CN116635374A - Amide derivatives and use thereof - Google Patents

Amide derivatives and use thereof Download PDF

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CN116635374A
CN116635374A CN202280008454.6A CN202280008454A CN116635374A CN 116635374 A CN116635374 A CN 116635374A CN 202280008454 A CN202280008454 A CN 202280008454A CN 116635374 A CN116635374 A CN 116635374A
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alkyl
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楚洪柱
魏用刚
叶飞
孙毅
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Kangbaida Sichuan Biopharmaceutical Technology Co ltd
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Chengdu Baiyu Pharmaceutical Co Ltd
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    • A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
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    • C07C311/14—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of rings other than six-membered aromatic rings
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    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract

An amide derivative and application thereof in medicine, in particular to an amide derivative of a formula (I) or pharmaceutically acceptable salts thereof or all stereoisomers, tautomers and deuterated compounds thereof, and a pharmaceutical composition containing the compound, wherein the compound or the composition can be used as an NLRP3 inhibitor, and each substituent group in the formula (I) is defined as the specification,

Description

Amide derivatives and use thereof Technical Field
the present application relates to amide derivatives or pharmaceutically acceptable salts thereof or all stereoisomers, tautomers and deuterated forms thereof, pharmaceutical compositions comprising the same and use thereof in the preparation of NLRP3 inhibitors.
Background
The NOD-Like Receptors (NLRs) of the nucleotide binding oligomerization domain (nucleotide-binding oligomerization domain, NOD) are a cytoplasmic located class of pattern recognition Receptors (Pattern Recognition Receptors, PRRs) within cells of mammals that play a very important role in the innate immune response. NLRs are a group of cytoplasmic proteins with signal transduction function, which are widely involved in the inflammatory response of the body. The NLRs family includes NODs, NALPs (NLRPs), CIITA (NLRA) and IPAF (NLRC), where NLRPs and NLRC subfamilies are the major two types of NOD-like receptors (NLRs), and NLRPs can be divided into inflammatory small members of NLRP1, NLRP3, NLRP6, NLRP7 and NLRP 12. NLRP3 inflammatory corpuscles are a polyprotein complex consisting of NLRP3 protein itself, caspase-1 and apoptosis-related plaque-specific-like protein containing CARD (ASC) capable of recognizing a variety of pathogenic microorganisms and stress-related endogenous signaling molecules. Classical NLRP3 inflammatory small body activation is stimulated and activated by two signals together, wherein the first signal activates a TLR4 (Toll like receptor) signal path, promotes nuclear transcription factor kB to enter the nucleus, and induces the generation of precursors such as IL-1 beta, IL-18 and the like. The second signal promotes the formation of the NLRP3/ASC/pro-caspase-1 complex, i.e., when activated, polymerizes with Apoptosis-related spot-like proteins (ASC, apoptisis-Associated Specklike Protein containing a CARD) containing caspase activation and recruitment domains, which in turn interact with cysteine protease caspase-1 to form a complex called an inflammatory body, and the precursor form of caspase (pro-caspase-1) self-cleaves into the activated form, (Wen, H., miao, E.A.) and Ting, J.P.message of NOD-like receptor-associated inflammasome activation 39,432-441 (2013)), cleaves the precursor form of pro-inflammatory cytokines IL-1 beta and IL-18, causing them to be converted into the active forms IL-1 beta and IL-18 and release to the extracellular, recruiting inflammatory cell aggregation, inflammatory response. ASC spot-like proteins can also recruit and activate caspase-8 (caspase-8), cleaving precursor forms of IL-I beta and IL-18 to convert to mature forms and initiate apoptosis. Non-classical NLRP3 inflammatory body activation does not depend on TLR4 signaling pathway activation, it is that caspase-11 directly recognizes intracellular LPS, initiates NLRP3 inflammatory body activation, and promotes activation and release of Gasderm D to mediate cell death. (Lamkanfi, M. & Dixit, v.m. mechanisms and functions of inprimmas.cell 157,1013-1022 (2014)).
Abnormal activation of NLRP3 inflammatory bodies is closely related to the occurrence of genetic CAPS disease Mu Keer-wels syndrome (mWS), familial cold autoinflammatory syndrome, neonatal onset multisystem inflammatory disease, alzheimer's disease, parkinson's disease, nonalcoholic fatty liver, atherosclerosis, asthma, kidney disease, enteritis, tumor, gout, neurodegenerative disease, diabetes, and obesity.
Current drugs for the treatment of NLRP3 related diseases include the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1 beta antibody canakinumab, and the soluble IL-1 receptor trap rilonacept, all of which are biologicals. In recent years, rebecca C col et al report that a novel sulfonylurea small molecule NLRP3 inhibitor compound MCC950 inhibits NLRP3 inflammatory body activity in nanomolar scale, and other small molecule compounds have been shown to inhibit NLRP3 inflammatory bodies, such as: glibenclamide, parthenolide, 3, 4-Methylenedioxy-beta-nitrostyrene (He, Y.et al 3, 4-methylendioxy-beta-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasiome.J.biol. Chem.289,1142-1150 (2014)) and dimethyl sulfoxide (DMSO). However, the above drugs or small molecules have problems of low specificity or poor activity. Therefore, there is a need to develop a new generation of small molecule NLRP3 inhibitors with high specificity and high activity for the treatment of autoimmune diseases caused by NLRP3 mutations.
Disclosure of Invention
The object of the present application is to provide novel amide derivatives or pharmaceutically acceptable salts thereof or all stereoisomers, tautomers and deuterides thereof, pharmaceutical compositions thereof and use thereof for the preparation of NLRP3 inhibitors.
One or more embodiments of the present application provide compounds of formula (I) or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers and deuterated forms thereof:
wherein the method comprises the steps of
Q is a 5-membered heteroaryl group comprising 1 or 2 heteroatoms selected from N, O and S, said 5-membered heteroaryl group optionally being substituted with 1 cyano or C 1-6 Alkyl substitution;
l is- (CR) a R b )-；
R a Is C 1-6 An alkyl group;
R b is C 1-6 Alkyl, and the C 1-6 Alkyl is substituted with 1 OH;
w is O or NH;
y is- (CR) d R e )-；
R d 、R e Each independently is H or C 1-6 An alkyl group;
r and R 1 Each independently is H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 10 membered carbocyclyl or 4 to 10 membered heterocyclyl, said 4 to 10 membered heterocyclyl comprising 1, 2 or 3 heteroatoms selected from N, O and S, said C 1-6 Alkyl, 3-to 10-membered carbocyclyl or 4-to 10-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 groups selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Substituents for alkoxy, 3-to 6-membered carbocyclyl, and 5-to 6-membered heterocyclyl;
Alternatively, R and R 1 Together with the atoms to which they are attached, form a 4 to 6 membered ring;
c is a 3-to 5-membered cycloalkyl group;
R 2 is H or halogen;
G 1 、G 2 、G 3 each independently is N or CH;
r, q are each independently 0, 1 or 2;
n is 0, 1, 2 or 3.
In one or more embodiments:
q is furyl, thiazolyl or thienyl, optionally substituted with 1 cyano group;
l is- (CR) a R b )-；
R a Is C 1-3 An alkyl group;
R b is C 1-3 Alkyl, and the C 1-3 Alkyl is substituted with 1 OH;
w is O or NH;
y is- (CR) d R e )-；
R d 、R e Each independently is H or C 1-3 An alkyl group;
r and R 1 Each independently is H, halogen, cyano, C 1-3 Alkyl or pyridyl, said C 1-3 Alkyl or pyridyl optionally substituted with 1 to 4 groups selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy and 3 to 5 membered cycloalkyl;
alternatively, R and R 1 Together with the atoms to which they are attached, form a 4 to 5 membered ring;
c is a 3-to 5-membered cycloalkyl group;
R 2 is H;
G 1 、G 2 、G 3 each independently is N or CH;
r, q are each independently 0, 1 or 2.
In one or more embodiments:
is that
Is that
W is O or NH.
In one or more embodiments:
q is furyl, thiazolyl or thienyl, optionally substituted with 1 cyano group;
L is- (CR) a R b )-；
R a Is C 1-3 An alkyl group;
R b is C 1-3 Alkyl, and the C 1-3 Alkyl is substituted with 1 OH;
w is O or NH;
y is- (CR) d R e )-；
R d 、R e Each independently is H or C 1-3 An alkyl group;
r and R 1 Each independently is H or halogen; alternatively, R and R 1 Together with the atoms to which they are attached, form a 4 to 5 membered ring;
c is a 3-to 5-membered cycloalkyl group;
R 2 is H;
G 1 、G 2 、G 3 each independently CH;
r, q are each independently 0 or 1.
In one or more embodiments:
is that
Is thatOr alternatively
In one or more embodiments, the compound is:
one or more embodiments of the present application provide pharmaceutical compositions comprising a compound of the present application, or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers and deuterides thereof, and one or more pharmaceutically acceptable carriers and/or excipients.
One or more embodiments of the present application provide the use of a compound of the present application or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers, or deuterated forms thereof, or a pharmaceutical composition of the present application, in the manufacture of a medicament for the treatment of an inflammatory disease, an autoimmune disease, a cardiovascular disease, a cancer, a renal system disease, a gastrointestinal disease, a respiratory disease, an endocrine system disease, or a central nervous system disease.
One or more embodiments of the present application provide the use of a compound of the present application or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers, or deuterated forms thereof, or a pharmaceutical composition of the present application, for the manufacture of a medicament for the treatment of cryptopyrene related periodic syndrome (CAPS), mu Keer-weiles syndrome (MWS), familial cold auto-inflammatory syndrome (FCAS), neonatal Onset Multisystemic Inflammatory Disease (NOMID), familial Mediterranean Fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft versus host disease, multiple Sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, alzheimer's disease, atherosclerosis, gout, or chronic kidney disease.
One or more embodiments of the present application provide the use of a compound of the present application or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers, or deuterides thereof, or a pharmaceutical composition of the present application, in the preparation of an NLRP3 inhibitor.
One or more embodiments of the present application provide compounds of formula (I'), or stereoisomers thereof:
wherein:
q is selected from 5 membered heteroaryl, which may contain 1 to 2 heteroatoms selected from N, O or S, which heteroaryl may be substituted with 0 or 1 cyano group;
L is selected from- (CR) a R b )-；
R a Selected from C 1-6 An alkyl group;
R b selected from C 1-6 Alkyl, and said alkyl is further substituted with 1 OH;
w is selected from O or NH;
y is selected from- (CR) d R e )-；
R d 、R e Each independently selected from H or C 1-6 An alkyl group;
r and R 1 Each independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 10 membered carbocyclyl or 4 to 10 membered heterocyclyl, said heterocyclyl may contain 1 to 3 heteroatoms selected from N, O or S, wherein said alkyl, carbocycle or heterocycle may be further substituted with 1 to 4 halogen, cyano, C 1-6 Alkyl, C 1-6 Substituted with an alkoxy, 3-to 6-membered carbocyclyl, or 5-to 6-membered heterocyclyl substituent;
or alternativelyR and R 1 Can form a 4 to 6 membered ring together with the atoms to which they are attached;
c is selected from 3-to 5-membered cycloalkyl;
R 2 selected from H or halogen;
G 1 、G 2 、G 3 each independently selected from N or CH;
q, r are selected from 0, 1 or 2;
n is selected from 0, 1, 2 or 3.
In one or more embodiments:
q is selected from furyl, thiazolyl or thienyl, and Q may be further substituted with cyano;
l is selected from- (CR) a R b ) -or 3 to 4 membered cycloalkyl, and said L is optionally further substituted with 0 to 2-OH;
R a 、R b each independently selected from H or C 1-3 An alkyl group;
w is selected from O or NH;
y is selected from- (CR) d R e )-；
R d 、R e Each independently selected from H or C 1-3 An alkyl group;
r and R 1 Each independently selected from H, halogen, cyano, C 1-3 Alkyl or pyridyl, said C 1-3 Alkyl or pyridyl may further be substituted with 1 to 4 halogens, cyano, C 1-3 Alkyl, C 1-3 Alkoxy or a 3 to 5 membered cycloalkyl;
alternatively, R and R 1 May form a 4 to 5 membered ring together with the atoms to which they are attached;
c is selected from 3-to 5-membered cycloalkyl;
R 2 selected from H;
G 1 、G 2 、G 3 each independently selected from N or CH;
q, r are selected from 0, 1 or 2;
n is selected from 0, 1, 2 or 3.
In one or more embodiments:
selected from the group consisting ofOr alternatively
Selected from the group consisting of Or alternatively
W is selected from O or NH.
In one or more embodiments, the compound is:
or alternatively
One or more embodiments of the present application provide pharmaceutical compositions comprising a compound of the present application, or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers and/or excipients.
One or more embodiments of the present application provide for the use of a pharmaceutical composition of the present application or a compound of the present application or a stereoisomer thereof in the preparation of an NLRP3 inhibitor.
In one or more embodiments, the diseases associated with NLRP3 include: inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancers, diseases of the renal system, gastrointestinal diseases, respiratory diseases, endocrine diseases or central nervous system diseases.
In one or more embodiments, the diseases associated with NLRP3 include: cryptothermal protein related periodic syndrome (CAPS), mu Keer-Welsh syndrome (MWS), familial Cold Autoinflammatory Syndrome (FCAS), neonatal Onset Multisystem Inflammatory Disease (NOMID), familial Mediterranean Fever (FMF), nonalcoholic steatohepatitis, alcoholic liver disease, graft versus host disease, multiple Sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, alzheimer's disease, atherosclerosis, gout, chronic kidney disease.
One or more embodiments provide compounds of the present application or pharmaceutically acceptable salts thereof or all stereoisomers, tautomers and deuterated forms thereof and compositions thereof for use as a medicament.
One or more embodiments provide compounds of the application or pharmaceutically acceptable salts thereof or all stereoisomers, tautomers and deuterated forms thereof and compositions thereof for use in methods of treating diseases associated with NLRP 3.
One or more embodiments provide compounds of the application or pharmaceutically acceptable salts thereof or all stereoisomers, tautomers and deuterated forms thereof and compositions thereof for use as NLRP3 inhibitors.
One or more embodiments provide a compound of the present application or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers, and deuterated forms and compositions thereof, for use in a method of treating an inflammatory disease, an autoimmune disease, a cardiovascular disease, cancer, a renal disease, a gastrointestinal disease, a respiratory disease, an endocrine disease, or a central nervous system disease.
One or more embodiments provide a compound of the application or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers and deuterated forms thereof, and compositions thereof, for use in a method of treating cryptopyrene related periodic syndrome (CAPS), mu Keer-wils syndrome (MWS), familial cold auto-inflammatory syndrome (FCAS), neonatal Onset Multisystemic Inflammatory Disease (NOMID), familial Mediterranean Fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple Sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, alzheimer's disease, atherosclerosis, gout or chronic kidney disease.
One or more embodiments provide a method of treating/preventing a disease associated with NLRP3 comprising administering a compound of the application or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterides thereof or a composition of the application to a subject in need thereof.
One or more embodiments provide a method of treating/preventing a disease, which is a treatment of an inflammatory disease, an autoimmune disease, a cardiovascular system disease, cancer, a renal system disease, a gastrointestinal disease, a respiratory system disease, an endocrine system disease, or a central nervous system disease, comprising administering to a subject in need thereof a compound of the application or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers, and deuterated forms thereof, or a composition of the application.
One or more embodiments provide a method of treating/preventing a disease, which is a crypto-protein associated periodic syndrome (CAPS), mu Keer-wels syndrome (MWS), familial cold auto-inflammatory syndrome (FCAS), neonatal Onset Multisystem Inflammatory Disease (NOMID), familial Mediterranean Fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple Sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, alzheimer's disease, atherosclerosis, gout, or chronic kidney disease, comprising administering a compound of the application or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers, and deuterated thereof, or a composition of the application to a subject in need thereof.
One or more embodiments provide a method of inhibiting NLRP3 comprising administering a compound of the application or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers, and deuterides thereof, or a composition of the application to a subject in need thereof.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the application each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the application are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include 16 O、 17 O and 18 isotopes of O, sulfur include 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen include 14 N and 15 isotopes of N, fluorine include 17 F and F 19 Isotopes of F, chlorine include 35 Cl and Cl 37 Isotopes of Cl, bromine include 79 Br and 81 Br。
"alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, still more preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; when the alkyl group is substituted, it may optionally be further substituted with 1 or more substituents.
"alkoxy" refers to a group formed by substitution of at least 1 carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy and cyclobutoxy. The alkyl group is as defined above for the "alkyl" group.
"alkenyl" means an alkenyl group containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 8 carbon atoms, even more preferably 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecen-3-yl. The alkenyl group may optionally be further substituted with 1 or more substituents.
"alkynyl" refers to alkynyl groups containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, straight or branched chain unsaturated aliphatic hydrocarbon groups consisting of 2 to 20 carbon atoms, preferably 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, more preferably alkynyl groups of 2 to 8 carbon atoms, even more preferably alkynyl groups of 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3-dimethylbutyyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodyn-4-yl. The alkynyl group may be optionally further substituted with one or more substituents.
"aryl" refers to a substituted or unsubstituted aromatic ring which may be a 5 to 8 membered (e.g., 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system which may be a bridged or spiro ring, non-limiting examples including phenyl, naphthyl. The aryl group may optionally be further substituted with 1 or more substituents.
"heteroaryl" refers to a substituted or unsubstituted aromatic ring which may be a 3 to 8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5 to 8 membered heteroaryl, with 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the heteroaryl ring being oxidizable to various oxidation states. Heteroaryl groups may be attached to a heteroatom or carbon atom, and heteroaryl groups may be bridged or spiro rings, non-limiting examples include cyclic pyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridyl, pyrrolopyridinyl. Heteroaryl is optionally further substituted with 1 or more substituents.
"carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When aromatic, the definition is the same as for "aryl" above; when non-aromatic, it may be a 3 to 10 membered (e.g., 3,4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which may be bridged or spiro, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl,The "carbocyclyl" or "carbocycle" is optionally further substituted with 1 or more substituents.
"heterocyclyl" or "heterocycle" refers to a saturated or unsaturated aromatic or non-aromatic heterocycle, which, when aromatic, is as defined above for "heteroaryl"; when a non-aromatic heterocycle, it may be a 3 to 10 membered (e.g. 3,4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (e.g. 10, 11, 12, 13, 14, 15 membered) tricyclic ring system and contains 1 to 4 (e.g. 1,2,3, 4) heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclyl. 1 to 4 (e.g., 1,2,3, 4) N, S optionally substituted by "heterocyclyl" or a ring of "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" may be attached to a heteroatom or carbon atom; "heterocyclyl" or "heterocycle" may be bridged or spiro. Non-limiting examples of "heterocyclyl" or "heterocycle" include epoxy ethyl, epoxy propyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, oxepinyl, thiepanyl, oxazepine, diazanyl, thiazepine, pyridinyl, piperidinyl, homopiperidinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaalkyl, 1, 3-dithianyl, dihydrofuranyl, dithianyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyranyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxapentyl, pyrazolinyl, dithianyl, dithiadienyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3, 4-tetrahydroisoquinolyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, azabicyclo [ 2.2.2.2 ] hexyl, 3H-indolylquinolizinyl, N-pyridyl urea, 1-dioxothiomorpholinyl, azabicyclo [3.2.1] octyl, azabicyclo [5.2.0] nonyl, oxatricyclic [5.3.1.1] dodecyl, azaadamantyl and oxaspiro [3.3] heptyl. The "heterocyclyl" or "heterocycle" may be optionally further substituted with 1 or more substituents.
"cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which may be a 3 to 10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 20 membered (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 membered) polycyclic ring system, the ring carbon atoms preferably being 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1, 5-cyclooctadienyl, 1, 4-cyclohexanedienyl, cycloheptatrienyl, and the like. When cycloalkyl is substituted, it may optionally be further substituted with 1 or more substituents.
"heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring radical which may be a 3 to 8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic, 4 to 12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system and contains 1, 2, or 3 heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclyl. Optionally substituted 1, 2 or 3N, S of the "heterocycloalkyl" rings can be oxidized to various oxidation states; "heterocycloalkyl" may be attached to a heteroatom or carbon atom; "heterocycloalkyl" may be a bridged or spiro ring. Non-limiting examples of "heterocycloalkyl" include epoxy, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, piperidinyl, piperdinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo [3.2.1] octanyl, azabicyclo [5.2.0] nonanyl, oxatricyclo [5.3.1.1] dodecyl, azaadamantyl, and oxaspiro [3.3] heptanyl.
