CN111212830A - N- (substituted sulfonyl) benzamide derivative and preparation method and medical application thereof - Google Patents
N- (substituted sulfonyl) benzamide derivative and preparation method and medical application thereof Download PDFInfo
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Abstract
The invention relates to N- (substituted sulfonyl) benzamide derivatives, a preparation method and medical application thereof. In particular to an N- (substituted sulfonyl) benzamide derivative shown in a general formula (I), a preparation method thereof, a medicinal salt thereof and application thereof as a therapeutic agent, in particular as a Nav1.7 inhibitor, whereinThe definition of each substituent in the general formula (I) is the same as that in the specification.
Description
The invention relates to an N- (substituted sulfonyl) benzamide derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative as a therapeutic agent, in particular as a Nav1.7 inhibitor.
Voltage-gated sodium ion channels (VGSC) have inward currents that are important components of central and peripheral neuronal action potential generation and conduction, while increased neuronal excitability or increased responsiveness to stimuli are important mechanisms for development of various pain events.A Voltage-gated sodium ion channel is composed of two subunits, α (260kDa) and β (33-36kDa), where α is a functional subunit that is the core subunit constituting the channel, and β subunit assists in the localization and stability of α subunit on the membrane.A α subunit contains about 1700-2000 amino acids, consists of four structurally similar inactivating structures (DI-DIV), each domain consists of six transmembrane α helical fragments (S1-S6). A highly conserved fragment is included between S5 and S6, controls the ion selectivity of the channel and the transmembrane inactivation.A S1-S4 fragment contains positively charged arginine and lysine residues, and regulates the Voltage-mediated receptor signaling, and regulates the Voltage-mediated activation of neuronal activation and neuronal activation.
Extensive studies on the protein family of sodium channels are currently being carried out which are involved in a number of important body functions, producing variants with a major change in sodium ion channel function and activity of the α subunit which can ultimately lead to major pathophysiological symptoms members of this protein family are denoted nav1.x, where x ═ 1 to 9.
Nav1.1 and Nav1.2 in the brain is highly expressed and is vital to normal brain function. Some loss-of-function mutations in Nav1.1 in humans result in epilepsy because these channels are expressed in inhibitory neurons. Therefore, blocking Nav1.1 in the central nerve may produce opposite effects, as it may produce hyperexcitability. However, Nav1.1 also in the peripheral nervous system expression and block the possibility of obtaining analgesic activity. Nav1.3 is mainly in fetal central nervous system expression, in the peripheral nervous system with very low levels or not at all expression, but in the nervous system injury, in rat dorsal horn sensory neurons in the upregulation. Thus, after nerve injury, it serves as an inducible target for the treatment of pain. Nav1.4 is mainly in skeletal muscle expression, the gene mutation on muscle function (including paralysis) has a profound effect. Nav1.5 is mainly in cardiac muscle cells expression, including atrial, ventricular, sinus node, atrioventricular node and heart Purkinje fibers. The rapid rise in cardiac action potential (upstroke) and the rapid conduction of pulses through the cardiac tissue is due to the opening of Nav1.5. An abnormality in Nav1.5 function can lead to the development of a variety of arrhythmias. Nav1.6 is found throughout the central nervous system and peripheral nervous system in the widely distributed voltage-gated sodium channel. It is expressed at high density in the Langerhans (Ranvier) node with medullary neurons. Nav1.8 is mainly in the peripheral nervous system of sensory ganglia, such as dorsal root ganglion expression. There were no human mutations identified for Nav1.8 that produced altered pain responses. Nav1.8 is different from most neuronal Nav, because it is not sensitive to blockade by tetrodotoxin. Thus, tetrodotoxin can be used to isolate the current carried through the channel. Nav1.8 is considered to be a promising target for analgesics. Nav1.9 mainly in dorsal root ganglion neurons in expression of tetrodotoxin insensitive sodium channel, which is in intestinal neurons, especially intestinal plexus expression.
Nav1.7 is the transmembrane protein encoded by SCN9A, expressed specifically in the cell membrane of DRG, sympathetic ganglia in the spinal cord. Nav1.7 has the characteristics of slow opening and slow closing inactivation, and can be quickly recovered from the inactivated state, so that Nav1.7 can generate a large amount of ramp current, the subthreshold stimulation signal of Nav1.7 can be increased, the action potential threshold can be reduced, the Nav1.7 can be activated by small depolarization ramp current, and the sensitivity of neurons to external stimulation can be improved. The characteristic of Nav1.7 in the localized distribution of sensory terminals and its electrophysiological characteristics determine its important role in the transmission of pain stimuli. Therefore, the activation of Nav1.7 ion channels is inhibited, and the sensitivity of neurons to external stimuli is reduced, so that the analgesic effect is achieved.
Based on the genetic and functional research on Nav1.7, Nav1.7 is closely related to the occurrence and development of various pains. Studies have shown that knocking out nav1.7 expression in a subset of sensory neurons that are predominantly nociceptive results in resistance to inflammatory pain. It has been reported that mutation of the SCN9A gene of Nav1.7 results in "erythromelalgia", and that mutation of the SCN9A gene encoding a voltage-gated Nav1.7 channel is associated with causing no pain in the inherited individual. In addition, in rat inflammatory pain model, DRG neurons on Nav1.7 expression increase phenomenon. Further studies have shown that voltage-gated Nav1.7 channels expressed in DRG neurons have a gate function that is involved in the generation of pain signals and that controls the afferent pain signals. The above studies suggest that the Nav1.7 channel may be a drug target for selective treatment of pain without side effects.
A series of nav1.7 inhibitor patents including WO 2015031036, WO2015038533, WO2017037682 and the like have been disclosed, and although some progress has been made in the current nav1.7 inhibitors, the research on them is far from sufficient, and there is still a need to research and develop new nav1.7 inhibitors.
Disclosure of Invention
One purpose of the invention is to disclose a new N- (substituted sulfonyl) benzamide derivative, such as a compound shown in a general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,
wherein:
(i) ring a is selected from monocyclic heterocyclyl; n is 1,2, 3,4, 5 or 6;
R2each independently selected from hydrogen atom, hydroxyl, halogen, nitro, cyano, alkoxy, -NR9R10、-C(O)NR9R10、-C(O)R11、-C(O)OR11or-NR9C(O)R10Wherein said alkoxy is optionally further substituted with one or more halogens; preferably, R2Each independently selected from a hydrogen atom or a halogen, wherein at least one R2Selected from halogens;
(ii) ring A is selected from spiro heterocyclic group or fused heterocyclic group, wherein said spiro heterocyclic group or fused heterocyclic group and L1The atom to which it is attached is an N atom; n is 1,2, 3,4, 5, 6, 7 or 8;
R2each independently selected from hydrogen atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, -NR9R10、-C(O)NR9R10、-C(O)R11、-C(O)OR11or-NR9C(O)R10Wherein said alkyl or alkoxy is optionally further substituted with one or more halogens;
L1is selected from- (CR)aRb) -or-C (═ O) -;
L2is selected from- (CR)aRb)-O-(CRaRb)-；
RaAnd RbEach independently selected from a hydrogen atom, an alkyl group or a halogen; preferably a hydrogen atom or an alkyl group; more preferably RaIs alkyl, RbIs a hydrogen atom; most preferably RaSelected from methyl or ethyl, RbIs a hydrogen atom;
R1each independently selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, -NR9R10、-C(O)NR9R10、-C(O)R11、-C(O)OR11or-NR9C(O)R10Wherein said alkyl or alkoxy is optionally further substituted with one or more halogens;
R3、R4、R5and R6Each independently selected from a hydrogen atom, a halogen, a cyano, an alkyl, a cycloalkyl, a heterocyclyl or an alkoxy, wherein said alkyl, cycloalkyl, heterocyclyl or alkoxy is optionally further substituted by one or more halogens;
R7selected from hydrogen atoms or alkyl groups, wherein said alkyl groups are optionally further substituted by one or more halogens; preferably a hydrogen atom;
R8selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl or-NR9R10Wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR9R10、 -C(O)NR9R10、-C(O)R11、-C(O)OR11or-NR9C(O)R10Substituted with the substituent(s); r8Preferably methyl, ethyl, cyclicPropyl, tert-butyl, isobutyl, substituted or unsubstituted alkyl, or substituted or unsubstituted,
R9、R10And R11Each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR12R13、-C(O)NR12R13、-C(O)R14、-C(O)OR14or-NR12C(O)R13Substituted with the substituent(s);
or, R9And R10Together with the N atom to which they are attached form a 4-to 8-membered heterocyclic group containing one or more N, O, S (O) atoms in the 4-to 8-membered heterocyclic grouppAnd 4-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -NR12R13、-C(O)NR12R13、-C(O)R14、-C(O)OR14or-NR12C(O)R13Substituted with the substituent(s);
R12、R13and R14Each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl group, aryl group, heteroaryl group, carboxyl group, or carboxylate group;
m is 0, 1,2, 3,4 or 5; m is preferably 0, 1 or 2; and is
p is 0, 1 or 2.
In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
wherein:
Raselected from alkyl groups;
R1～R8、L2m and n are as defined in formula (I).
In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
wherein:
Raselected from alkyl groups;
R1～R8、L2m and n are as defined in formula (I).
In a preferred embodiment of the present invention, a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
the ring A is selected from a 4-6-membered monocyclic heterocyclic group, preferably piperidyl or N-heterocyclic butyl;
R2each independently selected from a hydrogen atom or a halogen, wherein at least one R2Selected from halogens.
In a preferred embodiment of the present invention, a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
ring a is selected from the group consisting of a mono spiroheterocyclyl group, preferably a 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl group;
the said mono-spiroheterocyclyl and L1The atom to which it is attached is an N atom; and is
R2Selected from each independently a hydrogen atom or a halogen.
In a preferred embodiment of the invention, a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of:
in a preferred embodiment of the invention, the compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is1Each independently selected from fluoro, chloro, methyl or trifluoromethyl.
In a preferred embodiment of the present invention, a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
R4selected from halogen, preferably fluorine;
R5selected from cycloalkyl, preferably cyclopropyl; and is
R3And R6Each independently selected from hydrogen atoms.
In a preferred embodiment of the present invention, a compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
(i) the ring A is selected from 4-6 membered monocyclic heterocyclic group; r2Each independently selected from a hydrogen atom or a halogen, wherein at least one R2Selected from halogens;
(ii) ring A is selected from the group consisting of a mono-spiroheterocyclyl group, wherein said mono-spiroheterocyclyl group is joined to L1The atom to which it is attached is an N atom; r2Each independently selected from a hydrogen atom or a halogen;
R1selected from halogen, preferably fluorine or chlorine;
R3and R6Each independently selected from a hydrogen atom;
R4selected from halogen, preferably fluorine; and is
R5Is selected from C3-C6Cycloalkyl, preferably cyclopropyl.
In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
wherein:
L1is selected from- (CR)aRb) -or-C (═ O) -;
R1selected from halogen, preferably fluorine or chlorine;
R2each independently selected from a hydrogen atom or a halogen, wherein halogen is preferably fluorine or chlorine;
R7selected from hydrogen atoms or C1-C6Alkyl, wherein said C1-C6Alkyl is optionally further substituted with one or more halogens; wherein R is7Preferably a hydrogen atom;
R8is selected from C1-C6Alkyl radical, C3-C6Cycloalkyl or C3-C6The heterocyclic group is preferably a methyl group, an ethyl group, a cyclopropyl group, a tert-butyl group,
RaAnd RbEach independently selected from a hydrogen atom or C1-C6An alkyl group;
m is selected from 0, 1 or 2; and is
n is selected from 0, 1 or 2.
In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
wherein:
L1is selected from- (CR)aRb) -or-C (═ O) -;
R1selected from halogen, preferably fluorine or chlorine;
R2each independently selected from a hydrogen atom or a halogen, wherein halogen is preferably fluorine or chlorine;
R7selected from hydrogen atoms or C1-C6Alkyl, wherein said C1-C6Alkyl is optionally further substituted with one or more halogens; wherein R is7Preferably a hydrogen atom;
R8is selected from C1-C6Alkyl radical, C3-C6Cycloalkyl or C3-C6The heterocyclic group is preferably a methyl group, an ethyl group, a cyclopropyl group, a tert-butyl group,
RaAnd RbEach independently selected from a hydrogen atom or C1-C6An alkyl group;
m is selected from 0, 1 or 2; and is
n is selected from 0, 1 or 2.
In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (VI) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
wherein:
L1is selected from- (CR)aRb) -or-C (═ O) -;
R1selected from halogen, preferably fluorine or chlorine;
R2each independently selected from a hydrogen atom or a halogen, wherein halogen is preferably fluorine or chlorine;
R7selected from hydrogen atoms or C1-C6Alkyl, wherein said C1-C6Alkyl is optionally further substituted with one or more halogens; preferably a hydrogen atom;
R8is selected from C1-C6Alkyl radical, C3-C6Cycloalkyl or C3-C6The heterocyclic group is preferably a methyl group, an ethyl group, a cyclopropyl group, a tert-butyl group,
RaAnd RbEach independently selected from a hydrogen atom or C1-C6An alkyl group;
m is selected from 0, 1 or 2; and is
n is selected from 0, 1 or 2.
Typical compounds of the invention include, but are not limited to:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Further, the present invention provides a process for the preparation of a compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which comprises:
under the alkaline condition, carrying out condensation reaction on the general formula (IA) and the general formula (IB) in the presence of a condensing agent to obtain a compound of the general formula (I);
wherein:
L1is selected from-C (═ O) -; and is
Ring A, L2、R1～R8M and n are as defined in formula (I).
Further, the present invention provides a process for the preparation of a compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which comprises:
carrying out substitution reaction on the general formula (IA) or the salt thereof and the general formula (IC) to obtain a compound of the general formula (I);
wherein:
L1is selected from- (CR)aRb)-；
G is a leaving group, preferably halogen, methanesulfonyloxy or p-toluenesulfonyloxy;
Ra、Rbeach independently selected from a hydrogen atom or an alkyl group, preferably a hydrogen atom, a methyl group or an ethyl group; and is
Ring A, L2、R1～R8M and n are as defined in formula (I).
Further, the present invention provides a process for the preparation of a compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which comprises:
carrying out condensation reaction on the general formula (ID) and the general formula (Ib) to obtain a compound of the general formula (I);
wherein: ring A, L1、L2、R1～R8M and n are as defined in formula (I).
Further, the present invention provides a compound of the general formula (IA) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
wherein: ring A, L2、R2～R8And n is as defined in formula (I).
Typical compounds of formula (IA) of the present invention include, but are not limited to:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Typical compounds of formula (IA) of the present invention include, but are not limited to:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
The present invention provides a process for the preparation of a compound of general formula (IA) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which process comprises:
carrying out condensation reaction on the general formula (Ia) and the general formula (Ib) under alkaline conditions in the presence of a condensation reagent to obtain a compound of the general formula (Ic); removing the protecting group PG from the general formula (Ic) under acidic conditions to obtain a compound of the general formula (IA) or a salt thereof;
wherein:
PG is selected from amino protecting groups, preferably tert-butoxycarbonyl; and is
Ring A, L2、R2～R8And n is as defined in formula (I).
In the preparation method, the acidic condition is provided by organic acid or inorganic acid, and the organic acid is preferably trifluoroacetic acid; the mineral acid is preferably hydrochloric acid. The basic condition is provided by organic base or inorganic base, the organic base is selected from diisopropylethylamine, pyridine, triethylamine, piperidine, N-methyl piperazine, 4-dimethylaminopyridine, and preferably 4-dimethylaminopyridine; the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, lithium hydroxide, preferably cesium carbonate and potassium carbonate.
Condensing agents include, but are not limited to: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 2- (7-azobenzotriazol) -N, n, N '-tetramethyluronium hexafluorophosphate, bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride, N-dicyclohexylcarbodiimide, N-diisopropylcarbodiimide, o-benzotriazol-N, N' -Tetramethyluronium Borate (TBTU), preferably 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride.
Further, the present invention provides a compound of the general formula (ID) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
wherein: ring A, L1、L2、R1～R6M and n are as defined in formula (I). Typical compounds of the general formula (ID) of the present invention include, but are not limited to:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
The present invention provides a process for the preparation of a compound of general formula (ID) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which process comprises:
further hydrolysis of the compound of formula (If) to give a compound of formula (ID);
wherein:
Rcselected from alkyl groups; preferably methylOr a tert-butyl group;
ring A, L1、L2、R1～R6M and n are as defined in formula (I).
Further, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.
The present invention provides a method of inhibiting Nav1.7 comprising contacting said ion channel with a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
The invention provides an application of a compound shown in a general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a Nav1.7 inhibitor.
The present invention provides the use of a compound of formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a disease associated with nav1.7, wherein the disease is preferably pain, wherein the pain is preferably neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-operative pain, labor pain, neurogenic bladder disorder, ulcerative colitis, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, dental pain and/or peripheral nerve injury.
The present invention provides a method of treating a disease associated with Nav1.7, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, wherein the disease is preferably pain, wherein the pain is preferably neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-operative pain, labor pain, neurogenic bladder disorder, ulcerative colitis, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, dental pain and/or peripheral nerve injury.
The invention provides a method for inhibiting Nav1.7 channels, which comprises the step of combining a compound shown in a general formula (I) of Nav1.7 protein or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
Detailed description of the invention
Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:
"alkyl" when taken as a group or part of a group means including C1-C20Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C10Alkyl, more preferably C1-C6An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.
An "alkylene" is a divalent alkyl group. Preferably C1-C10Alkylene, more preferably C1-C6An alkylene group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, and,
N-propylene, and the like. The alkylene group may be substituted or unsubstituted.
"CycloalkanesBy "radical" is meant saturated or partially saturated monocyclic, fused, bridged, and spiro carbocyclic rings. Preferably C3-C12Cycloalkyl, more preferably C3-C8Cycloalkyl, most preferably C3-C6A cycloalkyl group. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred.
"spirocycloalkyl" refers to a 5 to 18 membered polycyclic group having two or more cyclic structures with single rings sharing a single carbon atom (called the spiro atom) with each other, containing 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified according to the number of spiro atoms shared between rings into mono-, di-or multi-spiro cycloalkyl groups, preferably mono-and di-spiro cycloalkyl groups, preferably 4-membered/5-membered (meaning that 4-membered monocyclic rings and 5-membered monocyclic rings share one carbon atom with each other), 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.
"fused cycloalkyl" refers to a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, pyridone or polycyclic fused alkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl groups. Non-limiting examples of "fused ring alkyl" include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, decalinyl or tetradecaphenanthryl.
"bridged cycloalkyl" means a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing two non-directly attached carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, pyridone or polycyclic bridged cycloalkyl groups according to the number of constituent rings, and are preferably bicyclic, tricyclic or pyridone, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" groups include, but are not limited to: (1s,4s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1s,5s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1r,5r) -bicyclo [3.3.2] decyl.
The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted.
"Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein and all refer to non-aromatic heterocyclic groups in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, nitrogen, sulfur, and the like, including monocyclic, fused, bridged, and spiro rings. Preferably having a 4 to 7 membered monocyclic ring or a 7 to 10 membered bi-or tricyclic ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, and piperazinyl. The heterocyclic group may be substituted or unsubstituted.
"spiroheterocyclyl" refers to a 5-to 18-membered polycyclic group having two or more cyclic structures wherein the individual rings share an atom with one another and which contains 1 or more double bonds within the ring, but none of the rings have a fully conjugated pi-electron aromatic system wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O)p(wherein p is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are divided into mono-spiroheterocyclyl groups, di-spiroheterocyclyl groups, according to the number of spiro atoms shared between ringsHeterocyclic or polyspiroheterocyclic groups, preferably monospiroheterocyclic and dispiroheterocyclic groups. More preferred are 4-membered/4-membered (meaning that 2 4-membered monocyclic rings share one atom with each other), 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono-spiroheterocyclic groups. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5]]Decyl, 2-oxa-7-azaspiro [4.4]Nonyl, 7-azaspiro [3.5]]Nonyl, 7-oxaspiro [3.5]]Nonyl and 5-oxaspiro [2.4]]A heptyl group.
"fused heterocyclyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of which rings may contain one or more double bonds, but none of which rings has a fully conjugated pi-electron aromatic system, wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)p(wherein p is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, pyridone or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-membered/3-membered/, 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo [3,4-c]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0]Hexyl, octahydrobenzo [ b ]][1,4]Dioxins (dioxines).
"bridged heterocyclyl" means a 5-to 14-membered, 5-to 18-membered polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O)p(wherein p is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, pyridone or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or pyridone, more preferably bicyclic or tricyclic. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2]Octyl and 2-azabicyclo [3.3.2]A decyl group. The heterocyclyl ring may be fused to an aryl groupA heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl. The heterocyclic group may be optionally substituted or unsubstituted.
"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferably aryl is C6-C10Aryl, more preferably aryl is phenyl and naphthyl, most preferably phenyl. The aryl group may be substituted or unsubstituted. The "aryl" may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples include, but are not limited to:
"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 9-to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, and benzisoxazolyl. Heteroaryl groups may be substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples include, but are not limited to:
"alkoxy" means(alkyl-O-). Wherein alkyl is as defined herein. C1-C6Alkoxy groups of (4) are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
"hydroxy" means-OH.
"halogen" means fluorine, chlorine, bromine and iodine, preferably chlorine, bromine and iodine.
"amino" means-NH2。
"cyano" means-CN.
"nitro" means-NO2。
"benzyl" means-CH2-phenyl.
"carboxy" refers to-C (O) OH.
"carboxylate" refers to-C (O) O (alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
"DMSO" refers to dimethyl sulfoxide.
"Boc" refers to tert-butoxycarbonyl.
"Ms" refers to sulfonyl.
