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WO2025195241A1 - Inhibiteur du récepteur gpr17 et son utilisation - Google Patents

Inhibiteur du récepteur gpr17 et son utilisation

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Publication number
WO2025195241A1
WO2025195241A1 PCT/CN2025/081976 CN2025081976W WO2025195241A1 WO 2025195241 A1 WO2025195241 A1 WO 2025195241A1 CN 2025081976 W CN2025081976 W CN 2025081976W WO 2025195241 A1 WO2025195241 A1 WO 2025195241A1
Authority
WO
WIPO (PCT)
Prior art keywords
trifluoromethyl
methoxy
reaction
sulfonamide
indole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/081976
Other languages
English (en)
Chinese (zh)
Inventor
王昊
张恩歌
陈昊
赵树海
杨民民
耿柏林
陈一
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Myrobalan Therapeutics Nanjing Co Ltd
Original Assignee
Myrobalan Therapeutics Nanjing Co Ltd
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Filing date
Publication date
Application filed by Myrobalan Therapeutics Nanjing Co Ltd filed Critical Myrobalan Therapeutics Nanjing Co Ltd
Publication of WO2025195241A1 publication Critical patent/WO2025195241A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • G protein-coupled receptor 17 is a rhodopsin-like class A orphan GPCR primarily expressed in oligodendrocytes. It possesses a typical seven-helix transmembrane structure. Human GPR17 is located on chromosome 2q21 and primarily interacts with G proteins linked to the Gialpha subunit. It also associates with the Gqalpha subunit and shares 31% homology with cysteinyl leukotrienes (CysLT1). GPR17 is primarily distributed in organs susceptible to ischemia-reperfusion injury, such as the brain, kidneys, heart, and vascular endothelium.
  • GPR17 is implicated in diseases characterized by neuronal or myelin dysfunction, such as stroke, spinal cord injury, and multiple sclerosis.
  • Zhan TW et al. suggest that GPR17 antagonists mitigate bleomycin-induced pulmonary fibrosis by inhibiting GPR17-mediated production of inflammatory cytokines, including TNF- ⁇ , IL-6, and transforming growth factor- ⁇ 1.
  • overexpression of GPR17 inhibits myelin development, while GPR17 deficiency accelerates myelin development and promotes remyelination after injury.
  • GPR17 can be activated by emergency signals, sterols that promote atherosclerosis, and synthetic compounds with a wide range of structures, which are related to its ligand activation and interaction with other G protein-coupled receptors.
  • Montelukast a GPR17 signaling pathway inhibitor, targets CysLT receptor 1 and is being used clinically for the long-term and preventive treatment of allergic and non-allergic diseases caused by LTC4 and LTD4.
  • Studies in neurological diseases have shown that GPR17 is highly expressed in mature oligodendrocyte precursors but not in mature oligodendrocytes. Therefore, downregulation of GPR17 is necessary to promote the differentiation of precursor cells into oligodendrocytes, which promote myelin production and formation.
  • GPR17 expression was significantly increased in the central nervous system tissues of animal models of ischemia, experimental autoimmune encephalomyelitis and focal demyelination, and in the central tissues of patients with brain damage due to ischemia, trauma and multiple sclerosis.
  • the use of Montelukast can reduce the inflammatory response in rat models of age-related cognitive impairment, promote hippocampal neurogenesis, and improve learning and memory.
  • GPR17 is a sensor of central nervous system damage, participating in damage repair by clearing and/or promoting the remyelination of damaged neurons caused by various injuries (including aging). GPR17 has now been identified as an important candidate drug target for the treatment of multiple sclerosis and brain trauma in humans.
  • GBM Human glioblastoma multiforme
  • a stage IV glioma is one of the most common intrinsic and aggressive brain tumors in adults, with a median survival of 14.6 months.
  • GBM is considered one of the most difficult tumors to treat, and even with combined treatment with surgery, radiotherapy, and chemotherapy with DNA alkylating agents such as temozolomide, it often relapses and becomes resistant to current therapies.
  • GPR17 is located between uracil nucleotides and CysLTs, and transmits signals through the G ⁇ i protein to inhibit the activity of adenylate cyclase.
  • GPR17 is also considered a potential target for GBM treatment.
  • GPR17 is a very promising potential target in the field of innovative drug research and development, and has great potential to become a therapeutic target for related diseases.
  • the present application provides a class of compounds that can be used as GPR17 receptor inhibitors, and their use in preparing drugs for preventing or treating GPR17-mediated related diseases and their uses.
  • the present application provides a compound shown in the following formula I:
  • W is selected from
  • Ring A is selected from a 4- to 7-membered saturated cycloalkyl or heterocyclic group
  • R2 is selected from hydrogen, deuterium, C1 - C6 alkyl, deuterated C1 - C6 alkyl, halogenated C1 - C6 alkyl, cyano C1 - C6 alkyl, C2-C6 alkenyl, C2 - C6 alkynyl, halogen, cyano, nitro, -C ( O)NRaRb, -C(O)Ra, -C(O)ORa, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRaRb, -C(O)C(O)NRaRb, -NRaRb, -SRa, -S(O)Ra, -S(O) 2 Ra or a 3-10 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group containing 0-3 heteroatoms, wherein the alkyl, alkenyl, alkynyl
  • each Ra and Rb are independently selected from hydrogen, deuterium, C1 - C6 alkyl, deuterated C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, halogen, carbonyl, hydroxyl, cyano, nitro, -C(O)NRcRd, -C(O)Rc, -C(O)ORc, -ORc, -OC(O)Rc, -OC(O)ORc, -OC(O)NRcRd, -NRcRd, -SRc, -S(O)Rc, -S(O) 2Rc , or a 3-10 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl group containing 0-3 heteroatoms, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optional
  • Each Rc and Rd is independently selected from hydrogen, halogen, carbonyl, hydroxyl, cyano, nitro, phenyl, benzyl, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl or halogenated C 3 -C 6 cycloalkyl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • n' is selected from 0, 1, 2, 3 or 4.
  • W is selected from
  • Formula I is Formula Ia:
  • R 1 , R 2 , Ra, Rb, Rc, Rd, m, and n are as defined in claim 1 .
  • Formula I is Formula Ib:
  • R 1 , R 2 , Ra, Rb, Rc, Rd, m, and n are as defined in claim 1 .
  • R 1 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, hydroxyl,
  • R 1 is selected from hydrogen, methyl, methoxy, chloro, fluoro, bromo, iodo, trifluoromethyl, Hydroxyl,
  • R 2 is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, carbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkylhydroxyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocyclyl, halogenated C 3 -C 6 cycloalkyl,
  • R 2 is selected from hydrogen, deuterium, fluorine, chlorine, cyclopropyl, hydroxy, trifluoromethyl, methoxy, cyano, carbonyl, -CH 2 OH,
  • the compound of formula I is selected from:
  • the compound of formula I is selected from:
  • the present application provides the use of the aforementioned compound, its isomer or a pharmaceutically acceptable salt thereof for preparing a drug for a disease mediated by GPR17.
  • the aforementioned compound, its isomer or pharmaceutically acceptable salt thereof is used to prepare a method for treating and/or preventing a disease that is a neurodegenerative disease.
  • the GPR17-mediated neurodegenerative disease is caused by damage to inhibitory neurons, and the neurodegenerative disease includes multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, or Parkinson's disease.
  • the aforementioned compound, its isomer or pharmaceutically acceptable salt thereof is used for the preparation of a method for treating and/or preventing a GPR17-mediated disease that is a disease associated with dysmyelination.
  • the GPR17-mediated dysmyelination-related disease includes multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, or Parkinson's syndrome.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound, its isomers or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier or excipient.
  • isomer includes enantiomeric, diastereomeric, and geometric (or conformational) isomeric forms of a given structure.
  • the present application includes R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers, and enantiomeric, diastereomeric, and geometric (or conformational) isomer mixtures.
  • Suitable acid addition salts are formed from acids that form non-toxic salts, such as hydrochlorides/chlorides.
  • Suitable base salts are formed from bases that form non-toxic salts, such as calcium salts and sodium salts. Hemi-salts of acids and bases can also be formed, such as hemisulfate salts and hemicalcium salts.
  • terapéuticaally effective amount refers to an amount of a compound of the present invention that (i) treats a specific disease, condition, or disorder; (ii) alleviates, relieves, or eliminates one or more symptoms of a specific disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein.
  • pharmaceutically acceptable carrier or excipient refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated therewith.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms.
  • Non-limiting examples of lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.
  • alkenyl refers to an aliphatic hydrocarbon with at least one carbon-carbon double bond, including straight and branched chains with at least one carbon-carbon double bond.
  • the alkenyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms.
  • C2-6 alkenyl includes a straight or branched unsaturated group (with at least one carbon-carbon double bond) of 2 to 6 carbon atoms, including but not limited to vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc.
  • alkynyl refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond.
  • the alkynyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 3 to 6 carbon atoms.
  • C2-6 alkynyl includes straight or branched unsaturated groups (having at least one carbon-carbon triple bond) of 2 to 6 carbon atoms.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring comprises 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms (e.g., 3, 4, 5, or 6 carbon atoms), and most preferably 5 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.
  • spiroalkyl refers to a polycyclic group sharing a carbon atom (claiming spiral atom) between 5 to 20 yuan of monocycles, which can contain one or more double bonds, but each ring does not have a completely conjugated ⁇ electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7, 8, 9 or 10 yuan).