When "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "heterocyclyl", "heterocycle", "cycloalkyl", "heterocycloalkyl" or "heterocyclyl" described above is substituted, it may optionally be further substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 groups selected from F, cl, br, I, hydroxy, mercapto, nitro, cyano, amino, C 1-6 Alkylamino, = O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR q4 R q5 、＝NR q6 、-C(＝O)OC 1-6 Alkyl, -OC (=o) C 1-6 Alkyl, -C (=o) NR q4 R q5 、C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C (=o) OC 6-10 Aryl, -OC (=o) C 6-10 Aryl, -OC (=o) C 5-10 Heteroaryl, -C (=o) OC 5-10 Heteroaryl, -OC (=o) C 3-8 Heterocycloalkyl, -C (=o) OC 3-8 Heterocycloalkyl, -OC (=o) C 3-8 Cycloalkyl, -C (=o) OC 3-8 Cycloalkyl, -NHC (=o) C 3-8 Heterocycloalkyl, -NHC (=o) C 6-10 Aryl, -NHC (=o) C 5-10 Heteroaryl, -NHC (=o) C 3-8 Cycloalkyl, -NHC (=o) C 3-8 Heterocycloalkyl, -NHC (=o) C 2-6 Alkenyl or-NHC (=o) C 2-6 Substituted radicals of alkynyl radicalsSubstituted, and wherein said substituent C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -NHC (=o) C 6-10 Aryl, -NHC (=o) C 5-10 Heteroaryl, -NHC (=o) C 3-8 Heterocycloalkyl or-NHC (=o) C 3-8 Cycloalkyl is optionally further substituted with 1 to 3 substituents selected from OH, F, cl, br, I, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or = O; r is R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 An aryl group; r is R q2 、R q3 Selected from H or C 1-6 An alkyl group; wherein R is q4 、R q5 Selected from H, C 1-6 Alkyl, -NH (c=nr q1 )NR q2 R q3 、-S(＝O) 2 NR q2 R q3 、-C(＝O)R q1 or-C (=O) NR q2 R q3 Wherein said C 1-6 The alkyl group optionally being further substituted by 1 or more groups selected from OH, F, cl, br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 Heteroaryl, C 3-8 Cycloalkyl or C 3-8 Substituted by a substituent of heterocycloalkyl; or R is q4 And R is R q5 And the N atom forms a 3 to 8 membered heterocyclic ring which may contain 1 or more heteroatoms selected from N, O or S.
Halogen includes F, cl, br and I.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the application that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.
"pharmaceutical composition" refers to a mixture of one or more compounds of the present application, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance that is added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group, and cases where the heterocyclic group is not substituted with an alkyl group.
Drawings
FIG. 1 shows colon-plasma drug distribution of comparative example 1.
FIG. 2 shows colon-plasma drug profile of Compound 7-1.
Detailed Description
The following examples illustrate the technical aspects of the present application in detail, but the scope of the present application is not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). NMR shift (. Delta.) at 10 -6 Units of (ppm) are given. NMR was performed using a (Bruker Avance III and Bruker Avance 300) nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (dMSO-d) as the solvent 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS);
MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X14.6 mm, 3.5. Mu.M);
the thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm;
column chromatography generally uses 200-300 mesh silica gel of yellow sea of tobacco stand as carrier;
the known starting materials of the present application may be synthesized using or according to methods known in the art, or may be purchased from the companies taitan technology, an Naiji chemistry, shanzheimer, chengdouke, shanghuan chemical technology, carbofuran technology, etc.;
The nitrogen atmosphere means that the reaction flask is connected with a nitrogen balloon with the volume of about 1L;
the hydrogen atmosphere means that the reaction flask is connected with a hydrogen balloon with the volume of about 1L;
the hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times;
the examples are not specifically described, and the reaction is carried out under a nitrogen atmosphere;
the examples are not specifically described, and the solution refers to an aqueous solution;
the embodiment has no special description, the reaction temperature is room temperature, and the optimum reaction temperature of the room temperature is 20-30 ℃;
DCM: dichloromethane;
EA: ethyl acetate;
HCl: hydrochloric acid;
THF: tetrahydrofuran;
DMF: n, N-dimethylformamide;
PE is petroleum ether;
TLC, thin layer chromatography;
SFC: supercritical fluid chromatography;
NCS: n-chlorosuccinimide;
Pd(dppf)Cl 2 : [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride;
AD-mix-beta, hydrogenated quinidine 1, 4-naphthyridine diyl ether mixture;
(dHQD) 2 AQN hydrogenated quinidine (anthraquinone-1, 4-diyl) diether.
Intermediate 1
(R) -5- (1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-amine (intermediate 1)
(R)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine
The first step:
(4-amino-2, 3-dihydro-1H-inden-5-yl) (cyclopropyl) methanone (1 b)
(4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclopropyl)methanone
In a 500mL three-necked flask under the protection of nitrogen, compound 1a (20.0 g,150.16 mmol) was dissolved in 1, 2-dichloroethane (200 mL), the ice-salt bath was cooled to 0 ℃, a dichloromethane solution of boron trichloride (150 mL,1M,150.16 mmol) was slowly added dropwise, after the dropwise addition was completed, the temperature was kept for 10min, and then aluminum trichloride (22.0 g,165.20 mmol) and cyclopropylnitrile (15.1 g,225.24 mmol) were added; the reaction system is heated to 80 ℃ for reaction for 4 hours, cooled to room temperature, 160mL (2M HCl) is added under ice bath, and the temperature is raised and the reflux is carried out for 1 hour after the dropwise addition. At the end of the reaction, cooled to room temperature, extracted with DCM (200 ml×3), the organic phase was washed with 160mL of 2M sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, the organic solvent removed under reduced pressure, and the residue purified by column chromatography (petroleum ether: ethyl acetate=20:1) to give compound 1b as a white solid (17.1 g, 57.2% yield).
1 H NMR(400MHz,DMSO-d6)δ＝7.87(d,1H),6.90(br,2H),6.54(d,1H),2.84(t,2H),2.80-2.74(m,1H),2.67(t,2H),2.06-1.98(m,2H),0.96-0.87(m,4H)。
LCMS m/z(ESI)＝202.1[M+1]。
And a second step of:
5- (1-cyclopropylvinyl) -2, 3-dihydro-1H-inden-4-amine (1 c)
5-(1-Cyclopropylvinyl)-2,3-dihydro-1H-inden-4-amine
In a 500mL three-necked flask under the protection of nitrogen, the compound methyltriphenyl phosphorus bromide (24.8 g,69.6 mmol) was dissolved in THF (300 mL), the ice-salt bath was cooled to 0 ℃, potassium tert-butoxide (7.8 g,69.6 mmol) was slowly added, after maintaining this temperature for 30min, compound 1b (7.0 g,34.8 mmol) was added, the reaction was carried out at room temperature for 4h, the reaction was completed, water quenching was added, EA (100 mL. Times.3) extraction, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=30:1) to give compound 1c as a pale yellow oil (6.4 g, yield 92.3%).
1 H NMR(400MHz,DMSO-d6)δ＝6.64(d,1H),6.45(d,1H),5.15(d,1H),4.78(d,1H),4.37(br,2H),2.77(t,2H),2.64(t,2H),2.02-1.96(m,2H),1.62-1.57(m,1H),0.69-0.64(m,2H),0.40-0.36(m,2H)。
LC-MS m/z(ESI)＝200.1[M+1]。
And a third step of:
(R) -5- (1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-amine (intermediate 1)
(R)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine
The synthesis of intermediate 1 was carried out with reference to patent CN 108017559. Into a 500mL autoclave, 1c (8.3 g,41.7 mmol) and methylene chloride (90 mL) were added, and ruthenium [ (R) -2,2' -bis (diphenylphosphine) -1, 11-binaphthyl ] diacetate (1.8 g,2.09 mmol) as a catalyst was added, and after the addition, the autoclave was tightly sealed, replaced with hydrogen 3 times, charged with hydrogen, the pressure gauge on the autoclave was 12atm, and the reaction was carried out at room temperature for 30 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30:1) to give intermediate 1 as a pale yellow oil (8.2 g, yield 97.8%,97.74% ee). Chiral HPLC (chiral column CHIRALPAK AY-3 (4.6x100 mm), mobile phase methanol, column temperature 35 ℃, mobile phase methanol/n-hexane=15/85, column pressure 2000psi, flow rate 2mL/min, detector signal path 215nm@4.8nm, diode array detector start-stop wavelength 200-400 nm, rt=3.295 min).
1 H NMR(400MHz,DMSO-d6)δ＝6.92(d,1H),6.45(d,1H),4.43(s,2H),2.75(t,2H),2.62(t,2H),2.26–2.20(m,1H),2.00–1.92(m,2H),1.14(d,3H),1.02-0.96(m,1H),0.50–0.44(m,1H),0.34–0.28(m,1H),0.17–0.11(m,1H),0.06–0.00(m,1H)。
LCMS m/z(ESI)＝202.1[M+1]。
Intermediate 2
(S) -5- (1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-amine (intermediate 2)
(S)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine
The synthesis of intermediate 2 was carried out with reference to patent CN 108017559. Into a 500mL autoclave, 1c (7.3 g,36.7 mmol) and methylene chloride (80 mL) were added, and ruthenium [ (S) -2,2' -bis (diphenylphosphine) -1, 11-binaphthyl ] diacetate (1.54 g,1.83 mmol) as a catalyst was added, and after the addition, the autoclave was tightly sealed, replaced with hydrogen 3 times, charged with hydrogen, the gauge pressure on the autoclave was 12atm, and the reaction was carried out at room temperature for 30 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30:1) to give intermediate 2 as a pale yellow oil (7.1 g, yield 96.3%,98.18% ee). Chiral HPLC (chiral column CHIRALPAK AY-3 (4.6x100 mm), mobile phase methanol, column temperature 35 ℃, mobile phase methanol/n-hexane=15/85, column pressure 2000psi, flow rate 2mL/min, detector signal path 215nm@4.8nm, diode array detector start wavelength 200-400 nm, rt= 2.802 min).
1 H NMR(400MHz,DMSO-d6)δ＝6.92(d,1H),6.46(d,1H),4.43(s,2H),2.75(t,2H),2.63(t,2H),2.26–2.20(m,1H),2.00–1.93(m,2H),1.15(d,3H),1.02–0.96(m,1H),0.50–0.44(m,1H),0.36–0.28(m,1H),0.17–0.11(m,1H),0.06–0.01(m,1H)。
LCMS m/z(ESI)＝202.1[M+l]。
Intermediate 3
N- (tert-Butyldimethylsilyl) -4- (2-hydroxy-prop-2-yl) furan-2-sulfonylimid-amide (intermediate 3)
N-(Tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
The first step:
furan-3-carboxylic acid ethyl ester (3 b)
Ethyl furan-3-carboxylate
Compound 3a (50 g, 0.4476 mol) was dissolved in 300mL of absolute ethanol in an ice bath, and thionyl chloride (65 mL,0.892 mol) was slowly added dropwise, and after the addition was completed, the temperature was raised to reflux for 2 hours. TLC monitored complete reaction, after concentrating under reduced pressure to remove solvent and excess thionyl chloride, water (200 mL), ethyl acetate extraction (150 mL. Times.3) was added and the organic phases combined. The organic phase was washed with saturated brine (100 ml×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:50 to 1:10) to give compound 3b as a light brown oil (38.1 g, yield 61%).
And a second step of:
4-Ethyl formate-2-sulfonylchlorofuran (3 c)
Ethyl furan-2-sulfonyl chloride-4-formate
Compound 3b (22.00 g,0.157 mol) was dissolved in 250mL DCM at room temperature, cooled to-15 ℃ in an ice-salt bath, sulfonyl chloride (23.31 g,0.173 mol) was slowly added dropwise and the temperature was controlled to be no higher than-10 ℃, and the reaction was carried out at room temperature for 12h after the addition was completed; pyridine (13.66 g,0.173 mol) is slowly added dropwise after the temperature is reduced below-15 ℃ in an ice salt bath, phosphorus pentachloride (36.00 g,0.137 mol) is added in batches, the temperature is controlled to be not more than-10 ℃, and the reaction is completed at room temperature for 2 hours. TLC monitored completion of the reaction, quenched the reaction in 200mL ice water, extracted with EA (200 ml×3) and the organic phases combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure to give compound 3c as a brown oil (33.00 g, yield 90%) which was taken directly into the next step without purification.
And a third step of:
furan-2-sulfonamide-4-carboxylic acid ethyl ester (3 d)
Furan-2-sulfonamide-4-ethyl formate
Compound 3c (33.00 g,0.138 mol) was dissolved in 350mL of acetone at room temperature, saturated aqueous ammonium bicarbonate (49.74 g,0.553 mol) was added dropwise at room temperature, reacted for 3h at room temperature, and TLC monitored the reaction was complete. Extracted with EA (200 mL. Times.3) and the organic phases combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure to give compound 3d as a brown solid powder (23 g, yield 77%).
1 H NMR(400MHz,DMSO-d6)δ＝8.64(s,1H),7.97(s,2H),7.13(s,1H),4.27(q,2H),1.28(t,3H)。
LCMS m/z＝218.2[M-l]。
Fourth step:
4- (2-hydroxypropyl) furan-2-sulfonamide (3 e)
4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide
Compound 3d (23 g,0.105 mol) was dissolved in 500mL dry THF at room temperature, the ice-salt bath was cooled to-15℃and methyl magnesium bromide (140 mL,0.418 mol) was slowly added dropwise while maintaining the temperature at no more than 0℃and reacted at room temperature for 4h after the dropwise addition, and TLC monitored the reaction was complete. The reaction mixture was quenched in 200mL ice water, extracted with EA (200 mL. Times.3), and the organic phases combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:4 to 1:1) to give compound 3e as a white solid powder (16 g, yield 76%).
LCMS m/z＝204.2[M-l]。
Fifth step:
n- (tert-Butyldimethylsilyl) -4- (2-hydroxypropyl) furan-2-sulfonamide (3 f)
N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide
Compound 3e (5.0 g,24.39 mmol) was dissolved in 50mL of dry THF at room temperature, the ice-salt bath was cooled to-10deg.C, sodium hydride (0.9 g,36.58 mmol) was slowly added to control the temperature below-10deg.C, and a solution of t-butyldimethylchlorosilane (4.8 g,31.70 mmol) in THF (50 mL) was then added and reacted at room temperature for 12h, and TLC monitored to complete the reaction. The reaction solution was poured into 20mL of ice water to quench, extracted with EA (50 ml×3), the organic phases were combined, dried with saturated brine (50 mL), concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:2 to 2:1) to give compound 3f as a white solid (5.1 g, yield 66%).
1 H NMR(400MHz,CDCl3)δ＝7.85(s,1H),7.68(s,1H),6.93(s,1H),5.07(s,1H),1.38(s,6H),0.88(s,9H),0.16(s,6H)。
LCMS m/z＝320.2[M+l]。
Sixth step:
n- (tert-Butyldimethylsilyl) -4- (2-hydroxypropyl-2-yl) furan-2-sulfonylimid-mide (intermediate 3)
N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
In a 250mL three-necked flask, under the protection of nitrogen, DCM (100 mL) and triphenylphosphine dichloride (11.3 g,33.86 mmol) are added, the temperature is reduced to 0 ℃ in an ice bath, diisopropylethylamine (5.8 g,45.16 mmol) is slowly added dropwise, and the reaction is carried out for 10min at room temperature after the dropwise addition; cooling the reaction system to 0 ℃, dropwise adding a 3f (3.6 g,11.29 mmol) dichloromethane (10 mL) solution, keeping the temperature at 0 ℃ after the dropwise adding, continuing to react for 30min, and introducing ammonia gas into the reaction system for 15min; restoring room temperature for reaction for 2 hours; TLC monitoring of the completion of the reaction, concentration under reduced pressure to remove the solvent, purification of the crude product by column chromatography (petroleum ether: ethyl acetate=2:1) gave intermediate 3 as a white solid (816 mg, yield 23%)
1 H NMR(400MHz,DMSO-d6)δ＝7.56(s,1H),6.86(s,2H),6.73(s,1H),5.01(s,1H),1.37(s,6H),0.85(s,9H),0.03(s,3H),0.01(s,3H)。
LCMS m/z＝319.2[M+l]。
Intermediate 4
N- (tert-Butyldimethylsilyl) -2- (-1- ((tert-Butyldimethylsilyl) oxy) -2-hydroxypropan-2-yl) thiazole-5-sulfonylimid-mide (intermediate 4)
N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide
The first step:
1- ((tert-Butyldimethylsilanyloxy) -2- (thiazol-2-yl) propan-2-ol (4 b)
1-((Tert-butyldimethylsilyl)oxy)-2-(thiazol-2-yl)propan-2-ol
Compound 4a (50.48 g,0.31 mol) was dissolved in 1L of dry THF at room temperature, nitrogen-protected, and cooled to-78 ℃. 2.5M n-BuLi in n-hexane (136 mL,0.34 mol) was slowly added dropwise at a temperature not exceeding-70℃and stirred for 1h after the completion of the dropwise addition, then 1- (t-butyldimethylsilyloxy) -2-propanone (70 g,0.37 mol) was slowly added dropwise for 1h, and the TLC monitored the reaction was complete. Adding saturated NH into the reaction system 4 The reaction was quenched with Cl solution, extracted with EA (200 mL. Times.3), and the organic phases combined. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, to give a black residue, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:30 to 1:20) to give compound 4b as a pale yellow oil (50 g, yield 59%).
1 H NMR(400MHz,DMSO-d 6 )δ7.70(s,1H),7.56(s,1H),5.26(s,1H),3.34-3.69(m,2H),1.47(s,3H),0.84(s,6H),0.79(s,9H),0.15(s,6H)。
LCMS m/z＝274.1[M+l]。
And a second step of:
2- (1- ((tert-Butyldimethylsilanyloxy) -2-hydroxypropyl-2-yl) thiazole-5-sulfonamide (4 c)
2-(1-((Tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide
Compound 4b (7 g,25.6 mmol) was dissolved in 200mL dry THF at room temperature, nitrogen blanketed, and cooled to-78 ℃. Slowly dropwise adding 2.5. 2.5M n-BuLi n-hexane solution (21.5 mL,53.8 mmol) at a temperature of not more than-70deg.C, reacting for 1 hr after the completion of the dropwise addition, and then adding 1, 4-diazabicyclo [2.2.2 ]]Octane-1, 4-diimmonium-1, 4-disulfonic acid (9.2 g,38.4 mmol) was reacted at a constant temperature for 1h, and the dry ice bath was removed and stirred at a constant temperature for 2h. Adding saturated NH into the reaction system 4 The reaction was quenched with 200mL of Cl solution, the aqueous phase was extracted with EA (100 mL. Times.2), added to a 500mL three-necked flask, cooled to-10deg.C, sequentially added with potassium acetate (10.05 g,102.4 mmol) and hydroxylamine sulfonic acid (11.6 g,102.4 mmol), and then allowed to warm naturally overnight. Extracted with EA (200 mL. Times.5) and the organic phases combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure to give a residue, which was purified by silica gel column chromatography to give compound 4c as a pale yellow oil (2.8 g, yield 46%).
LCMS m/z＝239[M+l]。
And a third step of:
n- (tert-Butyldimethylsilyl) -2- (1- ((tert-Butyldimethylsilyl) oxy) -2-hydroxypropan-2-yl) thiazole-5-sulfonamide (4 d)
N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide
Sodium hydride (1.92 g,60%,48 mmol) was added in portions to a solution of 4c (3.80 g,16.0 mmol) in 50mL of tetrahydrofuran under nitrogen at 0deg.C and stirring was continued for 30 minutes. Tert-butyldimethylchlorosilane (5.79 g,38.4 mmol) was added, the reaction was completed by TLC at room temperature for 16h, 200mL of water was added under ice-bath cooling, and extraction was performed with ethyl acetate (100 mL. Times.3). The organic phases were combined, washed with saturated brine (100 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel (petroleum ether: ethyl acetate=10:1 to 6:1) afforded 4d as a tan oil (4.72 g, 63.2% yield).
1 H NMR(400MHz,DMSO-d 6 )δ8.08(s,1H),8.00(s,1H),6.15(s,1H),3.74-3.67(m,2H),1.46(s,3H),0.88(s,9H),0.79(s,9H),0.15(s,6H),0.05(s,6H)。LC-MS m/z(ESI)＝467.2[M+1]。
Fourth step:
n- (tert-Butyldimethylsilyl) -2- (-1- ((tert-Butyldimethylsilyl) oxy) -2-hydroxypropan-2-yl) thiazole-5-sulfonylimid-mide (intermediate 4)
N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide
In a 100mL round bottom flask, triphenylphosphine (1.58 g,6.02 mmol), hexachloroethane (1.67 g,7.05 mmol) and chloroform (25 mL) were added in sequence under nitrogen and refluxed at 85℃for 30 min. TLC monitored complete conversion and cooled to room temperature. Further cooled to-30℃N, N-diisopropylethylamine (1.14 g,8.82 mmol) was slowly added dropwise. 4d (2.35 g,5.03 mmol) in chloroform (5 mL) was slowly added dropwise under ice-bath stirring for 10min, and stirring was continued for 3h. Ammonia gas was introduced at-30 ℃ for 1h, and the reaction was allowed to slowly warm to room temperature overnight. TLC monitored complete reaction and reaction was complete. The reaction mixture was poured into water, and the organic phase was extracted with dichloromethane (100 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate=10:1 to 4:1) to give intermediate 4 as a pale yellow solid (873 mg, yield 37.3%).
LC-MS m/z(ESI)＝467.2[M+1]。
Intermediate 5
N- (tert-Butyldimethylsilyl) -2- (-1- ((tert-Butyldimethylsilyl) oxy) -2-hydroxypropan-2-yl) thiazole-5-sulfonylimid-mide (intermediate 5)
N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide
The first step:
2- (1- ((tert-Butyldimethylsilanyloxy) -2-hydroxypropyl-2-yl) thiazole-5-sulfonamide (5 a)
2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide
5a reference is made to the method of 4c, which uses 4b as the starting material for the synthesis.
