WO2022237780A1 - 酰胺衍生物及其应用 - Google Patents
酰胺衍生物及其应用 Download PDFInfo
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- WO2022237780A1 WO2022237780A1 PCT/CN2022/091982 CN2022091982W WO2022237780A1 WO 2022237780 A1 WO2022237780 A1 WO 2022237780A1 CN 2022091982 W CN2022091982 W CN 2022091982W WO 2022237780 A1 WO2022237780 A1 WO 2022237780A1
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- Prior art keywords
- alkyl
- reaction
- compound
- carbamoyl
- add
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- 125000002541 furyl group Chemical group 0.000 claims description 11
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- 206010016207 Familial Mediterranean fever Diseases 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 9
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 9
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- 125000003118 aryl group Chemical group 0.000 description 15
- 238000000034 method Methods 0.000 description 15
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- 238000000746 purification Methods 0.000 description 12
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 11
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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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Definitions
- the application relates to an amide derivative or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated products thereof, a pharmaceutical composition containing the above compound and its use in the preparation of an NLRP3 inhibitor.
- NLRs The NOD-Like Receptors (NLRs) of the nucleotide-binding oligomerization domain (NOD) are a class of Pattern Recognition receptors (Pattern Recognition receptors) located in the cytoplasm of mammalian cells. , PRRs), play a very important role in the innate immune response. NLRs are a group of cytoplasmic proteins with signal transduction functions, which are widely involved in the body's inflammatory response.
- the NLRs family includes NODs, NALPs (NLRPs), CIITA (NLRA) and IPAF (NLRC), among which NLRPs and NLRC subfamilies are the main two types of NOD-like receptors (NLRs), NLRPs can be divided into NLRP1, NLRP3, NLRP6, Inflammasome members such as NLRP7 and NLRP12.
- the NLRP3 inflammasome is a multiprotein complex composed of the NLRP3 protein itself, caspase-1, and apoptosis-associated speck-like protein containing CARD (ASC). Identify a variety of pathogenic microorganisms and stress-related endogenous signaling molecules.
- the classic NLRP3 inflammasome activation is activated by co-stimulation of two signals.
- the first signal activates the TLR4 (Toll like receptor4) signaling pathway, promotes the nuclear transcription factor ⁇ B into the nucleus, and induces the production of precursors such as IL-1 ⁇ and IL-18 .
- TLR4 Toll like receptor4
- the second signal promotes the formation of the NLRP3/ASC/pro-caspase-1 complex, which, when activated, associates with the Apoptosis-Associated Specklike Protein containing caspase activation and recruitment domains (ASC, Apoptosis-Associated Specklike Protein containing a CARD) polymerizes, ASC then interacts with cysteine protease caspase-1 to form a complex called inflammasome, the pro-caspase-1 self-cleaves into the activated form, (Wen , H., Miao, E.A. & Ting, J.P. Mechanisms of NOD-like receptor-associated inflammasome activation.
- caspase-1 Activated pro-inflammatory caspase-1 (caspase-1) cleavage precursor form Cytokines IL-1 ⁇ and IL-18, which are converted into active forms of IL-1 ⁇ and IL-18 and released extracellularly, recruit inflammatory cells to gather and expand the inflammatory response.
- ASC speck-like protein can also recruit and activate caspase-8 (caspase-8), cleave the precursor forms of IL-1 ⁇ and IL-18 to convert them into mature forms and trigger cell death.
- caspase-8 caspase-8
- Muckle-Wells syndrome mWS
- familial cold autoinflammatory syndrome neonatal-onset multisystem inflammatory disease
- Al Alzheimer's disease Parkinson's disease
- non-alcoholic fatty liver disease atherosclerosis
- asthma nephropathy
- enteritis tumor
- gout neurodegenerative disease
- diabetes and obesity are closely related to the occurrence process of various inflammatory diseases.
- NLRP3-related diseases include recombinant IL-1 receptor antagonist anakinra, neutralizing IL-1 ⁇ antibody canakinumab, and soluble IL-1 receptor decoy rilonacept, all of which are biological products.
- IL-1 receptor antagonist anakinra neutralizing IL-1 ⁇ antibody canakinumab
- soluble IL-1 receptor decoy rilonacept all of which are biological products.
- Rebecca C Coll et al. reported a new sulfonylurea small-molecule NLRP3 inhibitor compound MCC950, which inhibits the activity of NLRP3 inflammasome at the nanomolar level.
- Other small molecule compounds have been shown to inhibit NLRP3 inflammasome, such as: Glycine urea, parthenolide, 3,4-methylenedioxy- ⁇ -nitrostyrene (He, Y. et al.
- the purpose of this application is to provide novel amide derivatives or their pharmaceutically acceptable salts or all stereoisomers, tautomers and their deuterated products, their pharmaceutical compositions and their use in the preparation of NLRP3 inhibitors .
- One or more embodiments of the present application provide a compound of formula (I) or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated products thereof:
- Q is a 5-membered heteroaryl group, the 5-membered heteroaryl group contains 1 or 2 heteroatoms selected from N, O and S, and the 5-membered heteroaryl group is optionally replaced by 1 cyano group or C 1- 6 alkyl substitutions;
- L is -(CR a R b )-
- R a is C 1-6 alkyl
- R b is C 1-6 alkyl, and said C 1-6 alkyl is substituted by 1 OH;
- W is O or NH
- Y is -(CR d R e )-
- R d and Re are each independently H or C 1-6 alkyl
- R and R are each independently H, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy , 3 to 10 membered carbocyclyl or 4 to 10 membered heterocyclic group, the 4 to 10 membered heterocyclic group
- the 10-membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S, and the C 1-6 alkyl, 3 to 10-membered carbocyclic group or 4 to 10-membered heterocyclic group is optionally Substituted by 1, 2, 3 or 4 substituents selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered carbocyclyl and 5 to 6 membered heterocyclyl ;
- R and R together form a 4 to 6 membered ring with the atoms to which they are attached;
- C is 3 to 5 membered cycloalkyl
- R 2 is H or halogen
- G 1 , G 2 , and G 3 are each independently N or CH;
- r and q are each independently 0, 1 or 2;
- n 0, 1, 2 or 3.
- Q is furyl, thiazolyl or thienyl, said furyl, thiazolyl or thienyl is optionally substituted by 1 cyano group;
- L is -(CR a R b )-
- R a is C 1-3 alkyl
- R b is C 1-3 alkyl, and said C 1-3 alkyl is substituted by 1 OH;
- W is O or NH
- Y is -(CR d R e )-
- R d and Re are each independently H or C 1-3 alkyl
- R and R are each independently H, halogen, cyano, C 1-3 alkyl or pyridyl, and said C 1-3 alkyl or pyridyl is optionally replaced by 1 to 4 members selected from halogen, cyano Substituents of radical, C 1-3 alkyl, C 1-3 alkoxy and 3 to 5 membered cycloalkyl;
- R and R together form a 4 to 5 membered ring with the atoms to which they are attached;
- C is 3 to 5 membered cycloalkyl
- R2 is H ;
- G 1 , G 2 , and G 3 are each independently N or CH;
- r and q are 0, 1 or 2 each independently.
- W is O or NH.
- Q is furyl, thiazolyl or thienyl, said furyl, thiazolyl or thienyl is optionally substituted by 1 cyano group;
- L is -(CR a R b )-
- R a is C 1-3 alkyl
- R b is C 1-3 alkyl, and said C 1-3 alkyl is substituted by 1 OH;
- W is O or NH
- Y is -(CR d R e )-
- R d and Re are each independently H or C 1-3 alkyl
- R and R 1 are each independently H or halogen; or, R and R 1 together form a 4 to 5-membered ring with the atoms to which they are attached;
- C is 3 to 5 membered cycloalkyl
- R2 is H ;
- G 1 , G 2 , and G 3 are each independently CH;
- r and q are each independently 0 or 1.
- the compound is:
- One or more embodiments of the present application provide a pharmaceutical composition comprising the compound of the present application or a pharmaceutically acceptable salt thereof or all stereoisomers, tautomers and deuterated products thereof And one or more pharmaceutically acceptable carriers and/or excipients.
- One or more embodiments of the present application provide the compound of the present application or its pharmaceutically acceptable salt or all stereoisomers, tautomers and deuterated products thereof or the pharmaceutical composition of the present application for preparation Use in medicines for treating inflammatory diseases, autoimmune diseases, cardiovascular system diseases, cancer, renal system diseases, gastrointestinal tract diseases, respiratory system diseases, endocrine system diseases or central nervous system diseases.
- One or more embodiments of the present application provide the compound of the present application or its pharmaceutically acceptable salt or all stereoisomers, tautomers and deuterated products thereof or the pharmaceutical composition of the present application for preparation
- cryptothermic protein-associated periodic syndrome CRS
- Mukel-Wells syndrome MFS
- familial cold autoinflammatory syndrome FCAS
- NOMID neonatal-onset multisystem inflammatory disease
- Familial Mediterranean fever FMF
- nonalcoholic steatohepatitis nonalcoholic steatohepatitis
- alcoholic liver disease graft versus host disease
- MS multiple sclerosis
- rheumatoid arthritis type 1 diabetes, type 2 diabetes, psoriasis
- Al Use in medicine for Alzheimer's disease, atherosclerosis, gout or chronic kidney disease.
- One or more embodiments of the present application provide the compound of the present application or its pharmaceutically acceptable salt or all stereoisomers, tautomers and deuterated products thereof or the pharmaceutical composition of the present application in the preparation of NLRP3 Use in inhibitors.
- One or more embodiments of the present application provide a compound of general formula (I'), or a stereoisomer thereof:
- Q is selected from a 5-membered heteroaryl group, the heteroaryl group may contain 1 to 2 heteroatoms selected from N, O or S, and the heteroaryl group may be substituted by 0 or 1 cyano group;
- L is selected from -(CR a R b )-;
- R is selected from C 1-6 alkyl ;
- R b is selected from C 1-6 alkyl, and said alkyl is further substituted by 1 OH;
- W is selected from O or NH
- Y is selected from -(CR d R e )-;
- R d and R e are each independently selected from H or C 1-6 alkyl
- R and R are 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 heterocyclic group, the heterocyclyl
- the cyclic group can contain 1 to 3 heteroatoms selected from N, O or S, wherein said alkyl, carbocyclic or heterocyclic ring can be further replaced by 1 to 4 halogen, cyano, C 1-6 alkyl, Substituents of C 1-6 alkoxy, 3 to 6-membered carbocyclyl or 5 to 6-membered heterocyclic group;
- R and R may together form a 4 to 6 membered ring with the atoms to which they are attached;
- C is selected from 3 to 5 membered cycloalkyl groups
- R 2 is selected from H or halogen
- G 1 , G 2 , and G 3 are each independently selected from N or CH;
- q and r are selected from 0, 1 or 2;
- n is selected from 0, 1, 2 or 3.
- Q is selected from furyl, thiazolyl or thienyl, and Q can be further substituted by cyano;
- L is selected from -(CR a R b )- or 3 to 4 membered cycloalkyl, and said L is optionally further substituted by 0 to 2 -OH;
- R a and R b are each independently selected from H or C 1-3 alkyl
- W is selected from O or NH
- Y is selected from -(CR d R e )-;
- R d and R e are each independently selected from H or C 1-3 alkyl
- R and R are each independently selected from H, halogen, cyano, C 1-3 alkyl or pyridyl, and the C 1-3 alkyl or pyridyl can be further replaced by 1 to 4 halogen, cyano, C Substituents of 1-3 alkyl, C 1-3 alkoxy or 3 to 5 membered cycloalkyl;
- R and R may together form a 4 to 5 membered ring with the atoms to which they are attached;
- C is selected from 3 to 5 membered cycloalkyl groups
- R is selected from H
- G 1 , G 2 , and G 3 are each independently selected from N or CH;
- q and r are selected from 0, 1 or 2;
- n is selected from 0, 1, 2 or 3.
- W is selected from O or NH.
- the compound is:
- One or more embodiments of the present application provide a pharmaceutical composition comprising the 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 the use of the pharmaceutical composition of the present application or the compound of the present application or a stereoisomer thereof in the preparation of an NLRP3 inhibitor.
- diseases related to NLRP3 include: inflammatory diseases, autoimmune diseases, cardiovascular system diseases, cancer, renal system diseases, gastrointestinal diseases, respiratory system diseases, endocrine system diseases or central nervous system diseases systemic disease.
- diseases associated with NLRP3 include: cryptotherm-associated periodic syndrome (CAPS), Mukel-Wells 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.
- CAPS cryptotherm-associated periodic syndrome
- MFS Mukel-Wells syndrome
- FCAS familial cold autoinflammatory syndrome
- NOMID neonatal-onset multisystem inflammatory disease
- FMF familial Mediterranean fever
- nonalcoholic steatohepatitis alcoholic liver disease
- graft-versus-host disease multiple sclerosis (MS)
- rheumatoid Arthritis type 1 diabetes, type 2 diabetes, psoriasis
- One or more embodiments provide a compound of the present application, or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers, and deuterated products thereof, and compositions thereof for use as a medicament.
- One or more embodiments provide the compound of the present application or its pharmaceutically acceptable salt or all stereoisomers, tautomers and their deuterated products and compositions, which are used to treat diseases related to NLRP3 Methods.
- One or more embodiments provide the compound of the present application, or a pharmaceutically acceptable salt thereof, or all stereoisomers, tautomers, deuterated products and compositions thereof, for use as an NLRP3 inhibitor.
- One or more embodiments provide the compound of the present application or its pharmaceutically acceptable salt or all stereoisomers, tautomers and their deuterated products and compositions, which are used for the treatment of inflammatory diseases, self Methods for diseases of the immune system, cardiovascular system, cancer, renal system, gastrointestinal tract, respiratory system, endocrine system or central nervous system.
- One or more embodiments provide the compound of the present application or its pharmaceutically acceptable salt or all stereoisomers, tautomers and their deuterated products and compositions, which are used for the treatment of cryptotherm-related cycles syndrome (CAPS), Mukel-Wells 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, arterial A method for atherosclerosis, gout or chronic kidney disease.
- CAPS cryptotherm-related cycles syndrome
- MFS Mukel-Wells syndrome
- FCAS familial cold autoinflammatory syndrome
- NOMID neonatal-onset multisystem inflammatory disease
- FMF familial Mediterranean fever
- nonalcoholic steatohepatitis alcoholic liver disease
- One or more embodiments provide a method for the treatment/prevention of diseases associated with NLRP3, which comprises the compound of the present application or its pharmaceutically acceptable salt or all stereoisomers, tautomers and deuterium thereof Substitutes or compositions of the present application are given to objects in need.
- One or more embodiments provide a method for treating/preventing diseases, which includes the compound of the present application or its pharmaceutically acceptable salt or all stereoisomers, tautomers and deuterated products thereof or the present application
- the composition is administered to a subject in need thereof, and the disease is for the treatment of inflammatory diseases, autoimmune diseases, cardiovascular system diseases, cancer, renal system diseases, gastrointestinal tract diseases, respiratory system diseases, endocrine system diseases or central nervous system diseases disease.
- One or more embodiments provide a method for treating/preventing diseases, which includes the compound of the present application or its pharmaceutically acceptable salt or all stereoisomers, tautomers and deuterated products thereof or the present application
- the composition of the invention is administered to a subject in need thereof, and the diseases are cryptotherin-associated periodic syndrome (CAPS), Mukel-Wells 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, or chronic kidney disease.
- CAPS cryptotherin-associated periodic syndrome
- MFS Mukel-Wells syndrome
- FCAS familial cold autoinflammatory syndrome
- NOMID Neonatal-onset multisystem inflammatory disease
- FMF familial Mediterranean
- One or more embodiments provide a method for inhibiting NLRP3, which comprises the compound of the present application or its pharmaceutically acceptable salt or all stereoisomers, tautomers and deuterated products thereof or the combination of the present application Give things to those in need.
- the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, and I involved in the groups and compounds described in this application include their isotopes, and the carbon involved in the groups and compounds described in this application , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D, Also called heavy hydrogen), tritium (T, also called super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
- the isotopes of carbon include 12 C, 13 C and 14
- Alkyl refers to a straight chain or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (eg 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms An alkyl group, more preferably an alkyl group of 1 to 6 carbon atoms, and 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 Its various branched chain isomers; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.
- Alkoxy refers to a group in which at least one carbon atom in an alkyl group is replaced by an oxygen atom.
- Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentoxy, n-hexyloxy, cyclopropoxy group and cyclobutoxy group.
- the definition of alkyl is the same as the definition of "alkyl" mentioned above.
- Alkenyl means a straight group consisting of 2 to 20 carbon atoms containing 1 to 10 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds. Chain or branched unsaturated aliphatic hydrocarbon group, preferably alkenyl group with 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 12 An alkenyl group having 8 carbon atoms, more preferably an alkenyl group having 2 to 6 carbon atoms.
- Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hex En-3-yl, Hepten-2-yl, Hepten-3-yl, Hepten-4-yl, Octen-3-yl, Nonen-3-yl, Decen-4-yl and Undecenyl -3-base.
- the alkenyl group may be optionally further substituted by one or more substituents.
- Alkynyl means a group containing 1 to 10 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, consisting of 2 to 20 carbon atoms Straight chain or branched unsaturated aliphatic hydrocarbon group, preferably 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) alkynyl groups of carbon atoms, more preferably 2 An alkynyl group of 8 to 8 carbon atoms, more preferably an alkynyl group 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, 3,3-dimethyl Butyn-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, Dodecyn-4-yl.
- the alkynyl group may be optionally further substituted by one or more substituents.
- Aryl refers to a substituted or unsubstituted aromatic ring, which can be a 5 to 8 membered (eg 5, 6, 7, 8 membered) monocyclic ring, a 5 to 12 membered (eg 5, 6, 7 , 8, 9, 10, 11, 12 membered) bicyclic rings or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring systems, which may be bridged or spiro rings, non-limiting examples Including phenyl, naphthyl.
- the aryl group may be optionally further substituted by one or more substituents.
- Heteroaryl refers to a substituted or unsubstituted aromatic ring, which can be a 3- to 8-membered (eg, 3, 4, 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (eg, 5, 6, 7, 8, 9, 10, 11, 12) bicyclic or 10 to 15 (such as 10, 11, 12, 13, 14, 15) tricyclic system, and contains 1 to 6 (such as 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5 to 8 membered heteroaryl, 1 to 4 (eg 1, 2 , 3, 4) N, S can be oxidized into various oxidation states.
- Heteroaryl groups can be attached to heteroatoms or carbon atoms, heteroaryl groups can be bridged rings or spiro rings, non-limiting examples include cyclopyridyl, furyl, thienyl, pyryl, pyrrolyl, pyrimidyl, pyrimidinyl, Azidinyl, pyridazinyl, imidazolyl, piperidylbenzimidazolyl, benzopyridyl, pyrrolopyridyl. Heteroaryl is optionally further substituted with one or more substituents.
- Carbocyclyl or “carbocycle” refers to a saturated or unsaturated aromatic or non-aromatic ring. When it is an aromatic ring, its definition is the same as the definition of "aryl”above; when it is a non-aromatic ring, it can be 3 to 10 members (such as 3, 4, 5, 6, 7, 8, 9, 10 member) monocyclic ring, 4 to 12 membered (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 member) tricyclic ring system, which may be bridged or spiro, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2- Alkenyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-en
- Heterocyclic group or “heterocyclic ring” refers to a saturated or unsaturated aromatic heterocyclic ring or non-aromatic heterocyclic ring.
- aromatic heterocyclic ring When it is an aromatic heterocyclic ring, its definition is the same as that of "heteroaryl” above; when When it is a non-aromatic heterocycle, it can be a monocyclic ring with 3 to 10 members (for example, 3, 4, 5, 6, 7, 8, 9, 10 members), a 4 to 12 member (for example, 4, 5, 6, 7, 8, 9, 10, 11, 12) bicyclic or 10 to 15 (such as 10, 11, 12, 13, 14, 15) tricyclic system, and contains 1 to 4 (such as 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group.