"Ts" refers to 4-methylbenzenesulfonyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
As used herein, "substituted" or "substituted," unless otherwise specified, means that the group may be substituted with one or more groups selected from: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio,Amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, ═ O, -OR11、-NR9R10、-C(O)NR9R10、-C(O)R11、-C(O)OR11or-NR9C(O)R10；
R9、R10And R11Each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR12R13、-C(O)NR12R13、-C(O)R14、-C(O)OR14or-NR12C(O)R13Substituted with the substituent(s);
or, R9And R10Together with the N atom to which they are attached form a 4-to 8-membered heterocyclic group containing one or more N, O, S (O) atoms in the 4-to 8-membered heterocyclic grouppAnd 4-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -NR12R13、-C(O)NR12R13、-C(O)R14、-C(O)OR14or-NR12C(O)R13Substituted with the substituent(s);
R12、R13and R14Each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl group, aryl group, heteroaryl group, carboxylic acid, or carboxylic acid ester;
p is 0, 1 or 2.
"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, and includes all three of cis-trans isomers, enantiomers and conformers.
"tautomers" are isomers in which the structure of certain organic compounds is transformed into a equilibrium between two functional isomers.
"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain their biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds represented by formula (I) may be metal salts, preferably alkali metal, alkaline earth metal salts, amine salts formed with suitable acids, including inorganic and organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like.
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
Synthesis of the Compounds of the invention
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
the preparation method of the compound or the salt thereof of the general formula (I) comprises the following steps:
under the alkaline condition, carrying out condensation reaction on the general formula (IA) and the general formula (IB) in the presence of a condensing agent to obtain a compound of the general formula (I);
wherein:
L1is selected from-C (═ O) -; and is
Ring A, L2、R1～R8M and n are as defined in formula (I).
The preparation method of the compound or the salt thereof of the general formula (I) comprises the following steps:
under alkaline conditions, carrying out substitution reaction on the general formula (IA) or the salt thereof and the general formula (IC) to obtain a compound of the general formula (I);
wherein:
L1is selected from- (CR)aRb)-；
G is a leaving group, preferably halogen, methanesulfonyloxy or p-toluenesulfonyloxy;
Ra、Rbeach independently selected from a hydrogen atom or an alkyl group, preferably a hydrogen atom, a methyl group or an ethyl group; and is
Ring A, L2、R1～R8M and n are as defined in formula (I).
The preparation method of the compound or the salt thereof of the general formula (I) comprises the following steps:
carrying out condensation reaction on the general formula (ID) and the general formula (Ib) to obtain a compound of the general formula (I);
wherein: ring A, L1、L2、R1～R8M and n are as defined in formula (I).
The invention relates to a preparation method of a compound described by a general formula (IA) or a salt thereof, which comprises the following steps:
hydrolyzing the general formula (Id) under an acidic condition, and simultaneously removing the protecting group PG to obtain a compound of a general formula (Ie); reacting the general formula (Ie) with an N protective reagent, preferably di-tert-butyl dicarbonate to obtain a compound of the general formula (Ia); carrying out condensation reaction on the general formula (Ia) and the general formula (Ib) under alkaline conditions in the presence of a condensation reagent to obtain a compound of the general formula (Ic); deprotection of formula (Ic) under acidic conditions to give a compound of formula (IA) or a salt thereof;
wherein:
R2selected from alkyl, preferably methyl or ethyl;
Rcselected from alkyl groups, preferably tert-butyl groups;
PG is selected from amino protecting groups, preferably tert-butoxycarbonyl; and is
Ring A, L2、R2～R8And n is as defined in formula (I).
The process for producing a compound represented by the general formula (ID) or a salt thereof according to the present invention comprises the steps of:
wherein:
Rcselected from alkyl groups; preferably methyl or tert-butyl;
ring A, L1、L2、R1～R6M and n are as defined in formula (I).
The process for producing a compound represented by the general formula (If) of the present invention or a salt thereof, comprises the steps of:
under alkaline conditions, carrying out condensation reaction on the general formula (Ig) and the general formula (IB) in the presence of a condensing agent to obtain a compound of the general formula (If);
wherein:
L1is selected from-C (═ O) -; and is
Ring A, L2、R1～R6M and n are as defined in formula (I).
The process for producing a compound represented by the general formula (If) of the present invention or a salt thereof, comprises the steps of:
under alkaline conditions, carrying out substitution reaction on the general formula (Ih) or the salt thereof and the general formula (IC) to obtain a compound of the general formula (If); wherein:
L1is selected from- (CR)aRb)-；
G is a leaving group, preferably halogen, methanesulfonyloxy or p-toluenesulfonyloxy;
Ra、Rbeach independently selected from a hydrogen atom or an alkyl group, preferably a hydrogen atom, a methyl group or an ethyl group; rcSelected from alkyl groups; preferably methyl or tert-butyl; and is
Ring A, L2、R1～R6M and n are as defined in formula (I).
In the preparation method, the acidic condition is provided by organic acid or inorganic acid, and the organic acid is preferably trifluoroacetic acid; the mineral acid is preferably hydrochloric acid.
The basic condition is provided by organic base or inorganic base, the organic base is selected from diisopropylethylamine, pyridine, triethylamine, piperidine, N-methyl piperazine, 4-dimethylaminopyridine, and preferably 4-dimethylaminopyridine; the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, lithium hydroxide, preferably cesium carbonate and potassium carbonate.
Condensing agents include, but are not limited to: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 2- (7-azobenzotriazol) -N, n, N '-tetramethyluronium hexafluorophosphate, bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride, N-dicyclohexylcarbodiimide, N-diisopropylcarbodiimide, o-benzotriazol-N, N' -Tetramethyluronium Borate (TBTU), preferably 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride.
FIG. 1 is a voltage program diagram of a manual patch clamp test in the Nav1.7 ion channel test in test example 1.
FIG. 2 is a voltage program diagram of a manual patch clamp test in the Nav1.5 ion channel test in test example 2.
FIG. 3 is a voltage program diagram of whole cell patch clamp in the hERG potassium channel assay in test example 3.
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
Examples
The examples show the preparation of representative compounds represented by formula (I) and the associated structural identification data. It must be noted that the following examples are intended to illustrate the invention and are not intended to limit the invention.1The H NMR spectrum was obtained using a Bruker instrument (400MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00ppm) was used.1Method for H NMR expression: s is singlet, d is doublet, t is triplet, m is multiplet, br is broadened, dd is doublet of doublet, dt is doublet of triplet. If a coupling constant is provided, it is in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and unless otherwise indicated, the various starting materials and reagents are commercially available or synthesized according to known methods, and none of the commercially available materials and reagents are used without further purification, and unless otherwise indicated, commercially available manufacturers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Prov Chemical science Inc. and Sci Chemical science Inc., and the like.
CD3OD: deuterated methanol.
CDCl3: deuterated chloroform.
DMSO-d6: deuterated dimethyl sulfoxide.
The argon atmosphere means that the reaction flask is connected with an argon balloon having a volume of about 1L.
In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.
Purifying the compound by silica gel column chromatography using an eluent system selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: dichloromethane and methanol systems; c: dichloromethane: ethyl acetate; the volume ratio of the solvent is different according to the polarity of the compound, and a small amount of acidic or basic reagent such as acetic acid or triethylamine can be added for adjustment.
Example 1
5-cyclopropyl-4- (((7- (3, 5-difluorobenzoyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
(4-bromo-2-chloro-5-fluorophenyl) methanol
4-bromo-2-chloro-5-fluorobenzoic acid 1a (25g,100mmol) was dissolved in 50mL of tetrahydrofuran, and borane-tetrahydrofuran solution (300mL,1M/THF) was added dropwise at 0 ℃ and reacted at room temperature for 3 hours. 20mL of methanol was slowly added to the reaction mixture at 0 ℃ to quench the reaction. Concentrating under reduced pressure, and removing solvent. 300mL of water was added, extraction was performed with ethyl acetate (200 mL. times.3), the organic phases were combined, washed with a saturated sodium chloride solution (200 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (4-bromo-2-chloro-5-fluorophenyl) methanol 1b (23.6g, white solid), yield: 99 percent.
Second step of
1-bromo-4- (bromomethyl) -5-chloro-2-fluorobenzene
(4-bromo-2-chloro-5-fluorophenyl) methanol 1b (23.6g,98.6mmol) was dissolved in 300mL of dichloromethane, 14mL of phosphorus tribromide was added at 0 ℃, the mixture was stirred at 0 ℃ for 1 hour, and the reaction was continued at room temperature for 10 hours. The reaction was quenched by addition of 200mL of a saturated sodium chloride solution, extracted with dichloromethane (200mL × 3), the aqueous layer was separated, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give 1-bromo-4- (bromomethyl) -5-chloro-2-fluorobenzene 1c (24g, colorless liquid) in yield: 83 percent.
The third step
2- (((4-bromo-2-chloro-5-fluorobenzyl) oxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
2- (hydroxymethyl) -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 1d (5.0g,20mmol) was dissolved in 20mL N, N-dimethylformamide at 0 deg.C, sodium hydride (1.6g,40mmol) was slowly added, and stirring was continued at 0 deg.C for 0.5 h. 1-bromo-4- (bromomethyl) -5-chloro-2-fluorobenzene 1c (6.0g,20mmol) was dissolved in 2ml of N, N-dimethylformamide, and slowly added dropwise to the above reaction solution at 0 ℃ for 0.5 hour at 0 ℃. The reaction mixture was quenched with 20mL of water, extracted with ethyl acetate (50 mL. times.3), the organic phases were combined, washed with saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (eluent: System A) to give tert-butyl 2- (((4-bromo-2-chloro-5-fluorobenzyl) oxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylate 1e (7.4g, yellow solid) in yield: 78 percent. MS m/z (ESI): 421.0[ M-55]
The fourth step
2- (((4- (tert-Butoxycarbonyl) -2-chloro-5-fluorobenzyl) oxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
Under argon, tert-butyl 2- (((4-bromo-2-chloro-5-fluorobenzyl) oxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylate 1e (7.4g,16mmol) was dissolved in 50mL of tetrahydrofuran, isopropyl magnesium chloride Grignard reagent (24mL,2M/THF) was slowly added dropwise at 0 ℃ and stirred at 0 ℃ for 1 hour. Di-tert-butyl dicarbonate (17.4g,80mmol) was dissolved in 5mL of tetrahydrofuran, and the resulting solution was added dropwise to the reaction mixture at 0 ℃ and reacted at room temperature for 3 hours. The reaction mixture was quenched with 20mL of water, extracted with ethyl acetate (100 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent: System A) to give tert-butyl 2- (((4- (tert-butoxycarbonyl) -2-chloro-5-fluorobenzyl) oxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylate 1f (6.2g, colorless oil) in yield: 78 percent.
MS m/z(ESI)：387.9[M-110]
The fifth step
2- (((4- (tert-Butoxycarbonyl) -2-cyclopropyl-5-fluorobenzyl) oxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
Under the protection of argon, tert-butyl 2- (((4- (tert-butoxycarbonyl) -2-chloro-5-fluorobenzyl) oxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylate 1f (6.2g,12mmol), cyclopropylboronic acid (3.1g,36mmol), palladium acetate (268mg,1.2mmol), tricyclohexylphosphine fluoroborate (883mg,2.4mmol) and potassium phosphate (10.2g,48mmol) were dissolved in a mixed solvent of 100mL of toluene and water (V: V ═ 9:1) and reacted at 120 ℃ for 10 hours. Filtration was carried out to remove solid insoluble matter, the filtrate was concentrated under reduced pressure, 50mL of water was added, extraction was carried out with ethyl acetate (50 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to give 1g (5.0g, yellow oil) of tert-butyl 2- (((4- (tert-butoxycarbonyl) -2-cyclopropyl-5-fluorobenzyl) oxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylate, yield: 83 percent.
The sixth step
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid
Tert-butyl 2- (((4- (tert-butoxycarbonyl) -2-cyclopropyl-5-fluorobenzyl) oxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylate 1g (5.0g,10.0mmol) was dissolved in 50mL of dichloromethane, and 20mL of trifluoroacetic acid was added to react at room temperature for 0.5 hour. Concentration under reduced pressure removed dichloromethane and remaining trifluoroacetic acid to give crude 4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid 1h (3.5g, yellow oil) yield: 100 percent.
Seventh step
4- (((7- (tert-butoxycarbonyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid 1h (3.5g,10mmol) was dissolved in 50mL of dichloromethane, triethylamine (4.0g,40mmol) was added, di-tert-butyl dicarbonate (6.5g,30mmol) was added at 0 ℃ and the reaction was carried out at room temperature for 10 hours. Concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 4- (((7- (tert-butoxycarbonyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid 1i (1.0g, yellow oil), yield: 22 percent.
Eighth step
2- (((2-cyclopropyl-5-fluoro-4- ((methylsulfonyl) carbamoyl) benzyl) oxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
4- (((7- (tert-butoxycarbonyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid 1i (3.0g,6.7mmol), methanesulfonamide (1.27g,13.4mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (2.6g,13.4mmol) and 4-dimethylaminopyridine (1.6g,13.4mmol) were dissolved in 50mL of dichloromethane and reacted at room temperature for 2 hours. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give tert-butyl 2- (((2-cyclopropyl-5-fluoro-4- ((methylsulfonyl) carbamoyl) benzyl) oxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylate 1j (2.8g, yellow foamy solid) in yield: 80 percent.
MS m/z(ESI)：469.9[M-55]
The ninth step
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide hydrochloride
Tert-butyl 2- (((2-cyclopropyl-5-fluoro-4- ((methylsulfonyl) carbamoyl) benzyl) oxy) methyl) -7-azaspiro [3.5] nonane-7-carboxylate 1j (2.8g,5.3mmol) was dissolved in 150mL of 1M ethyl acetate hydrochloride solution and reacted at room temperature for 5 hours. Concentrated under reduced pressure and the solvent removed to give crude 4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide hydrochloride 1k (2.0g, white solid) in yield: 83 percent.
MS m/z(ESI)：424.9[M+1]
The tenth step
5-cyclopropyl-4- (((7- (3, 5-difluorobenzoyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide hydrochloride 1k (50mg,0.11mmol), 3, 5-difluorobenzoic acid 1l (20mg,0.12mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (42mg,0.22mmol) and 4-dimethylaminopyridine (13mg,0.11mmol) were dissolved in 10mL of dichloromethane and reacted at room temperature for 4 hours. To the reaction solution was added 20mL of 1M diluted hydrochloric acid, extracted with dichloromethane (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developer: system B) to give 5-cyclopropyl-4- (((7- (3, 5-difluorobenzoyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 1(12mg, white solid) in yield: 19 percent.
MS m/z(ESI)：564.8[M+1]
1H NMR(400MHz,CDCl3)δ7.71(d,J＝7.6Hz,1H),7.24(s,1H),6.93-6.88(m,2H),6.86-6.82(m,1H),4.70(s,2H),3.74-3.63(m,1H),3.56(d,J＝6.0Hz,2H),3.40(s,3H),3.36-3.20(m,2H),2.75-2.57(m,1H),2.07-1.94(m,2H),1.80-1.72(m,2H),1.68-1.58(m,4H),1.25-1.15(m,2H),0.96(d,J＝7.6Hz,2H),0.67(d,J＝4.8Hz,2H).
Example 2
5-cyclopropyl-4- (((7- (3, 5-dichlorobenzoyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
5-cyclopropyl-4- (((7- (3, 5-dichlorobenzoyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide hydrochloride 1k (300mg,0.65mmol), 3, 5-dichlorobenzoic acid 2a (111mg,0.65mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (244mg,1.3mmol) and 4-dimethylaminopyridine (78mg,0.65mmol) were dissolved in 20mL of dichloromethane and reacted at room temperature for 4 hours. To the reaction solution was added 30mL of 1M diluted hydrochloric acid, extracted with dichloromethane (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((7- (3, 5-dichlorobenzoyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 2(165mg, white solid) in yield: and 43 percent.
MS m/z(ESI)：596.8[M+1]
1H NMR(400MHz,CDCl3)δ8.83(d,J＝15.6Hz,1H),7.26(d,J＝8.0Hz,1H),7.41-7.39(m,2H),7.30(s,1H),7.26-7.25(m,1H),4.71(s,2H),3.78-3.65(m,1H),3.57(d,J＝6.0Hz,2H),3.43(s,3H),3.32-3.25(m,2H),2.74-2.56(m,1H),2.07-1.99(m,2H),1.83-1.73(m,3H),1.69-1.65(m,4H),1.55-1.47(m,1H),0.99-0.95(m,2H),0.70-0.66(m,2H).
Example 3
5-cyclopropyl-4- (((7- (3, 4-dichlorobenzoyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
5-cyclopropyl-4- (((7- (3, 4-dichlorobenzoyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide hydrochloride 1k (300mg,0.65mmol), 3, 4-dichlorobenzoic acid 3a (111mg,0.65mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (244mg,1.3mmol) and 4-dimethylaminopyridine (78mg,0.65mmol) were dissolved in 20mL of dichloromethane and reacted at room temperature for 4 hours. To the reaction solution was added 30mL of 1M diluted hydrochloric acid, extracted with dichloromethane (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((7- (3, 4-dichlorobenzoyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 3(170mg, white solid) in yield: and 43 percent.
MS m/z(ESI)：596.7[M+1]
1H NMR(400MHz,CDCl3)δ8.70(d,J＝15.6Hz,1H),7.23(d,J＝7.6Hz,1H),7.50-7.45(m,2H),7.24-7.21(m,2H),4.71(s,2H),3.76-3.63(m,1H),3.57(d,J＝6.4Hz,2H),3.43(s,3H),3.30-3.20(m,2H),2.74-2.57(m,1H),2.04-1.99(m,2H),1.80-1.76(m,3H),1.69-1.65(m,4H),1.56-1.48(m,1H),0.99-0.95(m,2H),0.70-0.66(m,2H).
Example 4
5-cyclopropyl-4- (((7- (2-chloro-4-fluorobenzoyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
5-cyclopropyl-4- (((7- (2-chloro-4-fluorobenzoyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide hydrochloride 1k (300mg,0.65mmol), 2-chloro-4-fluorobenzoic acid 4a (113mg,0.65mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (244mg,1.3mmol) and 4-dimethylaminopyridine (78mg,0.65mmol) were dissolved in 20mL of dichloromethane and reacted at room temperature for 4 hours. To the reaction solution was added 30mL of 1M diluted hydrochloric acid, extracted with dichloromethane (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((7- (2-chloro-4-fluorobenzoyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 4(170mg, white solid) in yield: 45 percent.
MS m/z(ESI)：580.8[M+1]
1H NMR(400MHz,CDCl3)δ8.82(dd,J＝15.2Hz,3.2Hz,1H),7.75-7.70(m,1H),7.26-7.23(m,2H),7.18-7.14(m,1H),7.06-7.10(m,1H),4.70(d,J＝4.8Hz,2H),3.80-3.75(m,1H),3.67(t,J＝5.6Hz,1H),3.57(t,J＝7.2Hz,2H),3.42(d,J＝2.0Hz,3H),3.25-3.02(m,2H),2.72-2.55(m,1H),2.08-1.95(m,2H),1.82-1.70(m,3H),1.68-1.55(m,4H),0.99-0.95(m,2H),0.69-0.66(m,2H).
Example 5
5-cyclopropyl-4- (((7- (3, 5-difluorobenzyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
(3, 5-difluorophenyl) methanol
3, 5-difluorobenzoic acid 1l (5.0g,31.65mmol) was dissolved in 50mL tetrahydrofuran, and borane tetrahydrofuran solution (95mL,95mmol,1M/THF) was added dropwise at 0 ℃ and reacted at room temperature for 2 hours. The reaction was quenched by the addition of 50mL of 10% sodium hydroxide solution at 0 ℃. Extraction with ethyl acetate (50mL × 3), combination of organic phases, washing with saturated aqueous sodium chloride (50mL), drying of the organic phase over anhydrous sodium sulfate, and concentration under reduced pressure gave (3, 5-difluorophenyl) methanol 5a (4.3g, white solid) in yield: 94.3 percent.
1H NMR(400MHz,CDCl3)δ6.70-6.85(m,2H),6.74(m,1H),4.67(m,2H),1.89(s,1H).
Second step of
3, 5-Difluorobenzyl methanesulfonate
(3, 5-difluorophenyl) methanol 5a (300mg,2.08mmol) and triethylamine (631mg,6.25mmol) were dissolved in 10mL of dichloromethane, methanesulfonyl chloride (355.7mg,3.12mmol) was added dropwise at 0 ℃ and reacted at room temperature for 6 hours. 50mL of 10% citric acid solution was added, extraction was performed with dichloromethane (50 mL. times.3), the organic phases were combined, washed successively with saturated aqueous sodium bicarbonate (50mL) and saturated sodium chloride solution (50 mL. times.1), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3, 5-difluorobenzyl methanesulfonate 5b (461mg, white solid), yield: 100 percent.
The third step
5-cyclopropyl-4- (((7- (3, 5-difluorobenzyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide hydrochloride 1k (100mg,0.22mmol), 3, 5-difluorobenzyl methanesulfonate 5b (300mg,1.35mmol) and potassium carbonate (186mg,1.35mmol) were dissolved in 5mL of N, N-dimethylformamide and reacted at 80 ℃ for 5 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((7- (3, 5-difluorobenzyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 5(11mg, white solid) in yield: 10 percent.
MS m/z(ESI)：550.9[M+1]
1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.0Hz,1H),7.24(s,1H),7.09-7.01(m,2H),6.81-6.71(m,1H),4.70(s,2H),3.75-3.65(m,2H),3.54(d,J＝6.0Hz,2H), 3.41(s,3H),2.70-2.50(m,4H),1.96(t,J＝11.2Hz,2H),1.90-1.84(m,2H),1.80-1.70(m,4H),1.62(t,J＝9.6Hz,2H),0.99-0.94(m,2H),0.69-0.64(m,2H).
Example 6
5-cyclopropyl-4- (((7- (3, 5-dichlorobenzyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
(3, 5-dichlorophenyl) methanol
3, 5-Dichlorobenzoic acid 2a (5.0g,26.32mmol) was dissolved in 50mL of tetrahydrofuran, and borane tetrahydrofuran solution (52.6mL,52.64mmol,1M/THF) was added dropwise at 0 ℃ and reacted at room temperature for 2 hours. The reaction was quenched by the addition of 50mL of 10% sodium hydroxide solution at 0 ℃. Extraction with ethyl acetate (50mL × 3), combination of organic phases, washing with saturated sodium chloride solution (50mL), drying of the organic phase over anhydrous sodium sulfate, and concentration under reduced pressure gave (3, 5-dichlorophenyl) methanol 6a (4.0g, white solid) in yield: 86.9 percent.