  • spiroalkyl is divided into single spiral alkyl, double spiral alkyl or multiple spiral alkyl, preferably single spiral alkyl and double spiral alkyl, more preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan of single spiral alkyl.
  • fused cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but each ring does not have a completely conjugated ⁇ electron system.
  • it is 6- to 14-membered, more preferably 7- to 10-membered.
  • bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl group preferably a bicyclic or tricyclic group, and more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl group.
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. It may contain one or more double bonds, but each ring does not have a completely conjugated ⁇ -electron system. It is preferably 6- to 14-membered, and more preferably 7- to 10-membered.
  • bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen, or S(O)m (wherein m is an integer from 0 to 2), excluding the ring portion of -O-O-, -O-S-, or -S-S-, and the remaining ring atoms are carbon.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl is preferably 5- to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- or 6-membered, containing 1 to 2 heteroatoms; examples include imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, and pyridazinyl.
  • the heteroaryl group includes a heteroaryl group as described above fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • saturated or unsaturated ring includes the aforementioned aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • deuterated alkoxy refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy is as defined above.
  • cycloalkylalkyl refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.
  • cycloalkyloxy refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined above.
  • heterocyclylalkyl refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.
  • arylalkyl refers to an alkyl group substituted with one or more aryl groups, wherein aryl and alkyl are as defined above.
  • hydroxy refers to an -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • Methyl 6-chloro-pyrazolo[1,5-a]pyridine-3-carboxylate (2.00 g, 9.496 mmol) was added to 50% H 2 SO 4 (30 mL) and heated to 120°C for 4 hours. The mixture was cooled and poured into 100 mL of ice water. The pH of the system was adjusted to 7-8 with sodium carbonate. The mixture was extracted with ethyl acetate three times with 20 mL each. The filtrate was concentrated and purified by flash liquid column chromatography to obtain compound 6-chloro-pyrazolo[1,5-a]pyridine (1.2) (1.15 g, yield 79.4%).
  • 6-Chloro-pyrazolo[1,5-a]pyridine (500 mg, 3.277 mmol) was dissolved in acetonitrile (10 mL), chlorosulfonic acid (1 mL) was added dropwise, and the mixture was stirred for 10 minutes. The solvent was concentrated and removed, and thionyl chloride (10 mL) was added. The mixture was heated to 70°C for 20 minutes. Most of the thionyl chloride was removed by concentration, and the reaction was quenched by pouring into 30 ml of ice water. The mixture was extracted with ethyl acetate 3 times with 20 mL each time. The organic phase was dried over magnesium sulfate, filtered, and the filtrate was concentrated to obtain the product 6-chloro-pyrazolo[1,5-a]pyridine-3-sulfonyl chloride (1.3) (823 mg, yield 100%).
  • 2,5-Difluoropyridine (10.00 g, 86.896 mmol) was dissolved in dichloromethane (150 mL), and urea peroxide (24.52 g, 260.658 mmol) was added. After the addition, trifluoroacetic anhydride (45.63 g, 217.254 mmol) was added dropwise while maintaining the reaction system at 25°C. After the addition, the reaction was maintained at 25°C for 16 hours. TLC monitoring indicated the reaction was complete. The reaction solution was then poured into 100 mL of ice water, and the pH of the system was adjusted to 7-8 with saturated aqueous sodium carbonate solution.
  • reaction was quenched by adding saturated aqueous sodium sulfite solution until the starch potassium iodide test paper did not turn blue.
  • the reaction system was extracted with 50 mL dichloromethane for a total of 20 times. The organic phases were combined and dried over anhydrous sodium sulfate. Filtered, and the filtrate was spin-dried to obtain the crude product 2,5-difluoropyridine 1-oxide (1.5) (6.11 g).
  • the compound 2-chloro-3,6-difluoropyridine (1.6) (6.11 g, 40.863 mmol) was added dropwise to fuming nitric acid (30 mL) while controlling the reaction temperature at 20°C. Concentrated sulfuric acid (30 mL) was added dropwise while maintaining the reaction at 20°C. After the addition, the temperature of the reaction system was raised to 60°C and stirred for 4 hours. TLC monitoring showed that the reaction was complete.
  • the reaction solution was slowly added to 500 mL of ice water and the reaction system was extracted with 100 mL of dichloromethane twice. The organic phases were collected and combined, and washed with 50 mL of saturated sodium chloride solution. The organic phases were then collected and dried over anhydrous sodium sulfate.
  • the product 2-chloro-3,6-difluoro-5-nitropyridine (1.7) (3.26 g) was obtained by filtration and the filtrate was dried.
  • Step 8 Synthesis of 6-(3,3-difluorocyclobutyloxy)-5-fluoro-2-methoxypyridin-3-amine (1.10)
  • Step 9 Synthesis of 6-chloro-N-(6-(3,3-difluorocyclobutyloxy)-5-fluoro-2-methoxypyridin-3-yl)pyrazolo[1,5-a]pyridine-3-sulfonamide (1)
  • 6-(3,3-difluorocyclobutyloxy)-5-fluoro-2-methoxypyridin-3-amine (80 mg, 322.319 ⁇ mol) was dissolved in anhydrous pyridine (1 mL), and 6-chloro-pyrazolo[1,5-a]pyridine-3-sulfonyl chloride (1.3) (67 mg, 266.837 ⁇ mol) was added. The reaction was maintained at 23°C for 18 hours. LC-MS monitored the reaction completion. The solvent was removed by spin drying and the product was purified by flash liquid column chromatography.
  • Step 5 Synthesis of 6-chloro-N-(6-(difluoromethoxy-d)-5-fluoro-2-(methoxy-d3)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-sulfonamide (2)
  • 6-(Difluoromethoxy-d)-5-fluoro-2-(methoxy-d3)pyridin-3-amine (2.4) (60 mg, 282.802 ⁇ mol) was dissolved in anhydrous pyridine (1 mL), and 6-chloropyrazolo[1,5-a]pyridine-3-sulfonyl chloride (1.3) (59 mg, 234.976 ⁇ mol) was added. After the addition, the reaction was maintained at 22°C for 3 hours. TLC monitored the reaction completion.
  • 6-(2,2-difluoroethoxy)-5-fluoro-2-(methoxy-d3)pyridin-3-amine (82 mg, 364.149 ⁇ mol) was added to pyridine (3 mL), and then 6-(difluoromethyl)pyrazolo[1,5-a]pyridine-3-sulfonyl chloride (3.5) (80 mg, 300.016 ⁇ mol) was added while maintaining the reaction at 0°C. After addition, the reaction was maintained at 85°C for 3 hours. LC-MS monitoring showed that the reaction was complete.
  • Step 1 Synthesis of 8-((trimethylsilyl)ethynyl)-1,4-dioxaspiro[4.5]decan-8-ol (23.2)
  • Step 3 Synthesis of 4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1-toluenesulfonyl-1H-1,2,3-triazole (23.4)
  • Step 4 Synthesis of 1-p-toluenesulfonyl-1,4,5,7-tetrahydrospiro[indole-6,2'-[1,3]dioxolane] (23.5)
  • Step 5 Synthesis of 1-p-toluenesulfonyl-1,4,5,7-tetrahydro-6H-indol-6-one (23.6)
  • Step 6 Synthesis of 1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-6-ol (23.7)
  • Step 7 Synthesis of 6-(methoxy-d3)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (23.8)
  • reaction solution was poured into saturated ammonium chloride solution (100 mL), and the aqueous phase was extracted with two 30 mL portions of ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate. After filtration and concentration, purification by flash liquid column chromatography gave the product 6-(methoxy-d3)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (23.8) (450 mg, yield 86.6%).
  • 5-Fluoro-2-methoxy-3-nitropyridine (23.10) (10.000 g, 58.101 mmol) was dissolved in methanol (150 mL) and 10% palladium on carbon (2.000 g) was added. The reaction was maintained at 50°C under H2 protection for 16 hours. TLC monitoring indicated the reaction was complete. The reaction solution was filtered and the filtrate was dried to obtain the product, 5-fluoro-2-methoxypyridin-3-amine (23.11) (7.80 g).
  • 6-Bromo-5-fluoro-2-methoxypyridin-3-amine (23.12) (4.000 g, 18.097 mmol) was dissolved in acetonitrile (50 mL), and benzyl bromide (9.286 g, 54.292 mmol) and potassium carbonate (12.506 g, 90.487 mmol) were added. After the addition was complete, the reaction was maintained at 80°C for 72 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was filtered and the filtrate was collected. The filtrate was concentrated and purified by flash liquid chromatography to obtain the product N,N-bisbenzyl-6-bromo-5-fluoro-2-methoxypyridin-3-amine (23.13) (5.30 g, 73.0% yield).
  • Step 12 Synthesis of N,N-bisbenzyl-5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-amine (23.14)
  • N,N-bisbenzyl-5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-amine (3.14) (500 mg, 1.281 mmol) was dissolved in methanol (10 mL) and 10% palladium on carbon (100 mg) was added. After the addition was complete, the reaction was maintained at 50°C under hydrogen protection for 12 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was filtered and concentrated. Purification by flash liquid column chromatography gave the product 5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-amine (23.15) (120 mg, yield 44.587%).