- Heterocyclyl or 1 to 4 (eg 1, 2, 3, 4) N, S optionally substituted in the ring of “heterocyclic ring” can be oxidized to various oxidation states; "heterocyclyl” or A “heterocycle” can be attached to a heteroatom or a carbon atom; a “heterocyclyl” or “heterocycle” can be a bridged ring or a spiro ring.
- heterocyclyl or “heterocycle” include oxiranyl, epoxypropyl, aziridyl, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, oxepyl, thiepanyl, oxynitrogen Pyridine, diazepinyl, thiazepinyl, pyridyl, piperidyl, homopiperidyl, furyl, thienyl, pyryl, N-alkylpyrrolyl, pyrimidyl, pyrazine Base, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxyl, 1,3-d
- Cycloalkyl refers to a saturated cyclic hydrocarbon group
- the ring can be 3 to 10 members (such as 3, 4, 5, 6, 7, 8, 9, 10 members) monocyclic, 4 to 12 members (such as 4 , 5, 6, 7, 8, 9, 10, 11, 12 yuan) double ring or 10 to 20 yuan (such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 yuan) more
- the ring carbon atoms preferably have 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, cyclohexene group, cycloheptenyl group, 1,5-cyclooctadienyl group, 1,4-cyclohexadienyl group and cycloheptatrienyl group etc.
- the cycloalkyl group When the cycloalkyl group is substituted, it may be optionally further substituted with one or more substituents.
- Heterocycloalkyl refers to a substituted or unsubstituted saturated non-aromatic ring group, which can be 3 to 8 membered (eg 3, 4, 5, 6, 7, 8 membered) monocyclic, 4 to 12 membered (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12 members) bicyclic rings or 10 to 15 membered (e.g. 10, 11, 12, 13, 14, 15 members) tricyclic ring systems, and comprising 1, 2 or 3 heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group.
- heterocycloalkyl can be oxidized into various oxidation states; "heterocycloalkyl” can be connected to a heteroatom or a carbon atom; “heterocycle” “Alkyl” can be a bridged ring or a spiro ring.
- heterocycloalkyl include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxo Pentyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, Tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonyl, oxatri Cyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl.
- Halogen includes F, Cl, Br and I.
- “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the present application maintains the biological effectiveness and characteristics of the free acid or free base, and the free acid is mixed with a non-toxic inorganic base or Organic base, the salt obtained by reacting the free base with a non-toxic inorganic acid or organic acid.
- “Pharmaceutical composition” refers to a mixture of one or more compounds described in this application, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein, “other chemical components” refers to pharmaceutically acceptable acceptable carrier, excipient and/or one or more other therapeutic agents.
- Carrier refers to a material that does not produce significant irritation to an organism and that does not abrogate the biological activity and properties of the administered compound.
- Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of the 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 disintegrants.
- Stepoisomer refers to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
- Optional or “optionally” or “optional” or “optionally” means that the subsequently described event or circumstance may, but need not, occur, and that the description includes the circumstances in which the event or circumstance occurs and the circumstances in which it is not what happened.
- heterocyclyl optionally substituted with an alkyl group means that the alkyl group may but need not be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group, and cases where the heterocyclyl group is not substituted with an alkyl group.
- Figure 1 shows the colon-plasma drug distribution of Comparative Example 1.
- Figure 2 shows the colon-plasma drug distribution of compound 7-1.
- NMR nuclear magnetic resonance
- MS mass spectroscopy
- HPLC HPLC-based high pressure liquid chromatograph
- the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
- the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.20mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. -0.5mm;
- the known starting materials of this application can be synthesized by or according to methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, etc. company;
- Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a volume of about 1L;
- the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L;
- the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated 3 times;
- reaction is carried out under nitrogen atmosphere
- solution refers to aqueous solution
- the reaction temperature is room temperature, and the most suitable reaction temperature at room temperature is 20°C-30°C;
- THF Tetrahydrofuran
- PE petroleum ether
- NCS N-chlorosuccinimide
- Pd(dppf)Cl 2 [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;
- AD-mix- ⁇ Hydroquinidine 1,4-naphthyridine diyl ether mixture
- intermediate 1 is prepared with reference to patent CN108017559.
- 1c (8.3 g, 41.7 mmol) and dichloromethane (90 mL)
- the catalyst [(R)-2,2'-bis(diphenylphosphine)-1,11-binaphthyl] Ruthenium diacetate (1.8g, 2.09mmol)
- the autoclave device was tightened and sealed, replaced with hydrogen 3 times, filled with hydrogen, the pressure gauge on the autoclave showed 12atm, and reacted at room temperature for 30 hours.
- Dissolve compound 3b (22.00g, 0.157mol) in 250mL DCM at room temperature, cool down to -15°C in an ice-salt bath, slowly add sulfuryl chloride (23.31g, 0.173mol) dropwise and control the temperature not higher than -10°C, drop After the addition is complete, react at room temperature for 12 hours; cool the ice-salt bath to below -15°C and slowly add pyridine (13.66g, 0.173mol) dropwise, then add phosphorus pentachloride (36.00g, 0.137mol) in batches and control the temperature not to exceed -10°C, add to room temperature and react for 2h.
- reaction solution was quenched by adding 200 mL of ice water, extracted with EA (200 mL ⁇ 3), and the organic phases were combined.
- the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain compound 3c as a brown oil (33.00 g, yield 90%), which was directly used in the next step without purification.
- triphenylphosphine (1.58 g, 6.02 mmol), hexachloroethane (1.67 g, 7.05 mmol) and 25 mL of chloroform were sequentially added under nitrogen protection, and refluxed at 85° C. for 30 minutes. The complete conversion was monitored by TLC and cooled to room temperature. After further cooling to -30°C, N,N-diisopropylethylamine (1.14 g, 8.82 mmol) was slowly added dropwise. After stirring for 10 min, 4d (2.35 g, 5.03 mmol) dissolved in chloroform (5 mL) was slowly added dropwise under ice cooling, and stirred for 3 h.
- 5a was synthesized by referring to the method of 4c and using 4b as a raw material.
- 5b was synthesized by referring to the method of 4d and using 5a as a raw material.
- triphenylmethylphosphonium bromide 8g, 22mmol
- anhydrous tetrahydrofuran 40mL
- Step ten
- Dissolve 6B (28g, 93.29mol) in 500mL dry THF at room temperature, cool down to -15°C in an ice-salt bath, slowly add methylmagnesium bromide (155.48mL, 466.45mol) dropwise and keep the temperature not exceeding 0°C, After the dropwise addition, the reaction was carried out at room temperature for 4 h, and the reaction was monitored by TLC to complete. The reaction solution was quenched by pouring into 200 mL of ice water, extracted with EA (200 mL ⁇ 3), and the organic phases were combined.
- Chiral HPLC (AS), mobile phase: n-hexane/ethanol 90/10; column temperature: 35°C; column pressure: 80bar; flow rate: 1mL/min; detector signal channel: 215nm@4.8nm; diode array detector Start and stop wavelength: 200 ⁇ 400nm.
- Human monocytic cell line THP-1 ( TIB-202TM) were cultured in RPMI-1640 medium containing 10% FBS, 1 mM pyruvate, 0.05 mM ⁇ -mercaptoethanol and 1% double antibody, and the culture conditions were 37° C., 5% CO 2 .
- THP-1 cells per well were seeded in a 96-well plate, added with 20 nM PMA, and induced with 5% CO 2 at 37°C for 48 hours. The medium was discarded, and 100 ⁇ L of serum-free RPMI-1640 medium containing 1 ⁇ g/mL LPS was added. Add 5 ⁇ L of compound or solvent control, starting from the highest dose of 10 ⁇ M, and then serially dilute 3 times, and set 10 gradient concentrations in total. Incubate for 3 h at 37 °C in 5% CO2 .
- the LC/MS/MS method was used to determine the drug concentration in plasma, tissue and intestinal contents, and the colon tissue samples were homogenized before testing.
- the average drug concentration at each time point is shown in Figure 1 and Figure 2, wherein Figure 1 shows the colon-plasma drug distribution of Control Example 1, and Figure 2 shows the colon-plasma drug distribution of Compound 7-1.
- Comparative example 1 is 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-sulfonyl]urea), prepared by referring to the compound 1 method in Synthetic Communications (2003), 33(12), 2029-2043.
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Abstract
一种酰胺衍生物及其在医药上的应用,具体而言涉及式(I)的酰胺衍生物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物,以及包含上述化合物的药物组合物,上述化合物或组合物可作为NLRP3抑制剂,式(I)中各取代基的定义与说明书的定义相同。
Description
本申请涉及酰胺衍生物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物,包含上述化合物的药物组合物以及在其制备NLRP3抑制剂的用途。
核苷酸结合寡聚化结构域(nucleotide-binding oligomerization domain,NOD)的NOD样受体(NOD-Like Receptors,NLRs)是哺乳动物内细胞内一类位于细胞质的模式识别受体(Pattern Recognition receptors,PRRs),在先天性免疫应答中起着十分重要的作用。NLRs是一组具有信号转导功能的胞质蛋白,广泛参与机体的炎症应答反应。NLRs家族包括NODs、NALPs(NLRPs)、CIITA(NLRA)与IPAF(NLRC),其中NLRPs和NLRC亚家族是NOD样受体(NLRs)主要的两种类型,NLRPs可分为NLRP1、NLRP3、NLRP6、NLRP7和NLRP12等炎性小体成员。NLRP3炎性小体是一种多蛋白复合体,是由NLRP3蛋白本身、半胱天冬酶-1以及凋亡相关斑点样蛋白(apoptosis-associated speck-like protein containing CARD,ASC)组成,它能够识别多种病原微生物及应激相关内源性信号分子。经典的NLRP3炎性小体活化由两种信号共同刺激激活,第一信号激活TLR4(Toll like receptor4)信号通路,促进核转录因子κB入核,诱导IL-1β和IL-18等前体的产生。第二信号促进NLRP3/ASC/pro-caspase-1复合体形成,即在被激活时与含有半胱天冬酶活化和募集结构域的凋亡相关斑点样蛋白(ASC,Apoptosis-Associated Specklike Protein containing a CARD)聚合,ASC再与cysteine protease caspase-1相互作用形成称为炎性体的复合物,前体形式的半胱天冬酶(pro-caspase-1)自剪切成活化形式,(Wen,H.,Miao,E.A.&Ting,J.P.Mechanisms of NOD-like receptor-associated inflammasome activation.Immunity 39,432–441(2013))活化的半胱天冬酶-1(caspase-1)切割前体形式的促炎细胞因子IL-1β和IL-18,使其转化为活性形式的IL-1β和IL-18并释放到胞外,募集炎症细胞聚集,扩大炎症反应。ASC斑点样蛋白还可以募集并活化胱天蛋白酶-8(caspase-8),切割前体形式的IL-Ιβ和IL-18使其转变为成熟形式并引发细胞焦亡。非经典的NLRP3炎性小体活化不依赖于TLR4信号通路活化,它是由半胱天冬酶-11直接识别胞内的LPS,启动NLRP3炎性小体活化,促进Gasdermin D的活化与释放从而介导细胞死亡。(Lamkanfi,M.&Dixit,V.M.Mechanisms and functions of inflammasomes.Cell 157,1013–1022(2014)。)。
NLRP3炎症小体异常活化与遗传性CAPS疾病穆克尔-韦尔斯综合征(muckle-Wells syndrome)(mWS)、家族性寒冷性自身炎性综合征、新生儿发病多系统炎性疾病、阿尔兹海默症、帕金森、非酒精性脂肪肝、动脉粥样硬化、哮喘、肾病、肠炎、肿瘤、痛风、神经退行性疾病、糖尿病和肥胖等多种炎症性疾病的发生过程密切相关。
当前治疗NLRP3相关疾病药物包括重组IL-1受体拮抗剂anakinra、中和IL-1β抗体canakinumab和可溶性IL-1受体诱捕剂rilonacept,以上均是生物制品。近年Rebecca C Coll等报道了一种新的磺酰脲类小分子NLRP3抑制剂化合物MCC950,以纳摩尔级抑制NLRP3炎症体活性,其他小分子化合物显示可抑制NLRP3炎性小体,如:格列本脲、小白菊素(parthenolide)、3,4-亚甲基二氧基-β-硝基苯乙烯(He,Y.et al.3,4-Methylenedioxy-β-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasome.J.Biol.Chem.289,1142–1150(2014))和二甲基亚砜(DMSO)。然而上述药物或者小分子尚存在特异性不高或者活性较差等问题。因此,有必要开发新一代的具备高特异性及高活性的小分子NLRP3抑制剂,用于治疗由NLRP3突变导致的自身免疫病。
发明内容
本申请的目的是提供新型酰胺衍生物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物,其药物组合物以及其在制备NLRP3抑制剂的用途。
本申请的一个或多个实施方式提供式(I)的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物:
其中
Q为5元杂芳基,所述5元杂芳基包含1或2个选自N、O和S的杂原子,所述5元杂芳基任选地被1个氰基或者C
1-6烷基取代;
L为-(CR
aR
b)-;
R
a为C
1-6烷基;
R
b为C
1-6烷基,且所述C
1-6烷基被1个OH取代;
W为O或NH;
Y为-(CR
dR
e)-;
R
d、R
e各自独立地为H或C
1-6烷基;
R和R
1各自独立地为H、卤素、氰基、C
1-6烷基、C
1-6烷氧基、3至10元碳环基或4至10元杂环基,所述4至10元杂环基包含1、2或3个选自N、O和S的杂原子,所述C
1-6烷基、3至10元碳环基或4至10元杂环基任选地被1、2、3或4个选自卤素、氰基、C
1-6烷基、C
1-6烷氧基、3至6元碳环基和5至6元杂环基的取代基取代;
或者,R与R
1与其相连的原子一起形成4至6元环;
C为3至5元环烷基;
R
2为H或者卤素;
G
1、G
2、G
3各自独立为N或CH;
r、q各自独立地为0、1或2;
n为0、1、2或3。
在一个或多个实施方式中:
Q为呋喃基、噻唑基或噻吩基,所述呋喃基、噻唑基或噻吩基任选地被1个氰基取代;
L为-(CR
aR
b)-;
R
a为C
1-3烷基;
R
b为C
1-3烷基,且所述C
1-3烷基被1个OH取代;
W为O或NH;
Y为-(CR
dR
e)-;
R
d、R
e各自独立地为H或C
1-3烷基;
R和R
1各自独立地为H、卤素、氰基、C
1-3烷基或吡啶基,所述的C
1-3烷基或吡啶基任选地被1至4个选自卤素、氰基、C
1-3烷基、C
1-3烷氧基和3至5元环烷基的取代基取代;
或者,R与R
1与其相连的原子一起形成4至5元环;
C为3至5元环烷基;
R
2为H;
G
1、G
2、G
3各自独立为N或CH;
r、q各自独立地为0、1或者2。
在一个或多个实施方式中:
W为O或者NH。