1H NMR(400MHz,CDCl3)δ7.27-7.25(m,3H),4.67(s,2H),1.87(s,1H).
Second step of
3, 5-Dichlorobenzyl methanesulfonate
(3, 5-dichlorophenyl) methanol 6a (500mg,2.84mmol) and triethylamine (860mg,8.52mmol) were dissolved in 10mL of dichloromethane, and methanesulfonyl chloride (481mg,4.26mmol) was added dropwise at 0 ℃ to react at room temperature for 6 hours. 50mL of 10% citric acid solution was added, extraction was performed with dichloromethane (50 mL. times.3), the organic phases were combined, washed successively with saturated sodium bicarbonate solution (50mL) and saturated sodium chloride solution (50mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3, 5-dichlorobenzyl methanesulfonate 6b (724mg, white solid), yield: 100 percent.
1H NMR(400MHz,CDCl3)δ7.31-7.28(m,3H),4.50(s,2H),3.68(s,3H).
The third step
5-cyclopropyl-4- (((7- (3, 5-dichlorobenzyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide hydrochloride 1k (200mg,0.43mmol), 3, 5-dichlorobenzyl methanesulfonate 6b (220mg,0.86mmol) and potassium carbonate (178mg,1.29mmol) were dissolved in 10mL of N, N-dimethylformamide and reacted at 80 ℃ for 5 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((7- (3, 5-dichlorobenzyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 6(100mg, white solid) in yield: 40 percent.
MS m/z(ESI)：582.8[M+1]
1H NMR(400MHz,CDCl3)δ8.85(s,1H),7.32(d,J＝7.6Hz,1H),7.45(s,1H),7.39(s,2H),7.22(s,1H),4.70(s,2H),4.08(s,2H),3.56-3.53(m,2H),3.43(s,3H),3.41-3.30(m,1H),2.72-2.53(m,3H),2.18-1.92(m,6H),1.79-1.63(m,4H),0.99-0.95(m,2H),0.70-0.66(m,2H).
Example 7
5-cyclopropyl-4- (((7- (3, 4-dichlorobenzyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
(3, 4-dichlorophenyl) methanol
3, 4-Dichlorobenzoic acid 3a (5.0g,26.32mmol) was dissolved in 50mL of tetrahydrofuran, and borane tetrahydrofuran solution (52.6mL,52.64mmol,1M/THF) was added dropwise at 0 ℃ and reacted at room temperature for 2 hours. The reaction was quenched by the addition of 50mL of 10% aqueous sodium hydroxide at 0 ℃. Extraction with ethyl acetate (50mL × 3), combination of organic phases, washing with saturated sodium chloride solution (50mL), drying of the organic phase over anhydrous sodium sulfate, and concentration under reduced pressure gave (3, 4-dichlorophenyl) methanol 7a (4.4g, white solid) in yield: 94.4 percent.
Second step of
3, 4-Dichlorobenzyl methanesulfonate
(3, 4-dichlorophenyl) methanol 7a (500mg,2.84mmol) and triethylamine (860mg,8.52mmol) were dissolved in 10mL of dichloromethane, and methanesulfonyl chloride (481mg,4.26mmol) was added dropwise at 0 ℃ to react at room temperature for 6 hours. 50mL of 10% citric acid solution was added, extraction was performed with dichloromethane (50 mL. times.3), the organic phases were combined, washed successively with saturated sodium bicarbonate solution (50mL) and saturated sodium chloride solution (50 mL. times.1), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3, 4-dichlorobenzyl methanesulfonate 7b (724mg, white solid) in yield: 100 percent.
The third step
5-cyclopropyl-4- (((7- (3, 4-dichlorobenzyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide hydrochloride 1k (200mg,0.43mmol), 3, 4-dichlorobenzyl methanesulfonate 7b (220mg,0.86mmol) and potassium carbonate (178mg,1.29mmol) were dissolved in 10mL of N, N-dimethylformamide and reacted at 80 ℃ for 5 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((7- (3, 4-dichlorobenzyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 7(95mg, white solid) in yield: 38 percent.
MS m/z(ESI)：582.8[M+1]
1H NMR(400MHz,DMSO)δ11.09-11.06(m,1H),7.68-7.65(m,2H),7.39(dd,J＝8.0Hz,1.6Hz,1H),7.25(d,J＝7.2Hz,1H),7.91(d,J＝11.6Hz,1H),4.64(s,2H),3.88(s,2H),3.47(d,J＝6.8Hz,2H),3.06(s,3H),2.79-2.69(m,4H),2.55-2.52(m,1H),1.94-1.82(m,3H),1.72-1.63(m,2H),1.60-1.50(m,4H),0.94-0.86(m,2H),0.64-0.57(m,2H).
Example 8
5-cyclopropyl-4- (((7- (2-chloro-4-fluorobenzyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
(2-chloro-4-fluorophenyl) methanol
2-chloro-4-fluorobenzoic acid 4a (5.0g,28.7mmol) was dissolved in 50mL of tetrahydrofuran, and borane-tetrahydrofuran solution (86.2mL,86.2mmol,1M/THF) was added dropwise at 0 ℃ and reacted at room temperature for 2 hours. The reaction was quenched by the addition of 50mL of 10% sodium hydroxide solution at 0 ℃. Extraction with ethyl acetate (50mL × 3), combination of organic phases, washing with saturated sodium chloride solution (50mL), drying of the organic phase over anhydrous sodium sulfate, and concentration under reduced pressure gave (2-chloro-4-fluorophenyl) methanol 8a (4.2g, white solid) in yield: 91.3 percent.
Second step of
2-chloro-4-fluorobenzyl methanesulfonate
(2-chloro-4-fluorophenyl) methanol 8a (300mg,1.87mmol) and triethylamine (568mg,5.6mmol) were dissolved in 10mL of dichloromethane, and methanesulfonyl chloride (319mg,2.8mmol) was added dropwise at 0 ℃ to react at room temperature for 6 hours. 50mL of 10% citric acid solution was added, extraction was performed with dichloromethane (50 mL. times.3), the organic phases were combined, washed successively with saturated sodium bicarbonate solution (50mL) and saturated aqueous sodium chloride solution (50 mL. times.1), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-chloro-4-fluorobenzyl methanesulfonate 8b (445mg, white solid) in yield: 100 percent.
The third step
5-cyclopropyl-4- (((7- (2-chloro-4-fluorobenzyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide hydrochloride 1k (200mg,0.43mmol), 2-chloro-4-fluorobenzyl methanesulfonate 8b (306mg,1.29mmol) and potassium carbonate (178mg,1.29mmol) were dissolved in 10mL of N, N-dimethylformamide and reacted at 80 ℃ for 5 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((7- (2-chloro-4-fluorobenzyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 8(65mg, white solid), yield: 27 percent.
MS m/z(ESI)：566.8[M+1]
1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),δ7.84-7.76(m,1H),7.72(d,J＝7.6Hz,1H),7.25-7.19(m,2H),7.15-7.05(m,1H),4.70(s,2H),4.35(s,2H),3.58-3.53(m,2H),3.51-3.45(m,1H),3.43(s,3H),2.88-2.77(m,1H),2.74-2.57(m,4H),2.12-1.92(m,4H),1.80-1.65(m,4H),1.00-0.93(m,2H),0.70-0.63(m,2H).
Example 9
5-cyclopropyl-4- (((7- (1- (3-chloro-5-fluorophenyl) ethyl) -7-aza-spiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
3-chloro-5-fluorobenzoyl chloride
3-chloro-5-fluorobenzoic acid 9a (5.0g,28.7mmol) was dissolved in 50mL of thionyl chloride and reacted for 5 hours under reflux. Concentration under reduced pressure removed thionyl chloride to give crude 3-chloro-5-fluorobenzoyl chloride 9b (5.5g, yellow oil) in yield: 100 percent.
Second step of
3-chloro-5-fluoro-N-methoxy-N-methylbenzamide
3-chloro-5-fluorobenzoyl chloride 9b (5.5g,28.7mmol), N, O-dimethylhydroxylamine hydrochloride (2.8g,28.7mmol) and pyridine (2.3g,28.7mmol) were dissolved in 50mL of dichloromethane and reacted at room temperature for 12 hours. Concentration under reduced pressure and purification of the obtained residue by silica gel column chromatography (eluent: system a) gave 3-chloro-5-fluoro-N-methoxy-N-methylbenzamide 9c (5.3g, yellow oil), yield: 85 percent.
MS m/z(ESI)：217.9[M+1]
The third step
1- (3-chloro-5-fluorophenyl) ethanone
3-chloro-5-fluoro-N-methoxy-N-methylbenzamide 9c (1.0g,4.6mmol) was dissolved in 20mL of dry tetrahydrofuran, and methyl magnesium bromide reagent (9.2mL,9.2mmol,1M/THF) was added dropwise at 0 ℃ and reacted at room temperature for 2 hours. The reaction was quenched by the addition of 20mL of saturated ammonium chloride solution. Extraction with ethyl acetate (50mL × 3) and combined organic phases, dried over anhydrous sodium sulfate and concentrated under reduced pressure gave 1- (3-chloro-5-fluorophenyl) ethanone 9d (775mg, colorless oil), yield: 98.1 percent.
The fourth step
1- (3-chloro-5-fluorophenyl) ethanol
1- (3-chloro-5-fluorophenyl) ethanone 9d (775mg,4.5mmol) was dissolved in 10mL of methanol, and sodium borohydride (510mg,13.5mmol) was slowly added thereto at 0 ℃ to complete the reaction at room temperature for 5 hours. Concentration under reduced pressure and the obtained residue were purified by silica gel column chromatography (eluent: system a) to give 1- (3-chloro-5-fluorophenyl) ethanol 9e (700mg, colorless oil), yield: 89.4 percent.
The fifth step
1- (3-chloro-5-fluorophenyl) ethyl methanesulfonate
1- (3-chloro-5-fluorophenyl) ethanol 9e (200mg,1.1mmol) and triethylamine (348mg,3.4mmol) were dissolved in 10mL of dichloromethane, and methanesulfonyl chloride (189mg,1.65mmol) was added dropwise at 0 ℃ to react at room temperature for 4 hours. 50mL of 10% citric acid solution was added, extraction was performed with dichloromethane (20 mL. times.3), the organic phases were combined, washed successively with saturated sodium bicarbonate solution (30mL) and saturated sodium chloride solution (30mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1- (3-chloro-5-fluorophenyl) ethyl methanesulfonate 9f (250mg, yellow oil), yield: 90.2 percent.
The sixth step
5-cyclopropyl-4- (((7- (1- (3-chloro-5-fluorophenyl) ethyl) -7-aza-spiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide hydrochloride 1k (320mg,0.70mmol), 1- (3-chloro-5-fluorophenyl) ethyl methanesulfonate 9f (353mg,1.4mmol) and potassium carbonate (289mg,2.1mmol) were dissolved in 10mL of N, N-dimethylformamide and reacted at 80 ℃ for 5 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((7- (1- (3-chloro-5-fluorophenyl) ethyl) -7-aza-spiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 9(180mg, white solid) in yield: 44 percent.
MS m/z(ESI)：580.8[M+1]
1H NMR(400MHz,CDCl3)δ7.70(d,J＝7.4Hz,1H),7.25-7.24(m,1H),7.14(s,1H),7.04-6.98(m,2H),4.68(s,2H),3.53-3.49(m,3H),3.39(s,3H),2.58-2.33(m,4H),1.90(t,J＝10.0Hz,2H),1.77-1.73(m,3H),1.61-1.52(m,4H),1.44-1.39(m,3H),0.96-0.94(m,2H),0.87-0.86(m,1H),0.67-0.66(m,2H).
Example 10
5-cyclopropyl-4- (((7- (1- (3-chloro-5-fluorophenyl) propyl) -7-aza-spiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
1- (3-chloro-5-fluorophenyl) propan-1-one
3-chloro-5-fluoro-N-methoxy-N-methylbenzamide 9c (1.0g,4.6mmol) was dissolved in 20mL of dry tetrahydrofuran, and ethyl magnesium chloride reagent (9.2mL,9.2mmol,1M/THF) was added dropwise at 0 ℃ and reacted at room temperature for 2 hours. The reaction was quenched by the addition of 20mL of saturated ammonium chloride solution. Extraction with ethyl acetate (50mL × 3) and combined organic phases, dried over anhydrous sodium sulfate and concentrated under reduced pressure gave 1- (3-chloro-5-fluorophenyl) propan-1-one 10a (804mg, colorless oil), yield: 94.0 percent.
Second step of
1- (3-chloro-5-fluorophenyl) propan-1-ol
1- (3-chloro-5-fluorophenyl) propan-1-one 10a (804mg,4.3mmol) was dissolved in 10mL of methanol, and sodium borohydride (487mg,12.9mmol) was slowly added thereto at 0 ℃ to complete the reaction, followed by reaction at room temperature for 5 hours. Concentration under reduced pressure and the obtained residue were purified by silica gel column chromatography (eluent: system a) to give 1- (3-chloro-5-fluorophenyl) propan-1-ol 10b (768mg, colorless oil), yield: 95 percent.
The third step
1- (3-chloro-5-fluorophenyl) propyl methanesulfonate
1- (3-chloro-5-fluorophenyl) propan-1-ol 10b (200mg,1.06mmol) and triethylamine (322mg,3.2mmol) were dissolved in 10mL of dichloromethane, methanesulfonyl chloride (181mg,1.6mmol) was added dropwise at 0 ℃ and reacted at room temperature for 4 hours. 50mL of 10% citric acid solution was added, extraction was performed with dichloromethane (20 mL. times.3), the organic phases were combined, washed successively with saturated sodium bicarbonate solution (30mL) and saturated aqueous sodium chloride solution (30mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1- (3-chloro-5-fluorophenyl) propyl methanesulfonate 10c (259mg, white solid), yield: 92 percent.
The fourth step
5-cyclopropyl-4- (((7- (1- (3-chloro-5-fluorophenyl) propyl) -7-aza-spiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide hydrochloride 1k (190mg,0.41mmol), 1- (3-chloro-5-fluorophenyl) propyl methanesulfonate 10c (218mg,0.82mmol) and potassium carbonate (170mg,1.23mmol) were dissolved in 5mL of N, N-dimethylformamide and reacted at 80 ℃ for 5 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: system B) to give 5-cyclopropyl-4- (((7- (1- (3-chloro-5-fluorophenyl) propyl) -7-aza-spiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 10(20mg, white solid) in yield: 8 percent.
MS m/z(ESI)：594.8[M+1]
1H NMR(400MHz,CDCl3)δ7.71(d,J＝7.6Hz,1H),7.21(dd,J＝11.7,6.4Hz,3H),7.10(d,J＝8.4Hz,1H),4.68(s,2H),4.03(d,J＝8.4Hz,1H),3.51(s,2H),3.43(s,3H),2.60-2.30(m,2H),2.15-2.08(m,2H),1.97-1.87(m,3H),1.79-1.55(m,9H),0.98-0.93(m,2H),0.77(t,J＝7.2Hz,3H),0.68-0.64(m,2H).
Example 11
5-cyclopropyl-4- (((7- (1- (3, 5-difluorophenyl) propyl) -7-aza-spiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
3, 5-difluorobenzoyl chloride
1l (5.0g,31.6mmol) of 3, 5-difluorobenzoic acid was dissolved in 50mL of thionyl chloride and reacted for 5 hours under reflux. Concentration under reduced pressure removed thionyl chloride to give crude 3, 5-difluorobenzoyl chloride 11a (5.56g, yellow oil), yield: 100 percent.
Second step of
3, 5-difluoro-N-methoxy-N-methylbenzamide
5-Difluorobenzoyl chloride 11a (5.56g,31.6mmol), N, O-dimethylhydroxylamine hydrochloride (3.08g,31.6mmol) and pyridine (2.5g,31.6mmol) were dissolved in 50mL of dichloromethane and reacted at room temperature for 12 hours. Concentration under reduced pressure and purification of the obtained residue by silica gel column chromatography (eluent: system a) gave 3, 5-difluoro-N-methoxy-N-methylbenzamide 11b (5.6g, yellow oil), yield: 89 percent.
The third step
1- (3, 5-difluorophenyl) propan-1-one
3, 5-difluoro-N-methoxy-N-methylbenzamide 11b (1.0g,4.98mmol) was dissolved in 20mL of dry tetrahydrofuran, and ethyl magnesium chloride reagent (10mL,10mmol,1M/THF) was added dropwise at 0 ℃ and reacted at room temperature for 2 hours. The reaction was quenched by the addition of 20mL of saturated ammonium chloride solution. Extraction with ethyl acetate (50mL × 3) and combined organic phases, dried over anhydrous sodium sulfate and concentrated under reduced pressure gave 1- (3, 5-difluorophenyl) propan-1-one 11c (796mg, colorless oil), yield: 94 percent.
The fourth step
1- (3, 5-difluorophenyl) propan-1-ol
1- (3, 5-difluorophenyl) propan-1-one 11c (796mg,4.68mmol) was dissolved in 10mL of methanol, and sodium borohydride (531mg,14.0mmol) was slowly added thereto at 0 ℃ to complete the reaction, and the reaction was carried out at room temperature for 5 hours. Concentration under reduced pressure and the obtained residue were purified by silica gel column chromatography (eluent: system a) to give 1- (3, 5-difluorophenyl) propan-1-ol 11d (732mg, white solid) in yield: 91 percent.
The fifth step
1- (3, 5-difluorophenyl) propyl methanesulfonate
1- (3, 5-difluorophenyl) propan-1-ol 11d (200mg,1.16mmol) and triethylamine (351mg,3.5mmol) were dissolved in 10mL of dichloromethane, methanesulfonyl chloride (198mg,1.74mmol) was added dropwise at 0 ℃ and reacted at room temperature for 4 hours. 50mL of 10% citric acid solution was added, extraction was performed with dichloromethane (20 mL. times.3), the organic phases were combined, washed successively with saturated sodium bicarbonate solution (30mL) and saturated sodium chloride solution (30mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1- (3, 5-difluorophenyl) propyl methanesulfonate 11e (267mg, white solid) in yield: 92 percent.
The sixth step
5-cyclopropyl-4- (((7- (1- (3, 5-difluorophenyl) propyl) -7-aza-spiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide hydrochloride 1k (120mg,0.26mmol), 1- (3, 5-difluorophenyl) propyl methanesulfonate 11e (130mg,0.52mmol) and potassium carbonate (108mg,0.78mmol) were dissolved in 5mL of N, N-dimethylformamide and reacted at 80 ℃ for 5 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: system B) to give 5-cyclopropyl-4- (((7- (1- (3, 5-difluorophenyl) propyl) -7-aza-spiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 11(35mg, white solid), yield: 23 percent.
MS m/z(ESI)：578.9[M+1]
1H NMR(400MHz,CDCl3)δ7.71(d,J＝7.9Hz,1H),7.28-7.24(m,1H),6.80-6.77(m,2H),6.71-6.68(m,1H),4.67(s,2H),3.51(d,J＝6.5Hz,2H),3.41(s,3H),3.27-3.23(m,1H),2.41-2.27(m,4H),2.02-1.97(m,2H),1.91-1.84(m,2H),1.78-1.65(m,4H),1.57-1.48(m,4H),0.98-0.93(m,2H),0.73(t,J＝7.2Hz,3H),0.68-0.64(m,2H).
Example 12
5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-aza-spiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
3, 5-Dichlorobenzoyl chloride
3, 5-Dichlorobenzoic acid 2a (5.0g,26.2mmol) was dissolved in 50mL of thionyl chloride and reacted for 5 hours under reflux. Concentration under reduced pressure removed thionyl chloride to give crude 3, 5-dichlorobenzoyl chloride 12a (5.5g, yellow oil) in yield: 100 percent.
Second step of
3, 5-dichloro-N-methoxy-N-methylbenzamide
3, 5-Dichlorobenzoyl chloride 12a (5.5g,26.2mmol), N, O-dimethylhydroxylamine hydrochloride (2.6g,28.7mmol) and pyridine (2.1g,26.2mmol) were dissolved in 50mL of dichloromethane and reacted at room temperature for 12 hours. Concentration under reduced pressure and purification of the obtained residue by silica gel column chromatography (eluent: system a) gave 3, 5-dichloro-N-methoxy-N-methylbenzamide 12b (5.4g, yellow oil), yield: 88 percent.
MS m/z(ESI)：234.1[M+1]
The third step
1- (3, 5-dichlorophenyl) propan-1-one
3, 5-dichloro-N-methoxy-N-methylbenzamide 12b (1.0g,4.27mmol) was dissolved in 20mL of dry tetrahydrofuran, and ethyl magnesium chloride reagent (8.5mL,8.5mmol,1M/THF) was added dropwise at 0 ℃ and reacted at room temperature for 2 hours. The reaction was quenched by the addition of 20mL of saturated ammonium chloride solution. Extraction with ethyl acetate (50mL × 3) and combined organic phases, dried over anhydrous sodium sulfate and concentrated under reduced pressure gave 1- (3, 5-dichlorophenyl) propan-1-one 12c (825mg, colorless oil) in: 95.2 percent.
MS m/z(ESI)：203.1[M+1]
The fourth step
1- (3, 5-dichlorophenyl) propan-1-ol
1- (3, 5-dichlorophenyl) propan-1-one 12c (825mg,4.05mmol) was dissolved in 10mL of methanol, and sodium borohydride (461mg,12.2mmol) was slowly added thereto at 0 ℃ to complete the reaction at room temperature for 5 hours. Concentration under reduced pressure and the obtained residue were purified by silica gel column chromatography (eluent: system a) to give 1- (3, 5-dichlorophenyl) propan-1-ol 12e (730mg, colorless oil), yield: 88 percent.
1H NMR(400MHz,CDCl3)δ7.25-7.22(m,3H),4.56(t,J＝6.8Hz,1H),2.20(s,1H),1.76-1.71(m,2H),0.92(t,J＝7.2Hz,3H).