And a second step of:
n- (tert-Butyldimethylsilyl) -2- (1- ((tert-Butyldimethylsilyl) oxy) -2-hydroxypropan-2-yl) thiazole-5-sulfonamide (5 b)
N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide
5b reference is made to the method of 4d, using 5a as starting material for the synthesis.
And a third step of:
n- (tert-Butyldimethylsilyl) -2- (-1- ((tert-Butyldimethylsilyl) oxy) -2-hydroxypropan-2-yl) thiazole-5-sulfonylimid-mide (intermediate 5)
N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide
Intermediate 5 was synthesized starting from 5b by referring to the procedure for intermediate 4, yielding 1.0g of pale yellow solid.
LC-MS m/z(ESI)＝467.2[M+1]。
Intermediate 6-1 and intermediate 6-2
(S) -N' - (tert-butyldimethylsilyl) -2- ((S) -1- ((tert-butyldimethylsilyl) oxy) -2-hydroxyprop-2-yl) -N- ((S) -1- (4-methoxyphenyl) ethyl) thiazole-5-sulfonylimid-mide and
(R) -N' - (tert-butyldimethylsilyl) -2- ((S) -1- ((tert-butyldimethylsilyl) oxy) -2-hydroxypropyl-2-yl) -N- ((S) -1- (4-methoxyphenyl) ethyl) thiazole-5-sulfonylimid-mide (intermediate 6-1 and intermediate 6-2)
(S)-N'-(tert-butyldimethylsilyl)-2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide and
(R)-N'-(tert-butyldimethylsilyl)-2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
The first step:
2-Isopropenylthiazole (6 b)
2-(Prop-1-en-2-yl)thiazole
In a 500mL three-necked flask, 300mL of anhydrous tetrahydrofuran and methyltriphenyl phosphorus bromide (56.2 g,157.3 mmol) were added, the temperature was reduced to-15℃under nitrogen protection, potassium tert-butoxide (17.6 g,157.3 mmol) was added, the mixture was stirred for 1.5 hours at room temperature, 6a (10 g,78.6 mmol) was added, the reaction was completed by TLC after 2 hours at room temperature, 100mL of water was added to quench the reaction, EA (100 mL. Times.2) was extracted, the organic phase was combined, the saturated brine was washed (100 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel (petroleum ether: ethyl acetate=10:1 to 6:1) gave 6b as a pale yellow oil (4.5 g, yield 45.9%).
1 HNMR(400MHz,DMSO-d 6 )δ8.08(s,1H),8.00(s,1H),5.33(s,1H),4.96(s,1H),2.12(s,3H)。
And a second step of:
(S) -2- (thiazol-2-yl) propane-1, 2-diol (6 c)
(S)-2-(thiazol-2-yl)propane-1,2-diol
Into a 2L three-necked flask, 600mL of t-butanol, 600mL of tetrahydrofuran, and 600mL of water were added, followed by AD-mix-. Beta.mixture (4478 g,320 mmol), methylsulfonamide (30.4 g,0.32 mol), (DHQD) 2AQN catalyst (11.0 g,0.0128 mol) at room temperature. Cooling to 0deg.C, adding 6b (40 g,0.32 mol), naturally cooling to room temperature, stirring for 24h, TLC monitoring reaction completely, adding EA, extracting (500 mL×2) for several times, mixing organic phases, washing with saturated saline (200 mL×2), drying the organic phases with anhydrous sodium sulfate, filtering, and removing the organic solvent under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane: methanol=100:1 to 20:1) to give a crude product, which was recrystallized from ethyl acetate (70 mL), petroleum ether (210 mL) and methanol (5 mL) to give 6c (45 g, yield 70%, rt=7.506 min,99.8% ee) as a white solid. Chiral HPLC (AS) mobile phase n-hexane/ethanol=90/10; column temperature is 35 ℃; column pressure 80bar; the flow rate is 1mL/min; detector signal path 215nm@4.8nm; the start-stop wavelength of the diode array detector is 200-400 nm.
1 H NMR(400MHz,DMSO-d 6 )δ7.70(s,1H),7.53(s,1H),5.78(s,1H),4.80(s,1H),3.52-3.60(m,2H),1.48(s,3H)。
LC-MS m/z(ESI)＝160.2[M+1]。
And a third step of:
(S) -1- ((tert-Butyldimethylsilanyloxy) -2- (thiazol-2-yl) propan-2-ol (6 d)
(S)-1-((tert-butyldimethylsilyl)oxy)-2-(thiazol-2-yl)propan-2-ol
In a 500mL three-necked flask, 160mL of anhydrous tetrahydrofuran and 6c (8.6 g,0.054 mol) were added, the temperature was reduced to-5℃under nitrogen protection, sodium hydride (2.6 g,0.108 mol) was added, the mixture was stirred for 0.5h with heat preservation, tert-butyldimethylsilyl chloride (10 g,0.0648 mol) was then added, the reaction was completed by TLC after 2h at room temperature, 100mL of water was added for quenching reaction, EA extraction (100 mL. Times.2) was performed, the organic phase was combined, washed with saturated brine (100 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel (petroleum ether: ethyl acetate=10:1 to 6:1) gave 6d (12.6 g, yield 85.7%).
1 H NMR(400MHz,DMSO-d 6 )δ7.69(d,1H),7.56(d,1H),5.26(s,1H),3.70(d,2H), 1.47(s,3H),0.84(s,6H),0.79(s,9H):LC-MS m/z(ESI)＝274.4[M+1]。
Fourth step:
(S) -2- (1- ((tert-Butyldimethylsilanyloxy) -2-hydroxypropan-2-yl) thiazole-5-sulfonylimid-amide (6 e)
(S)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide
In a 100mL three-necked flask, 40mL of anhydrous tetrahydrofuran, 6d (2.0 g,7.31 mmol) and nitrogen were added under nitrogen. Cooling to-78 ℃, slowly dropwise adding N-butyllithium (6.14 mL,15.3 mmol), reacting at-78 ℃ for 2h after the dropwise adding is finished, then adding tert-butoxy-N-oxysulfide (1.18 g,8.772 mmol), naturally heating to room temperature after the adding is finished, reacting for 12h, performing TLC (thin layer chromatography) central control reaction completely, adding 30mL of water for quenching reaction, performing EA extraction (50 mL multiplied by 2) for times, combining organic phases, washing (100 mL multiplied by 2) with saturated saline, drying the organic phases through anhydrous sodium sulfate, filtering, and removing the organic solvent under reduced pressure. Purification of the residue by column chromatography on silica gel (petroleum ether: ethyl acetate=10:1 to 2:1) gave 6e as a white solid (1.6 g, yield 64.1%).
LC-MS m/z(ESI)＝353.5[M+1]。
Fifth step:
(S) -N- (tert-Butyldimethylsilyl) -2- (1- ((tert-Butyldimethylsilyl) oxy) -2-hydroxypropan-2-yl) thiazole-5-sulfonylimid-amide (6 f)
(S)-N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide
To a solution of 6e (4.0 g,11.3 mmol) in 50mL of tetrahydrofuran was added sodium hydride (1.2 g,60%,24 mmol) in portions under nitrogen at 0deg.C and stirred for 30 minutes after the addition. Tert-butyldimethylchlorosilane (2.4 g,4.08 mmol) was added, the reaction was allowed to proceed at room temperature for 4h.TLC was monitored to completion, 100mL of water was added with ice-bath cooling, and extraction was performed with ethyl acetate (100 mL. Times.3). The organic phases were combined, washed with saturated brine (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel (petroleum ether: ethyl acetate=10:1 to 6:1) gave 6f as a pale yellow oil (4.72 g, yield 63.2%).
1 H NMR(400MHz,DMSO-d 6 )δ7.93(s,1H),7.85(s,1H),5.61(s,1H),3.64-3.55(m,2H),1.31(s,3H),0.73(s,9H),0.63(s,9H),0.15(s,6H),0.05(s,6H)。
LC-MS m/z(ESI)＝467.2[M+1]。
Sixth step:
(S) -N' - (tert-butyldimethylsilyl) -2- ((S) -1- ((tert-butyldimethylsilyl) oxy) -2-hydroxypropan-2-yl) -N- ((S) -1- (4-methoxyphenyl) ethyl) thiazole-5-sulfonylimid-mide (intermediate 6)
(S)-N'-(tert-butyldimethylsilyl)-2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
6f (8.0 g,21.4 mmol) was dissolved in 50mL of dichloroethane at-10deg.C under nitrogen, then added to the now-prepared solution of triphenylphosphine dichloride in dichloroethane (32.1 mmol) and stirred for 2h. TLC monitored completion of the reaction followed by addition of S-1- (4-methoxyphenyl) ethane-1-amine (3.88 g,25.68 mmol), stirring at room temperature for 3h, after completion of the reaction, 100mL of water was added and dichloromethane (100 mL. Times.3) was used for extraction. The organic phases were combined, washed with saturated brine (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=50:1 to 20:1) to give compound intermediate 6-1, a pale yellow oil (3.0 g, yield 30%) and intermediate 6-2 (3.5 g, yield 35%).
Intermediate 6-1: 1 H NMR(400MHz,DMSO-d 6 )δ7.50(s,1H),7.07(d,2H),6.72(d,2H),5.91(s,1H),4.39-4.32(m,1H),3.68(s,3H),3.61(s,2H),1.37(s,3H),1.22(d,3H),0.89(s,9H),0.80(s,9H),0.06(s,3H),0.03(s,3H),-0.04(s,3H),-0.06(s,3H)。
LC-MS m/z(ESI)＝600.2[M+1]。
intermediate 6-2: 1 H NMR(400MHz,DMSO-d 6 )δ7.55(s,1H),7.19-6.94(m,2H),6.70(s,2H),5.83(s,1H),4.61-4.11(m,1H),3.58(s,3H),3.51(s,2H),1.32(s,3H),1.20(d,3H),0.88(s,9H),0.81(s,9H),0.78(s,3H),0.20(s,3H),0.16(s,3H),0.06(s,3H)。
LC-MS m/z(ESI)＝600.2[M+1]。
intermediates 7-1 and 7-2
(S) -N' - (tert-butyldimethylsilyl) -2- ((R) -1- (tert-butyldimethylsilyl) oxy) -2-hydroxypropan-2-yl) -N- (S) -1- (4-methoxyphenyl) ethyl) thiazole-5-sulfonylimide
(R) -N' - (tert-butyldimethylsilyl) -2- ((R) -1- ((tert-butyldimethylsilyl) oxy) -2-hydroxypropan-2-yl) -N- (S) - (S) -1- (4-methoxyphenyl) ethyl) thiazole-5-sulfonylimide (intermediate 7-1 and intermediate 7-2)
(S)-N'-(tert-butyldimethylsilyl)-2-((R)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
(R)-N'-(tert-butyldimethylsilyl)-2-((R)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
Intermediate 7-1 and intermediate 7-2 are prepared by reference to the synthetic methods of intermediate 6-1 and intermediate 6-2
Example 1
N- ((5- ((S) -1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -2- ((S) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimid-amide (Compounds 1-1 and 1-2)
N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
The first step:
n- ((5- ((S) -1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -2- ((S) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimid amide (1A)
N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
In a 25mL round bottom flask, intermediate 2 (129 mg, 0.640 mmol), dry tetrahydrofuran 3mL, diisopropylethylamine (166 mg,1.29 mmol) and 2, 2-trichloroethyl chloroformate (163 mg,0.77 mmol) were added sequentially under nitrogen and stirred for 30min with complete conversion monitored by TLC. The reaction mixture was added with 5mL of water, extracted with ethyl acetate (10 mL. Times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, and spun-dried. 3mL of dry tetrahydrofuran was added and dissolved as solution B. In another 50mL three-necked flask, intermediate 4 (300 mg,0.644 mmol) and 3mL dry tetrahydrofuran were added, and sodium hydride (31 mg,60%,0.77 mmol) was added while cooling with ice, and the reaction was stirred for 1h. Solution B was slowly added dropwise under ice bath, the reaction was allowed to warm to room temperature for 1h, and completion of the reaction was monitored by LC-MS, triethylamine trihydrofluoride salt (103 mg,0.644 mmol) was slowly added dropwise. The reaction was carried out at room temperature overnight, TLC monitored the end of the reaction, the reaction solution was poured into water, ethyl acetate (20 ml×2), the combined organic phases were dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile/water=30%) to give 1A as a pale yellow solid (200 mg, yield 66.8%).
LC-MS m/z(ESI)＝465.2[M+1]。
And a second step of:
n- ((5- ((S) -1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -2- ((S) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimid-amide (Compounds 1-1 and 1-2)
N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
1A (180 mg,0.387 mmol) was resolved by SFC to give compound 1-1 (72 mg, 40.0% yield, RT=20.010min, 100% ee) and compound 1-2 (85 mg, 47.2% yield, RT=24.571min, 100% ee). Chiral HPLC (AS) mobile phase n-hexane/ethanol=95/5; column temperature is 35 ℃; column pressure 80bar; the flow rate is 1mL/min; detector signal path 215nm@4.8nm; the start-stop wavelength of the diode array detector is 200-400 nm.
Compound 1-1: 1 H NMR(400MHz,DMSO-d 6 )δ8.28(s,1H),8.05(s,1H),7.82(s,2H),7.12(d,1H),7.04(d,1H),6.11(s,1H),5.00(t,1H),3.54(d,2H),2.82(t,2H),2.73–2.62(m,2H),2.29–2.10(m,1H),2.00–1.86(m,2H),1.44(s,3H),1.08(d,3H),1.00–0.88(m,1H),0.49–0.40(m,1H),0.270–0.160(m,1H),0.15–0.08(m,1H),0.075–0.02(m,1H)。
LCMS m/z(ESI)＝465.2[M+1]。
compound 1-2: 1 H NMR(400MHz,DMSO-d 6 )δ8.27(s,1H),8.04(s,1H),7.82(s,2H),7.13(d,1H),7.04(d,1H),6.10(s,1H),5.00(t,1H),3.55(d,2H),2.82(t,2H),2.78–2.57(m, 2H),2.27–2.16(m,1H),2.00–1.855(m,2H),1.44(s,3H),1.10(d,3H),0.98–0.85(m,1H),0.47–0.36(m,1H),0.23–0.13(m,1H),0.12–0.026(m,1H),0.023–0.085(m,1H)。
LCMS m/z(ESI)＝465.2[M+1]。
example 2
N- ((3- ((R) -1-cyclopropylethyl) bicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) carbamoyl) -2- (1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimid-amide (Compounds 2-1 and 2-2)
N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
The first step:
2- (2, 6-dibromophenyl) ethan-1-ol (2B)
2-(2,6-Dibromophenyl)ethan-1-ol
Into a 1L three-necked flask, 2A (60.0 g,0.2 mol) and anhydrous tetrahydrofuran (300 mL) were charged, and a borane tetrahydrofuran solution (300 mL, 1M) was slowly added dropwise at 0℃under nitrogen protection. After the completion of the dropwise addition, the reaction was allowed to proceed to 80℃for 1h, followed by complete TLC monitoring and cooling to room temperature. Water (150 mL) was added to the ice-water bath, and the reaction was quenched with dilute hydrochloric acid (20 mL, 2N). Part of the reaction solution was concentrated under reduced pressure, then extracted with ethyl acetate (100 ml×3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give 2B as a white solid (50.0 g, yield 88%).
1 H NMR(400MHz,CDCl 3 )δ＝7.52(d,2H),6.94(t,1H),3.88(t,2H),3.33(t,2H)。
And a second step of:
1, 3-dibromo-2- (2-bromoethyl) benzene (2C)
1,3-Dibromo-2-(2-bromoethyl)benzene
In a 1L round bottom flask, 2B (50.0 g,0.18 mol), N-bromosuccinimide (38.0 g,0.2 mmol) and methylene chloride (400 mL) were added sequentially, and after stirring to dissolve, triphenylphosphine (65 g,0.2 mol) was slowly added to the ice-water bath, and after the addition was completed, the reaction was allowed to proceed to room temperature for 24 hours. TLC was monitored to completion and tert-butyl hydroperoxide (8 mL) was added to the reaction mixture for 2h to remove excess triphenylphosphine, saturated sodium bisulphite solution (200 mL) was added to quench the reaction, dichloromethane extraction (200 mL. Times.3), anhydrous sodium sulphate drying, concentration of the organic phase to a large solids precipitation, beating with n-hexane, suction filtration, concentration of the filtrate followed by column chromatography (petroleum ether: ethyl acetate=50:1) to give 2C as a white solid (60.0 g, 98% yield).
1 H NMR(400MHz,CDCl 3 )δ＝7.52(d,2H),6.97(t,1H),3.63–3.43(m,4H)。
And a third step of:
2-bromobicyclo [4.2.0] oct-1 (6), 2, 4-triene (2D)
2-Bromobicyclo[4.2.0]octa-1(6),2,4-triene
In a 250mL three-necked flask, 2C (5.0 g,15 mmol) and anhydrous tetrahydrofuran (150 mL) were sequentially added, and n-butyllithium (5.5 mL, 2.5M) was slowly added dropwise at-68℃under nitrogen protection, after the addition was completed, the reaction was completed at-68℃and the UPLC monitoring reaction was completed, the reaction was quenched by slowly adding water (20 mL) dropwise, extracted with ethyl acetate (100 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to give 2D as a pale yellow oil (2.5 g, yield 90%).
Fourth step:
tert-butylbicyclo [4.2.0] oct-1 (6), 2, 4-trien-2-ylcarbamate (2E)
Tert-butyl bicyclo[4.2.0]octa-1(6),2,4-trien-2-ylcarbamate
In a 250mL round bottom flask, 2D (2.3 g,0.013 mol), dioxane (50 mL), tert-butyl carbamate (2.2 g,0.019 mol), 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl (470 mg,1 mmol), cesium carbonate (8.0 g,0.025 mol), palladium acetate (132 mg,6 mmol) under nitrogen protection were added, the reaction was moved to 100℃for 2h, TLC was monitored to complete the reaction, after cooling to room temperature, saturated sodium bicarbonate (50 mL) was added to quench the reaction, ethyl acetate extraction (50 mL. Times.3), anhydrous sodium sulfate was dried, filtered, and the organic solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=20:1) to give 2E (2.3 g, brown oil, yield 83%).
1 H NMR(400MHz,CDCl 3 )δ＝7.27(d,1H),7.13(t,1H),6.76(d,1H),6.31(s,1H),3.27–3.16(m,2H),3.16–3.06(m,2H),1.52(s,9H)。
Fifth step:
bicyclo [4.2.0] oct-1 (6), 2, 4-triene-2-amine (2F)
Bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine
In a 100mL round bottom flask, 2E (2.3 g,10.5 mmol), dichloromethane (40 mL), trifluoroacetic acid (6 mL) were added sequentially, the reaction was carried out for 7h at room temperature, TLC was monitored to complete the reaction, saturated sodium bicarbonate solution (40 mL) was added to quench the reaction, dichloromethane extraction (50 mL. Times.3), drying over anhydrous sodium sulfate, filtration, removal of the organic solvent under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=10:1) to give 2F as a brown oil (1.0 g, yield 80%).
1 H NMR(400MHz,CDCl 3 )δ＝7.02(dd，1H),6.51(dd,2H),3.11(dd,2H),3.04(dd,2H)。
Sixth step:
(2-Aminobicyclo [4.2.0] oct-1 (6), 2, 4-trien-3-yl) (cyclopropyl) methanone (2G)
(2-Aminobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(cyclopropyl)methanone
To a 25mL three-necked flask, 2F (100 mg,0.84 mmol), dichloroethane (5 mL), after dissolving, was placed in an ice-water bath, and a boron trichloride toluene solution (900. Mu.L, 1M) was slowly added dropwise under nitrogen protection, and after 10min, anhydrous aluminum trichloride (123 mg,0.9 mmol) was added, followed by slowly adding cyclobutylnitrile (74. Mu.L, 1 mmol). After the completion of the dropwise addition, the reaction was carried out at 90℃for 3 hours, cooled to room temperature, diluted hydrochloric acid solution (1 mL, 2N) and water (5 mL) were added, refluxed for 30 minutes, the organic phase was separated, saturated sodium bicarbonate (10 mL) was washed to be weakly acidic, dichloromethane was extracted (10 mL. Times.3), anhydrous sodium sulfate was dried, filtered, and the organic solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=10:1) to give 2G as a brown oil (60 mg, yield 38%).
1 H NMR(400MHz,CDCl 3 )δ＝7.91(d,1H),6.51(d,1H),3.12–3.05(m,2H),3.04–2.95(m,2H),2.67–2.54(m,1H),1.19–1.10(m,2H),1.00–0.87(m,2H)。
Seventh step:
3- (1-Cyclopropylvinyl) bicyclo [4.2.0] oct-1 (6), 2, 4-trien-2-amine (2H)
3-(1-Cyclopropylvinyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine
To a 25mL three-necked flask, triphenylphosphine bromide (8G, 22 mmol) and anhydrous tetrahydrofuran (40 mL) were sequentially added, the solution was dissolved in an ice-water bath, potassium tert-butoxide (2.5G, 22 mmol) was added under nitrogen protection, a tetrahydrofuran solution (20 mL) of 2G (1.4G, 7.5 mmol) was added after 40min, the mixture was reacted at room temperature for 2H after 10min, quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.3), dried over anhydrous sodium sulfate, filtered and the organic solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=10:1) to give 2H (1.2G, brown oil, yield 85%).