在一个或多个实施方式中:
Q为呋喃基、噻唑基或噻吩基,所述呋喃基、噻唑基或噻吩基任选地被1个氰基取代;
L为-(CR
aR
b)-;
R
a为C
1-3烷基;
R
b为C
1-3烷基,且所述C
1-3烷基被1个OH取代;
W为O或者NH;
Y为-(CR
dR
e)-;
R
d、R
e各自独立地为H或C
1-3烷基;
R和R
1各自独立地为H或者卤素;或者,R与R
1与其相连的原子一起形成4至5元环;
C为3至5元环烷基;
R
2为H;
G
1、G
2、G
3各自独立为CH;
r、q各自独立地为0或者1。
在一个或多个实施方式中:
在一个或多个实施方式中,所述化合物为:
本申请的一个或多个实施方式提供药物组合物,所述药物组合物包含本申请的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物以及一种或多种药学上可接受的载体和/或赋形剂。
本申请的一个或多个实施方式提供本申请的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物或者本申请的药物组合物在制备用于治疗炎性疾病、自身免疫疾病、心血管系统疾病、癌症、肾系统疾病、胃肠道疾病、呼吸系统疾病、内分泌系统疾病或中枢神经系统疾病的药物中用途。
本申请的一个或多个实施方式提供本申请的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物或者本申请的药物组合物在制备用于治疗隐热蛋白相关周期综合征(CAPS)、穆克尔-韦尔斯综合征(MWS)、家族性寒冷性自身炎性综合征(FCAS)、新生儿发病多系统炎性疾病(NOMID)、家族性地中海热(FMF)、非酒精性脂肪性肝炎、酒精性肝病、移植物抗宿主病、多发性硬化(MS)、类风湿性关节炎、1型糖尿病、2型糖尿病、牛皮癣、阿尔茨海默氏病、动脉粥样硬化、痛风或慢性肾疾病的药物中用途。
本申请的一个或多个实施方式提供本申请的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物或者本申请的药物组合物在制备NLRP3抑制剂中的用途。
本申请的一个或多个实施方式提供通式(I’)的化合物,或者其立体异构体:
其中:
Q选自5元杂芳基,所述的杂芳基可以含有1至2个选自N、O或者S的杂原子,所述的杂芳基可被0个或者1个氰基取代;
L选自-(CR
aR
b)-;
R
a选自C
1-6烷基;
R
b选自C
1-6烷基,且所述的烷基进一步被1个OH取代;
W选自O或者NH;
Y选自-(CR
dR
e)-;
R
d、R
e各自独立选自H或者C
1-6烷基;
R和R
1各自独立选自H、卤素、氰基、C
1-6烷基、C
1-6烷氧基、3至10元碳环基或者4至10元杂环基,所述的杂环基可以含有1至3个选自N、O或者S的杂原子,其中所述的烷基、碳环或者杂环可以进一步被1至4个卤素、氰基、C
1-6烷基、C
1-6烷氧基、3至6元碳环基或者5至6元杂环基的取代基所取代;
或者,R与R
1可以与其相连的原子一起形成一个4至6元环;
C选自3至5元环烷基;
R
2选自H或者卤素;
G
1、G
2、G
3各自独立选自N或者CH;
q、r选自0、1或者2;
n选自0、1、2或者3。
在一个或多个实施方式中:
Q选自呋喃基、噻唑基或者噻吩基,且Q进一步可被氰基取代;
L选自-(CR
aR
b)-或者3至4元环烷基,且所述的L任选进一步被0至2个-OH取代;
R
a、R
b各自独立选自H或者C
1-3烷基;
W选自O或者NH;
Y选自-(CR
dR
e)-;
R
d、R
e各自独立选自H或者C
1-3烷基;
R和R
1各自独立选自H、卤素、氰基、C
1-3烷基或者吡啶基,所述的C
1-3烷基或者吡啶基可以进一步被1至4个卤素、氰基、C
1-3烷基、C
1-3烷氧基或者3至5元环烷基的取代基所取代;
或者,R与R
1可以与其相连的原子一起形成一个4至5元环;
C选自3至5元环烷基;
R
2选自H;
G
1、G
2、G
3各自独立选自N或者CH;
q、r选自0、1或者2;
n选自0、1、2或者3。
在一个或多个实施方式中:
W选自O或者NH。
在一个或多个实施方式中,所述化合物为:
本申请的一个或多个实施方式提供药物组合物,所述药物组合物包含本申请的化合物或其立体异构体和一种或者多种药学上可接受的载体和/或赋形剂。
本申请的一个或多个实施方式提供本申请的药物组合物或者本申请的化合物或其立体异构体在制备NLRP3抑制剂中的用途。
在一个或多个实施方式中,与NLRP3相关的疾病包括:炎性疾病、自身免疫疾病、心血管系统疾病、癌症、肾系统疾病、胃肠道疾病、呼吸系统疾病、内分泌系统疾病或者中枢神经系统疾病。
在一个或多个实施方式中,与NLRP3相关的疾病包括:隐热蛋白相关周期综合征(CAPS)、穆克尔-韦尔斯综合征(MWS)、家族性寒冷性自身炎性综合征(FCAS)、新生儿发病多系统炎性疾病(NOMID)、家族性地中海热(FMF)、非酒精性脂肪性肝炎、酒精性肝病、移植物抗宿主病、多发性硬化(MS)、类风湿性关节炎、1型糖尿病、2型糖尿病、牛皮癣、阿尔茨海默氏病、动脉粥样硬化、痛风、慢性肾疾病。
一个或多个实施方式提供本申请的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物和组合物,其用作药物。
一个或多个实施方式提供本申请的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物和组合物,其用于治疗与NLRP3相关的疾病的方法。
一个或多个实施方式提供本申请的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物和组合物,其用作NLRP3抑制剂。
一个或多个实施方式提供本申请的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物和组合物,其用于治疗炎性疾病、自身免疫疾病、心血管系统疾病、癌症、肾系统疾病、胃肠道疾病、呼吸系统疾病、内分泌系统疾病或中枢神经系统疾病的方法。
一个或多个实施方式提供本申请的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物和组合物,其用于治疗隐热蛋白相关周期综合征(CAPS)、穆克尔-韦尔斯综合征(MWS)、家族性寒冷性自身炎性综合征(FCAS)、新生儿发病多系统炎性疾病(NOMID)、家族性地中海热(FMF)、非酒精性脂肪性肝炎、酒精性肝病、移植物抗宿主病、多发性硬化(MS)、类风湿性关节炎、1型糖尿病、2型糖尿病、牛皮癣、阿尔茨海默氏病、动脉粥样硬化、痛风或慢性肾疾病的方法。
一个或多个实施方式提供治疗/预防与NLRP3相关的疾病的方法,其包括将本申请的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物或者本申请的组合物给予有此需要的对象。
一个或多个实施方式提供治疗/预防疾病的方法,其包括将本申请的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物或者本申请的组合物给予有此需要的对象,所述疾病为治疗炎性疾病、自身免疫疾病、心血管系统疾病、癌症、肾系统疾病、胃肠道疾病、呼吸系统疾病、内分泌系统疾病或中枢神经系统疾病。
一个或多个实施方式提供治疗/预防疾病的方法,其包括将本申请的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物或者本申请的组合物给予有此需要的对象,所述疾病为隐热蛋白相关周期综合征(CAPS)、穆克尔-韦尔斯综合征(MWS)、家族性寒冷性自身炎性综合征(FCAS)、新生儿发病多系统炎性疾病(NOMID)、家族性地中海热(FMF)、非酒精性脂肪性肝炎、酒精性肝病、移植物抗宿主病、多发性硬化(MS)、类风湿性关节炎、1型糖尿病、2型糖尿病、牛皮癣、阿尔茨海默氏病、动脉粥样硬化、痛风或慢性肾疾病。
一个或多个实施方式提供抑制NLRP3的方法,其包括将本申请的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物或者本申请的组合物给予有此需要的对象。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本申请所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括 它们的同位素情况,及本申请所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括
12C、
13C和
14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括
16O、
17O和
18O,硫的同位素包括
32S、
33S、
34S和
36S,氮的同位素包括
14N和
15N,氟的同位素包括
17F和
19F,氯的同位素包括
35Cl和
37Cl,溴的同位素包括
79Br和
81Br。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基,优选为1至8个(例如1、2、3、4、5、6、7、8个)碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体;当烷基被取代基时,可以任选进一步被1个或者多个取代基所取代。
“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。
“烯基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、10个)碳-碳双键,由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基,优选2至12个(例如2、3、4、5、6、7、8、9、10、11、12个)碳原子的烯基,更优选2至8个碳原子的烯基,进一步优选2至6个碳原子的烯基。非限制性实例包括乙烯基、丙烯-2-基、丁烯-2-基、丁烯-2-基、戊烯-2-基、戊烯-4-基、己烯-2-基、己烯-3基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任选进一步被1个或者多个取代基所取代。
“炔基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、或10个)碳-碳叁键,由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基,优选2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子的炔基,更优选2至8个碳原子的炔基,进一步优选2至6个碳原子的炔基。非限制性实例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戊炔-1-基、戊炔-2-基、己炔-1-基、1-庚炔-1-基、庚炔-3-基、庚炔-4-基、辛炔-3-基、壬炔-3-基、癸炔-4-基、十一炔-3-基、十二炔-4-基。所述的炔基可以任选进一步被一至多个取代基所取代。
“芳基”是指是指取代的或未取代的芳香环,其可以是5至8元(例如5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,其可以是桥环或者螺环,非限制性实例包括苯基、萘基。所述的芳基可以任选进一步被1个或者多个取代基所取代。
“杂芳基”是指取代的或未取代的芳香环,其可以是3至8元(例如3、4、5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1至6个(例如1、2、3、4、5、6个)选自N、O或S的杂原子,优选5至8元杂芳基,杂芳基的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态。杂芳基可以连接在杂原子或者碳原子上,杂芳基可以是桥环或者螺环,非限制性实例包括环吡啶基、呋喃基、噻吩基、吡喃基、吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基苯并咪唑基、苯并吡啶基、吡咯并吡啶基。杂芳基任选进一步被1个或多个取代基所取代。
“碳环基”或“碳环”是指饱和或者不饱和的芳香环或者非芳香环。当为芳香环时,其定义与上文“芳基”的定义相同;当为非芳香环时,其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,可以是桥环或者螺环,非限制性实例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、 环壬基、环癸基、环十一烷基、环十二烷基、
所述的“碳环基”或“碳环”任选进一步被1个或者多个取代基所取代。
“杂环基”或“杂环”是指饱和或不饱和的芳香性杂环或者非芳香性杂环,当为芳香性杂环时,其定义与上文“杂芳基”定义相同;当为非芳香性杂环时,其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1至4个(例如1、2、3、4个)选自N、O或S的杂原子,优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态;“杂环基”或“杂环”可以连接在杂原子或者碳原子上;“杂环基”或“杂环”可以为桥环或者螺环。“杂环基”或“杂环”的非限制性实例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻烷基、二氢呋喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的“杂环基”或“杂环”可以任选进一步被1个或者多个取代基所取代。
“环烷基”是指饱和的环烃基,其环可以为3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至20元(例如10、11、12、13、14、15、16、17、18、19、20元)多环体系,环碳原子优选3至10个碳原子,进一步优选3至8个碳原子。“环烷基”非限制性实例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当环烷基被取代时,可以任选进一步被1个或者多个取代基所取代。
“杂环烷基”是指取代的或未取代的饱和非芳香环基,其可以是3至8元(例如3、4、5、6、7、8元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1、2或3个选自N、O或S的杂原子,优选3至8元杂环基。“杂环烷基”的环中选择性取代的1、2或3个N、S可被氧化成各种氧化态;“杂环烷基”可以连接在杂原子或者碳原子上;“杂环烷基”可以为桥环或者螺环。“杂环烷基”非限制性实例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。
当上文所述的“烷基”、“烷氧基”、“烯基”、“炔基”、“芳基”、“杂芳基”、“碳环基”、“碳环”、“杂环基”、“杂环”、“环烷基”、“杂环烷基”或者“杂环基”被取代时,可以选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C
1-6烷基氨基、=O、C
1-6烷基、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、- NR
q4R
q5、=NR
q6、-C(=O)OC
1-6烷基、-OC(=O)C
1-6烷基、-C(=O)NR
q4R
q5、C
3-8环烷基、C
3-8杂环烷基、C
6-10芳基、C
5-10杂芳基、-C(=O)OC
6-10芳基、-OC(=O)C
6-10芳基、-OC(=O)C
5-10杂芳基、-C(=O)OC
5-10杂芳基、-OC(=O)C
3-8杂环烷基、-C(=O)OC
3-8杂环烷基、-OC(=O)C
3-8环烷基、-C(=O)OC
3-8环烷基、-NHC(=O)C
3-8杂环烷基、-NHC(=O)C
6-10芳基、-NHC(=O)C
5-10杂芳基、-NHC(=O)C
3-8环烷基、-NHC(=O)C
3-8杂环烷基、-NHC(=O)C
2-6烯基或者-NHC(=O)C
2-6炔基的取代基所取代,且其中所述的取代基C
1-6烷基、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、C
3-8环烷基、C
3-8杂环烷基、C
6-10芳基、C
5-10杂芳基、-NHC(=O)C
6-10芳基、-NHC(=O)C
5-10杂芳基、-NHC(=O)C
3-8杂环烷基或者-NHC(=O)C
3-8环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C
1-6烷基、C
1-6烷氧基、-NR
q4R
q5或者=O的取代基所取代;R
q1选自C
1-6烷基、C
1-6烷氧基或者C
6-10芳基;R
q2、R
q3选自H或者C
1-6烷基;其中,R
q4、R
q5选自H、C
1-6烷基、-NH(C=NR
q1)NR
q2R
q3、-S(=O)
2NR
q2R
q3、-C(=O)R
q1或者-C(=O)NR
q2R
q3,其中所述的C
1-6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C
1-6烷基、C
1-6烷氧基、C
6-10芳基、C
5-10杂芳基、C
3-8环烷基或者C
3-8杂环烷基的取代基所取代;或者R
q4与R
q5及N原子形成一个3至8元杂环,所述杂环可以含有1个或者多个选自N、O或者S的杂原子。
卤素包括F、Cl、Br和I。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本申请化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”是指一种或多种本申请所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物,其中,“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生,该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如,“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
图1表明对照例1的结肠-血浆药物分布。
图2表明化合物7-1的结肠-血浆药物分布。
以下实施例详细说明本申请的技术方案,但本申请的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移(δ)以10
-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(dMSO-d
6),氘代氯仿(CDCl
3),氘代甲醇(CD
3OD),内标为四甲基硅烷(TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm, 3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体;
本申请的己知起始原料可以采用或按照本领域已知的方法来合成,或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司;
氮气氛是指反应瓶连接一个约1L容积的氮气气球;
氢气氛是指反应瓶连接一个约1L容积的氢气气球;
氢化反应通常抽真空,充入氢气,反复操作3次;
实施例中无特殊说明,反应在氮气氛下进行;
实施例中无特殊说明,溶液是指水溶液;
实施例中无特殊说明,反应的温度为室温,室温最适宜的反应温度,为20℃-30℃;
DCM:二氯甲烷;
EA:乙酸乙酯;
HCl:盐酸;
THF:四氢呋喃;
DMF:N,N-二甲基甲酰胺;
PE:石油醚;
TLC:薄层色谱;
SFC:超临界流体色谱法;
NCS:N-氯代丁二酰亚胺;
Pd(dppf)Cl
2:[1,1'-双(二苯基膦)二茂铁]二氯化钯;
AD-mix-β:氢化奎尼定1,4-二氮杂萘二基醚混合物;
(dHQD)
2AQN:氢化奎尼定(蒽醌‐1,4‐二基)二醚。
中间体1
(R)-5-(1-环丙基乙基)-2,3-二氢-1H-茚-4-胺(中间体1)
(R)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine
第一步:
(4-氨基-2,3-二氢-1H-茚-5-基)(环丙基)甲酮(1b)
(4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclopropyl)methanone
氮气保护下,在500mL三口瓶中,将化合物1a(20.0g,150.16mmol)溶于1,2-二氯乙烷(200mL)中,冰盐浴降温至0℃,缓慢滴加三氯化硼(150mL,1M,150.16mmol)的二氯甲烷溶液,滴加完毕,保持此温度反应10min后,加入三氯化铝(22.0g,165.20mmol)和环丙基腈(15.1g,225.24mmol);反应体系升温至80℃反应4h,冷至室温,冰浴下加入160mL(2M HCl),滴加完毕升温回流1h。反应结束,冷至室温,DCM(200mL×3)萃取,有机相用160mL的2M氢氧化钠溶液洗涤、无水硫酸钠干燥、过滤,减 压移除有机溶剂,残留物通过柱层析(石油醚:乙酸乙酯=20:1)纯化得化合物1b,白色固体(17.1g,产率57.2%)。
1H 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]。
第二步:
5-(1-环丙基乙烯基)-2,3-二氢-1H-茚-4-胺(1c)
5-(1-Cyclopropylvinyl)-2,3-dihydro-1H-inden-4-amine
在氮气保护下,在500mL三口瓶中,将化合物甲基三苯基溴化磷(24.8g,69.6mmol)溶于THF(300mL)中,冰盐浴降温至0℃,缓慢加入叔丁醇钾(7.8g,69.6mmol),保持此温度反应30min后,加入化合物1b(7.0g,34.8mmol),室温反应4h,反应结束,加水淬灭,EA(100mL×3)萃取,无水硫酸钠干燥、过滤,减压移除有机溶剂,残留物通过柱层析(石油醚:乙酸乙酯=30:1)纯化得化合物1c,淡黄色油状物(6.4g,产率92.3%)。
1H 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]。
第三步:
(R)-5-(1-环丙基乙基)-2,3-二氢-1H-茚-4-胺(中间体1)
(R)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine
中间体1的合成参考专利CN108017559进行制备。在500mL高压釜中,加入1c(8.3g,41.7mmol)和二氯甲烷(90mL),加入催化剂[(R)-2,2'-双(二苯基膦)-1,11-联萘]二乙酸酸钌(1.8g,2.09mmol),加完后将高压釜装置拧紧密封,用氢气置换3次,充入氢气,高压釜上的压力表显12atm,室温下反应30小时。减压浓缩除去溶剂,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯=30:1)得到中间体1,淡黄色油状物(8.2g,收率97.8%,97.74%ee)。手性HPLC(手性柱:CHIRALPAK AY-3(4.6×100mm);流动相:甲醇;柱温:35℃;流动相:甲醇/正己烷=15/85;柱压:2000psi;流速:2mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm;RT=3.295min)。
1H 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]。
中间体2
(S)-5-(1-环丙基乙基)-2,3-二氢-1H-茚-4-胺(中间体2)
(S)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine
中间体2的合成参考专利CN108017559进行制备。在500mL高压釜中,加入1c(7.3g,36.7mmol)和二氯甲烷(80mL),加入催化剂[(S)-2,2'-双(二苯基膦)-1,11-联萘]二乙酸酸钌(1.54g,1.83mmol),加完后将高压釜装置拧紧密封,用氢气置换3次,充入氢气,高压釜上的压力表压力显12atm,室温下反应30小时。减压浓缩除去溶剂,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯=30:1)得到中间体2,淡黄色油状物(7.1g,收率96.3%,98.18%ee)。手性HPLC(手性柱:CHIRALPAK AY-3(4.6×100mm);流动相:甲醇;柱温:35℃;流动相:甲醇/正己烷=15/85;柱压:2000psi;流速:2mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起始波长:200~400nm;RT=2.802min)。
1H 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]。
中间体3
N-(叔丁基二甲基甲硅烷基)-4-(2-羟基丙-2-基)呋喃-2-磺酰亚胺酰胺(中间体3)
N-(Tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
第一步:
呋喃-3-甲酸乙酯(3b)
Ethyl furan-3-carboxylate
冰浴下将化合物3a(50g,0.446mol)溶解于300mL无水乙醇中,缓慢滴加氯化亚砜(65mL,0.892mol),滴加完毕后升温到回流反应2小时。TLC监控完全反应,减压浓缩除去溶剂和过量的氯化亚砜后,加入水(200mL)、乙酸乙酯萃取(150mL×3),合并有机相。有机相用饱和食盐水洗涤(100mL×2),无水硫酸钠干燥,减压除去溶剂,残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚=1:50~1:10)得到化合物3b,浅棕色油状物(38.1g,产率61%)。
第二步:
4-甲酸乙酯-2-磺酰氯呋喃(3c)
Ethyl furan-2-sulfonyl chloride-4-formate
室温下将化合物3b(22.00g,0.157mol)溶解于250mL DCM中,冰盐浴降温至-15℃,缓慢滴加磺酰氯(23.31g,0.173mol)并控制温度不高于-10℃,滴加完毕,室温下反应12h;冰盐浴降温至-15℃以下缓慢滴加吡啶(13.66g,0.173mol)后再分批次加入五氯化磷(36.00g,0.137mol)并控制温度不超过-10℃,加完室温反应2h。TLC监控反应完全,将反应液加入200mL冰水中淬灭,用EA萃取(200mL×3),合并有机相。有机相用饱和食盐水洗涤(100mL),无水硫酸钠干燥,减压浓缩除去溶剂,得到化合物3c,棕色油状物(33.00g,产率90%),未纯化直接投下一步。
第三步:
呋喃-2-磺酰胺-4-甲酸乙酯(3d)
Furan-2-sulfonamide-4-ethyl formate
室温下将化合物3c(33.00g,0.138mol),溶解于350mL丙酮中,室温滴加饱和碳酸氢铵(49.74g,0.553mol)水溶液,室温下反应3h,TLC监控反应完全。用EA萃取(200mL×3),合并有机相。有机相用饱和食盐水洗涤(100mL),无水硫酸钠干燥,减压浓缩除去溶剂,得到化合物3d,棕色固体粉末(23g,产率77%)。
1H 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]。
第四步:
4-(2-羟基丙基)呋喃-2-磺酰胺(3e)
4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide
室温下将化合物3d(23g,0.105mol)溶解于500mL干燥的THF中,冰盐浴降温到-15℃,缓慢滴加甲基溴化镁(140mL,0.418mol)并保持温度不超过0℃,滴加完毕室温下反应4h,TLC监控反应完全。将反应液倒入200mL冰水中淬灭,用EA萃取(200mL×3),合并有机相。有机相用饱和食盐水洗(100mL),无水硫酸钠干燥,减压浓缩除去溶剂,残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚=1:4~1:1)得到化合物3e,白色固体粉末(16g,产率76%)。
LCMS m/z=204.2[M-l]。
第五步:
N-(叔丁基二甲基硅基)-4-(2-羟基丙基)呋喃-2-磺酰胺(3f)
N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide
室温下将化合物3e(5.0g,24.39mmol)溶解于50mL干燥的THF中,冰盐浴降温到-10℃,缓慢加入氢化钠(0.9g,36.58mmol)控制温度低于-10℃,再加入叔丁基二甲基氯硅烷(4.8g,31.70mmol)的THF(50mL)溶液,室温下反应12h,TLC监控反应完全。将反应液倒入20mL冰水中淬灭,用EA萃取(50mL×3),合并有机相,有机相用饱和食盐水洗(50mL),无水硫酸钠干燥,减压浓缩除去溶剂,残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚=1:2~2:1)得到化合物3f,白色固体(5.1g,产率66%)。
1H 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]。
第六步:
N-(叔丁基二甲基硅基)-4-(2-羟丙基-2-基)呋喃-2-磺酰亚胺酰胺(中间体3)
N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
在250mL三口瓶中,氮气保护下,加入DCM(100mL)和三苯基二氯化膦(11.3g,33.86mmol),冰浴降温至0℃,缓慢滴加二异丙基乙胺(5.8g,45.16mmol),滴加完毕恢复至室温反应10min;反应体系降温至0℃,滴加3f(3.6g,11.29mmol)的二氯甲烷(10mL)溶液,滴加完毕保持0℃继续反应30min,向反应体系通氨气15min;恢复室温反应2h;TLC监控完全反应,减压浓缩除去溶剂,粗产品通过柱层析(石油醚:乙酸乙酯=2:1)纯化得中间体3,白色固体(816mg,产率23%)
1H 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]。
中间体4
N-(叔丁基二甲基硅基)-2-(-1-((叔丁基二甲基硅基)氧基)-2-羟基丙-2-基)噻唑-5-磺酰亚胺酰胺(中间体4)
N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide
第一步:
1-((叔丁基二甲基硅基)氧基)-2-(噻唑-2-基)丙-2-醇(4b)
1-((Tert-butyldimethylsilyl)oxy)-2-(thiazol-2-yl)propan-2-ol
室温下将化合物4a(50.48g,0.31mol)溶解于1L干燥的THF中,氮气保护,降温到-78℃。缓慢滴加2.5M n-BuLi的正己烷溶液(136mL,0.34mol)并保持温度不超过-70℃,滴加完毕后保温搅拌反应1h,然后缓慢滴加1-(叔丁基二甲基硅氧基)-2-丙酮(70g,0.37mol)反应1h,TLC监控反应完全。向反应体系中加入饱和NH
4Cl溶液淬灭反应,用EA萃取(200mL×3),合并有机相。有机相用饱和食盐水洗(200mL),无水硫酸钠干燥,减压浓缩除去溶剂,得到黑色残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚=1:30~1:20)得到化合物4b,淡黄色油状物(50g,产率59%)。
1H 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]。
第二步:
2-(1-((叔丁基二甲基硅基)氧基)-2-羟基丙-2-基)噻唑-5-磺酰胺(4c)
2-(1-((Tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide
室温下将化合物4b(7g,25.6mmol)溶解于200mL干燥的THF中,氮气保护,降温到-78℃。缓慢滴加2.5M n-BuLi的正己烷溶液(21.5mL,53.8mmol)并保持温度不超过-70℃,滴加完毕后反应1h,然后加入1,4-二氮杂双环[2.2.2]辛烷-1,4-二鎓-1,4-二亚磺酸(9.2g,38.4mmol)保温反应1h,移除干冰浴室温搅拌2h。向反应体系中加入饱和NH
4Cl溶液200mL淬灭反应,用EA萃取(100mL×2)水相,水相加入500mL三口瓶中,降温至-10℃,依次加入醋酸钾(10.05g,102.4mmol)、羟胺磺酸(11.6g,102.4mmol),然后自然升温反应过夜。用EA萃取(200mL×5),合并有机相。有机相用饱和食盐水洗(100mL),无水硫酸钠干燥,减压浓缩除去溶剂,得到残留物用硅胶柱色谱分离提纯得到化合物4c,淡黄色油状物(2.8g,产率46%)。
LCMS m/z=239[M+l]。
第三步:
N-(叔丁基二甲基硅基)-2-(1-((叔丁基二甲基硅基)氧基)-2-羟基丙-2-基)噻唑-5-磺酰胺(4d)
N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide
在氮气保护和0℃下,向4c(3.80g,16.0mmol)的50mL四氢呋喃溶液中分批加入氢化钠(1.92g,60%,48mmol),继续搅拌30分钟。加入叔丁基二甲基氯硅烷(5.79g,38.4mmol),室温反应16h.TLC监控反应完全,冰浴冷却下加入200mL水,乙酸乙酯(100mL×3)萃取。合并有机相,饱和食盐水洗涤(100mL×2),有机相通过无水硫酸钠干燥、过滤,减压除去有机溶剂。残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯=10:1~6:1)得到4d,棕黄色油状物(4.72g,收率63.2%)。
1H 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]。
第四步:
N-(叔丁基二甲基硅基)-2-(-1-((叔丁基二甲基硅基)氧基)-2-羟基丙-2-基)噻唑-5-磺酰亚胺酰胺(中间体4)
N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide
在100mL圆底烧瓶中,氮气保护下依次加入三苯基磷(1.58g,6.02mmol),六氯乙烷(1.67g,7.05mmol)和三氯甲烷25mL,85℃回流30分钟。TLC监控转化完全,冷却至室温。进一步冷却至-30℃,缓慢滴加N,N-二异丙基乙胺(1.14g,8.82mmol)。搅拌10min,冰浴下缓慢滴加溶于三氯甲烷(5mL)的4d(2.35g,5.03mmol),搅拌3h。-30℃下通氨气1h,缓慢升至室温反应过夜。TLC监控完全反应,反应结束。反应液倒入水中,将有机相萃取出,再用二氯甲烷(100mL×3)萃取。合并有机相,无水硫酸钠干燥、过滤、减压移除有机溶剂,粗产品通过柱层析(石油醚/乙酸乙酯=10:1~4:1)纯化得中间体4,淡黄色固体(873mg,收率37.3%)。
LC-MS m/z(ESI)=467.2[M+1]。
中间体5
N-(叔丁基二甲基硅基)-2-(-1-((叔丁基二甲基硅基)氧基)-2-羟基丙-2-基)噻唑-5-磺酰亚胺酰胺(中间体5)
N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide
第一步:
2-(1-((叔丁基二甲基硅基)氧基)-2-羟基丙-2-基)噻唑-5-磺酰胺(5a)
2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide
5a参考4c的方法,以4b为原料进行合成。
第二步:
N-(叔丁基二甲基硅基)-2-(1-((叔丁基二甲基硅基)氧基)-2-羟基丙-2-基)噻唑-5-磺酰胺(5b)
N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide
5b参考4d的方法,以5a为原料进行合成。
第三步:
N-(叔丁基二甲基硅基)-2-(-1-((叔丁基二甲基硅基)氧基)-2-羟基丙-2-基)噻唑-5-磺酰亚胺酰胺(中间体5)
N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide
中间体5参考中间体4的方法,以5b为原料进行合成,得到1.0g淡黄色固体。
LC-MS m/z(ESI)=467.2[M+1]。
中间体6-1和中间体6-2
(S)-N'-(叔丁基二甲基甲硅烷基)-2-((S)-1-((叔丁基二甲基甲硅烷基)氧基)-2-羟基丙-2-基)-N-((S)-1-(4-甲氧基苯基)乙基)噻唑-5-磺酰亚胺酰胺和
(R)-N'-(叔丁基二甲基甲硅烷基)-2-((S)-1-((叔丁基二甲基甲硅烷基)氧基)-2-羟基丙-2-基)-N-((S)-1-(4-甲氧基苯基)乙基)噻唑-5-磺酰亚胺酰胺(中间体6-1和中间体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
第一步:
2-异丙烯基噻唑(6b)
2-(Prop-1-en-2-yl)thiazole
在500mL三口瓶中,加入无水四氢呋喃300mL,甲基三苯基溴化磷(56.2g,157.3mmol),氮气保护,降温至-15℃,加入叔丁醇钾(17.6g,157.3mmol)后自然升至室温搅拌1.5h,加入6a(10g,78.6mmol),室温反应2h后TLC中控反应完全,加水100mL淬灭反应,EA萃取(100mL×2)次后,合并有机相,饱和食盐水洗涤(100mL×2),有机相通过无水硫酸钠干燥、过滤,减压除去有机溶剂。残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯=10:1~6:1)得到6b,淡黄色油状物(4.5g,收率45.9%)。
1HNMR(400MHz,DMSO-d
6)δ8.08(s,1H),8.00(s,1H),5.33(s,1H),4.96(s,1H),2.12(s,3H)。
第二步:
(S)-2-(噻唑-2-基)丙烷-1,2-二醇(6c)
(S)-2-(thiazol-2-yl)propane-1,2-diol
室温条件下,在2L三口瓶中,加入叔丁醇600mL,四氢呋喃600mL,水600mL,然后加入AD-mix-β混合物(448g,320mmol),甲基磺酰胺(30.4g,0.32mol),(DHQD)2AQN催化剂(11.0g,0.0128mol)。降温至0℃,加入6b(40g,0.32mol)后自然升至室温搅拌24h,TLC监控反应完全,加入EA萃取(500mL×2)次后,合并有机相,饱和食盐水洗涤(200mL×2),有机相通过无水硫酸钠干燥、过滤,减压除去有机溶剂。残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇=100:1~20:1)得到粗品,粗品使用乙酸乙酯(70mL),石油醚(210mL),甲醇(5mL)再次重结晶得到白色固体6c(45g,收率70%,RT=7.506min,99.8%ee)。手性HPLC(AS)流动相:正己烷/乙醇=90/10;柱温:35℃;柱压:80bar;流速:1mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm。
1H 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]。
第三步:
(S)-1-((叔丁基二甲基硅基)氧基)-2-(噻唑-2-基)丙烷-2-醇(6d)
(S)-1-((tert-butyldimethylsilyl)oxy)-2-(thiazol-2-yl)propan-2-ol
在500mL三口瓶中,加入无水四氢呋喃160mL,6c(8.6g,0.054mol),氮气保护,降温至-5℃,加入氢化钠(2.6g,0.108mol)后保温搅拌0.5h,然后加入叔丁基二甲基氯硅烷(10g,0.0648mol),室温反应2h后TLC中控反应完全,加水100mL淬灭反应,EA萃取(100mL×2)次后,合并有机相,饱和食盐水洗涤(100mL×2),有机相通过无水硫酸钠干燥、过滤,减压除去有机溶剂。残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯=10:1~6:1)得到6d,(12.6g,收率85.7%)。
1H 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]。
第四步:
(S)-2-(1-((叔丁基二甲基硅基)氧基)-2-羟基丙烷-2-基)噻唑-5-磺酰亚胺酰胺(6e)
(S)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide
在100mL三口瓶中,加入无水四氢呋喃40mL,6d(2.0g,7.31mmol),氮气保护。降温至-78℃,缓慢滴加正丁基锂(6.14mL,15.3mmol)滴加完毕后在-78℃反应2h,然后加入叔丁氧基-N-硫氧化物(1.18g,8.772mmol),加毕自然升至室温反应12h,TLC中控反应完全,加水30mL淬灭反应,EA萃取(50mL×2)次后,合并有机相,饱和食盐水洗涤(100mL×2),有机相通过无水硫酸钠干燥、过滤,减压除去有机溶剂。残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯=10:1~2:1)得到6e,白色固体物(1.6g,收率64.1%)。
LC-MS m/z(ESI)=353.5[M+1]。
第五步:
(S)-N-(叔丁基二甲基硅基)-2-(1-((叔丁基二甲基硅基)氧基)-2-羟基丙烷-2-基)噻唑-5-磺酰亚胺酰胺(6f)
(S)-N-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide
氮气保护,0℃下,向6e(4.0g,11.3mmol)的50mL四氢呋喃溶液中分批加入氢化钠(1.2g,60%,24mmol),加毕搅拌30分钟。加入叔丁基二甲基氯硅烷(2.4g,4.08mmol),室温反应4h.TLC监控反应完全,冰浴冷却下加入100mL水,乙酸乙酯(100mL×3)萃取。合并有机相,饱和食盐水洗涤(50mL×2),有机相通过无水硫酸钠干燥、过滤,减压除去有机溶剂。残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯=10:1~6:1)得到6f,淡黄色油状物(4.72g,收率63.2%)。
1H 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]。
第六步:
(S)-N'-(叔丁基二甲基硅基)-2-((S)-1-((叔丁基二甲基硅基)氧基)-2-羟基丙烷-2-基)-N-((S)-1-(4-甲氧基苯基)乙基)噻唑-5-磺酰亚胺酰胺(中间体6)
(S)-N'-(tert-butyldimethylsilyl)-2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
氮气保护,-10℃下,将6f(8.0g,21.4mmol)溶于50mL二氯乙烷,然后加入到现制的三苯基二氯化磷-二氯乙烷溶液(32.1mmol)中,搅拌2h。TLC监控反应完全,然后加入S-1-(4-甲氧基苯基)乙烷-1-胺(3.88g,25.68mmol),室温搅拌3h,反应完全后加入100mL水,二氯甲烷(100mL×3)萃取。合并有机相,饱和食盐水洗涤(50mL×2),有机相通过无水硫酸钠干燥、过滤,减压除去有机溶剂。残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯=50:1~20:1)得到化合物中间体6-1,淡黄色油状物(3.0g,收率30%)和中间体6-2(3.5g,收率35%)。
中间体6-1:
1H 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]。
中间体6-2:
1H 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]。
中间体7-1和7-2
(S)-N'-(叔丁基二甲基硅基)-2-((R)-1-(叔丁基二甲基硅烷基)氧基)-2-羟基丙烷-2-基)-N-(S)-1-(4-甲氧基苯基)乙基)噻唑-5-磺酰亚胺
(R)-N'-(叔丁基二甲基硅基)-2-((R)-1-((叔丁基二甲基硅烷基)氧基)-2-羟基丙烷-2-基)-N-(S)-(S)-1-(4-甲氧基苯基)乙基)噻唑-5-磺酰亚胺(中间体7-1和中间体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
参照中间体6-1和中间体6-2的合成方法制备中间体7-1和中间体7-2
实施例1
N-((5-((S)-1-环丙基乙基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)-2-((S)-1,2-二羟基丙-2-基)噻唑-5-磺酰亚胺酰胺(化合物1-1和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
第一步:
N-((5-((S)-1-环丙基乙基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)-2-((S)-1,2-二羟基丙-2-基)噻唑-5-磺酰亚胺酰胺(1A)
N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
在25mL圆底烧瓶中,氮气保护下依次加入中间体2(129mg,0.644mmol)、干燥四氢呋喃3mL、二异丙基乙胺(166mg,1.29mmol)和氯甲酸-2,2,2-三氯乙酯(163mg,0.77mmol),搅拌反应30min,TLC监控转化完全。反应液加入水5mL,乙酸乙酯萃取(10mL×2),合并有机相,无水硫酸钠干燥,旋干。加入3mL干燥的四氢呋喃溶解为溶液B。在另一50mL三口瓶中加入中间体4(300mg,0.644mmol)和3mL干燥的四氢呋喃,冰浴下加入氢化钠(31mg,60%,0.77mmol),搅拌反应1h。冰浴下缓慢滴加溶液B,升至室温反应1h,LC-MS监测反应完全,缓慢滴加三乙胺三氢氟酸盐(103mg,0.644mmol)。室温反应过夜,TLC监测反应结束,反应液倒入水中,加入乙酸乙酯(20mL×2),合并有机相,无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化纯化得1A,淡黄色固体(200mg,收率66.8%)。
LC-MS m/z(ESI)=465.2[M+1]。
第二步:
N-((5-((S)-1-环丙基乙基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)-2-((S)-1,2-二羟基丙-2-基)噻唑-5-磺酰亚胺酰胺(化合物1-1和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(180mg,0.387mmol)通过SFC拆分得到化合物1-1(72mg,收率40.0%,RT=20.010min,100%ee)和化合物1-2(85mg,收率47.2%,RT=24.571min,100%ee)。手性HPLC(AS)流动相:正己烷/乙醇=95/5;柱温:35℃;柱压:80bar;流速:1mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm。
化合物1-1:
1H 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]。
化合物1-2:
1H 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]。
实施例2
N-((3-((R)-1-环丙基乙基)双环[4.2.0]辛-1,3,5-三烯-2-基)氨基甲酰基)-2-(1,2-二羟基丙-2-基)噻唑-5-磺酰亚胺酰胺(化合物2-1和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
第一步:
2-(2,6-二溴苯基)乙-1-醇(2B)
2-(2,6-Dibromophenyl)ethan-1-ol
在1L的三口烧瓶中,加入2A(60.0g,0.2mol)和无水四氢呋喃(300mL),氮气保护,于0℃缓慢滴加硼烷四氢呋喃溶液(300mL,1M)。滴加完毕后,升至80℃反应1h,TLC监测反应完全,冷却至室温。于冰水浴加入水(150mL),稀盐酸(20mL,2N) 淬灭反应。减压浓缩部分反应液,然后加入乙酸乙酯(100mL×3)萃取,无水硫酸钠干燥、过滤、减压移除有机溶剂,残留物通过柱层析(石油醚:乙酸乙酯=5:1)纯化得2B,白色固体(50.0g,收率88%)。
1H NMR(400MHz,CDCl
3)δ=7.52(d,2H),6.94(t,1H),3.88(t,2H),3.33(t,2H)。
第二步:
1,3-二溴-2-(2-溴乙基)苯(2C)
1,3-Dibromo-2-(2-bromoethyl)benzene
在1L的圆底烧瓶中,依次加入2B(50.0g,0.18mol),N-溴代丁二酰亚胺(38.0g,0.2mmol)和二氯甲烷(400mL),搅拌溶清后,至于冰水浴,缓慢加入三苯基膦(65g,0.2mol),加完后,移至室温反应24h。TLC监测反应完全,加入叔丁基过氧化氢(8mL)反应2h除去过量的三苯基膦,加入饱和亚硫酸氢钠溶液(200mL)淬灭反应,二氯甲烷萃取(200mL×3),无水硫酸钠干燥,浓缩有机相至大量固体析出,加入正己烷打浆,抽滤,滤液浓缩后通过柱层析(石油醚:乙酸乙酯=50:1)纯化得2C,白色固体(60.0g,收率98%)。
1H NMR(400MHz,CDCl
3)δ=7.52(d,2H),6.97(t,1H),3.63–3.43(m,4H)。
第三步:
2-溴双环[4.2.0]辛-1(6),2,4-三烯(2D)
2-Bromobicyclo[4.2.0]octa-1(6),2,4-triene
在250mL的三口瓶中,依次加入2C(5.0g,15mmol)和无水四氢呋喃(150mL),氮气保护,于-68℃缓慢滴加正丁基锂(5.5mL,2.5M),滴加完毕,在-68℃反应2h,UPLC监测反应完全,缓慢滴加水(20mL)淬灭反应,乙酸乙酯萃取(100mL×3),无水硫酸钠干燥、过滤、减压移除有机溶剂得2D,淡黄色油状物(2.5g,收率90%)。
第四步:
叔丁基双环[4.2.0]辛-1(6),2,4-三烯-2-基氨基甲酸酯(2E)
Tert-butyl bicyclo[4.2.0]octa-1(6),2,4-trien-2-ylcarbamate
在250mL的圆底烧瓶中,依次加入2D(2.3g,0.013mol),二氧六环(50mL),氨基甲酸叔丁酯(2.2g,0.019mol),2-二环己基磷-2,4,6-三异丙基联苯(476mg,1mmol),碳酸铯(8.0g,0.025mol),氮气保护下加入醋酸钯(132mg,6mmol),移至100℃反应2h,TLC监测反应完全,冷却至室温后,加入饱和碳酸氢钠(50mL)淬灭反应,乙酸乙酯萃取(50mL×3),无水硫酸钠干燥、过滤、减压移除有机溶剂,粗产品通过柱层析(石油醚:乙酸乙酯=20:1)纯化得2E(2.3g,棕色油状物,收率83%)。
1H 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)。
第五步:
双环[4.2.0]辛-1(6),2,4-三烯-2-胺(2F)
Bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine
在100mL圆底烧瓶中,依次加入2E(2.3g,10.5mmol),二氯甲烷(40mL),三氟乙酸(6mL),室温反应7h,TLC监测反应完全,加入饱和碳酸氢钠溶液(40mL)淬灭反应,二氯甲烷萃取(50mL×3),无水硫酸钠干燥、过滤、减压移除有机溶剂,粗产品通过柱层析(石油醚:乙酸乙酯=10:1)纯化得2F,棕色油状物(1.0g,收率80%)。
1H NMR(400MHz,CDCl
3)δ=7.02(dd,1H),6.51(dd,2H),3.11(dd,2H),3.04(dd,2H)。
第六步:
(2-氨基双环[4.2.0]辛-1(6),2,4-三烯-3-基)(环丙基)甲酮(2G)
(2-Aminobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(cyclopropyl)methanone
在25mL三口烧瓶中依次加入2F(100mg,0.84mmol),二氯乙烷(5mL),溶清后至于冰水浴,于氮气保护下缓慢滴加三氯化硼甲苯溶液(900μL,1M),10min后加入无水三氯化铝(123mg,0.9mmol),再缓慢滴加环丁基腈(74μL,1mmol)。滴加完毕,于90℃反应3h,冷却至室温,加入稀盐酸溶液(1mL,2N)和水(5mL),回流30min,分出有机相,饱和碳酸氢钠(10mL)洗至弱酸性,二氯甲烷萃取(10mL×3),无水硫酸钠干燥、过滤、减压移除有机溶剂,粗产品通过柱层析(石油醚:乙酸乙酯=10:1)纯化得2G,棕色油状物(60mg,收率38%)。
1H 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)。
第七步:
3-(1-环丙基乙烯基)双环[4.2.0]辛-1(6),2,4-三烯-2-胺(2H)
3-(1-Cyclopropylvinyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine
在25mL三口烧瓶中依次加入三苯基甲基溴化磷(8g,22mmol),无水四氢呋喃(40mL),溶清后至于冰水浴,于氮气保护下加入叔丁醇钾(2.5g,22mmol),40min后加入2G(1.4g,7.5mmol)的四氢呋喃溶液(20mL),10min后于室温反应2h,加入水(20mL)淬灭,乙酸乙酯(20mL×3)萃取,无水硫酸钠干燥、过滤、减压移除有机溶剂,残留物通过柱层析(石油醚:乙酸乙酯=10:1)纯化得2H(1.2g,棕色油状物,收率85%)。
1H 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)。
第八步:
(R)-3-(1-环丙基乙基)双环[4.2.0]辛-1(6),2,4-三烯-2-胺(2I)
(R)-3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine
在500mL高压釜中,加入2H(500mg,2.7mmol)和二氯甲烷(50mL),加入催化剂[(R)-2,2'-双(二苯基膦)-1,11-联萘]二乙酸酸钌(113mg,0.14mmol),加完后将高压釜装置拧紧密封,用氢气置换3次,充入氢气,高压釜上的压力表压力显14atm,室温下反应5h。减压浓缩除去溶剂,粗产品通过柱层析(石油醚:乙酸乙酯=10:1)纯化得2I(470mg,淡黄色油状物,收率94%)。
1H 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)。
第九步
N-((3-((R)-1-环丙基乙基)双环[4.2.0]辛-1,3,5-三烯-2-基)氨基甲酰基)-2-((S)-1,2-二羟基丙-2-基)噻唑-5-磺酰亚胺酰胺(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
