CN111303118B - Compounds and their use in the treatment of hepatitis B - Google Patents

Compounds and their use in the treatment of hepatitis B Download PDF

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CN111303118B
CN111303118B CN202010097534.6A CN202010097534A CN111303118B CN 111303118 B CN111303118 B CN 111303118B CN 202010097534 A CN202010097534 A CN 202010097534A CN 111303118 B CN111303118 B CN 111303118B
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CN111303118A (en
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刘刚
王春廷
裴亚蒙
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Tsinghua University
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Abstract

The invention provides a compound, a pharmaceutical composition containing the compound and an application of the compound, wherein the compound is a compound shown in a formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown in the formula (I). The compounds of the present invention interfere with the shell assembly process of hepatitis b virus, thereby inhibiting replication of hepatitis b virus. In addition, the compound has good absorption, higher biological activity and utilization degree, low toxicity, especially strong stability in vivo, difficult decomposition and long drug effect time, thereby playing a role in treating hepatitis B and having good application prospect.

Description

Compounds and their use in the treatment of hepatitis B
Technical Field
The present invention relates to the field of medicine. In particular, the invention relates to compounds and their use in the treatment of hepatitis b.
Background
Hepatitis b is a type of infectious disease caused by hepatitis b virus. Although the prevalence of hepatitis b vaccines has greatly reduced the incidence of hepatitis b, there are still about 2.5 million people in the world carrying hepatitis b virus and about 88 million people dying from cirrhosis or liver cancer caused by hepatitis b in 2015, so hepatitis b remains a serious disease threatening human health. Currently, drugs for the clinical treatment of hepatitis b include interferons and nucleoside analogs (lamivudine, adefovir, entecavir, telbivudine, or tenofovir disoproxil). Interferon has a low cure rate on hepatitis B and causes great side effects; the oral nucleoside analogs are highly safe, but hepatitis B virus is not completely clear, and lifelong medication is required. In order to improve the therapeutic effect of hepatitis B and shorten the treatment period, many companies or organizations have been dedicated to developing new anti-hepatitis B drugs.
After hepatitis b virus infects hepatocytes, the genome is first transported into the nucleus of host cells, and the genome is repaired by an enzyme that repairs DNA in the host cells, thereby forming cccDNA. cccDNA is very stable and can exist in the host cell nucleus for a long time, which is the main reason that hepatitis b virus is difficult to remove. Expressing an intermediate required by virus replication by using cccDNA as a template, wherein capsid protein can be assembled into a capsid, wrapping pregenomic RNA into the capsid, completing reverse transcription in the capsid, and synthesizing a virus genome. Then, the viral particles are secreted outside the cells by encapsulation.
The assembly of the coat protein plays an important role in the replication cycle of the virus, and by interfering with this process, replication of the virus can be inhibited. Currently, a plurality of candidate drugs targeting shell assembly enter clinical research (GLS4, JNJ-6379 and the like), and the curative effect of the drugs is proved. It was found that the modulator of shell assembly could not only directly inhibit viral replication but also cccDNA formation, but also directly inhibit e antigen. The shell assembly regulators with different structural types are developed, more candidate compounds are provided for clinical research, the clinical application of the medicine can be realized early, and the vast patients are benefited.
Therefore, hepatitis b virus inhibitors are still under investigation.
Disclosure of Invention
The present invention aims to solve at least to some extent at least one of the technical problems of the prior art. Therefore, the invention provides a compound, a pharmaceutical composition containing the compound and an application of the compound, wherein the compound can interfere the shell assembly process of hepatitis B virus so as to inhibit the replication of the hepatitis B virus. In addition, the compound has good absorption, higher biological activity and utilization degree, low toxicity, especially strong stability in vivo, difficult decomposition and long drug effect time, thereby playing a role in treating hepatitis B and having good application prospect.
To this end, in one aspect of the invention, the invention provides a compound. According to an embodiment of the invention, the compound is a compound of formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound of formula (I):
Figure BDA0002385652160000011
G. q, T, Y and X are each independently selected from C or N; z and V are each independently selected from C, N, S or O; r1Selected from hydrogen, C1～6Alkyl radical, C1～6Cycloalkyl radical, C1～6Heterocyclic radical, amino radical, C1～6Alkylamino, hydroxy, halogeno C1～6Alkyl radical, C2～6Alkenyl radical, C3～6Alkynyl, aryl or C1～5A heteroaryl group; r2、R3And R4Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, C1～6Alkyl, nitro, C1～6Alkoxy radical, C1～6Alkylamino radical, C3～6Cycloalkyl or C1～6A heterocycloalkyl group; r5And R6Each independently selected from hydrogen and C1～6Alkyl radical, C1～6Alkylaryl group, C1～6Cycloalkyl radical, C1～5Heterocyclyl, aryl, C1～5A heteroaryl group; l is selected from-C (═ O) -, -S (═ O)2-, -S (═ O) -, -C (═ O) NH-; w is selected from C or N; r7And R8Each independently selected from hydrogen and C1～6Alkyl, halo C1～6Alkyl radical, C2～6Alkenyl radical, C3～6Alkynyl, C3～6Cycloalkyl radical, C1～6Heterocycloalkyl, aryl, or C1～5A heteroaryl group; or R7W and R8Forming a ring selected from C1～6Cycloalkyl radical, C1～6Heterocyclic group, C4～8Condensed ring, C4～8Fused heterocycle, C4～8Spiro ring, C4～8Spiro-heterocyclic ring, C4～8Bridge ring or C4～8A bridged heterocyclic ring; wherein said amino, alkyl, hydroxy, carboxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkenyl, alkynyl, fused ring, spiro, bridged ring, and bridged heterocycle may optionally be substituted with one or more fluorine, chlorine, bromine, iodine, hydroxy, amino, carboxy, nitro, cyano, oxo, C1～6Alkyl, halo C1～6Alkyl radical, C1～6Alkoxy radical, C1～6Alkyl hydroxy, C1～6Alkylamino radical, C1～6Cycloalkyl radical, C1～6Heterocyclyl, aryl, C1～5Heteroaryl, -C (═ O) Ra、-C(＝O)ORa、-OC(＝O)Ra、-OC(＝O)RaN(Rb)Rc、-C(＝O)N(Ra)Rb、-N(Ra)C(＝O)ORb、-N(Ra)C(＝O)NRb、-C(＝O)NRaSubstituted, Ra、RbRc is selected from hydrogen and C1～6Alkyl or C1～6An alkylamino group.
The compounds according to embodiments of the present invention can interfere with the shell assembly process of hepatitis b virus, thereby inhibiting replication of hepatitis b virus. The compound has the advantages of good absorption, higher biological activity and utilization rate, low toxicity, strong stability in vivo, difficult decomposition and long drug effect time in pharmacokinetic experiments in animal bodies, thereby playing the role of treating hepatitis B and having good application prospect.
According to an embodiment of the invention, the above-mentioned compounds may also have the following additional technical features:
according to an embodiment of the invention, at least one of G, Q and T is N, X is C, at least one of Z and Y is N,v is N or O; r1Is selected from C1～4Cycloalkyl or C1～4A heterocyclic group; r2、R3And R4Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl or amino; r5Selected from aryl, C3～6Cycloalkyl radical, C3～5Heterocyclyl or C3～5Heteroaryl, said aryl, cycloalkyl, heterocyclyl and heteroaryl being optionally substituted by one or more fluorine, chlorine, bromine, iodine, halo C1～4Alkyl radical, C1～4Cycloalkyl or C1～4Heterocyclyl is substituted; r6Selected from hydrogen or C1～3An alkyl group; l is selected from-C (═ O) -, -S (═ O)2-, -S (═ O) -, -C (═ O) NH-; w is selected from C or N; r7W and R8Forming a ring selected from C3～6Heterocyclyl or C3～6Cycloalkyl, said cycloalkyl or heterocyclyl being optionally substituted by one or more of hydroxy, fluoro, chloro, bromo, iodo, C1～3Alkyl radical, C1～3Alkylhydroxy, -C (═ O) Ra、-C(＝O)ORa、-OC(＝O)Ra、-OC(＝O)RaN(Rb)Rc、-C(＝O)N(Ra)Rb、-N(Ra)C(＝O)ORb、-N(Ra)C(＝O)NRb、-C(＝O)NRaSubstituted, Ra、RbRc is selected from hydrogen and C1～4Alkyl or C1～4An alkylamino group.
According to an embodiment of the invention, G, Q and T are both C, X is C, at least one of Z and Y is N, and V is N or O; r1Is hydrogen, C1～4Alkyl radical, C1～4Cycloalkyl radical, C1～4Heterocyclyl, halo C1～4An alkyl group; r2、R3And R4Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, C1～4An alkyl group; r5And R6Each independently selected from hydrogen and C1～4Alkyl, cyano, aryl, C1～4Alkylaryl group, C3～5Heteroaryl group, C3～6Cycloalkyl radical, C1～4Heterocyclyl, wherein the alkyl, aryl, heteroaryl, alkylaryl, cycloalkyl or heterocyclyl may optionally be substituted by one or more fluorine, chlorineBromine, iodine, halogeno C1～4Alkyl radical, C1～4Cycloalkyl or C1～4A heterocyclic group; l is selected from-C (═ O) -, -S (═ O)2-, -S (═ O) -, -C (═ O) NH-; w is selected from C or N; r7And R8Each independently selected from hydrogen and C3～6Heterocyclic group, C1～4Alkyl or halo C1～4Alkyl, or R7W and R8Forming a ring selected from C1～6Cycloalkyl radical, C1～6Heterocyclic group, C4～8Condensed ring, C4～8Fused heterocycle, C4～8Spiro ring, C4～8Spiro-heterocyclic ring, C4～8Bridge ring or C4～8Bridged heterocycles, wherein the cycloalkyl, heterocyclyl, alkyl, haloalkyl, fused ring, spiro, bridged ring or bridged heterocycle may optionally be substituted with one or more hydroxy, fluoro, chloro, bromo, iodo, oxo, C1～4Alkyl radical, C1～4Alkylhydroxy, -C (═ O) ORa、-C(＝O)NRa，RaSelected from hydrogen or C1～4An alkyl group.
According to an embodiment of the present invention, when both G, Q and T are C, Z, Y and X have at least one N, R7W and R8When the ring is not formed, at least one of the following conditions is satisfied: (1) r1Is C3～6A cycloalkyl group; (2) when R is7Is hydrogen, R8Is C3～6When cycloalkyl, the cycloalkyl is substituted with hydroxy.
According to an embodiment of the present invention, the compound has a structure shown in one of the following or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof;
Figure BDA0002385652160000021
Figure BDA0002385652160000031
Figure BDA0002385652160000041
Figure BDA0002385652160000051
Figure BDA0002385652160000061
Figure BDA0002385652160000071
in another aspect of the invention, a pharmaceutical composition is provided. According to an embodiment of the invention, the pharmaceutical composition comprises: the compound and pharmaceutically acceptable adjuvant, carrier, excipient, solvent or their combination. Thus, the pharmaceutical composition according to the embodiment of the present invention can interfere with the shell assembly process of hepatitis b virus, thereby inhibiting replication of hepatitis b virus. In addition, the pharmaceutical composition has good absorption, higher biological activity and utilization degree, low toxicity, strong stability in vivo especially, difficult decomposition and long drug effect time, thereby having the effect of treating hepatitis B and good application prospect.
According to an embodiment of the invention, the pharmaceutical composition further comprises a therapeutic agent selected from at least one of the following: lamivudine, adefovir, entecavir, telbivudine, tenofovir disoproxil and interferon.
In a further aspect of the invention, the invention provides the use of a compound as hereinbefore described in the manufacture of a medicament. According to an embodiment of the invention, the medicament is for the treatment of an infectious disease. As described above, the compounds according to the embodiments of the present invention can interfere with the shell assembly process of hepatitis b virus, thereby inhibiting replication of hepatitis b virus. In addition, the compound has good absorption, higher biological activity and utilization degree, low toxicity, especially strong stability in vivo, difficult decomposition and long drug effect time, thereby playing a role in treating infectious diseases and having good application prospect.
According to an embodiment of the invention, the infectious disease is hepatitis b.
In yet another aspect of the invention, the invention provides a pharmaceutical combination. According to an embodiment of the invention, the pharmaceutical combination comprises: the compounds described hereinbefore; and at least one drug for treating hepatitis B. Thus, the drug combination according to embodiments of the present invention can interfere with the shell assembly process of hepatitis b virus, thereby inhibiting replication of hepatitis b virus. In addition, the compound has good absorption, higher biological activity and utilization degree, low toxicity, especially strong stability in vivo, difficult decomposition and long drug effect time, thereby playing a role in treating hepatitis B and having good application prospect.
According to an embodiment of the invention, the drug is selected from at least one of the following: lamivudine, adefovir, entecavir, telbivudine, tenofovir disoproxil and interferon.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
figure 1 shows electron micrographs of compounds 59 and 101 according to an embodiment of the invention affecting capsid assembly;
FIG. 2 shows the effect of compounds 59 and 101 on replication of hepatitis B virus according to an embodiment of the present invention;
fig. 3 shows antiviral activity of compounds 59 and 109 according to an example of the present invention on a hydrodynamic injection HBV mouse model.
Detailed Description
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
Definitions or general terms
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.
"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York,1994.
Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1～6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The compounds of the invention may be independently optionally substituted with one or more substituents, as described herein, in the general formula above, or as specified in the examples, subclasses, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "independently optionally," whether preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure may be substituted or unsubstituted with a particular substituent 1. Unless otherwise indicated, an optional substituent group may have one substituent group 1 substituted or unsubstituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents 1 selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein said substituent 1 may be, but is not limited to: oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aldehyde, aminoacyl, alkoxy, aminoalkyl, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, benzyl, cyclopropyl, phenyl, or alkoxyalkyl, and the like. The substituent 1 can, where appropriate, be further monosubstituted by the substituent 2 or polysubstituted identically or differently. Wherein said substituent 2 may be, but is not limited to: oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aldehyde, aminoacyl, alkoxy, aminoalkyl, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, benzyl, cyclopropyl, phenyl, or alkoxyalkyl, and the like.
The term "alkyl" as used herein includes saturated straight or branched chain monovalent hydrocarbon groups of 1 to 20 carbon atoms, wherein the alkyl groups may independently be optionally substituted with one or more substituents described herein. In some of these embodiments, the alkyl group contains 1 to 10 carbon atoms; in other embodiments, the alkyl group contains 1 to 8 carbon atoms; in other embodiments, the alkyl group contains 1 to 6 carbon atoms, and in other embodiments, the alkyl group contains 1 to 4 carbon atoms; in other embodiments, the alkyl group contains 1 to 3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (-CH)3) Ethyl (-CH)2CH3) N-propyl (-CH)2CH2CH3) Isopropyl group (-CH (CH)3)2) N-butyl (-CH)2CH2CH2CH3) 2-methylpropyl or isobutyl (-CH)2CH(CH3)2) 1-methylpropyl or sec-butyl (-CH (CH)3)CH2CH3) Tert-butyl (-C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2)3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3)N-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" as used herein, both include straight and branched saturated carbon chains. Alkyl groups may be substituted with the substituents described herein.
The term "haloalkyl" denotes a situation where an alkyl group may be substituted by one or more of the same or different halogen atoms. Wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, trifluoromethyl, 2, 2-difluoroethyl, 3,3, 3-trifluoropropyl, and the like. Haloalkyl groups may be substituted with substituents described herein.
The term "aminoalkyl" means that the alkyl group may be substituted with one or more of the same or different amino groups or that the amino groups are each independently substituted with one or two alkyl groups, wherein alkyl has the meaning described herein.
The term "alkoxy", as used herein, relates to an alkyl group, as defined herein, attached to the main carbon chain through an oxygen atom. Such examples include, but are not limited to, methoxy, ethoxy, propoxy, and the like. Alkoxy groups may be substituted with the substituents described herein.
The term "cycloalkyl" refers to a mono-or polyvalent, non-aromatic, saturated or partially unsaturated ring, and does not contain heteroatoms, including monocyclic rings of 3 to 12 carbon atoms or bicyclic or tricyclic rings of 7 to 12 carbon atoms. The carbocycle having 7 to 12 atoms may be bicyclo [4,5 ]]，[5,5]，[5,6]Or [6,6 ]]The system, the carbocycle having 9 or 10 atoms at the same time, may be bicyclo [5,6 ]]Or [6,6 ]]And (4) preparing the system. Suitable cycloalkyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of cycloalkyl groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, and the like. Depending on the structure, cycloalkyl groups can be monovalent or divalent groups, i.e., cycloalkylene. C4Cycloalkyl means cyclobutyl, C5Cycloalkyl means cyclopentyl, C7Cycloalkyl refers to cycloheptyl. Cycloalkyl groups may be substituted with substituents described herein.
The term "aryl" may be monocyclic, bicyclic, and tricyclic carbocyclic ring systems in which at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms and only one attachment point is attached to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", e.g., aromatic rings may include phenyl, naphthyl, and anthracene. Depending on the structure, the aryl group can be a monovalent group or a divalent group, i.e., an arylene group. The aryl group may be substituted with the substituent described in the present invention.
The terms "heteroaryl", "heteroaryl ring" and "heteroaromatic ring" are used interchangeably herein and all refer to monocyclic, bicyclic, tricyclic or tetracyclic ring systems in which the bicyclic, tricyclic or tetracyclic heteroaromatic ring systems form a ring in fused form. Wherein at least one ring system of the heteroaromatic ring system is aromatic and one or more atoms of the ring is independently optionally substituted by a heteroatom (heteroatom selected from N, O, P, S, where S or P is independently optionally substituted by one or more oxygen atoms to give a compound like SO, SO2，PO，PO2The group of (1). The heteroaryl system may be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable compound. The heteroaryl group may be a monocyclic ring of 3 to 7 atoms, or a bicyclic ring of 7 to 10 atoms, or a tricyclic ring of 10 to 15 atoms. The bicyclic ring having 7 to 10 atoms may be bicyclo [4,5 ]]，[5,5]，[5,6]Or [6,6 ]]The tricyclic ring having 10 to 15 atoms may be a tricyclic [5,5,6 ]]，[5,7,6]Or [6,5,6 ]]And (4) preparing the system.
The terms "heterocyclyl", "heterocycle", "heteroalicyclic" or "heterocyclic" are used interchangeably herein and all refer to monocyclic, bicyclic, tricyclic or tetracyclic ring systems in which one or more atoms of the ring is independently optionally substituted with a heteroatom, the ring being fully saturated or containing one or more degrees of unsaturation, but in no way aromatic. The heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable compound. One or more of the ring hydrogen atoms are independently optionally substituted with one or more substituents described herein. Some of the examples are "heterocyclyl", "heterocycle", "heteroalicyclic" or "heterocyclic" groups which are monocyclic (1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S) having 3 to 7 members rings, where S or P is independently optionally substituted with one or more oxygen atoms to give compounds such as SO, SO2，PO，PO2A group of (a) and (b) simultaneously, -CH2-the groups may independently optionally be replaced by-C (═ O) -; when the ring is a three-membered ring, wherein there is only one heteroatom), or a 7-10 atom bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where N, S or P are independently optionally substitutedBy substitution by one or more oxygen atoms to give radicals like NO, NO2，SO，SO2，PO，PO2A group of (a) and (b) simultaneously, -CH2-the groups may independently optionally be replaced by-C (═ O) -; ).
"heterocyclyl" may be a carbon or heteroatom radical. "Heterocyclyl" also includes heterocyclic groups fused to saturated or partially unsaturated carbocyclic or heterocyclic rings. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, thiaxanyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, epoxypropyl, N-morpholinyl, N-piperazinyl, 2-piperazinyl, 3-piperazinyl, homopiperazinyl, oxazazepinyl, diazepinyl, thiazazepinyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dioxolanyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrazolyl, dihydropyrimidyl, dihydropyrrolyl, furanonyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, imidazopyridinyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, morpholinyl, oxazolidinedionyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, pyrazolidinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydrothienyl, thiomorpholinyl, thiazolidinyl.
In addition, unless otherwise expressly indicated, the descriptions "… and … are each independently," "… and … are each independently," and "… and … are each independently" used throughout this document are interchangeable and should be broadly construed to mean that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other. For example, "H- (C (R))3)2)n-O-(C(R3)2)n1-C(＝O)-(C(R3)2)n- "middle" R3Watch (watch)Represent identical or different radicals and do not influence one another; "n" means the same or different values and do not affect each other.
The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastrointestinal upset, dizziness and the like, when administered to a human. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by a federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
The term "carrier" refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, particularly injectable solutions. Suitable Pharmaceutical carriers are described in e.w. martin, "Remington's Pharmaceutical Sciences".
The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "stereoschemistry of Organic Compounds", John Wiley & Sons, Inc., New York,1994. All stereoisomeric forms of the compounds of the present invention, including, but in no way limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereo structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.
"isomers" are different compounds having the same molecular formula. "stereoisomers" are isomers that differ only in the spatial arrangement of the atoms. The term "isomer" as used herein includes any and all geometric isomers and stereoisomers. For example, "isomers" include cis and trans isomers, E-and Z-isomers, R-and S-enantiomers, diastereomers, (d) isomers, (l) -isomers, racemic mixtures thereof, and other mixtures thereof falling within the scope of the present specification.
The "hydrate" of the present invention refers to the compound or salt thereof provided by the present invention, which further comprises water bonded by non-covalent intermolecular forces in a chemical amount or in a non-chemical equivalent amount, and may be said to be an association of solvent molecules with water.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.
"nitroxide" in the context of the present invention means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form the N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4 th edition, Jerry March, pages). In particular, the N-oxide may be prepared by the method of L.W.Deady (Syn.Comm.1977,7,509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
The compounds may exist in a number of different geometric isomers and tautomers and the compounds of formula (I) -formula (III) include all such forms. For the avoidance of doubt, when a compound exists as one of several geometric isomers or tautomers and only one is specifically described or shown, it is clear that all other forms are included in formula (I) -formula (III).
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I) -formula (III). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery,2008,7, 255-.
Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention.
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
Various pharmaceutically acceptable salt forms of the compounds of the present invention are useful. The term "pharmaceutically acceptable salts" means those salt forms that are readily apparent to the pharmaceutical chemist as being substantially non-toxic and providing the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. Other factors, more practical in nature, are also important for selection, these are: cost of raw materials, ease of crystallization, yield, stability, hygroscopicity and, as a result, flowability of the drug substance. Briefly, the pharmaceutical composition can be prepared by combining the active ingredient with a pharmaceutically acceptable carrier.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the descriptive pharmaceutical acceptable salts in detail in J. pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, nitrate and the like, and organic acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, citrate, benzoate, mandelate, methanesulfonate, ethanesulfonate, toluenesulfonate, sulfosalicylate and the like, or obtained by other methods described in the literature such as ion exchange.
Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, and benzeneSulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodiates, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4A salt.
The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. The alkali metal or alkaline earth metal salt includes sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, aluminum salt and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates and aromatic sulfonates. Amine salts such as, but not limited to, N '-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methyl reduced glucamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1' -ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris (hydroxymethyl) aminomethane; alkaline earth metal salts such as, but not limited to, barium, calcium and magnesium; a transition metal salt such as, but not limited to, zinc.
In this specification, a structure is dominant if there is any difference between the chemical name and the chemical structure.
Abbreviations for any protecting groups, amino acids and other compounds used in the present invention shall be based on their commonly used, accepted abbreviations unless otherwise indicated, or refer to IUPAC-IUB Commission on Biochemical Nomenclature (see biochem.1972, 11: 942-944).
The invention provides a pharmaceutical composition, which comprises a therapeutically effective amount of a compound shown in formula (I) or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials, carriers, excipients, menstruum or a combination thereof. When the compound of the present invention is administered in the form of a medicament to a mammal such as a human, it may be administered in the form of the compound itself or may be administered in the form of a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of an active ingredient and a pharmaceutically acceptable carrier.
"combination" means a fixed combination or a kit of parts for combined administration in the form of a single dosage unit, wherein the compounds disclosed herein and the combination partners (drugs for the treatment of tumor diseases, AIDS, inflammatory reactions and immunodeficiency diseases) can be administered separately at the same time or can be administered separately at certain intervals, in particular such that the combination partners show a cooperative, e.g. synergistic, effect. The term "pharmaceutical composition" as used herein means a product resulting from mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, such as the disclosed compounds and combination partners, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, such as the compounds disclosed in this invention and the combination partners, are both administered to the patient as separate entities simultaneously, jointly or sequentially with no specific time limitation.
The phrase "pharmaceutically acceptable carrier" is art-recognized and includes pharmaceutically acceptable materials, compositions or carriers suitable for administration of the compounds of the invention to a mammal. The carrier comprises a liquid or solid filler, diluent, excipient, solvent or encapsulating material which is involved in carrying the subject substance or transferring it from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc powder; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline water; ringer's solution; ethanol; phosphate buffer; and other non-toxic compatible materials used in pharmaceutical formulations.
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.
Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants such as ascorbyl palmitate, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
Pharmaceutical compositions of the present invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form is generally that amount of the compound which produces a therapeutic effect. Generally, the amount is from about 1% to about 99% active ingredient, preferably from about 5% to about 70%, most preferably from about 10 to about 30%, in units of one percent.
The term "treatment" is used to refer to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of complete or partial prevention of the disease or symptoms thereof, and/or may be therapeutic in terms of a partial or complete cure for the disease and/or adverse effects resulting from the disease. As used herein, "treatment" encompasses diseases in mammals, particularly humans, including: (a) preventing the occurrence of a disease or disorder in an individual who is susceptible to the disease but has not yet been diagnosed with the disease; (b) inhibiting a disease, e.g., arresting disease progression; or (c) alleviating the disease, e.g., alleviating symptoms associated with the disease. As used herein, "treatment" encompasses any administration of a drug or compound to an individual to treat, cure, alleviate, ameliorate, reduce, or inhibit a disease in the individual, including, but not limited to, administering a drug containing a compound described herein to an individual in need thereof.
General synthetic methods
In general, the compounds of the invention can be prepared by the methods described herein, unless otherwise indicated, wherein the definitions of the substituents are given above. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents than those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
In the examples described below, all temperatures are given in degrees Celsius (. degree. C.) unless otherwise indicated. Reagents for the experiments were purchased from Beijing coupling technologies, Inc., Bailingwei technologies, Inc., Acros Organics, Alfa Aesar, Sigma-Aldrich, and TCI, unless otherwise specified, and used without purification. The solvents used in the experiments were purchased mainly from Beijing chemical plant and Shigaku chemical Co., Ltd, and were used without further treatment except for THF and DMF which were further treated by the solvent purification system of VAC corporation. GF254 thin layer chromatography silica gel plate, GF254 silica gel thick preparation plate and silica gel powder (60-100 mesh, 160-.
UPLC-MS analyzer: the Acquity UPLC-MS system of Waters corporation includes a binary solvent manager, a sample manager, a chromatography column manager, a PDA detector, and an SQ mass spectrometer. The chromatographic column is Acquisty of Waters corporation
Figure BDA0002385652160000141
BEH C18 column (1.7 μm,2.1 mm. times.50 mm). The mobile phase was acetonitrile containing 0.05% HCOOH and water. The linear gradient eluted 5:95(v: v) acetonitrile-H2O to 95:5(v: v) acetonitrile-H2O over a period of 3minutes at a flow rate of 0.3 mL/min. UV detection wavelength 254 nm. The SQ mass spectrometer adopts a positive ion or negative ion scanning mode and an electrospray ionization source (ESI). The method is mainly used for reaction monitoring and primary determination of compound purity.
Nuclear magnetic resonance apparatus: bruker Avance 400MHz, the solvent is CDCl3, DMSO-d6, Acetone-d6or Methanol-d 4.
Example Synthesis of 5- (3- ((3-chloro-4-fluorophenyl) amino) -1H-indazolyl) sulfonyl) piperidin-4-ol
Figure BDA0002385652160000151
Synthesis of 5- (benzylthio) -1H-indazole (1-2): 1-1(390mg,2mmol), Pd were added to a 100ml round bottom flask in sequence2(dba)3(91mg,0.1mmol), Xantphos (117mg,0.2mmol),20mL of 1, 4-dioxane, DIPEA (660. mu.L, 4mmol), benzyl mercaptan (372mg,3mmol), the gas in the flask was replaced three times with argon, heated to 90 ℃ and reacted for 4 hours. Detecting the reaction solution by LC-MS, cooling and filtering after the reaction is finishedThe filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to give 440mg of an orange oil in 92% yield.
Synthesis of 1- ((5-1H-indazolyl) sulfonyl) piperidin-4-ol (1-3): 420mg (1.75mmol) of 1-2 was dissolved in 10ml of acetonitrile, 100. mu.L of water and acetic acid were sequentially added, the mixture was cooled to-30 ℃ and 1, 3-dichloro-5, 5-dimethylhydantoin (520mg,2.62mmol) was added in portions, the reaction mixture was raised to-15 ℃ and reacted for 1 hour. The reaction mixture was transferred to a separatory funnel, diluted with ethyl acetate and washed with saturated brine, and the ethyl acetate layer was separated and dried over anhydrous sodium sulfate for 30 min. Filtering, and evaporating ethyl acetate under reduced pressure. Adding dichloromethane for redissolution, adding 4-hydroxypiperidine (520mg,5.2mmol) and triethylamine (1.0ml,7.86mmol), reacting at room temperature for 30 minutes, diluting with dichloromethane, washing with 1N hydrochloric acid, drying with anhydrous sodium sulfate, and separating with C18 to obtain 200mg, wherein the yield is 41%.
Synthesis of acetic acid-4- (1- (5- (3-bromo-1- (2-tetrahydro-2H-pyranyl) -1H-indazolyl) sulfonyl) piperidine) ester (1-5): dissolving 1-2(93mg,0.33mmol) in chloroform, adding 65mg (0.37mmol) NBS, reacting at 60 deg.C, monitoring by LC-MS, diluting the reaction solution with dichloromethane, sequentially adding saturated Na2S2O3The solution was washed with saturated brine, and the dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and dichloromethane was distilled off under reduced pressure to give intermediates 1 to 4. Redissolving by using ethyl acetate, adding 3, 4-dihydro-2H-pyran (55mg,0.66mmol) and p-toluenesulfonic acid monohydrate (19mg,0.1mmol), refluxing for 16 hours, monitoring the reaction liquid by LC-MS, adding 67 mu L (0.66mmol) of acetic anhydride into the reaction liquid after complete conversion, continuing the reaction, monitoring by LC-MS, cooling after the reaction is finished, adding ethyl acetate for dilution, washing by water, drying by using anhydrous sodium sulfate, filtering, and separating by column chromatography to obtain 138mg, wherein the yield is 86%.
Synthesis of 1- (5- (3- ((3-chloro-4-fluorophenyl) amino) -1- (2-tetrahydro-2H-pyranyl) -1H-indazolyl) sulfonyl) piperidin-4-ol (1-6): 1-5(131mg,0.27mol), 3-chloro-4-fluoroaniline (58mg,0.4mmol), Pd (OAc)2(3mg,0.014mmol)、Xantphos(15mg,0.027mmol)、Cs2CO3(176mg,0.54mmol) and 1, 4-dioxane (3ml), and the gas in the reaction flask was purged with argonThe displacement was carried out three times, and the reaction was carried out at 110 ℃ for 12 hours. After the reaction was completed, it was cooled, filtered, and the filtrate was concentrated under reduced pressure. Adding THF and water to dissolve, adding LiOH (20mg,0.84mmol), reacting at room temperature for 1 hr, adding ethyl acetate and water to the reaction solution, separating ethyl acetate phase, and separating with silica gel column chromatography to obtain 122mg, with yield of 89%.
Synthesis of the title compound: dissolving 1-6 in anhydrous ethanol (5ml), adding 1ml hydrochloric acid, reacting at room temperature, adjusting pH to 8-9 with 1N NaOH solution after reaction, separating out solid, filtering, and washing with water and a little methanol sequentially to obtain the target compound.1H NMR(400MHz,DMSO-d6)δ12.63(s,1H),9.53(s,1H),8.56(s,1H),8.11(s,1H),7.92–7.45(m,3H),7.35(t,J＝9.3Hz,1H),4.65(s,1H),3.49(s,1H),3.16(s,2H),2.71(s,2H),1.74(s,2H),1.44(s,2H).13C NMR(101MHz,DMSO-d6)δ151.27(d,J＝237.9Hz),146.25,141.74,140.03,126.01,125.69,122.46,119.53(d,J＝18.1Hz),117.43(d,J＝21.6Hz),117.08,116.53(d,J＝6.1Hz),113.89,110.83,64.29,43.75,33.38.
Example 21 synthesis of- (5- (3- ((3-chloro-4-fluorophenyl) amino)) - (1-methyl) -1H-indazolyl) sulfonyl) piperidin-4-ol:
Figure BDA0002385652160000161
synthesis of 5-bromo-1-methyl-1H-indazole (2-1): 5-bromo-1H-indazole (394mg,2mmol) is dissolved in 15mL of acetone, and methyl iodide (6mmol), K, are added sequentially2CO3(552mg,4mmol) was reacted at 80 ℃ for 12 hours. The reaction mixture was filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to give 250mg of a white solid with a yield of 59%.1H NMR(400MHz,Chloroform-d)δ7.95(d,J＝1.0Hz,1H),7.89(dd,J＝1.8,0.7Hz,1H),7.49(dd,J＝8.9,1.8Hz,1H),7.31(dt,J＝8.9,0.9Hz,1H),4.09(s,3H).
Synthesis of 5- (benzylthio) -1-methyl-1H-indazole (2-2): according to the synthesis method of the compound 1-2.
Synthesis of 1- ((5- (1-methyl) 1H-indazolyl) sulfonyl) piperidin-4-ol (2-3): according to the synthesis method of the compound 1-3, the yield is 66%.
Synthesis of 1- ((5- (3-bromo-1-methyl) -1H-indazolyl) sulfonyl) piperidin-4-ol (2-4): according to the synthesis method of the compounds 1-4.
Synthesis of the title compound: according to the synthesis method of the compounds 1-6,1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.56(d,J＝1.5Hz,1H),8.04(dd,J＝6.6,2.7Hz,1H),7.76–7.65(m,2H),7.60(ddd,J＝9.1,4.1,2.7Hz,1H),7.37(t,J＝9.1Hz,1H),4.65(s,1H),3.99(s,3H),3.51(dt,J＝7.9,4.0Hz,1H),3.23–3.10(m,2H),2.72(ddd,J＝11.8,8.5,3.4Hz,2H),1.76(ddd,J＝13.1,6.9,3.5Hz,2H),1.44(dtd,J＝12.2,8.0,3.5Hz,2H).
example synthesis of 31- ((5- (3- (3-chloro-4-fluorophenyl) (methyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidin-4-ol:
Figure BDA0002385652160000162
synthesis of 1-cyclopropyl-5-bromo-1H-indazole (3-1): a round-bottomed flask was charged with 5-bromo-1H-indazole (985mg,5mmol), cyclopropylboronic acid (859mg,10mmol), anhydrous copper acetate (900mg,5mmol), 2' -bipyridine (780mg,5mmol), sodium carbonate (1.0g,10mmol), and 1, 2-dichloroethane (30ml) and reacted at 70 ℃ for 2 hours. The reaction solution was filtered, concentrated under reduced pressure, then dissolved in ethyl acetate, washed with saturated copper sulfate solution for 2 times, the organic layer was dried over anhydrous sodium sulfate, filtered, and ethyl acetate was evaporated under reduced pressure to dryness, and the next step was carried out without further purification.
Synthesis of 5- (benzylthio) -1-cyclopropyl-1H-indazole (3-2): the product is dissolved in 20mL of 1, 4-dioxane, Pd is added2(dba)3(229mg,0.025mmol), Xantphos (289mg,0.5mmol), DIPEA (1650. mu.L, 10mmol), and benzylmercaptan (930mg,7.5mmol), the contents of the flask were replaced with argon three times, heated to 90 ℃ and reacted for 4 hours. And detecting the reaction liquid by LC-MS, cooling after the reaction is finished, filtering, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography (petroleum ether/ethyl acetate 8/1) to obtain 854mg of yellow solid with the yield of 61%.1H NMR(400MHz,Chloroform-d)δ7.84(d,J＝0.9Hz,1H),7.66(dd,J＝1.7,0.8Hz,1H),7.48(dt,J＝8.7,0.9Hz,1H),7.35(dd,J＝8.7,1.6Hz,1H),7.28–7.16(m,5H),4.06(s,2H),3.56(tt,J＝7.1,3.7Hz,1H),1.24–1.18(m,2H),1.18–1.10(m,2H).
Synthesis of 1- ((5- (1-cyclopropyl) 1H-indazolyl) sulfonyl) piperidin-4-ol (3-3): the synthesis of compounds 1-3 was carried out without purification.
Synthesis of acetic acid-4- (1- (5- (3-bromo-1-cyclopropyl-1H-indazolyl) sulfonyl) piperidine) ester (3-4): the above product (0.5mmol) was dissolved in CH3CN/AcOH (4/2mL), NBS (133mg,0.75mmol) was added and the reaction was allowed to proceed overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with saturated NaHCO3 solution, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 10mL of ethyl acetate, and acetic anhydride (510. mu.L, 5mmol) and pyridine (160. mu.L, 2mmol) were added to the solution, followed by reflux overnight. The reaction solution was washed with saturated copper sulfate solution and saturated salt water in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether/ethyl acetate 4/1) to give 140mg of a white solid with a yield of 64%.
Synthesis of the title compound: 3-4(44mg,0.1mol), 3-chloro-4-fluoro-N-methylaniline (24mg,0.15mmol), Pd (OAc) were added to a reaction flask in this order2(2.2mg,0.01mmol)、Xantphos(5.7mg,0.01mmol)、Cs2CO3(65mg,0.2mmol) and 1, 4-dioxane (2ml), the gas in the reaction flask was replaced with argon three times, and the reaction was carried out at 130 ℃ for 3 hours. After the reaction was completed, it was cooled, filtered, and the filtrate was concentrated under reduced pressure. Adding THF and water to dissolve, adding LiOH (12mg,0.5mmol), reacting at room temperature for 1 hr, adding ethyl acetate and water to the reaction solution, separating ethyl acetate phase, and separating by silica gel column chromatography to obtain the target product.
Example synthesis of 41- ((5- (3- (3-chloro-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidin-4-ol:
Figure BDA0002385652160000171
the synthesis procedure of example 3 was followed.1H NMR(400MHz,DMSO-d6)δ9.57(d,J＝1.9Hz,1H),8.55(s,1H),8.01(dd,J＝5.8,3.0Hz,1H),7.72(s,2H),7.62(ddt,J＝9.0,4.5,2.3Hz,1H),7.37(td,J＝9.1,1.9Hz,1H),4.66(t,J＝2.7Hz,1H),3.76–3.61(m,1H),3.52(dt,J＝9.1,4.5Hz,1H),3.23–3.07(m,2H),2.73(t,J＝9.8Hz,2H),1.83–1.68(m,2H),1.53–1.37(m,3H),1.18–1.09(m,4H).
Example synthesis of 51- ((5- (3- (3,4, 5-trifluorophenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidin-4-ol:
Figure BDA0002385652160000172
the synthesis procedure of example 3 was followed.1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.52(s,1H),7.74(d,J＝1.8Hz,2H),7.57(dt,J＝10.9,5.0Hz,2H),4.66(d,J＝3.9Hz,1H),3.69(ddd,J＝10.6,6.9,4.3Hz,1H),3.51(tq,J＝7.5,3.7Hz,1H),3.29–3.09(m,2H),2.73(ddd,J＝11.6,8.4,3.4Hz,2H),1.76(ddt,J＝13.9,7.2,3.6Hz,2H),1.45(dtd,J＝12.0,8.0,3.6Hz,2H),1.24–1.09(m,4H).13C NMR(101MHz,DMSO-d6)δ150.84(ddd,J＝242.6,9.9,6.1Hz),144.71,141.92,139.39–138.31(m),132.73(dt,J＝239.8,16.1Hz),126.51,126.38,122.40,114.83,110.57,100.41(d,J＝24.7Hz),64.20,43.69,33.35,29.67,6.85.
Example synthesis of 61- ((5- (3- (3,4, 5-trifluorophenyl) amino) - (1-cyclopropyl) - (7-fluoro) -1H-indazolyl) sulfonyl) piperidin-4-ol:
Figure BDA0002385652160000181
synthesis of intermediate 6-1: the substrate (5.1g,36mmol) was dissolved in 25mL concentrated sulfuric acid, NBS (7.7g,43.2mmol) was added in portions, and reacted at 60 ℃ overnight. The reaction solution was poured into ice water, extracted 4 times with n-hexane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 40/1) to give 1.82g, 23% yield.1H NMR(400MHz,Chloroform-d)δ10.32(s,1H),7.80(dtd,J＝5.1,2.4,1.5Hz,1H),7.62(ddd,J＝9.2,6.9,2.5Hz,1H).
Synthesis of intermediate 6-2: dissolving the intermediate 6-1(1.79g,8.1mmol) in 20mL of ethylene glycol dimethyl ether, adding methoxyamine hydrochloride (1.33g,16mmol) and potassium carbonate (3.3g,24mmol), reacting at 45 ℃, filtering after the reaction is finished, concentrating the filtrate under reduced pressure, adding ethyl acetate to dissolve, washing with water and saturated salt water in sequence, drying with anhydrous sodium sulfate, filtering, and evaporating to dryness under reduced pressure.
Synthesis of intermediate 6-3: dissolving 6-2(160mg,0.64mmol) in 1.5mL of hydrazine hydrate and tetrahydrofuran, reacting at 150 ℃ for 10 minutes in a microwave reaction instrument, adding ethyl acetate into reaction liquid for dilution, washing with water, drying, and evaporating under reduced pressure. A small amount of dichloromethane was added, stirred, filtered and the solid collected, 79mg, yield 57%.
Synthesis of intermediate 6-4: according to the synthesis method of the intermediate 3-1, the yield is 42%.
Synthesis of intermediates 6 to 5: according to the synthesis method of the intermediate 3-2, the yield is 93%.
Synthesis of intermediates 6 to 6: according to the synthesis method of the intermediates 1-3.
Synthesis of intermediates 6 to 7: intermediate 6-6(119mg, 0.35mmol) was dissolved in 50mL of ethyl acetate, acetyl chloride (82. mu.L, 1.05mmol) and pyridine (112. mu.L, 1.4mmol) were added, and after completion of the reflux reaction, the reaction solution was washed with a saturated copper sulfate solution and a saturated salt solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. 5mL of acetic acid was added thereto to dissolve the mixture, NBS (187mg,1.05mmol) was added thereto, the mixture was reacted at 40 ℃ overnight, an equal amount of NBS was added again, the reaction was continued for 8 hours, the mixture was concentrated under reduced pressure, and the mixture was separated by silica gel column chromatography (petroleum ether/ethyl acetate 4/1) to obtain 45mg of a product with a yield of 29%.
Synthesis of the title compound: according to the synthesis method of the embodiment 3,1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.34(s,1H),7.58–7.44(m,3H),4.68(d,J＝3.9Hz,1H),3.83(tt,J＝7.2,3.7Hz,1H),3.51(tq,J＝7.6,3.6Hz,1H),3.19(ddd,J＝10.6,6.2,3.4Hz,2H),2.75(ddd,J＝11.8,8.3,3.4Hz,2H),1.76(ddt,J＝13.8,7.3,3.6Hz,2H),1.45(dtd,J＝12.3,8.3,3.7Hz,2H),1.25–1.19(m,2H),1.15–1.09(m,2H).13C NMR(101MHz,DMSO-d6)δ150.80(ddd,J＝242.8,10.0,6.0Hz),147.46(d,J＝252.4Hz),144.92(d,J＝2.2Hz),138.64–138.17(m),134.35–131.49(m),131.39(d,J＝13.6Hz),126.93(d,J＝4.4Hz),118.62(d,J＝6.0Hz),118.45(d,J＝3.7Hz),111.37(d,J＝20.7Hz),100.53(d,J＝24.9Hz),64.24,43.75,33.38,31.97(d,J＝2.6Hz),7.81(d,J＝3.0Hz).
example synthesis of- ((5- (3- (3,4, 5-trifluorophenyl) amino) - (1-cyclopropyl) - (6-fluoro) -1H-indazolyl) sulfonyl) piperidin-4-ol:
Figure BDA0002385652160000191
synthesis of intermediate 7-1: the substrate (1.25g,10mmol) was dissolved in chloroform, NBS (1.96g,11mmol) was added thereto, and the reaction mixture was reacted at room temperature for 12 hours, followed by concentration under reduced pressure and separation by silica gel column chromatography (petroleum ether/ethyl acetate 6/1) to obtain 1.2g, yield 60%.
Synthesis of intermediate 7-2: intermediate 7-1(1.2g,6mmol) was mixed with 10mL of water, cooled in an ice water bath, added with sodium nitrite (621mg,9mmol), concentrated hydrochloric acid (2.5mL,30 mmol), monitored by LC/MS, and evaporated to dryness under reduced pressure after the reaction was complete. Chloroform was added thereto, followed by mixing, and then potassium acetate (1.17g,12mmol) was added thereto to conduct a reaction at room temperature. After completion, the mixture was evaporated to dryness under reduced pressure, water and ethyl acetate were added, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The next step was carried out without further purification
Synthesis of intermediate 7-3: according to the synthesis method of the intermediate 3-1, the yield of the two steps is 29 percent.
Synthesis of intermediate 7-4: according to the synthesis method of the intermediate 3-2, the yield is 70 percent.
Synthesis of intermediates 7-5: according to the synthesis method of the intermediate 3-3.
Synthesis of intermediates 7-6: according to the synthesis method of the intermediate 6-7, the total yield of the two steps is 31 percent.
Synthesis of the title compound: according to the synthesis method of the embodiment 3,1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),8.59(d,J＝6.6Hz,1H),7.60(d,J＝11.2Hz,1H),7.53(dd,J＝11.0,6.2Hz,2H),4.71(d,J＝4.0Hz,1H),3.66(p,J＝5.3Hz,1H),3.62–3.51(m,1H),2.89(ddd,J＝12.0,8.3,3.2Hz,2H),1.76(ddt,J＝13.4,7.1,3.5Hz,2H),1.43(dtd,J＝12.5,8.3,3.7Hz,2H),1.13(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ158.3(d,J＝251.3Hz),150.8(ddd,J＝243.0,10.1,6.4Hz),144.9,142.4(d,J＝12.5Hz),138.5(t,J＝12.6Hz),132.8(d,J＝240.9Hz),125.6(d,J＝3.1Hz),117.5(d,J＝19.1Hz),111.5,100.5(d,J＝24.4Hz),97.5(d,J＝27.7Hz),64.5,43.3,33.7,29.8,6.8.
example synthesis of 81- ((5- (3- (3,4, 5-trifluorophenyl) amino) - (1-cyclopropyl) - (4-fluoro) -1H-indazolyl) sulfonyl) piperidin-4-ol:
Figure BDA0002385652160000192
synthesis of intermediate 8-1: the substrate (1.25g,10mmol) was dissolved in acetonitrile, NBS (1.96g,11mmol) was added, and the reaction mixture was reacted at room temperature for 12 hours, followed by concentration under reduced pressure and separation by silica gel column chromatography (petroleum ether/ethyl acetate 4/1) to obtain 1.68g, yield 82%.1H NMR(400MHz,Chloroform-d)δ7.13(t,J＝8.1Hz,1H),6.37(dt,J＝8.7,1.2Hz,1H),3.71(s,2H),2.09(t,J＝1.4Hz,3H).
Synthesis of intermediate 8-2: the yield was 86% according to the synthesis method of intermediate 7-2.
Synthesis of intermediate 8-3: according to the synthesis method of the intermediate 3-1, the yield is 80%.
Synthesis of intermediate 8-4: according to the synthesis method of the intermediate 3-2, the yield is 45 percent.
Synthesis of intermediates 8 to 5: 215mg (0.72mmol) of 8-4 was dissolved in 5ml of acetonitrile, 100. mu.L of water and acetic acid were added in this order, the mixture was cooled to-15 ℃ and 1, 3-dichloro-5, 5-dimethylhydantoin (284mg,1.44mmol) was added in portions and reacted at-15 ℃ for 1 hour. The reaction mixture was transferred to a separatory funnel, diluted with ethyl acetate and washed with saturated brine, and the ethyl acetate layer was separated and dried over anhydrous sodium sulfate for 30 min. Filtering, and evaporating ethyl acetate under reduced pressure. Adding dichloromethane for redissolution, adding 4-hydroxypiperidine (144mg,1.4mmol) and triethylamine (0.39ml,2.8mmol), reacting at room temperature for 30 minutes, diluting with dichloromethane, washing with 1N hydrochloric acid, drying with anhydrous sodium sulfate, filtering, and evaporating under reduced pressure. Adding ethyl acetate for redissolution, adding acetyl chloride (411 mu L,5.76mmol) and triethylamine (511 mu L,2.88mmol), reacting at 50 ℃, washing with water, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure, and separating by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to obtain 150mg with yield of 55%.
Synthesis of intermediates 8 to 6: the intermediate 8-5(76mg,0.2mmol) was dissolved in acetic acid, 1, 3-dibromo-5, 5-dimethylhydantoin (86mg,0.3mmol) was added, the reaction was allowed to proceed overnight at 40 ℃, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to give 64mg, yield 70%.
