GPR17 receptor inhibitor and use thereof

Abstract

Provided in the present application are a compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, and the use thereof in the preparation of a drug for treating GPR17-mediated diseases.

Description

GPR17 receptor inhibitors and uses thereof Technical Field

[0001] The present application belongs to the field of chemical medicine, and specifically relates to a GPR17 inhibitor and its use. Background Art

[0002] G protein-coupled receptors (GPCRs) are a general term for a large class of membrane protein receptors that are coupled to G proteins. GPCRs bind to corresponding ligands in the cell's surrounding environment and can activate a series of signaling pathways within the cell through various pathways, ultimately participating in regulating cell function. The mechanisms of action of GPCRs include: (1) activating the corresponding G protein, activating a series of signaling pathways, which is the classic signaling pathway of GPCRs; (2) through receptor internalization; and (3) through homo- or hetero-dimerization between receptors. GPCRs are closely related to many diseases, and currently about 40% of clinical drugs target GPCRs.

[0003] G protein-coupled receptor 17 (GPR17) 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. It participates in numerous physiological and pathological processes, including brain injury, spinal cord injury, oligodendrocyte development and maturation, and regulation of systemic energy homeostasis. For example, 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 alleviate bleomycin-induced pulmonary fibrosis by inhibiting GPR17-mediated inflammatory cytokines, including TNF-α, IL-6, and transforming growth factor-β1. Studies have shown that overexpression of GPR17 inhibits myelin development, while GPR17 deficiency accelerates myelin development and promotes remyelination after injury. Furthermore, GPR17 can be activated by emergency signals, atherogenic steroids, and synthetic compounds with a wide range of structures, which are related to its ligand activation and interaction with other G protein-coupled receptors. Currently, 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. At the same time, the study also found that 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. The study also found that 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.

[0004] Glioblastoma multiforme (GBM) is a stage IV glioma and one of the most common endogenous 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 and DNA alkylating agents such as temozolomide, it often relapses and becomes resistant to current treatments. GPR17 is located between uracil nucleotides and CysLTs, and transmits signals through the Gαi protein to inhibit the activity of adenylate cyclase. Many neuronal cancer cells have also been shown to have different levels of GPR17 expression, namely, the expression level of neuronal GPR17 increases sharply after ischemia, and studies based on second-generation sequencing technology have also revealed high expression of GPR17 in various GBM samples. Therefore, GPR17 is also considered a potential target for GBM treatment.

[0005] In summary, 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. Summary of the Invention

[0006] 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.

[0007] In a first aspect, the present application provides a compound shown in the following formula I:

[0008] or a tautomer, mesomer, racemate, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof;

[0009] Wherein, W is selected from

[0010] Ring A is selected from a 4- to 7-membered saturated cycloalkyl or heterocyclic group;

[0011] T, V, X, Y, and Z are independently selected from C or -N=;

[0012] R is selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo 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)2Ra, or 3-10 membered cycloalkyl containing 0-3 heteroatoms, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, 3-10 membered cycloalkyl containing 0-3 heteroatoms, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 Ra;

[0013] R is selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo 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)2Ra, or 3-10 membered cycloalkyl containing 0-3 heteroatoms, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, 3-10 membered cycloalkyl containing 0-3 heteroatoms, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 R;

[0014] or for

[0015] 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 optionally substituted with 1-3 Rc;

[0016] Each Rc and Rd is independently selected from hydrogen, halogen, carbonyl, hydroxyl, cyano, nitro, phenyl, benzyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C6 cycloalkyl or halo C3-C6 cycloalkyl;

[0017] n is selected from 0, 1, 2, 3, 4 or 5;

[0018] m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; and

[0019] m' is selected from 0, 1, 2, 3 or 4.

[0020] In some embodiments, W is selected from

[0021] In other embodiments, Formula I is Formula Ia:

[0022] Wherein, T and Z are selected from C or -N=;

[0023] R1, R2, Ra, Rb, Rc, Rd, m, and n are as defined in claim 1.

[0024] In other embodiments, Formula I is Formula Ib:

[0025] Wherein, X, Z are selected from C or -N=;

[0026] R1, R2, Ra, Rb, Rc, Rd, m, and n are as defined in claim 1.

[0027] In some embodiments, R1 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, hydroxyl,

[0028] In other embodiments, R1 is selected from hydrogen, methyl, methoxy, chloro, fluoro, bromo, iodo, trifluoromethyl, Hydroxyl,

[0029] In some embodiments, R2 is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, carbonyl, C1-C6 alkyl, C1-C6 alkylhydroxyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocyclyl, halogenated C3-C6 cycloalkyl,

[0030] In other embodiments, R2 is selected from hydrogen, deuterium, fluorine, chlorine, cyclopropyl, hydroxy, trifluoromethyl, methoxy, cyano, carbonyl, -CH2OH,

[0031] In other embodiments, the compound of formula I is selected from:

[0032] In other embodiments, the compound of formula I is selected from:

[0033] In a second aspect, 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.

[0034] In some embodiments, 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.

[0035] In other embodiments, 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.

[0036] In other embodiments, 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.

[0037] In other embodiments, the GPR17-mediated dysmyelination-related disease includes multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, or Parkinson's syndrome.

[0038] In a third aspect, the present application provides 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.

[0039] the term:

[0040] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0041] The term "isomer" includes enantiomeric, diastereomeric, and geometric (or conformational) isomeric forms of a given structure. For example, 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.

[0042] The term "pharmaceutically acceptable salt" refers to, for example, acid addition salts and / or base salts thereof. 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.

[0043] The term "therapeutically 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.

[0044] The term "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.

[0045] The term "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.

[0046] The term "alkenyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond. In some embodiments, 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. For example, the term "C 2-6 The term "alkenyl" includes straight or branched unsaturated groups of 2 to 6 carbon atoms (having at least one carbon-carbon double bond), including but not limited to ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.

[0047] The term "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. In some embodiments, 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. For example, "C 2-6"Alkynyl" includes straight or branched chain unsaturated groups (having at least one carbon-carbon triple bond) of 2 to 6 carbon atoms.

[0048] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

[0049] The term "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.

[0050] The term " 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 π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between ring and ring, 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.

[0051] The term "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 π electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a 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.

[0052] The term "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 π-electron system. It is preferably 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic.

[0053] The term "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), but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; and most preferably, it contains 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, preferably tetrahydropyranyl, piperidinyl, and pyrrolidinyl. Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls, and bridged heterocyclyls.

[0054] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having one atom (called spiro atom) shared between 5 to 20 rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but each ring does not have a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between rings, spiroheterocyclyl is divided into single spiroheterocyclyl, double spiroheterocyclyl or multiple spiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl, more preferably 4 / 4 members, 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members of single spiroheterocyclyl.

[0055] The term "fused heterocyclic radical" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system sharing a pair of atoms adjacent to other rings in the system, one or more rings may contain one or more double bonds, but each ring does not have a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5 / 5 or 5 / 6 member bicyclic fused heterocyclic groups.

[0056] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, wherein any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but each ring does not have a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.

[0057] The heterocyclic group includes the heterocyclic group as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

[0058] The term "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.

[0059] The term "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.

[0060] 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:

[0061] The term "saturated or unsaturated ring" includes the aforementioned aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups.

[0062] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0063] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0064] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0065] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0066] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy is as defined above.

[0067] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0068] The term "cycloalkyloxy" refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined above.

[0069] The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

[0070] The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, wherein aryl and alkyl are as defined above.

[0071] The term "hydroxy" refers to an -OH group.

[0072] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0073] The term "amino" refers to -NH2.

[0074] The term "cyano" refers to -CN.

[0075] The term "nitro" refers to -NO2.

[0076] The term "carboxy" refers to -C(O)OH. DETAILED DESCRIPTION

[0077] Example 1: Preparation of 6-chloro-N-(6-(3,3-difluorocyclobutyloxy)-5-fluoro-2-methoxypyridin-3-yl)pyrazolo[1,5-a]pyridine-3-sulfonamide (1)

[0078] Step 1: Synthesis of 6-chloro-pyrazolo[1,5-a]pyridine (1.2)

[0079] Methyl 6-chloro-pyrazolo[1,5-a]pyridine-3-carboxylate (2.00 g, 9.496 mmol) was added to 50% H2SO4 (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, 79.4% yield).

[0080] Step 2: Synthesis of 6-chloro-pyrazolo[1,5-a]pyridine-3-sulfonyl chloride (1.3)

[0081] 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%).

[0082] Step 3: Synthesis of 2,5-difluoropyridine 1-oxide (1.5)

[0083] 2,5-Difluoropyridine (1.4) (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. The 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).

[0084] Step 4: Synthesis of 2-chloro-3,6-difluoropyridine (1.6)

[0085] Dissolve 2,5-difluoropyridine 1-oxide (1.5) (6.11 g, 46.613 mmol) in dichloromethane (180 mL). Add phosphorus oxychloride (14.29 g, 93.196 mmol) dropwise while maintaining the reaction at 0°C. After the addition, stir the reaction mixture at 0°C for 5 minutes, then slowly add N,N-dimethylformamide (5 mL). After the addition, maintain the reaction mixture at 25°C for 16 hours. TLC monitoring indicates the reaction is complete. Pour the reaction mixture into 300 mL of water, control the temperature between 10-20°C, and then add saturated aqueous sodium carbonate to adjust the pH to approximately 8. Separate the liquid phases, and extract the aqueous phase with two 100 mL portions of dichloromethane. Combine the organic phases and dry them over anhydrous sodium sulfate. Filter the mixture, and spin dry the filtrate to obtain 2-chloro-3,6-difluoropyridine (1.6) (6.11 g).

[0086] Step 5: Synthesis of 2-chloro-3,6-difluoro-5-nitropyridine (1.7)

[0087] 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.

[0088] Step 6: Synthesis of 2-chloro-3-fluoro-6-methoxy-5-nitropyridine (1.8)

[0089] 2-Chloro-3,6-difluoro-5-nitropyridine (1.7) (680 mg, 3.496 mmol) was dissolved in methanol (70 mL), and then a 30% sodium methoxide methanol solution (6 mL) was added dropwise under the condition of controlling the temperature of the reaction system at -40 ° C. After the addition was completed, the reaction was stirred for 30 minutes while maintaining the temperature at -40 ° C. TLC monitored the reaction completion. The reaction solution was poured into 100 mL of water, and the reaction system was extracted with 50 mL of ethyl acetate three times each. The organic phases were combined, concentrated, and purified by flash liquid column chromatography. The compound 2-chloro-3-fluoro-6-methoxy-5-nitropyridine (1.8) (400 mg, yield 55.4%) was obtained.