1 H NMR(400MHz,CDCl 3 )δ＝6.87(d,1H),6.49(d,1H),5.17(d,1H),4.91(d,1H),3.09(dd,2H),3.03(dd,2H),1.63(tt,1H),0.77–0.67(m,2H),0.54–0.44(m,2H)。
Eighth step:
(R) -3- (1-cyclopropylethyl) bicyclo [4.2.0] oct-1 (6), 2, 4-trien-2-amine (2I)
(R)-3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine
Into a 500mL autoclave, 2H (500 mg,2.7 mmol) and methylene chloride (50 mL) were added, ruthenium [ (R) -2,2' -bis (diphenylphosphine) -1, 11-binaphthyl ] diacetate (113 mg,0.14 mmol) as a catalyst was added, the autoclave was tightly sealed after the addition, the autoclave was replaced with hydrogen 3 times, the pressure of the gauge on the autoclave was 14atm, and the reaction was carried out at room temperature for 5 hours. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=10:1) to give 2I (470 mg, pale yellow oil, yield 94%).
1 H NMR(400MHz,DMSO)δ＝6.95(d,1H),6.30(d,1H),2.88(s,4H),2.2(m,1H),1.23(d,3H),0.97(m,1H),0.46(m,1H),0.29(dt,1H),0.12(dt,1H),0.01(dt,1H)。
Ninth step
N- ((3- ((R) -1-cyclopropylethyl) bicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) carbamoyl) -2- ((S) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimid amide (2J)
N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
In a 25mL round bottom flask, 2I (133 mg,0.71 mmol), dry tetrahydrofuran (3 mL), diisopropylethylamine (191 mg,1.48 mmol) and 2, 2-trichloroethyl chloroformate (177 mg,0.84 mmol) were added sequentially under nitrogen and the reaction was stirred for 30min and TLC monitored for complete conversion. The reaction mixture was added with 5mL of water, extracted with ethyl acetate (10 mL. Times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, and spun-dried. 3mL of dry tetrahydrofuran was added and dissolved as solution C. In another 50mL three-necked flask, intermediate 4 (300 mg,0.644 mmol) and 3mL dry tetrahydrofuran were added, and sodium hydride (31 mg,60%,0.77 mmol) was added while cooling with ice, and the reaction was stirred for 1h. Solution C was slowly added dropwise under ice bath at room temperature for 1h, and the completion of the reaction was monitored by LC-MS, triethylamine trihydrofluoride (309 mg,1.92 mmol) was slowly added dropwise. The reaction was carried out at room temperature overnight, TLC monitored the end of the reaction, the reaction solution was poured into water, ethyl acetate (20 ml×2), the combined organic phases were dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile/water=30%) to give 2J as a white solid (244 mg, yield 84.1%). LCMS m/z (ESI) =451.1 [ m+1].
Tenth step:
n- ((3- ((R) -1-cyclopropylethyl) bicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) carbamoyl) -2- ((S) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimid-amide (Compounds 2-1 and 2-2)
N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
Resolution of 2J (210 mg, 0.463 mmol) by SFC gave compound 2-1 (100 mg, yield 47.6%, rt=19.8238 min,98.44% ee) and compound 2-2 (95 mg, yield 45.2%, rt=18.351 min,100% ee). Chiral HPLC (AS) mobile phase n-hexane/ethanol=95/5; column temperature is 35 ℃; column pressure 80bar; the flow rate is 1mL/min; detector signal path 215nm@4.8nm; the start-stop wavelength of the diode array detector is 200-400 nm.
Compound 2-1: 1 H NMR(600MHz,DMSO)δ8.28(s,1H),8.05(s,1H),7.85(s,2H),7.16(d,1H),6.84(d,1H),6.12(s,1H),5.01(t,1H),3.54(d,2H),3.03–2.89(m,3H),2.41–2.27(m,1H),1.44(s,3H),1.12(d,3H),0.95–0.88(m,1H),0.48–0.39(m,1H),0.27–0.18(m,1H),0.11–0.05(m,1H),0.04–0.00(m,1H)。
compound 2-2: 1 H NMR(600MHz,DMSO)δ8.29(s,1H),8.05(s,1H),7.87(s,2H),7.17(d,1H),6.84(d,1H),6.14(s,1H),5.02(t,1H),3.53(d,2H),2.98(d,3H),2.36–2.27(m,1H),1.44(s,3H),1.09(d,3H),1.00–0.88(m,1H),0.50–0.42(m,1H),0.28–0.19(m,1H),0.19–0.07(m,1H),0.05–0.01(m,1H)。
example 3
N- ((2- (cyclobutylmethyl) -4-fluoro-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -2- (1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimide amide (Compound 3)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
The first step:
(2-amino-3-bromo-5-fluorophenyl) (cyclobutyl) methanone (3B)
(2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanone
3A (40 g,210.4 mmol) was added sequentially to a 1L three-necked flask, dichloroethane (500 mL), after dissolving, was placed in an ice-water bath, and a boron trichloride toluene solution (252.8 mL, 1M) was slowly added dropwise under nitrogen protection, and after 10min, anhydrous aluminum trichloride (33.6 g,252 mmol) was added, followed by slowly adding cyclobutylnitrile (59.2 mL,632 mmol). After the completion of the dropwise addition, the reaction was carried out at 90℃for 24 hours, cooled to room temperature, diluted hydrochloric acid solution (30 mL, 2N) was added, refluxed for 30 minutes, the organic phase was separated, saturated sodium bicarbonate (50 mL) was washed to be weakly acidic, dichloromethane was extracted (50 mL. Times.3), and the crude product 3B was dried over anhydrous sodium sulfate, filtered and removed under reduced pressure as a pale yellow oil (4.8 g, yield 8.8%).
1 H NMR(400MHz DMSO)δ＝7.27(dd,1H),6.79(dd,1H),5.17(d,2H),4.14–4.10(m,1H),2.06–2.86(m,5H),1.82–1.68(m,1H)
And a second step of:
(2-amino-3-bromo-5-fluorophenyl) (cyclobutyl) methanol (3C)
(2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanol
In a 250mL round bottom flask, 3B (4.8 g,17.3 mmol), anhydrous methanol (20 mL), sodium borohydride (2.0 g,51.9 mmol) were added sequentially, the reaction was allowed to proceed at room temperature for 2h, TCL was monitored to completion, the reaction was quenched by slowly dropping water (20 mL), extracted with dichloromethane (20 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the organic solvent removed under reduced pressure, and the crude product purified by column chromatography (petroleum ether: ethyl acetate=30:1) to give 3C as a white powder (2.6 g, yield 54%).
1 H NMR(400MHz DMSO)δ＝7.21(dd,1H),6.94(dd,1H),5.48(d,1H),5.03(s,2H),4.54(dd,1H),2.74–2.62(m,2H),1.98–1.68(m,6H)。
And a third step of:
2-bromo-6- (cyclobutylmethyl) -4-fluoroaniline (3D)
2-Bromo-6-(cyclobutylmethyl)-4-fluoroaniline
In a 50mL round bottom flask, 3C (850 mg,3 mmol), dichloromethane (20 mL), triethylsilane (1.4 mL,9 mmol) and trifluoroacetic acid (1 mL,9 mmol) were added sequentially, the reaction was completed at room temperature for 2h, TLC was monitored to complete the reaction, the reaction was quenched by slowly dropping saturated sodium bicarbonate solution (20 mL), dichloromethane extraction (20 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=10:1) to give 3D as a brown oil (530 mg, yield 69%).
1 H NMR(400MHz,Chloroform-d)δ7.06(dd,1H),6.70(dd,1H),3.36(s,2H),2.65(dq,1H),2.58(d,2H),2.22–2.07(m,2H),1.98–1.81(m,2H),1.83–1.63(m,2H)。
Fourth step:
2- (Cyclobutyl methyl) -4-fluoro-6- (2-methoxypyridin-4-yl) aniline (3E)
2-(Cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)aniline
In a 50mL round bottom flask, 3D (500 mg,1.93 mmol), dioxane (20 mL), sodium carbonate (616 mg,5.8 mmol) and palladium dichloro-bis (triphenylphosphine) under nitrogen (67.7 mg,0.0965 mmol) were added, 2-methoxypyridine-4-boronic acid (383 mg,2.50 mmol) reacted at 80℃for 24h and TLC monitored for completion. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give 3E as a brown oil (350 mg, yield 63.3%).
LCMS m/z(ESI)＝287.2[M+l]。
Fifth step:
n- ((2- (cyclobutylmethyl) -4-fluoro-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -2- (1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimide amide (Compound 3)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
In a 25mL round bottom flask, 3E (221 mg,0.772 mmol), dry tetrahydrofuran (3 mL), diisopropylethylamine (191 mg,1.48 mmol) and 2, 2-trichloroethyl chloroformate (191 mg,0.901 mmol) were added sequentially under nitrogen, stirred for 30min, and TLC monitored for complete conversion. The reaction mixture was added with 5mL of water, extracted with ethyl acetate (10 mL. Times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. 3mL of dry tetrahydrofuran was added and dissolved as solution C. In another 50mL three-necked flask, intermediate 4 (300 mg,0.644 mmol) and 3mL dry tetrahydrofuran were added, and sodium hydride (31 mg,60%,0.77 mmol) was added while cooling with ice, and the reaction was stirred for 1h. Solution C was slowly added dropwise under ice bath at room temperature for 1h, and LC-MS monitored completion of the reaction, triethylamine trihydrofluoride (311 mg,1.93 mmol) was slowly added dropwise. The reaction was carried out at room temperature overnight, TLC monitored the end of the reaction, the reaction was poured into water, ethyl acetate (20 ml×2), the combined organic phases dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane/methanol=20:1) to give compound 3 as a white solid (311 mg, yield 87.9%).
1 H NMR(400MHz,DMSO)δ8.27(s,1H),8.10(d,1H),7.92(s,1H),7.78(s,2H),7.10–7.03(m,1H),7.03–6.96(m,1H),6.90(s,1H),6.76(s,1H),6.11(d,1H),5.06–4.95(m,1H),3.87(s,3H),3.55(t,2H),2.61(s,2H),1.97(s,2H),1.83–1.74(m,2H),1.66(s,2H),1.45(d,4H)。
LCMS m/z(ESI)＝550.2[M+1]。
Example 4
N- ((2- (cyclobutylmethyl) -4-fluoro-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -2- (1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimide amide (Compounds 4-1 and 4-2)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
The first step:
n- ((2- (cyclobutylmethyl) -4-fluoro-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -2- (1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimide amide (4A)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
In a 25mL round bottom flask, 3E (221 mg,0.772 mmol), dry tetrahydrofuran (3 mL), diisopropylethylamine (191 mg,1.48 mmol) and 2, 2-trichloroethyl chloroformate (191 mg,0.901 mmol) were added sequentially under nitrogen, stirred for 30min, and TLC monitored for complete conversion. The reaction mixture was added with 5mL of water, extracted with ethyl acetate (10 mL. Times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. 3mL of dry tetrahydrofuran was added and dissolved as solution C. In another 50mL three-necked flask, intermediate 5 (300 mg,0.644 mmol) and 3mL dry tetrahydrofuran were added, and sodium hydride (31 mg,60%,0.77 mmol) was added while cooling with ice, and the reaction was stirred for 1h. Solution C was slowly added dropwise under ice bath at room temperature for 1h, and LC-MS monitored completion of the reaction, triethylamine trihydrofluoride (311 mg,1.93 mmol) was slowly added dropwise. The reaction was carried out at room temperature overnight, TLC monitored the end of the reaction, the reaction was poured into water, ethyl acetate (20 ml×2), the combined organic phases dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane/methanol=20:1) to give 4A as a white solid (177 mg, yield 50.0%).
LCMS m/z(ESI)＝550.2[M+1]。
And a second step of:
n- ((2- (cyclobutylmethyl) -4-fluoro-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -2- (1, 2-dihydroxypropan-2-yl) thiazol-5-sulfinamide (compounds 4-1 and 4-2)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
4A (177 mg,0.322 mmol) was resolved by SFC to give compound 4-1 (79 mg, yield 44.6%, RT=6.348 min,99.54% ee) and compound 4-2 (68 mg, yield 38.4%, RT=9.3411 min,98.42% ee). Chiral HPLC (AS) mobile phase n-hexane/ethanol=95/5; column temperature is 35 ℃; column pressure 80bar; the flow rate is 1mL/min; detector signal path 215nm@4.8nm; the start-stop wavelength of the diode array detector is 200-400 nm.
Compound 4-1: 1 H NMR(600MHz,DMSO)δ8.26(s,1H),8.13–8.05(m,1H),7.91(s,1H),7.77(s,2H),7.06(dd,1H),7.03–6.97(m,1H),6.88(s,1H),6.76(s,1H),6.12(s,1H),5.02(t,1H),3.87(s,3H),3.55(d,2H),2.66–2.59(m,2H),2.55(s,1H),2.04–1.91(m,2H),1.84–1.75 (m,2H),1.73–1.59(m,2H),1.45(s,3H)。
compound 4-2: 1 H NMR(600MHz,DMSO)δ8.26(s,1H),8.10(d,1H),7.91(s,1H),7.76(br,2H),7.06(dd,1H),7.01(dd,1H),6.90(s,1H),6.76(s,1H),6.11(s,1H),5.02(t,1H),3.86(s,3H),3.56(d,2H),2.62(d,2H),2.59–2.53(m,1H),2.03–1.91(m,2H),1.84–1.76(m,2H),1.72–1.60(m,2H),1.46(s,3H)。
example 5
N- ((5- ((S) -1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -2- ((R) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimid amide (Compounds 5-1 and 5-2)
N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
The first step:
n- ((5- ((S) -1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -2- ((R) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimidamide (5A)
N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
In a 25mL round bottom flask, intermediate 2 (133 mg,0.71 mmol), dry tetrahydrofuran 3mL, diisopropylethylamine (191 mg,1.48 mmol) and 2, 2-trichloroethyl chloroformate (177 mg,0.84 mmol) were added sequentially under nitrogen and the reaction was stirred for 30min and monitored by TLC for complete conversion. The reaction mixture was added with 5mL of water, extracted with ethyl acetate (10 mL. Times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, and spun-dried. 3mL of dry tetrahydrofuran was added and dissolved as solution C. In another 50mL three-necked flask, intermediate 4 (300 mg,0.644 mmol) and 3mL dry tetrahydrofuran were added, and sodium hydride (31 mg,60%,0.77 mmol) was added while cooling with ice, and the reaction was stirred for 1h. Solution C was slowly added dropwise under ice bath at room temperature for 1h, and the completion of the reaction was monitored by LC-MS, triethylamine trihydrofluoride (309 mg,1.92 mmol) was slowly added dropwise. The reaction was carried out at room temperature overnight, TLC monitored the end of the reaction, the reaction was poured into water, ethyl acetate (20 ml×2), the combined organic phases dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile/water=30%) to give 5A as a white solid (76 mg, yield 26.2%).
LCMS m/z(ESI)＝451.1[M+1]。
And a second step of:
n- ((5- ((S) -1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -2- ((R) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimid amide (Compounds 5-1 and 5-2)
N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
Resolution of 5A (76 mg,0.168 mmol) by SFC gave compound 5-1 (28 mg, yield 36.8%, rt=6.298 min,100% ee) and compound 5-2 (33 mg, yield 43.4%, rt=8.351 min,99.04% ee). Chiral HPLC (AS) mobile phase n-hexane/ethanol=95/5; column temperature is 35 ℃; column pressure 80bar; the flow rate is 1mL/min; detector signal path 215nm@4.8nm; the start-stop wavelength of the diode array detector is 200-400 nm.
Compound 5-1: 1 H NMR(600MHz,DMSO)δ8.29(s,1H),8.04(s,1H),7.82(s,2H),7.12(d,1H),7.04(d,1H),6.12(s,1H),5.02(t,1H),3.53(d,2H),2.82(t,2H),2.63(d,2H),2.26–2.15(m,1H),1.99–1.87(m,2H),1.44(s,3H),1.23(s,1H),1.06(d,3H),0.99–0.90(m,1H),0.48–0.41(m,1H),0.24–0.16(m,1H),0.09(d,1H),0.05–0.00(m,1H)。
compound 5-2: 1 H NMR(600MHz,DMSO)δ8.27(s,1H),8.04(s,1H),7.81(s,2H),7.17–7.08(m,1H),7.04(d,1H),6.10(s,1H),5.01(t,1H),3.54(d,2H),2.82(t,2H),2.71–2.59(m,2H),2.30–2.16(m,1H),1.93(d,2H),1.44(s,3H),1.10(d,3H),0.98–0.89(m,1H),0.48–0.38(m,1H),0.23–0.13(m,1H),0.10–0.03(m,1H),0.02–0.08(m,1H),0.00–0.07(m,1H)。
example 6
3-cyano-N- (((5- (1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -5- (1, 2-dihydroxypropan-2-yl) thiophene-2-sulfonamide (compounds 6-1 and 6-2)
3-Cyano-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide
The first step:
4-bromo-5-sulfamoylthiophene-2-carboxylic acid methyl ester (6B)
Methyl 4-bromo-5-sulfamoylthiophene-2-carboxylate
A mixture of 6A (30.0 g,135.70 mmol) chlorosulfonic acid (44.67 mL,678.52 mmol) and thionyl chloride (14.78 mL,203.56 mmol) was added in portions at 0deg.C. The mixture was stirred at 0℃for 20 minutes and then allowed to react at 50℃for 1 hour. At the end of the reaction, cool to room temperature, add dropwise 400mL (1:1) of ammonium bicarbonate, water and acetone solution at 0deg.C, and stir overnight. TLC checked the reaction to completion, filtered, the solid washed with ethyl acetate (100 mL), aqueous ethyl acetate (200 mL) extracted, the organic phases combined and concentrated to a dark oil. Purification by beating with dichloromethane (200 mL) gave 6B as a pale yellow solid (28 g, 68.74% yield).
LC-MS m/z(ESI)＝300.03[M+1]。
And a second step of:
3-bromo-5- (2-hydroxy-prop-2-yl) thiophene-2-sulfonamide (6C)
3-Bromo-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide
6B (28 g,93.29 mol) was dissolved in 500mL dry THF at room temperature, the ice-salt bath was cooled to-15℃and methyl magnesium bromide (155.48 mL,466.45 mol) was slowly added dropwise while maintaining the temperature at no more than 0℃and reacted at room temperature for 4h after the completion of the dropwise addition, and TLC monitoring was complete. The reaction mixture was quenched in 200mL ice water, extracted with EA (200 mL. Times.3), and the organic phases combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was washed with (ethyl acetate: petroleum ether=1:20 to 1:10) to give 6C as a white solid powder (4.5 g, yield 47.4%).
LC-MS m/z(ESI)＝300.0[M+1]。
And a third step of:
3-cyano-5- (prop-1-en-2-yl) thiophene-2-sulfonamide (6D)
3-Cyano-5-(prop-1-en-2-yl)thiophene-2-sulfonamide
6C (4.0 g,13.33 mmol) and cuprous cyanide (1.43 g,15.99 mmol) were dissolved in N, N dimethylformamide (40 mL) in a 50mL round bottom flask under nitrogen protection, the reaction was monitored by TLC for completion of the reaction, the reaction solution was poured into a saturated solution of sodium bicarbonate (100 mL), ethyl acetate (50 mL. Times.10) was extracted, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=10:1 to 1:5) to give 6D as a pale yellow solid (1.0 g, yield 30.47%).
LC-MS m/z(ESI)＝229[M+1]。
Fourth step:
(R) -3-cyano-N- (((5- (1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -5- (prop-1-en-2-yl) thiophene-2-sulfonamide (6E)
(R)-3-cyano-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(prop-1-en-2-yl)thiophene-2-sulfonamide
In a 25mL round bottom flask, intermediate 1 (1.31 g,6.51 mmol), dry tetrahydrofuran 50mL, diisopropylethylamine (1.53 mg,11.84 mmol) and 2, 2-trichloroethyl chloroformate (1.63 g,7.70 mmol) were added sequentially under nitrogen and the reaction stirred for 30min with complete TLC monitoring. The reaction mixture was extracted with 50mL of water and ethyl acetate (100 mL. Times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, and spun-dried. 3mL of dry tetrahydrofuran was added and dissolved as solution C. In another 50mL three-necked flask, 6D (1.35 g,5.92 mmol) and 3mL dry tetrahydrofuran were added, sodium hydride (474 mg,60%,11.84 mmol) was added under ice-bath, the reaction was stirred for 1h, TLC was monitored for the completion of the reaction, the reaction solution was poured into water, ethyl acetate (20 mL. Times.2) was added, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum concentration, and the residue was purified by medium-pressure preparation (acetonitrile/water=30%) to give 6E as a pale yellow oily substance 1.35g, yield 50.1%).
LCMS m/z(ESI)＝451.1[M+1]。
Fifth step:
3-cyano-N- (((5- ((R) -1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -5- (1, 2-dihydroxypropan-2-yl) thiophene-2-sulfonamide (6F)
3-Cyano-N-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide
In a 250mL round bottom flask, 6E (1.35 g,2.97 mmol) was dissolved in a mixed solvent of tert-butanol/acetone (45 mL/45 mL), NMO (696 mg,5.94 mmol) was added with stirring, after stirring at room temperature for 10min, aqueous solution of potassium osmium dihydrate (109 mg, 0.297mmol) was added dropwise (45 mL water), the reaction was completed at room temperature after the dropwise addition, TLC monitored for the end of the reaction, sodium bisulphite aqueous solution quenched the reaction, EA extracted (100 mL. Times.3), dried over anhydrous sodium sulfate, filtered and the organic solvent was removed under reduced pressure, and the crude product was purified by column chromatography (EA: PE=1:30-1.5:1) to give 6F as a yellow solid (240 mg, yield 16.5%).