Synthesis of the title compound: according to the synthesis method of the embodiment 3,1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),7.68(dd,J＝8.9,6.2Hz,1H),7.59(dd,J＝11.2,6.3Hz,2H),7.55(d,J＝8.9Hz,1H),4.71(d,J＝4.0Hz,1H),3.73(tt,J＝7.0,4.0Hz,1H),3.56(dq,J＝8.1,4.1Hz,1H),3.28(dt,J＝11.3,4.7Hz,2H),2.88(ddd,J＝11.9,8.8,3.2Hz,2H),1.82–1.71(m,2H),1.45(dtd,J＝12.3,8.1,3.7Hz,2H),1.20–1.11(m,4H).13C NMR(101MHz,DMSO-d6)δ153.3(d,J＝263.6Hz),152.0–149.0(m),145.4(d,J＝8.7Hz),142.5(d,J＝2.2Hz),139.0,129.3,113.4(d,J＝11.3Hz),106.8(d,J＝3.9Hz),105.1(d,J＝20.1Hz),101.1(d,J＝24.9Hz),64.3,43.5,33.5,29.9,6.9.
example synthesis of 91- ((5- (3- (3,4, 5-trifluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3,4-b ] pyridinyl) sulfonyl) piperidin-4-ol:
Figure BDA0002385652160000201
synthesis of intermediate 9-1: according to the synthesis method of the intermediate 3-1, the yield is 42%.
Synthesis of intermediate 9-2: according to the synthesis method of the intermediate 3-2.
Synthesis of intermediate 9-3: according to the synthesis method of the intermediate 8-5, the total yield of the two steps is 73%.
Synthesis of intermediate 9-4: according to the synthesis method of the intermediate 8-6, the yield is 41 percent.
Synthesis of the title compound: according to the synthesis method of the embodiment 3,1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.82(d,J＝2.1Hz,1H),8.80(d,J＝2.1Hz,1H),7.49(dd,J＝10.8,6.2Hz,2H),4.68(d,J＝4.0Hz,1H),3.82(tt,J＝7.3,3.7Hz,1H),3.51(tq,J＝7.5,3.6Hz,1H),3.20(ddd,J＝13.1,6.1,3.0Hz,2H),2.76(ddd,J＝11.8,8.6,3.3Hz,2H),1.77(ddt,J＝13.5,6.6,3.5Hz,2H),1.45(dtd,J＝12.3,8.0,3.5Hz,2H),1.25–1.18(m,2H),1.18–1.10(m,2H).13C NMR(101MHz,DMSO-d6)δ151.11,150.84(ddd,J＝243.0,10.0,5.8Hz),148.62,143.57,138.15(td,J＝12.3,2.8Hz),133.02(dt,J＝240.5,15.9Hz),131.49,123.75,107.26,100.66(d,J＝24.3Hz),64.24,43.69,33.37,29.17,6.61.
example synthesis of 101- ((5- (3- (3,4, 5-trifluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3,4-c ] pyridinyl) sulfonyl) piperidin-4-ol:
Figure BDA0002385652160000211
synthesis of intermediate 10-1: 1.36g (6.3mmol) of the substrate was dissolved in tetrahydrofuran, Raney Ni was added, and the reaction was carried out overnight at room temperature under a hydrogen atmosphere. Filtered and evaporated to dryness under reduced pressure.
Synthesis of intermediate 10-2: the product was dissolved in tetrahydrofuran, acetic anhydride (964 μ L,9.45mmol) was added, the reaction was refluxed overnight, and after completion of the reaction, it was evaporated to dryness under reduced pressure.
Synthesis of intermediate 10-3: the above product was dissolved in toluene, acetic anhydride (2.55mL,25mmol), isoamyl nitrite (1.47g,12.6mmol), potassium acetate (1.86g,19mmol), 18-crown-6 (166mg,0.63mmol) were added in this order, and after completion of the reaction at 80 ℃, ethyl acetate was added for dilution, washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Dissolving in 10mL of tetrahydrofuran and water, adding sodium hydroxide (1.2g,30mmol), reacting at room temperature, evaporating under reduced pressure to remove tetrahydrofuran, adjusting pH to 5-6 with 2N hydrochloric acid, separating out solid, filtering, and drying. 549mg, total yield of three steps is 44%.
Synthesis of intermediate 10-4: according to the synthesis method of the intermediate 3-1.
Synthesis of intermediate 10-5: according to the synthesis method of the intermediate 3-2.
Synthesis of intermediate 10-6: according to the synthesis method of the intermediate 8-5, the yield is 60 percent.
Synthesis of intermediate 10-7: according to the synthesis method of the intermediate 8-6, the yield is 49 percent.
Synthesis of the title compound: according to the synthesis method of the embodiment 3,1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),9.15(s,1H),8.62(s,1H),7.48(dd,J＝10.9,6.1Hz,2H),4.69(d,J＝3.9Hz,1H),3.84(dq,J＝6.9,3.5,3.0Hz,1H),3.63–3.48(m,2H),3.41(dt,J＝11.4,4.5Hz,2H),2.94(ddd,J＝12.2,8.8,3.4Hz,2H),1.83–1.67(m,2H),1.52–1.33(m,2H),1.23–1.16(m,4H).13C NMR(101MHz,DMSO-d6)δ150.83(ddd,J＝242.6,10.0,5.8Hz),144.60,143.90,138.94–137.93(m),137.46,134.84,132.90(d,J＝240.7Hz),118.74,116.43,100.48(d,J＝24.7Hz),64.77,44.16,33.76,30.30,6.94.
example synthesis of 111- ((5- (3- (3,4, 5-trifluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [4,3-b ] pyridinyl) sulfonyl) piperidin-4-ol:
Figure BDA0002385652160000212
synthesis of intermediate 11-1: according to the synthesis method of the intermediate 10-3, the total yield of the three steps is 67%.
Synthesis of intermediate 11-3: according to the synthesis method of 3-2, the total yield of two steps is 66%.
Synthesis of intermediate 11-4: according to the synthesis method of the intermediate 8-5, the yield is 60 percent.
Synthesis of intermediate 11-5: according to the synthesis method of the intermediate 8-6, the yield is 63%.
Synthesis of the title compound: according to the synthesis method of the embodiment 3,1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.25(d,J＝8.8Hz,1H),7.94(d,J＝8.8Hz,1H),7.72(dd,J＝11.2,6.2Hz,2H),4.69(d,J＝4.0Hz,1H),3.81–3.67(m,1H),3.59–3.46(m,1H),3.41(dd,J＝12.4,5.6Hz,2H),2.95(ddd,J＝12.2,8.8,3.3Hz,2H),1.73(ddt,J＝13.6,7.0,3.6Hz,2H),1.40(dtd,J＝12.6,8.6,3.8Hz,2H),1.15(d,J＝5.2Hz,4H).
example synthesis of 121- ((5- (3- (3,4, 5-trifluorophenyl) amino) - (1- (3-oxetanyl)) -1H-indazolyl) sulfonyl) piperidin-4-ol:
Figure BDA0002385652160000221
synthesis of 4-methylbenzenesulfonic acid (3-oxetane) ester (12-1): 3-Oxetanol (222mg,3mmol) was dissolved in methylene chloride, and p-toluenesulfonyl chloride (860mg,4.5mmol), triethylamine (832. mu.L, 6mmol) and DMAP (36mg,0.3mmol) were added to react at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether/ethyl acetate 4/1) to give 648mg, yield 95%.
Synthesis of 1- (3-oxetanyl) -5-bromo-1H-indazole (12-2): 5-bromo-1H-indazole (329mg,1.67mmol) is dissolved in 15mL DMF and 12-1(570mg,2.5mmol), K, are added sequentially2CO3(691mg,5mmol), reaction at 110 deg.C for 12 hours, filtration, concentration under reduced pressure, silica gel column chromatography (petroleum ether/ethyl acetate 4/1).
Synthesis of 5- (benzylsulfanyl) -1- (3-oxetanyl) -1H-indazole (12-3): the product is dissolved in 10mL of 1, 4-dioxane, Pd is added2(dba)3(76mg,0.083mmol), Xantphos (96mg,0.17mmol), DIPEA (550. mu.L, 3.34mmol), and benzylmercaptan (310mg,2.5mmol), the contents of the flask were replaced with argon three times, heated to 90 ℃ and reacted for 4 hours. Detecting the reaction solution by LC-MS, cooling after the reaction is finished, filtering, concentrating the filtrate under reduced pressure, and separating by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) to obtain 453mg yellow oily substance with the yield of the two steps being 92%.
Synthesis of 1- ((5- (3-oxetanyl) -1H-indazolyl) sulfonyl) piperidin-4-ol (12-4): 296mg (1.0mmol) of 12-3 was dissolved in 10ml of acetonitrile, 100. mu.L of water and acetic acid were sequentially added, the mixture was cooled to-15 ℃,1, 3-dichloro-5, 5-dimethylhydantoin (394mg,2.0mmol) was added in portions, and the reaction was carried out for 1 hour. The reaction solution was transferred to a separatory funnel, diluted with ethyl acetate and washed with saturated brine, and the ethyl acetate layer was separated and dried over anhydrous sodium sulfate for 30 min. Filtering, and evaporating ethyl acetate under reduced pressure. Dissolving with dichloromethane, adding 4-hydroxypiperidine (200mg,2.0mmol) and triethylamine (0.41ml,3mmol), reacting at room temperature for 30min, diluting with dichloromethane, washing with 1N hydrochloric acid, drying with anhydrous sodium sulfate, and separating with silica gel column chromatography (dichloromethane/methanol 30/1) to obtain 310mg, yield 92%.
Synthesis of 4- (1- (5- (3-bromo-1- (3-oxetanyl) -1H-indazolyl) sulfonyl) piperidine) acetate (12-6): 12 to 6(232mg,0.69mmol) was dissolved in 10mL of ethyl acetate, acetyl chloride (217mg,2.76mmol) and triethylamine (379. mu.L, 2.76mmol) were added to the mixture to react at 50 ℃ and, after completion of the reaction, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether/ethyl acetate 2/3) to obtain 12 to 571 mg of an intermediate. 12-5(71mg,0.19mmol) was dissolved in a mixed solution of 2mL acetonitrile and 2mL glacial acetic acid, NBS (64mg,0.36mmol) was added, the reaction was carried out at 50 ℃ and monitored by LC-MS, after completion, concentration was carried out under reduced pressure, and silica gel column chromatography (petroleum ether/ethyl acetate 1/1) was carried out to obtain 46mg, which was 14% yield in two steps.
Synthesis of the title compound: according to the synthesis method of the embodiment 3,1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),8.54(s,1H),7.79(d,J＝8.9Hz,1H),7.71(d,J＝9.0Hz,1H),7.65(dd,J＝11.0,6.2Hz,2H),6.06(p,J＝7.0Hz,1H),5.09(t,J＝6.4Hz,2H),4.99(t,J＝7.1Hz,2H),4.63(d,J＝3.8Hz,1H),3.49(dq,J＝7.9,4.2Hz,1H),3.23–3.04(m,2H),2.83–2.61(m,2H),1.73(s,2H),1.43(dtd,J＝12.3,8.2,3.6Hz,2H).
example 13 synthesis of N-sec-butyl-5- (1-cyclopropyl-3- ((3,4, 5-trifluorophenyl) amino) -1H-indazole) sulfonamide:
Figure BDA0002385652160000231
synthesis of N-sec-butyl-5- (1-cyclopropyl-1H-indazole) sulfonamide (13-1): 140mg (0.5mmol) of 3-2 was dissolved in 10ml of acetonitrile, 100. mu.L of water and acetic acid were sequentially added, the mixture was cooled to-15 ℃ and 1, 3-dichloro-5, 5-dimethylhydantoin (197,1mmol) was added in portions, and the mixture was reacted at trans-15 ℃ for 1 hour. The reaction mixture was transferred to a separatory funnel, diluted with ethyl acetate and washed with saturated brine, and the ethyl acetate layer was separated and dried over anhydrous sodium sulfate for 30 min. Filtering, and evaporating ethyl acetate under reduced pressure. Adding dichloromethane for redissolution, reacting isobutylamine (100 μ L,1mmol) and triethylamine (277 μ L,2mmol) at room temperature for 30min, diluting with dichloromethane, washing with 1N hydrochloric acid, drying with anhydrous sodium sulfate, and separating with silica gel column chromatography to obtain 116mg with yield of 80%.
Synthesis of N-sec-butyl-5- (1-cyclopropyl-3-bromo-1H-indazole) sulfonamide (13-2): 13-1(117mg,0.4mmol) was dissolved in a mixed solution of 4mL acetonitrile and 2mL acetic acid, NBS (142mg,0.8mmol) was added thereto, and the mixture was reacted at room temperature, followed by dilution with ethyl acetate, washing with water and saturated brine in this order, and separation by silica gel column chromatography (Petroleum ether/ethyl acetate 2/1) to obtain 110mg, yield 74%.
Synthesis of the title compound: 13-2(37mg,0.1mol), 3,4, 5-trifluoroaniline (22mg,0.15mmol), Pd (OAc)2(2.2mg,0.01mmol)、Xantphos(5.7mg,0.01mmol)、Cs2CO3(65mg,0.2mmol) and 1, 4-dioxane (2ml), the gas in the reaction flask was replaced with argon three times, and the reaction was carried out at 130 ℃ for 3 hours. After the reaction was completed, it was cooled, filtered, and the filtrate was concentrated under reduced pressure. After adding 1mL of methanol, a white solid was precipitated and filtered to obtain 30mg of the desired product in a yield of 68%.1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.55(d,J＝1.6Hz,1H),7.81(dd,J＝8.9,1.7Hz,1H),7.74(d,J＝8.9Hz,1H),7.56(dd,J＝11.1,6.2Hz,2H),7.44(d,J＝7.7Hz,1H),3.68(ddd,J＝10.6,7.2,4.5Hz,1H),3.02(p,J＝6.7Hz,1H),1.30(p,J＝7.2Hz,2H),1.14(dd,J＝7.2,2.5Hz,4H),0.85(d,J＝6.6Hz,3H),0.70(t,J＝7.4Hz,3H).
Example 14 synthesis of N- (2-hydroxyethyl) -5- (1-cyclopropyl-3- ((3,4, 5-trifluorophenyl) amino) -1H-indazole) sulfonamide:
Figure BDA0002385652160000232
synthesis of acetic acid-2- (5- (3-bromo-1-cyclopropyl-1H-indazolyl) sulfonamide) ethyl ester (14-2): according to the synthesis method of the compound 3-4, the yield in three steps is 42%.
Synthesis of the title compound: according to the synthesis method of the example 3,1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.55(s,1H),7.80(d,J＝9.0Hz,1H),7.74(d,J＝8.9Hz,1H),7.56(dd,J＝11.1,6.2Hz,2H),7.49(t,J＝6.0Hz,1H),4.65(t,J＝5.6Hz,1H),3.67(tt,J＝6.9,4.1Hz,1H),3.40–3.34(m,2H),2.77(q,J＝6.3Hz,2H),1.14(t,J＝5.3Hz,4H).
example 15 synthesis of N, N-dimethyl-5- (1-cyclopropyl-3- ((3,4, 5-trifluorophenyl) amino) -1H-indazole) sulfonamide:
Figure BDA0002385652160000241
synthesis of intermediate 15-2: according to the synthesis method of 13-2, the total yield of the two steps is 67%.
Synthesis of the title compound: the synthesis procedure of example 3 was followed.
Example 16 synthesis of N- (4-hydroxycyclohexyl) -5- (1-cyclopropyl-3- ((3,4, 5-trifluorophenyl) amino) -1H-indazole) sulfonamide:
Figure BDA0002385652160000242
synthesis of N- (4-hydroxycyclohexyl) -5- (1-cyclopropyl-1H-indazole) sulfonamide (16-1): 140mg (0.5mmol) of 3-2 was dissolved in 5ml of acetonitrile, 100. mu.L of water and acetic acid were sequentially added, the mixture was cooled to-15 ℃ and 1, 3-dichloro-5, 5-dimethylhydantoin (197mg,1mmol) was added in portions and reacted for 1 hour. 4-aminocyclohexanol (115mg,1mmol) and triethylamine (206. mu.L, 1.5mmol) were dissolved in 2mL of acetonitrile, and the resulting solution was added to the reaction mixture and reacted at room temperature. After the reaction is finished, dichloromethane is added for dilution, the mixture is washed by water and saturated salt in sequence, dried by anhydrous sodium sulfate, filtered, and the dichloromethane is removed by evaporation under reduced pressure, and the next reaction is carried out without further purification.
Synthesis of acetic acid-4- ((5- (1-cyclopropyl-3-bromo-1H-indazole)) sulfonamide) cyclohexyl ester (16-2): the above product was dissolved in 10mL of ethyl acetate, and acetic anhydride (200. mu.L, 2mmol) and pyridine (200. mu.L, 2.5mmol) were added to the solution, followed by reflux overnight. After the reaction was completed, the mixture was washed with a saturated copper sulfate solution and a saturated salt solution in this order, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was distilled off under reduced pressure. To the above product were added 6mL of acetonitrile, 3mL of acetic acid, and 178mg of NBS, and the reaction was carried out at 50 ℃ for 1 hour. The reaction solution was washed with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain 60mg, with a total yield of 26% in the three steps.
Synthesis of the title compound: according to the synthesis method of the compound 3,1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),8.55(s,1H),7.81(d,J＝8.8Hz,1H),7.73(d,J＝9.0Hz,1H),7.55(dd,J＝10.1,5.7Hz,3H),4.46(d,J＝4.3Hz,1H),3.67(p,J＝5.0Hz,1H),3.26(q,J＝8.8Hz,1H),2.97–2.76(m,1H),1.80–1.63(m,2H),1.57(d,J＝12.5Hz,2H),1.26–1.08(m,6H),1.09–0.91(m,2H).13C NMR(101MHz,DMSO-d6)δ150.85(ddd,J＝242.2,9.6,5.6Hz),144.65,141.63,138.86(t,J＝12.3Hz),133.18,132.66(dt,J＝240.0,15.6Hz),125.54,120.98,114.20,110.92,100.34(d,J＝24.6Hz),68.03,52.13,34.09,31.44,29.67,6.84.
example 17 synthesis of N- (3,4, 5-trifluorophenyl) -3- (1-cyclopropyl-5- (morpholinesulfonyl) -1H-indazole) amine:
according to the synthesis method of the embodiment 13,1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.53(s,1H),7.78(d,J＝8.9Hz,1H),7.73(dd,J＝8.9,1.6Hz,1H),7.57(dd,J＝11.1,6.2Hz,2H),3.71(td,J＝6.5,3.3Hz,1H),3.65(t,J＝4.7Hz,4H),2.89(q,J＝5.5,4.6Hz,4H),1.16(t,J＝4.8Hz,4H).
Figure BDA0002385652160000243
example 18 synthesis of N- (4- (tetrahydro-2H-pyran)) -5- (1-cyclopropyl-3- ((3,4, 5-trifluorophenyl) amino) -1H-indazole) sulfonamide:
according to the synthesis method of the embodiment 13,1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.57(s,1H),7.88–7.79(m,1H),7.73(dd,J＝8.1,3.5Hz,2H),7.55(dd,J＝11.1,6.1Hz,2H),3.78–3.62(m,3H),3.26–3.06(m,3H),1.57–1.43(m,2H),1.43–1.27(m,2H),1.19–1.04(m,4H).13C NMR(101MHz,DMSO-d6)δ150.89(dd,J＝240.7,7.6Hz),144.66,141.65,138.82(t,J＝11.4Hz),133.11,135.14–130.82(m),125.53,121.09,114.21,111.02,100.34(d,J＝24.5Hz),66.00,49.69,33.72,29.67,6.86.
Figure BDA0002385652160000251
example 19 synthesis of N- (3,4, 5-trifluorophenyl) -3- (1-cyclopropyl-5- ((1-piperidinyl) sulfonyl) -1H-indazole) amine:
Figure BDA0002385652160000252
synthesis of intermediate 19-2: according to the synthesis method of 13-2, the total yield of the two steps is 68%.
Synthesis of the title compound: the synthesis of example 13 was followed.
Synthesis of examples 20-37: synthesis as in example 3
Figure BDA0002385652160000253
Example 204 synthesis of 1- ((5- (3- (4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol: according to the synthesis method of the embodiment 3,1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.58(d,J＝1.3Hz,1H),7.79–7.72(m,2H),7.70(d,J＝1.2Hz,2H),7.21–7.13(m,2H),4.69(s,1H),3.65(p,J＝5.3Hz,1H),3.51(tt,J＝7.6,3.6Hz,1H),3.18–3.11(m,2H),2.72(ddd,J＝11.8,8.4,3.4Hz,2H),1.76(ddt,J＝13.5,6.8,2.9Hz,2H),1.45(dtd,J＝12.0,7.8,3.6Hz,2H),1.13(d,J＝5.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ156.48(d,J＝235.7Hz),145.65,142.08,138.99(d,J＝2.1Hz),126.06(d,J＝26.0Hz),122.77,117.78(d,J＝7.4Hz),115.84,115.63,115.14,110.22,64.25,43.72,33.37,29.57,6.87.
Figure BDA0002385652160000254
example synthesis of 214- (1- ((5- (3- (3, 4-difluorophenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol: according to the synthesis method of the embodiment 3,1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),8.56(d,J＝1.2Hz,1H),7.96–7.82(m,1H),7.71(s,2H),7.48–7.31(m,2H),4.66(s,1H),3.76–3.60(m,1H),3.50(s,1H),3.14(dt,J＝11.2,4.0Hz,2H),2.72(ddd,J＝11.7,8.4,3.4Hz,2H),1.82–1.67(m,2H),1.44(dtd,J＝12.1,8.1,3.7Hz,2H),1.18–1.05(m,4H).13C NMR(101MHz,DMSO-d6)δ151.40–146.76(m),145.17,143.45(dd,J＝237.0,12.4Hz),142.01,139.63(dd,J＝9.7,2.2Hz),126.30,126.23,122.65,117.96(d,J＝17.7Hz),114.97,112.62(dd,J＝5.3,2.8Hz),110.40,105.05(d,J＝22.3Hz),64.22,43.71,33.36,29.62,6.86.
Figure BDA0002385652160000261
example the synthesis of 224- (1- ((5- (3- (3-methyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol,1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),8.56(s,1H),7.68(s,2H),7.63(dt,J＝8.2,3.6Hz,1H),7.53(dd,J＝6.9,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),4.66(s,1H),3.64(p,J＝5.3Hz,1H),3.50(tt,J＝7.9,3.6Hz,1H),3.22–3.07(m,2H),2.71(ddd,J＝11.9,8.6,3.5Hz,2H),2.24(s,3H),1.74(ddd,J＝13.9,7.3,3.6Hz,2H),1.44(dtd,J＝12.3,8.2,3.6Hz,2H),1.12(d,J＝5.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.16(d,J＝234.8Hz),145.67,142.06,138.67(d,J＝2.2Hz),126.01(d,J＝29.0Hz),124.46(d,J＝18.0Hz),122.78,119.17(d,J＝4.0Hz),115.49,115.24(d,J＝4.1Hz),115.19,115.15,110.18,64.24,43.71,33.37,29.57,15.13(d,J＝2.9Hz),6.84.
Figure BDA0002385652160000262
example 234 synthesis of 1- ((5- (3- (3-cyano-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol,1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.54(s,1H),8.18(dd,J＝5.5,2.9Hz,1H),8.02–7.87(m,1H),7.72(s,2H),7.48(t,J＝9.1Hz,1H),4.64(d,J＝3.8Hz,1H),3.68(p,J＝5.4Hz,1H),3.51(tt,J＝7.7,3.6Hz,1H),3.15(tt,J＝7.0,3.2Hz,2H),2.73(ddd,J＝11.8,8.5,3.5Hz,2H),1.84–1.66(m,2H),1.45(dtd,J＝12.3,8.2,3.7Hz,2H),1.15(d,J＝6.4Hz,4H).13C NMR(101MHz,DMSO-d6)δ156.53(d,J＝248.2Hz),144.85,142.02,139.58(d,J＝2.2Hz),126.46,126.35,123.49(d,J＝7.5Hz),122.53,119.07,117.58(d,J＝20.5Hz),115.00,114.89,110.50,100.15(d,J＝16.0Hz),64.22,43.69,33.37,29.67,6.87.
Figure BDA0002385652160000263
example 244- (1- ((5- (3- (4- (2-methylpyridinyl)) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol,1H NMR(400MHz,DMSO)δ9.82(s,1H),8.59(s,1H),8.23(d,J＝5.7Hz,1H),7.74(q,J＝8.9Hz,2H),7.50(d,J＝4.3Hz,1H),7.44(s,1H),4.71(s,1H),3.72(dt,J＝10.2,5.2Hz,1H),3.51(s,1H),3.15(s,2H),2.72(t,J＝8.4Hz,2H),2.42(s,3H),1.83–1.68(m,2H),1.45(d,J＝8.4Hz,2H),1.16(d,J＝4.8Hz,4H).13C NMR(101MHz,DMSO-d6)δ158.43,149.88,148.61,144.41,141.96,126.53,126.23,122.66,115.22,110.56,109.93,108.70,64.20,43.72,33.35,29.74,24.95,6.90.
Figure BDA0002385652160000264
example 254- (1- ((5- (3- (4-chlorophenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol,1H NMR(400MHz,DMSO)δ9.51(s,1H),8.58(s,1H),7.74(dd,J＝14.7,10.6Hz,4H),7.45–7.30(m,2H),4.66(d,J＝3.6Hz,1H),3.72–3.59(m,1H),3.51(s,1H),3.15(s,2H),2.71(d,J＝8.1Hz,2H),1.75(s,2H),1.53–1.38(m,2H),1.13(d,J＝4.6Hz,4H).13C NMR(101MHz,DMSO-d6)δ145.27,142.03,141.34,129.10,126.23,126.02,123.40,122.74,118.01,115.15,110.32,64.23,43.73,33.36,29.61,6.93.