[0090] Step 7: Synthesis of 2-(3,3-difluorocyclobutyloxy)-3-fluoro-6-methoxy-5-nitropyridine (1.9)

[0091] 2-Chloro-3-fluoro-6-methoxy-5-nitropyridine (1.8) (100 mg, 484.124 μmol) was dissolved in tetrahydrofuran (4 mL), and 3,3-difluorocyclobutanol (58 mg, 536.608 μmol) was added. NaH (20 mg, 500.042 μmol, 60% purity) was added while the reaction system was kept at 0°C. After addition, the reaction was stirred at 23°C for 17 hours. TLC confirmed the reaction was complete. 10 mL of water was added to the reaction system, followed by extraction with two 5 mL portions of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The product was filtered and purified by flash liquid chromatography. This yielded 2-(3,3-difluorocyclobutyloxy)-3-fluoro-6-methoxy-5-nitropyridine (1.9) (130 mg, 96.5% yield).

[0092] Step 8: Synthesis of 6-(3,3-difluorocyclobutyloxy)-5-fluoro-2-methoxypyridin-3-amine (1.10)

[0093] 2-(3,3-difluorocyclobutyloxy)-3-fluoro-6-methoxy-5-nitropyridine (1.9) (130 mg, 467.316 μmol) was dissolved in methanol (5 mL), followed by the addition of 10% palladium on carbon (26 mg). After the addition was complete, the reaction was stirred under H2 and 23 ° C for 3 hours. TLC monitored the complete reaction. The reaction solution was filtered and the filtrate was collected. After concentrating the filtrate, it was separated by fast liquid column chromatography. The product 6-(3,3-difluorocyclobutyloxy)-5-fluoro-2-methoxypyridine-3-amine (1.10) (80 mg, yield 69.0%) was obtained.

[0094] 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)

[0095] 6-(3,3-difluorocyclobutyloxy)-5-fluoro-2-methoxypyridin-3-amine (1.10) (80 mg, 322.319 μmol) was dissolved in anhydrous pyridine (1 mL), and 6-chloro-pyrazolo[1,5-a]pyridine-3-sulfonyl chloride (1.3) (67 mg, 266.837 μmol) 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. The compound 6-chloro-N-(6-(3,3-difluorocyclobutyloxy)-5-fluoro-2-methoxypyridin-3-yl)pyrazolo[1,5-a]pyridine-3-sulfonamide (1) (70 mg, yield 56.7%) was obtained. 1H NMR (400MHz, DMSO-d6) δ9.79(s,1H),9.27(s,1H),8.23(s,1H),7.67(d,J=1.2Hz,2H),7.62(d,J=10.2Hz,1H),5.02( s,1H),3.28(s,3H),3.11(ddd,J=19.7,15.0,7.3Hz,2H),2.76(ddd,J=19.5,15.1,5.5Hz,2H).MS(m / z):463.1[M+H] +

[0096] Example 2: Preparation of 6-chloro-N-(6-(difluoromethoxy-d)-5-fluoro-2-(methoxy-d3)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-sulfonamide (2)

[0097] Step 1: Synthesis of 2-chloro-3-fluoro-6-(methoxy-d3)-5-nitropyridine (2.1)

[0098] 2-Chloro-3,6-difluoro-5-nitropyridine (1.7) (2.00 g, 10.282 mmol) was dissolved in tetrahydrofuran (30 mL), and deuterated methanol-d4 (0.408 g, 11.312 mmol) was added. NaH (0.493 g, 12.326 mmol, 60%) was then added portionwise while maintaining the reaction system at -40°C. After addition, the reaction was maintained at -40°C for 2 hours. TLC confirmed the reaction was complete. The reaction solution was added to 30 mL of saturated aqueous ammonium chloride, separated, and the organic phase was collected. The aqueous phase was extracted with two 10 mL portions of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and purified by flash liquid chromatography to yield 2-chloro-3-fluoro-6-(methoxy-d3)-5-nitropyridine (2.1) (0.700 g, 32.5% yield).

[0099] Step 2: Synthesis of 3-fluoro-6-(methoxy-d3)-5-nitropyridine-2-ol (2.2)

[0100] 2-Chloro-3-fluoro-6-(methoxy-d3)-5-nitropyridine (2.1) (0.700 g, 3.340 mmol) was dissolved in a mixed solvent of water (7 mL) and tetrahydrofuran (7 mL). KOH (0.468 g, 8.341 mmol) was then added. After addition, the reaction was maintained at 20°C for 16 hours. TLC confirmed the completion of the reaction. The reaction solution was separated and the aqueous phase was collected. The aqueous phase was washed with 10 mL of ethyl acetate. The pH of the aqueous phase was adjusted to 3, and the extraction was performed with 10 mL of dichloromethane three times. The organic phases were collected and combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain the compound 3-fluoro-6-(methoxy-d3)-5-nitropyridine-2-ol (2.2) (0.200 g).

[0101] Step 3: Synthesis of 2-(difluoromethoxy-d)-3-fluoro-6-(methoxy-d3)-5-nitropyridine (2.3)

[0102] 3-Fluoro-6-(methoxy-d3)-5-nitropyridine-2-ol (2.2) (0.170 g, 889.439 μmol) was dissolved in deuterated acetonitrile (10 mL), and diethyl bromofluoromethylphosphonate (1.90 g, 7.116 mmol) and potassium deuterium oxide (1.02 g, 7.144 mmol, 40% purity) were added. The reaction was maintained at 50°C for 2 hours. TLC confirmed the reaction was complete. The reaction solution was poured into 10 mL of ice water and extracted with ethyl acetate twice, 10 mL each time. The organic phases were collected and combined, dried over anhydrous magnesium sulfate, filtered, and purified by flash liquid chromatography to obtain compound 2-(difluoromethoxy-d)-3-fluoro-6-(methoxy-d3)-5-nitropyridine (2.3) (0.100 g, 46.4% yield).

[0103] Step 4: Synthesis of 6-(difluoromethoxy-d)-5-fluoro-2-(methoxy-d3)pyridin-3-amine (2.4)

[0104] 2-(Difluoromethoxy-d)-3-fluoro-6-(methoxy-d3)-5-nitropyridine (2.3) (0.100 g, 412.975 μmol) was dissolved in methanol (10 mL) and 10% palladium on carbon (0.020 g) was added. After the addition was complete, the reaction was maintained under H2 at 20°C for 16 hours. TLC monitored the reaction completion. The reaction solution was filtered, the filtrate was dried, and purified by flash liquid column chromatography. Compound 6-(difluoromethoxy-d)-5-fluoro-2-(methoxy-d3)pyridin-3-amine (2.4) (60 mg, yield 68.5%) was obtained.

[0105] 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)

[0106] 6-(Difluoromethoxy-d)-5-fluoro-2-(methoxy-d3)pyridin-3-amine (2.4) (60 mg, 282.802 μmol) was dissolved in anhydrous pyridine (1 mL), and 6-chloropyrazolo[1,5-a]pyridine-3-sulfonyl chloride (1.3) (59 mg, 234.976 μmol) was added. After the addition, the reaction was maintained at 22°C for 3 hours. TLC monitored the reaction completion. The reaction solution was dried and purified by flash liquid column chromatography to obtain the compound 6-chloro-N-(6-(difluoromethoxy-d)-5-fluoro-2-(methoxy-d3)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-sulfonamide (2) (93 mg, 217.905 μmol, yield 92.7%). 1 H NMR (400MHz, DMSO-d6) δ10.07(s,1H),9.28(s,1H),8.29(s,1H),7.83(dd,J=17.5,9.7Hz,2H),7.71(d,J=9.5Hz,1H).MS(m / z):424.9[MH] -

[0107] Example 3: Preparation of N-(6-(2,2-difluoroethoxy)-5-fluoro-2-(methoxy-d3)pyridin-3-yl)-6-(difluoromethyl)pyrazolo[1,5-a]pyridine-3-sulfonamide (3)

[0108] Step 1: Synthesis of pyrazolo[1,5-a]pyridin-6-ylmethanol (3.2)

[0109] Maintaining the reaction under N2 protection at -20°C, lithium aluminum hydride (3.393 g, 89.401 mmol) was added to tetrahydrofuran (100 mL). Subsequently, a solution of methyl pyrazolo[1,5-a]pyridine-6-carboxylate (15.00 g, 85.144 mmol) in tetrahydrofuran (50 mL) was slowly added dropwise at -20°C, maintaining the reaction under N2 protection. After the addition, the reaction was allowed to proceed at 20°C under N2 protection for 4 hours. TLC monitoring indicated completion of the reaction. The reaction temperature was lowered to -10°C, and 3.4 mL of water, 3.4 mL of 15% NaOH solution, and 10.2 mL of water were slowly added sequentially to quench the reaction. The filtrate was collected by filtration. The filter cake was washed with 80 mL of a 10:1 mixture of tetrahydrofuran and methanol. The organic phases were combined and purified by flash liquid chromatography. The product pyrazolo[1,5-a]pyridin-6-ylmethanol (3.2) (10.00 g, yield 79.3%) was obtained.

[0110] Step 2: Synthesis of pyrazolo[1,5-a]pyridine-6-carbaldehyde (3.3)

[0111] Pyrazolo[1,5-a]pyridin-6-ylmethanol (3.2) (10.00 g, 67.494 mmol) was dissolved in dichloromethane (200 mL). Dess-Martin periodinane (42.940 g, 101.241 mmol) was added while maintaining the reaction at 0°C. After addition, the reaction was maintained at 20°C for 2 hours. TLC monitoring indicated the reaction was complete. 50 mL of saturated sodium bicarbonate solution and 50 g of solid sodium thiosulfate were added to the reaction solution to quench the reaction. The liquid phases were separated and the organic phase was collected. The aqueous phase was extracted with 200 mL of dichloromethane. The organic phases were combined and purified by flash liquid column chromatography. The product, pyrazolo[1,5-a]pyridine-6-carboxaldehyde (3.3) (8.56 g, 86.8% yield), was obtained.

[0112] Step 3: Synthesis of 6-(difluoromethyl)pyrazolo[1,5-a]pyridine (3.4)

[0113] Pyrazolo[1,5-a]pyridine-6-carboxaldehyde (3.3) (8.56 g, 58.572 mmol) was dissolved in dichloromethane (100 mL). Diethylaminosulfur trifluoride (14.162 g, 87.857 mmol) was slowly added dropwise, maintaining the reaction temperature at 0°C. After addition, the reaction was maintained at 20°C for 12 hours. TLC monitoring indicated the reaction was complete. Saturated sodium bicarbonate solution was added to the reaction system to adjust the pH to approximately 7.0. The mixture was separated, the organic phase collected, and the aqueous phase was extracted with two 100 mL portions of dichloromethane. The organic phases were combined and purified by flash liquid column chromatography to obtain the product, 6-(difluoromethyl)pyrazolo[1,5-a]pyridine (3.4) (5.58 g, 56.7% yield).