LCMS m/z(ESI)＝490.1[M+1]。
Sixth step:
3-cyano-N- (((5- ((R) -1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -5- (1, 2-dihydroxypropan-2-yl) thiophene-2-sulfonamide (compounds 6-1 and 6-2)
3-Cyano-N-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide
Resolution of 6F (240 mg,0.491 mmol) by SFC gave compound 6-1 (39 mg, 16.3% yield, rt=8.630 min,99.22% ee) and compound 6-2 (43 mg, 17.9% yield, rt=15.803 min,99.40% ee). Chiral HPLC (AS) mobile phase n-hexane/ethanol=95/5; column temperature is 35 ℃; column pressure 80bar; the flow rate is 1mL/min; detector signal path 215nm@4.8nm; the start-stop wavelength of the diode array detector is 200-400 nm.
Compound 6-1: 1 H NMR(600MHz,DMSO)δ11.75(s,1H),9.46(s,1H),7.47(s,1H),7.22(d,1H),7.15(d,1H),6.03(s,1H),5.20(t,1H),3.49–3.41(m,2H),2.87(t,2H),2.78(t,2H),2.36–2.28(m,1H),2.03–1.98(m,2H),1.48(s,3H),1.21(d,3H),1.04–0.97(m,1H),0.54–0.40(m,1H),0.33–0.24(m,1H),0.17–0.10(m,1H),0.07–0.04(m,1H)。
Compound 6-2: 1 H NMR(600MHz,DMSO)δ11.74(s,1H),9.48(s,1H),7.47(s,1H),7.22(d,1H),7.16(d,1H),6.03(s,1H),5.21(t,1H),3.48–3.39(m,2H),2.88(t,2H),2.78(t,2H),2.37–2.29(m,1H),2.04–1.97(m,2H),1.49(s,3H),1.21(d,3H),1.04–0.97(m,1H),0.54–0.40(m,1H),0.33–0.24(m,1H),0.18–0.11(m,1H),0.08–0.05(m,1H)。
example 7
3-cyano-N- (((3- ((R) -1-cyclopropylethyl) bicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) carbamoyl) -5- (1, 2-dihydroxypropan-2-yl) thiophene-2-sulfonamide (compounds 7-1 and 7-2)
3-Cyano-N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide
The first step:
(R) -3-cyano-N- (((3- (1-cyclopropylethyl) bicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) carbamoyl) -5- (prop-1-en-2-yl) thiophene-2-sulfonamide (7A)
(R)-3-cyano-N-((3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-5-(prop-1-en-2-yl)thiophene-2-sulfonamide
In a 25mL round bottom flask, 2I (1.1 g,5.76 mmol), dry tetrahydrofuran (50 mL), diisopropylethylamine (1.4 g,10.48 mmol) and 2, 2-trichloroethyl chloroformate (1.45 g,6.81 mmol) were added sequentially under nitrogen and the reaction stirred for 30min with complete conversion monitored by TLC. The reaction mixture was extracted with 50mL of water and ethyl acetate (100 mL. Times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, and spun-dried. 3mL of dry tetrahydrofuran was added and dissolved as solution C. In another 50mL three-necked flask, 6D (1.2 g,5.24 mmol) and 3mL dry tetrahydrofuran were added, sodium hydride (420 mg,60%,10.48 mmol) was added under ice-bath, the reaction was stirred for 1h, TLC was monitored for the end of the reaction, the reaction solution was poured into water, ethyl acetate (20 mL. Times.2) was added, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by medium-pressure preparation (acetonitrile/water=30%) to give 7A as a pale yellow oil (1.14 g, yield 49.4%).
LCMS m/z(ESI)＝442.1[M+1]。
And a second step of:
3-cyano-N- (((5- ((R) -1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -5- (1, 2-dihydroxypropan-2-yl) thiophene-2-sulfonamide (7B)
3-Cyano-N-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide
In a 250mL round bottom flask, 7A (442 mg,1 mmol) was dissolved in a mixed solvent of tert-butanol/acetone (25 mL/25 mL), NMO (235 mg,2.0 mmol) was added with stirring, after stirring at room temperature for 10min, aqueous solution (45 mL) of potassium osmium dihydrate (37 mg,0.10 mmol) was added dropwise, the reaction was monitored at room temperature after the addition was completed, TLC monitored for the end of the reaction, aqueous solution of sodium bisulphite quenched the reaction, EA extraction (100 mL. Times.3), anhydrous sodium sulfate dried, filtered, and the organic solvent was removed under reduced pressure, and the crude product was purified by column chromatography (EA: PE=1:30-1.5:1) to give 7B as a yellow solid (210 mg, yield 44.2%).
LCMS m/z(ESI)＝476.1[M+1]。
And a third step of:
3-cyano-N- (((3- ((R) -1-cyclopropylethyl) bicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) carbamoyl) -5- (1, 2-dihydroxypropan-2-yl) thiophene-2-sulfonamide (compounds 7-1 and 7-2)
3-Cyano-N-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide
Resolution of 7B (210 mg,0.442 mmol) by SFC gave compound 7-1 (76 mg, yield 36.2%, rt=5.565 min,100% ee) and compound 7-2 (93 mg, yield 44.2%, rt=12.071min, 100% ee). Chiral HPLC (AS) mobile phase n-hexane/ethanol=95/5; column temperature is 35 ℃; column pressure 80bar; the flow rate is 1mL/min; detector signal path 215nm@4.8nm; the start-stop wavelength of the diode array detector is 200-400 nm.
Compound 7-1: 1 H NMR(600MHz,DMSO)δ9.87(s,1H),7.48(s,1H),7.26(d,1H),6.93(d,1H),6.03(s,1H),5.21(t,1H),3.47–3.38(m,2H),3.16(d,2H),3.03(t,2H),2.41–2.33(m,1H),1.48(d,3H),1.25(d,3H),1.11–1.02(m,1H),0.60–0.49(m,1H),0.37–0.30(m,1H),0.19–0.11(m,1H),0.09–0.02(m,1H)。
compound 7-2: 1 H NMR(600MHz,DMSO)δ9.84(s,1H),7.28(d,1H),7.00–6.84(m,1H),5.96(s,1H),5.21(s,1H),3.52-3.46(m,2H),3.20(d,2H),3.07(s,2H),2.49–2.42(m,1H),1.54(s,3H),1.29(d,3H),1.12–1.06(m,1H),0.62–0.54(m,1H),0.40–0.32(m,1H),0.26–0.19(m,1H),0.17–0.09(m,1H)。
example 8
N- ((3- ((S) -1-cyclopropylethyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) carbamoyl) -2- (1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimid amide (Compound 8)
N-((3-((S)-1-cyclopropylethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
The first step:
(6, 7-dihydro-5H-cyclopentyl [ B ] pyridin-4-yl) carbamic acid tert-butyl ester (8B)
Tert-butyl(6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate
In a 500mL three-necked flask, 8A (25 g,162.75 mmol), tert-butyl carbamate (28.7 g,244.12 mmol), X-phos (7.8 g,16.3 mmol), palladium acetate (1.83 g,8.14 mmol), cesium carbonate (105.8 g,325.5 mmol) and 1, 4-dioxane (400 mL) were sequentially added, the reaction was monitored for completion by TLC at 100℃under nitrogen, cooled to room temperature, quenched with water, extracted with ethyl acetate (200 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the crude product was slurried with ethyl acetate (60 mL) to give 8B as a pale yellow solid (24.1 g, yield 62.7%).
LC-MS m/z(ESI)＝235.3[M+1]。
And a second step of:
(3-bromo-6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) carbamic acid tert-butyl ester (8C)
Tert-butyl(3-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate
8B (24 g,102.13 mmol), NBs (27.3 g,153.2 mmol) and acetonitrile (200 mL) were added sequentially to a 500mL round bottom, the reaction was carried out for 8h at 60℃and monitored by TLC, cooled to room temperature, quenched with sodium bisulphite, extracted with ethyl acetate (200 mL. Times.3), dried over anhydrous sodium sulphate, filtered and the organic solvent removed under reduced pressure, and the crude product was purified by column chromatography (EA: PE=1:10-1:2) to give 8C as a pale yellow solid (35.2 g, 81.3% yield).
1 H NMR(400MHz,DMSO)δ9.18(s,1H),8.41(s,1H),2.89(t,2H),2.82(t,2H),2.10–1.98(m,2H),1.46(d,9H)。
LC-MS m/z(ESI)＝314.2[M+1]。
And a third step of:
(3- (1-Cyclopropylvinyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) carbamic acid tert-butyl ester (8D)
Tert-butyl(3-(1-cyclopropylvinyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate
8C (25 g,79.87 mmol), 2- (1-cyclopropylvinyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (18.6 g,95.85 mmol), (1, 1' -bis (diphenylphosphino) ferrocene) palladium dichloride (8.8 g,11.98 mmol), potassium phosphate (33.9 g,159.74 mmol) and 1, 4-dioxane/water mixed solvent (200 mL/50 mL) were added sequentially to a 500mL round bottom under nitrogen protection, reaction was performed at 100deg.C for 8h, TLC was monitored for reaction completion, cooled to room temperature, quenched with water, extracted with ethyl acetate (200 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the crude product was purified by column chromatography (EA: PE=1:30-1:5) to give 8D as a white solid (15.2 g, yield 63.3%).
LC-MS m/z(ESI)＝301.2[M+1]。
Fourth step:
(3- (1-Cyclopropylvinyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) carbamic acid tert-butyl ester (8E)
Tert-butyl(3-(1-cyclopropylvinyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate
8D (15 g,49.83 mmol) and dichloromethane (150 mL) were added sequentially to a 500mL round bottom, boron trifluoride diethyl etherate (28.4 g,200 mmol) was slowly added dropwise, the reaction was completed at room temperature after the addition, TLC was monitored to completion, water was added to quench, saturated sodium bicarbonate solution was adjusted to pH neutral, DCM was extracted (100 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the crude product was purified by column chromatography (EA: PE=1:30-1:3) to give 8E as a brown oil (3 g, yield 30%).
LC-MS m/z(ESI)＝201.1[M+1]。
Fifth step:
(S) -5- (1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-amine (8F)
(S)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine
The synthesis of 8F was carried out with reference to patent CN 108017559. Into a 250mL autoclave, 8E (480 mg,4.1 mmol) and methylene chloride (30 mL) were added, and ruthenium [ (S) -2,2' -bis (diphenylphosphine) -1, 11-binaphthyl ] diacetate (346 mg,0.41 mmol) as a catalyst was added, and after the addition, the autoclave was tightly sealed, replaced with hydrogen 3 times, charged with hydrogen, the pressure on the autoclave was 30atm, and the reaction was carried out at room temperature for 30 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (dCM/meoh=30:1-15:1) to give 8F as a pale yellow oil (343 mg, yield 41.5%,92.70% ee). Chiral HPLC (CHIRALPAK AY-3 (4.6x100 mm), mobile phase: methanol, column temperature: 35 ℃, mobile phase: methanol/n-hexane=15/85, column pressure: 2000psi, flow rate: 2mL/min, detector signal path: 215nm@4.8nm, diode array detector start-stop wavelength: 200-400 nm, rt= 8.765 min).
1 H NMR(400MHz,DMSO)δ7.88(s,1H),5.40(s,2H),2.70(t,2H),2.62(t,2H),2.22–2.18(m,1H),2.00–1.94(m,2H),1.17(d,3H),1.11–1.00(m,1H),0.54–0.45(m,1H),0.40–0.29(m,1H),0.19–0.09(m,1H),0.07–0.00(m,1H)。
LCMS m/z(ESI)＝202.1[M+1]。
Sixth step:
n- ((3- ((S) -1-cyclopropylethyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) carbamoyl) -2- ((S) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimid amide (Compound 8)
N-((3-((S)-1-cyclopropylethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2- ((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
In a 25mL round bottom flask, 8F (144 mg, 0.218 mmol), dry tetrahydrofuran 50mL, diisopropylethylamine (167 mg,1.288 mmol) and 2, 2-trichloroethyl chloroformate (164 mg,0.773 mmol) were added sequentially under nitrogen and the reaction stirred for 30min with complete conversion monitored by TLC. The reaction mixture was extracted with 50mL of water and ethyl acetate (100 mL. Times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, and spun-dried. 3mL of dry tetrahydrofuran was added and dissolved as solution C. In another 50mL three-necked flask, intermediate 4 (300 mg,0.644 mmol) and 3mL dry tetrahydrofuran were added, sodium hydride (52 mg,60%,1.288 mmol) was added under ice-bath, the reaction was stirred for 1h, TLC was monitored for the end of the reaction, the reaction solution was poured into water, ethyl acetate (20 mL. Times.2) was added, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by medium-pressure preparation (acetonitrile/water=30%) to give compound 8 as a pale yellow solid (92 mg, yield 30.7%).
1 H NMR(600MHz,DMSO)δ8.61(s,1H),8.27(s,1H),8.05(d,1H),7.78(s,2H),6.14(d,1H),5.06–4.98(m,1H),3.54(t,2H),2.84(t,2H),2.74–2.61(m,2H),2.31–2.21(m,1H),2.06–1.90(m,2H),1.44(s,3H),1.22–1.10(m,3H),1.07–0.95(m,1H),0.53–0.38(m,1H),0.31–0.18(m,1H),0.18–0.07(m,1H),0.04–-0.00(m,1H)。
LCMS m/z(ESI)＝466.2[M+1]。
Example 9
(N- ((5- ((S) -1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (1, 2-dihydroxypropan-2-yl) furan-2-sulfonylimidamide (Compounds 9-1 and 9-2)
N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
The first step:
(R) -N' - (tert-butyldimethylsilyl) -N- (((5- (1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (2-hydroxypropan-2-yl) furan-2-sulfonylimidamide (9A)
(R)-N'-(tert-butyldimethylsilyl)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
In a 100mL round bottom flask, intermediate 2 (3.1 g,15.4 mmol), triethylamine (1.87 g,18.5 mmol) and tetrahydrofuran (100 mL) were added sequentially under nitrogen protection, triphosgene (1.83 g,6.2 mmol) was added under ice bath, the reaction was heated to reflux for 2h, the solid was removed by filtration, intermediate 3 (4.9 g,15.4 mmol) and sodium methoxide (1.66 g,30.8 mmol) were added to the filtrate, and the reaction was carried out at room temperature for 12h. TLC monitored complete reaction, and the reaction was completed to give compound 9A, which was taken directly to the next step without purification.
LCMS m/z(ESI)＝546.3[M+l]。
And a second step of:
(R) -N- ((5- (1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -4- (2-hydroxypropan-2-yl) furan-2-sulfonylimidamide (9B)
(R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
Tetrabutylammonium fluoride (6.2mL,61.6mmol,1M in THF) was added to the reaction system for the previous step of synthesizing compound 9A, the reaction was carried out at room temperature overnight, TLC was monitored to end the reaction, the reaction solution was poured into water, ethyl acetate (100 ml×3) was extracted, the organic phases were combined, washed once with 1M diluted HCl, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile/water=50%) to give 9B as a transparent solid (1.2 g, yield 18.2%).
LCMS m/z(ESI)＝432.2[M+l]。
And a third step of:
n- (((5-1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (2-hydroxypropan-2-yl) furan-2-sulfonylimidamide (9C)
N-((5-(-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
Resolution of racemate 9B by SFC afforded 9C (537 mg, yield 44.8%,98.80% ee, rt= 14.041 min), chiral HPLC (OZ); mobile phase n-hexane/ethanol=90/10; column temperature is 35 ℃; column pressure 80bar; the flow rate is 1mL/min; detector signal path 215nm@4.8nm; the initial wavelength of the diode array detector is 200nm; the diode array detector terminates at a wavelength of 400nm.
1 H NMR(400MHz,DMSO-d6)δ＝8.23(br,1H),7.67(s,1H),7.62(br,1H),7.12(d,1H),7.04(d,1H),6.96(br,1H),5.09(s,1H),2.82(t,2H),2.71–2.62(m,2H),2.33–2.19(m,1H),1.94–1.91(m,2H),1.38(s,6H),1.09(d,3H),0.98–0.91(m,1H),0.48–0.45(m,1H),0.23–0.20(m,1H),0.13–0.10(m,1H),0.06–0.05(m,1H)。
LCMS m/z(ESI)＝432.2[M+l]。
Fourth step:
(S) -N- (((5- ((S) -1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (2-hydroxypropan-2-yl) furan-2-sulfonylimidamide (9D)
(S)-N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
9C (2.0 g,4.63 mmol) was dissolved in tetrahydrofuran (40 mL) in a 100mL single-necked flask under nitrogen protection, the temperature was lowered to 0℃in an ice bath, and a Buerger's reagent (2.2 g,9.26 mmol) was slowly added thereto, and after keeping the temperature for 10 minutes, the reaction system was returned to room temperature for 2 hours. At the end of the reaction, ethyl acetate (50 ml×3) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol=60:1) to give 9D as a white solid (1.0 g, yield 52.1%).
LCMS m/z(ESI)＝414.20[M+1]。
Fifth step:
(S) -N- (((5- (1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (1, 2-dihydroxypropan-2-yl) furan-2-sulfonylimidamide (9E)
(S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2- dihydroxypropan-2-yl)furan-2-sulfonimidamide
In a 100mL single-necked flask, 9D (1.0 g,2.42 mmol) was dissolved in t-butanol under nitrogen: in acetone (10 mL:10 mL), the ice-salt bath was cooled to 0 ℃, 4-methylmorpholine-N-oxide (566 mg,4.84 mmol) was added, an aqueous solution (10 mL) of potassium osmium carbonate monohydrate (88 mg,0.24 mmol) was slowly added dropwise, after the addition was completed, the reaction was allowed to proceed to room temperature for 10min, the reaction was allowed to proceed to room temperature for 1h, the reaction was ended, cooled to room temperature, quenched with saturated aqueous sodium hydrogen sulfite solution, extracted with ethyl acetate (50 mL. Times.3), the organic phase was washed with saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol=30:1) to give 9E as a white solid (0.5 g, yield 46.2%).
Sixth step:
(N- ((5- ((S) -1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (1, 2-dihydroxypropan-2-yl) furan-2-sulfonylimidamide (Compounds 9-1 and 9-2)
N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
9E (500 mg,1.116 mmol) was resolved by SFC to give compound 9-1 (200 mg, 40.0% yield, RT=6.441 min,99.02% ee) and compound 9-2 (205 mg, 40.1% yield, RT=5.036 min,100% ee). Chiral HPLC (AS) mobile phase n-hexane/ethanol=95/5; column temperature is 35 ℃; column pressure 80bar; the flow rate is 1mL/min; detector signal path 215nm@4.8nm; the start-stop wavelength of the diode array detector is 200-400 nm.
Compound 9-1: 1 H NMR(400MHz,Methanol-d 4 )δ7.58(s,1H),7.16(d,1H),7.06(d,1H),7.00(s,1H),3.60–3.45(m,2H),2.89–2.83(t,2H),2.80–2.73(m,2H),2.33–2.26(m,1H),2.05–1.98(m,2H),1.44(s,3H),1.21–1.19(d,3H),1.01–0.93(m,1H),0.59–0.47(m,1H),0.33–0.27(m,1H),0.19–0.05(m,2H)。
LCMS m/z(ESI)＝448.20[M+1]。
compound 9-2: 1 H NMR(400MHz,Methanol-d 4 )δ7.59(s,1H),7.16(d,1H),7.06(d,1H),7.00(s,1H),3.55–3.46(m,2H),2.89–2.83(t,2H),2.81–2.73(m,2H),2.33–2.26(m,1H),2.07–1.96(m,2H),1.45(s,3H),1.20(d,3H),1.00–0.92(m,1H),0.55–0.47(m,1H),0.22–0.07(m,2H)。
LCMS m/z(ESI)＝448.20[M+1]。
example 10
N- ((5- ((R) -1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (1, 2-dihydroxypropan-2-yl) furan-2-sulfonylimid-amide (Compounds 10-1 and 10-2)
N-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
The first step:
(S) -N' - (tert-butyldimethylsilyl) -N- (((5- (1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (2-hydroxypropan-2-yl) furan-2-sulfonylimidamide (10A)
(S)-N'-(tert-butyldimethylsilyl)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
In a 100mL round bottom flask, add intermediate 1 (2.6 g,12.9 mmol), triethylamine (1.57 g,15.5 mmol) and tetrahydrofuran 100mL in sequence under nitrogen protection, add triphosgene (1.54 g,5.2 mmol) under ice bath, heat up and reflux reaction for 2h, filter to remove solids, add intermediate 3 (4.1 g,12.9 mmol) and sodium methoxide (1.4 g,25.8 mmol) to the filtrate, and react at room temperature for 12h. TLC monitored complete reaction, and the reaction was completed to give compound 10A, which was taken directly to the next step without purification.