Figure BDA0002385652160000271
example 264- (1- ((5- (3- (4-fluoro-2-methylphenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol,1H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.16(s,1H),7.81–7.61(m,3H),7.07(dd,J＝9.7,2.9Hz,1H),7.02–6.93(m,1H),4.65(d,J＝3.8Hz,1H),3.65–3.54(m,1H),3.54–3.45(m,1H),3.14(td,J＝11.1,10.7,5.0Hz,2H),2.78–2.64(m,2H),2.32(s,3H),1.85–1.66(m,2H),1.54–1.36(m,2H),1.14–0.97(m,4H).13C NMR(101MHz,DMSO-d6)δ157.83(d,J＝237.9Hz),146.71,142.63,137.02(d,J＝2.5Hz),131.57(d,J＝7.7Hz),125.90,123.11,122.05(d,J＝8.3Hz),117.16(d,J＝22.0Hz),115.14,112.86(d,J＝21.6Hz),110.29,64.25,43.68,33.38,29.45,18.71,6.83.
Figure BDA0002385652160000272
example 274- (1- ((5- (3- (5-fluoro-2-methylphenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol,1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.26(s,1H),7.83–7.63(m,3H),7.17(t,J＝7.6Hz,1H),6.66(td,J＝8.3,2.6Hz,1H),4.67(d,J＝3.8Hz,1H),3.74–3.63(m,1H),3.51(dd,J＝7.1,3.5Hz,1H),3.15(d,J＝7.0Hz,2H),2.72(t,J＝8.4Hz,2H),2.34(s,3H),1.75(dd,J＝12.4,3.4Hz,2H),1.45(dt,J＝16.7,6.4Hz,2H),1.15–1.04(m,4H).13C NMR(101MHz,DMSO-d6)δ161.33(d,J＝238.1Hz),145.34,142.41,142.12(d,J＝11.0Hz),131.72(d,J＝9.5Hz),126.23,125.99,123.30,122.49(d,J＝2.7Hz),115.48,110.49,107.16(d,J＝21.1Hz),104.87(d,J＝26.4Hz),64.25,43.72,33.38,29.61,18.10,6.86.
Figure BDA0002385652160000273
example 284- (1- ((5- (3- (2-chloro-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol,1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),8.54(d,J＝1.5Hz,1H),8.03(dd,J＝9.2,5.6Hz,1H),7.80–7.64(m,2H),7.47(dd,J＝8.5,3.0Hz,1H),7.22(td,J＝8.6,3.0Hz,1H),4.66(d,J＝3.8Hz,1H),3.71–3.60(m,1H),3.53(tq,J＝7.6,3.7Hz,1H),3.16(ddt,J＝11.2,7.3,4.5Hz,2H),2.74(ddd,J＝11.8,8.5,3.4Hz,2H),1.86–1.68(m,2H),1.46(dtd,J＝12.1,8.0,3.6Hz,2H),1.15–1.05(m,4H).13C NMR(101MHz,DMSO-d6)δ156.71(d,J＝240.9Hz),145.40,142.51,135.99(d,J＝3.0Hz),126.35,126.01,123.44(d,J＝10.5Hz),123.33,121.77(d,J＝8.2Hz),117.01(d,J＝25.7Hz),115.32,114.95(d,J＝21.8Hz),110.45,64.23,43.69,33.37,29.59,6.87.
Figure BDA0002385652160000281
example 294- (1- ((5- (3- (4-methylphenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol,1H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.60(t,J＝1.3Hz,1H),7.72–7.67(m,2H),7.67–7.61(m,2H),7.12(d,J＝8.3Hz,2H),4.68(d,J＝3.3Hz,1H),3.64(p,J＝5.3Hz,1H),3.52(d,J＝8.6Hz,1H),3.16(ddd,J＝11.1,6.9,3.7Hz,2H),2.72(ddd,J＝11.8,8.4,3.4Hz,2H),2.26(s,3H),1.76(ddt,J＝13.5,6.8,2.9Hz,2H),1.46(dtd,J＝12.0,7.9,3.5Hz,2H),1.13(d,J＝5.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ145.84,142.08,140.06,129.66,128.66,126.10,125.76,122.86,116.64,115.31,110.08,64.27,43.74,33.38,29.55,20.81,6.86.
Figure BDA0002385652160000282
example 304- (1- ((5- (3- (4-fluorobenzyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol,1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.64–7.57(m,1H),7.55(d,J＝8.9Hz,1H),7.45(dd,J＝8.4,5.6Hz,2H),7.16(t,J＝8.7Hz,2H),7.07(t,J＝5.9Hz,1H),4.64(d,J＝3.8Hz,1H),4.42(d,J＝5.7Hz,2H),3.61–3.42(m,2H),3.10(t,J＝8.8Hz,2H),2.75–2.59(m,2H),1.84–1.64(m,2H),1.53–1.32(m,2H),1.02(t,J＝6.4Hz,4H).13C NMR(100MHz,DMSO-d6)δ161.6(d,J＝242.0Hz),150.3,143.2,136.6(d,J＝2.9Hz),130.2(d,J＝8.0Hz),125.9,124.9,123.0,115.3(d,J＝21.2Hz),114.5,109.8,64.3,46.3,43.7,33.4,29.2,6.7.
Figure BDA0002385652160000283
example 314- (1- ((5- (3-phenylamino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol,1H NMR(400MHz,DMSO)δ9.34(s,1H),8.61(s,1H),7.83–7.64(m,4H),7.32(t,J＝7.9Hz,2H),6.87(t,J＝7.3Hz,1H),4.66(d,J＝3.8Hz,1H),3.66(dt,J＝10.4,5.3Hz,1H),3.59–3.45(m,1H),3.16(s,2H),2.72(t,J＝8.3Hz,2H),1.76(dd,J＝12.3,3.4Hz,2H),1.46(dd,J＝8.2,3.8Hz,2H),1.14(d,J＝5.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ145.61,142.46,142.04,129.28,126.14,125.85,122.85,120.08,116.54,115.30,110.19,64.25,43.74,33.37,29.58,6.88.
Figure BDA0002385652160000284
example 324- (1- ((5- (3- (3-fluoro-4-methylphenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol,1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.58(s,1H),7.80–7.62(m,3H),7.32(dd,J＝8.3,2.2Hz,1H),7.19(t,J＝8.7Hz,1H),4.67(s,1H),3.74–3.61(m,1H),3.50(dq,J＝7.5,4.0,3.5Hz,1H),3.24–3.09(m,2H),2.72(ddd,J＝12.0,8.6,3.4Hz,2H),2.18(d,J＝1.6Hz,3H),1.76(ddt,J＝13.5,6.9,3.4Hz,2H),1.45(dtd,J＝12.4,8.1,3.6Hz,2H),1.18–1.05(m,4H).13C NMR(101MHz,DMSO-d6)δ161.21(d,J＝239.6Hz),145.38,142.03,141.92(d,J＝11.4Hz),131.89(d,J＝7.0Hz),126.21,126.09,122.71,115.11,114.72(d,J＝17.6Hz),112.54(d,J＝2.7Hz),110.28,103.26(d,J＝27.6Hz),64.25,43.72,33.38,29.60,6.86.
Figure BDA0002385652160000291
example 334- (1- ((5- (3-benzylamino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol,1H NMR(400MHz,DMSO-d6)δ8.34(d,J＝1.6Hz,1H),7.65–7.50(m,2H),7.42(d,J＝7.2Hz,2H),7.34(t,J＝7.4Hz,2H),7.25(t,J＝7.3Hz,1H),7.07(t,J＝5.8Hz,1H),4.66(s,1H),4.45(d,J＝5.8Hz,2H),3.48(qt,J＝6.8,3.8Hz,2H),3.11(ddd,J＝11.2,6.9,3.7Hz,2H),2.66(ddd,J＝11.8,8.5,3.4Hz,2H),1.73(ddt,J＝13.9,7.2,3.5Hz,2H),1.43(dtd,J＝12.2,8.2,3.7Hz,2H),1.03(dt,J＝8.3,2.8Hz,4H).13C NMR(101MHz,DMSO-d6)δ150.40,143.17,140.44,128.63,128.28,127.21,125.84,124.86,123.09,114.50,109.72,64.28,47.04,43.70,33.37,29.23.
Figure BDA0002385652160000292
example 344- (1- ((5- (3- (2- (5-fluoropyridinyl)) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol,1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.71(d,J＝1.2Hz,1H),8.23(d,J＝3.0Hz,1H),8.05(dd,J＝9.2,3.9Hz,1H),7.78–7.66(m,3H),4.65(d,J＝3.8Hz,1H),3.69(tt,J＝6.6,4.5Hz,1H),3.52(tq,J＝7.4,3.6Hz,1H),3.18–3.10(m,2H),2.73(ddd,J＝11.8,8.4,3.4Hz,2H),1.76(ddt,J＝14.0,7.2,3.5Hz,2H),1.46(dtd,J＝11.9,7.9,3.6Hz,2H),1.19–1.07(m,4H).13C NMR(101MHz,DMSO-d6)δ154.47(d,J＝243.3Hz),151.52,144.20,142.24,135.23(d,J＝24.7Hz),126.50,126.09,125.85(d,J＝19.9Hz),123.72,115.41,111.14(d,J＝4.0Hz),110.26,64.26,43.71,33.38,29.64,6.84.
Figure BDA0002385652160000293
example 354- (1- ((5- (3- (2- (5-fluoro-4-methylpyridinyl)) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol,1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.66(s,1H),8.10(s,1H),7.86(d,J＝5.6Hz,1H),7.78–7.66(m,2H),4.64(d,J＝3.8Hz,1H),3.71(td,J＝6.3,3.2Hz,1H),3.52(tq,J＝7.6,3.7Hz,1H),3.16(ddt,J＝11.2,7.2,4.2Hz,2H),2.73(ddd,J＝11.7,8.2,3.3Hz,2H),2.31(s,3H),1.76(ddt,J＝14.0,7.2,3.5Hz,2H),1.46(dtd,J＝12.1,8.1,3.6Hz,2H),1.19–1.07(m,4H).13C NMR(101MHz,DMSO-d6)δ153.91(d,J＝242.1Hz),151.36(d,J＝1.9Hz),144.20,142.27,135.85(d,J＝16.1Hz),134.46(d,J＝25.7Hz),126.46,126.01,123.78,115.54,112.12,110.25,64.26,43.70,33.38,29.66,15.05(d,J＝2.8Hz),6.80.
Figure BDA0002385652160000301
example 364- (1- ((5- (3- (4-fluoro-3-trifluoromethylphenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol,1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.56(s,1H),8.17(dd,J＝6.3,2.8Hz,1H),8.01(dt,J＝9.1,3.6Hz,1H),7.81–7.69(m,2H),7.49(t,J＝9.8Hz,1H),4.65(d,J＝3.9Hz,1H),3.72(p,J＝5.3Hz,1H),3.51(dh,J＝7.8,3.7Hz,1H),3.25–3.07(m,2H),2.74(ddd,J＝11.8,8.5,3.4Hz,2H),1.76(ddt,J＝10.6,6.9,3.5Hz,2H),1.45(dtd,J＝11.9,7.9,3.5Hz,2H),1.15(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ154.28–150.91(m),145.01,142.00,139.20(d,J＝2.2Hz),126.33(d,J＝3.3Hz),123.29(q,J＝271.8Hz),122.56,121.74(d,J＝7.5Hz),118.20,117.99,116.88(qd,J＝32.0,13.0Hz),114.96,113.81(q,J＝5.3,4.8Hz),110.41,64.21,43.69,33.36,29.66,6.71.
Figure BDA0002385652160000302
example 374- (1- ((5- (3- (4-fluoro-3-cyclopropylphenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol,1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.55(s,1H),7.70(s,2H),7.62–7.52(m,1H),7.31(dd,J＝6.8,2.8Hz,1H),7.09(t,J＝9.5Hz,1H),4.65(d,J＝3.8Hz,1H),3.75–3.61(m,1H),3.51(tt,J＝7.6,3.9Hz,1H),3.15(ddd,J＝11.2,6.7,3.5Hz,2H),2.72(dd,J＝20.2,3.4Hz,2H),2.07(dp,J＝8.5,5.1Hz,1H),1.75(ddd,J＝11.3,7.4,3.6Hz,2H),1.45(dtd,J＝12.3,8.2,3.6Hz,2H),1.12(d,J＝2.3Hz,4H),1.03(dt,J＝8.7,3.2Hz,2H),0.78–0.66(m,2H).13C NMR(101MHz,DMSO-d6)δ155.58(d,J＝235.3Hz),145.61,142.00,138.95(d,J＝2.0Hz),130.42(d,J＝15.3Hz),126.16,125.85,122.70,115.35(d,J＝23.1Hz),115.14,114.54(d,J＝7.5Hz),113.41(d,J＝3.4Hz),110.14,64.24,43.71,33.36,29.59,8.94(d,J＝4.7Hz),8.53,6.67.
Figure BDA0002385652160000303
example synthesis of 384- (1- ((5- (3- (cyclohexylamino)) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol:
Figure BDA0002385652160000304
synthesis of acetic acid-4- (1- (5- (3-iodo-1-cyclopropyl-1H-indazolyl) sulfonyl) piperidine) ester (38-2): 38-1(363mg,1mmol) was dissolved in acetonitrile (8mL) and sulfuric acid (2mL), NIS (562mg,2.5mmol) was added, and the reaction was allowed to proceed at room temperature for 48 hours. The reaction mixture was diluted with ethyl acetate, washed successively with a saturated sodium bicarbonate solution, a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to obtain 180mg, yield 37%.
Synthesis of the title compound: compound 38-2(49mg,0.1mmol), cyclohexylamine (20mg,0.2mmol), cuprous iodide (3.8mg,0.02mmol), D-proline (4.6mg,0.04mmol), and potassium phosphate anhydrous (63mg,0.3mmol) were dissolved in 2mL of DMSO, replaced with argon three times, reacted at 90 ℃ for 3 hours, after completion of the reaction, diluted with ethyl acetate, washed with saturated brine 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated. Adding THF and water to dissolve, adding LiOH (12mg,0.5mmol), reacting at room temperature for 1 hr, adding ethyl acetate and water to the reaction solution, separating ethyl acetate phase, and separating with silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to obtain the target product.1H NMR(400MHz,DMSO-d6)δ8.34(d,J＝1.6Hz,1H),7.58(dd,J＝8.8,1.7Hz,1H),7.51(d,J＝8.8Hz,1H),6.40(d,J＝7.3Hz,1H),4.64(d,J＝3.8Hz,1H),3.51(qt,J＝7.3,4.2Hz,2H),3.44(tt,J＝6.9,3.8Hz,1H),3.12(ddd,J＝11.1,7.1,3.8Hz,2H),2.68(ddd,J＝11.7,8.4,3.4Hz,2H),2.11–2.01(m,2H),1.80–1.70(m,4H),1.61(dt,J＝12.7,3.8Hz,1H),1.45(ddt,J＝12.7,8.3,4.0Hz,2H),1.37–1.22(m,5H),1.09–0.98(m,4H).13C NMR(101MHz,DMSO-d6)δ149.75,142.97,125.77,124.51,123.14,114.83,109.52,64.27,51.55,43.70,33.38,32.99,29.15,26.15,25.14,6.82.
Example synthesis of 394- (1- ((5- (3- (cyclopentylamino)) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) alcohol: following the synthetic procedure of example 38,1H NMR(400MHz,DMSO-d6)δ8.32(d,J＝1.5Hz,1H),7.58(dd,J＝8.9,1.7Hz,1H),7.52(d,J＝8.8Hz,1H),6.51(d,J＝6.4Hz,1H),4.64(d,J＝3.6Hz,1H),3.97(p,J＝6.3Hz,1H),3.49(dtt,J＝16.8,6.8,3.8Hz,2H),3.12(ddd,J＝11.1,7.1,3.7Hz,2H),2.68(ddd,J＝11.7,8.4,3.4Hz,2H),2.05–1.90(m,2H),1.80–1.65(m,4H),1.63–1.50(m,4H),1.44(dtd,J＝12.1,8.0,3.5Hz,2H),1.03(t,J＝5.1Hz,4H).13C NMR(101MHz,DMSO-d6)δ150.26,142.97,125.74,124.55,123.09,114.75,109.53,64.28,54.54,43.70,33.38,32.90,29.17,23.97,6.77.
Figure BDA0002385652160000311
example 40 synthesis of N- (4-fluorophenyl) -3- (1-cyclopropyl-5- (morpholinosulfonyl) -1H-indazole) amine: according to the synthesis method of the embodiment 13,1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.60(d,J＝1.4Hz,1H),7.75(dd,J＝9.1,4.7Hz,2H),7.73–7.67(m,2H),7.17(t,J＝8.9Hz,2H),3.74–3.59(m,5H),2.97–2.80(m,4H),1.14(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ156.50(d,J＝235.7Hz),145.70,142.18,138.94(d,J＝2.0Hz),126.23,124.75,123.17,117.79(d,J＝7.4Hz),115.75(d,J＝22.0Hz),115.17,110.36,65.74,46.42,29.59,6.87.
Figure BDA0002385652160000312
example 414- (1- ((5- (3- (3-chloro-4-fluorophenyl) (methyl)) Synthesis of amino) - (1-methyl) -1H-indazolyl) sulfonyl) piperidine) alcohol: according to the synthesis method of the example 2,1H NMR(400MHz,DMSO-d6)δ7.79(dd,J＝8.9,2.0Hz,1H),7.63(dt,J＝9.0,2.0Hz,1H),7.38(td,J＝9.0,2.2Hz,1H),7.30(dq,J＝6.9,4.3,3.3Hz,1H),7.19(d,J＝1.8Hz,1H),7.14(ddt,J＝9.1,4.1,2.6Hz,1H),4.69(d,J＝3.6Hz,1H),4.02(d,J＝2.1Hz,3H),3.48(s,1H),3.36(d,J＝2.1Hz,2H),3.09–2.92(m,2H),2.59–2.52(m,2H),1.82–1.62(m,2H),1.51–1.33(m,2H).
Figure BDA0002385652160000313
example synthesis of 421- ((5- (3- (4-fluorophenyl) amino) - (1-cyclopropyl) - (6-fluoro) -1H-indazolyl) sulfonyl) piperidin-4-ol: the intermediate 7-6 is used as a raw material, according to the synthesis method of the embodiment 3,1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),8.66(d,J＝6.8Hz,1H),7.80–7.67(m,2H),7.54(d,J＝11.3Hz,1H),7.17(t,J＝8.9Hz,2H),4.72(d,J＝4.0Hz,1H),3.70–3.53(m,2H),3.36–3.28(m,2H),2.89(ddd,J＝12.0,8.5,3.2Hz,2H),1.77(ddt,J＝13.5,7.1,3.5Hz,2H),1.44(dtd,J＝12.4,8.3,3.6Hz,2H),1.12(dq,J＝6.1,2.4Hz,4H).13C NMR(101MHz,DMSO-d6)δ158.61(d,J＝173.9Hz),156.19(d,J＝159.3Hz),145.83,142.58(d,J＝12.4Hz),138.77(d,J＝2.2Hz),125.97(d,J＝3.2Hz),117.88(d,J＝7.4Hz),116.71(d,J＝19.0Hz),115.75(d,J＝22.2Hz),111.82,97.18(d,J＝27.5Hz),64.53,43.36,33.66,29.70,6.83.
Figure BDA0002385652160000321
example synthesis of 431- ((5- (3- (3-methyl-4-fluorophenyl) amino) - (1-cyclopropyl) - (6-fluoro) -1H-indazolyl) sulfonyl) piperidin-4-ol: the intermediate 7-6 is used as a raw material, according to the synthesis method of the embodiment 3,1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.65(d,J＝6.3Hz,1H),7.68–7.57(m,1H),7.53(t,J＝8.2Hz,2H),7.09(t,J＝9.2Hz,1H),4.73(s,1H),3.60(dtd,J＝18.7,8.1,7.6,4.2Hz,2H),3.31(dd,J＝11.9,6.1Hz,2H),2.88(ddd,J＝12.3,8.4,3.5Hz,2H),2.24(d,J＝4.1Hz,3H),1.85–1.69(m,2H),1.44(dt,J＝8.4,4.1Hz,2H),1.15–1.02(m,4H).13C NMR(101MHz,DMSO-d6)δ158.22(d,J＝250.5Hz),155.25(d,J＝235.4Hz),145.87,142.56(d,J＝12.4Hz),138.46(d,J＝2.2Hz),125.97(d,J＝3.1Hz),124.49(d,J＝18.0Hz),119.29(d,J＝4.1Hz),116.66(d,J＝19.0Hz),115.42(d,J＝14.3Hz),115.27,111.87,97.14(d,J＝27.5Hz),64.53,43.35,33.66,29.71,15.10(d,J＝2.9Hz),6.79.
Figure BDA0002385652160000322
example 44 synthesis of N- (4-fluoro-3-methylphenyl) -3- (1-cyclopropyl-5- (morpholinosulfonyl) -1H-indazole) amine:
Figure BDA0002385652160000323
synthesis of intermediate 44-2: the overall yield in both steps was 62%.
Synthesis of the title compound: according to the synthesis method of the embodiment 13,1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.59(d,J＝1.5Hz,1H),7.78–7.67(m,2H),7.67–7.60(m,1H),7.54(dd,J＝6.9,2.8Hz,1H),7.10(t,J＝9.2Hz,1H),3.75–3.59(m,5H),2.87(dd,J＝5.6,3.4Hz,4H),2.25(s,3H),1.14(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.18(d,J＝235.1Hz),145.74,142.16,138.63(d,J＝2.2Hz),126.19,124.70,124.48(d,J＝18.1Hz),123.20,119.19(d,J＝4.0Hz),110.30,65.74,46.41,29.58,15.12(d,J＝3.0Hz),6.83.
example 45 synthesis of N- (4-fluoro-phenyl) -3- (1-cyclopropyl-5- (morpholinosulfonyl) -6-fluoro-1H-indazole) amine:
Figure BDA0002385652160000331
synthesis of intermediate 45-1: the synthesis of intermediates 1-3 was followed using 0.6mmol of substrate.
Synthesis of intermediate 45-2: the above product was dissolved in 5mL of acetic acid, NBS (214mg,1.2mmol) was added, reacted at 40 ℃ for 24 hours, evaporated to dryness under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to give 81mg, with a total yield of 34% in two steps.
Synthesis of the title compound: according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.67(d,J＝6.6Hz,1H),7.80–7.68(m,2H),7.56(d,J＝11.3Hz,1H),7.16(t,J＝8.9Hz,2H),3.64(t,J＝10.5Hz,5H),3.04(t,J＝4.5Hz,4H),1.16–1.07(m,4H).13C NMR(101MHz,DMSO-d6)δ158.60(d,J＝172.4Hz),156.18(d,J＝157.5Hz),145.87,142.68(d,J＝12.4Hz),138.73(d,J＝2.0Hz),126.32(d,J＝3.2Hz),117.88(d,J＝7.3Hz),115.78(d,J＝22.2Hz),115.50(d,J＝19.0Hz),111.88,97.31(d,J＝27.5Hz),66.00,46.05,29.71,6.86.
example 46 Synthesis of N- (3-tetrahydrofuryl) -5- (1-cyclopropyl-3- ((4-fluorophenyl) amino) -1H-indazole) sulfonamide:
Figure BDA0002385652160000332
synthesis of intermediate 46-2: according to the synthesis method of 13-2, the total yield of two steps is 66%.
Synthesis of the title compound: synthesis according to example 13
Example 473 synthesis of- (1- ((5- (3- (4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) pyrrolidine) alcohol: according to the synthesis method of the example 3,1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.64(s,1H),7.85–7.71(m,3H),7.67(d,J＝8.8Hz,1H),7.17(t,J＝8.7Hz,2H),4.91(s,1H),4.14(s,1H),3.64(p,J＝5.2Hz,1H),3.25(ddd,J＝15.8,9.8,6.2Hz,3H),3.01(dd,J＝10.4,2.4Hz,1H),1.72(dtd,J＝13.3,8.6,4.9Hz,1H),1.61(ddt,J＝13.3,7.0,3.6Hz,1H),1.13(d,J＝5.4Hz,4H).13C NMR(101MHz,DMSO-d6)δ156.47(d,J＝235.5Hz),145.69,142.08,139.02(d,J＝2.2Hz),126.71,126.17,122.65,117.75(d,J＝7.4Hz),115.72(d,J＝22.2Hz),115.07,110.16,69.42,56.28,46.62,34.09,29.56,6.85.
Figure BDA0002385652160000333
example synthesis of 484- (1- ((5- (3- (4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) one:
Figure BDA0002385652160000334
synthesis of intermediate 48-2: the synthesis method according to 13-2.