[0114] Step 4: Synthesis of 6-(difluoromethyl)pyrazolo[1,5-a]pyridine-3-sulfonyl chloride (3.5)

[0115] Dissolve 6-(Difluoromethyl)pyrazolo[1,5-a]pyridine (3.4) (4.50 g, 26.763 mmol) in acetonitrile (30 mL). After addition, slowly add chlorosulfonic acid (9.356 g, 80.289 mmol, 5.337 mL) dropwise while maintaining the reaction at 0°C. After addition, maintain the reaction at 20°C for 2 hours. TLC analysis indicates the reaction is complete. Drain the reaction solvent and lower the temperature of the reaction system to 0°C. Add thionyl chloride (70 mL). After addition, maintain the reaction at 70°C for 2 hours. TLC analysis indicates the reaction is complete. Add the reaction solution to 100 mL of ice water and extract with three 20 mL portions of dichloromethane. Combine the organic phases and purify by flash liquid chromatography. The compound 6-(difluoromethyl)pyrazolo[1,5-a]pyridine-3-sulfonyl chloride (3.5) (2.82 g, 10.576 mmol, yield 39.5%) was obtained.

[0116] Step 5: Synthesis of 2,3,6-trifluoro-5-nitropyridine (3.7)

[0117] Maintaining the reaction at 0°C, slowly add 2,3,6-trifluoropyridine (3.6) (24.000 g, 180.355 mmol) to fuming nitric acid (100 mL). After the addition is complete, maintain the reaction at 0°C and slowly add concentrated sulfuric acid (100 mL). After the addition is complete, maintain the reaction at 60°C and stir for 3 hours. TLC indicates product formation. Cool the reaction solution to 10-20°C and then slowly add it to 1 kg of crushed ice. Simultaneously, extract the reaction solution with 7 200 mL portions of dichloromethane. Combine the organic phases, wash twice with 200 mL of water, then twice with 200 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and spin-dry the solvent to obtain 2,3,6-trifluoro-5-nitropyridine (3.7) (19.000 g).

[0118] Step 6: Synthesis of 2-(2,2-difluoroethoxy)-3,6-difluoro-5-nitropyridine (3.8)

[0119] 2,2-Difluoroethanol (3.225 g, 39.311 mmol) was dissolved in tetrahydrofuran (100 mL). Under nitrogen, NaH (1.887 g, 47.173 mmol, 60% purity) was slowly added at 0°C. The reaction was then maintained at 0°C for 1 hour. The temperature of the reaction system was then lowered to -78°C, and 2,3,6-trifluoro-5-nitropyridine (3.7) (7.000 g, 39.311 mmol) was slowly added. The reaction was maintained at -78°C for 3 hours. TLC monitoring indicated the reaction was complete. Saturated ammonium chloride solution was added to the reaction system to quench the reaction, followed by extraction with three 50 mL portions of ethyl acetate. The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was purified by flash liquid chromatography. The product 2-(2,2-difluoroethoxy)-3,6-difluoro-5-nitropyridine (3.8) (4.600 g, yield 48.7%) was obtained.

[0120] Step 7: Synthesis of 2-(2,2-difluoroethoxy-3-fluoro-6-(methoxy-d3)-5-nitropyridine (3.9)

[0121] Deuterated methanol-D4 (744 mg, 20.628 mmol) was dissolved in tetrahydrofuran (70 mL). NaH (900 mg, 22.502 mmol) was slowly added at 0°C under nitrogen. The reaction was maintained at 0°C for 1 hour. Then, 2-(2,2-difluoroethoxy)-3,6-difluoro-5-nitropyridine (3.8 g) (4.500 g, 18.741 mmol) was added, still maintaining the reaction at 0°C. After addition, the reaction was stirred at 25°C for 2 hours. TLC monitoring indicated completion of the reaction. The reaction solution was quenched by addition into 15 mL of saturated aqueous ammonium chloride and extracted with ethyl acetate three times, 25 mL each. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the product was purified by flash liquid chromatography. The product 2-(2,2-difluoroethoxy-3-fluoro-6-(methoxy-d3)-5-nitropyridine (3.9) (4.463 g, yield 93.3%) was obtained.

[0122] Step 8: Synthesis of 6-(2,2-difluoroethoxy)-5-fluoro-2-(methoxy-d3)pyridin-3-amine (3.10)

[0123] 2-(2,2-Difluoroethoxy-3-fluoro-6-(methoxy-d3)-5-nitropyridine (3.9) (4.463 g, 17.492 mmol) was added to acetic acid (40 mL). Iron powder (10.775 g, 192.410 mmol) was slowly added while maintaining the reaction at 0°C. After addition, the reaction was stirred at 26°C for 2.5 hours. TLC monitoring indicated the reaction was complete. The solvent was evaporated, 100 mL of water was added, and solid sodium carbonate was added to adjust the pH of the system to 8-9. The reaction system was extracted with ethyl acetate three times in 50 mL increments. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was purified by flash liquid chromatography to obtain the product, 6-(2,2-difluoroethoxy)-5-fluoro-2-(methoxy-d3)pyridin-3-amine (3.10) (2.250 g, 57.1% yield).

[0124] Step 9: Synthesis of N-(6-(2,2-difluoroethoxy)-5-fluoro-2-(methoxy-d3)pyridin-3-yl)-6-(difluoromethyl)pyrazolo[1,5-a]pyridine-3-sulfonamide (3)

[0125] 6-(2,2-difluoroethoxy)-5-fluoro-2-(methoxy-d3)pyridin-3-amine (3.10) (82 mg, 364.149 μmol) was added to pyridine (3 mL), and then 6-(difluoromethyl)pyrazolo[1,5-a]pyridine-3-sulfonyl chloride (3.5) (80 mg, 300.016 μmol) 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. The solvent was dried and the product was purified by flash liquid column chromatography to obtain the product N-(6-(2,2-difluoroethoxy)-5-fluoro-2-(methoxy-d3)pyridin-3-yl)-6-(difluoromethyl)pyrazolo[1,5-a]pyridine-3-sulfonamide (3) (33 mg, yield 24.2%). 1 H NMR (400MHz, DMSO-d6) δ9.88(s,1H),9.26(s,1H),8.32(s,1H),7.90(d,J=9.2Hz,1H),7.76(d,J=9.3 Hz,1H),7.66(d,J=10.2Hz,1H),7.31-7.04(m,1H),6.52-6.25(m,1H),4.57(td,J=14.8,3.4Hz,2H). MS(m / z):455.9[M+H] +

[0126] Example 4: Preparation of N-(6-(2,2-difluoroethoxy)-5-fluoro-2-(methoxy-d3)pyridin-3-yl)-6-(difluoromethoxy)pyrazolo[1,5-a]pyridine-3-sulfonamide (4)

[0127] Step 1: Synthesis of 6-(difluoromethoxy)pyrazolo[1,5-a]pyridine (4.2)

[0128] Pyrazolo[1,5-a]pyridine-6-ol (2.000 g, 14.910 mmol) was dissolved in N,N-dimethylformamide (60 mL), and sodium difluorochloroacetate (3.410 g, 22.366 mmol) and cesium carbonate (9.716 g, 29.821 mmol) were added. After the addition, the reaction was stirred at 100°C for 3 hours under N2 protection. TLC monitoring indicated that the reaction was complete. The reaction solution was filtered, and the filtrate was collected and purified by flash liquid column chromatography. The product, 6-(difluoromethoxy)pyrazolo[1,5-a]pyridine (4.2) (600 mg, 21.9% yield) was obtained.

[0129] Step 2: Synthesis of 6-(difluoromethoxy)pyrazolo[1,5-a]pyridine-3-sulfonyl chloride (4.3)

[0130] 6-(Difluoromethoxy)pyrazolo[1,5-a]pyridine (4.2) (600 mg, 3.258 mmol) was dissolved in acetonitrile (10 mL). Chlorosulfonic acid (5 mL) was slowly added while maintaining the reaction at 0°C. After addition, the reaction was stirred at 26°C for 1 hour. TLC monitoring indicated the reaction was complete. The solvent was evaporated. The temperature of the reaction system was lowered to 0°C, and thionyl chloride (10 mL) was added. After addition, the reaction system was stirred at 65°C for 1 hour. LC-MS monitoring indicated the reaction was complete. The reaction solution was added dropwise to 50 mL of ice water. The reaction system was extracted with ethyl acetate three times with 30 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the product was purified by flash liquid column chromatography. This afforded 6-(difluoromethoxy)pyrazolo[1,5-a]pyridine-3-sulfonyl chloride (4.3) (500 mg, 54.3% yield).

[0131] Step 3: Synthesis of N-(6-(2,2-difluoroethoxy)-5-fluoro-2-(methoxy-d3)pyridin-3-yl)-6-(difluoromethoxy)pyrazolo[1,5-a]pyridine-3-sulfonamide (4)

[0132] 6-(2,2-difluoroethoxy)-5-fluoro-2-(methoxy-d3)pyridin-3-amine (3.10) (96 mg, 426.32 μmol) was dissolved in anhydrous pyridine (3 mL), and 6-(difluoromethoxy)pyrazolo[1,5-a]pyridine-3-sulfonyl chloride (4.3) (100 mg, 353.793 μmol) was added. After the addition was completed, the reaction was stirred at 85°C for 3 hours. LC-MS monitoring showed that the reaction was complete. The solvent was dried and purified by flash liquid column chromatography. The product N-(6-(2,2-difluoroethoxy)-5-fluoro-2-(methoxy-d3)pyridin-3-yl)-6-(difluoromethoxy)pyrazolo[1,5-a]pyridine-3-sulfonamide (4) (33 mg, yield 19.8%) was obtained. 1 H NMR(400MHz,DMSO-d6)δ9.85(s,1H),9.07(s,1H),8.24(s,1H),7.83(d,J=9.6Hz,1H),7.72-7.56 (m,2H),7.51-7.14(m,1H),6.53-6.26(m,1H),4.58(td,J=14.9,3.5Hz,2H).MS(m / z):471.9[M+H] +

[0133] Examples 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22 were prepared according to the above method.

[0134] Example 23: 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 (23)

[0135] Step 1: Synthesis of 8-((trimethylsilyl)ethynyl)-1,4-dioxaspiro[4.5]decan-8-ol (23.2)

[0136] Trimethylsilyl acetylene (65.404 g, 665.904 mmol, 94.106 mL) was added to tetrahydrofuran (800 mL). While maintaining the reaction at -20°C, n-butyl lithium (42.654 g, 665.904 mmol, 2.5 M, 266.362 mL) was slowly added dropwise under nitrogen. After addition, the reaction mixture was maintained at 0°C for 1 hour. Subsequently, a solution of 1,4-dioxaspiro[4.5]decan-8-one (23.1) (80.00 g, 512.234 mmol) in tetrahydrofuran (400 mL) was slowly added under nitrogen at -20°C. The temperature was naturally raised to 20°C, and the reaction mixture was maintained under nitrogen for 2 hours. TLC monitoring indicated the reaction was complete. After completion, the reaction temperature was lowered to -5°C, and 2 L of saturated ammonium chloride solution was added to quench the reaction. 2 L of saturated brine was added to the reaction system, and the system was extracted with 500 mL of ethyl acetate twice. The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered and the solvent was dried to obtain the product 8-((trimethylsilyl)ethynyl)-1,4-dioxaspiro[4.5]decan-8-ol (23.2) (130.00 g).