The fifth step
1- (3, 5-dichlorophenyl) propyl methanesulfonate
1- (3, 5-dichlorophenyl) propan-1-ol 12e (200mg,0.98mmol) and triethylamine (297mg,2.94mmol) were dissolved in 10mL of dichloromethane, methanesulfonyl chloride (168mg,1.47mmol) was added dropwise at 0 ℃ and reacted at room temperature for 4 hours. 50mL of 10% citric acid solution was added, extraction was performed with dichloromethane (20 mL. times.3), the organic phases were combined, washed successively with saturated sodium bicarbonate solution (30mL) and saturated sodium chloride solution (30mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1- (3, 5-dichlorophenyl) propyl methanesulfonate 12f (266mg, white solid) in yield: 96 percent.
The sixth step
5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-aza-spiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide hydrochloride 1k (110mg,0.24mmol), 1- (3, 5-dichlorophenyl) propyl methanesulfonate 12f (135.8mg,0.48mmol) and potassium carbonate (99mg,0.72mmol) were dissolved in 5mL of N, N-dimethylformamide and reacted at 80 ℃ for 5 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: system B) to give 5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-aza-spiro [3.5] non-2-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 12(20mg, white solid), yield: 15 percent.
MS m/z(ESI)：610.9[M+1]
1H NMR(400MHz,CDCl3)δ7.71(d,J＝7.8Hz,1H),7.47(s,1H),7.31(s,2H),7.22(d,J＝13.1Hz,1H),4.68(s,2H),4.05-4.01(m,1H),3.53-3.49(m,2H),3.43(s,3H),2.38-2.28(m,1H),2.15-2.12(m,3H),1.92-1.89(m,3H),1.74-1.68(m,8H),1.59-1.52(m,1H),0.98-0.93(m,2H),0.79-0.76(m,3H),0.69-0.64(m,2H).
Example 13
5-cyclopropyl-4- (((1- (3, 5-difluorobenzoyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
4-fluoro-4- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester
1- (tert-Butoxycarbonyl) -4-fluoropiperidine-4-carboxylic acid 13a (5.0g,20mmol) was dissolved in 50mL of tetrahydrofuran, and a borane-tetrahydrofuran solution (50mL,1M/THF) was added dropwise at 0 ℃ to complete the addition, and the reaction was carried out at room temperature for 5 hours. 20mL of methanol was slowly added to the reaction mixture at 0 ℃ to quench the reaction. Concentrating under reduced pressure, and removing solvent. After adding 50mL of water and extracting with ethyl acetate (50 mL. times.3), the organic phases were combined, washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl 4-fluoro-4- (hydroxymethyl) piperidine-1-carboxylate 13b (4.7g, colorless oil), yield: 100 percent.
Second step of
4- (((4-bromo-2-chloro-5-fluorobenzyl) oxy) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester
4-fluoro-4- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester 13b (4.7g,10.4mmol) was dissolved in 20mL N, N-dimethylformamide at 0 deg.C, sodium hydride (832mg,20.8mmol) was slowly added, and the mixture was stirred at 0 deg.C for 0.5 hour. 1-bromo-4- (bromomethyl) -5-chloro-2-fluorobenzene 1c (3.1g,10.4mmol) was dissolved in 2ml of N, N-dimethylformamide, and slowly added dropwise to the above reaction solution at 0 ℃ for 0.5 hour at 0 ℃. The reaction mixture was quenched with 20mL of water, extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give 4- (((4-bromo-2-chloro-5-fluorobenzyl) oxy) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester 13c (4.0g, yellow solid), yield: 85 percent.
MS m/z(ESI)：398.8[M-55]
The third step
4- (((4- (tert-butoxycarbonyl) -2-chloro-5-fluorobenzyl) oxy) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester
Under argon, 4- (((4-bromo-2-chloro-5-fluorobenzyl) oxy) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester 13c (4.0g,8.8mmol) was dissolved in 20mL tetrahydrofuran, isopropyl magnesium chloride Grignard reagent (13.2mL,26.4mmol,2M/THF) was slowly added dropwise at 0 ℃ and stirred at 0 ℃ for 1 hour. Di-tert-butyl dicarbonate (5.8g,26.4mmol) was dissolved in 5mL of tetrahydrofuran, and the resulting solution was added dropwise to the reaction mixture at 0 ℃ and reacted at room temperature for 10 hours. The reaction mixture was quenched with 20mL of water, extracted with ethyl acetate (50 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent: System A) to give 4- (((4- (tert-butoxycarbonyl) -2-chloro-5-fluorobenzyl) oxy) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester 13d (3.5g, yellow oil), yield: 92 percent.
MS m/z(ESI)：365.8[M-110]
The fourth step
4- (((4- (tert-Butoxycarbonyl) -2-cyclopropyl-5-fluorobenzyl) oxy) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester
Under the protection of argon, tert-butyl 4- (((4- (tert-butoxycarbonyl) -2-chloro-5-fluorobenzyl) oxy) methyl) -4-fluoropiperidine-1-carboxylate 13d (3.5g,7.4mmol), cyclopropylboronic acid (1.9g,22.2mmol), palladium acetate (166mg,0.74mmol), tricyclohexylphosphine fluoroborate (544mg,3.7mmol) and potassium phosphate (6.2g,29.6mmol) were dissolved in 20mL of a mixed solvent of toluene and water (V: V ═ 9:1) and reacted with a microwave at 115 ℃ for 45 minutes. Filtration was carried out to remove solid insoluble substances, the filtrate was concentrated under reduced pressure, 20mL of water was added, extraction was carried out with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give 4- (((4- (tert-butoxycarbonyl) -2-cyclopropyl-5-fluorobenzyl) oxy) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester 13e (3.5g, yellow oil), yield: 92 percent.
MS m/z(ESI)：371.0[M-110]
The fifth step
5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) benzoic acid
Tert-butyl 4- (((4- (tert-butoxycarbonyl) -2-cyclopropyl-5-fluorobenzyl) oxy) methyl) -4-fluoropiperidine-1-carboxylate 13e (3.5g,7.3mmol) was dissolved in 30mL of dichloromethane, and 30mL of trifluoroacetic acid was added to react at room temperature for 0.5 hour. Concentration under reduced pressure removed dichloromethane and remaining trifluoroacetic acid to give crude 5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) benzoic acid 13f (2.5g, yellow oil), yield: 81 percent.
MS m/z(ESI)：325.9[M+1]
The sixth step
4- (((1- (tert-butoxycarbonyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid
13f (3.5g,10.8mmol) of 5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) benzoic acid was dissolved in 20mL of methylene chloride, triethylamine (4.4g,43mmol) was added thereto, di-tert-butyl dicarbonate (3.5g,16.1mmol) was added at 0 ℃ and the reaction was carried out at room temperature for 10 hours. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 13g (2.6g, yellow oil) of 4- (((1- (tert-butoxycarbonyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid, yield: 56.8 percent.
MS m/z(ESI)：325.9[M-100]
Seventh step
4- (((2-cyclopropyl-5-fluoro-4- ((methylsulfonyl) carbamoyl) benzyl) oxy) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester
13g (2.6g,6.1mmol) of 4- (((1- (tert-butoxycarbonyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid, 1.16g,12.2mmol of methanesulfonamide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (2.3g,12.2mmol) and 4-dimethylaminopyridine (744mg,6.1mmol) were dissolved in 50mL of dichloromethane and reacted at room temperature for 2 hours. Concentration under reduced pressure and purification of the resulting residue by silica gel column chromatography (eluent: system B) gave 4- (((2-cyclopropyl-5-fluoro-4- ((methylsulfonyl) carbamoyl) benzyl) oxy) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester 13h (400mg, white solid) in yield: 13 percent.
Eighth step
5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) -N- (methylsulfonyl) benzamide hydrochloride
Tert-butyl 4- (((2-cyclopropyl-5-fluoro-4- ((methylsulfonyl) carbamoyl) benzyl) oxy) methyl) -4-fluoropiperidine-1-carboxylate 13h (400mg,0.79mmol) was dissolved in 100mL of 1M ethyl acetate hydrochloride solution and reacted at room temperature for 10 hours. Concentrated under reduced pressure and the solvent removed to give crude 5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) -N- (methylsulfonyl) benzamide hydrochloride 13i (330mg, white solid) in yield: 95 percent.
MS m/z(ESI)：402.9[M+1]
The ninth step
5-cyclopropyl-4- (((1- (3, 5-difluorobenzoyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) -N- (methylsulfonyl) benzamide hydrochloride 13i (60mg,0.137mmol), 3, 5-difluorobenzoic acid 1l (20mg,0.137mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (47.1mg,0.27mmol) and 4-dimethylaminopyridine (16.8mg,0.137mmol) were dissolved in 6mL of dichloromethane and reacted at room temperature for 4 hours. To the reaction solution was added 20mL of 1M diluted hydrochloric acid, extracted with dichloromethane (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developer: system B) to give 5-cyclopropyl-4- (((1- (3, 5-difluorobenzoyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 13(23mg, white solid) in yield: 31 percent.
MS m/z(ESI)：542.8[M+1]
1H NMR(400MHz,CDCl3)δ7.71(m,1H),7.25-7.13(m,1H),6.90(m,3H),4.78(s,2H),3.36(m,1H),3.66-3.61(m,3H),3.36(s,2H),3.22-3.01(m,1H),2.05-1.93(m,2H),1.79-1.1.71(m,2H),1.28-1.26(m,2H),0.98-0.94(m,2H),0.89-0.86(m,1H),0.66-0.65(m,2H).
Example 14
5-cyclopropyl-4- (((1- (3, 5-dichlorobenzoyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
5-cyclopropyl-4- (((1- (3, 5-dichlorobenzoyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) -N- (methylsulfonyl) benzamide hydrochloride 13i (40mg,0.09mmol), 3, 5-difluorobenzoic acid 2a (17mg,0.09mmol), 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide (35mg,0.18mmol), and 4-dimethylaminopyridine (11mg,0.09mmol) were dissolved in 5mL of dichloromethane and reacted at room temperature for 4 hours. To the reaction solution was added 10mL of 1M diluted hydrochloric acid, extracted with dichloromethane (10mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developer: system B) to give 5-cyclopropyl-4- (((1- (3, 5-dichlorobenzoyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 14(20mg, white solid) in yield: 39 percent.
MS m/z(ESI)：574.7[M+1]
1H NMR(400MHz,CDCl3)δ8.82(d,J＝16.0Hz,1H),7.75(d,J＝8.0Hz,1H),7.44-7.43(m,1H),7.29-7.28(m,3H),4.81(s,2H),4.65-4.53(m,1H),3.68-3.63(m,2H),3.43(s,3H),3.28-3.05(m,1H),2.08-1.97(m,2H),1.81-1.73(m,2H),1.30-1.24(m,2H),1.01-0.96(m,2H),0.89-0.85(m,1H),0.70-0.66(m,2H).
Example 15
5-cyclopropyl-4- (((1- (3, 4-dichlorobenzoyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
5-cyclopropyl-4- (((1- (3, 4-dichlorobenzoyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) -N- (methylsulfonyl) benzamide hydrochloride 13i (200mg,0.456mmol), 3, 4-dichlorobenzoic acid 3a (104mg,0.547mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (175mg,0.912mmol) and 4-dimethylaminopyridine (111mg,0.912mmol) were dissolved in 10mL of dichloromethane and reacted at room temperature for 10 hours. To the reaction solution was added 10mL of 1M diluted hydrochloric acid, extracted with dichloromethane (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((1- (3, 4-dichlorobenzoyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 15(110mg, white solid) in yield: 41.9 percent.
MS m/z(ESI)：574.7[M+1]
1H NMR(400MHz,CDCl3)δ8.84(d,J＝15.6Hz,1H),7.73(d,J＝7.5Hz,1H),7.55-7.48(m,2H),7.31-7.22(m,2H),4.80(s,2H),3.36-3.22(m,1H),3.65(d,J＝19.1Hz,3H),3.50-3.45(m,1H),3.43(s,3H),3.31-3.15(m,1H),2.21-1.85(m,3H),1.81-1.72(m,2H),1.02-0.94(m,2H),0.70-0.66(m,2H).
Example 16
5-cyclopropyl-4- (((1- (2-chloro-4-fluorobenzoyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
5-cyclopropyl-4- (((1- (2-chloro-4-fluorobenzoyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) -N- (methylsulfonyl) benzamide hydrochloride 13i (200mg,0.456mmol), 2-chloro-4-fluorobenzoic acid 4a (95.5mg,0.547mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (175mg,0.912mmol) and 4-dimethylaminopyridine (111mg,0.912mmol) were dissolved in 10mL of dichloromethane and reacted at room temperature for 10 hours. To the reaction solution was added 10mL of 1M diluted hydrochloric acid, extracted with dichloromethane (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((1- (2-chloro-4-fluorobenzoyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 16(78mg, white solid) in yield: 30.6 percent.
MS m/z(ESI)：558.8[M+1]
1H NMR(400MHz,CDCl3)δ8.82(d,J＝15.6Hz,1H),7.74(d,J＝7.5Hz,1H),7.35-7.20(m,2H),7.18(s,1H),7.11-7.03(m,1H),4.83-4.76(m,2H),4.75-4.68(m,1H),3.66(d,J＝18.6Hz,2H),3.43(s,3H),3.39-3.33(m,2H),3.26-3.23(m,1H),2.13-2.07(m,1H),1.98-1.93(m,2H),1.78-1.73(m,2H),0.99-0.95(m,2H),0.73-0.66(m,2H).
Example 17
5-cyclopropyl-4- (((1- (3, 5-difluorobenzyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
5-cyclopropyl-4- (((1- (3, 5-difluorobenzyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) -N- (methylsulfonyl) benzamide hydrochloride 13i (100mg,0.23mmol), 3, 5-difluorobenzyl methanesulfonate 5b (102.1mg,0.46mmol) and potassium carbonate (158mg,1.15mmol) were dissolved in 5mL of N, N-dimethylformamide and reacted at 80 ℃ for 5 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: system B) to give 5-cyclopropyl-4- (((1- (3, 5-difluorobenzyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 17(18mg, white solid), yield: 15.5 percent.
MS m/z(ESI)：528.9[M+1]
1H NMR(400MHz,DMSO)δ11.76(s,1H),7.20-7.15(m,5H),4.74(s,2H),3.73-3.55(m,4H),3.21(s,3H),2.73(s,2H),2.44(d,J＝10.1Hz,2H),1.88(dd,J＝14.7,9.1Hz,4H),1.75(d,J＝12.1Hz,1H),0.95-0.87(m,2H),0.66(q,J＝5.7Hz,2H).
Example 18
5-cyclopropyl-4- (((1- (3, 5-dichlorobenzyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
5-cyclopropyl-4- (((1- (3, 5-dichlorobenzyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) -N- (methylsulfonyl) benzamide hydrochloride 13i (120mg,0.27mmol), 3, 5-dichlorobenzyl methanesulfonate 6b (137.7mg,0.54mmol) and potassium carbonate (186.3mg,1.35mmol) were dissolved in 5mL of N, N-dimethylformamide and reacted at 80 ℃ for 5 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: system B) to give 5-cyclopropyl-4- (((1- (3, 5-dichlorobenzyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 18(20mg, white solid), yield: 13.2 percent.
MS m/z(ESI)：560.8[M+1]
1H NMR(400MHz,CDCl3)δ7.73(d,J＝7.7Hz,1H),7.34-7.32(m,2H),7.29(s,2H),4.80(s,2H),3.66-3.61(d,J＝12.0Hz,2H),3.56(s,2H),3.43(s,3H),2.86-2.73(m,2H),2.47-2.39(m,2H),1.99-1.96(m,3H),1.29-1.26(m,2H),1.00-0.95(m,2H),0.69-0.65(m,2H).
Example 19
5-cyclopropyl-4- (((1- (3, 4-dichlorobenzyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
5-cyclopropyl-4- (((1- (3, 4-dichlorobenzyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) -N- (methylsulfonyl) benzamide hydrochloride 13i (200mg,0.46mmol), 3, 4-dichlorobenzyl methanesulfonate 7b (175.9mg,0.69mmol) and potassium carbonate (190.4mg,1.38mmol) were dissolved in 5mL of N, N-dimethylformamide and reacted at 80 ℃ for 5 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((1- (3, 4-dichlorobenzyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 19(42mg, white solid), yield: 15 percent.
MS m/z(ESI)：560.7[M+1]
1H NMR(400MHz,CDCl3)δ7.72(d,J＝15.6Hz,1H),7.47(s,1H),7.39(d,J＝7.5Hz,1H),7.28(s,1H),7.20-7.18(m,1H),4.79(s,2H),3.64(s,1H),3.59(s,1H),3.52(s,1H),3.41(s,3H),2.75-2.73(m,2H),2.44-2.38(m,2H),2.34(s,1H),1.99-1.93(m,3H),1.78-1.75(m,2H),1.00-0.92(m,2H),0.72-0.63(m,2H).
Example 20
5-cyclopropyl-4- (((1- (2-chloro-4-fluorobenzyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
5-cyclopropyl-4- (((1- (2-chloro-4-fluorobenzyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) -N- (methylsulfonyl) benzamide hydrochloride 13i (400mg,0.87mmol), 2-chloro-4-fluorobenzyl methanesulfonate 8b (311mg,1.3mmol) and potassium carbonate (360mg,2.61mmol) were dissolved in 6mL of N, N-dimethylformamide and reacted at 80 ℃ for 5 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((1- (2-chloro-4-fluorobenzyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 20(320mg, white solid), yield: 65 percent.
MS m/z(ESI)：544.8[M+1]
1H NMR(400MHz,CDCl3)δ7.68(d,J＝7.6Hz,1H),7.54(dd,J＝8.5,6.3Hz,1H),7.27(d,J＝12.0Hz,1H),7.12(dd,J＝8.5,2.6Hz,1H),6.97(td,J＝8.3,2.6Hz,1H),4.78(s,2H),3.75(s,2H),3.62(d,J＝20.3Hz,2H),3.36(s,3H),2.86(d,J＝11.6Hz,2H),2.56(t,J＝10.4Hz,2H),2.02-1.90(m,3H),1.89-1.71(m,2H),0.97-0.94(m,2H),0.69-0.64(m,2H).
Example 21
5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) -N- (methylsulfonyl) benzamide hydrochloride 13i (500mg,1.14mmol), 1- (3-chloro-5-fluorophenyl) ethyl methanesulfonate 9f (655mg,2.6mmol) and potassium carbonate (470mg,3.42mmol) were dissolved in 10mL of N, N-dimethylformamide and reacted at 80 ℃ for 5 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 21(160mg, white solid) in yield: 25 percent.
MS m/z(ESI)：558.8[M+1]
1H NMR(400MHz,CD3OD)δ7.42-7.35(m,1H),7.32(s,1H),7.25-7.1(m,3H),4.78(s,2H),3.96-3.85(m,1H),3.62(d,J＝6.0Hz,2H),3.25(s,3H),3.24-3.15(m,1H),2.95-2.82(m,1H),2.74-2.55(m,2H),2.11-1.75(m,5H),1.53(d,J＝8.0Hz,3H),0.98-0.91(m,2H),0.71-0.62(m,2H).
Example 22
5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) propyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) propyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) -N- (methylsulfonyl) benzamide hydrochloride 13i (500mg,1.14mmol), 1- (3-chloro-5-fluorophenyl) propyl methanesulfonate 10c (690mg,2.6mmol) and potassium carbonate (470mg,3.42mmol) were dissolved in 10mL of N, N-dimethylformamide and reacted at 80 ℃ for 5 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) propyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 22(150mg, white solid) in yield: 23 percent.
MS m/z(ESI)：572.8[M+1]
1H NMR(400MHz,CDCl3)δ8.98-8.75(m,1H),7.72(d,J＝7.6Hz,1H),7.25-7.22(m,3H),7.11(d,J＝8.4Hz,1H),4.76(s,2H),4.04(d,J＝12.8Hz,1H),3.71-3.64(m,2H),3.42(s,3H),3.32-3.02(m,2H),2.98-2.79(m,2H),2.50-2.22(m,3H),2.21-2.05(m,3H),1.78-1.69(m,1H),0.99-0.94(m,2H),0.81(t,J＝7.2Hz,3H),0.68-0.62(m,2H).
Example 23
5-cyclopropyl-4- (((1- (1- (3, 5-difluorophenyl) propyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
5-cyclopropyl-4- (((1- (1- (3, 5-difluorophenyl) propyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) -N- (methylsulfonyl) benzamide hydrochloride 13i (500mg,1.14mmol), 1- (3, 5-difluorophenyl) propyl methanesulfonate 11e (570mg,2.28mmol) and potassium carbonate (472mg,3.42mmol) were dissolved in 10mL of N, N-dimethylformamide and reacted at 80 ℃ for 5 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((1- (1- (3, 5-difluorophenyl) propyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 23(80mg, white solid), yield: 13 percent.
MS m/z(ESI)：556.8[M+1]
1H NMR(400MHz,CDCl3)δ7.70(d,J＝7.6Hz,1H),7.22(d,J＝12.8Hz,1H),7.01-6.92(m,3H),4.76(s,2H),4.06(d,J＝10.0Hz,1H),3.72-3.64(m,2H),3.42(s,3H),3.37-3.11(m,2H),2.98-2.83(m,2H),2.46-2.26(m,3H),2.18-2.09(m,3H),1.78-1.68(m,1H),0.99-0.93(m,2H),0.81(t,J＝7.2Hz,3H),0.68-0.61(m,2H).
Example 24
5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) -N- (methylsulfonyl) benzamide hydrochloride 13i (200mg,0.46mmol), 1- (3, 5-dichlorophenyl) propyl methanesulfonate 12f (400mg,1.4mmol) and potassium carbonate (200mg,1.4mmol) were dissolved in 10mL of N, N-dimethylformamide and reacted at 80 ℃ for 5 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (50mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 24(25mg, white solid), yield: 9 percent.