在25mL圆底烧瓶中,氮气保护下依次加入2I(133mg,0.71mmol)、干燥四氢呋喃3mL、二异丙基乙胺(191mg,1.48mmol)和氯甲酸-2,2,2-三氯乙酯(177mg,0.84mmol),搅拌反应30min,TLC监控转化完全。反应液加入水5mL,乙酸乙酯萃取(10mL×2),合并有机相,无水硫酸钠干燥,旋干。加入3mL干燥的四氢呋喃溶解为溶液C。在另一50mL三口瓶中加入中间体4(300mg,0.644mmol)和3mL干燥的四氢呋喃,冰浴下加入氢化钠(31mg,60%,0.77mmol),搅拌反应1h。冰浴下缓慢滴加溶液C,室温反应1h,LC-MS监测反应完全,缓慢滴加三乙胺三氢氟酸盐(309mg,1.92mmol)。室温反应过夜,TLC监测反应结束,反应液倒入水中,加入乙酸乙酯(20mL×2),合并 有机相,无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化纯化得2J,白色固体(244mg,收率84.1%)。LCMS m/z(ESI)=451.1[M+1]。
第十步:
N-((3-((R)-1-环丙基乙基)双环[4.2.0]辛-1,3,5-三烯-2-基)氨基甲酰基)-2-((S)-1,2-二羟基丙-2-基)噻唑-5-磺酰亚胺酰胺(化合物2-1和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
2J(210mg,0.466mmol)通过SFC拆分得到化合物2-1(100mg,收率47.6%,RT=19.828min,98.44%ee)和化合物2-2(95mg,收率45.2%,RT=18.351min,100%ee)。手性HPLC(AS)流动相:正己烷/乙醇=95/5;柱温:35℃;柱压:80bar;流速:1mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm。
化合物2-1:
1H 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)。
化合物2-2:
1H 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)。
实施例3
N-((2-(环丁基甲基)-4-氟-6-(2-甲氧基吡啶-4-基)苯基)氨基甲酰基)-2-(1,2-二羟基丙-2-基)噻唑-5-磺酰亚胺酰胺(化合物3)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
第一步:
(2-氨基-3-溴-5-氟苯基)(环丁基)甲酮(3B)
(2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanone
在1L三口烧瓶中依次加入3A(40g,210.4mmol),二氯乙烷(500mL),溶清后置于冰水浴,于氮气保护下缓慢滴加三氯化硼甲苯溶液(252.8mL,1M),10min后加入无水三氯化铝(33.6g,252mmol),再缓慢滴加环丁基腈(59.2mL,632mmol)。滴加完毕,于90℃反应24h,冷却至室温,加入稀盐酸溶液(30mL,2N),回流30min,分出有机相,饱和碳酸氢钠(50mL)洗至弱酸性,二氯甲烷萃取(50mL×3),无水硫酸钠干燥、过滤、减压移除的粗产物3B,淡黄色油状物(4.8g,收率8.8%)。
1H 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)
第二步:
(2-氨基-3-溴-5-氟苯基)(环丁基)甲醇(3C)
(2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanol
在250mL圆底烧瓶中,依次加入3B(4.8g,17.3mmol),无水甲醇(20mL),硼氢化钠(2.0g,51.9mmol),室温反应2h,TCL监测反应完全,缓慢滴加水(20mL)淬灭反应,二氯甲烷萃取(20mL×3),无水硫酸钠干燥,过滤,减压移除有机溶剂,粗产品通过柱层析(石油醚:乙酸乙酯=30:1)纯化得3C,白色粉末(2.6g,收率54%)。
1H 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)。
第三步:
2-溴-6-(环丁基甲基)-4-氟苯胺(3D)
2-Bromo-6-(cyclobutylmethyl)-4-fluoroaniline
在50mL圆底烧瓶中,依次加入3C(850mg,3mmol),二氯甲烷(20mL),三乙基硅烷(1.4mL,9mmol)和三氟乙酸(1mL,9mmol),室温反应2h,TLC监测反应完全,缓慢滴加饱和碳酸氢钠溶液(20mL)淬灭反应,二氯甲烷萃取(20mL×3),无水硫酸钠干燥,过滤,减压移除有机溶剂,粗产品通过柱层析(石油醚:乙酸乙酯=10:1)纯化得3D,棕色油状物(530mg,收率69%)。
1H 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)。
第四步:
2-(环丁甲基)-4-氟-6-(2-甲氧基吡啶-4-基)苯胺(3E)
2-(Cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)aniline
在50mL圆底烧瓶中,依次加入3D(500mg,1.93mmol),二氧六环(20mL),碳酸钠(616mg,5.8mmol),氮气保护下加入二氯二(三苯基磷)化钯(67.7mg,0.0965mmol),2-甲氧基吡啶-4-硼酸(383mg,2.50mmol)于80℃反应24h,TLC监测反应完全。减压浓缩除去溶剂,粗产品通过柱层析(石油醚:乙酸乙酯=5:1)纯化得3E,棕色油状物(350mg,收率63.3%)。
LCMS m/z(ESI)=287.2[M+l]。
第五步:
N-((2-(环丁基甲基)-4-氟-6-(2-甲氧基吡啶-4-yl)苯基)氨基甲酰基)-2-(1,2-二羟基丙-2-基)噻唑-5-磺酰亚胺酰胺(化合物3)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
在25mL圆底烧瓶中,氮气保护下依次加入3E(221mg,0.772mmol)、干燥四氢呋喃3mL、二异丙基乙胺(191mg,1.48mmol)和氯甲酸-2,2,2-三氯乙酯(191mg,0.901mmol),搅拌反应30min,TLC监控转化完全。反应液加入水5mL,乙酸乙酯萃取(10mL×2),合并有机相,无水硫酸钠干燥,减压浓缩除去溶剂。加入3mL干燥的四氢呋喃溶解为溶液C。在另一50mL三口瓶中加入中间体4(300mg,0.644mmol)和3mL干燥的四氢呋喃,冰浴下加入氢化钠(31mg,60%,0.77mmol),搅拌反应1h。冰浴下缓慢滴加溶液C,室温反应1h,LC-MS监测反应完全,缓慢滴加三乙胺三氢氟酸盐(311mg,1.93mmol)。室温反应过夜,TLC监测反应结束,反应液倒入水中,加入乙酸乙酯(20mL×2),合并有机相,无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过硅胶柱色谱分离(二氯甲烷/甲醇=20:1)纯化得化合物3,白色固体(311mg,收率87.9%)。
1H 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]。
实施例4
N-((2-(环丁基甲基)-4-氟-6-(2-甲氧基吡啶-4-yl)苯基)氨基甲酰基)-2-(1,2-二羟基丙-2-基)噻唑-5-磺酰亚胺酰胺(化合物4-1和4-2)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
第一步:
N-((2-(环丁基甲基)-4-氟-6-(2-甲氧基吡啶-4-yl)苯基)氨基甲酰基)-2-(1,2-二羟基丙-2-基)噻唑-5-磺酰亚胺酰胺(4A)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
在25mL圆底烧瓶中,氮气保护下依次加入3E(221mg,0.772mmol)、干燥四氢呋喃3mL、二异丙基乙胺(191mg,1.48mmol)和氯甲酸-2,2,2-三氯乙酯(191mg,0.901mmol),搅拌反应30min,TLC监控转化完全。反应液加入水5mL,乙酸乙酯萃取(10mL×2),合并有机相,无水硫酸钠干燥,减压浓缩除去溶剂。加入3mL干燥的四氢呋喃溶解为溶液C。在另一50mL三口瓶中加入中间体5(300mg,0.644mmol)和3mL干燥的四氢呋喃,冰浴下加入氢化钠(31mg,60%,0.77mmol),搅拌反应1h。冰浴下缓慢滴加溶液C,室温反应1h,LC-MS监测反应完全,缓慢滴加三乙胺三氢氟酸盐(311mg,1.93mmol)。室温反应过夜,TLC监测反应结束,反应液倒入水中,加入乙酸乙酯(20mL×2),合并有机相、无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过硅胶柱色谱分离(二氯甲烷/甲醇=20:1)纯化得4A,白色固体(177mg,收率50.0%)。
LCMS m/z(ESI)=550.2[M+1]。
第二步:
N-((2-(环丁基甲基)-4-氟-6-(2-甲氧基吡啶-4-基)苯基)氨基甲酰基)-2-(1,2-二羟基丙烷-2-基)噻唑-5-亚磺酰胺(化合物4-1和4-2)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
4A(177mg,0.322mmol)通过SFC拆分得到化合物4-1(79mg,收率44.6%,RT=6.348min,99.54%ee)和化合物4-2(68mg,收率38.4%,RT=9.341min,98.42%ee)。手性HPLC(AS)流动相:正己烷/乙醇=95/5;柱温:35℃;柱压:80bar;流速:1mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm。
化合物4-1:
1H 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)。
化合物4-2:
1H 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)。
实施例5
N-((5-((S)-1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-2-((R)-1,2-二羟基丙烷-2-基)噻唑-5-磺酰亚胺酰胺(化合物5-1和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
第一步:
N-((5-((S)-1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-2-((R)-1,2-二羟基丙烷-2-基)噻唑-5-磺酰亚胺酰胺(5A)
N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((R)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
在25mL圆底烧瓶中,氮气保护下依次加入中间体2(133mg,0.71mmol)、干燥四氢呋喃3mL、二异丙基乙胺(191mg,1.48mmol)和氯甲酸-2,2,2-三氯乙酯(177mg,0.84mmol),搅拌反应30min,TLC监控转化完全。反应液加入水5mL,乙酸乙酯萃取(10mL×2),合并有机相,无水硫酸钠干燥,旋干。加入3mL干燥的四氢呋喃溶解为溶液C。在另一50mL三口瓶中加入中间体4(300mg,0.644mmol)和3mL干燥的四氢呋喃,冰浴下加入氢化钠(31mg,60%,0.77mmol),搅拌反应1h。冰浴下缓慢滴加溶液C,室温反应1h,LC-MS监测反应完全,缓慢滴加三乙胺三氢氟酸盐(309mg,1.92mmol)。室温反应过夜,TLC监测反应结束,反应液倒入水中,加入乙酸乙酯(20mL×2),合并有机相、无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化纯化得5A,白色固体(76mg,收率26.2%)。
LCMS m/z(ESI)=451.1[M+1]。
第二步:
N-((5-((S)-1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-2-((R)-1,2-二羟基丙 烷-2-基)噻唑-5-磺酰亚胺酰胺(化合物5-1和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
5A(76mg,0.168mmol)通过SFC拆分得到化合物5-1(28mg,收率36.8%,RT=6.298min,100%ee)和化合物5-2(33mg,收率43.4%,RT=8.351min,99.04%ee)。手性HPLC(AS)流动相:正己烷/乙醇=95/5;柱温:35℃;柱压:80bar;流速:1mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm。
化合物5-1:
1H 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)。
化合物5-2:
1H 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)。
实施例6
3-氰基-N-(((5-(1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-5-(1,2-二羟基丙烷-2-基)噻吩-2-磺酰胺(化合物6-1和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
第一步:
4-溴-5-氨磺酰基噻吩-2-羧酸甲酯(6B)
Methyl 4-bromo-5-sulfamoylthiophene-2-carboxylate
在0℃下分批加入6A(30.0g,135.70mmol)的氯磺酸(44.67mL,678.52mmol)和 氯化亚砜(14.78mL,203.56mmol)的混合物。将混合物在0℃搅拌20分钟后置于50℃反应1小时。反应结束,冷至室温,在0℃下滴加入碳酸氢铵、水和丙酮溶液400mL(1:1),搅拌过夜。TLC检测反应结束,过滤,固体用乙酸乙酯(100mL)洗涤,水相乙酸乙酯(200mL)萃取,合并有机相,浓缩得深色油状物。经二氯甲烷(200mL)打浆得纯化得6B,浅黄色固体(28g,产率68.74%)。
LC-MS m/z(ESI)=300.03[M+1]。
第二步:
3-溴-5-(2-羟基丙-2-基)噻吩-2-磺酰胺(6C)
3-Bromo-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide
室温下将6B(28g,93.29mol)溶解于500mL干燥的THF中,冰盐浴降温到-15℃,缓慢滴加甲基溴化镁(155.48mL,466.45mol)并保持温度不超过0℃,滴加完毕室温下反应4h,TLC监控反应完全。将反应液倒入200mL冰水中淬灭,用EA萃取(200mL×3),合并有机相。有机相用饱和食盐水洗(100mL),无水硫酸钠干燥,减压浓缩除去溶剂,残留物用(乙酸乙酯:石油醚=1:20~1:10)得到6C,白色固体粉末(4.5g,产率47.4%)。
LC-MS m/z(ESI)=300.0[M+1]。
第三步:
3-氰基-5-(丙-1-烯-2-基)噻吩-2-磺酰胺(6D)
3-Cyano-5-(prop-1-en-2-yl)thiophene-2-sulfonamide
氮气保护下,在50mL圆底烧瓶中,将6C(4.0g,13.33mmol)和氰化亚铜(1.43g,15.99mmol)溶于N,N二甲基甲酰胺(40mL)中,150℃反应4小时,TLC监测反应完全,将反应液倒入碳酸氢钠饱和溶液(100mL),乙酸乙酯(50mL×10)萃取,无水硫酸钠干燥、过滤,减压移除有机溶剂,残留物通过柱层析(石油醚:乙酸乙酯=10:1~1:5)纯化得6D,淡黄色固体(1.0g,产率30.47%)。
LC-MS m/z(ESI)=229[M+1]。
第四步:
(R)-3-氰基-N-(((5-(1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-5-(丙-1-烯-2-基)噻吩-2-磺酰胺(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
在25mL圆底烧瓶中,氮气保护下依次加入中间体1(1.31g,6.51mmol)、干燥四氢呋喃50mL、二异丙基乙胺(1.53mg,11.84mmol)和氯甲酸-2,2,2-三氯乙酯(1.63g,7.70mmol),搅拌反应30min,TLC监控转化完全。反应液加入水50mL,乙酸乙酯萃取(100mL×2),合并有机相,无水硫酸钠干燥,旋干。加入3mL干燥的四氢呋喃溶解为溶液C。在另一50mL三口瓶中加入6D(1.35g,5.92mmol)和3mL干燥的四氢呋喃,冰浴下加入氢化钠(474mg,60%,11.84mmol),搅拌反应1h,TLC监测反应结束,反应液倒入水中,加入乙酸乙酯(20mL×2),合并有机相、无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化纯化得6E,淡黄色油状物1.35g,收率50.1%)。
LCMS m/z(ESI)=451.1[M+1]。
第五步:
3-氰基-N-(((5-((R)-1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-5-(1,2-二羟 基丙烷-2-基)噻吩-2-磺酰胺(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
在250mL圆底烧瓶中,将6E(1.35g,2.97mmol)溶于叔丁醇/丙酮(45mL/45mL)的混合溶剂中,搅拌下加入NMO(696mg,5.94mmol),室温搅拌10min后,滴加二水合锇酸钾(109mg,0.297mmol)的水溶液(45mL水),滴加完毕室温反应,TLC监测反应结束,亚硫酸氢钠水溶液淬灭反应,EA萃取(100mL×3),无水硫酸钠干燥,过滤,减压移除有机溶剂,粗产物通过柱层析(EA:PE=1:30-1.5:1)纯化得6F,黄色固体(240mg,收率16.5%)。
LCMS m/z(ESI)=490.1[M+1]。
第六步:
3-氰基-N-(((5-((R)-1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-5-(1,2-二羟基丙烷-2-基)噻吩-2-磺酰胺(化合物6-1和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
6F(240mg,0.491mmol)通过SFC拆分得到化合物6-1(39mg,收率16.3%,RT=8.630min,99.22%ee)和化合物6-2(43mg,收率17.9%,RT=15.807min,99.40%ee)。手性HPLC(AS)流动相:正己烷/乙醇=95/5;柱温:35℃;柱压:80bar;流速:1mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm。
化合物6-1:
1H 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)。
化合物6-2:
1H 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)。
实施例7
3-氰基-N-(((3-((R)-1-环丙基乙基)双环[4.2.0]辛-1,3,5-三烯-2-基)氨基甲酰基)-5-(1,2-二羟基丙烷-2-基)噻吩-2-磺酰胺(化合物7-1和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
第一步:
(R)-3-氰基-N-(((3-(1-环丙基乙基)双环[4.2.0]辛-1,3,5-三烯-2-基)氨基甲酰基)-5-(丙-1-烯-2-基)噻吩-2-磺酰胺(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
在25mL圆底烧瓶中,氮气保护下依次加入2I(1.1g,5.76mmol)、干燥四氢呋喃50mL、二异丙基乙胺(1.4g,10.48mmol)和氯甲酸-2,2,2-三氯乙酯(1.45g,6.81mmol),搅拌反应30min,TLC监控转化完全。反应液加入水50mL,乙酸乙酯萃取(100mL×2),合并有机相,无水硫酸钠干燥,旋干。加入3mL干燥的四氢呋喃溶解为溶液C。在另一50mL三口瓶中加入6D(1.2g,5.24mmol)和3mL干燥的四氢呋喃,冰浴下加入氢化钠(420mg,60%,10.48mmol),搅拌反应1h,TLC监测反应结束,反应液倒入水中,加入乙酸乙酯(20mL×2),合并有机相、无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化纯化得7A,淡黄色油状物(1.14g,收率49.4%)。
LCMS m/z(ESI)=442.1[M+1]。
第二步:
3-氰基-N-(((5-((R)-1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-5-(1,2-二羟基丙烷-2-基)噻吩-2-磺酰胺(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
在250mL圆底烧瓶中,将7A(442mg,1mmol)溶于叔丁醇/丙酮(25mL/25mL)的混合溶剂中,搅拌下加入NMO(235mg,2.0mmol),室温搅拌10min后,滴加二水合锇酸钾(37mg,0.10mmol)的水溶液(45mL),滴加完毕室温反应,TLC监测反应结束,亚硫酸氢钠水溶液淬灭反应,EA萃取(100mL×3),无水硫酸钠干燥、过滤,减压移除有机溶剂,粗产物通过柱层析(EA:PE=1:30-1.5:1)纯化得7B,黄色固体(210mg,收率44.2%)。
LCMS m/z(ESI)=476.1[M+1]。
第三步:
3-氰基-N-(((3-((R)-1-环丙基乙基)双环[4.2.0]辛-1,3,5-三烯-2-基)氨基甲酰基)-5-(1,2-二羟基丙烷-2-基)噻吩-2-磺酰胺(化合物7-1和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
7B(210mg,0.442mmol)通过SFC拆分得到化合物7-1(76mg,收率36.2%,RT=5.568min,100%ee)和化合物7-2(93mg,收率44.2%,RT=12.071min,100%ee)。手性HPLC(AS)流动相:正己烷/乙醇=95/5;柱温:35℃;柱压:80bar;流速:1mL/min; 检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm。
化合物7-1:
1H 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)。
化合物7-2:
1H 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)。
实施例8
N-((3-((S)-1-环丙基乙基)-6,7-二氢-5H-环戊[b]吡啶-4-基)氨基甲酰基)-2-(1,2-二羟基丙烷-2-基)噻唑-5-磺酰亚胺酰胺(化合物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
第一步:
(6,7-二氢-5H-环戊基[b]吡啶-4-基)氨基甲酸叔丁酯(8B)
Tert-butyl(6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate
在500mL三口瓶中依次加入8A(25g,162.75mmol)、氨基甲酸叔丁酯(28.7g,244.12mmol)、X-phos(7.8g,16.3mmol)、醋酸钯(1.83g,8.14mmol)、碳酸铯(105.8g,325.5mmol)和1,4-二氧六环(400mL),氮气保护下100℃反应6h,TLC监测反应完成,冷至室温,加水淬灭,乙酸乙酯萃取(200mL×3),无水硫酸钠干燥、过滤、减压移除有机溶剂,粗产物通过乙酸乙酯(60mL)打浆得8B,淡黄色固体(24.1g,收率62.7%)。
LC-MS m/z(ESI)=235.3[M+1]。
第二步:
(3-溴-6,7-二氢-5H-环戊[b]吡啶-4-基)氨基甲酸叔丁酯(8C)
Tert-butyl(3-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate
在500mL圆底中依次加入8B(24g,102.13mmol)、NBs(27.3g,153.2mmol)和乙腈(200mL),60℃反应8h,TLC监测反应完成,冷至室温,亚硫酸氢钠淬灭,乙酸乙酯萃 取(200mL×3),无水硫酸钠干燥、过滤、减压移除有机溶剂,粗产物通过柱层析(EA:PE=1:10–1:2)纯化得8C,淡黄色固体(35.2g,收率81.3%)。
1H 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]。
第三步:
(3-(1-环丙基乙烯基)-6,7-二氢-5H-环戊[b]吡啶-4-基)氨基甲酸叔丁酯(8D)
Tert-butyl(3-(1-cyclopropylvinyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate
氮气保护下,在500mL圆底中依次加入8C(25g,79.87mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(18.6g,95.85mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯(8.8g,11.98mmol)、磷酸钾(33.9g,159.74mmol)和1,4-二氧六环/水混合溶剂(200mL/50mL),100℃反应8h,TLC监测反应完成,冷至室温,加水淬灭,乙酸乙酯萃取(200mL×3),无水硫酸钠干燥,过滤,减压移除有机溶剂,粗产物通过柱层析(EA:PE=1:30-1:5)纯化得8D,白色固体(15.2g,收率63.3%)。
LC-MS m/z(ESI)=301.2[M+1]。
第四步:
(3-(1-环丙基乙烯基)-6,7-二氢-5H-环戊[b]吡啶-4-基)氨基甲酸叔丁酯(8E)
Tert-butyl(3-(1-cyclopropylvinyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate
在500mL圆底中依次加入8D(15g,49.83mmol)、二氯甲烷(150mL),缓慢滴加三氟化硼乙醚(28.4g,200mmol),滴加完毕室温反应,TLC监测反应完成,加水淬灭,饱和碳酸氢钠溶液调节pH至中性,DCM萃取(100mL×3),无水硫酸钠干燥、过滤、减压移除有机溶剂,粗产物通过柱层析(EA:PE=1:30-1:3)纯化得8E,褐色油状物(3g,收率30%)。
LC-MS m/z(ESI)=201.1[M+1]。
第五步:
(S)-5-(1-环丙基乙基)-2,3-二氢-1H-茚-4-胺(8F)
(S)-5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-amine
8F的合成参考专利CN108017559进行制备。在250mL高压釜中,加入8E(820mg,4.1mmol)和二氯甲烷(30mL),加入催化剂[(S)-2,2'-双(二苯基膦)-1,11-联萘]二乙酸酸钌(346mg,0.41mmol),加完后将高压釜装置拧紧密封,用氢气置换3次,充入氢气,高压釜上的压力表显30atm,室温下反应30小时。减压浓缩除去溶剂,残留物用硅胶柱色谱分离提纯(dCM/MeOH=30:1-15:1)得到8F,淡黄色油状物(343mg,收率41.5%,92.70%ee)。手性HPLC(CHIRALPAK AY-3(4.6×100mm);流动相:甲醇;柱温:35℃;流动相:甲醇/正己烷=15/85;柱压:2000psi;流速:2mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm;RT=8.765min)。