LCMS m/z(ESI)＝546.3[M+l]。
And a second step of:
(S) -N- ((5- (1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -4- (2-hydroxypropan-2-yl) furan-2-sulfonylimidamide (10B)
(S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
Tetrabutylammonium fluoride (5.2 mL,51.7mmol, 1M/THF) was added to the reaction system for the previous step to synthesize compound 10A, the reaction was carried out overnight at room temperature, TLC was monitored to end the reaction, the reaction solution was poured into water, ethyl acetate (100 mL. Times.3) was extracted, the organic phases were combined, washed once with 1M diluted HCl, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile/water=50%) to give racemate 10B as a transparent solid (2.6 g, yield 46.6%).
LCMS m/z(ESI)＝432.2[M+l]。
And a third step of:
n- (((5-1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (2-hydroxypropan-2-yl) furan-2-sulfonylimidamide (10C)
N-((5-(-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
Racemate 10B was resolved by SFC to give 10C (1.17 g, 45% yield, 99.70% ee, rt= 14.463 min). Chiral HPLC (OZ); mobile phase n-hexane/ethanol=90/10; column temperature is 35 ℃; column pressure 80bar; the flow rate is 1 mL/min; detector signal path 215nm@4.8nm; the initial wavelength of the diode array detector is 200nm; the termination wavelength of the diode array detector is 400nm; rt= 14.463min.
1 H NMR(400MHz,DMSO-d6)δ＝8.24(br,1H),7.67(s,1H),7.62(br,1H),7.12(d,1H),7.04(d,1H),6.97(br,1H),5.09(s,1H),2.82(t,2H),2.74–2.66(m,2H),2.28–2.19(m,1H),1.94–1.91(m,2H),1.38(s,6H),1.11(d,3H),0.98–0.85(m,1H),0.48–0.43(m,1H),0.23–0.14(m,1H),0.11–0.08(m,1H),0.04–0.01(m,1H)。
LCMS m/z(ESI)＝432.2[M+l]。
Fourth step:
(R) -N- (((5- (1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (prop-1-en-2-yl) furan-2-sulfonylimidamide (10D)
(R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide
10C (3.0 g,6.96 mmol) was dissolved in tetrahydrofuran (40 mL) in a 100mL single-necked flask under nitrogen protection, the temperature was lowered to 0℃in an ice bath, p-toluenesulfonic acid monohydrate (2.6 g,13.92 mmol) was slowly added, the temperature was kept for 10min, and the reaction system was returned to room temperature for 2h. At the end of the reaction, ethyl acetate (50 ml×3) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol=60:1) to give 10D as a white solid (1.8 g, yield 62.4%).
LCMS m/z(ESI)＝414.20[M+1]。
Fifth step:
(S) -N- (((5- (1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (1, 2-dihydroxypropan-2-yl) furan-2-sulfonylimidamide (10E)
(S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
10D (1.8 g,4.36 mmol) was dissolved in t-butanol in a 100mL single-necked flask under nitrogen: in acetone (18 mL:18 mL), the ice-salt bath was cooled to 0 ℃, 4-methylmorpholine-N-oxide (1.02 g,8.72 mmol) was added, an aqueous solution (10 mL) of potassium osmium carbonate monohydrate (161.9 mg,0.44 mmol) was slowly added dropwise, after the addition was completed, the reaction was allowed to proceed to room temperature for 10min, the reaction was allowed to proceed to room temperature for 1h, the reaction was completed, cooled to room temperature, quenched with saturated aqueous sodium hydrogen sulfite solution, extracted with ethyl acetate (50 mL. Times.3), the organic phase was washed with saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol=30:1) to give 10E as a white solid (0.9 g, yield 45.8%).
LCMS m/z(ESI)＝448.20[M+1]。
Sixth step:
n- ((5- (1-cyclopropylethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (1, 2-dihydroxypropan-2-yl) furan-2-sulfonylimid amide (Compounds 10-1 and 10-2)
N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
10E (900 mg,2.008 mmol) was resolved by SFC to give compound 10-1 (290 mg, yield 32.2%, RT=6.220 min,99.06% ee) and compound 10-2 (270 mg, yield 40.1%, RT=4.909 min,98.09% ee). Chiral HPLC (AS) mobile phase n-hexane/ethanol=90/10; column temperature is 35 ℃; column pressure 80bar; the flow rate is 1mL/min; detector signal path 215nm@4.8nm; the start-stop wavelength of the diode array detector is 200-400 nm.
Compound 10-1: 1 H NMR(400MHz,DMSO-d 6 )δ8.25(s,1H),7.68–7.63(m,3H),7.12(d,1H),7.04(d,1H),6.96(s,1H),5.04(s,1H),4.87(t,1H),3.35(d,2H),2.83–2.78(t,2H),2.74–2.61(m,2H),2.28–2.19(m,1H),1.94–1.88(m,2H),1.33(s,3H),1.11(d,3H),1.04–0.84(m,1H),0.46–0.40(m,1H),0.31–0.15(m,1H),0.13–0.07(m,1H),0.01–0.07(m,1H)。
LCMS m/z(ESI)＝448.20[M+1]。
compound 10-2: 1 H NMR(400MHz,DMSO-d 6 )δ8.16(s,1H),7.60–7.53(m,3H),7.02(d,1H),6.94(d,1H),6.86(s,1H),4.90(s,1H),4.73(t,1H),2.74–2.69(t,2H),2.62–2.52(m,2H),2.17–2.12(m,1H),1.86–1.80(m,2H),1.23(s,3H),1.02(d,3H),0.87–0.79(m,1H),0.38–0.30(m,1H),0.11–0.07(m,1H),0.06–0.11(m,1H)。
LCMS m/z(ESI)＝448.20[M+1]。
example 11
N- (((5- (cyclobutylmethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (prop-1-en-2-yl) furan-2-sulfonylimido amide (Compounds 11-1 and 11-2)
N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide
The first step:
(4-amino-2, 3-dihydro-1H-inden-5-yl) (cyclobutyl) methanone (11B)
(4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl)methanone
Compound 11A (5.0 g,37.54 mmol) was dissolved in 1, 2-dichloroethane (50 mL) in a 500mL three-necked flask under the protection of nitrogen, the ice-salt bath was cooled to 0℃and a solution of boron trichloride (37.5 mL,1M,37.54 mmol) in methylene chloride was slowly added dropwise, the reaction was carried out at this temperature for 10 minutes after the dropwise addition was completed, and then aluminum trichloride (5.5 g,41.3 mmol) and cyclobutylnitrile (4.55 g,56.3 mmol) were added; the reaction system is heated to 80 ℃ for reaction for 4 hours, cooled to room temperature, 40mL (2M HCl) is added under ice bath, and the temperature is raised and the reflux is carried out for 1 hour after the dropwise addition. At the end of the reaction, cooled to room temperature, extracted with DCM (75 ml×3), the organic phase was washed with 40mL of 2M sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, the organic solvent removed under reduced pressure, and the residue purified by column chromatography (petroleum ether: ethyl acetate=20:1) to give compound 11B as a white solid (2.6 g, yield 32.2%).
1 H NMR(400MHz,CDCl 3 )δ＝7.45(d,1H),6.56(d,1H),2.91(t,2H),2.70(t,2H),2.44–2.3(m,3H),2.25(m,2H),2.14–2.08(m,2H),2.07–2.00(m,1H),1.90–1.81(m,1H)。
LC-MS m/z(ESI)＝216.1[M+1]。
And a second step of:
(4-amino-2, 3-dihydro-1H-inden-5-yl) (cyclobutyl) methanol (11C)
(4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl)methanol
In a 50mL round bottom flask, ethanol (20 mL) and compound 11B (2.0 g,9.30 mmol) were added under nitrogen protection, the ice bath was cooled to 0 ℃, sodium borohydride (703 mg,18.60 mmol) was slowly added, and the reaction was resumed at room temperature for 1h; the reaction was quenched by dropwise addition of 20mL of water, extracted with DCM (30 ml×3), dried over anhydrous sodium sulfate, filtered, the solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 11C as a colorless oil (1.8 g, 89% yield).
LCMS m/z(ESI)＝200.1[M-l7]。
And a third step of:
5- (Cyclobutylmethyl) -2, 3-dihydro-1H-inden-4-amine (11D)
5-(Cyclobutylmethyl)-2,3-dihydro-1H-inden-4-amine
11C (1.3 g,5.98 mmol) and triethylsilane (2.1 g,17.94 mmol) were dissolved in DCM (20 mL) under nitrogen, ice-cooled to 0deg.C, trifluoroacetic acid (3.5 g,29.90 mmol) was slowly added dropwise, the reaction was allowed to react overnight at room temperature after the addition, the reaction was completed, saturated sodium bicarbonate water quenched, DCM (50 mL. Times.3) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, the organic solvent removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=20:1) to give 11D as a colorless oil (1.0 g, 83.1% yield).
1 H NMR(400MHz,CDCl 3 )δ＝6.83(d,1H),6.66(d,1H),2.89(t,2H),2.74(t,2H),2.66–2.62(m,1H),2.59(d,2H),2.13–2.07(m,4H),1.88–1.83(m,2H),1.77–1.70(m,2H)。
LC-MS m/z(ESI)＝201.1[M+1]。
Fourth step:
n- (tert-Butyldimethylsilyl) -N' - ((5- (cyclobutylmethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (2-hydroxypropan-2-yl) furan-2-sulfonylimid amide (11E)
N-(Tert-butyldimethylsilyl)-N'-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
Under nitrogen protection, 11D (1.5 g,7.46 mmol), triethylamine (11.02 g,8.95 mmol) and tetrahydrofuran (10 mL) were added sequentially, triphosgene (103 mg,0.40 mmol) was added under ice-bath, the reaction was heated to reflux for 2h, the solid was removed by filtration, intermediate 3 (1.1 g,2.98 mmol) and sodium methoxide (806 mg,14.9 mmol) were added to the filtrate, and the reaction was carried out at room temperature for 12h. The reaction was completed and used directly in the next step without purification. TLC monitored completion of the reaction, quench the reaction solution with water (50 mL), extract with DCM (100 mL. Times.3), dry the organic phase over anhydrous sodium sulfate, filter, remove the organic solvent, and purify the crude product by thin layer chromatography to give 11E as a pale yellow oily solid (1.43 g, 44.0% yield).
LCMS m/z(ESI)＝546.3[M+l]。
Fifth step:
n- ((5- (cyclobutylmethyl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -4- (2-hydroxypropan-2-yl) furan-2-sulfonylamide (11F)
N-((5-(Cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2- yl)furan-2-sulfonimidamide
Slowly dropwise adding tetrabutylammonium fluoride (15mL,1M in THF,15mmol) into the reaction system for synthesizing the compound 11E in the previous step under the protection of nitrogen, and recovering to room temperature after the dropwise adding is completed for reaction for 2 hours; at the end of the reaction, quench with water, extract with ethyl acetate (30 ml×3), dry the organic phase over anhydrous sodium sulfate, filter, remove the residue under reduced pressure, purify under medium pressure (acetonitrile/water=50%) to give 11F as a white solid (1.43 g, 44.0% yield).
LCMS m/z(ESI)＝432.2[M+l]。
Sixth step:
n- ((5- (cyclobutylmethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (2-hydroxypropan-2-yl) furan-2-sulfonylamino amide (11G)
N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
Racemate 11F was resolved by SFC to give 11G (680 mg,99.45% ee, rt= 10.896 min). Chiral HPLC (OX-3); mobile phase methanol; column temperature is 35 ℃; column pressure 80bar; the flow rate is 1mL/min; detector signal path 215nm@4.8nm; the initial wavelength of the diode array detector is 200nm; the diode array detector terminates at a wavelength of 400nm.
1 H NMR(400MHz,DMSO-d6)δ＝8.30(s,1H),7.69(d,1H),7.67(s,2H),6.99(s,1H),6.95(d,1H),6.86(d,1H),5.09(s,1H),2.80(t,2H),2.66(d,2H),2.58(d,2H),2.00–1.84(m,4H),1.83–1.70(m,2H),1.63(dd,2H),1.38(s,6H)。
LCMS m/z(ESI)＝432.2[M+l]。
Seventh step:
(S) -N- (((5- (cyclobutylmethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (prop-1-en-2-yl) furan-2-sulfonylimido amide (11H)
(S)-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide
11G (1.0G, 2.32 mmol) was dissolved in tetrahydrofuran (40 mL) in a 100mL single-necked flask under the protection of nitrogen, the temperature was lowered to 0℃in an ice bath, p-toluenesulfonic acid monohydrate (788 mg,4.64 mmol) was slowly added, the temperature was kept for reaction for 10min, and the reaction system was returned to room temperature for reaction for 2h. At the end of the reaction, ethyl acetate (50 ml×3) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol=60:1) to give 11H as a white solid (0.6 g, yield 62.5%).
LCMS m/z(ESI)＝414.20[M+1]。
Eighth step:
(S) -N- (((5- (cyclobutylmethyl) -2, 3-dihydro-1H-indan-4-yl) carbamoyl) -4- (1, 2-dihydroxypropan-2-yl) furan-2-sulfonylimido amide (11I)
(S)-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
Under nitrogen, 11H (0.6 g,1.45 mmol) was dissolved in t-butanol in a 100mL single-necked flask: in acetone (6 mL:6 mL), the ice-salt bath was cooled to 0 ℃, 4-methylmorpholine-N-oxide (399 mg,2.90 mmol) was added, an aqueous solution (6 mL) of potassium osmium carbonate monohydrate (55.2 mg,0.15 mmol) was slowly added dropwise, after the addition was completed, the reaction was allowed to proceed to room temperature for 10min, the reaction was allowed to proceed to room temperature for 1h, the reaction was completed, cooled to room temperature, quenched with saturated aqueous sodium hydrogen sulfite solution, extracted with ethyl acetate (50 mL. Times.3), the organic phase was washed with saturated aqueous saline solution, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol=30:1) to give compound 11I as a white solid (0.3 g, yield 46.2%).
LCMS m/z(ESI)＝448.20[M+1]。
Ninth step:
n- (((5- (cyclobutylmethyl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -4- (prop-1-en-2-yl) furan-2-sulfonylimido amide (Compounds 11-1 and 11-2)
N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide
11I (300 mg,0.669 mmol) was resolved by SFC to give compound 11-1 (105 mg, yield 35.0%, RT=12.374min, 98.60% ee) and compound 11-2 (99 mg, yield 33.0%, RT=7.3838 min,98.32% ee). Chiral HPLC (AS), mobile phase n-hexane/ethanol=90/10; column temperature is 35 ℃; column pressure 80bar; the flow rate is 1mL/min; detector signal path 215nm@4.8nm; the start-stop wavelength of the diode array detector is 200-400 nm.
Compound 11-1: 1 H NMR(400MHz,DMSO-d 6 )δ8.29(s,1H),7.65(d,1H),7.60(s,2H),6.98–6.92(m,2H),6.86(d,1H),5.00(s,1H),4.83(t,1H),2.80(t,2H),2.68–2.64(m,1H),2.59–2.55(d,2H),2.53–2.51(m,1H),1.94–1.88(m,4H),1.81–1.73(m,2H),1.66–1.58(m,2H),1.33(s,3H)。
LCMS m/z(ESI)＝448.20[M+1]。
compound 11-2: 1 H NMR(400MHz,DMSO-d 6 )δ8.28(s,1H),7.66(d,1H),7.60(s,2H),6.98–6.92(m,2H),6.86(d,1H),5.00(s,1H),4.83(t,1H),2.80(t,2H),2.76–2.60(m,1H),2.59–2.56(d,2H),2.51–2.48(m,1H),1.94–1.88(m,4H),1.83–1.73(m,2H),1.66–1.60(m,2H),1.33(s,3H)。
LCMS m/z(ESI)＝448.20[M+1]。
example 12
N- (((3, 5-bis (cyclobutylmethyl) pyridin-4-yl) carbamoyl) -2- (1, 2-dihydroxypropan-2-yl) thiazole-4-sulfonylimid amide (Compounds 12-1 and 12-2)
N-((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-4-sulfonimidamide
The first step:
3, 5-bis (cyclobutylmethyl) pyridin-4-amine (12B)
3,5-Bis(cyclobutylmethyl)pyridin-4-amine
In a 100mL three-necked flask, 12A (1.0G, 6.13 mmol), potassium cyclobutylmethyltrifluoroborate (4.3G, 24.54 mmol), potassium carbonate (5.1G, 36.78 mmol), ruphos Pd-G3 (775 mg,0.919 mmol) and toluene/water mixed solvent (40 mL/10 mL) were successively added, the reaction was refluxed for 5h, TLC detection was completed, cooled to room temperature, quenched with water, extracted with ethyl acetate (20 mL. Times.3), dried over anhydrous sodium sulfate, filtered and the organic solvent was removed under reduced pressure, and the crude product was purified by column chromatography (EA: PE=1:20 to 1:5) to give 12B as a pale yellow oil (1G, yield 36%).
And a second step of:
n- (((3, 5-bis (cyclobutylmethyl) pyridin-4-yl) carbamoyl) -2- (1, 2-dihydroxypropan-2-yl) thiazole-4-sulfonylimid amide (12C)
N-((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-4-sulfonimidamide
12B (115 mg,0.5 mmol), tetrahydrofuran (10 mL), N, N-diisopropylethylamine (177. Mu.L, 1.0 mmol) and 2, 2-trichloroethyl chloroformate (234. Mu.L, 1.5 mmol) were added sequentially to a 100mL round-bottomed flask under nitrogen and reacted at room temperature for 1h. Quench with water (10 mL), extract with ethyl acetate (20 mL. Times.3), dry over anhydrous sodium sulfate, filter, remove the organic solvent under reduced pressure, dissolve in tetrahydrofuran (10 mL), add intermediate 4 (510 mg,1.5 mmol) and sodium hydride (54 mg,2.25 mmol), and react at room temperature for 2h. Triethylamine hydrofluoric acid salt (284 mg,3 mmol) was added thereto, and the mixture was reacted at room temperature for 5 hours. TLC monitored complete reaction, quenched with water (20 mL), extracted with ethyl acetate (30 ml×3), dried over anhydrous sodium sulfate, filtered, the organic solvent removed and the crude product purified by medium pressure preparation (acetonitrile/water=60%) to give 12C as a pale yellow oil (420 mg, 75.3% yield).
And a third step of:
n- (((3, 5-bis (cyclobutylmethyl) pyridin-4-yl) carbamoyl) -2- (1, 2-dihydroxypropan-2-yl) thiazole-4-sulfonylimid amide (Compounds 12-1 and 12-2)
N-((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-4-sulfonimidamide
12C (120 mg) was resolved by SFC to give compound 12-1 (48 mg, yield 40%, RT=3.376 min,100% ee) and compound 12-2 (52 mg, yield 43.3%, RT=4.4476 min,100% ee). Chiral HPLC (AS) mobile phase n-hexane/ethanol=90/10; column temperature is 35 ℃; column pressure 80bar; the flow rate is 1mL/min; detector signal path 215nm@4.8nm; the start-stop wavelength of the diode array detector is 200-400 nm.
LC-MS m/z(ESI)＝493.18.
Compound 12-1: 1 H NMR(400MHz,DMSO-d6)δ8.18(s,2H),8.06(s,1H),7.92(s,2H),6.11(s,1H),5.06(s,1H),3.53(d,2H),2.59–2.54(m,4H),2.48–2.42(m,2H),1.90–1.83(m,4H),1.76–1.71(m,4H),1.65–1.58(m,4H),1.46(s,3H)。
compound 12-2: 1 H NMR(400MHz,DMSO-d6)δ8.14(s,2H),8.08(s,1H),7.91(s,2H),6.11(s,1H),5.00(s,1H),3.53(d,2H),2.59–2.56(m,4H),2.49–2.45(m,2H),1.90-1.82(m,4H),1.76–1.71(m,4H),1.61–1.55(m,4H),1.44(s,3H)。
example 13
(R) -N- (((2- (cyclobutylmethyl) -4-fluoro-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -4- (1, 2-dihydroxypropan-2-yl) furan-2-sulfonylimido amide (Compound 13)
(R)-N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
The first step:
(2-amino-3-bromo-5-fluorophenyl) (cyclobutyl) methanone (13B)
(2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanone
13A (40 g,210.4 mmol), dichloroethane (500 mL), after dissolving, was placed in an ice-water bath, and a solution of boron trichloride in toluene (252.8 mL, 1M) was slowly added dropwise under nitrogen protection, and after 10min, anhydrous aluminum trichloride (33.6 g,252 mmol) was added, followed by slowly adding cyclobutylnitrile (59.2 mL,632 mmol). After the completion of the dropwise addition, the reaction was carried out at 90℃for 24 hours, cooled to room temperature, diluted hydrochloric acid solution (30 mL, 2N) was added, refluxed for 30 minutes, the organic phase was separated, saturated sodium bicarbonate (50 mL) was washed to be weakly acidic, dichloromethane was extracted (50 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the crude product 13B was removed under reduced pressure as a pale yellow oil (4.8 g, yield 8.8%).