MS m/z(ESI)：588.8[M+1]
1H NMR(400MHz,CDCl3)δ8.93-8.79(m,1H),7.72(d,J＝7.2Hz,1H),7.50(s,1H),7.34(s,1H),7.26-7.24(m,1H),7.22(s,1H),4.76(s,2H),4.01(d,J＝10.8Hz,1H),3.70-3.64(m,2H),3.43(s,3H),3.36-3.34(m,1H),2.93-2.81(m,2H),2.54-2.29(m,3H),2.24-2.08(m,4H),1.80-1.68(m,1H),1.00-0.90(m,2H),0.82(m,J＝7.2Hz,3H),0.69-0.63(m,2H).
Example 25
5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
1-chloro-3- (1-chloroethyl) -5-fluorobenzene
1- (3-chloro-5-fluorophenyl) ethanol 9e (5g,28.7mmol) was dissolved in 30mL of thionyl chloride and reacted at 60 ℃ for 2 hours. Concentration under reduced pressure, quenching of the residual thionyl chloride by adding 50mL of saturated sodium bicarbonate solution, extraction with ethyl acetate (50 mL. times.3), combination of the organic phases, drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure and purification of the obtained residue by silica gel column chromatography (eluent: system A) gave 1-chloro-3- (1-chloroethyl) -5-fluorobenzene 25a (4.9g, pale yellow oil) in yield: 90 percent.
1H NMR(400MHz,CDCl3)δ7.20(s,1H),7.07-7.02(m,2H),4.99(q,J＝7.2Hz,1H),1.81(d,J＝6.8Hz,3H).
Second step of
3-fluoro-3- (hydroxymethyl) azetidine-1-carboxylic acid tert-butyl ester
1- (tert-Butoxycarbonyl) -3-fluoroazetidine-3-carboxylic acid 25b (10.0g,4.6mmol) was dissolved in 100mL of tetrahydrofuran and borane tetrahydrofuran solution (100mL,1M/THF) was added dropwise at 0 ℃ and reacted at room temperature for 4 hours. 20mL of methanol was slowly added to the reaction mixture at 0 ℃ to quench the reaction. Concentrated under reduced pressure, 200mL of a saturated sodium bicarbonate solution was added to the residue, extracted with ethyl acetate (200mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (150mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 3-fluoro-3- (hydroxymethyl) azetidine-1-carboxylate 25c (8.9g, pale yellow oil), yield: 92 percent.
1H NMR(400MHz,CDCl3)δ4.11-3.98(m,4H),3.87(d,J＝20.8Hz,2H),2.36(s,1H),1.47(s,9H).
The third step
3- (((4-bromo-2-chloro-5-fluorobenzyl) oxy) methyl) -3-fluoroazetidine-1-carboxylic acid tert-butyl ester
3-fluoro-3- (hydroxymethyl) azetidine-1-carboxylic acid tert-butyl ester 25c (8.9g,43.4mmol) was dissolved in 70mL N, N-dimethylformamide at 0 deg.C, sodium hydride (3.47g,86.8mmol) was slowly added, and the mixture was stirred at 0 deg.C for 15 minutes. 1-bromo-4- (bromomethyl) -5-chloro-2-fluorobenzene 1c (13.0g,43.4mmol) was dissolved in 60mL of N, N-dimethylformamide, and slowly added dropwise to the above reaction solution at 0 ℃ for 0.5 hour at 0 ℃. The reaction solution was quenched with 40mL of water, extracted with ethyl acetate (100mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (100mL), the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give 3- (((4-bromo-2-chloro-5-fluorobenzyl) oxy) methyl) -3-fluoroazetidine-1-carboxylic acid tert-butyl ester 25d (8.9g, pale yellow oil), yield: 48 percent. MS m/z (ESI): 369.7[ M-55]
The fourth step
3- (((4- (tert-butoxycarbonyl) -2-chloro-5-fluorobenzyl) oxy) methyl) -3-fluoroazetidine-1-carboxylic acid tert-butyl ester
3- (((4-bromo-2-chloro-5-fluorobenzyl) oxy) methyl) -3-fluoroazetidine-1-carboxylic acid tert-butyl ester 25d (8.9g,19.9mmol) was dissolved in 60mL of tetrahydrofuran under argon, isopropylmagnesium chloride (30mL,2M/THF) was slowly added dropwise at 0 deg.C, and stirred at 0 deg.C for 1 hour. Di-tert-butyl dicarbonate (21.7g,99.5mmol) was dissolved in 20mL of tetrahydrofuran, and the resulting solution was added dropwise to the reaction mixture at 0 ℃ and reacted at room temperature for 4 hours. The reaction solution was quenched with 20mL of water, extracted with ethyl acetate (100mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to obtain tert-butyl 3- (((4- (tert-butoxycarbonyl) -2-chloro-5-fluorobenzyl) oxy) methyl) -3-fluoroazetidine-1-carboxylate 25e (4.5g, pale yellow oil), yield: 47.7 percent.
MS m/z(ESI)：337.8[M-110]
The fifth step
3- (((4- (tert-butoxycarbonyl) -2-cyclopropyl-5-fluorobenzyl) oxy) methyl) -3-fluoroazetidine-1-carboxylic acid tert-butyl ester
Under the protection of argon, tert-butyl 3- (((4- (tert-butoxycarbonyl) -2-chloro-5-fluorobenzyl) oxy) methyl) -3-fluoroazetidine-1-carboxylate 25e (3.9g,8.7mmol), cyclopropylboronic acid (2.3g,26.1mmol), palladium acetate (587mg,2.61mmol), tricyclohexylphosphine fluoroborate (962mg,2.61mmol) and potassium phosphate (7.4g,34.8mmol) were dissolved in 44mL of a mixed solvent of toluene and water (V: V ═ 10:1) and reacted at 120 ℃ for 4 hours. Filtration was carried out to remove solid insoluble matter, the filtrate was concentrated under reduced pressure, 50mL of water was added, extraction was carried out with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give tert-butyl 3- (((4- (tert-butoxycarbonyl) -2-cyclopropyl-5-fluorobenzyl) oxy) methyl) -3-fluoroazetidine-1-carboxylate 25f (3.5g, pale yellow oil), yield: 90 percent. MS m/z (ESI): 341.9[ M-55]
The sixth step
5-cyclopropyl-2-fluoro-4- (((3-fluoroazetidin-3-yl) methoxy) methyl) benzoic acid
Tert-butyl 3- (((4- (tert-butoxycarbonyl) -2-cyclopropyl-5-fluorobenzyl) oxy) methyl) -3-fluoroazetidine-1-carboxylate 25f (3.5g,7.7mmol) was dissolved in 30mL of dichloromethane and 20mL of trifluoroacetic acid was added and reacted at room temperature for 0.5 hour. Concentration under reduced pressure removed dichloromethane and remaining trifluoroacetic acid to give 25g (2.3g, yellow oil) of crude 5-cyclopropyl-2-fluoro-4- (((3-fluoroazetidin-3-yl) methoxy) methyl) benzoic acid, yield: 100 percent.
MS m/z(ESI)：298.0[M+1]
Seventh step
5-cyclopropyl-2-fluoro-4- (((3-fluoroazetidin-3-yl) methoxy) methyl) benzoic acid methyl ester
25g (2.3g,7.7mmol) of 5-cyclopropyl-2-fluoro-4- (((3-fluoroazetidin-3-yl) methoxy) methyl) benzoic acid was dissolved in 40mL of methanol, and 4mL of thionyl chloride was slowly added dropwise thereto, and the reaction was carried out at 60 ℃ for 2 hours. Concentration under reduced pressure and purification of the resulting residue by silica gel column chromatography (eluent: system B) gave methyl 5-cyclopropyl-2-fluoro-4- (((3-fluoroazetidin-3-yl) methoxy) methyl) benzoate 25h (2.3g, yellow oil), yield: 98 percent.
MS m/z(ESI)：311.9[M+1]
Eighth step
5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid methyl ester
Methyl 5-cyclopropyl-2-fluoro-4- (((3-fluoroazetidin-3-yl) methoxy) methyl) benzoate 25h (298mg,0.96mmol), 1-chloro-3- (1-chloroethyl) -5-fluorobenzene 25a (190mg,0.96mmol), potassium carbonate (268mg,1.92mmol) and sodium iodide (290mg,1.92mmol) were dissolved in 15mL of acetonitrile and reacted at 80 ℃ for 50 minutes. Filtration and concentration of the filtrate under reduced pressure gave a residue which was purified by silica gel column chromatography (eluent: system a) to give methyl 5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoate 25i (120mg, colorless oil), yield: 24.5 percent.
MS m/z(ESI)：467.9[M+1]
The ninth step
5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid
Methyl 5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoate 25i (120mg,0.256mmol) and lithium hydroxide (210mg,1.28mmol) were dissolved in 6mL of a mixed solvent of tetrahydrofuran, methanol and water (V/V ═ 1:1:1) and reacted at room temperature for 3 hours. 1N diluted hydrochloric acid is added dropwise to adjust the reaction liquid to acidity. Extraction with dichloromethane (30mL × 3), combination of the organic phases, drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure and purification of the resulting residue by silica gel column chromatography (eluent: system B) gave 5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid 25j (116mg, pale yellow solid) in yield: 100 percent.
MS m/z(ESI)：453.8[M+1]
The tenth step
5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid 25j (116mg,0.256mmol), methanesulfonamide (50mg,0.53mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (102mg,0.53mmol) and 4-dimethylaminopyridine (65mg,0.53mmol) were dissolved in 5mL of dichloromethane and reacted at room temperature for 5 hours. 20mL of 0.5N diluted hydrochloric acid was added to the reaction solution, the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give 5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 25(15mg, white solid) in yield: 12 percent.
MS m/z(ESI)：530.8[M+1]
1H NMR(400MHz,CDCl3)δ8.91(s,1H),7.71(d,J＝7.6Hz,1H),7.19(m,4H),4.81(s,2H),4.79-4.69(m,1H),4.38-4.23(m,1H),4.18(d,J＝6.3Hz,1H),4.00(t,J＝18.5Hz,3H),3.81(s,1H),3.42(s,3H),1.79-1.70(m,1H),1.65(d,J＝6.2Hz,3H),0.98(d,J＝7.8Hz,2H),0.67(d,J＝4.8Hz,2H).
Example 26
5-cyclopropyl-4- (((1- (1- (3, 5-difluorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
1- (1-chloropropyl) -3, 5-difluorobenzene
1- (3, 5-difluorophenyl) propan-1-ol 11d (7.6g,44.1mmol) was dissolved in 50mL of thionyl chloride and reacted at 60 ℃ for 2 hours. Concentrated under reduced pressure, 50mL of a saturated sodium bicarbonate solution was added to the residue, extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system a) to give 1- (1-chloropropyl) -3, 5-difluorobenzene 26a (6.3g, pale yellow oil), yield: 75 percent.
Second step of
5-cyclopropyl-4- (((1- (1- (3, 5-difluorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid methyl ester
Methyl 5-cyclopropyl-2-fluoro-4- (((3-fluoroazetidin-3-yl) methoxy) methyl) benzoate 25h (298mg,0.96mmol), 1- (1-chloropropyl) -3, 5-difluorobenzene 26a (184mg,0.96mmol), potassium carbonate (397mg,2.88mmol) and sodium iodide (432mg,2.88mmol) were dissolved in 15mL of acetonitrile and reacted at 80 ℃ for 3 h. Filtration and concentration of the filtrate under reduced pressure gave a residue which was purified by silica gel column chromatography (eluent: system a) to give methyl 5-cyclopropyl-4- (((1- (1- (3, 5-difluorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoate 26b (180mg, colorless oil), yield: 40 percent.
MS m/z(ESI)：465.9[M+1]
The third step
5-cyclopropyl-4- (((1- (1- (3, 5-difluorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid
Methyl 5-cyclopropyl-4- (((1- (1- (3, 5-difluorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoate 26b (180mg,0.39mmol) and lithium hydroxide (80mg,1.93mmol) were dissolved in 6mL of a mixed solvent of tetrahydrofuran, methanol and water (V: V ═ 1:1:1), and reacted at room temperature for 3 hours. 1N diluted hydrochloric acid is added dropwise to adjust the reaction liquid to acidity. Extraction with dichloromethane (30mL × 3), combination of organic phases, drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure and purification of the resulting residue by silica gel column chromatography (eluent: system B) gave 26c 5-cyclopropyl-4- (((1- (1- (3, 5-difluorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid (85mg, white solid) in yield: 49 percent.
MS m/z(ESI)：451.9[M+1]
The fourth step
5-cyclopropyl-4- (((1- (1- (3, 5-difluorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
5-cyclopropyl-4- (((1- (1- (3, 5-difluorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid 26c (85mg,0.19mmol), methanesulfonamide (36mg,0.38mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (73mg,0.38mmol) and 4-dimethylaminopyridine (47mg,0.38mmol) were dissolved in 5mL of dichloromethane and reacted at room temperature for 2 hours. 20mL of 0.5N diluted hydrochloric acid was added to the reaction solution to wash, the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: System B) to give 5-cyclopropyl-4- (((1- (1- (3, 5-difluorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 26(22mg, pale yellow solid), yield: 22 percent.
MS m/z(ESI)：528.8[M+1]
1H NMR(400MHz,CDCl3)δ8.97(s,1H),7.72(d,J＝7.2Hz,1H),7.21(d,J＝12.6Hz,1H),7.06(s,2H),6.93(s,1H),4.84(m,1H),4.82(s,2H),4.31(d,J＝12.6Hz,1H),3.70-3.40(m,5H),3.44(s,3H),2.12-1.91(m,2H),1.78(s,1H),1.28(t,J＝6.0Hz,3H),0.99(d,J＝6.8Hz,2H),0.67(d,J＝6.8Hz,2H).
Example 27
5-cyclopropyl-4- (((1- (3, 5-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
1, 3-dichloro-5- (chloromethyl) benzene
(3, 5-dichlorophenyl) methanol 6a (7.5g,42.6mmol) was dissolved in 50mL of thionyl chloride and reacted at 60 ℃ for 2 hours. Concentrated under reduced pressure, 50mL of a saturated sodium bicarbonate solution was added to the residue, extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system a) to give 1, 3-dichloro-5- (chloromethyl) benzene 27a (6.8g, pale yellow liquid), yield: 82 percent.
1H NMR(400MHz,CDCl3)δ7.31(s,1H),7.28(s,2H),4.49(s,2H).
Second step of
5-cyclopropyl-4- (((1- (3, 5-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid methyl ester
Methyl 5-cyclopropyl-2-fluoro-4- (((3-fluoroazetidin-3-yl) methoxy) methyl) benzoate 25h (298mg,0.96mmol), 1, 3-dichloro-5- (chloromethyl) benzene 27a (185mg,0.96mmol), potassium carbonate (268mg,1.92mmol) and sodium iodide (290mg,1.92mmol) were dissolved in 15mL of acetonitrile and reacted at 80 ℃ for 3 h. Filtration was carried out, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give methyl 5-cyclopropyl-4- (((1- (3, 5-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoate 27b (200mg, colorless oil), yield: 44 percent.
MS m/z(ESI)：469.8[M+1]
The third step
5-cyclopropyl-4- (((1- (3, 5-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid
Methyl 5-cyclopropyl-4- (((1- (3, 5-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoate 27b (200mg,0.43mmol) and lithium hydroxide (180mg,4.3mmol) were dissolved in 6mL of a mixed solvent of tetrahydrofuran, methanol and water (V: V ═ 1:1:1) and reacted at room temperature for 3 hours. 1N diluted hydrochloric acid is added dropwise to adjust the reaction liquid to acidity. Extraction with dichloromethane (30mL × 3), combination of the organic phases, drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure and purification of the resulting residue by silica gel column chromatography (eluent: system B) gave 27c (190mg, white solid) of 5-cyclopropyl-4- (((1- (3, 5-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid in yield: 97 percent.
MS m/z(ESI)：455.8[M+1]
The fourth step
5-cyclopropyl-4- (((1- (3, 5-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
5-cyclopropyl-4- (((1- (3, 5-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid 27c (190mg,0.42mmol), methanesulfonamide (80mg,0.84mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (160mg,0.84mmol) and 4-dimethylaminopyridine (102mg,0.84mmol) were dissolved in 8mL of dichloromethane and reacted at room temperature for 2 hours. 20ml of 0.5N diluted hydrochloric acid was added to the reaction solution to wash, the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 5-cyclopropyl-4- (((1- (3, 5-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 27(80mg, white solid) in yield: 36 percent.
MS m/z(ESI)：532.8[M+1]
1H NMR(400MHz,CDCl3)δ9.49(s,1H),7.61(s,1H),7.50(s,2H),7.24-7.22(m,2H),4.78(s,2H),4.19(s,2H),4.15-3.97(m,2H),3.94-3.88(m,3H),3.34(s,3H),3.09-3.07(m,1H),1.93-1.85(m,1H),0.91-0.89(m,2H),0.69-0.67(m,2H).
Example 28
5-cyclopropyl-4- (((1- (3, 4-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
1, 2-dichloro-4- (chloromethyl) benzene
(3, 4-dichlorophenyl) methanol 7a (7.5g,42.6mmol) was dissolved in 50mL of thionyl chloride and reacted at 60 ℃ for 2 hours. Concentrated under reduced pressure, 50mL of a saturated sodium bicarbonate solution was added to the residue, extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system a) to give 1, 2-dichloro-4- (chloromethyl) benzene 28a (6.8g, pale yellow liquid), yield: 82 percent.
1H NMR(400MHz,CDCl3)δ7.49-7.48(m,1H),7.43(d,J＝8.0Hz,1H),7.23-7.21(m,1H),4.51(s,2H).
Second step of
5-cyclopropyl-4- (((1- (3, 4-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid methyl ester
Methyl 5-cyclopropyl-2-fluoro-4- (((3-fluoroazetidin-3-yl) methoxy) methyl) benzoate 25h (298mg,0.96mmol), 1, 2-dichloro-4- (chloromethyl) benzene 28a (185mg,0.96mmol), potassium carbonate (268mg,1.92mmol) and sodium iodide (290mg,1.92mmol) were dissolved in 15mL of acetonitrile and reacted at 80 ℃ for 3 h. Filtration was carried out, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give methyl 5-cyclopropyl-4- (((1- (3, 4-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoate 28b (300mg, colorless oil), yield: 67%.
MS m/z(ESI)：469.8[M+1]
The third step
5-cyclopropyl-4- (((1- (3, 4-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid
Methyl 5-cyclopropyl-4- (((1- (3, 4-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoate 28b (200mg,0.43mmol) and lithium hydroxide (180mg,4.3mmol) were dissolved in 6mL of a mixed solvent of tetrahydrofuran, methanol and water (V: V ═ 1:1:1), and reacted at room temperature for 3 hours. 1N diluted hydrochloric acid is added dropwise to adjust the reaction liquid to acidity. Extraction with dichloromethane (30mL × 3), combination of the organic phases, drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure and purification of the resulting residue by silica gel column chromatography (eluent: system B) gave 28c 5-cyclopropyl-4- (((1- (3, 4-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid (160mg, white solid) in yield: 82 percent.
MS m/z(ESI)：455.8[M+1]
The fourth step
5-cyclopropyl-4- (((1- (3, 4-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
28c (160mg,0.35mmol) of 5-cyclopropyl-4- (((1- (3, 4-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid, methanesulfonamide (66mg,0.70mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (133.7mg,0.70mmol) and 4-dimethylaminopyridine (85.4mg,0.70mmol) were dissolved in 8mL of dichloromethane and reacted at room temperature for 2 hours. 20mL of 0.5N diluted hydrochloric acid was added to the reaction solution, the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give 5-cyclopropyl-4- (((1- (3, 4-dichlorobenzyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 28(80mg, white solid) in yield: 36 percent.
MS m/z(ESI)：532.8[M+1]
1H NMR(400MHz,CDCl3)δ7.71(d,J＝7.6Hz,1H),7.53-7.51(m,2H),7.23-7.20(m,2H),4.83(s,2H),4.52-4.37(m,2H),4.25(s,2H),4.00-3.95(m,3H),3.42(s,3H),3.19-3.07(m,1H),1.82-1.72(m,1H),1.00-0.96(m,2H),0.69-0.65(m,2H).
Example 29
5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
1, 3-dichloro-5- (1-chloropropyl) benzene
1- (3, 5-dichlorophenyl) propan-1-ol 12e (3.2g,15.7mmol) was dissolved in 10mL of thionyl chloride and reacted at 60 ℃ for 2 hours. Concentrated under reduced pressure, 20mL of a saturated sodium bicarbonate solution was added to the residue, extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system a) to give 1, 3-dichloro-5- (1-chloropropyl) benzene 29a (2.8g, colorless oil), yield: 81 percent.
1H NMR(400MHz,CDCl3)δ7,.28-7.27(m,1H),7.25-7.24(m,1H),7.16(s,1H),4.66(t,J＝6.8Hz,1H),2.07-2.00(m,2H),0.99(t,J＝7.6Hz,3H).
Second step of
5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-
Fluorobenzoic acid methyl ester
Methyl 5-cyclopropyl-2-fluoro-4- (((3-fluoroazetidin-3-yl) methoxy) methyl) benzoate 25h (311mg,1mmol), 1, 3-dichloro-5- (1-chloropropyl) benzene 29a (335mg,1.5mmol), potassium carbonate (414mg, 3mmol) and sodium iodide (450mg,3mmol) were dissolved in 7mL of acetonitrile and reacted at 80 ℃ for 4 h. Filtration and concentration of the filtrate under reduced pressure gave a residue which was purified by silica gel column chromatography (eluent: system a) to give methyl 5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoate 29b (300mg, colorless oil), yield: 60 percent.
MS m/z(ESI)：497.8[M+1]
The third step
5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid
Methyl 5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoate 29b (300mg,0.60mmol) and lithium hydroxide (252mg,6.0mmol) were dissolved in 15mL of a mixed solvent of tetrahydrofuran, methanol and water (V: V ═ 1:1:1) and reacted at room temperature for 3 hours. 1N diluted hydrochloric acid is added dropwise to adjust the reaction liquid to acidity. Extraction with dichloromethane (30mL × 3), combination of the organic phases, drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure and purification of the resulting residue by silica gel column chromatography (eluent: system B) gave 29c 5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid (100mg, white solid) in yield: 35 percent.