[0137] Step 2: Synthesis of 8-ethynyl-1,4-dioxaspiro[4.5]decane-7-ene (23.3)

[0138] Dissolve 8-((Trimethylsilyl)ethynyl)-1,4-dioxaspiro[4.5]decan-8-ol (23.2) (130.0 g, 511.013 mmol) in dichloromethane (1300 mL). Maintain the reaction at -20°C and add triethylamine (155.127 g, 1.533 mol, 213.086 mL). Slowly add ethylsulfonyl chloride (85.416 g, 664.317 mmol, 62.945 mL) dropwise. Maintain the reaction at 20°C for 16 hours. TLC monitoring indicates the reaction is complete. Add 300 mL of water and tetrabutylammonium fluoride (200 mL) to the reaction system. Maintain the reaction temperature at 20°C and continue stirring for 30 minutes. Concentrate the reaction solution and purify it by column chromatography. The product 8-ethynyl-1,4-dioxaspiro[4.5]decane-7-ene (23.3) was obtained (67.00 g, yield 79.8%).

[0139] Step 3: Synthesis of 4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1-toluenesulfonyl-1H-1,2,3-triazole (23.4)

[0140] 8-Ethynyl-1,4-dioxaspiro[4.5]decane-7-ene (23.3) (67.00 g, 408.037 mmol) was dissolved in toluene (1200 mL), and p-toluenesulfonyl azide (107.297 g, 408.037 mmol) and copper(I) thiophene-2-carboxylate (7.781 g, 40.804 mmol) were added. The reaction was maintained at 20°C for 16 hours. TLC monitoring indicated the reaction was complete. The filtrate was concentrated and purified by flash liquid chromatography to yield the product, 4-(1,4-dioxaspiro[4.5]decane-7-en-8-yl)-1-p-toluenesulfonyl-1H-1,2,3-triazole (23.4) (130.000 g, 88.2% yield).

[0141] Step 4: Synthesis of 1-p-toluenesulfonyl-1,4,5,7-tetrahydrospiro[indole-6,2'-[1,3]dioxolane] (23.5)

[0142] In each of ten batches, 4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1-(p-toluenesulfonyl)-1H-1,2,3-triazole (23.4) (12.00 g, 33.203 mmol) was dissolved in 1,2-dichloroethane (140 mL), and Rh2(esp)2 (161 mg, 332.538 μmol) was added. After addition, the reaction was maintained at 80°C under nitrogen for 3 hours. LC-MS monitoring indicated completion of the reaction. The reaction mixtures from all ten batches were combined, the solvent was evaporated, and the product was purified by flash liquid chromatography. A total of 16.80 g, 15.2% yield, of 1-(p-toluenesulfonyl)-1,4,5,7-tetrahydrospiro[indole-6,2'-[1,3]dioxolane] (23.5) was obtained from these ten batches.

[0143] Step 5: Synthesis of 1-p-toluenesulfonyl-1,4,5,7-tetrahydro-6H-indol-6-one (23.6)

[0144] 1-p-Toluenesulfonyl-1,4,5,7-tetrahydrospiro[indole-6,2'-[1,3]dioxolane] (23.5) (16.80 g, 50.390 mmol) was dissolved in tetrahydrofuran (150 mL) and 4N hydrochloric acid (150 mL) was added. After the addition, the reaction was maintained at 50°C for 16 hours. TLC monitoring showed that the reaction was complete. After the solvent was dried, methyl tert-butyl ether (50 mL) was added to the reaction system and slurry was performed. After filtration and drying of the solvent, the product 1-p-Toluenesulfonyl-1,4,5,7-tetrahydro-6H-indole-6-one (23.6) (12.00 g, yield 82.3%) was obtained.

[0145] Step 6: Synthesis of 1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-6-ol (23.7)

[0146] 1-(p-Toluenesulfonyl)-1,4,5,7-tetrahydro-6H-indol-6-one (23.6) (800 mg, 2.765 mmol) was dissolved in tetrahydrofuran (20 mL). Cesium carbonate (1.171 g, 3.594 mmol) and trifluoromethyltrimethylsilane (472 mg, 3.319 mmol, 490.644 μL) were added while maintaining the reaction at 0°C. The reaction was then maintained at 20°C for 16 hours. The filtrate was then filtered and collected. Tetrabutylammonium fluoride (498 mg, 2.212 mmol, 1 M, 2.212 mL) was added to the filtrate. The reaction was maintained at 20°C for an additional hour. LCMS monitoring indicated the reaction was complete. The reaction mixture was concentrated and purified by flash liquid column chromatography to obtain the product 1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-6-ol (23.7) (600 mg, yield 60.4%).

[0147] Step 7: Synthesis of 6-(methoxy-d3)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (23.8)

[0148] 1-(p-Toluenesulfonyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-6-ol (23.7) (600 mg, 1.670 mmol) was dissolved in N,N-dimethylformamide (10 mL). Deuterated iodomethane (400 mg, 2.818 mmol) and NaH (112 mg, 2.800 mmol) were slowly added while maintaining the reaction at 0°C. The reaction was maintained at 20°C for 0.5 hours. LCMS monitoring indicated the reaction was complete. The 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%).

[0149] Step 8: Synthesis of 5-fluoro-2-methoxy-3-nitropyridine (23.10)

[0150] 5-Fluoro-3-nitropyridin-2(1H)-one (23.9) (30.000 g, 189.769 mmol) was added to chloroform (500 mL), followed by silver carbonate (63.716 g, 379.537 mmol) and iodomethane (269.354 g, 1.898 mol). The reaction was maintained at 20°C for 16 hours. TLC monitoring indicated the reaction was complete. Aqueous sodium carbonate solution (300 mL) was added to the reaction solution, and the reaction was maintained at 20°C for 15 minutes. The reaction solution was filtered and extracted with ethyl acetate twice, 200 mL each. The organic phases were combined and concentrated. Purification by flash liquid column chromatography afforded the product, 5-fluoro-2-methoxy-3-nitropyridine (23.10) (20.0 g, 61.2% yield).

[0151] Step 9: Synthesis of 5-fluoro-2-methoxypyridin-3-amine (23.11)

[0152] 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 showed that 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).

[0153] Step 10: Synthesis of 6-bromo-5-fluoro-2-methoxypyridin-3-amine (23.12)

[0154] 5-Fluoro-2-methoxypyridin-3-amine (23.11) (4.000 g, 28.143 mmol) was dissolved in N,N-dimethylformamide (60 mL), and N-bromosuccinimide (4.007 g, 22.514 mmol) was added portionwise. The reaction was maintained at 40°C for 30 minutes. LCMS monitoring showed that the reaction was complete. The reaction solution was poured into water (200 mL), and the aqueous phase was extracted with 40 mL of ethyl acetate three times. The organic phases were combined, dried, and purified by flash liquid column chromatography to obtain the product 6-bromo-5-fluoro-2-methoxypyridin-3-amine (23.12) (5.90 g, yield 94.8%).

[0155] Step 11: Synthesis of N,N-bisbenzyl-6-bromo-5-fluoro-2-methoxypyridin-3-amine (23.13)

[0156] 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).

[0157] Step 12: Synthesis of N,N-bisbenzyl-5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-amine (23.14)

[0158] Dissolve N,N-bisbenzyl-6-bromo-5-fluoro-2-methoxypyridin-3-amine (23.13) (1.000 g, 2.492 mmol) in N,N-dimethylformamide (10 mL), then add methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.436 g, 7.476 mmol) and cuprous iodide (950 mg, 4.988 mmol). After addition, maintain the reaction at 100°C under nitrogen for 16 hours. LC-MS monitoring indicates completion of the reaction. Pour the reaction solution into water (40 mL), and extract the aqueous phase with three 10 mL portions of ethyl acetate. Combine the organic phases and concentrate. The product was purified by flash liquid column chromatography to obtain N,N-bisbenzyl-5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-amine (23.14) (900 mg, yield 92.5%).

[0159] Step 13: Synthesis of 5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-amine (23.15)

[0160] N,N-bisbenzyl-5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-amine (23.14) (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%).

[0161] 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)

[0162] The intermediate 6-methoxy-d3-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (23.8) was expanded to 2.50 g and separated by supercritical fluid chromatography to obtain 700 mg of product (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).

[0163] 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)

[0164] Dissolve (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 g) (700 mg, 1.860 mmol) in acetonitrile (20 mL). Add chlorosulfonic acid (650 mg, 5.578 mmol) dropwise while maintaining the reaction at -30°C. After addition, maintain the reaction at 20°C for 30 minutes. TLC monitoring indicates the reaction is complete. The reaction solution is spun dry, and thionyl chloride (10 mL) is added while maintaining the reaction at 0°C. After addition, maintain the reaction at 70°C for 1 hour. LCMS monitoring indicates the reaction is complete. Cool the reaction solution to 20°C and then slowly add dropwise to 200 g of crushed ice. The aqueous phase was extracted with 50 mL of ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was dried, and purified by flash liquid chromatography. The product (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) (700 mg, yield 79.2%) was obtained.

[0165] Step 16: 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 (23.18)

[0166] 5-Fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-amine (23.15) (150 mg, 713.848 μmol) was added to anhydrous pyridine (1 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) (200 mg, 421.126 μmol). After the addition, the reaction was maintained at 115°C in a microwave oven for 1 hour. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to give the product (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 (23.18) (200 mg, yield 73.2%).

[0167] Step 17: 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 (23)

[0168] (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 (23.18) (200 mg, 308.364 μmol) was added to a mixture of methanol (6 mL) and water (3 mL), and potassium carbonate (426 mg, 3.082 mmol) was added. After the addition was complete, the 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 system was adjusted to 3-6 by adding 2N dilute hydrochloric acid. After the solvent was dried, the mixture was purified by flash liquid column chromatography to obtain the product (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 (23) (100 mg, yield 65.6%). 1 H NMR (400MHz, DMSO-d6) δ11.42(s,1H),10.23(s,1H),7.62(d,J=11.5Hz,1H),7.48(d,J=3.0Hz,1H),3.87(s,3H),2.79(dt,J=16 .9,11.5Hz,3H),2.45(dd,J=16.4,5.3Hz,1H),2.18(dd,J=13.7,5.2Hz,1H),1.78(td,J=13.3,6.0Hz,1H).MS(m / z):493.0[MH] - .