1 H NMR(400MHz DMSO)δ＝7.27(dd,1H),6.79(dd,1H),5.17(d,2H),4.14-4.10(m,1H),2.06–2.86(m,5H),1.82–1.68(m,1H)。
And a second step of:
(2-amino-3-bromo-5-fluorophenyl) (cyclobutyl) methanol (13C)
(2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanol
In a 250mL round bottom flask, 13B (4.8 g,17.3 mmol), anhydrous methanol (20 mL), sodium borohydride (2.0 g,51.9 mmol) were added sequentially, the reaction was carried out at room temperature for 2h, TCL was monitored to be complete, water (20 mL) was slowly added dropwise to quench the reaction, dichloromethane extraction (20 mL. Times.3), drying over anhydrous sodium sulfate, filtration, removal of the organic solvent under reduced pressure, purification of the crude product by column chromatography (petroleum ether: ethyl acetate=30:1) gave 13C as a white powder (2.6 g, yield 54%).
1 H NMR(400MHz DMSO)δ＝7.21(dd,1H),6.94(dd,1H),5.48(d,1H),5.03(s,2H), 4.54(dd,1H),2.74–2.62(m,2H),1.98–1.68(m,6H)。
And a third step of:
2-bromo-6- (cyclobutylmethyl) -4-fluoroaniline (13D)
2-Bromo-6-(cyclobutylmethyl)-4-fluoroaniline
In a 50mL round bottom flask, 13C (850 mg,3 mmol), dichloromethane (20 mL), triethylsilane (1.4 mL,9 mmol) and trifluoroacetic acid (1 mL,9 mmol) were added sequentially, the reaction was completed at room temperature for 2h, TLC was monitored to complete, the reaction was quenched by slowly dropping saturated sodium bicarbonate solution (20 mL), dichloromethane extraction (20 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=10:1) to give 13D as a brown oil (530 mg, yield 69%).
1 H NMR(400MHz,Chloroform-d)δ7.06(dd,1H),6.70(dd,1H),3.36(s,2H),2.65(dq,1H),2.58(d,2H),2.22–2.07(m,2H),1.98–1.81(m,2H),1.83–1.63(m,2H)。
Fourth step:
2- (Cyclobutyl methyl) -4-fluoro-6- (2-methoxypyridin-4-yl) aniline (13E)
2-(Cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)aniline
13D (500 mg,1.93 mmol), dioxane (20 mL), sodium carbonate (616 mg,5.8 mmol) and palladium dichloro-bis (triphenylphosphine) under nitrogen (67.7 mg,0.0965 mmol) were added in sequence to a 50mL round bottom flask, 2-methoxypyridine-4-boronic acid (383 mg,2.50 mmol) reacted at 80℃for 24h and TLC monitored for completion. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give 13E as a brown oil (350 mg, yield 63.3%).
LCMS m/z(ESI)＝287.2[M+l]。
Fifth step:
n- (((2- (cyclobutylmethyl) -4-fluoro-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -4- (2-hydroxypropyl-2-yl) furan-2-sulfonylimido amide (13F)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
13E (719 mg,1.5 mmol), tetrahydrofuran (10 mL), triphosgene (177.6 mg,0.6 mmol) and triethylamine (181.8, 1.8 mmol) were added sequentially to a 100mL round bottom flask under nitrogen protection, reacted at room temperature for 1h, filtered, intermediate 3 (510 mg,1.5 mmol) and sodium hydride (54 mg,2.25 mmol) were added and reacted at room temperature for 2h. Triethylamine hydrofluoric acid salt (284 mg,3 mmol) was added thereto, and the mixture was reacted at room temperature for 1 hour. TLC monitored complete reaction, quench the reaction with water (20 mL), extract with ethyl acetate (30 ml×3), dry the organic phase over anhydrous sodium sulfate, filter, remove the organic solvent, purify the crude product by medium pressure preparation (acetonitrile/water=30%) to give 13F as a white solid (260 mg, yield 30.1%).
Sixth step:
n- (((2- (cyclobutylmethyl) -4-fluoro-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -4- (2-hydroxypropyl-2-yl) furan-2-sulfonylimido amide (13G)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
13F (260 mg) was resolved by SFC to give 13G (110 mg, yield 38.6%, RT=3.786 min,100% ee). Chiral HPLC (AS) mobile phase n-hexane/ethanol=90/10; column temperature is 35 ℃; column pressure 80bar; the flow rate is 1mL/min; detector signal path 215nm@4.8nm; the start-stop wavelength of the diode array detector is 200-400 nm.
LC-MS m/z(ESI)＝516.18.
13G： 1 H NMR(400MHz,DMSO-d6)δ8.20(s,1H),8.15(d,1H),7.66(s,1H),7.63(s,2H),7.09(dd,1H),7.00(dd,1H),6.94(s,1H),6.74(s,1H),5.09(s,1H),3.88(s,3H),2.62- 2.59(m,2H),1.99-1.91(m,2H),1.83-1.80(m 2H),1.73-1.67(m,2H),1.38(s,6H)。
Seventh step:
n- (((2- (cyclobutylmethyl) -4-fluoro-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -4- (prop-1-en-2-yl) furan-2-sulfonylimido amide (13H)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide
13G (60 mg,0.12 mmol) was dissolved in tetrahydrofuran (5 mL) in a 100mL single-necked flask under the protection of nitrogen, the temperature was lowered to 0℃in an ice bath, a Buerger's reagent (88G, 0.36 mmol) was slowly added, the temperature was kept for 10min, and the reaction system was returned to room temperature for 2h. At the end of the reaction, ethyl acetate (10 ml×3) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile/water=20%) to give 13H as a white solid (37 mg, yield 61.7%).
LCMS m/z(ESI)＝498.17[M+1]。
Eighth step:
n- (((2- (cyclobutylmethyl) -4-fluoro-6- (2-methoxypyridin-4-yl) phenyl) carbamoyl) -4- (1, 2-dihydroxypropan-2-yl) furan-2-sulfonylimido amide (Compound 13)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
13H (40 mg,0.08 mmol) was dissolved in t-butanol: acetone (2 mL:2 mL) under nitrogen protection in a 100mL single-port flask, the ice-salt bath was cooled to 0 ℃, 4-methylmorpholine-N-oxide (18.7 mg,0.16 mmol) was added, an aqueous solution (2 mL) of potassium osmium carbonate monohydrate (4.4 mg,0.012 mmol) was slowly added dropwise, after this temperature reaction was maintained for 10min after the addition, the reaction system was returned to room temperature for 1H, the reaction ended, cooled to room temperature, quenched with saturated aqueous sodium hydrogen sulfite solution, extracted with ethyl acetate (10 mL. Times.3), the organic phase was washed with saturated brine solution, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile/water=30%) to give compound 13 as a white solid (10 mg, yield 25.8%).
LCMS m/z(ESI)＝532.18[M+1]。
Example 14
N- (((2- (2-cyanopyridin-4-yl) -6- (cyclobutylmethyl) -4-fluorophenyl) carbamoyl) -4- (1, 2-dihydroxypropan-2-yl) furan-2-sulfonylimido amide (Compound 14)
N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
The first step:
4- (2-amino-3- (cyclobutylmethyl) -5-fluorophenyl) pyridine carbonitrile (14A)
4-(2-Amino-3-(cyclobutylmethyl)-5-fluorophenyl)picolinonitrile
In a 100mL three-necked flask, 13D (1.5 g,5.8 mol) and 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridinin (2.01 g,8.6 mmol), 1,4 dioxane (30 mL), cesium carbonate (1.54 g,14.5 mmol) and catalyst [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (424 mg,0.58 mmol) were added and reacted at 90℃under reflux for 8h. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (PE: ea=8:1) to give 14A as a green solid (520 mg, yield 94%).
1 H NMR(400MHz,DMSO-d6)δ8.15(d,1H),7.66(s,2H),7.62(s,1H)7.63(m,2H),7.05(dd,1H),7.01(dd,1H),2.62-2.60(m,2H),2.53-2.51(m,1H)1.99-1.95(m,2H),1.83-1.80(m,2H),1.73-1.67(m,2H)。
LC-MS m/z(ESI)＝281.13.
And a second step of:
n- ((2- (2-cyanopyridin-4-yl) -6- (cyclobutylmethyl) -4-fluorophenyl) carbamoyl) -4- (2-hydroxypropan-2-yl) furan-2-sulfonylimid amide (14B)
N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
In a 100mL round bottom flask under nitrogen protection, 14A (719 mg,1.5 mmol), tetrahydrofuran (10 mL), triphosgene (177.6 mg,0.6 mmol) and triethylamine (181.8, 1.8 mmol) were added sequentially, reacted at room temperature for 1h, filtered, intermediate 3 (510 mg,1.5 mmol) and sodium hydride (54 mg,2.25 mmol) were added and reacted at room temperature for 2h. Triethylamine hydrofluoric acid salt (284 mg,3 mmol) was added thereto, and the mixture was reacted at room temperature for 1 hour. TLC monitored complete reaction, quench the reaction with water (20 mL), extract with ethyl acetate (30 ml×3), dry the organic phase over anhydrous sodium sulfate, filter, remove the organic solvent, quench the crude product, extract with ethyl acetate (30 ml×3), dry the organic phase over anhydrous sodium sulfate, filter, remove the organic solvent, purify the crude product by medium pressure preparation (acetonitrile/water=30%) to 14B, white solid (220 mg, yield 28.6%).
And a third step of:
n- ((2- (2-cyanopyridin-4-yl) -6- (cyclobutylmethyl) -4-fluorophenyl) carbamoyl) -4- (2-hydroxypropan-2-yl) furan-2-sulfonylimid amide (14C)
N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
14B (220 mg) was resolved by SFC to give 14C (85 mg, yield 38.6%, rt=2.463 min,100% ee). Chiral HPLC (AS) mobile phase n-hexane/ethanol=90/10; column temperature is 35 ℃; column pressure 80bar; the flow rate is 1mL/min; detector signal path 215nm@4.8nm; the start-stop wavelength of the diode array detector is 200-400 nm;
LC-MS m/z(ESI)＝511.17；
1 H NMR(400MHz,DMSO-d6)δ8.24(s,1H),8.15(d,1H),7.66(s,1H),7.63(s,2H),7.05(dd,1H),7.01(dd,1H),6.94(s,1H),6.78(s,1H),5.09(s,1H),2.62-2.55(m,2H),1.99-1.95(m,2H),1.83-1.80(m 2H),1.73-1.67(m,2H),1.38(s,6H)。
fourth step:
n- (((2- (2-cyanopyridin-4-yl) -6- (cyclobutylmethyl) -4-fluorophenyl) carbamoyl-4- (prop-1-en-2-yl) furan-2-sulfonylimido amide (14D)
N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide
Compound 14C (60 mg,0.12 mmol) was dissolved in tetrahydrofuran (5 mL) in a 100mL single-necked flask under nitrogen protection, the temperature was lowered to 0℃in an ice bath, a Buerger's reagent (88 g,0.36 mmol) was slowly added, the temperature was kept for reaction for 10min, and the reaction system was returned to room temperature for reaction for 2h. At the end of the reaction, ethyl acetate (10 ml×3) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile/water=20%) to give compound 14D as a white solid (40 mg, yield 66.7%).
LCMS m/z(ESI)＝493.16[M+1]。
Fifth step:
n- (((2- (2-cyanopyridin-4-yl) -6- (cyclobutylmethyl) -4-fluorophenyl) carbamoyl) -4- (1, 2-dihydroxypropan-2-yl) furan-2-sulfonylimido amide (Compound 14)
N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
In a 100mL single-port flask under nitrogen atmosphere, compound 14D (40 mg,0.08 mmol) was dissolved in t-butanol: acetone (2 mL:2 mL), the ice-salt bath was cooled to 0 ℃, 4-methylmorpholine-N-oxide (18.7 mg,0.16 mmol) was added, an aqueous solution (2 mL) of potassium osmium carbonate monohydrate (4.4 mg,0.012 mmol) was slowly added dropwise, after the addition was completed, the reaction was allowed to stand at this temperature for 10min, the reaction system was returned to room temperature for 1h, the reaction was ended, cooled to room temperature, quenched with saturated aqueous sodium hydrogen sulfite solution, extracted with ethyl acetate (10 mL. Times.3), the organic phase was washed with saturated brine solution, dried over anhydrous sodium sulfate, filtered, the organic solvent was removed under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile/water=40%) to give compound 14 as a white solid (10 mg, yield 25.2%).
LCMS m/z(ESI)＝527.16[M+1]。
Example 15
N' - ((5- ((R) -1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -2- ((S) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimidamide (Compound 15)
N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
The first step:
2- ((S) -1- ((tert-Butyldimethylsilanyloxy) -2-hydroxypropan-2-yl) -N- ((S) -1- (4-methoxyphenyl) ethyl) thiazole-5-sulfonylimid amide (15A)
2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
Intermediate 6-1 (2.0 g,3.3 mmol) was dissolved in 32mL of acetonitrile and 8mL of water, formic acid (603 mg,13.3 mmol) was added dropwise at room temperature, followed by stirring for 2h. TLC monitored completion of the reaction, pH was adjusted to neutral by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with saturated brine (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel (petroleum ether: ethyl acetate=40:1 to 20:1) gave 15A as a pale yellow oil (1.34 g, yield 84%).
1 H NMR(400MHz,DMSO-d 6 )δ7.50(s,1H),7.07(d,2H),6.72(d,2H),5.91(s,1H),4.39-4.32(m,1H),3.68(s,3H),3.61(s,2H),1.37(s,3H),1.22(d,3H),0.89(s,9H),0.03(s,3H),-0.06(s,3H)。
LC-MS m/z(ESI)＝486.2[M+1]。
And a second step of:
2- ((S) -1- ((tert-Butyldimethylsilanyloxy) -2-hydroxypropan-2-yl) -N' - ((5- ((R) -1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -N- ((S) -1- (4-methoxyphenyl) ethyl) thiazole-5-sulfonylimide amide (15B)
2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
In a 25mL round bottom flask, intermediate 1 (201 mg,1 mmol), dry tetrahydrofuran 5mL, diisopropylethylamine (258.5 mg,2 mmol) and 2, 2-trichloroethyl chloroformate (254.3 mg,1.2 mmol) were added sequentially under nitrogen, the reaction was stirred for 30min and TLC monitored for complete conversion. The reaction mixture was extracted with 5mL of water (10 mL. Times.2) and the organic phases were combined, dried over anhydrous sodium sulfate, and spun-dried. 3mL of dry tetrahydrofuran was added and dissolved as solution B. In another 50mL three-necked flask, 15A (437 mg,0.9 mmol) and 8mL dry tetrahydrofuran were added, and sodium hydride (120 mg,60%,3.0 mmol) was added under ice-bath to stir the reaction for 1h. Solution B was slowly added dropwise under ice bath, warmed to room temperature and reacted for 1h, the reaction was complete by lc-MS monitoring, the reaction solution was poured into water, dichloromethane (20 ml×2) was added, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile/water=30%) to give 15B as a pale yellow solid (264 mg, yield 63.1%).
LC-MS m/z(ESI)＝714.0[M+1]。
And a third step of:
n' - ((5- ((R) -1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -2- ((S) -1, 2-dihydroxypropan-2-yl) -N- ((S) -1- (4-methoxyphenyl) ethyl) thiazole-5-sulfonylimid amide (15C)
N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
15B (200 mg,0.28 mmol) and 3mL of dry tetrahydrofuran were added to a 50mL three-necked flask, triethylamine trihydrofluoride salt (225 mg,1.4 mmol) was slowly added dropwise, the temperature was raised to 40℃for 2 hours, TLC was monitored for completion of the reaction, the reaction solution was poured into water, ethyl acetate (20 mL. Times.2) was added, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure, and the residue was purified by medium-pressure preparation (acetonitrile/water=30%) to give 15C as a pale yellow solid (104 mg, yield 62.1%).
1 H NMR(400MHz,DMSO-d 6 )δ8.37(s,1H),7.76(s,1H),7.19(d,2H),7.15(d,1H),7.06(d,1H),6.79(d,2H),6.04(s,1H),4.95(t,1H),4.52(d,1H),3.71(s,3H),3.48(d,2H),2.84(t,3H),2.80-2.61(m,2H),2.30(m,1H),2.10-1.88(m,2H),1.38(s,3H),1.29(d,3H),1.15(d,4H),0.96(s,1H),0.45(d,1H),0.22(d,1H),0.18-0.07(m,1H),-0.00(s,2H)。
Fourth step:
n' - ((5- ((R) -1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -2- ((S) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimidamide (Compound 15)
N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
15B (100 mg,0.167 mmol) and 3mL of dried dichloromethane were added to a 50mL three-necked flask, triethylsilane (100 mg,0.835 mmol) was added at room temperature, and trifluoroacetic acid (1.8 mL) was stirred at room temperature for 1h. LC-MS monitored completion of the reaction, the reaction was poured into 10mL of water, ethyl acetate (20 mL. Times.2) was added, the combined organic phases were dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile/water=30%) to give compound 15 as a white solid (60 mg, yield 77.3%).
1 H NMR(400MHz,DMSO-d6)δ8.24(s,1H),8.01(s,1H),7.72(s,2H),7.12(d,1H),7.04(d,1H),6.09(s,1H),5.00(t,1H),3.53(d,3H),2.82(t,3H),2.66(s,2H),2.32-2.16(m,1H),1.94(m,2H),1.44(s,4H),1.08(d,4H),0.94(m,1H),0.54-0.38(m,1H),0.20(m,1H),0.10(m,1H)；
LC-MS m/z(ESI)＝465.6[M+1]。
Example 16
N' - ((5- ((R) -1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -2- ((S) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimidamide (Compound 16)
N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
The first step:
2- ((S) -1- ((tert-Butyldimethylsilyl) oxy) -2-hydroxypropyl-2-yl) -N- ((S) -1- (4-methoxyphenyl) ethyl) thiazole-5-sulfonylimid amide (16A)
2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
Intermediate 6-2 (2.0 g,3.3 mmol) was dissolved in 32mL acetonitrile and 8mL water, formic acid (603 mg,13.3 mmol) was added dropwise at room temperature and the reaction was stirred for 2h. TLC monitored completion of the reaction, pH was adjusted to neutral by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with saturated brine (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel (petroleum ether: ethyl acetate=40:1 to 20:1) gave 16A as a pale yellow oil (1.37 g, yield 85.9%).
1 H NMR(400MHz,DMSO-d 6 )δ7.55(s,1H),7.19-6.94(m,2H),6.70(s,2H),5.83(s,1H),4.61-4.11(m,1H),3.58(s,3H),3.51(s,2H)1.32(s,3H),1.20(d,3H),0.88(s,9H),0.20(s,3H),0.16(s,3H)。
LC-MSm/z(ESI)＝486.2[M+1]。
And a second step of:
2- ((S) -1- ((tert-butyldimethylsilyloxy) -2-hydroxypropan-2-yl) -N' - ((5- ((R) -1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -N- ((S) -1- (4-methoxyphenyl) ethyl) thiazole-5-sulfonylimide amide (16B)
2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
In a 25mL round bottom flask, intermediate 1 (603 mg,3 mmol), dry tetrahydrofuran 5mL, diisopropylethylamine (775 mg,6 mmol) and 2, 2-trichloroethyl chloroformate (762.6 mg,3.6 mmol) were added sequentially under nitrogen and the reaction stirred for 30min with complete conversion monitored by TLC. The reaction mixture was extracted with 10mL of water (20 mL. Times.2) and the organic phases were combined, dried over anhydrous sodium sulfate, and spun-dried. 10mL of dry tetrahydrofuran was added and dissolved as solution B. In another 50mL three-necked flask, 16A (1.31 g,2.7 mmol) and 20mL dry tetrahydrofuran were added, and sodium hydride (360 mg,60%,8.1 mmol) was added while stirring to react for 1h. Solution B was slowly added dropwise under ice bath, warmed to room temperature and reacted for 1h, the reaction was complete by lc-MS monitoring, the reaction solution was poured into water, dichloromethane (50 ml×2) was added, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile/water=30%) to give 16B as a pale yellow solid (1.2 g, yield 56.1%).
LC-MS m/z(ESI)＝714.0[M+1]。
And a third step of:
n' - ((5- ((R) -1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -2- ((S) -1, 2-dihydroxypropan-2-yl) -N- ((S) -1- (4-methoxyphenyl) ethyl) thiazole-5-sulfonylimid amide (16C)
N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
16B (300 mg,0.42 mmol) and 3mL of dry tetrahydrofuran were added to a 50mL three-necked flask, triethylamine trihydrofluoride salt (338.5 mg,2.1 mmol) was slowly added dropwise, the temperature was raised to 40℃for 2 hours, TLC was monitored to finish the reaction, the reaction liquid was poured into water, ethyl acetate (40 mL. Times.2) was added, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by medium-pressure preparation (acetonitrile/water=30%) to give 16C as a pale yellow solid (180 mg, yield 71.7%).
1 H NMR(400MHz,DMSO-d 6 )δ8.42(d,1H),8.22(s,1H),7.70(s,1H),7.16-7.08(m,2H),7.04(d,1H),6.72(d,2H),5.99(s,1H),4.93(t,1H),4.51(s,1H),3.68(s,3H),2.82(t,2H),2.65(s,2H),2.23(s,1H),2.07-1.85(m,2H),1.36(m,6H),1.07(d,3H),0.94(s,1H),0.44(s,1H),0.21(s,1H),0.12(s,1H)。
Fourth step:
n' - ((5- ((R) -1-cyclopropylethyl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -2- ((S) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimidamide (Compound 16)
N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
16C (100 mg,0.167 mmol) and 3mL of dried dichloromethane were added to a 50mL three-necked flask, triethylsilane (100 mg,0.835 mmol) was added at room temperature, trifluoroacetic acid (1.8 mL) was added, and the reaction was stirred at room temperature for 1h; LC-MS monitored reaction was complete, the reaction was poured into water, ethyl acetate (20 ml×2), the combined organic phases dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile/water=30%) to give compound 16 as a white solid (55 mg, yield 55.1%).