MS m/z(ESI)：483.8[M+1]
The fourth step
5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
29c (100mg,0.21mmol) of 5-cyclopropyl-4- (((1- (1- (3, 5-difluorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid, methanesulfonamide (39mg,0.42mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (80mg,0.42mmol) and 4-dimethylaminopyridine (51mg,0.42mmol) were dissolved in 6mL of dichloromethane and reacted at room temperature for 2 hours. 20mL of 0.5N diluted hydrochloric acid was added to the reaction solution, the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give 5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 29(20mg, pale yellow solid) in yield: 17 percent.
MS m/z(ESI)：560.8[M+1]
1H NMR(400MHz,CDCl3)δ7.68(s,1H),7.56(s,2H),7.28-7.25(m,2H),4.79(s,2H),4.25-4.14(m,1H),3.97-3.91(m,1H),3.78-3.41(m,5H),3.36(s,3H),2.56-1.90(m,2H),1.79-1.63(m,1H),1.28(t,J＝6.0Hz,3H),0.93-0.91(m,2H),0.69-0.66(m,2H).
Example 30
(R) -5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
(S) -1- (3, 5-dichlorophenyl) propan-1-ol
Under the protection of argon, 1- (3, 5-dichlorophenyl) propan-1-one 12c (2.0g,9.9mmol) is dissolved in 20mL tetrahydrofuran, and (R) -2-methyl-CBS-oxazaborolidine (2mL,2mmol, 1M/toluene) and borane tetrahydrofuran solution (5.44mL,10.88mmol,2M/THF) are slowly added dropwise in sequence at 0 ℃, and after the addition, the reaction is carried out for 5 hours at 0 ℃. Concentration under reduced pressure and purification of the obtained residue by silica gel column chromatography (eluent: system A) gave (S) -1- (3, 5-dichlorophenyl) propan-1-ol 30a (2.0g, colorless oil), yield: 99%, 84.56% ee. (the ee value was determined by chiral HPLC conditions of ChiralPak AD-H, 250X 4.6mm I.D.,5 μm; 1.0 mL/min; mobile phase n-hexane/isopropanol/diethylamine ═ 95/5/0.1(V/V/V), 25 ℃, (S) -1- (3, 5-dichlorophenyl) propan-1-ol 30a retention time 7.21min, content 92.28%)
MS m/z(ESI)：205.1[M+1]
Second step of
(S) -1- (3, 5-dichlorophenyl) propyl-4-methylbenzenesulfonate
(S) -1- (3, 5-dichlorophenyl) propan-1-ol 30a (200mg,0.97mmol) was dissolved in 5mL of tetrahydrofuran, and sodium hydride (194mg,4.85mmol) was added at 0 ℃ and stirred at 0 ℃ for 30 minutes. P-toluenesulfonyl chloride (366mg,1.94mmol) was dissolved in 5mL of tetrahydrofuran, and added dropwise to the above reaction solution at 0 ℃ to react at 0 ℃ for 20 minutes, and then the reaction was continued at room temperature for 6 hours. The reaction was quenched by addition of 20mL of saturated ammonium chloride solution, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with saturated sodium chloride solution (30mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to give (S) -1- (3, 5-dichlorophenyl) propyl-4-methylbenzenesulfonate 30b (330mg, yellow oil), yield: 95%, 84.98% ee. (the ee value was determined by chiral HPLC conditions of ChiralPak OD-H, 250X 4.6mm I.D.,5 μm; 1.0 mL/min; mobile phase n-hexane/isopropanol/diethylamine ═ 95/5/0.1(V/V/V), 25 ℃, (S) -1- (3, 5-dichlorophenyl) propyl-4-methylbenzenesulfonate 30b retention time: 6.41min, content 92.49%)
1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.0Hz,2H),7.20-7.17(m,3H),6.95-6.94(m,2H),5.18(t,J＝6.4Hz,1H),2.39(s,3H),1.89-1.83(m,1H),1.83-1.73(m,1H),0.87(t,J＝7.2Hz,3H).
The third step
(R) -5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid methyl ester
Methyl 5-cyclopropyl-2-fluoro-4- (((3-fluoroazetidin-3-yl) methoxy) methyl) benzoate 25h (249mg,0.8mmol), (S) -1- (3, 5-dichlorophenyl) propyl 4-methylbenzenesulfonate 30b (322mg,0.9mmol) and potassium carbonate (165.6mg,1.2mmol) were dissolved in 5mL of acetonitrile and reacted at room temperature overnight. Filtration and concentration of the filtrate under reduced pressure gave a residue which was purified by silica gel column chromatography (eluent: system a) to give methyl (R) -5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoate 30c (238mg, colorless oil), yield: 60%, 69.86% ee. (the ee value was determined by chiral HPLC conditions of ChiralPak AD-H, 250X 4.6mm I.D.,5 μm; 1.0 mL/min; mobile phase: n-hexane/isopropanol/diethylamine ═ 99/1/0.1(V/V/V), 25 ℃; (R) -5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid methyl ester 30c retention time: 13.63min, content 84.93%)
MS m/z(ESI)：497.8[M+1]
The fourth step
(R) -5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid
Methyl (R) -5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoate 30c (238mg,0.48mmol) and lithium hydroxide (115mg,4.8mmol) were dissolved in 10mL of a mixed solvent of 1, 4-dioxane and water (V: V ═ 1:1) and reacted at room temperature for 8 hours. Concentration under reduced pressure, 20mL of ethyl acetate was added to the obtained residue, which was washed with 10% citric acid solution (30mL) and saturated sodium chloride solution (30mL) in this order, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give (R) -5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid 30d (100mg, white solid), yield: and 43 percent.
MS m/z(ESI)：483.8[M+1]
The fifth step
(R) -5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
(R) -5-cyclopropyl-4- (((1- (1- (3, 5-difluorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid 30d (100mg,0.21mmol), methanesulfonamide (39mg,0.42mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (80mg,0.42mmol) and 4-dimethylaminopyridine (51mg,0.42mmol) were dissolved in 6mL of dichloromethane and reacted at room temperature for 2 hours. 20mL of 1.0N diluted hydrochloric acid was added to the reaction solution to wash the reaction solution, the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to obtain (R) -5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 30(20mg, white solid) in yield: 17%, 70.22% ee. (the ee value was determined by chiral HPLC conditions of ChiralPak OD-H, 250X 4.6mm I.D.,5 μm; 0.8 mL/min; mobile phase: N-hexane/isopropanol/diethylamine ═ 70/30/0.1(V/V/V), 25 ℃, (R) -5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 30 retention time 15.46min, content 85.11%)
MS m/z(ESI)：560.8[M+1]
1H NMR(400MHz,DMSO-d6)δ12.13(s,1H),7.51(s,1H),7.33(s,2H),7.26(d,J＝3.2Hz,1H),7.23(s,1H),4.79(s,2H),3.85(d,J＝25.2Hz,2H),3.59-3.53(m,1H),3.36-3.35(m,1H),3.34(s,3H),3.28-3.18(m,2H),3.12-3.04(m,1H),1.93-1.89(m,1H),1.72-1.65(m,1H),1.46-1.38(m,1H),0.93-0.89(m,2H),0.71-0.67(m,2H),0.62(t,J＝7.2Hz,3H).
Example 31
(R) -5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
(S) -1- (3-chloro-5-fluorophenyl) ethanol
1- (3-chloro-5-fluorophenyl) ethanone 31a (1.0g,5.8mmol) is dissolved in 10mL of tetrahydrofuran under the protection of argon, and (R) -2-methyl-CBS-oxazaborolidine (0.58mL,0.58mmol, 1M/toluene) and borane tetrahydrofuran solution (3.48mL,6.95mmol,2M/THF) are slowly added dropwise in sequence at 0 ℃, and after the addition, the reaction is carried out for 5 hours at 0 ℃. Concentration under reduced pressure and purification of the obtained residue by silica gel column chromatography (eluent: system a) gave (S) -1- (3-chloro-5-fluorophenyl) ethanol 31b (1.0, colorless oil), yield: 99%, 87.46% ee. (the ee value was determined by chiral HPLC conditions of ChiralPak AD-H, 250X 4.6mm I.D.,5 μm; 1.0 mL/min; mobile phase n-hexane/isopropanol/diethylamine ═ 99/1/0.1(V/V/V), 25 ℃, (S) -1- (3-chloro-5-fluorophenyl) ethanol 31b retention time 25.54min, content 93.73%)
Second step of
(S) -1- (3-chloro-5-fluorophenyl) ethyl-4-methylbenzenesulfonate
(S) -1- (3-chloro-5-fluorophenyl) ethanol 31b (350mg,2mmol) was dissolved in 10mL of tetrahydrofuran, and sodium hydride (400mg,10mmol) was added thereto at 0 ℃ and stirred at 0 ℃ for 30 minutes. P-toluenesulfonyl chloride (764mg,4mmol) was dissolved in 5mL of tetrahydrofuran, and the solution was added dropwise to the reaction solution at 0 ℃ to react at 0 ℃ for 20 minutes, followed by reaction at room temperature for 1 hour. The reaction was quenched by the addition of 20mL of saturated ammonium chloride solution, extracted with ethyl acetate (25mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give (S) -1- (3-chloro-5-fluorophenyl) ethyl-4-methylbenzenesulfonate 31c (444mg, pale yellow solid), yield: 71 percent; 88.02% ee. (the ee value was determined by chiral HPLC conditions of ChiralPak OD-H, 250X 4.6mm I.D.,5 μm; 1.0 mL/min; mobile phase: n-hexane/isopropanol/diethylamine ═ 95/5/0.1(V/V/V), 25 ℃; (S) -1- (3-chloro-5-fluorophenyl) ethyl-4-methylbenzenesulfonate 31c retention time: 8.14min, content 94.01%)
1H NMR(400MHz,DMSO-d)δ7.70(d,J＝8.2Hz,2H),7.50(d,J＝7.9Hz,1H),7.39(d,J＝8.1Hz,2H),7.31(t,J＝14.5Hz,1H),7.22-7.13(m,1H),5.63(q,J＝6.5Hz,1H),2.41(d,J＝16.4Hz,3H),1.54-1.39(m,3H).
The third step
5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) benzoic acid methyl ester
5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) benzoic acid 13f (100mg,0.3mmol) was dissolved in 10mL of methanol, and 1mL of thionyl chloride was slowly added dropwise thereto, followed by reaction at 60 ℃ for 2 hours. Concentration under reduced pressure and purification of the obtained residue by silica gel column chromatography (eluent: system B) gave methyl 5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) benzoate 31d (102mg, yellow oil), yield: 100 percent.
MS m/z(ESI)：339.9[M+1]
The fourth step
(R) -4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid methyl ester
Methyl 5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) benzoate 31d (60mg,0.176mmol), (S) -1- (3-chloro-5-fluorophenyl) ethyl-4-methylbenzenesulfonate 31c (83mg,0.265mmol) and potassium carbonate (73mg,0.53mmol) were dissolved in 5mL of acetonitrile and reacted at room temperature overnight. Filtration was carried out, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give methyl (R) -4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoate 31e (44mg, colorless oil), yield: 50%, 89.88% ee. (the ee value is determined by chiral HPLC conditions on a chiral column ChiralPak AD-H, 250X 4.6mm I.D.,5 μm; 1.0 mL/min; mobile phase: n-hexane/isopropanol/diethylamine ═ 99/1/0.1(V/V/V), 25 ℃; (R) -4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid methyl ester 31e retention time: 19.70min, content 94.94%)
MS m/z(ESI)：495.9[M+1]
The fifth step
(R) -4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid
Methyl (R) -4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoate 31e (44mg,0.088mmol) and lithium hydroxide (75mg,1.77mmol) were dissolved in 4mL of a mixed solvent of 1, 4-dioxane and water (V: V ═ 1:1) and reacted at room temperature for 2 hours. Concentrated under reduced pressure, and 20mL of ethyl acetate was added to the obtained residue, washed with 10% citric acid solution (30mL) and saturated sodium chloride solution (30mL) in this order, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give (R) -4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid 31f (43mg, white solid), yield: 100 percent.
MS m/z(ESI)：481.9[M+1]
The sixth step
(R) -5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
(R) -4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid 31f (45mg,0.09mmol), methanesulfonamide (26mg,0.28mmol), 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide (100mg,0.523mmol) and 4-dimethylaminopyridine (22.8mg,0.186mmol) were dissolved in 5mL of dichloromethane and reacted at room temperature for 8 hours. To the reaction solution was added 20mL of 1.0N diluted hydrochloric acid to wash the reaction solution, the aqueous layer was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give (R) -5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 31 (10mg, white solid) in yield: 19%, 88.44% ee. (the ee value was determined by chiral HPLC conditions of ChiralPak AD-H, 250X 4.6mm I.D.,5 μm; 0.8 mL/min; mobile phase: N-hexane/isopropanol/diethylamine ═ 70/30/0.1(V/V/V), 25 ℃; (R) -5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 31 retention time: 16.64min, content 94.22%)
MS m/z(ESI)：558.8[M+1]
1H NMR(400MHz,CDCl3)δ7.73(d,J＝7.6Hz,1H),7.30(d,J＝13.6Hz,1H),7.13(s,1H),6.99-6.96(m,2H),4.79(s,2H),3.61(d,J＝20.0Hz,2H),3.47-3.44(m,1H),3.42(s,3H),2.83-2.81(m,1H),2.61-2.58(m,1H),2.39-2.31(m,2H),1.98-1.68(m,5H),1.34(d,J＝6.4Hz,3H),0.99-0.94(m,2H),0.69-0.65(m,2H).
Example 32
(S) -5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
First step of
(S) -5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide
5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 21(2.96g,5.30mmol) was further resolved into chiral isomers by preparative high performance liquid preparative chromatography and chiral column using Supercritical Fluid Chromatography (SFC) method (chiral column ChiralCel OJ, 150X 4.6mm I.D.,3 μm; 2.5 mL/min; mobile phase A for CO2and B for MEOH (0.05% DEA)) to give (S) -5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 32(1.22g, white solid), yield: 41.2 percent; 99.8% ee, retention time: 4.473 min; (R) -5-cyclopropyl-4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -2-fluoro-N- (methylsulfonyl) benzamide 31(1.31g, white solid), yield: 44.2 percent; 99.8% ee, retention time: 4.880 min.
32 MS m/z(ESI)：558.8[M+1]
1H NMR(400MHz,CDCl3)δ7.72(d,J＝7.6Hz,1H),7.30(d,J＝12.8Hz,1H),7.13(s,1H),6.99-6.96(m,2H),4.79(s,2H),3.61(d,J＝19.6Hz,2H),3.48-3.45(m, 1H),3.42(s,3H),2.84-2.80(m,1H),2.61-2.59(m,1H),2.39-2.31(m,2H),1.98-1.68(m,5H),1.35(d,J＝6.4Hz,3H),0.99-0.94(m,2H),0.69-0.65(m,2H).
Example 33
5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -N- (ethylsulfonyl) -2-fluorobenzamide
First step of
1- (3, 5-dichlorophenyl) propan-1-ol
1- (3, 5-dichlorophenyl) propan-1-one 12c (140g,0.69mol) was dissolved in 1.0L tetrahydrofuran, cooled to 0 ℃ in an ice-water bath, sodium borohydride (52g,1.38mol) was added in portions slowly, and after the addition, the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction was quenched by adding 500mL of ice water, extracted with ethyl acetate (500 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 1- (3, 5-dichlorophenyl) propan-1-ol 33a (140g), yield: 100 percent.
1H NMR(400MHz,CDCl3)δ7.25-7.24(m,1H),7.22-7.21(m,2H),4.55(t,J＝6.4Hz,1H),2.19(s,1H),1.77-1.69(m,2H),0.92(t,J＝7.2Hz,3H).
Second step of
1, 3-dichloro-5- (1-chloropropyl) benzene
1- (3, 5-dichlorophenyl) propan-1-ol 33a (140g,0.69mol) was dissolved in 300mL of thionyl chloride and reacted at 60 ℃ for 3 hours. Concentration under reduced pressure, addition of 500mL of ethyl acetate to dissolve the obtained residue, washing with saturated sodium bicarbonate solution (100mL × 2), drying of the organic phase with anhydrous sodium sulfate, filtration, concentration under reduced pressure and purification of the obtained residue by silica gel column chromatography (eluent: system a) to obtain 1, 3-dichloro-5- (1-chloropropyl) benzene 33b (120g), yield: 80 percent.
1H NMR(400MHz,CDCl3)δ7.29-7.25(m,2H),7.16(s,1H),4.67(t,J＝6.8Hz,1H),2.10-1.99(m,2H),1.00(t,J＝7.2Hz,3H).
The third step
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid methyl ester
4- (((7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid 1h (120g,346mmol) was dissolved in 800mL of methanol and thionyl chloride (41.2g,346mmol) was slowly added dropwise and reacted at 80 ℃ for 3 hours. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and 300mL of petroleum ether and 300mL of ethyl acetate were added to the obtained residue to precipitate a solid product, which was filtered to obtain methyl 4- (((7-azaspiro [3.5] non-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoate 33c (107g), yield: 85 percent.
MS m/z(ESI)：362.0[M+1]
The fourth step
5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluorobenzoic acid methyl ester
Methyl 4- (((7-azaspiro [3.5] non-2-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoate 33c (97g,225mmol), 1, 3-dichloro-5- (1-chloropropyl) benzene 33b (76g,337.5mmol), potassium carbonate (93g,675mmol) and sodium iodide (101g,675mmol) were dissolved in 600mL of acetonitrile and reacted at 90 ℃ for 2 hours. Filtration was carried out, the filter cake was washed with 500mL of ethyl acetate, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System A) to give methyl 5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluorobenzoate 33d (79g), yield: and 64 percent.
MS m/z(ESI)：547.9[M+1]
The fifth step
5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluorobenzoic acid
Methyl 5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluorobenzoate 33d (5g,9.12mmol) was dissolved in 40mL of a mixed solvent of 1, 4-dioxane and water (V: V ═ 1:1), and lithium hydroxide (1.9g,45.6mmol) was added to the solution, followed by reaction at room temperature for 3 hours. Concentrating under reduced pressure to remove 1, 4-dioxane, adjusting the pH of the reaction solution to 2-3 with 1N diluted hydrochloric acid, extracting with dichloromethane (100 mL. times.3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 33e (4.86g) of 5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluorobenzoic acid, in a yield of: 100 percent.
MS m/z(ESI)：533.8[M+1]
The sixth step
5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -N- (ethylsulfonyl) -2-fluorobenzamide
33e (200mg,0.374mmol) of 5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluorobenzoic acid, ethyl sulfonamide (81.6mg,0.748mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (143mg,0.748mmol) and 4-dimethylaminopyridine (91.4mg,0.748mmol) were dissolved in 10mL of dichloromethane and reacted overnight at room temperature. 10mL of a saturated citric acid solution was added, extraction was performed with dichloromethane (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give 5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -N- (ethylsulfonyl) -2-fluorobenzamide 33(37.5mg), yield: 16 percent.
MS m/z(ESI)：624.9[M+1]
1H NMR(400MHz,CDCl3)δ8.46(s,1H),7.67(d,J＝7.2Hz,1H),7.47(s,1H),7.32(s,2H),7.22(d,J＝12.4Hz,1H),4.68(s,2H),4.08-4.07(m,1H),3.67-3.65(m,1H),3.60(q,J＝7.2Hz,2H),3.51-3.50(m,2H),3.36-3.32(m,1H),2.58-2.45(m,3H),2.30-2.29(m,1H),2.10-2.19(m,3H),1.94-1.92(m,3H),1.76-1.74(m,3H),1.56-1.55(m,1H),1.45(t,J＝7.2Hz,3H),1.12(d,J＝8.4Hz,2H),0.77(s,3H),0.66(d,J＝4.8Hz,2H).
Example 34
N- (tert-Butylsulfonyl) -5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -2-fluorobenzamide
First step of
N- (tert-Butylsulfonyl) -5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -2-fluorobenzamide
33e (200mg,0.374mmol) of 5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluorobenzoic acid, tert-butylsulfonamide (102.7mg,0.748mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (143mg,0.748mmol) and 4-dimethylaminopyridine (91.4mg,0.748mmol) were dissolved in 10mL of dichloromethane and reacted overnight at room temperature. 10mL of a saturated citric acid solution was added, extraction was performed with dichloromethane (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give N- (tert-butylsulfonyl) -5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -2-fluorobenzamide 34(75.3mg), yield: 31 percent.
MS m/z(ESI)：652.8[M+1]
1H NMR(400MHz,CDCl3)δ8.46(s,1H),7.67(d,J＝7.2Hz,1H),7.48(s,1H),7.27(s,2H),7.21(d,J＝13.2Hz,1H),4.67(s,2H),4.08-4.06(m,1H),3.67-3.59(m,1H),3.54-3.47(m,2H),3.40-3.31(m,1H),2.58-2.44(m,3H),2.29-2.27(m,1H),2.10-2.09(m,3H),1.97-1.88(m,3H),1.77-1.72(m,3H),1.61-1.59(m,1H),1.55(s,9H),0.97-0.92(m,2H),0.78-0.77(m,3H),0.68-0.64(m,2H).
Example 35
5-cyclopropyl-N- (cyclopropylsulfonyl) -4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -2-fluorobenzamide
First step of
5-cyclopropyl-N- (cyclopropylsulfonyl) -4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -2-fluorobenzamide
33e (200mg,0.374mmol) of 5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] non-2-yl) methoxy) methyl) -2-fluorobenzoic acid, cyclopropylsulfonamide (90.7mg,0.748mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (143mg,0.748mmol) and 4-dimethylaminopyridine (91.4mg,0.748mmol) were dissolved in 10mL of dichloromethane and reacted overnight at room temperature. 10mL of a saturated citric acid solution was added, extraction was performed with dichloromethane (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give 5-cyclopropyl-N- (cyclopropylsulfonyl) -4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -2-fluorobenzamide 35(77.5mg), yield: 32.5 percent.