  • Step 14 Synthesis of (S)-6-(methoxy-d3)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole or (R)-6-(methoxy-d3)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (23.16)
  • Step 15 Synthesis of (S)-6-(methoxy-d3)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride or (R)-6-(methoxy-d3)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (23.17)
  • Example 24 Preparation of (S)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-(methoxy-d3)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (R)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-(methoxy-d3)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (24)
  • Step 1 Synthesis of (S)-6-(methoxy-d3)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole or (R)-6-(methoxy-d3)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (24.1)
  • Step 2 Synthesis of (S)-6-(methoxy-d3)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride or (R)-6-(methoxy-d3)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (24.2)
  • Step 3 Synthesis of (S)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-(methoxy-d3)-1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (R)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-(methoxy-d3)-1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (24.3)
  • Step 4 Synthesis of (S)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-(methoxy-d3)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (R)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-(methoxy-d3)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (24)
  • reaction solution temperature was lowered to 20°C, and 2N dilute hydrochloric acid was added to adjust the pH value of the system to 5-6.
  • the system was then extracted with 30 mL of ethyl acetate for a total of 3 times. The organic phases were combined and dried over anhydrous sodium sulfate. After the solvent was dried, it was purified by rapid liquid column chromatography.
  • Trimethylsilyl acetylene (19.803 g, 201.626 mmol) was added to tetrahydrofuran (300 mL). While maintaining the reaction at -30°C, n-butyl lithium (2.5 M, 89.956 mL) was slowly added dropwise under nitrogen. After addition, the reaction mixture was maintained at -30°C for 1 hour. Under nitrogen, a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-one (25.2 g) (37.6 g, 155.097 mmol) in tetrahydrofuran (200 mL) was slowly added. The temperature was naturally raised to 25°C, and the reaction mixture was maintained under nitrogen for 4.5 hours.
  • Step 3 Synthesis of tert-butyldimethyl((4-((trimethylsilyl)ethynyl)cyclohexyl-3-en-1-yl)methoxy)silyl (25.4)
  • Step 4 Synthesis of tert-butyl((4-ethylcyclohex-3-en-1-yl)methoxy)dimethylsilane (25.5 g)
  • Step 5 Synthesis of 4-(4-((tert-butyldimethyl)oxy)methyl)cyclohexyl-1-en-1-yl)-1-p-toluenesulfonyl-1H-1,2,3-triazole (25.6)
  • Step 6 Synthesis of 6-(((tert-butyldimethylsilyl)oxy)methyl)-1-toluenesulfonyl-4,5,6,7-tetrahydro-1H-indole (25.7)
  • Step 7 Synthesis of (1-toluenesulfonyl-4,5,6,7-tetrahydro-1H-indol-6-yl)methanol (25.8)
  • Step 8 Synthesis of 1-p-toluenesulfonyl-4,5,6,7-tetrahydro-1H-indole-6-carbaldehyde (25.9)
  • Step 9 Synthesis of 1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-6-carbaldehyde (25.10)
  • Step 10 Synthesis of 1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-6-carbaldehyde oxime (25.11)
  • Step 11 Synthesis of 1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-6-carbonitrile (25.12)
  • reaction solution was concentrated and purified by flash liquid column chromatography to obtain the product, 1-(p-Toluenesulfonyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-6-carbonitrile (25.12) (0.080 g).
  • Step 12 Synthesis of 6-cyano-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (25.13)
  • reaction solution was added to 20 g of crushed ice and extracted with three 20 mL portions of ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, and purified by flash liquid chromatography. The product 6-cyano-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (25.13) was obtained (0.080 g, yield 78.9%).
  • Step 13 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-cyano-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (25.14)
  • reaction solution was concentrated and purified by flash liquid chromatography to obtain the product, N-(4-bromo-2,5-difluorophenyl)-6-cyano-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (25.14) (0.080 g, 73.1% yield).
  • Step 14 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (25)
  • N-(4-bromo-2,5-difluorophenyl)-6-cyano-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (25.14) (0.080 g, 125.309 ⁇ mol) was added to a mixed solvent of methanol (5 mL) and water (5 mL), and potassium carbonate (173 mg, 1.252 mmol) was added. After the addition, the reaction was maintained at 80°C for 1 hour. TLC monitoring showed that the reaction was complete. Citric acid was added to the reaction solution to adjust the pH value of the system to about 4-5.
  • Example 26 Preparation of (R)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (S)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (26)
  • Example 25 was scaled up to 400 mg and resolved using supercritical fluid chromatography to yield 98 mg of (R)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (S)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (26).
  • the yield for this step was 24.5%.
  • Example 27 Preparation of (R)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (S)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (27)
  • Example 25 was scaled up to 400 mg and resolved using supercritical fluid chromatography to yield 102 mg of (R)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (S)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (27).
  • the yield for this step was 25.4%.
  • Step 1 Synthesis of 6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (28.1)
  • Step 2 Synthesis of 6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (28.2)
  • Step 3 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (28.3)
  • Step 4 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (28)
  • N-(4-Bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (28.3) (0.025 g, 36.796 ⁇ mol) was added to a mixture of water (2 mL) and methanol (3 mL), followed by potassium carbonate (51 mg, 369.014 ⁇ mol). After addition, the reaction system was stirred at 80°C for 1 hour. LC-MS monitoring indicated completion of the reaction. Citric acid was added to the reaction solution to adjust the pH to 5-6.
  • the reaction system was extracted with ethyl acetate three times, 30 mL each.
  • the organic phases were combined and washed with 100 mL of saturated brine.
  • the organic phase was dried over anhydrous sodium sulfate and filtered.
  • the filtrate was purified by flash liquid chromatography.
  • the product N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (28) was obtained (0.006 g, yield 31.0%).
  • Example 29 Synthesis of (S)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (29)
  • Step 1 Synthesis of (S)-6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole or (R)-6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (29.1)
  • Step 2 Synthesis of (S)-6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride or (R)-6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (29.2)
  • Step 3 Synthesis of (S)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (29.3)
  • Step 4 Synthesis of (S)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (29)
  • Step 1 Synthesis of (S)-6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole or (R)-6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (30.1)
  • Step 3 Synthesis of (S)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (30.3)
  • Step 2 Synthesis of 6-(difluoromethyl)-1-p-toluenesulfonyl-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (31.2)
  • Step 3 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-1-toluenesulfonyl-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (31.3)
  • Step 4 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (31.4)
  • N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-1-toluenesulfonyl-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (121 mg, 203.216 ⁇ mol) was dissolved in methanol (3 mL) and 2N aqueous NaOH solution (3 mL) was added. After the addition, the reaction was maintained at 65°C for 2 hours. LCMS monitoring showed that the reaction was complete.
  • Step 5 Synthesis of (R)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (S)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (31).
  • Example 33 Synthesis of (S)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-methoxy-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (R)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-methoxy-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (33)
  • Step 1 Synthesis of 6-methoxy-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (33.1)
  • Step 2 Synthesis of (S)-6-methoxy-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole or (R)-6-methoxy-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (33.2)
  • Step 3 Synthesis of (S)-6-methoxy-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride or (R)-6-methoxy-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (33.3)
  • Step 4 Synthesis of (S)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-methoxy-1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (R)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-methoxy-1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (33.4)
  • Step 5 Synthesis of (S)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-methoxy-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (R)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-methoxy-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (33)
  • reaction was maintained at 80°C for 1 hour. LCMS monitoring showed that the reaction was complete.
  • the reaction mixture was cooled to 20°C and the pH value of the reaction mixture was adjusted to 3-6 by adding 2N dilute hydrochloric acid.
  • Example 34 Synthesis of (S)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-methoxy-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (R)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-methoxy-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (34)
  • Step 1 Synthesis of (S)-6-methoxy-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole or (R)-6-methoxy-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (34.1)
  • Step 2 Synthesis of (S)-6-methoxy-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride or (R)-6-methoxy-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (34.2)
  • reaction solution was spun dry, and thionyl chloride (5 mL) was added while maintaining the reaction at 0°C. After the addition, the reaction was maintained at 70°C for 2 hours. LCMS monitoring indicated that the reaction was complete.
  • the reaction solution was cooled to 20°C and then slowly added dropwise to 100 g of crushed ice.
  • the aqueous phase was extracted with 30 mL of ethyl acetate three times.
  • the organic phases were combined, dried over anhydrous sodium sulfate, and then spin-dried and purified by flash liquid column chromatography.
  • Step 3 Synthesis of (S)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-methoxy-1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (R)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-methoxy-1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (34.3)
  • Step 4 Synthesis of (S)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-methoxy-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (R)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-methoxy-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (34)
  • Examples 035 and 036 were prepared according to the above method.
  • 6-Chloropyrazolo[1,5-a]pyridine (37.5g) (2.000g, 13.108mmol) was added to tetrahydrofuran (30mL). The reaction temperature was lowered to -65°C, and n-butyllithium (9.309g, 23.594mmol, 2.5M, 9.438mL) was slowly added dropwise under nitrogen. After addition, the reaction was maintained at -65°C for 1 hour. Hexachloroethane (6.206g, 26.216mmol) was slowly added dropwise. After addition, the reaction was maintained at -65°C for 1 hour, still under nitrogen. LCMS monitoring indicated completion of the reaction. The reaction was quenched by the addition of 15mL of saturated ammonium chloride.
  • Step 5 Synthesis of 6,7-dichloropyrazolo[1,5-a]pyridine-3-sulfonyl chloride (37.7)
  • Step 6 Synthesis of 6,7-dichloro-N-(5-fluoro-2-(methoxy-d3)-4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-3-sulfonamide (37.8)
  • Step 7 Synthesis of 6-chloro-N-(5-fluoro-2-(methoxy-d3)-4-(trifluoromethyl)phenyl)-7-hydroxypyrazolo[1,5-a]pyridine-3-sulfonamide (37)
  • Step 1 Synthesis of 6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-ol (38.1)
  • Step 2 Synthesis of 6-(difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole (38.2)
  • Step 3 Synthesis of 6-(difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonyl chloride (38.3)
  • Step 4 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (38.4)
  • reaction solution was dried and purified by flash liquid chromatography to obtain the product, N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (38.4) (0.450 g, 93.5% yield).