Synthesis of intermediate 48-3: the synthesis procedure of example 13 was followed.
Synthesis of the title compound: 48-3(23mg,0.05mmol) was dissolved in 2mL of acetone, and 1mL of concentrated hydrochloric acid was added to react at room temperature. After the reaction is finished, the acetone is evaporated under reduced pressure, the pH value is adjusted to be neutral, solid is separated out, and the mixture is filtered and dried.1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.67(s,1H),7.82–7.66(m,4H),7.16(t,J＝8.7Hz,2H),3.66(p,J＝5.4Hz,1H),3.33(d,J＝6.6Hz,4H),2.44(t,J＝6.1Hz,4H),1.19–1.07(m,4H).13C NMR(101MHz,DMSO-d6)δ205.96,156.50(d,J＝235.6Hz),145.73,142.15,138.96(d,J＝2.1Hz),126.29,125.98,122.94,117.79(d,J＝7.4Hz),115.73(d,J＝22.2Hz),115.21,110.45,45.63,29.58,6.86.
Example 491 Synthesis of- ((5- (1-cyclopropyl) - (3- (3-methyl-4-fluorophenyl) amino) -1H-indazolyl) sulfonyl) -1, 4-diazepin-5-one
Figure BDA0002385652160000341
Synthesis of intermediate 49-2: the synthesis method according to 13-2. The yield in both steps was 44%.
Synthesis of the title compound: the synthesis procedure of example 13 was followed.1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.58(t,J＝1.2Hz,1H),7.75–7.57(m,4H),7.53(dd,J＝6.9,2.8Hz,1H),7.10(t,J＝9.2Hz,1H),3.65(p,J＝5.3Hz,1H),3.24(dt,J＝5.8,3.6Hz,2H),3.16(ddd,J＝9.0,5.0,2.2Hz,4H),2.62–2.53(m,2H),2.25(d,J＝1.8Hz,3H),1.13(d,J＝5.3Hz,4H).
Example synthesis of 501- ((5- (1-cyclopropyl) - (3- (3, 4-difluorophenyl) amino) -1H-indazolyl) sulfonyl) -1, 4-diazepin-5-one: the synthesis of example 49 was followed.1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.58(s,1H),7.97–7.83(m,1H),7.72(s,2H),7.66(t,J＝5.4Hz,1H),7.48–7.32(m,2H),3.67(td,J＝6.8,6.3,3.3Hz,1H),3.24(q,J＝5.7
Hz,2H),3.17(q,J＝7.4,6.2Hz,4H),2.59–2.53(m,2H),1.19–1.09(m,4H).
Figure BDA0002385652160000342
Example 51 synthesis of N- (2, 3-dihydroxypropyl) -N-methyl-5- (1-cyclopropyl-3- ((3-methyl-4-fluorophenyl) amino) -1H-indazole) sulfonamide:
Figure BDA0002385652160000343
synthesis of intermediate 51-2: according to the synthesis method of 3-4. The total yield of the three steps is 49 percent.
Synthesis of the title compound: the synthesis procedure of example 3 was followed.1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.61(d,J＝1.5Hz,1H),7.76–7.67(m,2H),7.67–7.61(m,1H),7.54(dd,J＝6.9,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),4.86(d,J＝5.2Hz,1H),4.62(t,J＝5.6Hz,1H),3.72–3.58(m,2H),3.37–3.34(m,2H),3.08(dd,J＝13.4,4.4Hz,1H),2.85–2.71(m,4H),2.25(d,J＝1.8Hz,3H),1.13(d,J＝5.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.14(d,J＝235.0Hz),145.66,141.96,138.68(d,J＝2.2Hz),127.33,125.85,124.47(d,J＝18.1Hz),122.47,119.16(d,J＝4.2Hz),115.38(d,J＝23.0Hz),115.16(d,J＝7.3Hz),115.09,110.33,70.63,64.27,53.51,36.87,29.55,15.15(d,J＝2.9Hz),6.85.
Example synthesis of 521- (5- (1-cyclopropyl-3- ((3-methyl-4-fluorophenyl) amino) -1H-indazole) sulfonamide) -4-hydroxymethylpiperidin-4-ol:
Figure BDA0002385652160000351
synthesis of intermediate 52-2: the synthesis method according to 13-2. The yield thereof was found to be 11%.
Synthesis of the title compound: the synthesis procedure of example 13 was followed.1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.56(s,1H),7.69(s,2H),7.63(dt,J＝8.3,3.6Hz,1H),7.53(dd,J＝6.9,2.7Hz,1H),7.09(t,J＝9.2Hz,1H),4.62(t,J＝5.7Hz,1H),4.08(s,1H),3.64(dq,J＝6.8,4.3,3.4Hz,1H),3.44(d,J＝11.1Hz,2H),3.13(d,J＝5.7Hz,2H),2.49–2.37(m,2H),2.24(s,3H),1.62(td,J＝13.1,4.6Hz,2H),1.41(d,J＝13.4Hz,2H),1.18–1.07(m,4H).13C NMR(101MHz,DMSO-d6)δ155.16(d,J＝235.1Hz),145.64,142.06,138.69,126.21,125.75,124.46(d,J＝18.1Hz),122.78,119.19(d,J＝4.0Hz),115.49,115.25(d,J＝2.9Hz),115.18,110.18,69.87,68.21,42.36,32.74,29.58,15.12(d,J＝3.0Hz),6.84.
Example 534 synthesis of- (1- (5- (1-cyclopropyl-3- ((4-fluorophenyl) amino) -1H-indazole) sulfonamide) piperidine) alcohol:
Figure BDA0002385652160000352
synthesis of intermediate 53-2: the synthesis of compounds 3-4 was followed.
Synthesis of the title compound: the synthesis procedure of example 3 was followed.1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.58(d,J＝1.2Hz,1H),7.80–7.72(m,2H),7.70(d,J＝1.7Hz,2H),7.24–7.10(m,2H),4.98(d,J＝4.8Hz,1H),3.65(p,J＝5.3Hz,1H),3.55(tq,J＝8.8,4.1Hz,1H),3.46(dd,J＝10.9,4.2Hz,1H),3.30(s,1H),2.31(td,J＝11.1,2.5Hz,1H),2.18–2.07(m,1H),1.81–1.65(m,2H),1.47(qd,J＝11.7,10.6,3.7Hz,1H),1.13(d,J＝5.3Hz,4H),1.11–1.00(m,1H).13C NMR(101MHz,DMSO-d6)δ156.49(d,J＝235.5Hz),145.65,142.08,138.97(d,J＝2.0Hz),126.11,125.95,122.71,117.78(d,J＝7.3Hz),115.74(d,J＝22.1Hz),115.13,110.26,65.50,53.14,46.33,32.43,29.57,22.72,6.86.
Example 54 synthesis of (3- (1- (5- (1-cyclopropyl-3- ((3-methyl-4-fluorophenyl) amino) -1H-indazole) sulfonamide) pyrrolyl) methanol:
Figure BDA0002385652160000353
synthesis of intermediate 54-2: the synthesis method according to 13-2. The yield in both steps was 32%.
Synthesis of the title compound: the synthesis procedure of example 13 was followed.1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.64(d,J＝1.6Hz,1H),7.77(dd,J＝8.9,1.7Hz,1H),7.69(d,J＝8.9Hz,1H),7.64(ddd,J＝8.8,4.3,2.8Hz,1H),7.54(dd,J＝6.9,2.8Hz,1H),7.10(t,J＝9.2Hz,1H),4.62(t,J＝5.2Hz,1H),3.66(p,J＝5.3Hz,1H),3.29–3.06(m,5H),2.93(dd,J＝10.0,6.6Hz,1H),2.25(d,J＝1.8Hz,3H),2.13(dq,J＝14.1,7.5Hz,1H),1.75(dtd,J＝12.5,7.5,5.1Hz,1H),1.45(dq,J＝12.4,7.6Hz,1H),1.13(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.14(d,J＝235.0Hz),145.70,142.05,138.67(d,J＝2.2Hz),126.20,126.13,124.47(d,J＝18.0Hz),122.73,119.15(d,J＝4.1Hz),115.39(d,J＝22.8Hz),115.19,115.11,110.22,62.55,50.87,47.83,29.56,27.55,15.15(d,J＝3.0Hz),6.85.
Example 55 synthesis of (2- (4- (5- (1-cyclopropyl) -3- ((3-methyl-4-fluorophenyl) amino) -1H-indazole) sulfonyl) morpholinyl) methanol:
Figure BDA0002385652160000361
synthesis of intermediate 55-1: the synthesis method according to 13-1. The yield thereof was found to be 32%.
Synthesis of intermediate 55-2: the synthesis method according to 13-2. The yield thereof was found to be 69%.
Synthesis of the title compound: the synthesis procedure of example 13 was followed.1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.60(d,J＝1.5Hz,1H),7.72(d,J＝8.8Hz,1H),7.68(dd,J＝8.9,1.6Hz,1H),7.67–7.61(m,1H),7.55(dd,J＝6.9,2.8Hz,1H),7.10(t,J＝9.2Hz,1H),4.81(t,J＝5.7Hz,1H),3.91–3.84(m,1H),3.66(dq,J＝7.2,4.6Hz,1H),3.62–3.52(m,2H),3.52–3.38(m,3H),3.29(dt,J＝11.6,6.0Hz,1H),2.33–2.21(m,4H),2.02(t,J＝10.7Hz,1H),1.24–1.04(m,4H).13C NMR(101MHz,DMSO-d6)δ155.18(d,J＝235.1Hz),145.72,142.16,138.62(d,J＝2.2Hz),126.16,124.76,124.48(d,J＝18.0Hz),123.16,119.21(d,J＝4.1Hz),115.38(d,J＝23.5Hz),115.22,115.22(d,J＝7.6Hz),110.36,75.90,65.49,62.24,48.32,46.10,29.58,15.13(d,J＝2.9Hz),6.84.
Example 564 synthesis of 1- ((5- (3- (3-methyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine) one: the synthesis procedure of example 48 was followed.1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.65(d,J＝1.6Hz,1H),7.75(dd,J＝8.9,1.7Hz,1H),7.69(d,J＝8.8Hz,1H),7.64(ddd,J＝8.9,4.4,2.9Hz,1H),7.54(dd,J＝6.9,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),3.65(tt,J＝5.7,4.6Hz,1H),3.31(t,J＝6.2Hz,4H),2.44(t,J＝6.2Hz,4H),2.25(d,J＝1.8Hz,3H),1.18–1.07(m,4H).13C NMR(101MHz,DMSO-d6)δ205.94,155.18(d,J＝235.1Hz),145.74,142.13,138.62(d,J＝2.2Hz),126.19,125.94,124.49(d,J＝18.0Hz),122.91,119.17(d,J＝4.0Hz),115.39(d,J＝22.7Hz),115.25,115.20(d,J＝7.3Hz),110.41,45.63,29.58,15.12(d,J＝3.0Hz),6.83.
Figure BDA0002385652160000362
Example 575- (((1S,4S) -2-oxo-5-azabicyclo [2.2.1] hex-5-yl) sulfonyl) -1-cyclopropyl-N- (4-fluoro-3-methylphenyl) -1H-indazol-3-amine
Figure BDA0002385652160000363
Synthesis of intermediate 57-1: according to the synthesis method of 13-1, purification is not carried out.
Synthesis of intermediate 57-2: according to the synthetic method of 13-2, the yield is 70%.
Synthesis of the title compound: according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.67(d,J＝1.6Hz,1H),7.82(dd,J＝8.8,1.7Hz,1H),7.69(d,J＝8.8Hz,1H),7.64(ddd,J＝8.9,4.5,3.0Hz,1H),7.54(dd,J＝6.9,2.8Hz,1H),7.10(t,J＝9.2Hz,1H),4.46(d,J＝3.0Hz,2H),3.72–3.63(m,2H),3.60(dd,J＝7.6,1.8Hz,1H),3.23(d,J＝10.0Hz,1H),3.12(dd,J＝10.0,1.6Hz,1H),2.25(d,J＝1.9Hz,3H),1.62–1.49(m,1H),1.19–1.07(m,4H),0.96(dd,J＝10.1,2.3Hz,1H).
example 58 synthesis of N- (3,4, 5-trifluorophenyl) -3- (1-cyclopropyl-5- (morpholinesulfonyl) -1H-indazolo [3,4-c ] pyridine) amine:
Figure BDA0002385652160000371
synthesis of intermediate 58-1: according to the synthesis method of 1-3, the yield is 97%.
Synthesis of intermediate 58-2: dissolving the intermediate 58-1(92mg,0.3mmol) in 3mL of acetonitrile and acetic acid, adding 1, 3-dibromo-5, 5-dimethylhydantoin (129mg,0.45mmol), reacting at 50 ℃ for 48 hours, after the reaction is finished, evaporating to dryness under reduced pressure, and separating by silica gel column chromatography to obtain 68mg with the yield of 59%.
Synthesis of the title compound: according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),9.13(s,1H),8.73(s,1H),7.61(dt,J＝8.4,3.6Hz,1H),7.52(dd,J＝6.8,2.8Hz,1H),7.11(t,J＝9.2Hz,1H),3.83(tt,J＝7.0,3.8Hz,1H),3.64(t,J＝4.7Hz,4H),3.13(t,J＝4.7Hz,4H),2.26(d,J＝1.8Hz,3H),1.31–1.12(m,4H).13C NMR(101MHz,DMSO-d6)δ155.36(d,J＝235.5Hz),145.64,142.65,138.26(d,J＝2.2Hz),137.71,134.66,124.64(d,J＝18.0Hz),119.27(d,J＝4.2Hz),119.00,117.38,115.66–115.35(m),115.29,66.07,46.85,30.20,15.11(d,J＝2.9Hz),6.95.
example 591- ((5- (3- (3-methyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3, 4-c)]Pyridyl) sulfonyl) piperidin-4-ol synthesis: starting from intermediate 10-7, the preparation of example 13The preparation method comprises the steps of (1) preparing,1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),9.12(s,1H),8.71(s,1H),7.61(dt,J＝8.3,3.6Hz,1H),7.51(dd,J＝6.8,2.8Hz,1H),7.11(t,J＝9.2Hz,1H),4.70(d,J＝3.9Hz,1H),3.82(dq,J＝7.1,3.5Hz,1H),3.55(tt,J＝8.1,4.6Hz,1H),3.48–3.37(m,2H),2.94(ddd,J＝12.2,8.9,3.4Hz,2H),2.38–2.16(m,3H),1.83–1.68(m,2H),1.42(dtd,J＝12.6,8.6,3.7Hz,2H),1.28–1.13(m,4H).13C NMR(101MHz,DMSO-d6)δ155.34(d,J＝235.5Hz),145.59,143.45,138.29(d,J＝2.3Hz),137.64,134.47,124.62(d,J＝18.2Hz),119.26(d,J＝4.3Hz),119.05,116.87,115.59,115.36,115.30(d,J＝7.2Hz),64.79,44.18,33.77,30.19,15.11(d,J＝3.0Hz),6.94.
Figure BDA0002385652160000372
example 601- ((5- (3- (3, 4-difluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3, 4-c)]Pyridyl) sulfonyl) piperidin-4-ol synthesis: the intermediate 10-7 was used as a starting material, according to the synthesis method of example 13,1H NMR(400MHz,DMSO)δ9.73(s,1H),9.15(s,1H),8.68(s,1H),7.92–7.76(m,1H),7.40(dd,J＝16.9,7.9Hz,2H),4.69(d,J＝3.9Hz,1H),3.92–3.77(m,1H),3.55(dd,J＝7.4,3.7Hz,1H),3.49–3.36(m,2H),2.95(t,J＝9.0Hz,2H),1.84–1.66(m,2H),1.52–1.32(m,2H),1.31–1.12(m,4H).13C NMR(101MHz,DMSO-d6)δ149.72(dd,J＝242.1,13.2Hz),145.07,143.71,143.66(dd,J＝237.6,12.8Hz),139.23(dd,J＝9.3,2.2Hz),137.58,134.69,118.87,118.06(d,J＝18.0Hz),116.66,112.71(dd,J＝5.2,2.7Hz),105.14(d,J＝22.0Hz),64.78,44.17,33.77,30.25,6.95.
Figure BDA0002385652160000373
synthesis of examples 61-62:
Figure BDA0002385652160000381
synthesis of intermediate 61-1: the synthesis method according to 13-1 was carried out, with a yield of 69%.
Synthesis of intermediate 61-2: the synthesis method according to 13-2.
Example 61 synthesis of methyl (1- (5- (3- (4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) pyrrolidine-3-carboxylate: the synthesis procedure of example 13 was followed, with a yield of 71%.1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.66(s,1H),7.83–7.72(m,3H),7.70(d,J＝8.8Hz,1H),7.17(t,J＝8.7Hz,2H),3.66(p,J＝5.2Hz,1H),3.45–3.29(m,2H),3.30–3.13(m,2H),3.04(p,J＝7.3Hz,1H),1.98(dq,J＝13.8,7.2Hz,1H),1.88(dq,J＝13.6,7.1Hz,1H),1.13(d,J＝5.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ173.12,156.49(d,J＝235.8Hz),145.72,142.14,138.97(d,J＝2.0Hz),126.14,125.97,122.89,117.76(d,J＝7.4Hz),115.75(d,J＝22.1Hz),115.14,110.32,52.28,50.12,47.84,42.26,29.57,28.26,6.86.
Example 62 synthesis of (1- (5- (3- (4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) pyrrolidine-3-carboxylic acid: 30mg (0.065mmol) of compound 61 was dissolved in 1mL of THF and 1mL of water, and 12mg (0.3mmol) of lithium hydroxide monohydrate was added to react at room temperature. After completion, THF was distilled off under reduced pressure, the pH was adjusted to 2 with 1N hydrochloric acid, filtered and dried.1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),9.37(s,1H),8.66(s,1H),7.77(dt,J＝8.9,5.7Hz,3H),7.69(d,J＝8.9Hz,1H),7.17(t,J＝8.8Hz,2H),3.65(p,J＝5.3Hz,1H),3.43–3.28(m,2H),3.28–3.12(m,2H),2.94(p,J＝7.3Hz,1H),1.97(dd,J＝13.0,7.1Hz,1H),1.88(td,J＝14.6,12.8,7.9Hz,1H),1.14(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ174.26,156.48(d,J＝235.7Hz),145.71,142.14,138.99(d,J＝2.1Hz),126.16,126.04,122.86,117.77(d,J＝7.5Hz),115.74(d,J＝22.0Hz),115.13,110.30,50.21,47.89,42.52,29.57,28.37,6.86.
Example 631-Synthesis of cyclopropyl-5- (((2R,6S) -2, 6-dimethylmorpholine) sulfonyl) -N- (4-fluoro-3-methylphenyl) -1H-indazol-3-amine:
Figure BDA0002385652160000382
synthesis of intermediate 63-2: according to the synthesis method of 13-2, the yield is 70%.
Synthesis of the title compound: the synthesis procedure of example 13 was followed.1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.59(s,1H),7.83–7.59(m,3H),7.55(d,J＝6.8Hz,1H),7.10(t,J＝9.2Hz,1H),3.78–3.58(m,3H),3.53(d,J＝11.2Hz,2H),2.26(s,3H),1.86(t,J＝10.8Hz,2H),1.33–0.86(m,10H).13C NMR(101MHz,DMSO-d6)δ155.17(d,J＝235.1Hz),145.73,142.14,138.61(d,J＝2.3Hz),126.18,124.91,124.48(d,J＝18.0Hz),123.03,119.22(d,J＝4.0Hz),115.37(d,J＝23.3Hz),115.21,115.18,110.35,71.11,51.09,29.57,18.96,15.13(d,J＝3.2Hz),6.84.
Example 64 synthesis of (4- (1- (5- (1-cyclopropyl) -3- ((3-methyl-4-fluorophenyl) amino) -1H-indazole) sulfonyl) piperidine) methanol:
Figure BDA0002385652160000383
synthesis of intermediate 64-2: according to the synthesis method of 3-4, the yield of two steps is 76%.
Synthesis of the title compound: the synthesis procedure of example 3 was followed.1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.57(d,J＝1.4Hz,1H),7.84–7.70(m,3H),7.68(d,J＝1.2Hz,2H),7.16(t,J＝8.9Hz,2H),4.49(t,J＝5.1Hz,1H),3.75–3.58(m,3H),3.27–3.10(m,2H),2.17(td,J＝11.7,2.4Hz,2H),1.70(dd,J＝12.9,3.3Hz,2H),1.20–1.07(m,6H).13C NMR(101MHz,DMSO-d6)δ156.48(d,J＝235.9Hz),145.66,142.07,138.99(d,J＝2.2Hz),126.11(d,J＝8.7Hz),122.75,117.77(d,J＝7.3Hz),115.84,115.62,115.14,110.21,65.67,46.39,37.66,29.57,28.31,6.86.
Example 651-Synthesis of cyclopropyl-5- ((1, 4-oxazepan-4-yl) sulfonyl) -N- (4-fluoro-3-methylphenyl) -1H-indazol-3-amine:
Figure BDA0002385652160000391
synthesis of intermediate 65-2: according to the synthesis method of 13-2, the yield of two steps is 30%.
Synthesis of the title compound: according to the synthesis method of the embodiment 13,1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.64(d,J＝1.7Hz,1H),7.74(dd,J＝8.9,1.7Hz,1H),7.70–7.59(m,2H),7.55(dd,J＝6.9,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),3.64(dt,J＝13.0,5.2Hz,5H),3.37–3.27(m,4H),2.25(d,J＝1.9Hz,3H),1.79(p,J＝5.7Hz,2H),1.12(d,J＝4.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.16(d,J＝235.0Hz),145.69,141.95,138.68(d,J＝2.3Hz),128.91,125.45,124.47(d,J＝18.1Hz),122.16,119.16(d,J＝4.0Hz),115.36(d,J＝23.0Hz),115.17(d,J＝7.3Hz),115.09,110.43,69.89,69.09,50.97,47.00,30.49,29.56,15.11(d,J＝3.0Hz),6.81.
example 66 synthesis of N- (3, 4-difluorophenyl) -3- (1-cyclopropyl-5- (morpholinosulfonyl) -1H-indazole) amine: the intermediate 44-2 was used as a starting material, according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),8.57(s,1H),7.89(dd,J＝13.8,7.1Hz,1H),7.72(q,J＝8.9Hz,2H),7.45–7.33(m,2H),3.66(dt,J＝15.6,5.0Hz,5H),2.87(t,J＝4.5Hz,4H),1.15(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ149.71(dd,J＝241.7,12.9Hz),145.22,143.48(dd,J＝237.1,12.9Hz),142.11,139.58(dd,J＝9.6,2.2Hz),126.32,125.06,123.03,117.97(d,J＝17.8Hz),115.00,112.62(dd,J＝5.6,2.9Hz),110.53,105.06(d,J＝22.1Hz),65.74,46.40,29.64,6.86.
Figure BDA0002385652160000392
example 67 synthesis of N- (3, 4-difluorophenyl) -3- (1-cyclopropyl-5- (morpholinosulfonyl) -1H-indazole) amine: the intermediate 44-2 was used as a starting material, according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.58(d,J＝1.5Hz,1H),8.18(dd,J＝6.3,2.8Hz,1H),8.01(dt,J＝8.9,3.6Hz,1H),7.77(d,J＝8.9Hz,1H),7.72(dd,J＝8.8,1.7Hz,1H),7.49(t,J＝9.8Hz,1H),3.73(p,J＝5.3Hz,1H),3.65(dd,J＝5.8,3.6Hz,4H),2.97–2.80(m,4H),1.15(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ152.61(dd,J＝244.9,2.6Hz),145.09,142.09,139.16(d,J＝2.3Hz),126.33,125.16,123.28(q,J＝271.8Hz),123.00,121.75(d,J＝7.7Hz),118.07(d,J＝21.5Hz),116.89(qd，J＝31.8，13.1Hz)，115.01，113.81(q，J＝5.0Hz)，110.50，65.74，46.40，29.66，6.70.
Figure BDA0002385652160000393
example 68 synthesis of N- (2-hydroxyethyl) -5- (1-cyclopropyl-3- ((3-methyl-4-fluorophenyl) amino) -1H-indazole) sulfonamide: the intermediate 14-2 was used as a starting material, and the synthesis method of example 3 was followed.
Figure BDA0002385652160000401
Example 69 synthesis of N- (3,4, 5-trifluorophenyl) -3- (1-cyclopropyl-5- ((1- (4-fluoropiperidinyl)) sulfonyl) -1H-indazole) amine:
Figure BDA0002385652160000402
synthesis of intermediate 69-2: according to the synthesis method of 13-2, the total yield of the two steps is 67%.
