers, or pharmaceutically acceptable salts.
9. A pharmaceutical composition comprising a compound of any one of claims 1-8; and
it further comprises a pharmaceutically acceptable carrier, excipient, diluent, or combination thereof.
10. The pharmaceutical composition of claim 9, further comprising an additional therapeutic agent that is a drug for treating alzheimer's disease, a drug for treating a neurological disorder, or a combination thereof.
11. The pharmaceutical composition of claim 9, further comprising an additional therapeutic agent that is donepezil, nalmefene, risperidone, vitamins E, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, lu-AE58054, tacrine, rivastigmine, galantamine, memantine, mirtazapine, venlafaxine, descumulan, nortriptyline, zolpidem, zopiclone, nicergoline, piracetam, selegiline, pentoxifylline, or a combination thereof.
12. Use of a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to any one of claims 9 to 11 for the manufacture of a medicament for the prevention, treatment or alleviation of 5-HT 6 A receptor-associated disease;
wherein the said and 5-HT 6 The receptor-associated disease is a CNS disorder, a gastrointestinal disorder or obesity;
wherein said CNS disorder is attention deficit hyperactivity disorder, anxiety, a stress-related disorder, schizophrenia, obsessive compulsive disorder, manic-depressive disorders, neurological disorders, memory disorders, attention deficit disorder, parkinson's disease, amyotrophic lateral sclerosis, alzheimer's disease or Huntington's chorea.
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