  • Step 5 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (38)
  • N-(4-Bromo-2,5-difluorophenyl)-6-(difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (38.4) (0.450 g, 716.026 ⁇ mol) was added to a mixture of methanol (10 mL) and water (10 mL). Potassium carbonate (990 mg, 7.163 mmol) was added. After addition, the reaction was maintained at 80°C for 1 hour. TLC monitoring indicated completion of the reaction.
  • reaction temperature was lowered to 20°C, and the pH of the system was adjusted to 5 by adding 2N dilute hydrochloric acid.
  • the reaction system was extracted with ethyl acetate three times, 20 mL each. The organic phases were collected and combined, and then dried over anhydrous magnesium sulfate. The filtrate was filtered and dried, and then purified by flash liquid chromatography.
  • the product N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (38) was obtained (150 mg, yield 44.2%).
  • Example 39 Preparation of (S)-N-(4-chloro-2,5-difluorophenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-chloro-2,5-difluorophenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (39)
  • Step 1 Synthesis of (S)-N-(4-chloro-2,5-difluorophenyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-(4-chloro-2,5-difluorophenyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (39.1)
  • Example 40 Preparation of (S)-N-(4-iodo-2,5-difluorophenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-iodo-2,5-difluorophenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (40)
  • Step 1 Synthesis of (S)-N-(4-iodo-2,5-difluorophenyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-(4-iodo-2,5-difluorophenyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (40.1)
  • Step 2 Synthesis of (S)-N-(4-iodo-2,5-difluorophenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-iodo-2,5-difluorophenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (40)
  • Example 41 Preparation of (S)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (41)
  • N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (38) (0.150 g, 316.267 ⁇ mol) was subjected to supercritical fluid chromatography to obtain the product (S)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (41) (0.042 g , yield 28.0%) NMR (400MHz, DMSO-d6) ⁇ 11.
  • Example 42 Preparation of (S)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (42)
  • N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (38) (0.150 g, 316.267 ⁇ mol) was subjected to supercritical fluid chromatography to obtain the product (S)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (42) (0.038 g , yield 25.3%) NMR (400MHz, DMSO-d6) ⁇ 11.
  • Example 43 Preparation of (S)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (43)
  • Step 2 Synthesis of tert-butyl N-[4-(difluoromethoxy)-2,5-difluorophenyl]carbamate (43.2)
  • reaction solution was filtered, and the filtrate was collected and concentrated, and then purified by flash liquid column chromatography to obtain the product tert-butyl N-[4-(difluoromethoxy)-2,5-difluorophenyl]carbamate (43.2) (3.000 g, yield 73.1%).
  • Step 4 Synthesis of (S)-N-(4-difluoromethoxy-2,5-difluorophenyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-(4-difluoromethoxy-2,5-difluorophenyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (43.4)
  • Step 5 Synthesis of (S)-N-(4-difluoromethoxy-2,5-difluorophenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-difluoromethoxy-2,5-difluorophenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (43)
  • Example 44 Preparation of (S)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (44)
  • Step 1 Synthesis of (S)-N-(4-difluoromethoxy-2,5-difluorophenyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-(4-difluoromethoxy-2,5-difluorophenyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (44.1)
  • Step 2 Synthesis of (S)-N-(4-difluoromethoxy-2,5-difluorophenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-difluoromethoxy-2,5-difluorophenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (44)
  • reaction solution temperature was lowered to 20°C, and then 2N dilute hydrochloric acid was added to adjust the pH value of the system to 3-4. 10 mL of ethyl acetate was then added four times to extract the system. The organic phases were collected and combined, the solvent was dried, and then purified by rapid liquid column chromatography.
  • Example 45 Preparation of (S)-N-[4-(trifluoromethoxy)-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[4-(trifluoromethoxy)-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (45)
  • Step 1 Synthesis of tert-butyl N-[4-(trifluoromethoxy)-2,5-difluorophenyl]carbamate (45.1)
  • reaction solution was filtered, and the filtrate was collected and concentrated, and then purified by flash liquid column chromatography to obtain the product tert-butyl N-[4-(trifluoromethoxy)-2,5-difluorophenyl]carbamate (45.1) (2.000 g, yield 88.4%).
  • Step 3 Synthesis of (S)-N-(4-trifluoromethoxy-2,5-difluorophenyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-(4-trifluoromethoxy-2,5-difluorophenyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (45.3)
  • Step 4 Synthesis of (S)-N-(4-trifluoromethoxy-2,5-difluorophenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-trifluoromethoxy-2,5-difluorophenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (45)
  • Step 1 Synthesis of 6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (46.1)
  • Step 2 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (46.2)
  • reaction solution was dried and then purified by flash liquid chromatography to obtain the product, N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (46.2) (1.500 g, 99.2% yield).
  • Step 3 Synthesis of (S)-N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (46.3)
  • Step 4 Synthesis of (S)-N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (46)
  • Step 1 Synthesis of 6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbaldehyde (47.1)
  • Step 2 Synthesis of 6,6-bis(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole (47.2)
  • Step 3 Synthesis of 6,6-bis(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (47.3)
  • reaction solution was cooled to 20°C and added to 60 g of crushed ice.
  • the reaction system was then extracted with three 30 mL portions of ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, and purified by flash liquid chromatography.
  • the product 6,6-bis(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (47.3) was obtained (130 mg, yield 78.1%).
  • Step 4 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6,6-bis(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (47.4)
  • N-(4-bromo-2,5-difluorophenyl)-6,6-bis(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (47.4) 140 mg, 216.909 ⁇ mol was added to a mixture of methanol (5 mL) and water (2 mL), followed by potassium carbonate (300 mg, 2.171 mmol). After addition, the reaction was maintained at 80°C for 1 hour. TLC monitoring indicated completion of the reaction. Citric acid was added to the reaction solution to adjust the pH to approximately 4-6.
  • Example 48 Preparation of (S)-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-6-(methoxy-d3)-6-(trifluoromethane)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-6-(methoxy-d3)-6-(trifluoromethane)-1,4,5,7-tetrahydroindole-3-sulfonamide (48)
  • Step 2 Synthesis of (S)-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-6-(methoxy-d3)-6-(trifluoromethane)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-6-(methoxy-d3)-6-(trifluoromethane)-1,4,5,7-tetrahydroindole-3-sulfonamide (48)
  • Example 49 Preparation of (S)-N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (49)
  • Step 1 Synthesis of (S)-N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (49.1)
  • Step 2 Synthesis of (S)-N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (49)
  • Step 1 Synthesis of 1-(p-toluenesulfonyl)-6-vinyl-5,7-dihydro-4H-indol-6-ol (50.1)
  • reaction solution was slowly poured into 600 mL of saturated ammonium chloride and extracted with ethyl acetate three times in 200 mL increments.
  • the organic phases were collected and combined.
  • the organic phases were concentrated and purified by flash liquid chromatography to yield 1-(p-Toluenesulfonyl)-6-vinyl-5,7-dihydro-4H-indol-6-ol (50.1) (3.700 g, 33.7% yield).
  • Step 2 Synthesis of 1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-vinyl-5,7-dihydro-4H-indole (50.2)
  • Step 3 Synthesis of 1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-6-carbaldehyde (50.3)
  • Step 4 Synthesis of 1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-6-carbaldehyde oxime (50.4)
  • Step 5 Synthesis of 1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-6-carbonitrile (50.5)
  • reaction solution was concentrated and purified by flash liquid column chromatography to obtain the product 1-(p-Toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-6-carbonitrile (50.5) (250 mg).
  • Step 6 Synthesis of 6-cyano-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonyl chloride (50.6)
  • Step 7 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-cyano-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (50.7)
  • Step 8 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (50)
  • N-(4-bromo-2,5-difluorophenyl)-6-cyano-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (20 mg, 33.142 ⁇ mol) was added to a mixed solvent of methanol (3 mL) and water (1 mL), followed by the addition of potassium carbonate (137 mg, 991.274 ⁇ mol). After the addition, the reaction was maintained at 80°C for 1 hour. LCMS monitoring showed that the reaction was complete. Citric acid was added to the reaction solution to adjust the pH of the system to approximately 4-6. The reaction solution was concentrated and purified by flash liquid column chromatography.
  • Example 51 Preparation of (S)-N-(4-trifluoromethoxy-2,5-difluorophenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-trifluoromethoxy-2,5-difluorophenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (51)
  • Step 1 Synthesis of (S)-N-(4-trifluoromethoxy-2,5-difluorophenyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-(4-trifluoromethoxy-2,5-difluorophenyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (51.1)
  • Step 2 Synthesis of (S)-N-(4-trifluoromethoxy-2,5-difluorophenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-trifluoromethoxy-2,5-difluorophenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (51)
  • Step 4 Synthesis of (S)-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (52.4)
  • 6-(Difluoromethoxy)-5-fluoro-2-methoxypyridin-3-amine 60 mg, 288.271 ⁇ mol was added to anhydrous pyridine (0.5 mL), followed by (S)-6-(methoxy-d3)-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride or (R)-6-(methoxy-d3)-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (23.17) (90 mg, 189.507 ⁇ mol).