Synthesis of the title compound: according to the synthesis method of the embodiment 13,
example 70 synthesis of N-sec-butyl-5- (1-cyclopropyl-3- ((3-methyl-4-fluorophenyl) amino) -1H-indazole) sulfonamide: the intermediate 13-2 was used as a raw material, and according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.60(d,J＝1.6Hz,1H),7.77(dd,J＝8.9,1.7Hz,1H),7.68(d,J＝8.9Hz,1H),7.62(ddd,J＝8.8,4.4,2.9Hz,1H),7.52(dd,J＝6.9,2.8Hz,1H),7.39(d,J＝7.8Hz,1H),7.07(t,J＝9.2Hz,1H),3.63(p,J＝5.3Hz,1H),3.02(hept,J＝6.6Hz,1H),2.23(d,J＝1.9Hz,3H),1.30(p,J＝7.2Hz,2H),1.11(d,J＝5.3Hz,4H),0.85(d,J＝6.6Hz,3H),0.70(t,J＝7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ155.09(d,J＝234.9Hz),145.62,141.75,138.83(d,J＝2.2Hz),132.54,125.42,124.40(d,J＝18.0Hz),121.46,119.09(d,J＝4.0Hz),115.33(d,J＝23.0Hz),115.12(d,J＝7.3Hz),114.55,110.42,51.06,30.03,29.56,21.08,15.13(d,J＝3.0Hz),10.57,6.81.
Figure BDA0002385652160000403
example 71 synthesis of N- (3-tetrahydrofuryl) -5- (1-cyclopropyl-3- ((3-methyl-4-fluorophenyl) amino) -1H-indazole) sulfonamide: the intermediate 46-2 was used as a starting material, according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.63(d,J＝1.6Hz,1H),7.87–7.75(m,2H),7.71(d,J＝8.9Hz,1H),7.63(dt,J＝8.4,3.5Hz,1H),7.54(dd,J＝6.9,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),3.73–3.52(m,5H),3.37(dd,J＝8.4,4.0Hz,1H),1.96–1.79(m,1H),1.72–1.54(m,1H),1.13(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.12(d,J＝235.1Hz),145.66,141.89,138.78(d,J＝2.2Hz),131.25,125.35,124.43(d,J＝18.0Hz),121.99,119.12(d,J＝4.2Hz),115.34(d,J＝22.9Hz),115.16(d,J＝7.1Hz),114.70,110.61,72.50,66.59,53.56,32.60,29.57,15.13(d,J＝2.9Hz),6.83.
Figure BDA0002385652160000404
example 72 synthesis of N- (3-tetrahydrofuryl) -5- (1-cyclopropyl-3- ((3-trifluoromethyl-4-fluorophenyl) amino) -1H-indazole) sulfonamide: the intermediate 46-2 was used as a starting material, according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.62(d,J＝1.6Hz,1H),8.19(dd,J＝6.3,2.8Hz,1H),8.00(dt,J＝8.9,3.5Hz,1H),7.85(d,J＝6.1Hz,1H),7.82(dd,J＝8.9,1.7Hz,1H),7.76(d,J＝8.9Hz,1H),7.48(t,J＝9.8Hz,1H),3.77–3.51(m,5H),3.37(dd,J＝8.5,4.1Hz,1H),1.87(dq,J＝12.6,7.3Hz,1H),1.69–1.52(m,1H),1.14(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ154.25–150.53(m),144.99,141.82,139.30(d,J＝2.2Hz),131.69,125.53,123.29(q,J＝272.0Hz),121.76,121.68,118.06(d,J＝21.3Hz),116.70(td,J＝31.8,13.0Hz),114.45,113.74(q,J＝5.0Hz),110.85,72.49,66.59,53.57,32.60,29.66,6.71.
Figure BDA0002385652160000411
example 73 Synthesis of N- (3-oxetanyl) -5- (1-cyclopropyl-3- ((3-trifluoromethyl-4-fluorophenyl) amino) -1H-indazole) sulfonamide:
Figure BDA0002385652160000412
synthesis of intermediate 73-2: the synthesis method is as follows 13-2.
Synthesis of the title compound: according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.60(d,J＝1.6Hz,1H),8.41(d,J＝8.0Hz,1H),7.75(dd,J＝8.9,1.7Hz,1H),7.69(d,J＝8.9Hz,1H),7.66–7.58(m,1H),7.54(dd,J＝6.9,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),4.50(t,J＝6.6Hz,2H),4.35(h,J＝7.0Hz,1H),4.26(t,J＝6.2Hz,2H),3.64(q,J＝5.2Hz,1H),2.25(d,J＝1.8Hz,3H),1.12(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.14(d,J＝235.1Hz),145.69,141.93,138.75(d,J＝2.2Hz),131.03,125.11,124.44(d,J＝18.0Hz),121.79,119.15(d,J＝4.1Hz),115.35(d,J＝23.1Hz),115.18(d,J＝7.4Hz),114.82,110.60,77.52,47.53,29.57,15.12(d,J＝3.0Hz),6.82.
example 74 synthesis of N- (3-methyl-4-fluorophenyl) -3- (1-cyclopropyl-5- ((1-piperidinyl) sulfonyl) -1H-indazole) amine: the intermediate 19-2 was used as a raw material, and according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.57(s,1H),7.69(s,2H),7.64(dt,J＝8.4,3.6Hz,1H),7.54(dd,J＝6.9,2.7Hz,1H),7.09(t,J＝9.2Hz,1H),3.70–3.61(m,1H),2.88(t,J＝5.3Hz,4H),2.25(d,J＝1.8Hz,3H),1.56(t,J＝5.8Hz,4H),1.34(qd,J＝6.8,4.3,3.1Hz,2H),1.13(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.15(d,J＝235.0Hz),145.68,142.05,138.67(d,J＝2.1Hz),124.46(d,J＝18.2Hz),122.77,119.16(d,J＝4.0Hz),115.37(d,J＝23.0Hz),115.19,115.18(d,J＝7.3Hz),110.14,47.11,29.56,25.15,23.28,15.12(d,J＝3.0Hz),6.83.
Figure BDA0002385652160000413
example synthesis of N, N-dimethyl-5- (1-cyclopropyl-3- ((3-methyl-4-fluorophenyl) amino) -1H-indazole) sulfonamide: the intermediate 15-2 was used as a starting material, according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.60(s,1H),7.75–7.67(m,2H),7.68–7.59(m,1H),7.54(dd,J＝7.0,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),3.65(p,J＝5.3Hz,1H),2.61(s,6H),2.25(d,J＝1.9Hz,3H),1.13(d,J＝5.3Hz,4H).
Figure BDA0002385652160000421
example 76 starting from intermediate 57-2, the procedure of example 13 was followed,1H NMR(400MHz,DMSO)δ9.59(s,1H),8.64(s,1H),7.97–7.81(m,2H),7.74(d,J＝8.9Hz,1H),7.46–7.31(m,2H),4.47(s,2H),3.76–3.63(m,2H),3.61(d,J＝7.5Hz,1H),3.23(d,J＝10.0Hz,1H),3.12(d,J＝9.9Hz,1H),1.57(d,J＝9.8Hz,1H),1.15(d,J＝6.3Hz,4H),0.97(d,J＝10.0Hz,1H).13C NMR(101MHz,DMSO-d6)δ149.72(dd,J＝241.8,13.0Hz),145.25,143.48(dd,J＝237.1,12.8Hz),142.00,139.58(dd,J＝9.5,2.2Hz),128.27,126.02,122.56,117.94(d,J＝17.6Hz),114.90,112.60(dd,J＝5.6,3.0Hz),110.72,105.05(d,J＝22.1Hz),76.10,73.62，60.31，56.24，35.37，29.65，6.83.
Figure BDA0002385652160000422
synthesis of examples 77-78:
Figure BDA0002385652160000423
synthesis of intermediate 77-2: according to the synthesis method of 13-2, the total yield of two steps is 66%.
Example 77 synthesis of methyl (1- (5- (3- (3-methyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidine-4-carboxylate: according to the synthesis method of the embodiment 13,1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.56(d,J＝1.2Hz,1H),7.68(d,J＝1.1Hz,2H),7.62(ddd,J＝8.9,4.4,2.9Hz,1H),7.53(dd,J＝6.9,2.8Hz,1H),7.08(t,J＝9.2Hz,1H),3.65(tt,J＝5.7,4.5Hz,1H),3.56(s,5H),2.36(tt,J＝11.7,3.3Hz,3H),2.24(d,J＝1.8Hz,3H),1.91(dt,J＝13.6,3.5Hz,2H),1.58(qd,J＝11.4,3.9Hz,2H),1.17–1.07(m,4H).13C NMR(101MHz,DMSO-d6)δ174.50,155.17(d,J＝235.1Hz),145.69,142.09,138.64(d,J＝2.2Hz),126.12,125.77,124.47(d,J＝18.0Hz),122.84,119.17(d,J＝4.1Hz),115.38(d,J＝23.0Hz),115.23,115.15,110.25,51.99,45.65,39.15,29.58,27.62,15.12(d,J＝3.0Hz),6.83.
synthesis of intermediate 78-1: compound 77(340mg,0.7mmol) was dissolved in 5mL of tetrahydrofuran and 5mL of water, sodium hydroxide (280mg,7mmol) was added, heating and refluxing were performed, after completion of the reaction, the tetrahydrofuran was distilled off under reduced pressure, the pH was adjusted to 5 with 1N hydrochloric acid, filtered, and dried.
Example 78 synthesis of N-butyl-4- (1- (5- (3- (3-methyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolyl) sulfonyl) piperidinecarboxamide: intermediate 78-1(47mg,0.1mmol) was dissolved in 1mL of DMF, EDCI (38mg,0.2mmol) and HOSu (23mg,0.2mmol) were added, and the reaction was allowed to proceed at room temperature for 12 hours. After N-butylamine (0.4mL,0.4mmol) was added to the reaction mixture and reacted at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine in this order, dried, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography.1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),8.57(s,1H),7.70(s,2H),7.63(dt,J＝6.7,4.5Hz,2H),7.54(dd,J＝6.9,2.8Hz,1H),7.10(t,J＝9.2Hz,1H),3.66(p,J＝5.3Hz,1H),3.59(dt,J＝11.8,4.0Hz,2H),2.98(q,J＝6.6Hz,2H),2.35–2.20(m,5H),1.79–1.69(m,2H),1.67–1.51(m,2H),1.39–1.26(m,2H),1.21(dq,J＝14.1,7.1Hz,2H),1.13(d,J＝5.3Hz,4H),0.82(t,J＝7.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ173.67,155.17(d,J＝235.1Hz),145.70,142.07,138.66(d,J＝2.4Hz),126.11,125.85,124.46(d,J＝18.0Hz),122.82,119.18(d,J＝4.0Hz),115.36(d,J＝23.4Hz),115.20,115.16,110.16,45.90,40.82,38.45,31.66,29.57,28.26,19.94,15.11(d,J＝3.0Hz),14.06,6.82.
Example 791 Synthesis of- ((5- (3- (3,4, 5-trifluorophenyl) amino) - (1-ethyl) -1H-indazolyl) sulfonyl) piperidin-4-ol
Figure BDA0002385652160000431
Synthesis of intermediate 79-1: 5-bromoindazole (591mg,3mmol) was dissolved in 10mL DMF, ethyl iodide (936mg,6mmol) and potassium carbonate (1.24g,9mmol) were added in that order, reacted at 40 ℃ for 12 hours, evaporated to dryness under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 8/1) to give 125mg, 19% yield.1H NMR(400MHz,Chloroform-d)δ7.94(d,J＝1.1Hz,1H),7.88(d,J＝1.8Hz,1H),7.46(dd,J＝8.9,1.8Hz,1H),7.31(d,J＝8.9Hz,1H),4.43(q,J＝7.3Hz,2H),1.52(t,J＝7.3Hz,3H).
Synthesis of intermediate 79-2: the synthesis method is as follows 3-2.
Synthesis of intermediate 79-4: according to the synthesis method of 3-4, the total yield of the three steps is 79%.
Synthesis of the title compound: according to the synthesis method of the example 3,1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.52(s,1H),7.77(d,J＝8.9Hz,1H),7.69(dd,J＝9.0,1.7Hz,1H),7.59(dd,J＝11.1,6.2Hz,2H),4.65(d,J＝3.8Hz,1H),4.40(q,J＝7.1Hz,2H),3.57–3.46(m,1H),3.16(t,J＝8.5Hz,2H),2.73(t,J＝9.6Hz,2H),1.82–1.67(m,2H),1.52–1.34(m,5H).
example synthesis of 801- ((5- (3- (4-fluorophenyl) amino) - (1-ethyl) -1H-indazolyl) sulfonyl) piperidin-4-ol: the intermediate 79-4 is used as a raw material, according to the synthesis method of the embodiment 3,1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.59(d,J＝1.6Hz,1H),7.81–7.73(m,2H),7.72–7.62(m,2H),7.16(t,J＝8.9Hz,2H),4.66(d,J＝3.9Hz,1H),4.36(q,J＝7.1Hz,2H),3.52(tt,J＝7.8,3.9Hz,1H),3.18(ddd,J＝11.1,7.0,3.7Hz,2H),2.73(ddd,J＝11.8,8.6,3.4Hz,2H),1.76(ddt,J＝14.0,7.3,3.6Hz,2H),1.52–1.36(m,5H).13C NMR(101MHz,DMSO-d6)δ156.44(d,J＝235.7Hz),145.96,140.47,139.10(d,J＝2.2Hz),125.86,125.29,122.85,117.69(d,J＝7.3Hz),115.72(d,J＝22.0Hz),114.43,109.83,64.30,43.75,43.33,33.40,15.09.
Figure BDA0002385652160000432
example synthesis of 811- ((5- (3- (4-fluorophenyl) amino) - (1-isopropyl) -1H-indazolyl) sulfonyl) piperidin-4-ol:
Figure BDA0002385652160000441
synthesis of intermediate 81-1: 5-bromoindazole (296mg,1.5mmol) was dissolved in 10mL of DMF, and 2-iodoisopropane (510mg,3mmol) and DBU (456mg,3mmol) were sequentially added thereto, reacted at room temperature for 48 hours, evaporated to dryness under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) to obtain 160mg, yield 45%.
Synthesis of intermediate 81-2: the synthesis method is as follows 3-2.
Synthesis of intermediate 81-4: according to the synthesis method of 3-4, the total yield of the three steps is 68%.
Synthesis of the title compound: the synthesis procedure of example 3 was followed.1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.58(d,J＝1.6Hz,1H),7.82–7.74(m,2H),7.72(d,J＝9.0Hz,1H),7.64(dd,J＝8.9,1.7Hz,1H),7.17(t,J＝8.9Hz,2H),4.92(p,J＝6.5Hz,1H),4.66(d,J＝3.9Hz,1H),3.52(tt,J＝7.6,3.7Hz,1H),3.17(ddd,J＝11.1,7.0,3.8Hz,2H),2.73(ddd,J＝11.7,8.5,3.4Hz,2H),1.77(ddt,J＝13.7,7.1,3.2Hz,2H),1.54–1.41(m,8H).13C NMR(101MHz,DMSO-d6)δ156.38(d,J＝235.4Hz),145.74,139.96,139.20(d,J＝1.9Hz),125.70,125.21,122.84,117.57(d,J＝7.4Hz),115.74(d,J＝22.2Hz),114.36,109.82,64.27,49.62,43.75,33.39,22.26.
Example synthesis of 821- ((5- (3- (4-fluorophenyl) amino) - (1- (3-oxetanyl)) -1H-indazolyl) sulfonyl) piperidin-4-ol: the intermediate 12-6 is used as a raw material, according to the synthesis method of the embodiment 3,1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.61(s,1H),7.84(dd,J＝8.9,4.8Hz,2H),7.75(d,J＝8.9Hz,1H),7.69(d,J＝9.0Hz,1H),7.21(t,J＝8.7Hz,2H),6.04(p,J＝7.2Hz,1H),5.12(t,J＝6.4Hz,2H),4.97(t,J＝7.0Hz,2H),4.63(d,J＝3.8Hz,1H),3.50(dt,J＝8.2,3.9Hz,1H),3.16(dt,J＝11.2,4.6Hz,2H),2.72(ddd,J＝12.0,8.9,3.3Hz,2H),1.83–1.67(m,2H),1.44(dtd,J＝12.5,8.4,3.7Hz,2H).13C NMR(101MHz,DMSO-d6)δ156.62(d,J＝236.2Hz),146.57,141.06,138.91,126.23,126.09,122.81,117.93(d,J＝7.3Hz),115.85(d,J＝22.1Hz),114.98,110.11,76.91,64.24,51.42,43.72,33.35.
Figure BDA0002385652160000442
example 831 Synthesis of- ((5- (3- (4-fluorophenyl) amino) - (1-cyclobutyl) -1H-indazolyl) sulfonyl) piperidin-4-ol:
Figure BDA0002385652160000451
synthesis of intermediate 83-1: 5-bromoindazole (296mg,1.5mmol) was dissolved in 10mL of DMF, bromocyclobutane (405mg,3mmol) and NaH (180mg (60%), 4.5mmol) were sequentially added, the mixture was heated to 50 ℃ to react for 12 hours, the reaction mixture was evaporated to dryness under reduced pressure, and the product was separated by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) to obtain 170mg with a yield of 45%.
Synthesis of intermediate 83-4: according to the synthesis method of 3-4.
Synthesis of the title compound: according to the synthesis method of the example 3,1H NMR(400MHz,DMSO-d6)δ9.42(d,J＝2.6Hz,1H),8.57(s,1H),7.81(dt,J＝8.0,3.6Hz,2H),7.72(dd,J＝9.0,2.6Hz,1H),7.64(d,J＝8.5Hz,1H),7.19(td,J＝9.0,2.7Hz,2H),5.22(p,J＝9.0Hz,1H),4.66(t,J＝3.3Hz,1H),3.49(tt,J＝7.4,3.8Hz,1H),3.24–3.08(m,2H),2.69(q,J＝9.5,8.6Hz,4H),2.47–2.34(m,2H),1.95–1.80(m,2H),1.75(ddd,J＝13.6,7.0,3.5Hz,2H),1.45(ddt,J＝16.7,11.9,5.6Hz,2H).13C NMR(101MHz,DMSO-d6)δ156.47(d,J＝235.6Hz),145.98,140.24,139.11(d,J＝1.9Hz),125.88,125.55,122.81,117.69(d,J＝7.4Hz),115.79(d,J＝22.1Hz),114.61,109.95,64.31,51.71,43.76,33.40,29.85,14.94.
example 84 synthesis of N-sec-butyl-5- (1-cyclopropyl-3- ((3, 4-difluorophenyl) amino) -1H-indazole) sulfonamide: the intermediate 13-2 was synthesized as described in example 13,1H NMR(400MHz,DMSO-d6)δ9.58(d,J＝9.6Hz,1H),8.62(d,J＝8.9Hz,1H),7.89(ddt,J＝13.8,7.3,4.2Hz,1H),7.80(d,J＝9.0Hz,1H),7.70(d,J＝9.1Hz,1H),7.51–7.27(m,3H),3.64(p,J＝5.3Hz,1H),3.02(p,J＝6.7Hz,1H),1.29(p,J＝7.2Hz,2H),1.12(d,J＝5.3Hz,4H),0.85(d,J＝6.5Hz,3H),0.69(t,J＝7.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ149.71(dd,J＝241.6,13.1Hz),145.11,143.38(dd,J＝237.0,12.8Hz),141.68,139.76(dd,J＝9.8,2.1Hz),132.86,125.57,121.29,117.89(d,J＝17.7Hz),114.32,112.52(dd,J＝5.4,2.8Hz),110.61,104.95(d,J＝22.2Hz),51.08,30.02,29.59,21.07,10.55,6.84.
Figure BDA0002385652160000452
example 85 synthesis of N- (2- (1,1, 1-trifluoropropyl)) -5- (1-cyclopropyl-3- ((3, 4-difluorophenyl) amino) -1H-indazole) sulfonamide:
Figure BDA0002385652160000453
synthesis of intermediate 85-1: 140mg (0.5mmol) of the substrate was dissolved in 5ml of acetonitrile, 100. mu.L of water and acetic acid were sequentially added, the mixture was cooled to-15 ℃ and 1, 3-dichloro-5, 5-dimethylhydantoin (197mg,1.0mmol) was added in portions, and the reaction was carried out for 1 hour. The reaction solution was transferred to a separatory funnel, diluted with ethyl acetate and washed with saturated brine, and the ethyl acetate layer was separated and dried over anhydrous sodium sulfate for 30 min. Filtering, and evaporating ethyl acetate under reduced pressure. Adding acetonitrile to dissolve, adding 1,1, 1-trifluoro-2-propylamine hydrochloride (112mg,0.75mmol) and DIPEA (0.25ml,1.5mmol), reacting at 80 ℃ for 12 hours, adding dichloromethane to dilute, washing with 1N hydrochloric acid, drying with anhydrous sodium sulfate, filtering, decompressing and evaporating to dryness without purification.
Synthesis of intermediate 85-2: according to the synthesis method of 13-2, the total yield of the two steps is 35%.
Synthesis of the title compound: according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.65(d,J＝1.7Hz,1H),8.42(d,J＝8.0Hz,1H),7.94–7.80(m,2H),7.75(d,J＝8.9Hz,1H),7.47–7.27(m,2H),3.96(dt,J＝14.9,7.2Hz,1H),3.77–3.60(m,1H),1.22–1.08(m,4H),0.98(d,J＝7.0Hz,3H).
example 86 synthesis of N- (2- (1,1, 1-trifluoropropyl)) -5- (1-cyclopropyl-3- ((3-methyl-4-fluorophenyl) amino) -1H-indazole) sulfonamide: the intermediate 85-2 was used as a raw material, and according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.67(d,J＝1.7Hz,1H),8.39(d,J＝8.7Hz,1H),7.82(dd,J＝8.9,1.8Hz,1H),7.72(d,J＝8.9Hz,1H),7.63(dt,J＝8.5,3.5Hz,1H),7.54(dd,J＝6.9,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),3.94(h,J＝7.4Hz,1H),3.66(p,J＝5.3Hz,1H),2.25(d,J＝1.8Hz,3H),1.13(d,J＝5.3Hz,4H),0.98(d,J＝6.9Hz,3H).13C NMR(101MHz,DMSO-d6)δ155.12(d,J＝235.0Hz),145.73,141.86,138.72(d,J＝2.3Hz),131.36,130.36–121.91(m),125.21,124.46(d,J＝18.0Hz),121.87,119.09(d,J＝4.1Hz),115.38(d,J＝22.8Hz),115.14(d,J＝7.3Hz),114.59,110.70,50.74(q,J＝31.1Hz),29.58,15.15(d,J＝2.9Hz),14.26,6.86.
Figure BDA0002385652160000461
example synthesis of 875- (1-cyclopropyl-3- ((3-methyl-4-fluorophenyl) amino) -1H-indazole) sulfonamide:
Figure BDA0002385652160000462
synthesis of intermediate 87-1: 140mg (0.5mmol) of the substrate was dissolved in 5ml of acetonitrile, 100. mu.L of water and acetic acid were sequentially added, the mixture was cooled to-15 ℃ and 1, 3-dichloro-5, 5-dimethylhydantoin (197mg,1.0mmol) was added in portions, and the reaction was carried out for 1 hour. The reaction solution was transferred to a separatory funnel, diluted with ethyl acetate and washed with saturated brine, and the ethyl acetate layer was separated and dried over anhydrous sodium sulfate for 30 min. Filtering, and evaporating ethyl acetate under reduced pressure. Dissolving with dichloromethane, adding 7M ammonia methanol solution (1mL), reacting at room temperature, diluting with dichloromethane, washing with 1N hydrochloric acid, drying with anhydrous sodium sulfate, filtering, evaporating under reduced pressure, and purifying.
Synthesis of intermediate 87-2: according to the synthesis method of 13-2, the total yield of the two steps is 28%.
Synthesis of intermediate 87-3: intermediate 87-2(40mg,0.125mmol) was dissolved in 2mL of dichloromethane, DMAP (15mg,0.125mmol) and Boc were added2O (51. mu.L, 0.23mmol), reacted at room temperature, monitored by TLC, and after completion, diluted with dichloromethane, washed with aqueous solution of pH 3, saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to give 45mg, yield 87%.
Synthesis of intermediate 87-4: the synthesis of example 13 was followed.
Synthesis of the title compound: 30mg of intermediate 87-4 was dissolved in 1mL of dichloromethane and trifluoroacetic acid and stirred at room temperature. After completion of the reaction, it was evaporated to dryness under reduced pressure, water was added, the pH was adjusted to 8, filtered, the solid was collected and separated by thin layer chromatography (dichloromethane/methanol 20/1).1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.62(d,J＝1.6Hz,1H),7.84(dd,J＝8.9,1.7Hz,1H),7.68(d,J＝8.9Hz,1H),7.63(dt,J＝8.3,3.5Hz,1H),7.54(dd,J＝7.0,2.7Hz,1H),7.25(s,2H),7.08(t,J＝9.2Hz,1H),3.68–3.59(m,1H),2.24(d,J＝1.8Hz,3H),1.17–1.07(m,4H).