1 HNMR(400MHz,DMSO-d 6 )δ8.24(s,1H),8.01(s,1H),7.72(s,2H),7.12(d,1H),7.04(d,1H),6.09(s,1H),5.00(t,1H),3.53(d,2H),2.82(t,2H),2.66(s,2H),2.31-2.16(m,1H),1.94(m2H),1.44(s,3H),1.08(d,3H),0.94(m,1H),0.55-0.38(m,1H),0.20(m,1H),0.10(m,1H),0.02(d,2H)。
LC-MS m/z(ESI)＝465.6[M+1]。
Example 17
N' - ((3- ((R) -1-cyclopropylethyl) bicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) carbamoyl) -2- ((R) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimid amide (compound 17)
N'-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
The first step:
2- ((S) -1- ((tert-Butyldimethylsilyl) oxy) -2-hydroxypropyl-2-yl) -N- ((S) -1- (4-methoxyphenyl) ethyl) thiazole-5-sulfonylimid amide (17A)
2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
7G-1 (1.0G, 1.67 mmol) was dissolved in 24mL of acetonitrile and 6mL of water, and formic acid (307 mg,6.68 mmol) was added dropwise at room temperature and the reaction was stirred for 2h. TLC monitored completion of the reaction, pH was adjusted to neutral by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with saturated brine (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel (petroleum ether: ethyl acetate=40:1 to 20:1) gave 17A as a pale yellow oil (650 mg, yield 81.5%).
1 H NMR(400MHz,DMSO-d 6 )δ7.70(s,1H),7.13(d,2H),6.91-6.67(m,2H),5.97(s,1H),4.37(m,1H),3.69(s,3H),3.64(s,2H),1.41(s,3H),1.17(d,3H),0.81(s,9H),0.12-0.36(d,6H)。
LC-MS m/z(ESI)＝486.2[M+1]。
And a second step of:
2- ((R) -1- ((tert-Butyldimethylsilanyloxy) -2-hydroxypropan-2-yl) -N' - ((3- ((R) -1-cyclopropylethyl) bicyclo [4.2.0] oct-1 (6), 2, 4-trien-2-yl) carbamoyl) -N- ((S) -1- (4-methoxyphenyl) ethyl) thiazole-5-sulfonylimid-mide (17B)
2-((R)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N'-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
In a 25mL round bottom flask, 2I (187 mg,1 mmol), dry tetrahydrofuran (3 mL), diisopropylethylamine (258.5 mg,2 mmol) and 2, 2-trichloroethyl chloroformate (254.3 mg,1.2 mmol) were added sequentially under nitrogen and the reaction stirred for 30min and TLC monitored for complete conversion. The reaction mixture was extracted with 5mL of water (10 mL. Times.2) and the organic phases were combined, dried over anhydrous sodium sulfate, and spun-dried. 3mL of dry tetrahydrofuran was added and dissolved as solution B. To another 50mL three-necked flask, 17A (440 mg,0.9 mmol) and 3mL dry tetrahydrofuran were added, and sodium hydride (120 mg,60%,3.0 mmol) was added while stirring under ice to react for 1h. Solution B was slowly added dropwise under ice bath, warmed to room temperature and reacted for 1h, lc-MS monitored complete reaction, the reaction solution was poured into water, dichloromethane (20 ml×2) was added, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile/water=30%) to give 17B as a pale yellow solid (500 mg, yield 71.5%).
LC-MS m/z(ESI)＝700.2[M+1]。
And a third step of:
n' - ((3- ((R) -1-cyclopropylethyl) bicyclo [4.2.0] oct-1 (6), 2, 4-trien-2-yl) carbamoyl) -2- ((R) -1, 2-dihydroxypropan-2-yl) -N- ((S) -1- (4-methoxyphenyl) ethyl) thiazole-5-sulfonylimid amide (17C)
N'-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
17B (300 mg,0.43 mmol) and 3mL of dry tetrahydrofuran were added to a 50mL three-necked flask, triethylamine trihydrofluoride salt (311 mg,1.93 mmol) was slowly added dropwise, the temperature was raised to 40℃for 2 hours, TLC was monitored for completion of the reaction, the reaction solution was poured into water, ethyl acetate (20 mL. Times.2) was added, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by medium-pressure preparation (acetonitrile/water=30%) to give 17C as a pale yellow solid (180 mg, yield 71.7%).
LC-MS m/z(ESI)＝585.7[M+1]。
Fourth step:
n' - ((3- ((R) -1-cyclopropylethyl) bicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) carbamoyl) -2- ((R) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimid amide (compound 17)
N'-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
17C (180 mg,0.31 mmol) and 3mL of dried methylene chloride were added to a 50mL three-necked flask, triethylsilane (180 mg,1.55 mmol) was added at room temperature, and trifluoroacetic acid (1.8 mL) was added thereto, and the reaction was stirred at room temperature for 1h. LC-MS monitored reaction was complete, the reaction was poured into water, ethyl acetate (20 ml×2), the combined organic phases dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile/water=30%) to give compound 17 as a white solid (100 mg, yield 71.9%).
1 H NMR(400MHz,DMSO-d 6 )δ8.26(s,1H),8.05(s,1H),7.84(s,2H),7.16(d,1H),6.84(d,1H),6.11(s,1H),5.00(t,1H),3.54(d,2H),2.97(d,4H),2.45-2.25(m,1H),1.44(s,3H),1.12(d,3H),0.92(s,1H),0.44(m,1H),0.21(m,1H),0.09(m,1H),0.01(d,1H)
LC-MSm/z(ESI)＝451.5[M+1]。
Example 18
N' - ((3- ((R) -1-cyclopropylethyl) bicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) carbamoyl) -2- ((R) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimid amide (compound 18)
N'-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
The first step:
2- ((S) -1- ((tert-Butyldimethylsilyl) oxy) -2-hydroxypropyl-2-yl) -N- ((S) -1- (4-methoxyphenyl) ethyl) thiazole-5-sulfonylimid amide (18A)
2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
Intermediate 7-2 (1.2 g,2.0 mmol) was dissolved in 24mL acetonitrile and 6mL water, and formic acid (268 mg,8.0 mmol) was added dropwise at room temperature and the reaction was stirred for 2h. TLC monitored completion of the reaction, pH was adjusted to neutral by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with saturated brine (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel (petroleum ether: ethyl acetate=40:1 to 20:1) gave 18A as a pale yellow oil (710 mg, yield 73.1%).
1 HNMR(400MHz,DMSO-d 6 )δ7.75(s,1H),7.18(d,2H),6.96-6.73(m,2H),5.95(s,1H),4.42(m,1H),3.68(s,3H),3.64(s,2H),1.46(s,3H),1.22(d,3H),0.89-0.80(s,9H),0.06-0.01(d,6H)。
LC-MS m/z(ESI)＝486.2[M+1]。
And a second step of:
2- ((R) -1- ((tert-Butyldimethylsilanyloxy) -2-hydroxypropan-2-yl) -N' - ((3- ((R) -1-cyclopropylethyl) bicyclo [4.2.0] oct-1 (6), 2, 4-trien-2-yl) carbamoyl) -N- ((S) -1- (4-methoxyphenyl) ethyl) thiazole-5 sulfonylimide amide (18B)
2-((R)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N'-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
In a 25mL round bottom flask, 2I (400 mg,2.13 mmol), dry tetrahydrofuran (3 mL), diisopropylethylamine (550.6 mg,4.26 mmol) and 2, 2-trichloroethyl chloroformate (541.3 mg,2.77 mmol) were added sequentially under nitrogen, the reaction was stirred for 30min and the TLC monitored for complete conversion. The reaction mixture was extracted with 5mL of water (10 mL. Times.2) and the organic phase was combined, dried over anhydrous sodium sulfate and spun-dried. 3mL of dry tetrahydrofuran was added and dissolved as solution B. In another 50mL three-necked flask, 18A (937 mg,1.92 mmol) and 10mL dry tetrahydrofuran were added, and sodium hydride (260 mg,60%,6.39 mmol) was added under ice-bath to stir the reaction for 1h. Solution B was slowly added dropwise under ice bath, warmed to room temperature and reacted for 1h, lc-MS monitored complete reaction, the reaction solution was poured into water, dichloromethane (20 ml×2) was added, the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by medium pressure preparation (acetonitrile/water=30%) to give 18B as a pale yellow solid (1.06 g, yield 74.5%).
LC-MS m/z(ESI)＝700.2[M+1]。
And a third step of:
n' - ((3- ((R) -1-cyclopropylethyl) bicyclo [4.2.0] oct-1 (6), 2, 4-trien-2-yl) carbamoyl) -2- ((R) -1, 2-dihydroxypropan-2-yl) -N- ((S) -1- (4-methoxyphenyl) ethyl) thiazole-5-sulfonylimid amide (18C)
N'-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
In a 50mL three-necked flask were added 18B (300 mg,0.43 mmol) and 3mL dry tetrahydrofuran, triethylamine trihydrofluoride salt (311 mg,1.93 mmol) was slowly added dropwise, the temperature was raised to 40℃for 2 hours, TLC was monitored for completion of the reaction, the reaction solution was poured into water, ethyl acetate (20 mL. Times.2) was added, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by medium-pressure preparation (acetonitrile/water=30%) to give 18C as a pale yellow solid (150 mg, yield 59.8%).
LC-MS m/z(ESI)＝585.7[M+1]。
Fourth step:
n' - ((3- ((R) -1-cyclopropylethyl) bicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) carbamoyl) -2- ((R) -1, 2-dihydroxypropan-2-yl) thiazole-5-sulfonylimid amide (compound 18)
N'-((3-((R)-1-cyclopropylethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
In a 50mL three-necked flask, 18C (180 mg,0.31 mmol) and 3mL of dried methylene chloride were added, triethylsilane (180 mg,1.55 mmol) was added at room temperature, and trifluoroacetic acid (1.8 mL) was added, and the reaction was stirred at room temperature for 1h. LC-MS monitored reaction was complete, the reaction was poured into water, ethyl acetate (20 ml×2), the combined organic phases dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by medium pressure preparation (acetonitrile/water=30%) to give compound 18 as a white solid (90 mg, yield 64.8%).
1 H NMR(400MHz,DMSO-d6)δ8.27(s,1H),8.05(s,1H),7.85(s,1H),7.17(d,,1H),6.84(d,1H),6.12(s,1H),5.00(t,1H),3.53(d,2H),2.97(s,4H),2.32(s,1H),1.44(s,3H),1.09(d,3H),0.93(m,1H),0.46(m,1H),0.22(m,1H),0.11(m,1H),0.00(s,2H)。
LC-MS m/z(ESI)＝451.5[M+1]。
Biological test case
THP-1 cell culture
Human monocyte line THP-1%TIB-202. TM.) in RPMI-1640 medium containing 10% FBS,1mM pyruvic acid, 0.05mM beta-mercaptoethanol and 1% diabody at 37℃in 5% CO 2 。
THP-1 cell apoptosis assay
By cell counting, 50000 THP-1 cells per well were seeded in 96-well plates, 20nM PMA was added, and at 37℃CO was used at 5% concentration 2 Induction was carried out for 48 hours. The medium was discarded and 100. Mu.L of serum-free RPMI-1640 medium containing LPS at a concentration of 1. Mu.g/mL was added. 5 μl of compound or solvent control was added, starting with the highest dose of 10 μM, and a 3-fold gradient dilution was set for a total of 10 gradient concentrations. CO at 5% concentration at 37 °c 2 Incubate for 3 hours. After the incubation, 300g is centrifuged for 5 minutes, the culture medium is discarded, and the scorch analysis is carried out1 Inflammasome Assay kit) the detailed steps are carried out with reference to the kit instructions. Calculation of IC using GraphPad prism7.0 software 50 The results are shown in Table 1.
TABLE 1 inhibition of THP-1 cell apoptosis by the inventive compounds
Compounds of formula (I) IC 50 Compounds of formula (I) IC 50
1-1 A 2-1 A
2-2 B 3 B
4-1 B 5-1 B
6-1 A 7-1 A
7-2 A 8 B
9-1 A 9-2 A
10-1 A 10-2 A
11-1 A 11-2 A
12-2 B 17 A
Note that: a is less than or equal to 0.1uM, B is more than or equal to 0.1uM, C is more than or equal to 0.5uM, D is more than or equal to 1uM.
The results show that: the compound of the application can effectively inhibit the pyro-death of human monocyte series THP-1.
3. Human PBMC IL-1 beta Release assay
5mL of blood from human venous whole blood from healthy donors was placed in Li-heparin tubes. After PBMC were isolated using a PBMC isolation (sigma, 10771-100 mL) kit, cells were resuspended in RPMI-1640 medium containing 10% FBS and diluted to 2X 10 6 Each mL was placed in a petri dish at 37℃with 5% CO 2 Culturing in an incubator overnight. The next day, medium containing 10ng/mL LPS was added and incubated in the incubator for 3 hours. At a density of 1X 10 5 Cells were plated in 96-well plates per well. 25 μl of compound or solvent control was added per well, starting with the highest dose of 10 μM, diluted 3-fold gradient, set 8 gradient concentrations altogether, and incubated for 0.5 hours. 25. Mu.L of 5mM ATP was added to each well and incubated for 1 hour. After the incubation, the supernatant was collected by centrifugation at 1500rpm for 20 minutes, and the expression level of IL-1β was measured by ELISA (BD, human IL-1β ELISA Set II, cat# 557953). Calculation of IC using GraphPad prism7.0 software 50 . The results are shown in Table 2.
TABLE 2 inhibition of IL-1 beta Release by the Compounds of the application
Compounds of formula (I) IC 50 (nM)
2-1 18.7
7-1 9.8
7-2 5.8
The results show that: the compound can obviously inhibit the release of human PBMC IL-1 beta.
4. Human PBMC TNFα release assay
5mL of blood from human venous whole blood from healthy donors was placed in Li-heparin tubes. After PBMC were isolated using a PBMC isolation (sigma, 10771-100 mL) kit, cells were resuspended in RPMI-1640 medium containing 10% FBS and diluted to 2X 10 6 Each mL was placed in a petri dish at 37℃with 5% CO 2 Culturing in an incubator overnight. The next day according to 1X 10 5 Cells were seeded in 96-well plates per well. Subsequently, 25. Mu.L of compound or solvent control was added per well, starting from the highest dose of 10. Mu.M, diluted 5-fold in a gradient, set up a total of 9 gradient concentrations, at 37℃at 5% CO 2 Incubate for 24 hours. 25. Mu.L of LPS was added to each well at a final concentration of 100 ng/mL. 25. Mu.L of 5mM ATP was added to each well and incubated for 1.5 hours. After the incubation, the supernatant was collected by centrifugation at 1500rpm for 20 minutes, and the expression level of TNFα was measured by ELISA (BD, human TNFα ELISA Set II, cat# 555212). Calculation of IC using GraphPad P rism7.0 software 50 。
The results show that: the compound has no down regulation effect on the expression quantity of TNF alpha generated by PBMC induced by LPS.
5. Compound plasma and colon tissue distribution test
An appropriate amount of drug was weighed and formulated as a 5mg/mL solution using 5% DMSO and 30% HP-beta-CD. After healthy adult ICR mice are fasted overnight, the drugs to be tested (50 mg/kg) or a blank solvent are administrated by stomach irrigation, at four time points of 0.5, 2, 4 and 8 hours after administration, the animals are sacrificed through orbital veins Cong Caixie (EDTA-K2 anticoagulation), colon contents and colon tissues are collected, blood samples are centrifuged for 10min at 2000g at 4 ℃ to obtain plasma, the colon tissues are washed with ice-cold normal saline and then the moisture is absorbed, and all the samples are stored at-80 ℃ to be tested. Plasma and tissue were measured by LC/MS method, drug concentration in intestinal contents, and homogenization treatment was performed prior to colon tissue sample detection. The mean drug concentration at each time point is shown in fig. 1 and 2, wherein fig. 1 shows the colon-plasma drug profile of comparative example 1, and fig. 2 shows the colon-plasma drug profile of compound 7-1. Comparative example 1 was prepared as compound 1 procedure of 1- (1, 2,3,5,6, 7-hexahydro-s-indan-4-yl) -3- [4- (1-hydroxy-1-methyl-ethyl) -furan-2-sulfonyl ] urea (1- (1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methyl-ethyl) -furan-2-sulfofonyl ] urea), reference Synthetic Communications (2003), 33 (12), 2029-2043.
The results show that the compounds of the application have better gastrointestinal targeting than the control compounds.
While the specification describes in detail specific embodiments of the present application, those skilled in the art will recognize that the foregoing embodiments are illustrative and not to be construed as limiting the application, and that many variations and modifications of the application may be made without departing from the spirit of the application, which is intended to fall within the scope of the appended claims.

Claims (10)

  1. A compound of formula (I) or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterates thereof:
    wherein the method comprises the steps of
    Q is a 5-membered heteroaryl group comprising 1 or 2 heteroatoms selected from N, O and S, said 5-membered heteroaryl group optionally being substituted with 1 cyano or C 1-6 Alkyl substitution;
    l is- (CR) a R b )-；
    R a Is C 1-6 An alkyl group;
    R b is C 1-6 Alkyl, and the C 1-6 Alkyl is substituted with 1 OH;
    w is O or NH;
    y is- (CR) d R e )-；
    R d 、R e Each independently is H or C 1-6 An alkyl group;
    r and R 1 Each independently is H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 10 membered carbocyclyl or 4 to 10 membered heterocyclyl, said 4 to 10 membered heterocyclyl comprising 1, 2 or 3 heteroatoms selected from N, O and S, said C 1-6 Alkyl, 3-to 10-membered carbocyclyl or 4-to 10-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 groups selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Substituents for alkoxy, 3-to 6-membered carbocyclyl, and 5-to 6-membered heterocyclyl;
    alternatively, R and R 1 Together with the atoms to which they are attached, form a 4 to 6 membered ring;
    c is a 3-to 5-membered cycloalkyl group;
    R 2 is H or halogen;
    G 1 、G 2 、G 3 each independently is N or CH;
    r, q are each independently 0, 1 or 2;
    n is 0, 1, 2 or 3.
  2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers, and deuterates thereof, wherein
    Q is furyl, thiazolyl or thienyl, optionally substituted with 1 cyano group;
    l is- (CR) a R b )-；
    R a Is C 1-3 An alkyl group;
    R b is C 1-3 Alkyl, and the C 1-3 Alkyl is substituted with 1 OH;
    w is O or NH;
    y is- (CR) d R e )-；
    R d 、R e Each independently is H or C 1-3 An alkyl group;
    r and R 1 Each independently is H, halogen, cyano, C 1-3 Alkyl or pyridyl, said C 1-3 Alkyl or pyridyl optionally substituted with 1 to 4 groups selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy and 3 to 5 membered cycloalkyl;
    alternatively, R and R 1 Together with the atoms to which they are attached, form a 4 to 5 membered ring;
    C is a 3-to 5-membered cycloalkyl group;
    R 2 is H;
    G 1 、G 2 、G 3 each independently is N or CH;
    r, q are each independently 0, 1 or 2.
  3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers, and deuterates thereof, wherein:
    is that
    Is that
    W is O or NH.
  4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers, and deuterates thereof, wherein
    Q is furyl, thiazolyl or thienyl, optionally substituted with 1 cyano group;
    l is- (CR) a R b )-；
    R a Is C 1-3 An alkyl group;
    R b is C 1-3 Alkyl, and the C 1-3 Alkyl is substituted with 1 OH;
    w is O or NH;
    y is- (CR) d R e )-；
    R d 、R e Each independently is H or C 1-3 An alkyl group;
    r and R 1 Each independently is H or halogen; alternatively, R and R 1 Together with the atoms to which they are attached, form a 4 to 5 membered ring;
    c is a 3-to 5-membered cycloalkyl group;
    R 2 is H;
    G 1 、G 2 、G 3 each independently CH;
    r, q are each independently 0 or 1.
  5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers, and deuterates thereof, wherein
    Is that
    Is thatOr alternatively
  6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers, and deuterides thereof, wherein the compound is:
  7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterides thereof, and one or more pharmaceutically acceptable carriers and/or excipients.
  8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers thereof or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the treatment of an inflammatory disease, an autoimmune disease, a cardiovascular disease, cancer, a renal disease, a gastrointestinal disease, a respiratory disease, an endocrine disease or a central nervous system disease.
  9. Use of a compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers, or deuterated forms thereof, or a pharmaceutical composition of claim 7, for the manufacture of a medicament for the treatment of cryptopyrene related periodic syndrome (CAPS), mu Keer-weiles syndrome (MWS), familial Cold Autoinflammatory Syndrome (FCAS), neonatal Onset Multisystemic Inflammatory Disease (NOMID), familial Mediterranean Fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft versus host disease, multiple Sclerosis (MS), rheumatoid arthritis, type 1 diabetes, type 2 diabetes, psoriasis, alzheimer's disease, atherosclerosis, gout, or chronic kidney disease.
  10. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers, and deuterides thereof or a pharmaceutical composition according to claim 7 for the preparation of an NLRP3 inhibitor.
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