  • Step 5 Synthesis of (S)-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (52)
  • Example 53 Preparation of (S)-6-(difluoromethoxy)-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-6-(trifluoromethane)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-6-(trifluoromethane)-1,4,5,7-tetrahydroindole-3-sulfonamide (53)
  • Step 1 Synthesis of (S)-6-(difluoromethoxy)-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethane)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethane)-5,7-dihydro-4H-indole-3-sulfonamide (53.1)
  • Example 54 Preparation of (S)-6-(difluoromethoxy)-N-[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridyl]-6-(trifluoromethane)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridyl]-6-(trifluoromethane)-1,4,5,7-tetrahydroindole-3-sulfonamide (54)
  • 6-Bromo-5-fluoro-2-(methoxy-d3)pyridin-3-amine (54.3) (7.800 g, 34.814 mmol) was dissolved in acetonitrile (150 mL), and benzyl bromide (29.772 g, 174.072 mmol) and potassium carbonate (14.435 g, 104.443 mmol) were added. After the addition, the reaction was maintained at 80°C for 48 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was filtered and the filtrate was collected.
  • Step 5 Synthesis of N,N-bisbenzyl-5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)pyridin-3-amine (54.5)
  • N,N-bisbenzyl-5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)pyridin-3-amine (900 mg, 2.288 mmol) was dissolved in methanol (10 mL) and 10% palladium on carbon (120 mg) was added. After the addition was complete, the reaction was maintained at 50°C under H2 for 16 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was filtered and concentrated. Purification by flash liquid column chromatography gave the product 5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)pyridin-3-amine (54.6) (143 mg, yield 29.3%).
  • Step 7 Synthesis of (S)-6-(difluoromethoxy)-N-[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (54.7)
  • Step 8 Synthesis of (S)-6-(difluoromethoxy)-N-[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridyl]-6-(trifluoromethane)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridyl]-6-(trifluoromethane)-1,4,5,7-tetrahydroindole-3-sulfonamide (54)
  • 1,4-Difluoro-2-nitro-5-vinylbenzene (3.100 g, 16.745 mmol) was added to diethylene glycol dimethyl ether (60 mL), followed by sodium iodide (753 mg, 5.024 mmol). After the addition was complete, TMSCF 3 (14.286 g, 100.471 mmol) was added dropwise while maintaining the reaction at 135°C. After the addition was complete, the reaction system was maintained at 135°C for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated and purified by flash liquid column chromatography to obtain the product 1-(2,2-difluorocyclopropyl)-2,5-difluoro-4-nitrobenzene (55.2) (700 mg, yield 17.8%).
  • Step 4 Synthesis of (6S)-N-[4-(2,2-difluorocyclopropyl)-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (6R)-N-[4-(2,2-difluorocyclopropyl)-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (55.4)
  • Step 5 Synthesis of (6S)-N-[4-(2,2-difluorocyclopropyl)-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (6R)-N-[4-(2,2-difluorocyclopropyl)-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (55)
  • Example 56 Preparation of (S)-6-(difluoromethoxy)-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (56)
  • Step 1 Synthesis of (S)-6-(difluoromethoxy)-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (56.1)
  • 6-(Difluoromethoxy)-5-fluoro-2-methoxypyridin-3-amine (43 mg, 206.742 ⁇ mol) was added to anhydrous pyridine (0.5 mL), followed by (S)-6-(difluoromethoxy)-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride or (R)-6-(difluoromethoxy)-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (29.2) (70 mg, 137.828 ⁇ mol).
  • Step 2 Synthesis of (S)-6-(difluoromethoxy)-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (56)
  • 1,4-Difluoro-2-(methoxymethoxy)-5-nitrobenzene (57.1) (511 mg, 2.332 mmol) was dissolved in methanol (15 mL) and 10% palladium on carbon (103 mg) was added. After the addition, the reaction was maintained at 23°C under H2 for 4.5 hours. TLC monitoring indicated the reaction was complete. The reaction solution was filtered and the filtrate was concentrated. The product, 2,5-difluoro-4-(methoxymethoxy)aniline (57.2) (424 mg), was obtained.
  • Step 3 Synthesis of N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-6,6-difluoro-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (57.3)
  • 2,5-Difluoro-4-(methoxymethoxy)aniline (139 mg, 734.832 ⁇ mol) was added to anhydrous pyridine (1.5 mL), followed by 6,6-difluoro-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (200 mg, 487.977 ⁇ mol). After the addition was complete, the reaction was maintained at 70°C in a microwave oven for 1.5 hours. LCMS monitoring indicated the reaction was complete.
  • Step 4 Synthesis of N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-6,6-difluoro-1,4,5,7-tetrahydroindole-3-sulfonamide (57.4)
  • N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-6,6-difluoro-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (303 mg, 538.616 ⁇ mol) was added to methanol (3 mL), and 4N aqueous sodium hydroxide solution (3 mL) was added thereto. After the addition was complete, the reaction was maintained at 60°C for 1.5 hours. TLC monitoring showed that the reaction was complete. The reaction temperature was lowered to 20°C, and 1N dilute hydrochloric acid was added to adjust the pH value of the system to 3-4.
  • Step 5 Synthesis of N-(2,5-difluoro-4-hydroxyphenyl)-6,6-difluoro-1,4,5,7-tetrahydroindole-3-sulfonamide (57)
  • N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-6,6-difluoro-1,4,5,7-tetrahydroindole-3-sulfonamide (57.4) (211 mg, 516.692 ⁇ mol) was added to tetrahydrofuran (2 mL). 6N hydrochloric acid (0.7 mL) was slowly added while maintaining the system at 0°C. After addition, the reaction was maintained at 23°C for 2 hours. LCMS monitoring showed the formation of the product. The reaction solution was concentrated at low temperature, 15 mL of water was added, and the system was extracted with 3 5 mL portions of dichloromethane.
  • Example 58 Preparation of (S)-N-[6-(difluoromethoxy-d)-5-fluoro-2-(methoxy-d3)-3-pyridyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[6-(difluoromethoxy-d)-5-fluoro-2-(methoxy-d3)-3-pyridyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (58)
  • Step 1 Synthesis of (S)-N-6-(difluoromethoxy-d)-5-fluoro-2-(methoxy-d3)-3-pyridyl]-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-6-(difluoromethoxy-d)-5-fluoro-2-(methoxy-d3)-3-pyridyl]-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (58.1)
  • 6-(Difluoromethoxy-d)-5-fluoro-2-(methoxy-d3)pyridin-3-amine (2.4) (63 mg, 296.942 ⁇ mol) was added to anhydrous pyridine (0.5 mL), followed by (S)-6-(methoxy-d3)-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride or (R)-6-(methoxy-d3)-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (23.17) (70 mg, 147.394 ⁇ mol).
  • Example 60 Preparation of (S)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (60)
  • 6-Chloro-5-fluoro-2-iodopyridin-3-ol (15.000 g, 54.858 mmol) was added to N,N-dimethylformamide (80 mL), followed by cesium carbonate (53.622 g, 164.575 mmol) and sodium difluorochloroacetate (12.546 g, 82.288 mmol). After addition, the reaction was maintained at 80°C for 3 hours. TLC monitoring indicated completion of the reaction. The reaction solution was filtered, and the organic phase was collected. 400 mL of water was then added to the filtrate, and the system was extracted with ethyl acetate three times, 100 mL each. The organic phases were collected and combined.
  • 6-Chloro-3-(difluoromethoxy)-5-fluoropyridine-2-carbaldehyde (60.2) (1.000 g, 4.434 mmol) was dissolved in dichloromethane (20 mL). Diethylaminosulfur trifluoride (1.500 g, 9.306 mmol) was added dropwise while maintaining the reaction at 0°C. After addition, the reaction was maintained at 20°C for 2 hours. TLC monitoring indicated that the reaction was complete. The reaction solution was slowly poured into 50 mL of saturated sodium carbonate solution and extracted with ethyl acetate three times with 20 mL each. The organic phases were collected and combined.
  • Step 4 Synthesis of tert-butyl N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridinyl]carbamate (60.4)
  • reaction solution was filtered, and the filtrate was collected and concentrated, and then purified by flash liquid column chromatography to obtain the product tert-butyl N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridyl]carbamate (60.4) (670 mg, yield 56.1%).
  • Step 5 Synthesis of 5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoropyridin-2-amine (60.5)
  • Step 7 Synthesis of (S)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (60)
  • reaction solution temperature was lowered to 20°C, and saturated citric acid was added to adjust the pH value of the system to 3-4. 8 mL of water was added, and the system was extracted with 20 mL of ethyl acetate for a total of 3 times.
  • the organic phases were collected and combined, and after the solvent was dried, they were purified by rapid liquid column chromatography and reverse phase column chromatography.
  • Example 61 Preparation of (S)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (61)
  • Step 1 Synthesis of (S)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (61.1)
  • Step 2 Synthesis of (S)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (61)
  • Example 62 (6R)-N-[4-[(1R)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (6S)-N-[4-[(1R)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or Preparation of (6R)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (6
  • Step 1 (6R)-N-[4-[(1R)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (6S)-N-[4-[(1R)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (6 Synthesis of (R)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-1-(p-toluen
  • Step 2 (6R)-N-[4-[(1R)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (6S)-N-[4-[(1R)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or ( Synthesis of (6R)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (6S
  • reaction was maintained at 80°C for 2 hours. LCMS monitoring indicated the reaction was complete.
  • the reaction temperature was lowered to 20°C, 5 mL of water was added, and the pH of the system was adjusted to 4-6 with saturated citric acid.
  • the reaction solution was then extracted with ethyl acetate three times, 50 mL each.