Example 88N- (3-trifluoromethyl-4-fluorophenyl) -3- (1-cyclopropyl-5- (morpholinesulfonyl) -1H-indazolo [3, 4-c)]Pyridine) synthesis of amine: the intermediate 58-2 was used as a raw material, and according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),9.19(d,J＝1.1Hz,1H),8.70(d,J＝1.1Hz,1H),8.15(dd,J＝6.2,2.9Hz,1H),7.96(dt,J＝9.0,3.6Hz,1H),7.51(t,J＝9.8Hz,1H),3.94–3.83(m,1H),3.64(dd,J＝5.9,3.5Hz,4H),3.25–3.00(m,4H),1.21(ddt,J＝12.7,9.3,5.0Hz,4H).13C NMR(101MHz,DMSO-d6)δ152.79(d,J＝245.9Hz),144.96,142.94,138.82(d,J＝2.5Hz),137.64,134.95,128.87–123.58(m),121.92(d,J＝8.5Hz),118.79,118.26(d,J＝21.3Hz),117.13,117.25–116.64(m),113.83(d,J＝5.2Hz),66.06,46.84,30.31,6.85.
Figure BDA0002385652160000471
example 89N- (3, 4-difluorophenyl) -3- (1-cyclopropyl-5- (morpholinesulfonyl) -1H-indazolo [3, 4-c)]Pyridine) synthesis of amine: the intermediate 58-2 was used as a raw material, and according to the synthesis method of example 13,1H NMR(400MHz,DMSO)δ9.75(s,1H),9.17(s,1H),8.71(s,1H),7.85(dd,J＝12.8,6.6Hz,1H),7.41(dd,J＝17.8,7.7Hz,2H),3.85(d,J＝3.7Hz,1H),3.64(s,4H),3.13(s,4H),1.34–1.08(m,4H).13C NMR(101MHz,DMSO-d6)δ149.71(dd,J＝242.0,13.3Hz),145.11,143.66(dd,J＝237.7,12.8Hz),142.84,139.19(dd,J＝9.5,2.1Hz),137.63,134.88,118.81,118.09(d,J＝17.8Hz),117.21,112.72(dd,J＝5.7,3.0Hz),105.14(d,J＝22.2Hz),66.06,46.84,30.26,6.98.
Figure BDA0002385652160000472
example 90 synthesis of N- (3-methyl-4-fluorophenyl) -3- (5- (morpholinesulfonyl) -1H-indazole) amine:
Figure BDA0002385652160000473
synthesis of intermediate 90-2: taking 0.5mmol of the intermediate 1-2 as a raw material, and carrying out the next reaction according to the synthesis method of the intermediate 1-4 without purification.
Synthesis of intermediate 90-3: dissolving the product in 10mL ethyl acetate, adding 3, 4-2H-dihydropyran (1.5mmol) and p-toluenesulfonic acid monohydrate (19mg,0.1mmol), refluxing for 24 hours, washing with water after the reaction is finished, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating by silica gel column chromatography (petroleum ether/ethyl acetate 5/2) to obtain 150mg, wherein the total yield of the three-step reaction is 70%.
Synthesis of the title compound: according to the synthesis method of the embodiment 1,1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),9.25(s,1H),8.61(s,1H),7.78–7.40(m,4H),7.07(t,J＝9.3Hz,1H),3.65(s,5H),2.88(s,4H),2.25(s,3H).13C NMR(101MHz,DMSO-d6)δ155.04(d,J＝234.5Hz),146.88,141.92,138.95,125.90,124.40(d,J＝17.8Hz),124.19,123.09,119.00(d,J＝3.9Hz),115.36(d,J＝22.2Hz),115.18,114.14,110.73,65.76,46.45,15.09(d,J＝3.1Hz).
example synthesis of 911- (5- (3- ((3-methyl-4-fluorophenyl) amino) -1H-indazolyl) sulfonyl) piperidin-4-ol: taking the intermediates 1-5 as raw materials, according to the synthesis method of the embodiment 1,1H NMR(400MHz,DMSO-d6)δ12.49(s,1H),9.22(s,1H),8.59(d,J＝1.6Hz,1H),7.64(ddd,J＝8.8,5.9,2.2Hz,2H),7.60–7.52(m,2H),7.07(t,J＝9.2Hz,1H),4.65(d,J＝3.8Hz,1H),3.51(dq,J＝7.8,3.8Hz,1H),3.17(ddd,J＝11.1,6.9,3.7Hz,2H),2.71(ddd,J＝11.8,8.5,3.4Hz,2H),2.25(d,J＝1.8Hz,3H),1.76(ddt,J＝13.9,6.9,3.6Hz,2H),1.45(dtd,J＝12.2,8.2,3.7Hz,2H).13C NMR(101MHz,DMSO-d6)δ155.01(d,J＝234.7Hz),146.80,141.81,138.97(d,J＝2.1Hz),125.85,125.37,124.38(d,J＝17.8Hz),122.63,118.97(d,J＝4.0Hz),115.34(d,J＝23.1Hz),115.15,114.09,110.60,64.32,43.75,33.39,15.09(d,J＝3.0Hz).
Figure BDA0002385652160000481
example 92 Synthesis of N- (3-methyl-4-fluorophenyl) -3- (5- (morpholinosulfonyl) -1- (2-fluoroethyl) -1H-indazole) amine:
Figure BDA0002385652160000482
synthesis of intermediate 92-1: intermediate 1-2(240mg,1mmol) was dissolved in 10mL DMF,2-iodo-1-fluoroethane (2mmol), K was added in sequence2CO3(276mg,2mmol), and reacted at 80 ℃ for 12 hours. The reaction mixture was filtered, concentrated under reduced pressure, and separated by silica gel thin layer chromatography (petroleum ether/ethyl acetate 2/1) to give 186mg of a white solid with a yield of 66%.
Synthesis of intermediate 92-2: according to the synthesis method of the intermediate 13-2, the yield is 73%.
Synthesis of the title compound: according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.63(s,1H),7.74(d,J＝8.9Hz,1H),7.66(dd,J＝14.4,6.3Hz,2H),7.59(dd,J＝6.9,2.7Hz,1H),7.09(t,J＝9.2Hz,1H),4.86(dt,J＝47.3,4.7Hz,2H),4.68(dt,J＝27.7,4.8Hz,2H),3.64(d,J＝4.6Hz,4H),2.89(d,J＝4.6Hz,4H),2.26(s,3H).13C NMR(101MHz,DMSO-d6)δ155.23(d,J＝235.1Hz),146.52,142.00,138.61(d,J＝2.2Hz),126.13,124.53(d,J＝18.1Hz),124.49,123.20,119.25(d,J＝4.2Hz),115.41(d,J＝13.0Hz),115.26(d,J＝2.5Hz),114.75,110.24,82.65(d,J＝167.7Hz),65.75,49.04(d,J＝19.9Hz),46.44,15.10(d,J＝2.9Hz).
example 93 synthesis of N- (3-methyl-4-fluorophenyl) -3- (5- (morpholinosulfonyl) -1- (2,2, 2-trifluoroethyl) -1H-indazole) amine:
Figure BDA0002385652160000491
synthesis of intermediate 93-1: 90-2(69mg,0.2mmol) was dissolved in 2mL DMF and 2-iodo-1, 1, 1-trifluoroethane (0.4mmol), K, was added sequentially2CO3(52mg,0.44mmol), and reacted at 80 ℃ for 12 hours. The reaction mixture was filtered, concentrated under reduced pressure, and separated by silica gel thin layer chromatography (petroleum ether/ethyl acetate 2/1) to give 39mg of a white solid with a yield of 45%.
Synthesis of the title compound: according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),8.68(s,1H),7.89(d,J＝8.8Hz,1H),7.78(d,J＝9.0Hz,1H),7.65(dt,J＝8.2,3.6Hz,1H),7.59(d,J＝6.9Hz,1H),7.11(t,J＝9.2Hz,1H),5.39(q,J＝9.0Hz,2H),3.66(t,J＝4.6Hz,4H),2.90(t,J＝4.6Hz,4H),2.26(s,3H).13C NMR(101MHz,DMSO-d6)δ155.40(d,J＝235.5Hz),147.17,142.58,138.31(d,J＝2.2Hz),126.90,129.54–120.93(m),125.74,124.57(d,J＝18.0Hz),123.15,119.46(d,J＝4.0Hz),115.60,115.52,115.37(d,J＝16.7Hz),110.44,65.75,49.24(q,J＝32.8Hz),46.43,15.09(d,J＝3.0Hz).
example 94 synthesis of N- (3-methyl-4-fluorophenyl) -3- (5- (morpholinosulfonyl) -1- (2, 2-difluoroethyl) -1H-indazole) amine:
Figure BDA0002385652160000492
synthesis of intermediate 94-1: according to the synthesis method of 93-1, the yield is 55%.
Method of synthesis of the title compound: according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.64(s,1H),7.80(d,J＝8.9Hz,1H),7.71(d,J＝9.0Hz,1H),7.68–7.61(m,1H),7.58(d,J＝6.6Hz,1H),7.09(t,J＝9.2Hz,1H),6.48(t,J＝54.9Hz,1H),4.86(t,J＝14.8Hz,2H),3.64(t,J＝4.4Hz,4H),2.87(s,4H),2.25(s,3H).
example 95 synthesis of N- (3-methyl-4-fluorophenyl) -3- (5- (morpholinosulfonyl) -1- (difluoromethyl) -1H-indazole) amine:
Figure BDA0002385652160000493
synthesis of intermediate 95-1: the intermediate 1-2(240mg,1mmol) was dissolved in 5mL of acetonitrile, diethyl bromofluoromethylphosphate (534mg,2mmol) and potassium fluoride (115mg,2mmol) were added, and the mixture was reacted at 40 ℃ for 48 hours, after which it was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to obtain 245mg with a yield of 84%.
Synthesis of intermediate 95-2: according to the synthesis method of the intermediates 1 to 3, the yield is 80 percent.
Synthesis of intermediate 95-3: dissolving intermediate 95-2(90mg,0.31mmol) in 4mL acetonitrile and 2mL trifluoroacetic acid, adding NBS (83mg,0.465mmol), reacting at 80 ℃, monitoring by LC-MS, concentrating under reduced pressure after the reaction is finished, adding ethyl acetate for dissolving, washing with saturated sodium bicarbonate solution and saturated saline water in sequence, and separating by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to obtain 61mg, wherein the yield is 54%.
Synthesis of the title compound: according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.76(s,1H),8.23(t,J＝58.7Hz,1H),7.68(d,J＝1.4Hz,1H),7.29(dd,J＝7.0,2.5Hz,1H),7.25–7.12(m,2H),6.87(d,J＝1.4Hz,1H),3.76–3.53(m,4H),2.92(t,J＝4.7Hz,4H),2.23(d,J＝1.9Hz,3H).13C NMR(101MHz,DMSO-d6)δ157.09(d,J＝238.8Hz),144.07,137.37(d,J＝2.8Hz),136.81,131.30,127.44,125.31(d,J＝18.2Hz),124.93(d,J＝4.8Hz),121.20,121.10(d,J＝7.8Hz),116.00(d,J＝23.1Hz),113.17,111.18(t,J＝252.6Hz),100.66,65.92,46.36,14.83(d,J＝2.9Hz).
example 961 synthesis of 5- (3- ((3-methyl-4-fluorophenyl) amino) -1- (2, 2-difluoroethyl) -1H-indazolyl) sulfonyl) piperidin-4-ol: synthesis according to example 21H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.61(d,J＝1.6Hz,1H),7.78(d,J＝8.9Hz,1H),7.72(dd,J＝8.9,1.6Hz,1H),7.64(dt,J＝8.7,3.6Hz,1H),7.58(dd,J＝7.0,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),6.48(tt,J＝54.9,3.7Hz,1H),4.85(td,J＝15.1,3.7Hz,2H),4.66(d,J＝3.8Hz,1H),3.52(dd,J＝7.5,3.9Hz,1H),3.18(td,J＝7.5,4.3Hz,2H),2.82–2.66(m,2H),2.26(d,J＝1.7Hz,3H),1.85–1.70(m,2H),1.46(qd,J＝8.9,8.4,4.0Hz,2H).
Figure BDA0002385652160000501
Example 971 synthesis of 5- (3- (3,4, 5-trifluorophenylol) -1-cyclopropyl-1H-indazolyl) sulfonyl) piperidin-4-ol: intermediate 3-4(44mg,0.1mmol), 3,4, 5-trifluorophenol (29mg,0.2mmol), cuprous iodide (1.9mg,0.01mmol), N-dimethylglycine (2mg,0.02mmol) and cesium carbonate (65mg,0.2mmol) were mixed, 2mL of 1, 4-dioxane was added, the gas in the reaction flask was replaced with argon, and the reaction was carried out overnight at 120 ℃. The reaction mixture was filtered, concentrated under reduced pressure, dissolved in ethanol, and reacted at 60 ℃ with sodium hydroxide (20mg,0.5 mmol). After the reaction is finished, adding ethyl acetate for dilution, and adding waterWashed, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated on a silica gel thin layer chromatography plate (dichloromethane/methanol 20/1).1H NMR(400MHz,DMSO-d6)δ7.91(dd,J＝5.3,3.6Hz,2H),7.79(dd,J＝9.1,1.5Hz,1H),7.44(dd,J＝9.3,6.0Hz,2H),4.66(d,J＝3.8Hz,1H),3.75(p,J＝5.4Hz,1H),3.51(dq,J＝7.7,3.9Hz,1H),3.13(ddd,J＝11.3,7.1,3.7Hz,2H),2.73(ddd,J＝11.7,8.4,3.4Hz,2H),1.74(ddt,J＝11.3,7.1,3.5Hz,2H),1.44(ddd,J＝12.7,8.1,3.8Hz,2H),1.14(d,J＝5.3Hz,4H).
Figure BDA0002385652160000502
Example 981- (5- (3- (3-chloro-4-fluorophenol) -1-cyclopropyl-1H-indazolyl) sulfonyl) piperidin-4-ol synthesis: the intermediate 3-4 is used as a raw material, according to the synthesis method of the embodiment 97,1H NMR(400MHz,DMSO-d6)δ7.88(d,J＝8.9Hz,1H),7.83(d,J＝1.5Hz,1H),7.77(dd,J＝8.9,1.7Hz,1H),7.64(dd,J＝6.2,3.0Hz,1H),7.49(t,J＝9.0Hz,1H),7.36(dt,J＝9.1,3.5Hz,1H),4.65(s,1H),3.72(tt,J＝6.8,4.1Hz,1H),3.49(dq,J＝7.7,4.0Hz,1H),3.11(ddd,J＝11.2,7.1,3.7Hz,2H),2.69(ddd,J＝11.7,8.3,3.4Hz,2H),1.73(ddt,J＝13.9,7.2,3.5Hz,2H),1.42(dtd,J＝12.2,8.1,3.7Hz,2H),1.11(dq,J＝7.7,2.5Hz,4H).13C NMR(101MHz,DMSO-d6)δ154.54(d,J＝243.2Hz),153.04,152.17(d,J＝2.9Hz),143.23,128.42,126.33,121.27,120.97,120.55(d,J＝19.6Hz),119.72(d,J＝7.3Hz),118.10(d,J＝23.1Hz),112.40,111.87,64.19,43.64,33.35,29.97,6.91.
Figure BDA0002385652160000503
example 991 synthesis of- ((1-cyclopropyl-3- ((3- (difluoromethyl) -4-fluorophenyl) amino) -1H-indazol-5-yl) sulfonyl) piperidin-4-ol: the synthesis procedure of example 3 was followed, with a yield of 61%,1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.57(s,1H),7.96(td,J＝8.3,3.7Hz,2H),7.72(s,1H),7.37(d,J＝10.3Hz,1H),7.23(t,1H),4.67(d,J＝4.0Hz,1H),3.69(q,J＝5.3Hz,1H),3.51(dt,J＝7.9,3.8Hz,1H),3.16(p,J＝4.7Hz,2H),2.72(ddd,J＝11.8,8.3,3.8Hz,2H),1.86–1.61(m,2H),1.45(dp,J＝12.5,4.2Hz,2H),1.14(d,J＝5.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ153.7(dt,J＝242.3,5.6Hz),145.2,142.0,139.2(d,J＝2.2Hz),126.3,126.2,122.6,121.6(td,J＝22.7,13.5Hz),120.1(d,J＝7.3Hz),117.0(d,J＝21.1Hz),115.1,114.0(dt,J＝6.4,3.5Hz),112.3(td,J＝236.0,3.8Hz),110.3,64.2,43.7,33.4,29.6,6.8.
Figure BDA0002385652160000511
example 100N- (3-difluoromethyl-4-fluorophenyl) -3- (1-cyclopropyl-5- (morpholinesulfonyl) -1H-indazolo [3, 4-c)]Pyridine) synthesis of amine: according to the synthesis method of example 13,1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),9.17(s,1H),8.71(s,1H),7.95(d,J＝5.7Hz,1H),7.93–7.84(m,1H),7.38(d,J＝8.2Hz,1H),7.36–7.09(m,1H),3.86(q,J＝4.7,3.5Hz,1H),3.63(t,J＝4.4Hz,4H),3.13(t,J＝4.5Hz,4H),1.34–1.09(m,4H).13C NMR(101MHz,DMSO-d6)δ152.6(td),145.2,142.8,138.8(d,J＝2.2Hz),137.7,134.8,121.7(td,J＝22.6,13.2Hz),120.3(d,J＝7.5Hz),118.9,117.2,117.0,114.1(d,J＝4.3Hz),112.2(td,J＝236.1,3.9Hz),66.1,46.8,30.3,6.9.
Figure BDA0002385652160000512
example 1011- ((5- (3- (3-difluoromethyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3, 4-c)]Pyridyl) sulfonyl) piperidin-4-ol was synthesized according to the synthesis method of example 3,1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),9.15(d,J＝1.1Hz,1H),8.68(d,J＝1.1Hz,1H),7.94(dd,J＝6.2,2.8Hz,1H),7.89(dt,J＝8.0,3.7Hz,1H),7.42–7.35(m,1H),7.34(s,1H),4.68(d,J＝3.9Hz,1H),3.92–3.81(m,1H),3.54(tt,J＝8.0,4.0Hz,1H),3.46–3.36(m,2H),2.93(ddd,J＝12.3,8.9,3.4Hz,2H),1.74(dp,J＝13.3,3.4Hz,2H),1.41(dtd,J＝12.4,8.1,3.5Hz,2H),1.28–1.16(m,4H).13C NMR(101MHz,DMSO-d6)δ153.8(d,J＝243.0Hz),145.2,143.6,138.8(d,J＝2.3Hz),137.6,134.7,122.3–121.2(m),120.3(d,J＝7.5Hz),118.9,117.2(d,J＝21.3Hz),116.7,114.1(d,J＝5.6Hz),114.9–109.5(m),64.8,44.2,33.8,30.3,6.9.
Figure BDA0002385652160000513
example 102 Synthesis of N- (3-difluoromethyl-4-fluorophenyl) -3- (5- (morpholinosulfonyl) -1-cyclopropyl-1H-indazole) amine the procedure of example 13 was followed, giving a yield of 58%,1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),8.58(d,J＝1.7Hz,1H),8.04–7.88(m,2H),7.81–7.66(m,2H),7.40–7.09(m,2H),3.71(p,J＝5.4Hz,1H),3.68–3.58(m,4H),2.91–2.82(m,4H),1.20–1.08(m,4H).13C NMR(101MHz,DMSO-d6)δ153.7(dt,J＝242.3,5.7Hz),145.3,142.1,139.2(d,J＝2.3Hz),126.3,125.0,123.1,121.6(td,J＝22.7,13.5Hz),120.2(d,J＝7.6Hz),117.0(d,J＝21.3Hz),115.1,114.0(t,J＝5.7Hz),112.2(td,J＝235.9,3.8Hz),110.5,65.75,46.4,29.7,6.8.
Figure BDA0002385652160000521
example 1031- ((5- (3- (3-methyl-4-fluorophenyl) amino) -1-methyl-1H-indazolo [3, 4-c)]Pyridyl) sulfonyl) piperidin-4-ol was synthesized according to the synthesis method of example 3,1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.57(s,1H),7.65(s,2H),7.60(dd,J＝8.6,4.1Hz,1H),7.56(dd,J＝6.9,2.7Hz,1H),7.08(t,J＝9.2Hz,1H),3.96(s,3H),3.49(dq,J＝7.7,3.9Hz,1H),3.16(q,J＝6.8,5.6Hz,2H),2.70(ddd,J＝11.8,8.5,3.4Hz,2H),2.24(d,J＝1.8Hz,3H),1.74(ddd,J＝10.8,6.8,3.3Hz,2H),1.44(dtd,J＝12.3,8.3,3.5Hz,2H).
Figure BDA0002385652160000522
example 104N- (3-methyl-4-fluorophenyl) -3- (5-, (Synthesis of morpholinesulfonyl) -1-cyclopropyl-6-fluoro-1H-indazole) amine the procedure of example 13 was followed, giving a yield of 56%,1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.66(d,J＝6.7Hz,1H),7.61(ddd,J＝8.9,4.4,2.9Hz,1H),7.55(d,J＝11.3Hz,1H),7.52(dd,J＝6.8,2.8Hz,1H),7.08(t,J＝9.2Hz,1H),3.77–3.55(m,5H),3.03(dd,J＝5.7,3.5Hz,4H),2.24(d,J＝1.8Hz,3H),1.11(td,J＝5.2,4.6,3.1Hz,4H).13C NMR(101MHz,DMSO-d6)δ157.7(d,J＝250.6Hz),154.8(d,J＝235.3Hz),145.5,142.2(d,J＝12.5Hz),138.0(d,J＝2.2Hz),125.9(d,J＝3.2Hz),124.0(d,J＝18.1Hz),118.8(d,J＝4.0Hz),115.1(d,J＝11.7Hz),114.9(d,J＝6.2Hz),114.8(d,J＝2.1Hz),111.6,96.8(d,J＝27.7Hz),65.6,45.6,29.2,14.6(d,J＝3.0Hz),6.3.
Figure BDA0002385652160000523
example 105N, N-dimethylglycine-4- (1- ((5- (3- (3-methyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3, 4-c)]Pyridyl) sulfonyl) piperidine) ester synthesis: 44mg (0.1mmol) of compound 59 was dissolved in 2ml of dichloromethane, and DCC (0.3mmol,62mg), DMAP (0.12mmol,15mg) and N, N-dimethylglycine (0.3mmol,30mg) were added to the solution. The reaction was carried out at 40 ℃ for 3 hours, and after completion of the reaction, the reaction mixture was cooled to room temperature. Filtering the reaction solution, evaporating the filtrate under reduced pressure, and separating by C18 column chromatography to obtain yellow solid with yield of 90%.1H NMR(400MHz,Chloroform-d)δ8.43(dd,J＝4.0,1.1Hz,1H),7.45(dt,J＝8.9,3.6Hz,1H),7.39(dd,J＝6.6,3.0Hz,1H),6.98(t,J＝9.0Hz,1H),6.95(s,1H),4.86(tt,J＝7.9,3.8Hz,1H),3.63(tq,J＝11.6,3.5Hz,3H),3.18(ddd,J＝12.4,8.6,3.5Hz,2H),3.12(s,2H),2.37–2.25(m,9H),1.97–1.86(m,2H),1.77–1.68(m,2H),1.33–1.21(m,4H).13C NMR(101MHz,Chloroform-d)δ169.75,156.32(d,J＝238.4Hz),145.63,143.61,137.82,136.93(d,J＝2.5Hz),133.72,125.19(d,J＝18.4Hz),119.96(d,J＝4.4Hz),119.41,116.19,115.69(d,J＝7.4Hz),115.15(d,J＝23.4Hz),68.95,60.21,45.17,44.07,30.23,29.79,14.89(d,J＝3.3Hz),6.95.HRMS(ESI)calculated for C26H31O4N5F3S[M+H]+531.2184,found 531.2169.
Figure BDA0002385652160000531
Example 106L-valine-4- (1- ((5- (3- (3-methyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3, 4-c)]Pyridyl) sulfonyl) piperidine) ester trifluoroacetate synthesis: 44mg (0.1mmol) of Compound 5 was dissolved in 2ml of dichloromethane, and DCC (0.3mmol,62mg), DMAP (0.12mmol,15mg) and N-Boc-L-valine (0.3mmol,65mg) were added to the solution. The reaction was carried out at 40 ℃ for 3 hours, and after completion of the reaction, the reaction mixture was cooled to room temperature. Filtering the reaction solution, evaporating the filtrate under reduced pressure, and separating by silica gel column chromatography to obtain yellow solid. Dissolving in 2mL dichloromethane, adding 1mL trifluoroacetic acid, after the reaction is finished, evaporating the solvent under reduced pressure, adding ether, precipitating yellow solid, filtering, washing the solid with ether, and drying under reduced pressure to obtain yellow solid with the yield of 83%.1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),9.10(d,J＝1.1Hz,1H),8.73(d,J＝1.1Hz,1H),8.30(s,3H),7.60(dt,J＝8.7,3.6Hz,1H),7.50(dd,J＝6.9,2.8Hz,1H),7.11(t,J＝9.2Hz,1H),4.93(tt,J＝7.3,3.6Hz,1H),3.92–3.86(m,1H),3.82(dq,J＝7.0,4.2,3.5Hz,1H),3.37(ddt,J＝14.0,6.9,3.8Hz,2H),3.28–3.12(m,2H),2.25(d,J＝1.8Hz,3H),2.14–1.98(m,1H),1.91(s,2H),1.75–1.57(m,2H),1.29–1.13(m,4H),0.89(t,J＝6.4Hz,6H).13C NMR(101MHz,DMSO-d6)δ168.50,158.82(q,J＝32.5Hz),155.35(d,J＝235.7Hz),145.67,143.33,138.28,137.65,134.45,124.63(d,J＝18.1Hz),119.27(d,J＝4.1Hz),119.06,117.25(d,J＝297.5Hz),117.03,115.47(d,J＝23.4Hz),115.28,70.68,57.70,43.55,40.42,30.18,29.93,29.86,29.80,18.65,17.81,15.09(d,J＝3.0Hz),6.93.