1H 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]。
第六步:
N-((3-((S)-1-环丙基乙基)-6,7-二氢-5H-环戊[b]吡啶-4-基)氨基甲酰基)-2-((S)-1,2-二羟基丙烷-2-基)噻唑-5-磺酰亚胺酰胺(化合物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
在25mL圆底烧瓶中,氮气保护下依次加入8F(144mg,0.708mmol)、干燥四氢呋喃50mL、二异丙基乙胺(167mg,1.288mmol)和氯甲酸-2,2,2-三氯乙酯(164mg,0.773mmol),搅拌反应30min,TLC监控转化完全。反应液加入水50mL,乙酸乙酯萃取(100mL×2),合并有机相,无水硫酸钠干燥,旋干。加入3mL干燥的四氢呋喃溶解为溶液C。在另一50mL三口瓶中加入中间体4(300mg,0.644mmol)和3mL干燥的四氢呋喃,冰浴下加入氢化钠(52mg,60%,1.288mmol),搅拌反应1h,TLC监测反应结束,反应液倒入水中,加入乙酸乙酯(20mL×2),合并有机相、无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化纯化得化合物8,淡黄色固体(92mg,收率30.7%)。
1H 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]。
实施例9
(N-((5-((S)-1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(1,2-二羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(化合物9-1和9-2)
N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
第一步:
(R)-N'-(叔丁基二甲基甲硅烷基)-N-(((5-(1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(2-羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(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
在100mL圆底烧瓶中,氮气保护下依次加入中间体2(3.1g,15.4mmol),三乙胺(1.87g,18.5mmol)和四氢呋喃100mL,冰浴下加入三光气(1.83g,6.2mmol),升温 回流反应2h,过滤移除固体,滤液中加入中间体3(4.9g,15.4mmol)和甲醇钠(1.66g,30.8mmol),室温反应12h。TLC监控完全反应,反应结束,得到化合物9A,不需要纯化直接投下一步。
LCMS m/z(ESI)=546.3[M+l]。
第二步:
(R)-N-((5-(1-环丙基乙基)-2,3-二氢-1H-茚-4-基)氨甲酰基)-4-(2-羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(9B)
(R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
在上一步合成化合物9A的反应体系中加入四丁基氟化铵(6.2mL,61.6mmol,1M in THF),室温反应过夜,TLC监测反应结束,反应液倒入水中,乙酸乙酯(100mL×3)萃取,合并有机相,用1M稀HCl洗一次,无水硫酸钠干燥,过滤,减压移除有机溶剂,残留物通过中压制备(乙腈/水=50%)纯化得9B,透明状固体(1.2g,收率18.2%)。
LCMS m/z(ESI)=432.2[M+l]。
第三步:
N-(((5-1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(2-羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(9C)
N-((5-(-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
消旋体9B通过SFC拆分得到9C(537mg,收率44.8%,98.80%ee,RT=14.041min),手性HPLC(OZ);流动相:正己烷/乙醇=90/10;柱温:35℃;柱压:80bar;流速:1mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起始波长:200nm;二极管阵列检测器终止波长:400nm。
1H 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]。
第四步:
(S)-N-(((5-((S)-1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(2-羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(9D)
(S)-N-((5-((S)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
氮气保护下,在100mL单口瓶中,将9C(2.0g,4.63mmol)溶于四氢呋喃(40mL)中,冰浴降温至0℃,缓慢加入伯吉斯试剂(2.2g,9.26mmol),保持此温度反应10min后,反应体系恢复至室温反应2h。反应结束,乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压移除有机溶剂,残留物通过柱层析(二氯甲烷:甲醇=60:1)纯化得9D,白色固体(1.0g,产率52.1%)。
LCMS m/z(ESI)=414.20[M+1]。
第五步:
(S)-N-(((5-(1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(1,2-二羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(9E)
(S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2- dihydroxypropan-2-yl)furan-2-sulfonimidamide
氮气保护下,在100mL单口瓶中,将9D(1.0g,2.42mmol)溶于叔丁醇:丙酮(10mL:10mL)中,冰盐浴降温至0℃,加入4-甲基吗啡-N-氧化物(566mg,4.84mmol),缓慢滴加锇酸钾一水合物(88mg,0.24mmol)的水溶液(10mL),滴加完毕,保持此温度反应10min后,反应体系恢复至室温反应1h,反应结束,冷至室温,用饱和亚硫酸氢钠水溶液淬灭反应,乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水溶液洗涤,无水硫酸钠干燥,过滤,减压移除有机溶剂,残留物通过柱层析(二氯甲烷:甲醇=30:1)纯化得9E,白色固体(0.5g,产率46.2%)。
第六步:
(N-((5-((S)-1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(1,2-二羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(化合物9-1和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(500mg,1.116mmol)通过SFC拆分得到化合物9-1(200mg,收率40.0%,RT=6.441min,99.02%ee)和化合物9-2(205mg,收率40.1%,RT=5.036min,100%ee)。手性HPLC(AS)流动相:正己烷/乙醇=95/5;柱温:35℃;柱压:80bar;流速:1mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm。
化合物9-1:
1H 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]。
化合物9-2:
1H 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]。
实施例10
N-((5-((R)-1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(1,2-二羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(化合物10-1和10-2)
N-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
第一步:
(S)-N'-(叔丁基二甲基甲硅烷基)-N-(((5-(1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(2-羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(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
在100mL圆底烧瓶中,氮气保护下依次加入中间体1(2.6g,12.9mmol),三乙胺(1.57g,15.5mmol)和四氢呋喃100mL,冰浴下加入三光气(1.54g,5.2mmol),升温回流反应2h,过滤移除固体,滤液中加入中间体3(4.1g,12.9mmol)和甲醇钠(1.4g,25.8mmol),室温反应12h。TLC监控完全反应,反应结束,得到化合物10A,不用纯化直接投下一步。
LCMS m/z(ESI)=546.3[M+l]。
第二步:
(S)-N-((5-(1-环丙基乙基)-2,3-二氢-1H-茚-4-基)氨甲酰基)-4-(2-羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(10B)
(S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
在上一步合成化合物10A的反应体系中加入四丁基氟化铵(5.2mL,51.7mmol,1M/THF),室温反应过夜,TLC监测反应结束,反应液倒入水中,乙酸乙酯(100mL×3)萃取,合并有机相,用1M稀HCl洗一次,无水硫酸钠干燥,过滤,减压移除有机溶剂,残留物通过中压制备(乙腈/水=50%)纯化得消旋体10B,透明状固体(2.6g,收率46.6%)。
LCMS m/z(ESI)=432.2[M+l]。
第三步:
N-(((5-1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(2-羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(10C)
N-((5-(-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
消旋体10B通过SFC拆分得到10C(1.17g,收率45%,99.70%ee,RT=14.463min)。手性HPLC(OZ);流动相:正己烷/乙醇=90/10;柱温:35℃;柱压:80bar;流速:1 mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起始波长:200nm;二极管阵列检测器终止波长:400nm;RT=14.463min。
1H 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]。
第四步:
(R)-N-(((5-(1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(丙-1-烯-2-基)呋喃-2-磺酰亚胺酰胺(10D)
(R)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide
氮气保护下,在100mL单口瓶中,将10C(3.0g,6.96mmol)溶于四氢呋喃(40mL)中,冰浴降温至0℃,缓慢加入对甲苯磺酸一水合物(2.6g,13.92mmol),保持此温度反应10min后,反应体系恢复至室温反应2h。反应结束,乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压移除有机溶剂,残留物通过柱层析(二氯甲烷:甲醇=60:1)纯化得10D,白色固体(1.8g,产率62.4%)。
LCMS m/z(ESI)=414.20[M+1]。
第五步:
(S)-N-(((5-(1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(1,2-二羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(10E)
(S)-N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
氮气保护下,在100mL单口瓶中,将10D(1.8g,4.36mmol)溶于叔丁醇:丙酮(18mL:18mL)中,冰盐浴降温至0℃,加入4-甲基吗啡-N-氧化物(1.02g,8.72mmol),缓慢滴加锇酸钾一水合物(161.9mg,0.44mmol)的水溶液(10mL),滴加完毕,保持此温度反应10min后,反应体系恢复至室温反应1h,反应结束,冷至室温,用饱和亚硫酸氢钠水溶液淬灭反应,乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水溶液洗涤、无水硫酸钠干燥、过滤,减压移除有机溶剂,残留物通过柱层析(二氯甲烷:甲醇=30:1)纯化得10E,白色固体(0.9g,产率45.8%)。
LCMS m/z(ESI)=448.20[M+1]。
第六步:
N-((5-(1-环丙基乙基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(1,2-二羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(化合物10-1和10-2)
N-((5-(1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
10E(900mg,2.008mmol)通过SFC拆分得到化合物10-1(290mg,收率32.2%,RT=6.220min,99.06%ee)和化合物10-2(270mg,收率40.1%,RT=4.909min,98.09%ee)。手性HPLC(AS)流动相:正己烷/乙醇=90/10;柱温:35℃;柱压:80bar;流速:1mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm。
化合物10-1:
1H 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]。
化合物10-2:
1H 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]。
实施例11
N-(((5-(环丁基甲基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(丙-1-烯-2-基)呋喃-2-磺酰亚胺酰胺(化合物11-1和11-2)
N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide
第一步:
(4-氨基-2,3-二氢-1H-茚-5-基)(环丁基)甲酮(11B)
(4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl)methanone
氮气保护下,在500mL三口瓶中,将化合物11A(5.0g,37.54mmol)溶于1,2-二氯乙烷(50mL)中,冰盐浴降温至0℃,缓慢滴加三氯化硼(37.5mL,1M,37.54mmol)的二氯甲烷溶液,滴加完毕,保持此温度反应10min后,加入三氯化铝(5.5g,41.3mmol)和环丁基腈(4.55g,56.3mmol);反应体系升温至80℃反应4h,冷至室温,冰浴下加入40mL(2M HCl),滴加完毕升温回流1h。反应结束,冷至室温,DCM(75mL×3)萃 取,有机相用40mL的2M氢氧化钠溶液洗涤,无水硫酸钠干燥,过滤,减压移除有机溶剂,残留物通过柱层析(石油醚:乙酸乙酯=20:1)纯化得化合物11B,白色固体(2.6g,产率32.2%)。
1H 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]。
第二步:
(4-氨基-2,3-二氢-1H-茚-5-基)(环丁基)甲醇(11C)
(4-Amino-2,3-dihydro-1H-inden-5-yl)(cyclobutyl)methanol
在50mL圆底烧瓶中,氮气保护下,加入乙醇(20mL)和化合物11B(2.0g,9.30mmol),冰浴降温至0℃,缓慢添加硼氢化钠(703mg,18.60mmol),添加完毕恢复至室温反应1h;反应结束体系降温至0℃,滴加20mL水淬灭反应,DCM(30mL×3)萃取,无水硫酸钠干燥、过滤,滤液减压浓缩除去溶剂,粗产品通过柱层析(石油醚:乙酸乙酯=1:1)纯化得化合物11C,无色油状物(1.8g,产率89%)。
LCMS m/z(ESI)=200.1[M-l7]。
第三步:
5-(环丁基甲基)-2,3-二氢-1H-茚-4-胺(11D)
5-(Cyclobutylmethyl)-2,3-dihydro-1H-inden-4-amine
氮气保护下,将11C(1.3g,5.98mmol)和三乙基硅烷(2.1g,17.94mmol)溶于DCM(20mL)中,冰浴降温至0℃,缓慢滴加三氟乙酸(3.5g,29.90mmol),添加完毕室温反应过夜,反应结束,饱和碳酸氢钠水淬灭反应,DCM(50mL×3)萃取,有机相用无水硫酸钠干燥、过滤,减压移除有机溶剂,残留物通过柱层析(石油醚:乙酸乙酯=20:1)纯化得11D,无色油状物(1.0g,产率83.1%)。
1H 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]。
第四步:
N-(叔丁基二甲基甲硅烷基)-N'-((5-(环丁基甲基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(2-羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(11E)
N-(Tert-butyldimethylsilyl)-N'-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
氮气保护下,在100mL圆底烧瓶中,依次加入11D(1.5g,7.46mmol),三乙胺(11.02g,8.95mmol)和四氢呋喃10mL,冰浴下加入三光气(103mg,0.40mmol),升温回流反应2h,过滤移除固体,滤液中加入中间体3(1.1g,2.98mmol)和甲醇钠(806mg,14.9mmol),室温反应12h。反应结束,无需纯化直接用于下一步。TLC监控完全反应,反应液加水(50mL)淬灭,DCM(100mL×3)萃取,有机相通过无水硫酸钠干燥、过滤,移除有机溶剂,粗产品通过薄层层析纯化得11E,淡黄色油状固体(1.43g,收率44.0%)。
LCMS m/z(ESI)=546.3[M+l]。
第五步:
N-((5-(环丁基甲基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)-4-(2-羟基丙烷-2-基)呋喃-2-磺酰胺基酰胺(11F)
N-((5-(Cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2- yl)furan-2-sulfonimidamide
氮气保护下,在上一步合成化合物11E的反应体系中缓慢滴加四丁基氟化铵(15mL,1M in THF,15mmol),滴加完毕恢复至室温反应2h;反应结束,加水淬灭,乙酸乙酯(30mL×3)萃取,有机相通过无水硫酸钠干燥,过滤,减压移除得残留物,中压制备(乙腈/水=50%)纯化得11F,白色固体(1.43g,收率44.0%)。
LCMS m/z(ESI)=432.2[M+l]。
第六步:
N-((5-(环丁基甲基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(2-羟基丙烷-2-基)呋喃-2-磺酰胺基酰胺(11G)
N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
消旋体11F通过SFC拆分得到11G(680mg,99.45%ee,RT=10.896min)。手性HPLC(OX-3);流动相:甲醇;柱温:35℃;柱压:80bar;流速:1mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起始波长:200nm;二极管阵列检测器终止波长:400nm。
1H 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]。
第七步:
(S)-N-(((5-(环丁基甲基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(丙-1-烯-2-基)呋喃-2-磺酰亚胺酰胺(11H)
(S)-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide
氮气保护下,在100mL单口瓶中,将11G(1.0g,2.32mmol)溶于四氢呋喃(40mL)中,冰浴降温至0℃,缓慢加入对甲苯磺酸一水合物(788mg,4.64mmol),保持此温度反应10min后,反应体系恢复至室温反应2h。反应结束,乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水洗涤、无水硫酸钠干燥、过滤,减压移除有机溶剂,残留物通过柱层析(二氯甲烷:甲醇=60:1)纯化得11H,白色固体(0.6g,产率62.5%)。
LCMS m/z(ESI)=414.20[M+1]。
第八步:
(S)-N-(((5-(环丁基甲基)-2,3-二氢-1H-茚满-4-基)氨基甲酰基)-4-(1,2-二羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(11I)
(S)-N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
氮气保护下,在100mL单口瓶中,将11H(0.6g,1.45mmol)溶于叔丁醇:丙酮(6mL:6mL)中,冰盐浴降温至0℃,加入4-甲基吗啡-N-氧化物(339mg,2.90mmol),缓慢滴加锇酸钾一水合物(55.2mg,0.15mmol)的水溶液(6mL),滴加完毕,保持此温度反应10min后,反应体系恢复至室温反应1h,反应结束,冷至室温,用饱和亚硫酸氢钠水溶液淬灭反应,乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水溶液洗涤,无水硫酸钠干燥,过滤,减压移除有机溶剂,残留物通过柱层析(二氯甲烷:甲醇=30:1)纯化得化合物11I,白色固体(0.3g,产率46.2%)。
LCMS m/z(ESI)=448.20[M+1]。
第九步:
N-(((5-(环丁基甲基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)-4-(丙-1-烯-2-基)呋喃-2-磺酰亚胺酰胺(化合物11-1和11-2)
N-((5-(cyclobutylmethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide
11I(300mg,0.669mmol)通过SFC拆分得到化合物11-1(105mg,收率35.0%,RT=12.374min,98.60%ee)和化合物11-2(99mg,收率33.0%,RT=7.388min,98.32%ee)。手性HPLC(AS),流动相:正己烷/乙醇=90/10;柱温:35℃;柱压:80bar;流速:1mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm。
化合物11-1:
1H 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]。
化合物11-2:
1H 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]。
实施例12
N-(((3,5-双(环丁基甲基)吡啶-4-基)氨基甲酰基)-2-(1,2-二羟基丙烷-2-基)噻唑-4-磺酰亚胺酰胺(化合物12-1和12-2)
N-((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-4-sulfonimidamide
第一步:
3,5-双(环丁基甲基)吡啶-4-胺(12B)
3,5-Bis(cyclobutylmethyl)pyridin-4-amine
在100mL三口瓶中,依次加入12A(1.0g,6.13mmol)、环丁基甲基三氟硼酸钾(4.3g,24.54mmol)、碳酸钾(5.1g,36.78mmol)、Ruphos Pd-G3(775mg,0.919mmol)和甲苯/水混合溶剂(40mL/10mL),升温回流反应5h,TLC检测反应结束,冷至室温,加水淬灭,乙酸乙酯萃取(20mL×3),无水硫酸钠干燥、过滤,减压移除有机溶剂,粗产物通过柱层析(EA:PE=1:20~1:5)纯化得12B,淡黄色油状物(1g,收率36%)。
第二步:
N-(((3,5-双(环丁基甲基)吡啶-4-基)氨基甲酰基)-2-(1,2-二羟基丙烷-2-基)噻唑-4-磺酰亚胺酰胺(12C)
N-((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-4-sulfonimidamide
氮气保护下,在100mL圆底烧瓶中,依次加入12B(115mg,0.5mmol),四氢呋喃(10mL),N,N-二异丙基乙胺(177μL,1.0mmol)和氯甲酸-2,2,2-三氯乙酯(234μL,1.5mmol),室温反应1h。加水(10mL)淬灭,乙酸乙酯(20mL×3)萃取,无水硫酸钠干燥,过滤,减压移除有机溶剂后,将其溶于四氢呋喃(10mL),加入中间体4(510mg,1.5mmol)和氢化钠(54mg,2.25mmol),室温反应2h。加入三乙胺氢氟酸盐(484mg,3mmol),室温反应5h。TLC监控完全反应,反应液加水(20mL)淬灭,乙酸乙酯(30mL×3)萃取,有机相通过无水硫酸钠干燥、过滤,移除有机溶剂,粗产品通过中压制备(乙腈/水=60%)纯化得12C,淡黄色油状物(420mg,收率75.3%)。
第三步:
N-(((3,5-双(环丁基甲基)吡啶-4-基)氨基甲酰基)-2-(1,2-二羟基丙烷-2-基)噻唑-4-磺酰亚胺酰胺(化合物12-1和12-2)
N-((3,5-bis(cyclobutylmethyl)pyridin-4-yl)carbamoyl)-2-(1,2-dihydroxypropan-2-yl)thiazole-4-sulfonimidamide
12C(120mg)通过SFC拆分得到化合物12-1(48mg,收率40%,RT=3.376min,100%ee)和化合物12-2(52mg,收率43.3%,RT=4.446min,100%ee)。手性HPLC(AS)流动相:正己烷/乙醇=90/10;柱温:35℃;柱压:80bar;流速:1mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm。
LC-MS m/z(ESI)=493.18.