  • Example 63 (6R)-N-[4-[(1R)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (6S)-N-[4-[(1R)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or Preparation of (6R)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (6
  • Step 1 (6R)-N-[4-[(1R)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (6S)-N-[4-[(1R)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (6 Synthesis of (R)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-1-(p-toluen
  • Step 2 (6R)-N-[4-[(1R)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (6S)-N-[4-[(1R)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or ( Synthesis of (6R)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (6S
  • the reaction was maintained at 80°C for 1 hour. TLC monitoring indicated the reaction was complete.
  • the reaction temperature was lowered to 20°C, 5 mL of water was added, and the pH was adjusted to 4-6 with saturated citric acid.
  • the reaction solution was extracted with ethyl acetate three times, 50 mL each.
  • Example 64 Preparation of (S)-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (64)
  • 6-Bromo-5-fluoro-2-methoxypyridin-3-ol (0.200 g, 900.854 ⁇ mol) was added to N,N-dimethylformamide (10 mL), followed by cesium carbonate (880 mg, 2.701 mmol) and sodium difluorochloroacetate (280 mg, 1.813 mmol). After addition, the reaction was maintained at 80°C for 3 hours. LCMS monitoring indicated completion of the reaction. The reaction solution was filtered, and the organic phase was collected. 50 mL of water was added to the filtrate, and the system was extracted with ethyl acetate three times in 50 mL increments. The organic phases were collected and combined. The organic phase was dried over anhydrous sodium sulfate.
  • Step 2 Synthesis of tert-butyl N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]carbamate (64.2)
  • reaction solution was filtered, and the filtrate was collected and concentrated, and then purified by flash liquid column chromatography to obtain the product tert-butyl N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]carbamate (64.2) (90 mg, yield 52.9%).
  • Step 4 Synthesis of (S)-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (64.4)
  • Step 5 Synthesis of (S)-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (64)
  • reaction solution temperature was lowered to 20°C, and saturated citric acid was then added to adjust the pH value of the system to 3-5. 8 mL of water was added, and the system was extracted with 20 mL of ethyl acetate for a total of 3 times. The organic phases were collected and combined, and after the solvent was dried, they were purified by rapid liquid column chromatography and reverse phase column chromatography.
  • Example 65 Preparation of (S)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-hydroxy-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-hydroxy-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (65)
  • Step 1 Synthesis of (R)-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indol-6-ol or (S)-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indol-6-ol (65.1)
  • Step 2 Synthesis of (R)-6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride or (S)-6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (65.2)
  • Step 3 Synthesis of (S)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (65.3)
  • Step 4 Synthesis of (S)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-hydroxy-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-hydroxy-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (65)
  • Example 66 Preparation of (S)-N-[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridinyl]-6-hydroxy-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridinyl]-6-hydroxy-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (66)
  • Step 1 Synthesis of (S)-N-[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridinyl]-6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridinyl]-6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (66.1)
  • Step 2 Synthesis of (S)-N-[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridinyl]-6-hydroxy-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridinyl]-6-hydroxy-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (66)
  • Step 1 Synthesis of [6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-yl]methanol (67.1)
  • Step 2 Synthesis of methyl [6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-yl]acetate (67.2)
  • Step 3 Synthesis of methyl [3-chlorosulfonyl-6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-yl]acetate (67.3)
  • reaction solution was cooled to 20°C, added to 100 g of crushed ice, and extracted with three 50 mL portions of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash liquid column chromatography to obtain the product [3-chlorosulfonyl-6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-yl]acetate (67.3 mg) (600 mg, 80.1% yield).
  • Step 4 Synthesis of methyl [6-(difluoromethyl)-3-[[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridinyl]sulfamoyl]-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-yl]acetate (67.4)
  • Step 5 Synthesis of 6-(difluoromethyl)-N-[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridyl]-6-(hydroxymethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (67)
  • Step 1 Synthesis of 1-(p-toluenesulfonyl)-4,5,6,7-tetrahydroindole-6-ol (68.1)
  • Step 2 Synthesis of [1-(p-Toluenesulfonyl)-4,5,6,7-tetrahydroindol-6-yl]acetate (68.2)
  • Step 3 Synthesis of [3-chlorosulfonyl-1-(p-toluenesulfonyl)-4,5,6,7-tetrahydroindol-6-yl]acetate (68.3)
  • Step 4 Synthesis of [3-[(4-bromo-2,5-difluorophenyl)sulfamoyl]-1-(p-toluenesulfonyl)-4,5,6,7-tetrahydroindol-6-yl]acetate (68.4)
  • reaction solution was concentrated and purified by flash liquid chromatography to obtain the product [3-[(4-bromo-2,5-difluorophenyl)sulfamoyl]-1-(p-toluenesulfonyl)-4,5,6,7-tetrahydroindol-6-yl] acetate (68.4) (6.500 g, 10.771 mmol, 75.0% yield).
  • Step 5 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-1-(p-toluenesulfonyl)-4,5,6,7-tetrahydroindole-3-sulfonamide (68.5)
  • Step 6 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-oxo-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (68.6)
  • N-(4-Bromo-2,5-difluorophenyl)-6-hydroxy-1-(p-toluenesulfonyl)-4,5,6,7-tetrahydroindole-3-sulfonamide (68.5) (2.500 g, 4.453 mmol) was added to dichloromethane (50 mL), followed by Dess-Martin periodinane (5.666 g, 13.359 mmol). After addition, the reaction was maintained at 20°C for 12 hours. TLC monitoring indicated completion of the reaction. 50 mL of saturated sodium bicarbonate solution and 30 mL of saturated sodium bisulfite solution were added to the reaction mixture. The mixture was extracted with three 30 mL portions of dichloromethane.
  • Step 7 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-methoxyimino-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (68.7)
  • N-(4-bromo-2,5-difluorophenyl)-6-oxo-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (68.6) (1.000 g, 1.788 mmol) was added to ethanol (15 mL), followed by O-methylhydroxylamine hydrochloride (269 mg, 3.221 mmol) and sodium carbonate (758 mg, 7.152 mmol). After the addition, the reaction was maintained at 45°C for 1 hour. LCMS monitoring indicated that the reaction was complete. Saturated ammonium chloride solution was added to the reaction mixture to adjust the pH to 6-7.
  • Step 8 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-methoxyimino-1,4,5,7-tetrahydroindole-3-sulfonamide (68)
  • N-(4-Bromo-2,5-difluorophenyl)-6-methoxyimino-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (68.7) (1.000 g, 1.699 mmol) was added to methanol (24 mL), followed by an aqueous solution (8 mL) of potassium carbonate (1.174 g, 8.497 mmol). After addition, the reaction was maintained at 80°C for 2 hours. TLC monitoring indicated completion of the reaction. The reaction temperature was lowered to 20°C, and saturated ammonium chloride solution was added to the reaction mixture to adjust the pH to 6-7.
  • Example 69 (S)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-3-methoxy-6-methyl-2-pyridinyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-3-methoxy-6-methyl-2-pyridinyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (69)
  • Step 1 Synthesis of 5-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (69.1)
  • 6-Bromo-5-methoxy-2-methylpyridin-3-ol (69.3) (600 mg, 2.752 mmol) was added to N,N-dimethylformamide (10 mL), followed by cesium carbonate (2.160 g, 6.629 mmol) and sodium difluorochloroacetate (850 mg, 5.575 mmol). After the addition, the reaction was maintained at 80°C for 3 hours. LCMS monitoring indicated that the reaction was complete. The reaction solution was filtered and the filtrate was collected. 100 mL of water was added to the filtrate, and the system was extracted with ethyl acetate twice, each containing 100 mL. The organic phases were collected and combined. The organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. Purification by flash liquid column chromatography gave the product 2-bromo-5-(difluoromethoxy)-3-methoxy-6-methylpyridine (69.4) (500 mg, yield 67.8%).
  • Step 5 Synthesis of tert-butyl N-[5-(difluoromethoxy)-3-methoxy-6-methyl-2-pyridyl]carbamate (69.5)
  • reaction solution was filtered, and the filtrate was collected and concentrated, and then purified by flash liquid column chromatography to obtain the product N-[5-(difluoromethoxy)-3-methoxy-6-methyl-2-pyridyl]carbamic acid tert-butyl ester (69.5) (200 mg, yield 88.1%).
  • Step 7 Synthesis of (S)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-3-methoxy-6-methyl-2-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-3-methoxy-6-methyl-2-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (69.7)
  • Step 8 Synthesis of (S)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-3-methoxy-6-methyl-2-pyridinyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-3-methoxy-6-methyl-2-pyridinyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (69)
  • reaction solution temperature was lowered to 20°C, and saturated citric acid was added to adjust the pH value of the system to 5-6. 8 mL of water was added, and the system was extracted with 20 mL of ethyl acetate for a total of 3 times. The organic phases were collected and combined, and after the solvent was dried, they were purified by rapid liquid column chromatography and reverse phase column chromatography.
  • Example 70 N-(4-bromo-2,5-difluorophenyl)-6,6-dioxo-1,4,5,7-tetrahydrothiopyrano[3,4-b]pyrrole-3-sulfonamide (70)
  • Step 1 Synthesis of methyl 3-bromo-1-(p-toluenesulfonyl)pyrrole-2-carboxylate (70.1)
  • Methyl 3-bromo-1H-pyrrole-2-carboxylate (20.00 g, 98.029 mmol) was added to N,N-dimethylformamide (300 mL). The reaction was maintained at 0°C. NaH (7.842 g, 196.058 mmol, 60% purity) was added to the reaction solution. After addition, the reaction was maintained at 0°C for 30 minutes. p-Toluenesulfonyl chloride (28.033 g, 147.044 mmol) was added dropwise to the reaction solution, maintaining the reaction at 0°C, over a total of 30 minutes. The reaction was maintained at 20°C for 15 hours. TLC monitoring indicated completion of the reaction.