MS m/z(ESI)：636.9[M+1]
1H NMR(400MHz,CDCl3)δ8.99(s,1H),7.69(d,J＝7.2Hz,1H),7.47(s,1H),7.32(s,2H),7.21(d,J＝13.2Hz,1H),4.68(s,2H),4.06(d,J＝11.2Hz,1H), 3.67-3.57(m,1H),3.52-3.50(m,2H),3.38-3.29(m,1H),3.14-3.08(m,1H),2.58-2.43(m,3H),2.34-2.25(m,1H),2.12-2.10(m,3H),1.94-1.91(m,3H),1.76-1.71(m,3H),1.58-1.53(m,1H),1.46-1.45(m,2H),1.12(d,J＝6.8Hz,2H),0.95(d,J＝8.0Hz,2H),0.77(t,J＝6.8Hz,3H),0.66(d,J＝4.8Hz,2H).
Example 36
5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -2-fluoro-N- ((1-methylcyclopropyl) sulfonyl) -benzamide
First step of
5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -2-fluoro-N- ((1-methylcyclopropyl) sulfonyl) -benzamide
33e (200mg,0.374mmol) of 5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -2-fluorobenzoic acid, 1-methylcyclopropanesulfonamide (101.2mg,0.748mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (143mg,0.748mmol) and 4-dimethylaminopyridine (91.4mg,0.748mmol) were dissolved in 10mL of dichloromethane and reacted overnight at room temperature. 10mL of a saturated citric acid solution was added, extraction was performed with dichloromethane (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give 5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -2-fluoro-N- ((1-methylcyclopropyl) sulfonyl) -benzamide 36(81.5mg), yield: 33.4 percent.
MS m/z(ESI)：650.9[M+1]
1H NMR(400MHz,CDCl3)δ8.73(s,1H),7.68(d,J＝7.6Hz,1H),7.47(s,1H),7.31(s,2H),7.22(d,J＝12.8Hz,1H),4.67(s,2H),4.08-4.05(m,1H),3.66-3.58(m,1H),3.52-3.49(m,2H),3.38-3.30(m,1H),2.58-2.42(m,3H),2.29-2.28(m,1H),2.10-2.09(m,3H),1.97-1.88(m,3H),1.81-1.79(m,2H),1.75-1.71(m,3H),1.59(s,3H),1.56-1.53(m,1H),1.00-0.92(m,4H),0.79-0.76(m,3H),0.69-0.64(m,2H).
Example 37
4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-N- (ethylsulfonyl) -2-fluorobenzamide
First step of
1-chloro-3- (1-chloroethyl) -5-fluorobenzene
1- (3-chloro-5-fluorophenyl) ethanol 9e (19g,108.8mol) was dissolved in 100mL of thionyl chloride and reacted at 80 ℃ for 2 hours. Concentrated under reduced pressure, and 100mL of ethyl acetate was added to dissolve the obtained residue, washed with a saturated sodium bicarbonate solution (100mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to obtain 1-chloro-3- (1-chloroethyl) -5-fluorobenzene 37a (20g), yield: 95 percent.
1H NMR(400MHz,CDCl3)δ7.46-7.38(m,3H),5.37(q,J＝6.8Hz,1H),1.78(d,J＝6.8Hz,3H).
Second step of
4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid methyl ester
Methyl 5-cyclopropyl-2-fluoro-4- (((4-fluoropiperidin-4-yl) methoxy) methyl) benzoate 31d (4.5g,13.26mmol), 1-chloro-3- (1-chloroethyl) -5-fluorobenzene 37a (3.76g,39.78mmol), potassium carbonate (5.96g,39.78mmol) and sodium iodide (5.50g,39.78mmol) were dissolved in 60mL of acetonitrile and reacted at 90 ℃ for 3 hours. Filtration was carried out, the filter cake was washed with 50mL of ethyl acetate, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to give methyl 4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoate 37b (4.8g), yield: 73 percent.
MS m/z(ESI)：495.9[M+1]
The third step
4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid
Methyl 4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoate 37b (4.8g,9.68mmol) was dissolved in 70mL of a mixed solvent of 1, 4-dioxane and water (V: V ═ 1:1), and lithium hydroxide (3.48g,145.17mmol) was added to the solution, followed by reaction at room temperature for 2 hours. Concentration under reduced pressure was performed to remove 1, 4-dioxane, the pH of the reaction solution was adjusted to 2 to 3 with 1N diluted hydrochloric acid, extraction was performed with dichloromethane (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 37c (4.66g) of 4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid, yield: 100 percent.
MS m/z(ESI)：481.8[M+1]
The fourth step
4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-N- (ethylsulfonyl) -2-fluorobenzamide
4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid 37c (200mg,0.415mmol), ethylsulfonamide (90.6mg,0.83mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (158.7mg,0.83mmol) and 4-dimethylaminopyridine (101.4mg,0.83mmol) were dissolved in 10mL of dichloromethane and reacted at room temperature overnight. 10mL of a saturated citric acid solution was added, extraction was performed with dichloromethane (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give 4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-N- (ethylsulfonyl) -2-fluorobenzamide 37(51.81mg), yield: 22 percent.
MS m/z(ESI)：572.9[M+1]
1H NMR(400MHz,CDCl3)δ8.89(s,1H),7.67(d,J＝7.6Hz,1H),7.28(s,1H),7.24-7.17(m,3H),4.76(s,2H),4.33-4.28(m,1H),3.70-3.69(m,2H),3.65-3.64(m,1H),3.59(q,J＝7.6Hz,2H),3.37(d,J＝11.2Hz,1H),2.98-2.87(m,2H),2.45-2.32(m,2H),2.21-2.16(m,2H),1.79(d,J＝6.8Hz,3H),1.76-1.72(m,1H),1.44(t,J＝7.2Hz,3H),0.98-0.93(m,2H),0.67-0.63(m,2H).
Example 38
N- (tert-Butylsulfonyl) -4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzamide
First step of
N- (tert-Butylsulfonyl) -4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzamide
4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid 37c (200mg,0.415mmol), tert-butylsulfonamide (133.9mg,0.83mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (158.7mg,0.83mmol) and 4-dimethylaminopyridine (101.4mg,0.83mmol) were dissolved in 10mL of dichloromethane and reacted at room temperature overnight. 10mL of a saturated citric acid solution was added, extraction was performed with dichloromethane (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give N- (tert-butylsulfonyl) -4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzamide 38(115mg), yield: 46 percent.
MS m/z(ESI)：600.9[M+1]
1H NMR(400MHz,CDCl3)δ8.46(s,1H),7.68(d,J＝8.0Hz,1H),7.27(s,1H),7.23-7.16(m,3H),4.77(s,2H),4.28(q,J＝6.8Hz,1H),3.71-3.69(m,2H),3.65-3.64(m,1H),3.38-3.35(m,1H),2.98-2.87(m,2H),2.46-2.30(m,2H),2.21-2.12(m,2H),1.80(d,J＝6.4Hz,3H),1.77-1.70(m,1H),1.55(s,9H),0.97-0.93(m,2H),0.68-0.64(m,2H).
Example 39
4- (((1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- ((1-methylcyclopropyl) sulfonyl) benzamide
First step of
4- (((1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- ((1-methylcyclopropyl) sulfonyl) benzamide
4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid 37c (200mg,0.415mmol), 1-methylcyclopropanesulfonamide (112.2mg,0.83mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (158.7mg,0.83mmol) and 4-dimethylaminopyridine (101.4mg,0.83mmol) were dissolved in 10mL of dichloromethane and reacted at room temperature overnight. 10mL of a saturated citric acid solution was added, extraction was performed with dichloromethane (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give 4- (((1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluoro-N- ((1-methylcyclopropyl) sulfonyl) benzamide 39(96.3mg), yield: 38.7 percent.
MS m/z(ESI)：598.9[M+1]
1H NMR(400MHz,CDCl3)δ8.73(s,1H),7.69(d,J＝8.0Hz,1H),7.27(s,1H),7.24-7.16(m,3H),4.76(s,2H),4.28(q,J＝7.2Hz,1H),3.67-3.64(m,3H),3.36(d,J＝12.0Hz,1H),2.97-2.86(m,2H),2.45-2.32(m,2H),2.21-2.16(m,2H),1.81-1.79(m,5H),1.77-1.72(m,1H),1.60(s,3H),1.00-0.93(m,4H),0.68-0.44(m,2H).
Example 40
5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -N- (ethylsulfonyl) -2-fluorobenzamide
First step of
5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -N- (ethylsulfonyl) -2-fluorobenzamide
29c (200mg,0.413mmol) of 5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid, ethyl sulfonamide (90.14mg,0.826mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (158mg,0.826mmol) and 4-dimethylaminopyridine (100.9mg,0.826mmol) were dissolved in 10mL of dichloromethane and reacted overnight at room temperature. 10mL of a saturated citric acid solution was added, extraction was performed with dichloromethane (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give 5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -N- (ethylsulfonyl) -2-fluorobenzamide 40(123mg), yield: 52 percent.
MS m/z(ESI)：574.8[M+1]
1H NMR(400MHz,CDCl3)δ8.81(s,1H),7.66(d,J＝7.2Hz,1H),7.44(s,1H),7.38(s,2H),7.19(d,J＝12.4Hz,1H),4.80(s,2H),4.74-4.71(m,1H),4.34-4.27(m,1H),4.13-3.91(m,5H),3.59(q,J＝7.2Hz,2H),2.05-1.97(m,2H),1.77-1.75(m,1H),1.44(t,J＝7.6Hz,3H),0.99-0.96(m,2H),0.83(t,J＝7.6Hz,3H),0.66-0.65(m,2H).
EXAMPLE 41
N- (tert-Butylsulfonyl) -5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzamide
First step of
N- (tert-Butylsulfonyl) -5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzamide
29c (200mg,0.413mmol) of 5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid, tert-butylsulfonamide (102.7mg,0.826mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (158mg,0.826mmol) and 4-dimethylaminopyridine (100.9mg,0.826mmol) were dissolved in 10mL of dichloromethane and reacted overnight at room temperature. 10mL of a saturated citric acid solution was added, extraction was performed with dichloromethane (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give N- (tert-butylsulfonyl) -5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzamide 41(130.4mg), yield: 52.4 percent.
MS m/z(ESI)：602.8[M+1]
1H NMR(400MHz,CDCl3)δ8.49(s,1H),7.68-7.65(m,1H),7.45-7.44(m,1H),7.38(s,2H),7.18(d,J＝12.8Hz,1H),4.83-4.82(m,1H),4.79(s,2H),4.34-4.27(m,1H),4.11-3.90(m,5H),2.05-2.00(m,2H),1.77-1.74(m,1H),1.55(s,9H),0.99-0.94(m,2H),0.83(t,J＝7.2Hz,3H),0.66-0.65(m,2H).
Example 42
5-cyclopropyl-N- (cyclopropylsulfonyl) -4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzamide
First step of
5-cyclopropyl-N- (cyclopropylsulfonyl) -4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzamide
29c (200mg,0.413mmol) of 5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid, cyclopropylsulfonamide (100mg,0.826mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (158mg,0.826mmol) and 4-dimethylaminopyridine (100.9mg,0.826mmol) were dissolved in 10mL of dichloromethane and reacted overnight at room temperature. 10mL of a saturated citric acid solution was added, extraction was performed with dichloromethane (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give 5-cyclopropyl-N- (cyclopropylsulfonyl) -4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzamide 42(139.2mg), yield: 57.4 percent.
MS m/z(ESI)：586.8[M+1]
1H NMR(400MHz,CDCl3)δ8.95(s,1H),7.69(d,J＝7.6Hz,1H),7.44(s,1H),7.39(s,2H),7.19(d,J＝12.8Hz,1H),4.80(s,2H),4.77-4.71(m,1H),4.36-4.28(m,1H),4.03-3.91(m,5H),3.12-3.09(m,1H),2.04-1.97(m,2H),1.78-1.75(m,1H),1.46-1.45(m,2H),1.19-1.14(m,2H),0.99-0.96(m,2H),0.82(t,J＝7.2Hz,3H),0.66-0.65(m,2H).
Example 43
5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- ((1-methylcyclopropyl) sulfonyl) benzamide
First step of
5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- ((1-methylcyclopropyl) sulfonyl) benzamide
29c (200mg,0.413mmol) of 5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid, 1-methylcyclopropanesulfonamide (112mg,0.826mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (158mg,0.826mmol) and 4-dimethylaminopyridine (100.9mg,0.826mmol) were dissolved in 10mL of dichloromethane and reacted overnight at room temperature. 10mL of a saturated citric acid solution was added, extraction was performed with dichloromethane (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give 5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluoro-N- ((1-methylcyclopropyl) sulfonyl) benzamide 43(118.3mg), yield: 47.6 percent.
MS m/z(ESI)：600.9[M+1]
1H NMR(400MHz,CDCl3)δ8.80(s,1H),7.66(d,J＝7.6Hz,1H),7.44(s,1H),7.38(s,2H),7.19(d,J＝12.4Hz,1H),4.80(s,2H),4.76-4.72(m,1H),4.32-4.25(m,1H),4.12-3.90(m,5H),2.06-1.96(m,2H),1.81-1.76(m,3H),1.60(s,3H),1.00-0.95(m,4H),0.82(t,J＝7.6Hz,3H),0.68-0.64(m,2H).
Example 44
N- (azetidin-1-ylsulfonyl) -5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -2-fluorobenzamide
First step of
N- (azetidin-1-ylsulfonyl) -5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -2-fluorobenzamide
33e (230mg,0.43mmol) of 5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -2-fluorobenzoic acid, 1-azetidinesulfonamide (70mg,0.52mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (164.5mg,0.86mmol) and 4-dimethylaminopyridine (105mg,0.86mmol) were dissolved in 10mL of dichloromethane and reacted overnight at room temperature. 10mL of a saturated citric acid solution was added, extraction was performed with dichloromethane (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give N- (azetidin-1-ylsulfonyl) -5-cyclopropyl-4- (((7- (1- (3, 5-dichlorophenyl) propyl) -7-azaspiro [3.5] nonan-2-yl) methoxy) methyl) -2-fluorobenzamide 44(32.4mg), yield: 12 percent.
MS m/z(ESI)：651.9[M+1]
1H NMR(400MHz,CDCl3)δ8.75(s,1H),7.73(d,J＝6.8Hz,1H),7.48(s,1H),7.32(s,2H),7.23-7.20(m,1H),4.68(s,2H),4.26(t,J＝7.6Hz,4H),4.04-4.01(m,1H),3.53-3.49(m,2H),2.62-2.51(m,2H),2.30-2.25(m,3H),2.20-2.10(m,2H),2.04-1.90(m,3H),1.76-1.74(m,4H),1.67-1.61(m,1H),1.60-1.52(m,1H),0.96-0.95(m,2H),0.90-0.86(m,2H),0.78-0.76(m,3H),0.69-0.67(m,2H).
Example 45
N- (azetidin-1-ylsulfonyl) -4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzamide
First step of
N- (azetidin-1-ylsulfonyl) -4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzamide
4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid 37c (200mg,0.415mmol), 1-azetidinesulfonamide (67.8mg,0.498mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (158.7mg,0.83mmol) and 4-dimethylaminopyridine (101.4mg,0.83mmol) were dissolved in 10mL of dichloromethane and reacted overnight at room temperature. 10mL of a saturated citric acid solution was added, extraction was performed with dichloromethane (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give N- (azetidin-1-ylsulfonyl) -4- (((1- (1- (3-chloro-5-fluorophenyl) ethyl) -4-fluoropiperidin-4-yl) methoxy) methyl) -5-cyclopropyl-2-fluorobenzamide 45(86mg) in yield: 35 percent.
MS m/z(ESI)：599.9[M+1]
1H NMR(400MHz,CDCl3)δ8.74(s,1H),7.75(d,J＝8.0Hz,1H),7.29-7.28(m,1H),7.22-7.21(m,3H),4.77(s,2H),4.26(t,J＝7.6Hz,4H),3.37-3.34(m,1H),2.95-2.88(m,2H),2.54-2.39(m,2H),2.30-2.24(m,4H),2.19-2.15(m,2H),1.83(d,J＝5.6Hz,3H),1.77-1.73(m,1H),0.97-0.95(m,2H),0.88-0.86(m,2H),0.68-0.67(m,2H).
Example 46
N- (azetidin-1-ylsulfonyl) -5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzamide
First step of
N- (azetidin-1-ylsulfonyl) -5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzamide
29c (200mg,0.413mmol) of 5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzoic acid, 1-azetidinesulfonamide (67.5mg,0.495mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (158mg,0.826mmol) and 4-dimethylaminopyridine (100.9mg,0.826mmol) were dissolved in 10mL of dichloromethane and reacted overnight at room temperature. 10mL of a saturated citric acid solution was added, extraction was performed with dichloromethane (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to give N- (azetidin-1-ylsulfonyl) -5-cyclopropyl-4- (((1- (1- (3, 5-dichlorophenyl) propyl) -3-fluoroazetidin-3-yl) methoxy) methyl) -2-fluorobenzamide 46(114mg), yield: 46 percent.
MS m/z(ESI)：601.7[M+1]
1H NMR(400MHz,CDCl3)δ8.76(s,1H),7.74(d,J＝7.2Hz,1H),7.45-7.44(m,3H),7.22-7.19(m,1H),4.82(s,2H),4.26(t,J＝7.2Hz,4H),4.12-4.04(m,2H), 3.89-3.82(m,1H),2.30-2.24(m,2H),2.07-2.00(m,2H),1.79-1.78(m,2H),1.67-1.62(m,1H),0.99-0.97(m,2H),0.90-0.84(m,5H),0.69-0.68(m,2H).
Biological evaluation
Test example 1 inhibition of human Nav1.7 ion channel expressed in CHO-K1 cells at steady state by Compounds of the invention under in vitro conditions
1.1 cells
The experiment used CHO cells stably expressing human Nav1.7 sodium channel, the cell line was from Genionic, the cell incubator parameters were set to 37 ℃ humidified environment, and the air content was 5% CO2。
1.2 solutions
Extracellular solution (mM): NaCl 140, KCl 3, CaCl2 1，MgCl2 1，CdCl20.1, TEA-Cl20, HEPES 5, pH 7.3, osmolality-310 mOsm;
intracellular solution (mM): CsF 140, NaCl 10, EGTA 1, CsOH 5, HEPES 10, pH 7.3, osmolarity-285 mOsm.
1.3 preparation of Compounds
Dissolving test compounds in 100% DMSO to obtain stock solutions for different test concentrations; the stock solution was further diluted into extracellular fluid to reach the final concentration tested. Before the experiment, whether a precipitate exists or not (namely whether a compound is separated out or not) is observed; the final DMSO concentration was no greater than 0.30% for all concentrations of compound.
1.4 Manual patch-Clamp recording
The instrumentation was a manual patch clamp system (Axon multiclad 700B, Digidata 1440, pCLAMP 10, etc.), voltage program: see figure 1 for details.
1.5 test methods
(1) The Episodic stimulation model was used for recordings on pClamp software.
(2) During initial recording, peak current changes were observed until 5 sweep changes no more than 10% change were maintained stable. Once stabilized, drug perfusion was started from the lowest concentration and again at higher concentrations once the peak current had stabilized again, i.e. 5 sweep peak currents did not exceed 10% change. If the drug cannot be stabilized, the perfusion is continued for 5 minutes, and then the perfusion with the drug with higher concentration is performed. If the peak current is unchanged, a higher drug concentration is applied if necessary, otherwise the experiment is terminated and the cell dish is discarded.
1.6 data analysis
(1) Data analysis was performed using claupfit (V10.2, Molecular Devices), Excel 2013(Microsoft) and GraphPad Prism 5.0.
(2) In each cell record, the blocking rate was calculated for each concentration as (test concentration current/peak current) × 100%.
(3) The curve fitting equation is as follows:
I/Icontrol＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
wherein:
x is the concentration logarithm;
I/Icontrol is the ratio of the test concentration current to the initial current;
top is 1 and Bottom is equal to 0.
(4) If the inhibition obtained at the lowest concentration tested exceeds 50%, or at the highest concentration tested is less than 50%, the IC50Below the minimum concentration or above the maximum concentration, respectively. Specific IC50See table 1.
Test example 2 Effect of the Compounds of the invention on human Nav1.5 ion channels stably expressed in HEK293 cells in vitro
2.1 cells
This assay uses HEK293 cells stably expressing human Nav1.5 sodium channels.
2.2 formulation
The final concentrations of test compounds were all prepared the same day and re-dissolved in extracellular fluid. The extracellular fluid (mM) is NaCl, 137; KCl, 4; CaCl2,1.8；MgCl21, 1; HEPES, 10; glucose 10; pH 7.4(NaOH titration). All test and control compound solutions contained 0.3% DMSO.
2.3 electrophysiology
The cells were transferred to a perfusion chamber and perfused with extracellular fluid. Intracellular fluid (mM) was: CsCl, 130; MgCl25, 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2(KOH titration). The intracellular fluid was stored in small portions in a-80 ℃ freezer and thawed the day of the experiment. The electrode was drawn with PC-10(Narishige, Japan). Whole cell patch clamp recordings were made and noise was filtered at one fifth of the sampling frequency.
2.4 test procedures and results
Cells were clamped at-70 mV and then depolarized to-10 mV with a square wave lasting 10 milliseconds to give a Nav1.5 current (see FIG.). This procedure was repeated every 10 seconds. Detecting square wave induced maximum powerAfter the flow has stabilized, the test compound is perfused and, after the reaction has stabilized, the intensity of the block is calculated. Specific IC50See table 1. See in particular fig. 2.
TABLE 1 IC of inhibition of human Nav1.7 ion channels expressed in CHO-K1 cells at steady state and inhibition of human Nav1.5 ion channels expressed in HEK293 cells at steady state by the compounds of the invention50The value is obtained.
And (4) conclusion: the compound of the invention has obvious inhibition effect on human Nav1.7(hNav1.7) ion channels stably expressed in CHO-K1 cells, and is superior to the inhibition activity on human Nav1.5(hNav1.5) ion channels stably expressed in HEK293 cells, wherein:
example 12, example 18 and example 29 had superior inhibitory activity against the hnav1.7 channel than reference compound 1;
example 12 for Nav1.7 channel activity selectivity is hNav1.5 channel 83 times;
example 18 for hNav1.7 channel activity selectivity is hNav1.5 channel 650 times;
example 32 Activity selectivity for hNav1.7 channel is the IC of hNav1.5 channel50110 times the value;
the activity selectivity of reference Compound 1 for the hNav1.7 channel is IC of hNav1.5 channel50The value was 24 times;
the compounds of the examples of this patent have a high selectivity of the activity of hNav1.7 to hNav1.5.