Figure BDA0002385652160000532
Example 107L-alanine-4- (1- ((5- (3- (3-methyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3, 4-c)]Pyridyl) sulfonyl) piperidine) ester trifluoroacetate synthesis: the same as in example 106.1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),9.11(s,1H),8.73(s,1H),8.28(s,3H),7.60(dt,J＝7.7,3.4Hz,1H),7.50(dd,J＝6.9,2.8Hz,1H),7.11(t,J＝9.2Hz,1H),4.88(tt,J＝6.8,3.4Hz,1H),4.06(q,J＝7.0Hz,1H),3.82(tt,J＝6.9,4.0Hz,1H),3.53–3.25(m,2H),3.28–3.08(m,2H),2.25(s,3H),1.89(td,J＝8.8,4.6Hz,2H),1.67(p,J＝7.5,6.7Hz,2H),1.32(d,J＝7.2Hz,3H),1.27–1.13(m,4H).13C NMR(101MHz,DMSO-d6)δ169.65,158.76(q,J＝31.6Hz),155.35(d,J＝235.6Hz),145.66,143.47,138.29,137.66,134.52,124.63(d,J＝18.1Hz),119.27(d,J＝4.1Hz),119.05,116.95,115.48(d,J＝23.6Hz),115.28,70.55,48.37,43.49,30.19,29.87,29.82,16.12,15.10(d,J＝3.0Hz),6.94.
Figure BDA0002385652160000533
Example 108 Glycine-4- (1- ((5- (3- (3-methyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3, 4-c)]Pyridyl) sulfonyl) piperidine) ester trifluoroacetate synthesis: the same as in example 106.1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),9.12(d,J＝1.1Hz,1H),8.73(d,J＝1.1Hz,1H),8.17(s,3H),7.61(dt,J＝8.7,3.6Hz,1H),7.51(dd,J＝6.9,2.8Hz,1H),7.12(t,J＝9.2Hz,1H),4.90(td,J＝7.7,3.9Hz,1H),3.84(dq,J＝6.7,3.4,3.0Hz,1H),3.79(s,2H),3.48–3.39(m,2H),3.15(ddd,J＝12.3,8.3,3.7Hz,2H),2.25(d,J＝1.9Hz,3H),1.98–1.85(m,2H),1.65(dtd,J＝12.1,7.7,3.6Hz,2H),1.21(dddd,J＝12.0,9.5,6.7,3.0Hz,4H).
Figure BDA0002385652160000541
Example 109N, N-dimethylglycine-4- (1- ((5- (3- (3-methyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3, 4-c)]Pyridyl) sulfonyl) piperidine) acetate synthesis: compound 105(25mg) was dissolved in methylene chloride, and 1ml of acetic acid was added thereto, followed by stirring and mixing. Evaporating under reduced pressure to remove solvent, adding diethyl ether to precipitate yellow solid, filtering, washing the solid with diethyl ether, drying under reduced pressure to obtain yellow solid, and quantitatively converting.1H NMR(400MHz,DMSO-d6)δ11.93(s,2H),9.44(d,J＝3.2Hz,1H),9.12(d,J＝3.2Hz,1H),8.71(d,J＝3.2Hz,1H),7.60(dd,J＝8.6,4.3Hz,1H),7.55–7.44(m,1H),7.11(td,J＝9.3,3.3Hz,1H),4.78(s,1H),3.82(dq,J＝7.5,3.8Hz,1H),3.21–3.00(m,4H),2.25(s,3H),2.20(d,J＝3.2Hz,6H),1.98–1.78(m,5H),1.60(s,2H),1.19(t,J＝7.6Hz,4H).
Figure BDA0002385652160000542
Example 110N, N-dimethylglycine-4- (1- ((5- (3- (3-methyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3, 4-c)]Pyridyl) sulfonyl) piperidine) ester citrate synthesis: compound 105(530mg,1mmol) was dissolved in ethyl acetate, and citric acid solution (230mg,1.2mmol, in ethyl acetate and methanol) was added dropwise to the solution with stirring. After stirring overnight at room temperature, a yellow solid precipitated, which was filtered, washed with a mixture of ethyl acetate and methanol (10/1), and dried under reduced pressure to give a yellow solid with a yield of 91%.1H NMR(400MHz,DMSO-d6)δ10.99(s,2H),9.43(s,1H),9.12(s,1H),8.71(s,1H),7.60(dd,J＝8.3,4.1Hz,1H),7.50(dd,J＝6.8,2.8Hz,1H),7.11(t,J＝9.2Hz,1H),4.82(dt,J＝8.0,4.4Hz,1H),3.82(tt,J＝6.9,3.8Hz,1H),3.46–3.31(m,4H),3.13(ddd,J＝12.3,8.5,3.6Hz,2H),2.70(d,J＝15.3Hz,2H),2.60(d,J＝15.3Hz,2H),2.34(s,6H)，2.25(s，3H)，1.94–1.82(m，2H)，1.70–1.54(m，2H)，1.24–1.09(m，4H).
Figure BDA0002385652160000543
Example 111N, N-dimethylglycine-4- (1- ((5- (3- (3-methyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3, 4-c)]Pyridyl) sulfonyl) piperidine) ester disulfonate synthesis: dissolving compound 105(26mg,0.05mmol) in ethyl acetate, adding methanesulfonic acid ether solution (0.1mmol,6.5 μ L) dropwise to the solution, separating out orange-red solid, filtering, washing the solid with ether, drying under reduced pressure to obtain orange-red solid, and quantitatively converting.1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.45(s,1H),9.12(s,1H),8.73(s,1H),7.68–7.24(m,3H),7.11(t,J＝9.2Hz,1H),5.01–4.84(m,1H),4.15(d,J＝3.8Hz,2H),3.83(tt,J＝7.0,4.0Hz,1H),3.38(q,J＝7.2,6.8Hz,2H),3.17(t,J＝9.2Hz,2H),2.80(d,J＝3.3Hz,6H),2.35(s,6H),2.25(s,3H),1.92(t,J＝9.9Hz,2H),1.69(s,2H),1.27–1.13(m,4H).
Figure BDA0002385652160000544
Example 112N, N-dimethylglycine-4- (1- ((5- (3- (3-methyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3, 4-c)]Pyridyl) sulfonyl) piperidine) ester hydrochloride synthesis: hydrogen chloride gas was introduced into the ethyl acetate solution of the compound 05 to precipitate an orange-red solid, which was then filtered, washed with ethyl acetate, and dried under reduced pressure to give a yield of 49%.1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),9.59(s,1H),9.12(d,J＝3.3Hz,1H),8.79(d,J＝3.4Hz,1H),7.69–7.58(m,1H),7.58–7.49(m,1H),7.11(td,J＝9.4,3.4Hz,1H),4.93(s,1H),4.15(s,2H),3.90–3.77(m,1H),3.39(t,J＝9.6Hz,2H),3.19(t,J＝9.6Hz,2H),2.79(s,6H),2.25(s,3H),1.93(d,J＝12.8Hz,2H),1.68(d,J＝11.3Hz,2H),1.27–1.13(m,4H).
Figure BDA0002385652160000551
Example 113 NN-dimethylglycine-4- (1- ((5- (3- (3-methyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3, 4-c)]Pyridyl) sulfonyl) piperidine) ester maleate synthesis: the same procedure as in example 110 was repeated, except that the yield was 71%.1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),9.13(s,1H),8.73(s,1H),7.60(dt,J＝8.4,3.6Hz,1H),7.51(dd,J＝6.9,2.9Hz,1H),7.12(t,J＝9.2Hz,1H),6.06(s,2H),4.92(tt,J＝7.7,3.8Hz,1H),4.00(s,2H),3.84(tt,J＝6.9,3.9Hz,1H),3.64–3.23(m,2H),3.17(ddd,J＝12.3,8.2,3.8Hz,2H),2.71(s,6H),2.32–2.18(m,3H),1.93(ddt,J＝11.8,7.6,3.7Hz,2H),1.67(dtd,J＝12.3,7.9,3.8Hz,2H),1.20(t,J＝6.6Hz,4H).
Figure BDA0002385652160000552
Example 114 NN-dimethylglycine-4- (1- ((5- (3- (3-methyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3, 4-c)]Pyridyl) sulfonyl) piperidine) ester trifluoroacetate synthesis: the same as in example 109.1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),9.46(s,1H),9.13(s,1H),8.74(s,1H),7.61(dt,J＝8.7,3.5Hz,1H),7.52(dd,J＝6.9,2.8Hz,1H),7.12(t,J＝9.2Hz,1H),4.94(dq,J＝7.9,4.0Hz,1H),4.12(s,2H),3.84(tt,J＝7.0,3.9Hz,1H),3.45–3.36(m,2H),3.18(ddd,J＝12.1,8.2,3.6Hz,2H),2.79(s,6H),2.26(d,J＝1.8Hz,3H),2.01–1.85(m,2H),1.68(q,J＝9.4Hz,2H),1.26–1.13(m,4H).
Figure BDA0002385652160000553
Example 115N, N-dimethylglycine-4- (1- ((5- (3- (3-difluoromethyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3, 4-c)]Pyridyl) sulfonyl) piperidine) ester synthesis: the same as in example 11, yield 91%.1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),9.16(d,J＝1.2Hz,1H),8.70(d,J＝1.2Hz,1H),7.94(dd,J＝6.2,2.8Hz,1H),7.92–7.84(m,1H),7.40–7.35(m,1H),7.34(t,1H),4.78(tt,J＝7.8,3.7Hz,1H),3.96–3.79(m,1H),3.44–3.34(m,2H),3.18–3.06(m,4H),2.17(s,6H),1.94–1.82(m,2H),1.61(qd,J＝8.2,3.9Hz,2H),1.26–1.16(m,4H).
Figure BDA0002385652160000554
Example 116N, N-dimethylglycine-4- (1- ((5- (3- (3-difluoromethyl-4-fluorophenyl) amino) - (1-cyclopropyl) -1H-indazolo [3, 4-c)]Pyridyl) sulfonyl) piperidine) ester citrate synthesis: the same as in example 110.1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),9.17(s,1H),8.71(s,1H),7.96(dd,J＝6.1,2.8Hz,1H),7.90(dt,J＝7.7,3.6Hz,1H),7.42–7.36(m,1H),7.35(t,1H),4.84(dq,J＝8.1,3.9Hz,1H),3.88(tt,J＝7.0,3.9Hz,1H),3.52–3.28(m,4H),3.15(ddd,J＝12.2,8.4,3.6Hz,2H),2.71(d,J＝15.3Hz,2H),2.61(d,J＝15.3Hz,2H),2.35(s,6H),1.96–1.81(m,2H),1.65(ddd,J＝13.2,8.5,4.1Hz,2H),1.28–1.17(m,4H).
Figure BDA0002385652160000561
Anti-hepatitis B virus activity of compound on HepAD38 cell line
1. Preparation of test Compounds
The cell culture medium used for compound selection (selection medium) consisted of 1% penicillin/streptomycin, 5% FBS and 94% DMEM.
Diluting 100mM stock solution by 100 times with screening medium to prepare 1mM test solution, and then diluting 6 gradients according to the concentration gradient of 5 times or 10 times in turn according to the requirement, wherein the volume of each gradient is not less than 400 mu L, each concentration is 3 auxiliary holes, and each auxiliary hole is 100 mu L culture solution.
2. Cell culture
100μL 1×104HepAD38 cells were inoculated in a 96-well plate, the original culture medium was discarded after 16-20 hours, and 60. mu.L of cell supernatant per well was pipetted into a PCR eight-tube after 6 days of test compound addition and stored at 4 ℃. Wherein the medium is replaced with fresh medium containing the test compound after 3 days of action
3. Extraction of viral DNA
The collected 60. mu.L of cell supernatant was heat-denatured at 95 ℃ for 5 minutes, 10 minutes, 15 minutes and 20 minutes in a PCR instrument, centrifuged at 4000 rpm for 10 minutes, and then stored at 4 ℃.
4. Quantitative determination of viral DNA
(1) Configuration of the standard curve: pZAC1.2HBV plasmid is diluted into 80 ng/muL stock solution by ribozyme-free water, the concentration of the plasmid is equivalent to 1013HBV copy number, 2 muL of the stock solution is added with 18 muL of the ribozyme-free water to prepare 1012HBV copy number solution, 10 muL of the solution is added into 90 muL of the ribozyme-free water to prepare 1011HBV copy number solution, then 8 concentrations (1011 copy number to 104 copy number) are diluted by 10 times of gradient according to the dilution method, and the solution is stored at 4 ℃ for standby and is ready for use.
(2) The configuration of a fluorescent quantitative PCR reaction system: the method for measuring the virus content of cell supernatant adopts a Taqman fluorescent quantitative PCR method, and the primers and the probes are designed as follows: HBV forward primer: 5'-CCAAATGCCCCTATCCTATCA-3', HBV reverse primer: 5'-GAGGCGAGGGAGTTCTTCTTCTA-3', HBV Probe: 5 '-FAM-CGGAAACTACTGTTGTTAGACGACGAGGCAG-TAM-3'. The preparation method of the 20 mu L fluorescence quantitative PCR reaction system comprises the following steps: taqman Mix: 10 μ L, Rox: 0.4 μ L, HBV forward primer (10 nM): 1 μ L, HBV reverse primer (10 nM): 1 μ L, HBV probe: 0.25 μ L, H2O: 5.35 μ L. Adding 18 mu L of reaction system and 2 mu L of processed cell supernatant (template) or plasmid standard substances with different concentrations into each reaction tube, uniformly mixing three auxiliary holes of each sample, covering a cover for centrifugation, putting the prepared system into a fluorescent quantitative PCR instrument, and carrying out amplification detection reaction for 40 cycles at 95 ℃ for 10 minutes, 95 ℃ for 15 seconds and 60 ℃ for 1 minute. After the program is completed, data is collected for analysis.
5. Cytotoxicity assays
Preparing CCK-8 into a culture medium containing 20% of CCK-8 reagent by using a drug screening culture medium, and adding 50 mu L of the culture medium into each well after uniformly mixing. At 37 deg.C, 5% CO2The incubation is carried out in the constant temperature incubator for 20-30 minutes, and then the detection is carried out by an enzyme-labeling instrument. And (3) measuring the absorbance at the wavelength of 450nm, wherein the reference wavelength is 600nm, and the DMSO control group can be read when the OD value is about 1.5, and storing and collecting data. Examples the inhibitory activity against hepatitis B virus and the results of the cytotoxic effect against HepAD38 cells are shown in Table 1. Thus, it can be seen that the EC against hepatitis B virus of the compound of the present invention50Low toxicity to cells.
Table 1: example antiviral activity and cytotoxicity on AD38 cell line.
Figure BDA0002385652160000562
Figure BDA0002385652160000571
EC50Reducing the compound concentration of HBV DNA by 50% in the cell supernatant; CC (challenge collapsar)50The concentration of the compound that inhibits 50% of cell growth.
Stability experiments in human or murine liver microsomes
Test compound solution: DMSO solution at a concentration of 100. mu.M.
Liver microsome solution: phosphate buffer (50mM K)2HPO4pH 7.4) at a concentration of 1.27 mg/mL.
NADPH solution: phosphate buffer (50mM K)2HPO4pH 7.4) at a concentration of 5 mM.
Adding 2.5 mu L of the solution of the compound to be detected into 197.5 mu L of the solution of the liver microsome, uniformly mixing, incubating for 5min at 37 ℃, adding 50 mu L of ADPH solution, starting the reaction, taking out 30 mu L of the solution from the reaction system at 0min, 5min, 15min, 30min and 60min respectively, adding 300 mu L of the internal standard solution, uniformly shaking, centrifuging for 15min at 4000 rpm at 4 ℃, taking 100 mu L of the supernatant, diluting with 100 mu L of distilled water, and detecting by LC/MS/MS.
As can be seen from table 2, example 17 had a half-life greater than 60 minutes in both human and mouse liver microsomes and had better stability, and compounds 101 and 59 also had a half-life greater than 60 minutes in mouse liver microsomes and also had better stability.
TABLE 2 half-life and clearance in human and murine liver microsomes
Figure BDA0002385652160000581
Hepatitis B virus shell assembly and replication
mu.M of Compound 59 or Compound 101 was incubated overnight with 5. mu.M HBV capsid protein in a buffer pH7.4 containing 150mM sodium chloride and 50mM HEPES, and capsid assembly was observed under an electron microscope. As shown in FIG. 1, the number of capsids formed by treating the HBV capsid proteins with compounds 59 and 101 was significantly increased compared to the DMSO control, and the size and shape of the capsids formed were the same as those of the control.
HepAD38 cells and HepG2.2.15 cells were treated with 2. mu.M compound 59 or 101 for 4 days, with medium changes every two days. The content of DNA and RNA was measured by q-PCR and qRT-PCR, and the content of e-antigen and s-antigen was measured by ELISA, and the experimental data are expressed as mean ± standard deviation (n ═ 3). Statistical analysis of experimental results using a two-tailed t-test,. P < 0.05; p < 0.01; p < 0.001. As a result, as shown in FIG. 2, both compound 59 and 101 treatments inhibited replication of hepatitis B virus.
Anti-hepatitis B virus activity of compound in lamivudine drug-resistant cell line HepG2.A64 and multi-drug-resistant cell line HepG2.1403F
The anti-hepatitis B virus activity of compounds 59 and 101 in the lamivudine-resistant cell line HepG2.A64 and the multidrug-resistant cell line HepG2.1403F was investigated with reference to the above method regarding "anti-hepatitis B virus activity of compounds on HepAD38 cell line". As can be seen from table 3, compounds 59 and 101 are able to inhibit nucleic acid drug resistant viral strains, with compounds 59 and 101 having lower cytotoxicity compared to TDF and ETV.
TABLE 3 Activity of Compounds 59 and 101 against Lamivudine-resistant (HepG2.A64) and multidrug-resistant (HepG2.1403F) viral strains
Figure BDA0002385652160000582
Release of amino acid prodrugs in plasma and stability in buffers of different pH
Removing mouse eyeball to collect blood, centrifuging at 13000 rpm for 10min to obtain plasma, collecting 98 μ L plasma, adding 2 μ L DMSO stock solution (50mM) of the compound to be detected, incubating at 37 deg.C, adding 300 μ L acetonitrile into the reaction system at 0min, 5min, 15min, 30min and 60min respectively, quenching, and centrifuging at 10000 rpm for 10 min. Taking the supernatant for HPLC detection. As can be seen from Table 4, N, N-dimethylglycine prodrug 113 (compound 113) is hydrolyzed faster in plasma to release the proto-drug and is stable in pH1-7.4 buffer; valine prodrug 116 (compound 116) is hydrolyzed very slowly in both plasma and buffer; alanine prodrug 106 (compound 106) and glycine prodrug 107 (compound 107) hydrolyzed slightly faster in plasma and had less stability in buffer.
Figure BDA0002385652160000591
TABLE 4 stability of amino acid prodrugs in plasma and solutions of varying pH
Figure BDA0002385652160000592
a within three hours, no hydrolysis product is produced by HPLC; b is not detected.
Solubility of different salts
The solubility of the compound can be increased after the compound is salified, and the citrate 109 (compound 109) and the mesylate 110 (compound 110) have better solubility in a larger pH range.
TABLE 5 solubility of different salts
Figure BDA0002385652160000593
a0.067M phosphate buffer;b0.01M phosphate buffer.
Antiviral activity on hydrodynamic injection HBV mouse model
The administration was started the day after the molding, compounds 59 and 109 were administered by tail vein injection, ETV was administered once a day by gavage, blood was taken on day 1, day 3, day 5 and day 7 of the administration, respectively, and the content of HBV DNA in serum was measured and the results were expressed as mean ± SEM. Mice were sacrificed on day 8 of dosing, and DNA in the liver was extracted and the relative content of HBV DNA was determined with GAPDH as an internal control. ETV: entecavir, positive control. N-9, results were statistically analyzed by two-tailed t-test with P <0.05, P <0.01, P <0.001, and NS were not statistically different. As shown in FIG. 3, the results indicate that compounds 59 and 109 both inhibit replication of hepatitis B virus in vivo.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (8)

1. A compound of formula (I) or a tautomer, a pharmaceutically acceptable salt of a compound of formula (I):
Figure 881359DEST_PATH_IMAGE001
q is N;
G. t is C;
x is C, and X is C,
z, Y is N;
v is N; r1Is selected from C1~6A cycloalkyl group;
R2is absent;
R3and R4Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1~6An alkyl group;
R5selected from aryl groups, said aryl groups being monocyclic carbocyclic ring systems comprising 3 to 7 atoms;
R6selected from hydrogen, C1~6An alkyl group;
l is selected from-S (= O)2-；
W is selected from N;
R7w and R8Forming a ring selected from C1~6Cycloalkyl radical, C1~6A heterocyclic group;
wherein cycloalkyl, heterocyclyl, aryl may optionally be substituted by one or more of fluoro, chloro, bromo, iodo, hydroxy, C1~6Alkyl, halo C1~6Alkyl, -OC (= O) Ra、-OC(=O)RaN(Rb)RcSubstituted, Ra、RbRc is selected from hydrogen and C1~6Alkyl or C1~6An alkylamino group.
2.A compound of claim 1, wherein R is1Is selected from C1~4A cycloalkyl group;
R3and R4Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine;
R5selected from aryl groups, said aryl groups being monocyclic carbocyclic ring systems comprising 3 to 7 atoms, said aryl groups optionally being substituted by one or more fluorine, chlorine, bromine, iodine, haloC1~4Alkyl substituted;
R6selected from hydrogen or C1~3An alkyl group;
w is selected from N;
R7w and R8Forming a ring selected from C3~6Heterocyclyl or C3~6Cycloalkyl, said cycloalkyl or heterocyclyl being optionally substituted by one or more of hydroxy, fluoro, chloro, bromo, iodo, C1~3Alkyl, -OC (= O) Ra、-OC(=O)RaN(Rb)RcSubstituted, Ra、RbRc is selected from hydrogen and C1~4Alkyl or C1~4An alkylamino group.
3. A compound having a structure represented by one of the following or a tautomer, pharmaceutically acceptable salt thereof;
Figure 798500DEST_PATH_IMAGE002
Figure 109395DEST_PATH_IMAGE003
Figure 504605DEST_PATH_IMAGE004
Figure 318977DEST_PATH_IMAGE005
Figure 141439DEST_PATH_IMAGE006
Figure 408473DEST_PATH_IMAGE007
Figure 138531DEST_PATH_IMAGE008
Figure 807410DEST_PATH_IMAGE009
Figure 800774DEST_PATH_IMAGE010
Figure 555103DEST_PATH_IMAGE011
Figure 823273DEST_PATH_IMAGE012
Figure 346659DEST_PATH_IMAGE013
Figure 776503DEST_PATH_IMAGE014
Figure 18128DEST_PATH_IMAGE015
Figure 293252DEST_PATH_IMAGE016
Figure 467881DEST_PATH_IMAGE017
Figure 803048DEST_PATH_IMAGE018
Figure 531969DEST_PATH_IMAGE019
Figure 610784DEST_PATH_IMAGE020
Figure 639920DEST_PATH_IMAGE021
4. a pharmaceutical composition, comprising:
a compound according to any one of claims 1 to 3; and
pharmaceutically acceptable adjuvants, carriers, excipients, vehicles or combinations thereof.
5. The pharmaceutical composition of claim 4, further comprising a therapeutic agent selected from at least one of the following: lamivudine, adefovir, entecavir, telbivudine, tenofovir disoproxil and interferon.
6. Use of a compound according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of an infectious disease, wherein the infectious disease is hepatitis b.
7. A pharmaceutical combination, comprising:
a compound according to any one of claims 1 to 3; and
at least one medicine for treating hepatitis B.
8. The pharmaceutical combination of claim 7, wherein the drug is selected from at least one of the following: lamivudine, adefovir, entecavir, telbivudine, tenofovir disoproxil and interferon.
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CN104797561A (en) * 2012-08-28 2015-07-22 爱尔兰詹森科学公司 Fused bicyclic sulfamoyl derivatives and the use thereof as medicaments for the treatment of hepatitis B
WO2016183266A1 (en) * 2015-05-13 2016-11-17 Enanta Pharmaceuticals, Inc. Ehpatitis b antiviral agents

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WO2016183266A1 (en) * 2015-05-13 2016-11-17 Enanta Pharmaceuticals, Inc. Ehpatitis b antiviral agents

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