  • reaction solution was poured into 1 L of saturated ammonium chloride solution and extracted with ethyl acetate three times, 200 mL each.
  • the organic phases were collected and combined, the solvent was evaporated, and then purified by flash liquid chromatography.
  • the product methyl 3-bromo-1-(p-toluenesulfonyl)pyrrole-2-carboxylate (70.1) (35.00 g, yield 99.7%) was obtained.
  • Step 2 Synthesis of methyl 1-(p-toluenesulfonyl)-3-vinylpyrrole-2-carboxylate (70.2)
  • Step 3 Synthesis of methyl 3-(2-hydroxyethyl)-1-(p-toluenesulfonyl)pyrrole-2-carboxylate (70.3)
  • Methyl 1-(p-Toluenesulfonyl)-3-vinylpyrrole-2-carboxylate (70.2g) (13.500g, 44.212mmol) was added to tetrahydrofuran (100mL).
  • 9-BBN 131.7g, 530.505mmol, 0.5M, 1.061L was added dropwise to the reaction mixture, maintaining the reaction at 0°C for 2 hours. After the addition, the reaction mixture was maintained at 20°C for 6 hours.
  • Hydrogen peroxide (200.5g, 1.768mol, 30% purity) was added dropwise to the reaction mixture, maintaining the reaction at 0°C for 1 hour.
  • reaction solution was concentrated and purified by flash liquid chromatography to obtain 2-[2-(hydroxymethyl)-1-(p-toluenesulfonyl)pyrrol-3-yl]ethanol (70.4) as a red solid (700 mg, 76.6% yield).
  • Step 8 Synthesis of N-(4-bromo-2,5-difluorophenyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-thiopyrano[3,4-b]pyrrole-3-sulfonamide (70.8)
  • Step 9 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6,6-dioxo-1-(p-toluenesulfonyl)-5,7-dihydro-4H-thiopyrano[3,4-b]pyrrole-3-sulfonamide (70.9)
  • N-(4-Bromo-2,5-difluorophenyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-thiopyrano[3,4-b]pyrrole-3-sulfonamide (70.8 g) (40 mg, 70.991 ⁇ mol) was added to dichloromethane (5 mL). The reaction was maintained at 0°C. mCPBA (30 mg, 173.847 ⁇ mol) was then added to the reaction mixture. After addition, the reaction was maintained at 20°C for 1 hour. LCMS monitoring indicated completion of the reaction. Saturated sodium sulfite solution was added to the reaction mixture until the starch potassium iodide test paper did not change color.
  • Step 10 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6,6-dioxo-1,4,5,7-tetrahydrothiopyrano[3,4-b]pyrrole-3-sulfonamide (70)
  • N-(4-bromo-2,5-difluorophenyl)-6,6-dioxo-1-(toluenesulfonyl)-5,7-dihydro-4H-thiopyrano[3,4-b]pyrrole-3-sulfonamide (40 mg, 67.176 ⁇ mol) was added to methanol (2 mL), and an aqueous solution (2 mL) of potassium carbonate (200 mg, 1.447 mmol) was added thereto. After the addition was complete, the reaction was maintained at 80°C for 1 hour. LCMS monitoring showed that the product was generated. The reaction temperature was lowered to 20°C, and saturated citric acid was added to adjust the pH value of the system to 7.
  • Example 71 Preparation of (S)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (71)
  • Step 1 Synthesis of (S)-6-(difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole or (R)-6-(difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole (71.1)
  • Step 2 Synthesis of (S)-6-(difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonyl chloride or (R)-6-(difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonyl chloride (71.2)
  • LCMS monitoring indicates the reaction is complete. After the reaction solution is dried, add thionyl chloride (10 mL) while maintaining the reaction at 0°C. After addition, maintain the reaction at 80°C for 2 hours. LCMS monitoring indicates the reaction is complete. Cool the reaction solution to 20°C and slowly add dropwise to 50 g of crushed ice. The aqueous phase was extracted with ethyl acetate three times with 20 mL each time. The organic phases were combined, dried over anhydrous sodium sulfate, and then spin-dried and purified by flash liquid chromatography.
  • Step 3 Synthesis of (S)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (71.3)
  • 6-Benzyl-1H-pyrrolo[2,3-c]pyridin-6-ium (72.1) (12.200 g, 42.190 mmol) was added to methanol (100 mL) and the reaction was maintained at 0°C.
  • NaBH4 (4.000 g, 105.731 mmol) was added to the reaction solution. After addition, the reaction was maintained at 20°C for 4 hours. LCMS monitoring indicated the reaction was complete.
  • the reaction solution was poured into 200 mL of water and extracted with three 100 mL portions of dichloromethane. The organic phases were collected, combined, concentrated, and purified by flash liquid chromatography. The product, 6-benzyl-1,4,5,7-tetrahydropyrrolo[2,3-c]pyridine (72.2) (9.200 g), was obtained.
  • 6-Benzyl-1,4,5,7-tetrahydropyrrolo[2,3-c]pyridine (72.2) (8.000 g, 37.684 mmol) was added to N,N-dimethylformamide (120 mL) and the reaction was maintained at 0°C. NaH (3.014 g, 75.369 mmol, 60% purity) was added to the reaction solution. After the addition was complete, p-toluenesulfonyl chloride (14.369 g, 75.369 mmol) was added to the reaction solution while maintaining the reaction at 0°C. The reaction was then maintained at 20°C for 1 hour. LCMS monitoring indicated the reaction was complete.
  • Step 4 Synthesis of 1-(p-toluenesulfonyl)-4,5,6,7-tetrahydropyrrolo[2,3-c]pyridine (72.4)
  • 6-Benzyl-1-(p-toluenesulfonyl)-5,7-dihydro-4H-pyrrolo[2,3-c]pyridine (72.3) (6.500 g, 17.737 mmol) was added to 1,2-dichloroethane (50 mL), followed by 1-chloroethyl chloroformate (5.072 g, 35.473 mmol). After the addition was complete, the reaction was maintained at 80°C for 8 hours. The reaction solution was spin-dried to dryness, and methanol (50 mL) was added to the reaction system. After the addition was complete, the reaction system was maintained at 60°C for 16 hours. LCMS monitoring indicated that the reaction was complete.
  • Step 5 Synthesis of 6-methylsulfonyl-1-(p-toluenesulfonyl)-5,7-dihydro-4H-pyrrolo[2,3-c]pyridine (72.5)
  • Step 6 Synthesis of 6-methylsulfonyl-1-(p-toluenesulfonyl)-5,7-dihydro-4H-pyrrolo[2,3-c]pyridine-3-sulfonyl chloride (72.6)
  • Step 7 Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-methylsulfonyl-1-(p-toluenesulfonyl)-5,7-dihydro-4H-pyrrolo[2,3-c]pyridine-3-sulfonamide (72.7)
  • N-(4-Bromo-2,5-difluorophenyl)-6-methylsulfonyl-1-(p-toluenesulfonyl)-5,7-dihydro-4H-pyrrolo[2,3-c]pyridine-3-sulfonamide (72.7 g) (0.270 g, 432.349 ⁇ mol) was added to a mixture of methanol (10 mL) and water (3 mL). Potassium carbonate (299 mg, 2.163 mmol) was added. After addition, the reaction was maintained at 80°C for 2 hours. LCMS monitoring indicated completion of the reaction.
  • reaction temperature was lowered to 20°C, and the pH of the system was adjusted to 5-6 by adding 1N dilute hydrochloric acid.
  • the reaction system was extracted with ethyl acetate three times, 30 mL each. The organic phases were collected and combined, and then dried over anhydrous sodium sulfate. The filtrate was filtered and dried, and then purified by flash liquid chromatography and reversed-phase column chromatography.
  • the product N-(4-bromo-2,5-difluorophenyl)-6-methylsulfonyl-1,4,5,7-tetrahydropyrrolo[2,3-c]pyridine-3-sulfonamide (72) (0.116 g, yield 57.0%) was obtained.
  • Example 73 Preparation of (S)-6-(difluoromethoxy)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (73)
  • Step 1 Synthesis of (S)-6-(difluoromethoxy)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (73.1)
  • Step 2 Synthesis of (S)-6-(difluoromethoxy)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (73)
  • reaction solution temperature was lowered to 20°C, 3 mL of saturated ammonium chloride solution was added and stirred thoroughly, saturated citric acid was added to the system to adjust the pH value of the system to 5-6, 8 mL of water was added, and the system was extracted with 20 mL of ethyl acetate for a total of 3 times.
  • the organic phases were collected and combined, the solvent was dried, and then purified by rapid liquid column chromatography and reverse phase column chromatography.
  • Example 74 Preparation of (S)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (74)
  • Step 1 Synthesis of 6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbaldehyde oxime (74.1)
  • Step 2 Synthesis of 6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbonitrile (74.2)
  • reaction solution was concentrated and purified by flash liquid column chromatography to obtain the product 6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbonitrile (74.2) (0.660 g, 69.4% yield).
  • Step 3 Synthesis of (S)-6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbonitrile or (R)-6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbonitrile (74.3)
  • Step 4 Synthesis of (S)-6-cyano-6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride or (R)-6-cyano-6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (74.4)
  • Step 5 Synthesis of (S)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-1-p-toluenesulfonyl-6-(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-1-p-toluenesulfonyl-6-(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (74.5)
  • Step 6 Synthesis of (S)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (74)
  • reaction solution was concentrated and purified by flash liquid chromatography and reverse-phase column chromatography.