[0169] 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)

[0170] 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)

[0171] The intermediate 6-methoxy-d3-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (23.8) was expanded to 2.50 g and separated by supercritical fluid chromatography to give 750 mg of product (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).

[0172] 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)

[0173] Dissolve (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) (0.750 g, 1.993 mmol) in acetonitrile (10 mL). Add chlorosulfonic acid (697 mg, 5.982 mmol) dropwise while maintaining the reaction at -40°C. After addition, maintain the reaction at -40°C for 30 minutes. TLC monitoring indicates the reaction is complete. After the reaction solution is dried, add thionyl chloride (5 mL) while maintaining the reaction at 0°C. After addition, maintain the reaction at 70°C for 1 hour. LCMS monitoring indicates the reaction is complete. Cool the reaction solution to 20°C and slowly add 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 chromatography. The product (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) (0.400 g, yield 42.7%) was obtained.

[0174] 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)

[0175] 5-Fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-amine (23.15) (133 mg, 632.945 μmol) was added to anhydrous pyridine (0.6 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 (24.2) (200 mg, 421.126 μmol). After the addition, the reaction was maintained at 115°C in a microwave oven for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to give the product (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) (0.150 g, yield 54.9%).

[0176] 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)

[0177] (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) (0.150 g, 231.273 μmol) was added to a mixture of methanol (10 mL) and water (5 mL), and potassium carbonate (479 mg, 3.466 mmol) was added. After the addition was complete, the reaction was maintained at 80°C for 1 hour. LCMS monitoring showed that the reaction was complete. The 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. The product (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) (0.073 g, yield 63.8%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.40(s,1H),10.23(s,1H),7.60(d,J=11.6Hz,1H),7.46(d,J=3.0Hz,1H),3.87(s,3H),2.79(dt,J=16 .6,11.6Hz,3H),2.45(dd,J=16.6,5.4Hz,1H),2.18(dd,J=13.7,5.2Hz,1H),1.78(td,J=13.4,6.1Hz,1H).MS(m / z):493.0[MH] - .

[0178] Example 25: Preparation of N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (25)

[0179] Step 1: Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-one (25.2)

[0180] 4-(Hydroxymethyl)cyclohexane-1-one (23.20 g, 181.012 mmol) was dissolved in tetrahydrofuran (300 mL). Imidazole (36.968 g, 543.035 mmol) was added while maintaining the reaction at 0°C, followed by the slow addition of tert-butyldimethylsilyl chloride (19.379 g, 235.315 mmol). After addition, the reaction mixture was maintained at 25°C for 12 hours. TLC analysis indicated the reaction was complete. The insoluble material was removed by filtration, and the filtrate was dried and purified by liquid column chromatography. The product, 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-one (25.2 g), was obtained (37.6 g, 85.7% yield).

[0181] Step 2: Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)ethynyl)cyclohexane-1-ol (25.3)

[0182] 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. TLC monitoring indicated the reaction was complete. After completion, the reaction temperature was lowered to -20°C, and 150 mL of saturated ammonium chloride solution was added dropwise to quench the reaction. After being spin-dried for solvent, 500mL of methyl tert-butyl ether and 200mL of water were added to the reaction system, and liquid separation was performed. The organic phase was collected. At the same time, the aqueous phase was extracted with 500mL of methyl tert-butyl ether for a total of 3 times. The organic phases were combined and washed with 200mL of saturated sodium chloride solution. The organic phase was dried with anhydrous magnesium sulfate and filtered. The filtrate was spin-dried to obtain product 4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)ethynyl)cyclohexane-1-ol (25.3) (46.8g).

[0183] Step 3: Synthesis of tert-butyldimethyl((4-((trimethylsilyl)ethynyl)cyclohexyl-3-en-1-yl)methoxy)silyl (25.4)

[0184] 4-(((tert-Butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)ethynyl)cyclohexane-1-ol (25.3g) (46.8g, 137.386mmol) was dissolved in dichloromethane (500mL). Triethylamine (41.706g, 412.157mmol, 57.288mL) was added while maintaining the reaction at 0°C. Ethylsulfonyl chloride (22.964g, 178.601mmol, 16.923mL) was then slowly added dropwise. After addition, the reaction was maintained at 25°C for 15 hours. TLC monitoring indicated that the reaction was complete. 150mL of water was added to the reaction system to quench the reaction. The mixture was then separated and the organic phase was collected. The aqueous phase was extracted with two 100mL portions of dichloromethane. The organic phases were combined, dried, and separated by column chromatography. The product tert-butyldimethyl((4-((trimethylsilyl)ethynyl)cyclohexyl-3-en-1-yl)methoxy)silane (25.4) (35.00 g, yield 79.0%) was obtained.

[0185] Step 4: Synthesis of tert-butyl((4-ethylcyclohex-3-en-1-yl)methoxy)dimethylsilane (25.5 g)

[0186] Tert-butyldimethyl((4-((trimethylsilyl)ethynyl)cyclohexyl-3-en-1-yl)methoxy)silane (25.4) (35.000 g, 108.483 mmol) was dissolved in a mixed solvent of tetrahydrofuran (150 mL) and methanol (150 mL), and potassium carbonate (29.986 g, 216.966 mmol) was added. The reaction was maintained at 25°C for 2 hours. TLC monitoring showed that the reaction was complete. The reaction solution was filtered and the filtrate was concentrated. Water (200 mL) was then added and extracted with ethyl acetate three times in 100 mL increments. The organic phases were combined and dried over anhydrous magnesium sulfate. After filtering and drying the filtrate, the product tert-butyl((4-ethylcyclohex-3-en-1-yl)methoxy)dimethylsilane (25.5) (21.000 g) was obtained.

[0187] 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)

[0188] Tert-butyl((4-ethylcyclohex-3-en-1-yl)methoxy)dimethylsilane (25.5 g) (21.000 g, 83.849 mmol) was dissolved in toluene (250 mL), followed by the addition of p-toluenesulfonyl azide (22.049 g, 83.849 mmol) and copper(I) thiophene-2-carboxylate (1.599 g, 8.385 mmol). The reaction was maintained at 25°C for 15 hours. TLC monitoring indicated the reaction was complete. The filtrate was concentrated and purified by flash liquid chromatography to yield the product, 4-(4-((tert-butyldimethyl)oxy)methyl)cyclohexyl-1-en-1-yl)-1-p-toluenesulfonyl-1H-1,2,3-triazole (25.6 g) (30.000 g, 79.9% yield).

[0189] Step 6: Synthesis of 6-(((tert-butyldimethylsilyl)oxy)methyl)-1-p-toluenesulfonyl-4,5,6,7-tetrahydro-1H-indole (25.7)

[0190] In two batches, 4-(4-((tert-butyldimethyl)oxy)methyl)cyclohexyl-1-en-1-yl)-1-(p-toluenesulfonyl)-1H-1,2,3-triazole (25.6) (10.00 g, 22.338 mmol) was dissolved in 1,2-dichloroethane (200 mL) and Rh2(esp)2 (0.170 g, 224.137 μmol) was added in each batch. After addition, the reaction was maintained at 70°C under nitrogen for 16 hours. LC-MS monitoring indicated the reaction was complete. The solvent was then evaporated and the product was purified by flash liquid chromatography. A total of 6-(((tert-butyldimethylsilyl)oxy)methyl)-1-(p-toluenesulfonyl)-4,5,6,7-tetrahydro-1H-indole (25.7) (12.00 g, 64.0% yield) was obtained from the two batches.

[0191] Step 7: Synthesis of (1-toluenesulfonyl-4,5,6,7-tetrahydro-1H-indol-6-yl)methanol (25.8)

[0192] 6-(((tert-Butyldimethylsilyl)oxy)methyl)-1-(p-toluenesulfonyl)-4,5,6,7-tetrahydro-1H-indole (25.7) (3.000 g, 7.149 mmol) was dissolved in tetrahydrofuran (20 mL) and tetrabutylammonium fluoride (1 M, 15.000 mL) was added. After the addition, the reaction was maintained at 25°C for 15 hours. TLC monitoring showed that the reaction was complete. After the solvent was evaporated, 50 mL of water was added. The reaction system was extracted with 50 mL of ethyl acetate three times. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the product (1-(p-toluenesulfonyl)-4,5,6,7-tetrahydro-1H-indol-6-yl)methanol (25.8) (2.100 g).

[0193] Step 8: Synthesis of 1-p-toluenesulfonyl-4,5,6,7-tetrahydro-1H-indole-6-carbaldehyde (25.9)

[0194] (1-(p-Toluenesulfonyl)-4,5,6,7-tetrahydro-1H-indol-6-yl)methanol (25.8g) (2.100g, 6.876mmol) was dissolved in dichloromethane (40mL), and Dess-Martin periodinane (4.375g, 10.315mmol) was added. After addition, the reaction was maintained at 25°C for 4 hours. TLC monitoring indicated completion of the reaction. 50mL of saturated sodium bicarbonate solution and 10g of solid sodium thiosulfate were added to the reaction solution to quench the reaction. The reaction system was extracted with three 20mL portions of dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate and purified by flash liquid column chromatography to obtain the product, 1-(p-Toluenesulfonyl)-4,5,6,7-tetrahydro-1H-indole-6-carbaldehyde (25.9g) (1.800g, 86.3% yield).

[0195] Step 9: Synthesis of 1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-6-carbaldehyde (25.10)

[0196] 1-(p-Toluenesulfonyl)-4,5,6,7-tetrahydro-1H-indole-6-carbaldehyde (25.9g) (500mg, 1.648mmol) was dissolved in dichloromethane (10mL), and tetrahydropyrrole (234mg, 3.290mmol) and a 1M solution of trifluoromethyl iodide in N,N-dimethylformamide (10.000mL) were added. After the addition, the reaction was maintained at 25°C under white light for 60 hours. TLC monitoring showed the formation of the product. After the solvent was evaporated, the product was purified by flash liquid chromatography to obtain 1-(p-Toluenesulfonyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-6-carbaldehyde (25.10) (0.150g, 24.5% yield).

[0197] Step 10: Synthesis of 1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-6-carbaldehyde oxime (25.11)

[0198] Dissolve 1-(p-toluenesulfonyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-6-carbaldehyde (25.10) (0.100 g, 269.271 μmol) in ethanol (10 mL), add hydroxylamine hydrochloride (80 mg, 1.151 mmol) and sodium carbonate (120 mg, 1.132 mmol). After addition, maintain the reaction at 40°C for 1 hour. TLC monitoring indicates the reaction is complete. After filtration, the filtrate is concentrated to obtain the crude product, 1-(p-toluenesulfonyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-6-carbaldehyde oxime (25.11) (300 mg).

[0199] Step 11: Synthesis of 1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-6-carbonitrile (25.12)

[0200] 1-(p-Toluenesulfonyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-6-carbaldehyde oxime (25.11) (0.300 g, 776.422 μmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of carbonyldiimidazole (1.007 g, 6.211 mmol). After addition, the reaction was maintained at 60°C for 1 hour. TLC monitoring indicated that the reaction was complete. The 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).