化合物12-1:
1H 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)。
化合物12-2:
1H 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)。
实施例13
(R)-N-(((2-(环丁基甲基)-4-氟-6-(2-甲氧基吡啶-4-基)苯基)氨基甲酰基)-4-(1,2-二羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(化合物13)
(R)-N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
第一步:
(2-氨基-3-溴-5-氟苯基)(环丁基)甲酮(13B)
(2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanone
在1L三口烧瓶中依次加入13A(40g,210.4mmol),二氯乙烷(500mL),溶清后至于冰水浴,于氮气保护下缓慢滴加三氯化硼甲苯溶液(252.8mL,1M),10min后加入无水三氯化铝(33.6g,252mmol),再缓慢滴加环丁基腈(59.2mL,632mmol)。滴加完毕,于90℃反应24h,冷却至室温,加入稀盐酸溶液(30mL,2N),回流30min,分出有机相,饱和碳酸氢钠(50mL)洗至弱酸性,二氯甲烷萃取(50mL×3),无水硫酸钠干燥,过滤,减压移除的粗产物13B淡黄色油状物(4.8g,收率8.8%)。
1H 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)。
第二步:
(2-氨基-3-溴-5-氟苯基)(环丁基)甲醇(13C)
(2-Amino-3-bromo-5-fluorophenyl)(cyclobutyl)methanol
在250mL圆底烧瓶中,依次加入13B(4.8g,17.3mmol),无水甲醇(20mL),硼氢化钠(2.0g,51.9mmol),室温反应2h,TCL监测反应完全,缓慢滴加水(20mL)淬灭反应,二氯甲烷萃取(20mL×3),无水硫酸钠干燥,过滤,减压移除有机溶剂,粗产品通过柱层析(石油醚:乙酸乙酯=30:1)纯化得13C,白色粉末(2.6g,收率54%)。
1H 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)。
第三步:
2-溴-6-(环丁基甲基)-4-氟苯胺(13D)
2-Bromo-6-(cyclobutylmethyl)-4-fluoroaniline
在50mL圆底烧瓶中,依次加入13C(850mg,3mmol),二氯甲烷(20mL),三乙基硅烷(1.4mL,9mmol)和三氟乙酸(1mL,9mmol),室温反应2h,TLC监测反应完全,缓慢滴加饱和碳酸氢钠溶液(20mL)淬灭反应,二氯甲烷萃取(20mL×3),无水硫酸钠干燥,过滤,减压移除有机溶剂,粗产品通过柱层析(石油醚:乙酸乙酯=10:1)纯化得13D,棕色油状物(530mg,收率69%)。
1H 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)。
第四步:
2-(环丁甲基)-4-氟-6-(2-甲氧基吡啶-4-基)苯胺(13E)
2-(Cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)aniline
在50mL圆底烧瓶中,依次加入13D(500mg,1.93mmol),二氧六环(20mL),碳酸钠(616mg,5.8mmol),氮气保护下加入二氯二(三苯基磷)化钯(67.7mg,0.0965mmol),2-甲氧基吡啶-4-硼酸(383mg,2.50mmol)于80℃反应24h,TLC监测反应完全。减压浓缩除去溶剂,粗产品通过柱层析(石油醚:乙酸乙酯=5:1)纯化得13E,棕色油状物(350mg,收率63.3%)。
LCMS m/z(ESI)=287.2[M+l]。
第五步:
N-(((2-(环丁基甲基)-4-氟-6-(2-甲氧基吡啶-4-基)苯基)氨基甲酰基)-4-(2-羟基丙-2-基)呋喃-2-磺酰亚胺酰胺(13F)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
氮气保护下,在100mL圆底烧瓶中,依次加入13E(429mg,1.5mmol),四氢呋喃(10mL),三光气(177.6mg,0.6mmol)和三乙胺(181.8,1.8mmol),室温反应1h,过滤,加入中间体3(510mg,1.5mmol)和氢化钠(54mg,2.25mmol),室温反应2h。加入三乙胺氢氟酸盐(484mg,3mmol),室温反应1h。TLC监控完全反应,反应液加水(20mL)淬灭,乙酸乙酯(30mL×3)萃取,有机相通过无水硫酸钠干燥、过滤,移除有机溶剂,粗产品通过中压制备(乙腈/水=30%)纯化得化13F,白色固体(260mg,收率30.1%)。
第六步:
N-(((2-(环丁基甲基)-4-氟-6-(2-甲氧基吡啶-4-基)苯基)氨基甲酰基)-4-(2-羟基丙-2-基)呋喃-2-磺酰亚胺酰胺(13G)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
13F(260mg)通过SFC拆分得到13G(110mg,收率38.6%,RT=3.786min,100%ee)。手性HPLC(AS)流动相:正己烷/乙醇=90/10;柱温:35℃;柱压:80bar;流速:1mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm。
LC-MS m/z(ESI)=516.18.
13G:
1H 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)。
第七步:
N-(((2-(环丁基甲基)-4-氟-6-(2-甲氧基吡啶-4-基)苯基)氨基甲酰基)-4-(丙-1-烯-2-基)呋喃-2-磺酰亚胺酰胺(13H)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide
氮气保护下,在100mL单口瓶中,将13G(60mg,0.12mmol)溶于四氢呋喃(5mL)中,冰浴降温至0℃,缓慢加入伯吉斯试剂(88g,0.36mmol),保持此温度反应10min后,反应体系恢复至室温反应2h。反应结束,乙酸乙酯(10mL×3)萃取,有机相用饱和食盐水洗涤、无水硫酸钠干燥、过滤,减压移除有机溶剂,残留物通过中压制备(乙腈/水=20%)纯化得13H,白色固体(37mg,产率61.7%)。
LCMS m/z(ESI)=498.17[M+1]。
第八步:
N-(((2-(环丁基甲基)-4-氟-6-(2-甲氧基吡啶-4-基)苯基)氨基甲酰基)-4-(1,2-二羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(化合物13)
N-((2-(cyclobutylmethyl)-4-fluoro-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
氮气保护下,在100mL单口瓶中,将13H(40mg,0.08mmol)溶于叔丁醇:丙酮(2mL:2mL)中,冰盐浴降温至0℃,加入4-甲基吗啡-N-氧化物(18.7mg,0.16mmol),缓慢滴加锇酸钾一水合物(4.4mg,0.012mmol)的水溶液(2mL),滴加完毕,保持此温度反应10min后,反应体系恢复至室温反应1h,反应结束,冷至室温,用饱和亚硫酸氢钠水溶液淬灭反应,乙酸乙酯(10mL×3)萃取,有机相用饱和食盐水溶液洗涤、无水硫酸钠干燥、过滤,减压移除有机溶剂,残留物通过中压制备(乙腈/水=30%)纯化得化合物13,白色固体(10mg,产率25.8%)。
LCMS m/z(ESI)=532.18[M+1]。
实施例14
N-(((2-(2-氰基吡啶-4-基)-6-(环丁基甲基)-4-氟苯基)氨基甲酰基)-4-(1,2-二羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(化合物14)
N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
第一步:
4-(2-氨基-3-(环丁基甲基)-5-氟苯基)吡啶腈(14A)
4-(2-Amino-3-(cyclobutylmethyl)-5-fluorophenyl)picolinonitrile
在100mL三口瓶中,加入13D(1.5g,5.8mol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶啉(2.01g,8.6mmol),1,4二氧六环(30mL),加入碳酸铯(1.54g,14.5mmol)和催化剂[1,1'-双(二苯基膦基)二茂铁]二氯化钯(424mg,0.58mmol),氮气保护,90℃回流下反应8h。减压浓缩除去溶剂,粗产品通过柱层析(PE:EA=8:1)纯化得14A,绿色固体(520mg,收率94%)。
1H 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.
第二步:
N-((2-(2-氰基吡啶-4-基)-6-(环丁基甲基)-4-氟苯基)氨基甲酰基)-4-(2-羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(14B)
N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
氮气保护下,在100mL圆底烧瓶中,依次加入14A(429mg,1.5mmol),四氢呋喃(10mL),三光气(177.6mg,0.6mmol)和三乙胺(181.8,1.8mmol),室温反应1h,过滤,加入中间体3(510mg,1.5mmol)和氢化钠(54mg,2.25mmol),室温反应2h。加入三乙胺氢氟酸盐(484mg,3mmol),室温反应1h。TLC监控完全反应,反应液加水(20mL)淬灭,乙酸乙酯(30mL×3)萃取,有机相通过无水硫酸钠干燥,过滤,移除有机溶剂,粗产品灭,乙酸乙酯(30mL×3)萃取,有机相通过无水硫酸钠干燥、过滤,移除有机溶剂,粗产品通过中压制备(乙腈/水=30%)纯化得14B,白色固体(220mg,收率28.6%)。
第三步:
N-((2-(2-氰基吡啶-4-基)-6-(环丁基甲基)-4-氟苯基)氨基甲酰基)-4-(2-羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(14C)
N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide
14B(220mg)通过SFC拆分得到14C(85mg,收率38.6%,RT=2.463min,100% ee)。手性HPLC(AS)流动相:正己烷/乙醇=90/10;柱温:35℃;柱压:80bar;流速:1mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm;
LC-MS m/z(ESI)=511.17;
1H 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)。
第四步:
N-(((2-(2-氰基吡啶-4-基)-6-(环丁基甲基)-4-氟苯基)氨基甲酰基-4-(丙-1-烯-2-基)呋喃-2-磺酰亚胺酰胺(14D)
N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide
氮气保护下,在100mL单口瓶中,将化合物14C(60mg,0.12mmol)溶于四氢呋喃(5mL)中,冰浴降温至0℃,缓慢加入伯吉斯试剂(88g,0.36mmol),保持此温度反应10min后,反应体系恢复至室温反应2h。反应结束,乙酸乙酯(10mL×3)萃取,有机相用饱和食盐水洗涤、无水硫酸钠干燥、过滤,减压移除有机溶剂,残留物通过中压制备(乙腈/水=20%)纯化得化合物14D,白色固体(40mg,产率66.7%)。
LCMS m/z(ESI)=493.16[M+1]。
第五步:
N-(((2-(2-氰基吡啶-4-基)-6-(环丁基甲基)-4-氟苯基)氨基甲酰基)-4-(1,2-二羟基丙烷-2-基)呋喃-2-磺酰亚胺酰胺(化合物14)
N-((2-(2-cyanopyridin-4-yl)-6-(cyclobutylmethyl)-4-fluorophenyl)carbamoyl)-4-(1,2-dihydroxypropan-2-yl)furan-2-sulfonimidamide
氮气保护下,在100mL单口瓶中,将化合物14D(40mg,0.08mmol)溶于叔丁醇:丙酮(2mL:2mL)中,冰盐浴降温至0℃,加入4-甲基吗啡-N-氧化物(18.7mg,0.16mmol),缓慢滴加锇酸钾一水合物(4.4mg,0.012mmol)的水溶液(2mL),滴加完毕,保持此温度反应10min后,反应体系恢复至室温反应1h,反应结束,冷至室温,用饱和亚硫酸氢钠水溶液淬灭反应,乙酸乙酯(10mL×3)萃取,有机相用饱和食盐水溶液洗涤,无水硫酸钠干燥,过滤,减压移除有机溶剂,残留物通过中压制备(乙腈/水=40%)纯化得化合物14,白色固体(10mg,产率25.2%)。
LCMS m/z(ESI)=527.16[M+1]。
实施例15
N'-((5-((R)-1-环丙基乙基)-2,3-二氢-1H-茚-4-基)氨甲酰)-2-((S)-1,2-二羟基丙烷-2-基)噻唑-5-磺酰亚胺酰胺(化合物15)
N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
第一步:
2-((S)-1-((叔丁基二甲基硅基)氧基)-2-羟基丙烷-2-基)-N-((S)-1-(4-甲氧基苯基)乙基)噻唑-5-磺酰亚胺酰胺(15A)
2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
将中间体6-1(2.0g,3.3mmol)溶于32mL乙腈和8mL水中,室温条件下滴加甲酸(607mg,13.3mmol),然后搅拌2h。TLC监控反应完全,加入饱和碳酸氢钠溶液调节pH至中性,乙酸乙酯(50mL×3)萃取。合并有机相,饱和食盐水洗涤(50mL×2),有机相通过无水硫酸钠干燥、过滤,减压除去有机溶剂。残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯=40:1~20:1)得到15A,淡黄色油状物(1.34g,收率84%)。
1H 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]。
第二步:
2-((S)-1-((叔丁基二甲基硅氧基)-2-羟基丙烷-2-基)-N'-((5-((R)-1-环丙基乙基)-2,3-二氢-1H-茚-4-基)氨甲酰)-N-((S)-1-(4-甲氧基苯基)乙基)噻唑-5-磺酰亚胺酰胺(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
在25mL圆底烧瓶中,氮气保护下依次加入中间体1(201mg,1mmol)、干燥四氢呋喃5mL、二异丙基乙胺(258.5mg,2mmol)和氯甲酸-2,2,2-三氯乙酯(254.3mg,1.2mmol),搅拌反应30min,TLC监控转化完全。反应液加入水5mL,二氯甲烷萃取(10mL×2),合并有机相,无水硫酸钠干燥,旋干。加入3mL干燥的四氢呋喃溶解为溶液B。在另一50mL三口瓶中加入15A(437mg,0.9mmol)和8mL干燥的四氢呋喃,冰浴下加入氢化钠(120mg,60%,3.0mmol),搅拌反应1h。冰浴下缓慢滴加溶液B,升至室温反应1h,LC-MS监测反应完全,反应液倒入水中,加入二氯甲烷(20mL×2),合并有机相,无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化得15B,淡黄色固体(264mg,收率63.1%)。
LC-MS m/z(ESI)=714.0[M+1]。
第三步:
N’-((5-((R)-1-环丙基乙基)-2,3-二氢-1H-茚-4-基)氨甲酰)-2-((S)-1,2-二羟基丙烷-2-基)-N-((S)-1-(4-甲氧基苯基)乙基)噻唑-5-磺酰亚胺酰胺(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
在一50mL三口瓶中加入15B(200mg,0.28mmol)和3mL干燥的四氢呋喃,缓慢滴加三乙胺三氢氟酸盐(225mg,1.4mmol),升温至40℃反应2h,TLC监测反应结束,反应液倒入水中,加入乙酸乙酯(20mL×2),合并有机相、无水硫酸钠干燥、减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化得15C,淡黄色固体(104mg,收率62.1%)。
1H 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)。
第四步:
N'-((5-((R)-1-环丙基乙基)-2,3-二氢-1H-茚-4-基)氨甲酰)-2-((S)-1,2-二羟基丙烷-2-基)噻唑-5-磺酰亚胺酰胺(化合物15)
N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
在一50mL三口瓶中加入15B(100mg,0.167mmol)和3mL干燥的二氯甲烷,室温条件下加入三乙基硅烷(100mg,0.835mmol),三氟乙酸(1.8mL),室温搅拌反应1h。LC-MS监测反应完全,将反应液倒入10mL水中,加入乙酸乙酯(20mL×2),合并有机相,无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化得化合物15,白色固体(60mg,收率77.3%)。
1H 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]。
实施例16
N'-((5-((R)-1-环丙基乙基)-2,3-二氢-1H-茚-4-基)氨甲酰)-2-((S)-1,2-二羟基丙烷-2-基)噻唑-5-磺酰亚胺酰胺(化合物16)
N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
第一步:
2-((S)-1-((叔丁基二甲基甲硅烷基)氧基)-2-羟基丙-2-基)-N-((S)-1-(4-甲氧基苯基)乙基)噻唑-5-磺酰亚胺酰胺(16A)
2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
将中间体6-2(2.0g,3.3mmol)溶于32mL乙腈和8mL水中,室温条件下滴加甲酸(607mg,13.3mmol,)搅拌反应2h。TLC监控反应完全,加入饱和碳酸氢钠溶液调节pH至中性,乙酸乙酯(50mL×3)萃取。合并有机相,饱和食盐水洗涤(50mL×2),有机相通过无水硫酸钠干燥、过滤,减压除去有机溶剂。残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯=40:1~20:1)得到16A,淡黄色油状物(1.37g,收率85.9%)。
1H 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]。
第二步:
2-((S)-1-((叔丁基二甲基硅氧基)-2-羟基丙烷-2-基)-N'-((5-((R)-1-环丙基乙基)-2,3-二氢-1H-茚-4-基)氨甲酰)-N-((S)-1-(4-甲氧基苯基)乙基)噻唑-5-磺酰亚胺酰胺(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
在25mL圆底烧瓶中,氮气保护下依次加入中间体1(603mg,3mmol)、干燥四氢呋喃5mL、二异丙基乙胺(775mg,6mmol)和氯甲酸-2,2,2-三氯乙酯(762.6mg,3.6mmol),搅拌反应30min,TLC监控转化完全。反应液加入水10mL,二氯甲烷萃取(20mL×2),合并有机相,无水硫酸钠干燥,旋干。加入10mL干燥的四氢呋喃溶解为溶液B。在另一50mL三口瓶中加入16A(1.31g,2.7mmol)和20mL干燥的四氢呋喃,冰浴下加入氢化钠(360mg,60%,8.1mmol),搅拌反应1h。冰浴下缓慢滴加溶液B,升至室温反应1h,LC-MS监测反应完全,反应液倒入水中,加入二氯甲烷(50mL×2),合并有机相,无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化得16B,淡黄色固体(1.2g,收率56.1%)。
LC-MS m/z(ESI)=714.0[M+1]。
第三步:
N’-((5-((R)-1-环丙基乙基)-2,3-二氢-1H-茚-4-基)氨甲酰)-2-((S)-1,2-二羟基丙烷-2-基)-N-((S)-1-(4-甲氧基苯基)乙基)噻唑-5-磺酰亚胺酰胺(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
在50mL三口瓶中加入16B(300mg,0.42mmol)和3mL干燥的四氢呋喃,缓慢滴加三乙胺三氢氟酸盐(338.5mg,2.1mmol),升温至40℃反应2h,TLC监测反应结束,反应液倒入水中,加入乙酸乙酯(40mL×2),合并有机相,无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化得16C,淡黄色固体(180mg,收率71.7%)。
1H 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)。
第四步:
N'-((5-((R)-1-环丙基乙基)-2,3-二氢-1H-茚-4-基)氨甲酰)-2-((S)-1,2-二羟基丙烷-2-基)噻唑-5-磺酰亚胺酰胺(化合物16)
N'-((5-((R)-1-cyclopropylethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-((S)-1,2-dihydroxypropan-2-yl)thiazole-5-sulfonimidamide
在50mL三口瓶中加入16C(100mg,0.167mmol)和3mL干燥的二氯甲烷,室温条件下加入三乙基硅烷(100mg,0.835mmol),三氟乙酸(1.8mL),室温搅拌反应1h;LC-MS监测反应完全,反应液倒入水中,加入乙酸乙酯(20mL×2),合并有机相,无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化得化合物16,白色固体(55mg,收率55.1%)。
1HNMR(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]。
实施例17
N'-((3-((R)-1-环丙基乙基)双环[4.2.0]辛-1,3,5-三烯-2-基)氨甲酰)-2-((R)-1,2-二羟基丙烷-2-基)噻唑-5-磺酰亚胺酰胺(化合物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
第一步:
2-((S)-1-((叔丁基二甲基甲硅烷基)氧基)-2-羟基丙-2-基)-N-((S)-1-(4-甲氧基苯基)乙基)噻唑-5-磺酰亚胺酰胺(17A)
2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
将7G-1(1.0g,1.67mmol)溶于24mL乙腈和6mL水中,室温条件下滴加甲酸(307mg,6.68mmol)搅拌反应2h。TLC监控反应完全,加入饱和碳酸氢钠溶液调节pH至中性,乙酸乙酯(50mL×3)萃取。合并有机相,饱和食盐水洗涤(50mL×2),有机相通过无水硫酸钠干燥、过滤,减压除去有机溶剂。残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯=40:1~20:1)得到17A,淡黄色油状物(650mg,收率81.5%)。
1H 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]。
第二步:
2-((R)-1-((叔丁基二甲基硅基)氧基)-2-羟基丙烷-2-基)-N'-((3-((R)-1-环丙基乙基)双环[4.2.0]辛-1(6),2,4-三烯-2-基)氨甲酰)-N-((S)-1-(4-甲氧基苯基)乙基)噻唑-5-磺酰亚胺酰胺(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
在25mL圆底烧瓶中,氮气保护下依次加入2I(187mg,1mmol)、干燥四氢呋喃(3mL)、二异丙基乙胺(258.5mg,2mmol)和氯甲酸-2,2,2-三氯乙酯(254.3mg,1.2mmol),搅拌反应30min,TLC监控转化完全。反应液加入水5mL,二氯甲烷萃取(10mL×2),合并有机相,无水硫酸钠干燥,旋干。加入3mL干燥的四氢呋喃溶解为溶液B。在另一50mL三口瓶中加入17A(440mg,0.9mmol)和3mL干燥的四氢呋喃,冰浴下加入氢化钠(120mg,60%,3.0mmol),搅拌反应1h。冰浴下缓慢滴加溶液B,升至室温反应1h,LC-MS监测反应完全,,反应液倒入水中,加入二氯甲烷(20mL×2),合并有机相,无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化得17B,淡黄色固体(500mg,收率71.5%)。
LC-MS m/z(ESI)=700.2[M+1]。
第三步:
N’-((3-((R)-1-环丙基乙基)双环[4.2.0]辛-1(6),2,4-三烯-2-基)氨甲酰)-2-((R)-1,2-二羟基丙烷-2-基)-N-((S)-1-(4-甲氧基苯基)乙基)噻唑-5-磺酰亚胺酰胺(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
在一50mL三口瓶中加入17B(300mg,0.43mmol)和3mL干燥的四氢呋喃,缓慢滴加三乙胺三氢氟酸盐(311mg,1.93mmol),升温至40℃反应2h,TLC监测反应结束,反应液倒入水中,加入乙酸乙酯(20mL×2),合并有机相,无水硫酸钠干燥,,减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化得17C,淡黄色固体(180mg,收率71.7%)。
LC-MS m/z(ESI)=585.7[M+1]。
第四步:
N'-((3-((R)-1-环丙基乙基)双环[4.2.0]辛-1,3,5-三烯-2-基)氨甲酰)-2-((R)-1,2-二羟基丙烷-2-基)噻唑-5-磺酰亚胺酰胺(化合物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
在一50mL三口瓶中加入17C(180mg,0.31mmol)和3mL干燥的二氯甲烷,室温条件下加入三乙基硅烷(180mg,1.55mmol),三氟乙酸(1.8mL),室温搅拌反应1h。LC-MS监测反应完全,反应液倒入水中,加入乙酸乙酯(20mL×2),合并有机相,无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化得化合物17,白色固体(100mg,收率71.9%)。
1H 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]。
实施例18
N'-((3-((R)-1-环丙基乙基)双环[4.2.0]辛-1,3,5-三烯-2-基)氨甲酰)-2-((R)-1,2-二羟基丙烷-2-基)噻唑-5-磺酰亚胺酰胺(化合物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
第一步:
2-((S)-1-((叔丁基二甲基甲硅烷基)氧基)-2-羟基丙-2-基)-N-((S)-1-(4-甲氧基苯基)乙基)噻唑-5-磺酰亚胺酰胺(18A)
2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N-((S)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide
将中间体7-2(1.2g,2.0mmol)溶于24mL乙腈和6mL水中,室温条件下滴加甲酸(368mg,8.0mmol,)搅拌反应2h。TLC监控反应完全,加入饱和碳酸氢钠溶液调节pH至中性,乙酸乙酯(50mL×3)萃取。合并有机相,饱和食盐水洗涤(50mL×2),有机相通过无水硫酸钠干燥、过滤,减压除去有机溶剂。残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯=40:1~20:1)得到18A,淡黄色油状物(710mg,收率73.1%)。
1HNMR(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]。
第二步:
2-((R)-1-((叔丁基二甲基硅基)氧基)-2-羟基丙烷-2-基)-N'-((3-((R)-1-环丙基乙基)双环[4.2.0]辛-1(6),2,4-三烯-2-基)氨甲酰)-N-((S)-1-(4-甲氧基苯基)乙基)噻唑-5磺酰亚胺酰胺(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
在25mL圆底烧瓶中,氮气保护下依次加入2I(400mg,2.13mmol)、干燥四氢呋喃3mL、二异丙基乙胺(550.6mg,4.26mmol)和氯甲酸-2,2,2-三氯乙酯(541.3mg,2.77mmol),搅拌反应30min,TLC监控转化完全。反应液加入水5mL,二氯甲烷萃取(10mL×2),合并有机相、无水硫酸钠干燥、旋干。加入3mL干燥的四氢呋喃溶解为溶液B。在另一50mL三口瓶中加入18A(937mg,1.92mmol)和10mL干燥的四氢呋喃,冰浴下加入氢化钠(260mg,60%,6.39mmol),搅拌反应1h。冰浴下缓慢滴加溶液B,升至室温反应1h,LC-MS监测反应完全,,反应液倒入水中,加入二氯甲烷(20mL×2),合并有机相、无水硫酸钠干燥、减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化得18B,淡黄色固体(1.06g,收率74.5%)。
LC-MS m/z(ESI)=700.2[M+1]。
第三步:
N’-((3-((R)-1-环丙基乙基)双环[4.2.0]辛-1(6),2,4-三烯-2-基)氨甲酰)-2-((R)-1,2-二羟基丙烷-2-基)-N-((S)-1-(4-甲氧基苯基)乙基)噻唑-5-磺酰亚胺酰胺(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
在一50mL三口瓶中加入18B(300mg,0.43mmol)和3mL干燥的四氢呋喃,缓慢滴加三乙胺三氢氟酸盐(311mg,1.93mmol),升温至40℃反应2h,TLC监测反应结束,反应液倒入水中,加入乙酸乙酯(20mL×2),合并有机相,无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化得18C,淡黄色固体(150mg,收率59.8%)。
LC-MS m/z(ESI)=585.7[M+1]。
第四步:
N'-((3-((R)-1-环丙基乙基)双环[4.2.0]辛-1,3,5-三烯-2-基)氨甲酰)-2-((R)-1,2-二羟基丙烷-2-基)噻唑-5-磺酰亚胺酰胺(化合物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
在一50mL三口瓶中加入18C(180mg,0.31mmol)和3mL干燥的二氯甲烷,室温条件下加入三乙基硅烷(180mg,1.55mmol),三氟乙酸(1.8mL),室温搅拌反应1h。LC-MS监测反应完全,反应液倒入水中,加入乙酸乙酯(20mL×2),合并有机相,无水硫酸钠干燥,减压浓缩除去溶剂,残留物通过中压制备(乙腈/水=30%)纯化得化合物18,白色固体(90mg,收率64.8%)。
1H 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]。
生物测试例
1.THP-1细胞培养
2.THP-1细胞焦亡检测
通过细胞计数,按照每孔50000个THP-1细胞接种于96孔板,加入20nM PMA,在37℃下,用5%浓度的CO
2诱导48小时。弃培养基,加入100μL含1μg/mL浓度的LPS的无血清RPMI-1640培养基。加入5μL化合物或溶剂对照,由最高剂量10μM开始,3倍梯度稀释,共设置10个梯度浓度。在37℃,5%浓度的CO
2下孵育3小时。孵育结束后,300g离心5分钟,弃培养基,进行焦亡分析(
1 Inflammasome Assay kit)详细步骤参考试剂盒说明书进行。利用GraphPad Prism7.0软件计算IC
50,结果如表1所示。
表1本申请化合物对THP-1细胞焦亡的抑制
化合物 | IC 50 | 化合物 | 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 |
注:A≤0.1uM,0.1uM<B≤0.5uM,0.5uM<C≤1uM,D>1uM。
结果表明:本申请的化合物能有效抑制人单核细胞系THP-1的焦亡。
3.人PBMC IL-1β释放分析
取来自健康供体的人类静脉全血的血液5mL置于Li-heparin试管中。使用PBMC分离(sigma,10771-100mL)试剂盒分离PBMC后,加入含10%FBS的RPMI-1640培养基重悬细胞,并将其稀释到2×10
6个/mL,置于培养皿中于37℃,5%CO
2培养箱中过夜培养。次日,加入含10ng/mL LPS的培养基,在培养箱中孵育3小时。以密度为1×10
5个/孔,将细胞铺于96孔板。每孔加入25μL化合物或溶剂对照,由最高剂量10μM开始,3倍梯度稀释,共设置8个梯度浓度,孵育0.5小时。每孔加入25μL终浓度5mM ATP,孵育1小时。孵育结束后,1500rpm离心20分钟,收集上清液利用ELISA(BD,Human IL-1βELISA Set II,Cat#557953)法检测IL-1β的表达量。利用GraphPad Prism7.0软件计算IC
50。结果如表2所示。
表2本申请化合物对IL-1β释放的抑制
化合物 | IC 50(nM) |
2-1 | 18.7 |
7-1 | 9.8 |
7-2 | 5.8 |
结果表明:本申请化合物可以显著抑制人PBMC IL-1β的释放。
4.人PBMC TNFα释放分析
取来自健康供体的人类静脉全血的血液5mL置于Li-heparin试管中。使用PBMC分离(sigma,10771-100mL)试剂盒分离PBMC后,加入含10%FBS的RPMI-1640培养基重悬细胞,并将其稀释到2×10
6个/mL,置于培养皿中于37℃,5%CO
2培养箱中过夜培养。次日,按照1×10
5个/孔,将细胞接种于96孔板中。随后,每孔加入25μL化合物或溶剂对照,由最高剂量10μM开始,5倍梯度稀释,共设置9个梯度浓度,在37℃,5%浓度的CO
2孵育24小时。每孔加入25μL终浓度100ng/mL的LPS。每孔加入25μL终浓度5mM ATP,孵育1.5小时。孵育结束后,1500rpm离心20分钟,收集上清液利用ELISA(BD,Human TNFαELISA Set II,Cat#555212)法检测TNFα的表达量。利用GraphPad P rism7.0软件计算IC
50。
结果表明:本申请化合物对LPS诱导PBMC产生的TNFα表达量无下调作用。
5.化合物血浆、结肠组织分布测试
称取适量药物,使用5%DMSO和30%HP-β-CD将药物配制成5mg/mL的溶液。健康成年ICR小鼠禁食过夜后,灌胃给予待测药物(50mg/kg)或空白溶剂,于给药后0.5、2、4、8h四个时间点,经眼眶静脉丛采血(EDTA-K2抗凝),随后处死动物,收集结肠内容物及结肠组织,血液样本经4℃ 2000g离心10min分离得到血浆,结肠组织用冰冷生理盐水清洗后吸干水分,所有样本于-80℃保存待测。采用LC/MS/MS法测定血浆和组织,肠内容物内的药物浓度,结肠组织样本检测前进行匀浆处理。每个时间点平均药物浓度如图1和图2所示,其中图1表明对照例1的结肠-血浆药物分布,图2表明化合物7-1的结肠-血浆药物分布。对照例1为1-(1,2,3,5,6,7-六氢-s-茚满-4-基)-3-[4-(1-羟-1-甲基-乙基)-呋喃-2-磺酰基]脲(1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]urea),参考Synthetic Communications(2003),33(12),2029-2043中的化合物1方法制备得到。
结果表明,本申请的化合物比对照化合物有更好的胃肠道靶向性。
本申请说明书对具体实施方案进行了详细描述,本领域技术人员应认识到,上述实施方案是示例性的,不能理解为对本申请的限制,对于本领域技术人员来说,在不脱离本申请原理的前提下,通过对本申请进行若干改进和修饰,这些改进和修饰获得技术方案也落在本申请的权利要求书的保护范围内。
Claims (10)
- 式(I)的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物:其中Q为5元杂芳基,所述5元杂芳基包含1或2个选自N、O和S的杂原子,所述5元杂芳基任选地被1个氰基或者C 1-6烷基取代;L为-(CR aR b)-;R a为C 1-6烷基;R b为C 1-6烷基,且所述C 1-6烷基被1个OH取代;W为O或NH;Y为-(CR dR e)-;R d、R e各自独立地为H或C 1-6烷基;R和R 1各自独立地为H、卤素、氰基、C 1-6烷基、C 1-6烷氧基、3至10元碳环基或4至10元杂环基,所述4至10元杂环基包含1、2或3个选自N、O和S的杂原子,所述C 1-6烷基、3至10元碳环基或4至10元杂环基任选地被1、2、3或4个选自卤素、氰基、C 1-6烷基、C 1-6烷氧基、3至6元碳环基和5至6元杂环基的取代基取代;或者,R与R 1与其相连的原子一起形成4至6元环;C为3至5元环烷基;R 2为H或者卤素;G 1、G 2、G 3各自独立为N或CH;r、q各自独立地为0、1或2;n为0、1、2或3。
- 根据权利要求1所述化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物,其中Q为呋喃基、噻唑基或噻吩基,所述呋喃基、噻唑基或噻吩基任选地被1个氰基取代;L为-(CR aR b)-;R a为C 1-3烷基;R b为C 1-3烷基,且所述C 1-3烷基被1个OH取代;W为O或NH;Y为-(CR dR e)-;R d、R e各自独立地为H或C 1-3烷基;R和R 1各自独立地为H、卤素、氰基、C 1-3烷基或吡啶基,所述的C 1-3烷基或吡啶基任选地被1至4个选自卤素、氰基、C 1-3烷基、C 1-3烷氧基和3至5元环烷基的取代基取代;或者,R与R 1与其相连的原子一起形成4至5元环;C为3至5元环烷基;R 2为H;G 1、G 2、G 3各自独立为N或CH;r、q各自独立地为0、1或者2。
- 根据权利要求1所述化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物,其中Q为呋喃基、噻唑基或噻吩基,所述呋喃基、噻唑基或噻吩基任选地被1个氰基取代;L为-(CR aR b)-;R a为C 1-3烷基;R b为C 1-3烷基,且所述C 1-3烷基被1个OH取代;W为O或者NH;Y为-(CR dR e)-;R d、R e各自独立地为H或C 1-3烷基;R和R 1各自独立地为H或者卤素;或者,R与R 1与其相连的原子一起形成4至5元环;C为3至5元环烷基;R 2为H;G 1、G 2、G 3各自独立为CH;r、q各自独立地为0或者1。
- 药物组合物,所述药物组合物包含权利要求1至6中任一项所述的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物以及一种或多种药学上可接受的载体和/或赋形剂。
- 权利要求1至6中任一项所述的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物或者权利要求7所述的药物组合物在制备用于治疗炎性疾病、自身免疫疾病、心血管系统疾病、癌症、肾系统疾病、胃肠道疾病、呼吸系统疾病、内分泌系统疾病或中枢神经系统疾病的药物中用途。
- 权利要求1至6中任一项所述的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物或者权利要求7所述的药物组合物在制备用于治疗隐热蛋白相关周期综合征(CAPS)、穆克尔-韦尔斯综合征(MWS)、家族性寒冷性自身炎性综合征(FCAS)、新生儿发病多系统炎性疾病(NOMID)、家族性地中海热(FMF)、非酒精性脂肪性肝炎、酒精性肝病、移植物抗宿主病、多发性硬化(MS)、类风湿性关节炎、1型糖尿病、2型糖尿病、牛皮癣、阿尔茨海默氏病、动脉粥样硬化、痛风或慢性肾疾病的药物中用途。
- 权利要求1至6中任一项所述的化合物或者其药学上可接受的盐或其所有的立体异构体、互变异构体及其氘代物或者权利要求7所述的药物组合物在制备NLRP3抑制剂中的用途。
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WO2021093820A1 (zh) * | 2019-11-12 | 2021-05-20 | 成都百裕制药股份有限公司 | 酰胺衍生物及其制备方法和在医药上的应用 |
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