Remarking: reference compound 1 refers to the racemates of example 24 and example 25 disclosed in WO2016191312a1, and has the following structures:
test example 3: effect of Compounds of the invention on human hERG ion channels stably expressed in HEK293 cells
3.1 cells
HEK293 cells with steady expression of hERG ion channels.
3.2 test apparatus
Patch clamp instrument: batch clamp-505B
A micro-manipulation instrument: MP-225
Drawing an electrode instrument: PC-10(Narishige, Japan)
3.3 pharmaceutical formulation
The final concentrations of test compounds were all prepared the same day and re-dissolved in extracellular fluid.
The extracellular fluid (mM) is NaCl, 137; KCl, 4; CaCl2,1.8；MgCl2,1; HEPES, 10; glucose 10; pH 7.4(NaOH titration). All test and control compound solutions contained 0.3% DMSO.
Intracellular fluid (mM) was: k asparate, 130; MgCl25, 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2(KOH titration).
3.4 testing of Compounds
The compounds are perfused by adopting a perfusion system utilizing the self gravity. At least two cells were tested per concentration. After the current stabilized (or 5 minutes), the blocking effect of the compound was calculated by comparing the change in current level before and after the compound was used.
3.5 Positive control
The concentration of the positive control Cisapride is selected according to the sensitivity test of the Cisapride on cells, and the concentration with the blocking rate of about 90 percent is the optimal concentration of the positive control. The positive control Cisapride was defined as 100nM since Cisapride tested at 100nM, the blocking rate was around 90%. The procedure was the same as for the test compounds.
3.6 electrophysiology
The cells were transferred to a perfusion chamber and perfused with extracellular fluid. Intracellular fluid (mM) was: k asparate, 130; MgCl25, 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2(KOH titration). The intracellular fluid was stored in small portions in a-80 ℃ freezer and thawed the day of the experiment. The electrode was drawn with PC-10(Narishige, Japan). Recording, noise-recording using whole-cell patch clampOne fifth of the sampling frequency is filtered.
3.7 test procedures and results
Cells were clamped at-80 mV, then depolarized to 40mV with a 4 second lasting square wave, and hyperpolarized to-40 mV with a 2 second lasting square wave to give hERG tail currents (see below). This procedure was repeated every 20 seconds. The hERG tail current is pure hERG current. The maximum current induced by the second square wave is detected, after it has stabilized, the test compound is perfused, and when the reaction has stabilized, the intensity of the block is calculated. Specific IC50See table 2. See in particular fig. 3.
Table 2: IC for inhibition of hERG potassium channel by compounds of the invention50Value of
| Compound numbering | hERG inhibition solubility IC 50/mu M |
| Reference Compound 1 | ＞30 |
| 12 | 20 |
| 18 | 20 |
| 21 | ＞30 |
| 22 | ＞30 |
| 23 | ＞30 |
| 27 | ＞30 |
| 28 | ＞30 |
| 29 | ＞30 |
And (4) conclusion: the compounds of the invention have little inhibitory activity on the hERG potassium channel and thus have selective inhibition on the potassium channel.
Test example 4: in vivo pharmacokinetic study of SD rat
4.1 preparation of test solutions
Administration vehicle: (IV) -5% DMSO + 5% Solutol HS 15 (polyethylene glycol-15 hydroxystearate) + 90% normal saline;
oral administration (PO) -0.5% CMC-Na (sodium carboxymethylcellulose)
4.2 animals
Healthy adult SD male rats 30 were purchased from siepal-bika laboratory animals ltd.
4.3 animal dosing
1mg/kg of the preparation is administered by intravenous injection; 3mg/kg for intragastric administration; each group had 3 male rats.
All animals were fasted overnight (10-14 hours without water deprivation) before oral administration and were fed 4 hours after administration.
4.4 sample Collection and processing
Blood is collected by jugular venipuncture, about 0.20mL of each sample is collected, heparin sodium is anticoagulated, and the samples are placed on ice after collection. The blood sampling time points were as follows:
IV/PO: pre-dose, 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours post-dose.
Blood samples were collected and placed on ice, and plasma was centrifuged f centrifugation conditions: 8000 rpm, 6min, 2-8 deg.C. The collected plasma was stored in a-80 ℃ freezer before analysis.
4.6 pharmacokinetic analysis
According to the blood concentration data of the medicine, Phoenix is used
7.0 calculation of pharmacokinetic parameters to provide AUC(0-t)Cmax, and the like, as well as mean and standard deviation thereof.
4.5 pharmacokinetic results are given in Table 3
Table 3: pharmacokinetic parameters of SD rat
And (4) conclusion: in rat pharmacokinetic experiments, examples 12, 18 and 32 of the present invention had larger maximum blood concentration (Cmax), blood concentration (C) than reference Compound 1o) And a larger area under the time-of-drug curve fAUC(0-t))。
Test example 5: bigge in vivo pharmacokinetic study
5.1 preparation of test solutions
Administration vehicle: injection of (IV) -DMSO: solutol HS 15: normal saline 5:5:90, v/v/v:
oral administration of (PO) -0.5% CMC-Na
5.2 animals
The ventilation of the animal room is good, the air conditioner is arranged, the temperature is kept at 16-26 ℃, and the humidity is kept at 40% -70%. The dogs are independently fed with light and dark illumination for 12 hours respectively, and can freely eat and drink water.
5.3 animal dosing
0.5mg/kg of intravenous injection is adopted, and the concentration of the medicine is 0.4 mg/mL; 3mg/kg for intragastric administration, with drug concentration of 0.6 mg/mL: each group had 3 male beagle dogs.
Beagle dogs were fasted overnight the day before the experiment. On the day of the experiment, after weighing the body weight, the theoretical administration volume for each dog was calculated according to the following formula. The administration test solution should be prepared on the same day as the experiment. The actual dose and the time of plasma sample collection for each dog were recorded in detail in the corresponding tables. The beagle dogs can recover to eat after being administrated for 4 hours, and can freely drink water in the experimental process.
5.4 sample Collection and processing
Intravenous injection administration: blood was collected from jugular vein at 0.5mL before and 5 minutes, 15 minutes, 30 minutes, 1 hour, 2, 4 hours, 8 hours, 12 hours and 24 hours after administration, and placed in an anticoagulation tube containing EDTA-K2
Intragastric administration: before and 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after the administration, 0.5mL of blood was collected from the jugular vein and placed in an anticoagulation tube containing EDTA-K2.
All samples are centrifuged at 5500rpm/min for 10 minutes, then plasma is separated, and the storage conditions are-30 to-10 DEG C
5.5 pharmacokinetic analysis
According to the blood concentration data of the medicine, Phoenix is used
7.0 calculation of pharmacokinetic parameters, AUC0-t, Cmax and t1/2 parameters and their mean and standard deviation.
5.6 pharmacokinetic results are given in Table 4
Table 4: beagle pharmacokinetic parameters
And (4) conclusion: the compounds of examples 12 and 32 according to the invention had greater peak plasma concentrations (Cmax) and plasma concentrations (C) in beagle pharmacokinetic experiments than reference Compound 10) Has better pharmacokinetic property.
Test example 6 determination of inhibitory Effect of the Compound of the present invention on spinal nerve ligation-induced hypersensitivity to touch
This test was used to evaluate the inhibitory effect of the compounds of the present invention on spinal nerve ligation-induced tactile hypersensitivity in Sprague-Dawley rats.
6.1 preparation of test article
Blank dosing formulation:
dimethyl acetamide: solutol HS 15: normal saline 5:5:90(v/v/v)
Test compounds:
reference compound 1; the compounds of examples 32 and 33;
accurately weighing the compounds to be measured respectively, adding proper amount of dimethylacetamide and Solutol, and ultrasonically dissolving and suspending the compounds; and adding physiological saline, and performing ultrasonic vortex to fully dissolve and suspend the mixture, wherein the preparation concentration is 10mg/mL, and the weight ratio of dimethylacetamide: solutol: the saline solution was 5:5:90 (v/v/v).
The test compound is used for inhibiting rat spinal nerve ligation induced tactile allodynia after oral administration for 4 hours and 6 hours in a dosage of 100mg/kg and an administration volume of 10 mL/kg.
6.2 Experimental animals
Variety and strain: Sprague-Dawley rats, SPF, male, 6 weeks old, body weight around 140g, good health, 40, evenly divided into 4 groups of 10; license number: SCXK 2015-030, purchased from Sounda major laboratory animals Co.
Spinal nerve ligation model: anesthetizing a rat with isoflurane gas, flatly placing limbs on a test bed, and cushioning a thicker object on the abdomen; pinching the upper edge of pelvis with hand, making the middle position of the upper edge and the central line of spine as center, exposing muscle through about 2-3cm incisions, and detecting fascia part between bones with the knife tip; the muscle dissection was continued until the L5 transverse process was exposed, during which time a small roll of paper was used and was constantly rubbed with force. Cleaning muscle and blood beside transverse process of L5 to expose fascia, cutting a small opening obliquely along vertebra to four limbs with knife or scissors, extending into the small opening obliquely downwards and then probing back to L6 nerve with hook, tying with thread, and cutting off distal side; the transverse process of L5 was then opened by rongeur, the fascia was incised after removal, and the nerves L5 and L4 were also detected by hook; ligation with 6-0 line L5, L4 was immobilized; the fascia was sutured back, the skin was sutured, and placed in a cage.
6.3 Experimental procedures and data processing
Carrying out pain threshold baseline test on rats two days before administration, and selecting animals with baseline of 1-4g for group; 10 animals per group; followed by fasting without water deprivation for 8 hours. Animals were numbered and weighed according to the double blind principle and dosed orally by weight, and animals were tested for pain threshold 4 hours after dosing. The data were collated and a plot of pain threshold versus time was made.
50％PWT＝(10[Xf+kδ])/10000
Wherein:
50% PWT represents a threshold of 50% foot retraction;
xf represents the gram number of Von Freny test filaments;
k represents a correction coefficient;
δ represents the mechanical error, constant 0.224.
The 50% PWT at 4 hours for the compounds of the invention are shown in Table 5:
TABLE 5 Effect of Compounds on rat pain threshold
And (4) conclusion: the 50% PWT at 4 hours of inventive examples 32, 33 is superior to reference compound 1 and the pain effect is superior to reference compound 1.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (26)
- A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:wherein:(i) ring a is selected from monocyclic heterocyclyl; n is 1,2, 3,4, 5 or 6;R2each independently selected from hydrogen atom, hydroxyl, halogen, nitro, cyano, alkoxy, -NR9R10、-C(O)NR9R10、-C(O)R11、-C(O)OR11or-NR9C(O)R10Wherein said alkoxy is optionally further substituted with one or more halogens; preferably, R2Each independently selected from a hydrogen atom or a halogen, wherein at least one R2Selected from halogens;(ii) ring A is selected from spiro heterocyclic group or fused heterocyclic group, wherein said spiro heterocyclic group or fused heterocyclic group and L1The atom to which it is attached is an N atom; n is 1,2, 3,4, 5, 6, 7 or 8;R2each independently selected from hydrogen atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, -NR9R10、-C(O)NR9R10、-C(O)R11、-C(O)OR11or-NR9C(O)R10Wherein said alkyl or alkoxy is optionally further substituted with one or more halogens;L1is selected from- (CR)aRb) -or-C (═ O) -;L2is selected from- (CR)aRb)-O-(CRaRb)-；RaAnd RbEach independently selected from a hydrogen atom, an alkyl group or a halogen, preferably a hydrogen atom or an alkyl group; more preferably RaIs alkyl, RbIs a hydrogen atom; most preferably RaSelected from methyl or ethyl, RbIs a hydrogen atom;R1each independently selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, -NR9R10、-C(O)NR9R10、-C(O)R11、-C(O)OR11or-NR9C(O)R10Wherein said alkyl or alkoxy is optionally further substituted with one or more halogens;R3、R4、R5and R6Each independently selected from a hydrogen atom, a halogen, a cyano, an alkyl, a cycloalkyl, a heterocyclyl or an alkoxy, wherein said alkyl, cycloalkyl, heterocyclyl or alkoxy is optionally further substituted by one or more halogens;R7selected from hydrogen atoms or alkyl groups, wherein said alkyl groups are optionally further substituted by one or more halogens; preferably a hydrogen atom;R8selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl or-NR9R10Wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR9R10、-C(O)NR9R10、-C(O)R11、-C(O)OR11or-NR9C(O)R10Substituted with the substituent(s); r8Preferably methyl, ethyl, cyclopropyl, tert-butyl,R9、R10And R11Each independently selected from hydrogen atom, alkyl, alkoxy, cyano, cycloalkaneA group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted by one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR12R13、-C(O)NR12R13、-C(O)R14、-C(O)OR14or-NR12C(O)R13Substituted with the substituent(s);or, R9And R10Together with the N atom to which they are attached form a 4-to 8-membered heterocyclic group containing one or more N, O, S (O) atoms in the 4-to 8-membered heterocyclic grouppAnd 4-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -NR12R13、-C(O)NR12R13、-C(O)R14、-C(O)OR14or-NR12C(O)R13Substituted with the substituent(s);R12、R13and R14Each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl group, aryl group, heteroaryl group, carboxyl group, or carboxylate group;m is 0, 1,2, 3,4 or 5; m is preferably 0, 1 or 2; and isp is 0, 1 or 2.
- The compound according to claim 1, which is a compound represented by the general formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:wherein:Raselected from alkyl groups;R1～R8、L2m and n are as defined in claim 1.
- The compound according to claim 1, which is a compound represented by the general formula (III):wherein:Raselected from alkyl groups;R1～R8、L2m and n are as defined in claim 1.
- A compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:the ring A is selected from a 4-6-membered monocyclic heterocyclic group, preferably piperidyl or N-heterocyclic butyl;R2each independently selected from a hydrogen atom or a halogen, wherein at least one R2Selected from halogens.
- A compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:ring a is selected from the group consisting of a mono spiroheterocyclyl group, preferably a 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl group;the said mono-spiroheterocyclyl and L1The atom to which it is attached is an N atom; and isR2Each independently selected from a hydrogen atom or a halogen.
- The compound of claim 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of:
- a compound according to any one of claims 1 to 6, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1Each independently selected from fluoro, chloro, methyl or trifluoromethyl.
- A compound according to any one of claims 1 to 6, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:R4selected from halogen, preferably fluorine;R5selected from cycloalkyl, preferably cyclopropyl; and isR3And R6Each independently selected from hydrogen atoms.
- A compound according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:(i) the ring A is selected from 4-6 membered monocyclic heterocyclic group; r2Each independently selected from a hydrogen atom or a halogen, wherein at least one R2Selected from halogens;(ii) ring A is selected from the group consisting of a mono-spiroheterocyclyl group, wherein said mono-spiroheterocyclyl group is joined to L1The atom to which it is attached is an N atom; r2Each independently selected from a hydrogen atom or a halogen;R1selected from halogen, preferably fluorine or chlorine;R3and R6Each independently selected from a hydrogen atom;R4selected from halogen, preferably fluorine; and isR5Is selected from C3-C6Cycloalkyl, preferably cyclopropyl.
- A compound shown in a general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is a compound shown in a general formula (IV) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,wherein:L1is selected from- (CR)aRb) -or-C (═ O) -;R1selected from halogen, preferably fluorine or chlorine;R2each independently selected from a hydrogen atom or a halogen, wherein halogen is preferably fluorine or chlorine;R7selected from hydrogen atoms or C1-C6Alkyl, wherein said C1-C6Alkyl is optionally further substituted with one or more halogens; wherein R is7Preferably a hydrogen atom;R8is selected from C1-C6Alkyl radical, C3-C6Cycloalkyl or C3-C6The heterocyclic group is preferably a methyl group, an ethyl group, a cyclopropyl group, a tert-butyl group,RaAnd RbEach independently selected from a hydrogen atom or C1-C6An alkyl group;m is selected from 0, 1 or 2; and isn is selected from 0, 1 or 2.
- A compound shown in a general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is a compound shown in a general formula (V) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,wherein:L1is selected from- (CR)aRb) -or-C (═ O) -;R1selected from halogen, preferably fluorine or chlorine;R2each independently selected from a hydrogen atom or a halogen, wherein halogen is preferably fluorine or chlorine;R7selected from hydrogen atoms or C1-C6Alkyl, wherein said C1-C6Alkyl is optionally further substituted with one or more halogens; wherein R is7Preferably a hydrogen atom;R8is selected from C1-C6Alkyl radical, C3-C6Cycloalkyl or C3-C6The heterocyclic group is preferably a methyl group, an ethyl group, a cyclopropyl group, a tert-butyl group,RaAnd RbEach independently selected from a hydrogen atom or C1-C6An alkyl group;m is selected from 0, 1 or 2; and isn is selected from 0, 1 or 2.
- A compound shown in a general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is a compound shown in a general formula (VI) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,wherein:L1is selected from- (CR)aRb) -or-C (═ O) -;R1selected from halogen, preferably fluorine orChlorine;R2each independently selected from a hydrogen atom or a halogen, wherein halogen is preferably fluorine or chlorine;R7selected from hydrogen atoms or C1-C6Alkyl, wherein said C1-C6Alkyl is optionally further substituted with one or more halogens; preferably a hydrogen atom;R8is selected from C1-C6Alkyl radical, C3-C6Cycloalkyl or C3-C6The heterocyclic group is preferably a methyl group, an ethyl group, a cyclopropyl group, a tert-butyl group,RaAnd RbEach independently selected from a hydrogen atom or C1-C6An alkyl group;m is selected from 0, 1 or 2; and isn is selected from 0, 1 or 2.
- A compound according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
- a process for the preparation of a compound of formula (I) according to claim 1 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which comprises:carrying out condensation reaction on the general formula (IA) or the salt thereof and the general formula (IB) to obtain a compound of the general formula (I);wherein:L1is selected from-C (═ O) -; and isRing A, L2、R1～R8M and n are as defined in claim 1.
- A process for the preparation of a compound of general formula (I) according to claim 1 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which comprises:carrying out substitution reaction on the general formula (IA) or the salt thereof and the general formula (IC) to obtain a compound of the general formula (I);wherein: l is1Is selected from- (CR)aRb)-；G is a leaving group, preferably halogen, methanesulfonyloxy or p-toluenesulfonyloxy;Ra、Rbeach independently selected from a hydrogen atom or an alkyl group, preferably a hydrogen atom, a methyl group or an ethyl group; and isRing A, L2、R1～R8M and n are as defined in claim 1.
- A process for the preparation of a compound of general formula (I) according to claim 1 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which comprises:carrying out condensation reaction on the general formula (ID) and the general formula (Ib) to obtain a compound of the general formula (I);wherein: ring A, L1、L2、R1～R8M and n are as defined in claim 1.
- A compound of formula (IA) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:wherein: ring A, L2、R2～R8And n is as defined in claim 1.
- A compound of formula (IA) according to claim 17, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
- a compound of general formula (IA) according to claim 17, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
- a process for the preparation of a compound of general formula (IA) according to claim 17, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which comprises:carrying out condensation reaction on the general formula (Ia) and the general formula (Ib) to obtain a compound of the general formula (Ic); deprotection of formula (Ic) affords a compound of formula (IA) or a salt thereof;wherein:PG is selected from amino protecting groups, preferably tert-butoxycarbonyl; and isRing A, L2、R2～R8And n is as defined in claim 1.
- A compound represented by the general formula (ID) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:wherein: ring A, L1、L2、R1～R6M and n are as defined in claim 1.
- A compound of formula (ID) according to claim 21, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
- a process for the preparation of a compound of general formula (ID) according to claim 21, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which comprises:further hydrolysis of the compound of formula (If) to give a compound of formula (ID);wherein:Rcselected from alkyl groups; preferably methyl or tert-butyl;ring A, L1、L2、R1～R6M and n are as defined in claim 1.
- A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1-13, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
- Use of a compound according to any one of claims 1 to 13, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24, for the manufacture of a medicament for the treatment of a Nav1.7 inhibitor.
- Use of a compound according to any one of claims 1 to 13, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24, for the manufacture of a medicament for the treatment of a disease associated with nav1.7, wherein the disease is preferably pain, wherein the pain is preferably neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-operative pain, labor pain, neurogenic bladder disorder, ulcerative colitis, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, dental pain and/or peripheral nerve injury.
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| CN201710908313.0A CN109574927A (en) | 2017-09-29 | 2017-09-29 | N- (substituted sulphonyl) benzamide derivatives and preparation method thereof and medical usage |
| PCT/CN2018/108316 WO2019062848A1 (en) | 2017-09-29 | 2018-09-28 | N-(substituted sulfonyl)benzamide derivative, preparation method therefor, and pharmaceutical use thereof |
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| WO2020199683A1 (en) * | 2019-04-04 | 2020-10-08 | 上海海雁医药科技有限公司 | Nitrogen heterocycle substituted sulfonylbenzamide derivative, preparation method therefor and use thereof in medicine |
| WO2020220562A1 (en) * | 2019-04-29 | 2020-11-05 | 上海和誉生物医药科技有限公司 | Benzofuran-6-formamide derivative, preparation method therefor, and pharmaceutical application thereof |
| CN112759559B (en) * | 2019-11-06 | 2022-08-12 | 成都康弘药业集团股份有限公司 | Sulfonamide compounds as sodium channel blockers and uses thereof |
| CN115231989B (en) * | 2022-09-21 | 2023-02-24 | 广东银珠医药科技有限公司 | Preparation method of 3, 5-dichlorobenzyl alcohol |
| CN115819186B (en) * | 2023-02-14 | 2023-05-16 | 广东银珠医药科技有限公司 | Novel preparation method of 3, 5-dichlorobenzyl alcohol |
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- 2017-09-29 CN CN201710908313.0A patent/CN109574927A/en active Pending
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| CN111212830B (en) | 2023-07-04 |
| WO2019062848A1 (en) | 2019-04-04 |
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