[0201] Step 12: Synthesis of 6-cyano-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (25.13)

[0202] 1-(p-Toluenesulfonyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-6-carbonitrile (25.12) (0.080 g, 217.171 μmol) was dissolved in acetonitrile (5 mL). Chlorosulfonic acid (76 mg, 652.226 μmol) was then added while maintaining the temperature at -30°C. After addition, the reaction was maintained at -30°C for 1 hour. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated. Sulfonyl chloride (3 mL) was then added while maintaining the temperature at 0°C. After addition, the reaction was maintained at 60°C for 1 hour. TLC monitoring indicated the reaction was complete. The 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%).

[0203] 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)

[0204] 4-Bromo-2,5-difluoroaniline (71 mg, 341.341 μmol) was dissolved in anhydrous pyridine (3 mL), and 6-cyano-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (25.13) (0.080 g, 171.350 μmol) was added. After addition, the reaction was maintained at 25°C for 15 hours. TLC monitoring indicated completion of the reaction. The 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).

[0205] Step 14: Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (25)

[0206] 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 μmol) was added to a mixture of methanol (5 mL) and water (5 mL), followed by potassium carbonate (173 mg, 1.252 mmol). After addition, the reaction was maintained at 80°C for 1 hour. TLC monitoring indicated the reaction was complete. Citric acid was added to the reaction solution to adjust the pH to approximately 4-5. The reaction solution was concentrated and purified by flash liquid chromatography. The product N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (25) was obtained (0.030 g, yield 49.4%). 1 H NMR (400MHz, DMSO-d6) δ11.53(s,1H),10.19(s,1H),7.66(dd,J=9.6,6.4Hz,1H),7.33(d,J=3.0Hz,1H),7.25(dd,J=9.9,6.8Hz,1H),3.12(s, 2H),2.95(dd,J=17.2,4.7Hz,1H),2.65–2.55(m,1H),2.39(dd,J=13.2,4.9Hz,1H),2.02(td,J=12.6,5.6Hz,1H).MS(m / z):482.0;484.0[MH] - .

[0207] 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)

[0208] 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%. 1H NMR (400MHz, DMSO-d6) δ11.52(s,1H),10.20(s,1H),7.65(dd,J=9.6,6.4Hz,1H),7.32(d,J=3.0Hz,1H),7.25(dd,J=10.0,6.9Hz,1H) ,3.12(s,2H),2.95(dd,J=17.0,4.9Hz,1H),2.61(dd,J=20.4,8.7Hz,1H),2.39(dd,J=12.9,4.9Hz,1H),2.02(td,J=12.5,5.5Hz,1H). MS(m / z):482.1;484.1[MH] -

[0209] 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)

[0210] 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%. 1 H NMR (400MHz, DMSO-d6) δ11.52(s,1H),10.20(s,1H),7.65(dd,J=9.6,6.4Hz,1H),7.32(d,J=3.0Hz,1H),7.25(dd,J=10.0,6.9Hz,1H) ,3.12(s,2H),2.95(dd,J=17.0,4.9Hz,1H),2.61(dd,J=20.4,8.7Hz,1H),2.39(dd,J=12.9,4.9Hz,1H),2.02(td,J=12.5,5.5Hz,1H). MS(m / z):482.1;484.1[MH] -

[0211] Example 28: Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (28)

[0212] Step 1: Synthesis of 6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (28.1)

[0213] 1-(p-Toluenesulfonyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-6-ol (23.7) (10.00 g, 27.827 mmol) was dissolved in N,N-dimethylformamide (180 mL). NaH (2.800 g, 70.006 mmol) was added at 0°C. The reaction was stirred at 20°C for 16 hours under a chlorodifluoromethane atmosphere. LC-MS monitoring indicated the formation of the product. The reaction solution was slowly added to 500 mL of saturated ammonium chloride solution and extracted with ethyl acetate three times in 100 mL increments. The combined organic phases were dried over anhydrous magnesium sulfate. Filtered and purified by flash liquid chromatography. The product 6-(difluoromethoxy)-1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (28.1) was obtained (1.500 g, yield 13.2%).

[0214] Step 2: Synthesis of 6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (28.2)

[0215] Dissolve 6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (28.1) (0.020 g, 48.856 μmol) in 3 mL of dichloromethane. Chlorosulfonic acid (57 mg, 489.169 μmol) in dichloromethane (2 mL) was slowly added dropwise while maintaining the reaction at -50°C. Stir the reaction at -50°C for 1 hour. Then, oxalyl chloride (1.5 mL) and N,N-dimethylformamide (0.5 mL) were added dropwise while maintaining the reaction at -50°C. After addition, the reaction temperature was raised to 25°C and allowed to react for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was slowly added dropwise to 100 mL of ice water and extracted with three 30 mL portions of dichloromethane. The organic phases were combined and washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was purified by flash liquid column chromatography to obtain the product 6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (28.2) (0.020 g, yield 80.6%).

[0216] 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)

[0217] 4-Bromo-2,5-difluoroaniline (12 mg, 57.691 μmol) was dissolved in anhydrous pyridine (0.6 mL), and 6-(difluoromethoxy)-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (28.2) (0.020 g, 39.379 μmol) was added. After the addition, the reaction was maintained at 100°C in a microwave oven for 1 hour. LC-MS monitoring indicated the reaction was complete. The reaction solution was concentrated to yield the product, N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (28.3) (0.025 g).

[0218] Step 4: Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (28)

[0219] 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 μmol) was added to a mixture of water (2 mL) and methanol (3 mL), followed by potassium carbonate (51 mg, 369.014 μmol). 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%). 1H NMR (400MHz, DMSO-d6) δ11.37(s,1H),10.14(s,1H),7.78–7.47(m,1H),7.15(ddd,J=149.7,78.4,37.3H z, 3H), 3.01 (q, J = 16.9Hz, 2H), 2.76 (dd, J = 15.0, 5.9Hz, 1H), 2.43 (s, 2H), 1.95 (dd, J = 16.6, 12.0Hz, 1H). MS(m / z):522.9;524.9[MH] -

[0220] 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)

[0221] 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)

[0222] 1.40 g of intermediate 28.1 was separated by supercritical fluid chromatography to obtain compound (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 (configuration undetermined) (29.1) (240 mg, yield 17.1%).

[0223] 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)

[0224] (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) (240 mg, 586.266 μmol) was dissolved in 20 mL of dichloromethane. Chlorosulfonic acid (683 mg, 5.861 mmol) was slowly added dropwise while maintaining the reaction at -40°C. The reaction was stirred at -40°C for 1 hour. Oxalyl chloride (2 mL) and N,N-dimethylformamide (0.5 mL) were then added dropwise while maintaining the reaction at -40°C. After addition, the reaction system was heated to 20°C and allowed to react for 1 hour. LC-MS monitoring indicated the reaction was complete. The reaction solution was concentrated and purified by flash liquid chromatography. The product (S)-6-(difluoromethoxy)-1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride or (R)-6-(difluoromethoxy)-1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (29.2) was obtained (200 mg, yield 67.2%).

[0225] 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)

[0226] 4-Bromo-2,5-difluoroaniline (100 mg, 480.762 μmol) was dissolved in anhydrous pyridine (0.5 mL) and either (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) (100 mg, 196.897 μmol) was added. After addition, the reaction was maintained at 100°C in a microwave oven for 1 hour. LC-MS monitoring indicated the reaction was complete. The reaction solution was concentrated and purified by flash liquid column chromatography to give the product (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) (120 mg, yield 89.7%).

[0227] 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)

[0228] (S)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (29.3 mg, 176.621 μmol) was added to a mixture of water (2 mL) and methanol (5 mL), followed by potassium carbonate (244 mg, 1.765 mmol). After addition, the reaction system was stirred at 80°C for 1 hour. LC-MS monitoring indicated the reaction was complete. The reaction solution was adjusted to pH 3-6 by adding 2 M dilute hydrochloric acid, concentrated, and purified by flash liquid chromatography. The product (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) was obtained (75 mg, yield 80.8%). 1 H NMR (400MHz, DMSO-d6) δ11.40(s,1H),10.14(s,1H),7.65(dd,J=9.6,6.4Hz,1H),7.28(d,J=3.0Hz,1H),7.22(dd,J=10.0,6.9Hz,1H) ,7.02(t,J=72.1Hz,1H),3.01(q,J=16.9Hz,2H),2.76(dd,J=14.8,5.5Hz,1H),2.45(d,J=11.3Hz,2H),1.95(dd,J=16.3,12.4Hz,1H). MS(m / z):523.0,525.0[MH] -

[0229] Example 30: 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 (30)

[0230] 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)

[0231] 1.40 g of intermediate 28.1 was resolved by supercritical fluid chromatography to give compound (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) (0.400 g, yield 28.6%).

[0232] 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 (30.2)

[0233] (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) (0.400 g, 977.111 μmol) was dissolved in 15 mL of dichloromethane. Chlorosulfonic acid (1.139 g, 9.771 mmol) was slowly added dropwise while maintaining the reaction at -40°C. The reaction mixture was stirred at -40°C for 1 hour. Oxalyl chloride (3 mL) and N,N-dimethylformamide (2 mL) were then added dropwise while maintaining the reaction at -40°C. After addition, the reaction system was heated to 25°C and allowed to react for 11 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was concentrated and purified by flash liquid chromatography. The product (S)-6-(difluoromethoxy)-1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride or (R)-6-(difluoromethoxy)-1-p-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (30.2) was obtained (0.330 g, yield 66.5%).

[0234] 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)

[0235] 4-Bromo-2,5-difluoroaniline (93 mg, 447.108 μmol) was dissolved in anhydrous pyridine (1 mL). (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 (30.2) (0.150 g, 295.346 μmol) was added. After addition, the reaction was maintained at 100°C in a microwave oven for 1 hour. LC-MS monitoring indicated the reaction was complete. The reaction solution was concentrated and purified by flash liquid column chromatography to give the product (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) (0.120 g, yield 59.8%).