  • Example 75 Preparation of (S)-6-cyano-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-cyano-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (75)
  • Step 1 Synthesis of (S)-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-6-carbonitrile or (R)-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-6-carbonitrile (75.1)
  • Step 2 Synthesis of (S)-6-cyano-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride or (R)-6-cyano-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (75.2)
  • reaction solution was concentrated and purified by flash liquid column chromatography to obtain the product (S)-6-cyano-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride or (R)-6-cyano-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (75.2) (1.000 g, yield 98.6%).
  • Step 3 Synthesis of (S)-6-cyano-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-6-cyano-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (75.3)
  • Step 4 Synthesis of (S)-6-cyano-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-cyano-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (75)
  • Example 76 Preparation of (S)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (76)
  • Step 1 Synthesis of (S)-6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbonitrile or (R)-6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbonitrile (76.1)
  • Step 2 Synthesis of (S)-6-cyano-6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride or (R)-6-cyano-6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (76.2)
  • the reaction solution was concentrated. 3 mL of dichloromethane was added to the reaction solution. Oxalyl chloride (1.420 g, 11.190 mmol) and N,N-dimethylformamide (83 mg, 1.136 mmol) were then added while maintaining the temperature at 0°C. After the addition, the reaction was maintained at 20°C for 1 hour. TLC monitoring showed that the reaction was complete.
  • the reaction solution was concentrated and purified by flash liquid column chromatography.
  • Step 3 Synthesis of (S)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-1-p-toluenesulfonyl-6-(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-1-p-toluenesulfonyl-6-(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (76.3)
  • Step 4 Synthesis of (S)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (76)
  • Example 77 Preparation of (S)-6-cyano-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-cyano-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (77)
  • Step 1 Synthesis of (S)-6-cyano-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-6-cyano-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (77.1)
  • Step 2 Synthesis of (S)-6-cyano-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-cyano-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (77)
  • Example 78 Preparation of (S)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-methoxy-2-pyridyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-methoxy-2-pyridyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (78)
  • Step 1 Synthesis of 2-chloro-3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (78.1)
  • reaction solution was poured into 20 mL of saturated ammonium chloride solution and extracted with 30 mL portions of ethyl acetate for a total of three extractions.
  • the organic phases were collected and combined.
  • the organic phases were then concentrated.
  • the product was purified by flash liquid column chromatography to obtain 6-chloro-3-(difluoromethoxy)-5-methoxypyridine-2-carbaldehyde (78.5 g) (287 mg, yield 17.4%) as a yellow solid.
  • Step 6 Synthesis of 2-chloro-5-(difluoromethoxy)-6-(difluoromethyl)-3-methoxypyridine (78.6)
  • Step 7 Synthesis of tert-butyl N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-methoxy-2-pyridinyl]carbamate (78.7)
  • Step 8 Synthesis of 5-(difluoromethoxy)-6-(difluoromethyl)-3-methoxypyridin-2-amine (78.8)
  • Step 9 Synthesis of (S)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-methoxy-2-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-methoxy-2-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (78.9)
  • Step 10 Synthesis of (S)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-methoxy-2-pyridinyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-methoxy-2-pyridinyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (78)
  • reaction solution temperature was lowered to 20°C, and saturated citric acid was then added to adjust the pH value of the system to 6-7. 8 mL of water was added, and the system was extracted with 20 mL of ethyl acetate for a total of 3 times. The organic phases were collected and combined, and after the solvent was dried, they were purified by rapid liquid column chromatography and reverse phase column chromatography.
  • Example 79 Preparation of (S)-N-[4-bromo-5-(difluoromethyl)-2-fluorophenyl]-6-(difluoromethoxy)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[4-bromo-5-(difluoromethyl)-2-fluorophenyl]-6-(difluoromethoxy)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (79)
  • Step 5 Synthesis of (S)-N-[4-bromo-5-(difluoromethyl)-2-fluorophenyl]-6-(difluoromethoxy)-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-[4-bromo-5-(difluoromethyl)-2-fluorophenyl]-6-(difluoromethoxy)-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (79.5)
  • Step 6 Synthesis of (S)-N-[4-bromo-5-(difluoromethyl)-2-fluorophenyl]-6-(difluoromethoxy)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[4-bromo-5-(difluoromethyl)-2-fluorophenyl]-6-(difluoromethoxy)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (79)
  • the reaction was maintained at 80°C for 1 hour. LCMS monitoring indicated the reaction was complete.
  • the reaction temperature was lowered to 20°C, and saturated citric acid was added to adjust the pH to 6-7. 8 mL of water was added, and the system was extracted with 20 mL of ethyl acetate for a total of 3 times.
  • the organic phases were collected and combined, and after the solvent was dried, it was purified by rapid liquid column chromatography and reverse phase column chromatography.
  • Example 80 Preparation of (S)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-6-methoxy-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-6-methoxy-1,4,5,7-tetrahydroindole-3-sulfonamide (80)
  • Step 1 Synthesis of 6-(difluoromethyl)-6-methoxy-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole (80.1)
  • Step 2 Synthesis of (S)-6-(difluoromethyl)-6-methoxy-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole or (R)-6-(difluoromethyl)-6-methoxy-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole (80.2)
  • 6-(Difluoromethyl)-6-methoxy-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole 80.1 (800 mg, 2.251 mmol) was subjected to supercritical fluid chromatography to obtain the product (S)-6-(difluoromethyl)-6-methoxy-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole or (R)-6-(difluoromethyl)-6-methoxy-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole (80.2) (230 mg, yield 28.8%).
  • Step 3 Synthesis of (S)-6-(difluoromethyl)-6-methoxy-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride or (R)-6-(difluoromethyl)-6-methoxy-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (80.3)
  • reaction solution was spun dry, and dichloromethane (10 mL), oxalyl chloride (1.020 g, 8.037 mmol), and N,N-dimethylformamide (100 mg, 1.368 mmol) were added sequentially while maintaining the reaction at 0°C. After addition, the reaction was maintained at 20°C for 1 hour. LCMS monitoring showed that the reaction was complete.
  • reaction solution was concentrated and purified by flash liquid column chromatography to obtain the product (S)-6-(difluoromethyl)-6-methoxy-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride or (R)-6-(difluoromethyl)-6-methoxy-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (80.3) (150 mg, yield 51.1%).
  • Step 4 Synthesis of (S)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-6-methoxy-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-6-methoxy-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (80.4)
  • reaction solution was dried and purified by flash liquid column chromatography to obtain the product (S)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-6-methoxy-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-6-methoxy-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (80.4) (70 mg, yield 86.5%).
  • Step 5 Synthesis of (S)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-6-methoxy-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-6-methoxy-1,4,5,7-tetrahydroindole-3-sulfonamide (80)
  • reaction mixture was concentrated and purified by flash liquid column chromatography and reverse phase column chromatography to obtain the product (S)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-6-methoxy-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-6-methoxy-1,4,5,7-tetrahydroindole-3-sulfonamide (80) (28 mg, yield 53.5%).

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Abstract

La présente invention concerne un composé de formule (I), ou un tautomère, un mésomère, un racémate, un énantiomère, un diastéréoisomère ou un sel pharmaceutiquement acceptable de celui-ci, et son utilisation dans la préparation d'un médicament pour le traitement de maladies médiées par GPR17.
PCT/CN2025/081976 2024-03-19 2025-03-12 Inhibiteur du récepteur gpr17 et son utilisation Pending WO2025195241A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110121499A (zh) * 2016-12-28 2019-08-13 优时比制药有限公司 (氮杂)吲哚-、苯并噻吩-和苯并呋喃-3-磺酰胺类
WO2024017857A1 (fr) * 2022-07-20 2024-01-25 F. Hoffmann-La Roche Ag Nouveaux dérivés d'imidazopyridine et de pyrazolopyridine sulfonamide
WO2024017856A1 (fr) * 2022-07-20 2024-01-25 F. Hoffmann-La Roche Ag Nouveaux dérivés de sulfonamide d'isoquinolinone, de pyrrolopyridinone et de thiénopyridinone
WO2024104462A1 (fr) * 2022-11-20 2024-05-23 Myrobalan Therapeutics Nanjing Co. Ltd Modulateurs de gpr17 et leurs utilisations
WO2024115733A1 (fr) * 2022-12-02 2024-06-06 Rewind Therapeutics Nv Composés de pyrrolyl-sulfonamide condensés

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110121499A (zh) * 2016-12-28 2019-08-13 优时比制药有限公司 (氮杂)吲哚-、苯并噻吩-和苯并呋喃-3-磺酰胺类
WO2024017857A1 (fr) * 2022-07-20 2024-01-25 F. Hoffmann-La Roche Ag Nouveaux dérivés d'imidazopyridine et de pyrazolopyridine sulfonamide
WO2024017856A1 (fr) * 2022-07-20 2024-01-25 F. Hoffmann-La Roche Ag Nouveaux dérivés de sulfonamide d'isoquinolinone, de pyrrolopyridinone et de thiénopyridinone
WO2024104462A1 (fr) * 2022-11-20 2024-05-23 Myrobalan Therapeutics Nanjing Co. Ltd Modulateurs de gpr17 et leurs utilisations
WO2024115733A1 (fr) * 2022-12-02 2024-06-06 Rewind Therapeutics Nv Composés de pyrrolyl-sulfonamide condensés

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