[0236] 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 (30)

[0237] (S)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide or (R)-N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethoxy)-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (29.3 g) (0.120 g, 176.621 μmol) was added to a mixture of water (3 mL) and methanol (6 mL), followed by potassium carbonate (244 mg, 1.765 mmol). After addition, the reaction mixture was stirred at 80°C for 1 hour. LC-MS monitoring indicated the reaction was complete. 2N dilute hydrochloric acid was added to the reaction mixture to adjust the pH to 5-6. The reaction solution was then extracted with 30 mL of ethyl acetate three times, and the organic phases were combined. The organic phase was washed with 100 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and separated by reverse column chromatography. The product (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 (30) (0.065 g, yield 70.1%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.40(s,1H),10.15(s,1H),7.65(dd,J=9.6,6.4Hz,1H),7.28(d,J=3.0Hz,1H),7.26–7.21(m,1H),7. 21–6.82(m,1H),3.01(q,J=16.9Hz,2H),2.76(dd,J=14.7,5.8Hz,1H),2.43(t,J=10.8Hz,2H),1.95(dd,J=16.0,12.2Hz,1H). MS(m / z):522.9,524.9[MH] -

[0238] Example 31: 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)

[0239] Step 1: Synthesis of 6-(difluoromethyl)-1-p-toluenesulfonyl-4,5,6,7-tetrahydro-1H-indole (31.1)

[0240] 1-(p-Toluenesulfonyl)-4,5,6,7-tetrahydro-1H-indole-6-carbaldehyde (25.9g) (0.300g, 988.874μmol) was dissolved in dichloromethane (10mL). Diethylaminosulfur trifluoride (0.319g, 1.979mmol) was then added while maintaining the reaction at 0°C. After addition, the reaction was maintained at 0°C for 2 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was poured into 20mL of ice water, and the pH was adjusted to 7-8 with saturated aqueous sodium carbonate. The reaction mixture was then extracted with two 10mL portions of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to obtain 6-(difluoromethyl)-1-(p-Toluenesulfonyl)-4,5,6,7-tetrahydro-1H-indole (31.1g) (0.150g) as an off-white solid.

[0241] Step 2: Synthesis of 6-(difluoromethyl)-1-p-toluenesulfonyl-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (31.2)

[0242] Dissolve 6-(difluoromethyl)-1-toluenesulfonyl-4,5,6,7-tetrahydro-1H-indole (31.1) (0.150 g, 461.010 μmol) in acetonitrile (3 mL). Add chlorosulfonic acid (0.3 mL) while maintaining the reaction at 0°C. After addition, maintain the reaction at 20°C for 3 hours. TLC monitoring indicates that the reaction is complete. The reaction solution is spun dry. Add thionyl chloride (3 mL) to the reaction solution. After addition, maintain the reaction at 70°C for 1 hour. TLC monitoring indicates that the reaction is complete. Pour the reaction solution into 10 mL of ice water and extract the reaction system with 10 mL of ethyl acetate twice. Combine the organic phases and dry them over anhydrous sodium sulfate. After filtration, the filtrate is purified by flash liquid column chromatography. The product 6-(difluoromethyl)-1-p-toluenesulfonyl-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (31.2) was obtained (0.150 g, yield 76.7%).

[0243] 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)

[0244] 4-Bromo-2,5-difluoroaniline (53 mg, 254.804 μmol) was dissolved in anhydrous pyridine (1 mL), and 6-(difluoromethyl)-1-toluenesulfonyl-4,5,6,7-tetrahydro-1H-indole-3-sulfonyl chloride (31.2) (90 mg, 212.323 μmol) was added. After addition, the reaction was maintained at 23°C for 4 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid chromatography. The product, N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-1-toluenesulfonyl-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (31.3) (121 mg, 95.7% yield) was obtained.

[0245] Step 4: Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (31.4)

[0246] N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-1-toluenesulfonyl-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (31.3) (121 mg, 203.216 μmol) was dissolved in methanol (3 mL) and 2N aqueous NaOH (3 mL) was added. After addition, the reaction was maintained at 65°C for 2 hours. LCMS monitoring indicated completion of the reaction. 6N hydrochloric acid was added to the reaction solution to adjust the pH to 6-7. 10 mL of water was added, and the solution was extracted with ethyl acetate three times, 5 mL each. The organic phases were combined, the solvent was evaporated, and then purified by flash liquid column chromatography. The product, N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (31.4) (53 mg, 59.1% yield) was obtained.

[0247] 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).

[0248] N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (31.4) (53 mg, 120.117 μmol) was separated by supercritical fluid chromatography to obtain compound (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) (10 mg, yield 20.0%). 1 H NMR(400MHz, CDCl3)δ8.20(s,1H),7.42(dd,J=9.4,7.0Hz,1H),7.25(dd,J=9.5,6.0Hz,2H),6.74(s,1H),5.76(dt,J=56.5,4.5Hz,1H),2 .84(d,J=14.2Hz,1H),2.72(dd,J=15.1,5.3Hz,1H),2.49-2.58(m,2H),2.22-2.27(m,1H),2.05-2.10(m,1H).MS(m / z):439.0,441.0[MH] -

[0249] Example 32: 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 (32)

[0250] N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (31.4) (53 mg, 120.117 μmol) was separated by supercritical fluid chromatography to obtain compound (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 (32) (10 mg, yield 20.0%). 1H NMR (400MHz, DMSO-d6) δ10.94(s,1H),9.64(d,J=11.4Hz,1H),7.14-7.26(m,2H),7.00(dd,J=12.9,3.0Hz,1H),5.54- 5.88(m,1H),2.72(s,1H),2.55-2.62(m,1H),2.36-2.41(m,2H),2.07(s,1H),1.89(s,1H).MS(m / z):439.0,441.0[MH] -

[0251] 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)

[0252] Step 1: Synthesis of 6-methoxy-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (33.1)

[0253] Dissolve 1-(p-Toluenesulfonyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-6-ol (23.7 g) (0.800 g, 2.226 mmol) in N,N-dimethylformamide (10 mL). Slowly add iodomethane (475 mg, 3.347 mmol) and NaH (108 mg, 2.700 mmol) while maintaining the reaction at 0°C. Maintain the reaction at 25°C for 1 hour. TLC monitoring indicates the reaction is complete. Pour the reaction solution into saturated ammonium chloride solution (100 mL), and extract the aqueous phase with 30 mL portions of ethyl acetate. Combine the organic phases and dry over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by flash liquid column chromatography to obtain the product 6-methoxy-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (33.1) (0.650 g, yield 78.2%).

[0254] 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)

[0255] The intermediate 6-methoxy-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (33.1) (0.650 g, 1.741 mmol) was separated by supercritical fluid chromatography to give 185 mg of the product (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).

[0256] 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)

[0257] Dissolve (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) (180 mg, 482.071 μmol) in acetonitrile (10 mL). Add chlorosulfonic acid (168 mg, 1.442 mmol) dropwise while maintaining the reaction at -40°C. After addition, maintain the reaction at 20°C for 30 minutes. TLC 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 75°C for 1 hour. LCMS monitoring indicates the reaction is complete. Cool the reaction solution to 20°C and slowly add dropwise to 150 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. The product (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) (210 mg, yield 92.3%) was obtained.

[0258] 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)

[0259] 5-Fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-amine (23.15) (50 mg, 237.949 μmol) was added to anhydrous pyridine (0.5 mL), followed by (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) (80 mg, 169.528 μmol). After the addition, the reaction was maintained at 115°C in a microwave oven for 1 hour. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to give the product (S)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-methoxy-1-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-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (33.4) (80 mg, yield 73.1%).

[0260] 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)

[0261] (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) (80 mg, 123.922 μmol) was added to a mixture of methanol (5 mL) and water (2 mL), and potassium carbonate (172 mg, 1.245 mmol) was added. After the addition was complete, the 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. The solvent was dried and the mixture was purified by flash liquid column chromatography to obtain the product (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) (20 mg, yield 32.8%). 1 H NMR (400MHz, DMSO-d6) δ11.40(s,1H),10.22(s,1H),7.60(d,J=11.6Hz,1H),7.46(d,J=2.9Hz,1H),3.87(s,3H),3.21 (s,3H),2.80(dt,J=16.7,11.9Hz,3H),2.48–2.41(m,1H),2.18(dd,J=13.1,4.2Hz,1H),1.79(td,J=12.8,6.0Hz,1H). MS(m / z):490.0[MH] - .

[0262] 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)

[0263] 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)

[0264] The intermediate 6-methoxy-1-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole (33.1) (0.650 g, 1.741 mmol) was separated by supercritical fluid chromatography to obtain 190 mg of the product (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).

[0265] 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)

[0266] (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) (0.190 g, 508.852 μmol) was dissolved in acetonitrile (5 mL). Chlorosulfonic acid (178 mg, 1.528 mmol) was added dropwise while maintaining the reaction at -40°C. After the addition, the reaction was maintained at -40°C for 30 minutes. TLC monitoring indicated that the reaction was complete. The 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. The product (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) (0.190 g, yield 79.1%) was obtained.

[0267] 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)

[0268] 5-Fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-amine (23.15) (43 mg, 204.636 μmol) was added to anhydrous pyridine (0.5 mL), followed by (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) (80 mg, 169.528 μmol). After the addition, the reaction was maintained at 120°C in a microwave oven for 1.5 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to give the product (S)-N-(5-fluoro-2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6-methoxy-1-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-toluenesulfonyl-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-3-sulfonamide (34.3) (0.060 g, yield 54.8%).

[0269] 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)

[0270] (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) (0.060 g, 92.942 μmol) was added to a mixture of methanol (10 mL) and water (5 mL). Potassium carbonate (129 mg, 933.389 μmol) was added. After the addition was complete, the reaction was maintained at 80°C for 1 hour. LCMS monitoring showed the reaction was complete. The reaction mixture was cooled to 20°C and the pH value of the mixture was adjusted to 5-6 by adding 2N dilute hydrochloric acid. The aqueous phase was 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 filtration, the filtrate was dried and purified by rapid liquid column chromatography. The product (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) (0.023 g, yield 50.4%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.41(s,1H),10.22(s,1H),7.61(d,J=11.6Hz,1H),7.46(d,J=3.0Hz,1H),3.87(s,3H),3.21 (s,3H),2.80(dt,J=16.6,11.9Hz,3H),2.47–2.40(m,1H),2.18(dd,J=13.7,5.2Hz,1H),1.79(td,J=13.1,6.1Hz,1H). MS(m / z):490.0[MH] - .

[0271] Examples 035 and 036 were prepared according to the above method.

[0272] Example 37: Synthesis of 6-chloro-N-(5-fluoro-2-(methoxy-d3)-4-(trifluoromethyl)phenyl)-7-hydroxypyrazolo[1,5-a]pyridine-3-sulfonamide (37)

[0273] Step 1: Synthesis of 4-fluoro-2-nitro-5-(trifluoromethyl)phenol (37.2)

[0274] 4-Fluoro-3-(trifluoromethyl)phenol (23.000 g, 127.707 mmol) was added to acetic acid (200 mL). A solution of nitric acid (9.657 g, 153.249 mmol) in acetic acid (25 mL) was slowly added while maintaining the reaction at 0°C. The reaction was maintained at 26°C for 4 hours. TLC monitoring indicated the reaction was complete. The reaction solution was slowly poured into 500 mL of ice water and extracted with four 100 mL portions of dichloromethane. The organic phases were combined and washed with saturated brine. After drying over anhydrous sodium sulfate, the organic phase was concentrated and purified by flash liquid column chromatography. The product, 4-fluoro-2-nitro-5-(trifluoromethyl)phenol (37.2) (25.530 g, 88.8% yield) was obtained.

[0275] Step 2: Synthesis of 2-amino-4-fluoro-5-(trifluoromethyl)phenol (37.3)

[0276] 4-Fluoro-2-nitro-5-(trifluoromethyl)phenol (37.2) (25.530 g, 113.418 mmol) was added to methanol (30 mL), followed by the addition of 10% palladium on carbon (1.891 g). The reaction was maintained under hydrogen at 55 ° C for 16 hours. LCMS monitoring showed that the reaction was complete. The reaction solution was filtered, the filtrate was collected and the filtrate was dried. Purification was performed by flash liquid column chromatography. The product 2-amino-4-fluoro-5-(trifluoromethyl)phenol (37.3) (2.000 g, yield 57.7%) was obtained.

[0277] Step 3: Synthesis of 5-fluoro-2-(methoxy-d3)-4-(trifluoromethyl)aniline (37.4)

[0278] 2-Amino-4-fluoro-5-(trifluoromethyl)phenol (37.3) (2.000 g, 10.250 mmol) was added to N,N-dimethylformamide (25 mL), followed by potassium carbonate (2.125 g, 15.376 mmol) and deuterated iodomethane (1.634 g, 11.275 mmol). The reaction was maintained at 26°C for 12 hours. LCMS monitoring indicated completion of the reaction. The reaction solution was poured into 60 mL of saturated sodium bicarbonate aqueous solution, and the aqueous phase was extracted with 30 mL portions of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The product was then purified by flash liquid column chromatography to obtain 5-fluoro-2-(methoxy-d3)-4-(trifluoromethyl)aniline (37.4) (350 mg, 16.1% yield).

[0279] Step 4: Synthesis of 6,7-dichloropyrazolo[1,5-a]pyridine (37.6)

[0280] 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. Subsequently, 60mL of water was added, and the system was extracted with ethyl acetate three times in 30mL increments. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The product was purified by flash liquid chromatography. The product 6,7-dichloropyrazolo[1,5-a]pyridine (37.6) (2.120 g, yield 86.5%) was obtained.

[0281] Step 5: Synthesis of 6,7-dichloropyrazolo[1,5-a]pyridine-3-sulfonyl chloride (37.7)

[0282] Dissolve 6,7-dichloropyrazolo[1,5-a]pyridine (37.6 g) (2.120 g, 11.335 mmol) in acetonitrile (20 mL) and add chlorosulfonic acid (5 mL) dropwise while maintaining the reaction at 0°C. After addition, maintain the reaction at 26°C for 1.5 hours. TLC monitoring indicates the reaction is complete. After the reaction solution is dried by vortexing, add thionyl chloride (10 mL) while maintaining the reaction at 0°C. After addition, maintain the reaction at 75°C for 2 hours. TLC monitoring indicates the reaction is complete. Cool the reaction solution to 20°C and slowly add dropwise to 50 g of crushed ice. Extract the aqueous phase with 20 mL of ethyl acetate three times. Combine the organic phases, dry over anhydrous sodium sulfate, vortex to dryness, and purify by flash liquid chromatography. The product 6,7-dichloropyrazolo[1,5-a]pyridine-3-sulfonyl chloride (37.7 g) was obtained (1.300 g, yield 40.2%).

[0283] 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)

[0284] 5-Fluoro-2-(methoxy-d3)-4-(trifluoromethyl)aniline (37.4) (246 mg, 1.160 mmol) was dissolved in anhydrous pyridine (3 mL), and 6,7-dichloropyrazolo[1,5-a]pyridine-3-sulfonyl chloride (37.7) (300 mg, 1.051 mmol) was added. After the addition, the reaction was maintained at 80°C for 2 hours. TLC monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid chromatography. The product, 6,7-dichloro-N-(5-fluoro-2-(methoxy-d3)-4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-3-sulfonamide (37.8) (240 mg, 49.5% yield), was obtained.

[0285] Step 7: Synthesis of 6-chloro-N-(5-fluoro-2-(methoxy-d3)-4-(trifluoromethyl)phenyl)-7-hydroxypyrazolo[1,5-a]pyridine-3-sulfonamide (37)

[0286] 6,7-Dichloro-N-(5-fluoro-2-(methoxy-d3)-4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-3-sulfonamide (37.8) (100 mg, 216.810 μmol) was added to tert-butanol (10 mL), followed by sodium hydroxide (44 mg, 1.100 mmol). After the addition, the reaction was maintained at 130°C in a microwave oven for 6 hours. LCMS monitoring showed that the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography. The product 6-chloro-N-(5-fluoro-2-(methoxy-d3)-4-(trifluoromethyl)phenyl)-7-hydroxypyrazolo[1,5-a]pyridine-3-sulfonamide (37) (30 mg, yield 31.3%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ7.69(s,1H),7.08(d,J=8.8Hz,1H),6.85(d,J=15.5Hz,1H),6.66(d,J=7.7Hz,1H),6.45(d,J=8.8Hz,1H).MS(m / z):442.7[M+H] +

[0287] Example 38: Preparation of N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (38)

[0288] Step 1: Synthesis of 6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-ol (38.1)

[0289] Dissolve 1-p-Toluenesulfonyl-1,4,5,7-tetrahydro-6H-indol-6-one (23.6) (2.000 g, 6.912 mmol) in N,N-dimethylformamide (30 mL). Maintain the reaction at 0°C under N2 protection, add cesium fluoride (1.325 g, 20.045 mmol) and (difluoromethyl)trimethylsilane (2.490 g, 20.045 mmol). Maintain the reaction at 25°C for 15 hours. TLC analysis indicates the reaction is complete. Add the reaction solution to 150 mL of water and extract the reaction system with ethyl acetate three times, 50 mL each. Collect and combine the organic phases. Dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate the filtrate. The residue was then purified by flash liquid column chromatography to give the product 6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-ol (38.1) (0.350 g, yield 14.8%).

[0290] Step 2: Synthesis of 6-(difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole (38.2)

[0291] 6-(Difluoromethyl)-1-(p-Toluenesulfonyl)-5,7-dihydro-4H-indol-6-ol (38.1) (0.350 g, 1.025 mmol) was dissolved in N,N-dimethylformamide (10 mL). Deuterated iodomethane (446 mg, 3.077 mmol) and NaH (102 mg, 2.550 mmol, 60% purity) were slowly added while maintaining the reaction at 0°C. The reaction was maintained at 25°C for 15 hours. TLC monitoring indicated the reaction was complete. The reaction solution was poured into water (50 mL) and the aqueous phase was extracted with ethyl acetate three times, 10 mL each. 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-(difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole (38.2) (0.350 g, yield 95.2%).

[0292] Step 3: Synthesis of 6-(difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonyl chloride (38.3)

[0293] 6-(Difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole (38.2) (0.350 g, 976.515 μmol) was dissolved in acetonitrile (10 mL). Chlorosulfonic acid (340 mg, 2.918 mmol) was added dropwise while maintaining the reaction at -40°C. After the addition, the reaction was maintained at -40°C for 1 hour. TLC monitoring indicated the reaction was complete. The 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 60°C for 1 hour. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to 20°C and slowly added dropwise to 50 g of crushed ice. The aqueous phase was extracted with 10 mL of ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, spun dry, and purified by flash liquid chromatography. The product 6-(difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonyl chloride (38.3) was obtained (0.320 g, yield 64.0%).

[0294] 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)

[0295] 4-Bromo-2,5-difluoroaniline (320 mg, 1.538 mmol) was added to anhydrous pyridine (5 mL), followed by 6-(difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonyl chloride (38.3) (0.350 g, 765.988 μmol). After addition, the reaction was maintained at 80°C in a microwave oven for 1 hour. TLC monitoring indicated the reaction was complete. The 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).

[0296] Step 5: Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (38)

[0297] 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 μmol) 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. The 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%). 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),10.06(s,1H),7.69(dd,J=9.6,6.5Hz,1H),7.27–7.17(m,2H),6.11(t,J=55.0Hz,1H),2. 65(q,J=16.6Hz,3H),2.35(dd,J=18.6,8.3Hz,1H),2.09–2.00(m,1H),1.58(td,J=13.3,6.1Hz,1H).MS(m / z):472.0;474.0[MH] - .

[0298] 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)

[0299] 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)

[0300] 4-Chloro-2,5-difluoroaniline (60 mg, 366.855 μmol) was added to anhydrous pyridine (0.5 mL), followed by (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) (60 mg, 126.338 μmol). After addition, the reaction was maintained at 110°C in a microwave oven for 1 hour. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to obtain the product (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) (60 mg, yield 78.9%).

[0301] Step 2: Synthesis 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)

[0302] (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) (60 mg, 99.666 μmol) was added to a mixture of methanol (5 mL) and water (2 mL). Potassium carbonate (137 mg, 991.274 μmol) was added. After addition, the reaction was maintained at 80°C for 1 hour. TLC monitoring indicated that the reaction was complete. The reaction temperature was lowered to 20°C, and 2N dilute hydrochloric acid was then added to adjust the pH of the system to 3-6. After the solvent was dried, the product was purified by flash liquid column chromatography to obtain (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) (30 mg, yield 67.2%). 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),10.07(s,1H),7.63(dd,J=9.8,6.9Hz,1H),7.31–7.15(m,2H),2.82(dd,J=35.0,16.6Hz,2H),2. 68(dd,J=16.5,4.7Hz,1H),2.44–2.33(m,1H),2.15(dt,J=14.3,7.1Hz,1H),1.76(td,J=12.8,6.2Hz,1H).MS(m / z):446.0;448.0[MH] - .

[0303] 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)

[0304] 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)

[0305] 4-Iodo-2,5-difluoroaniline (90 mg, 352.937 μmol) was added to anhydrous pyridine (0.5 mL), followed by (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 mg) (60 mg, 126.338 μmol). After addition, the reaction was maintained at 110°C in a microwave oven for 1 hour. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to obtain the product (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) (60 mg, yield 68.5%).

[0306] 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)

[0307] (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) (60 mg, 86.523 μmol) was added to a mixture of methanol (10 mL) and water (2 mL). Potassium carbonate (24 mg, 173.654 μmol) was added. After addition, 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, and 2N dilute hydrochloric acid was added to adjust the pH to 3-6. After the solvent was dried, the product was purified by flash liquid column chromatography to obtain the product (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) (39 mg, yield 83.6%). 1 H NMR (400MHz, DMSO-d6) δ11.33(s,1H),10.06(s,1H),7.71(dd,J=9.4,5.8Hz,1H),7.23(d,J=3.0Hz,1H),7.13(dd,J=9.2,6.7Hz,1H ),2.81(dd,J=32.7,16.4Hz,2H),2.72–2.62(m,1H),2.45–2.33(m,1H),2.21–2.11(m,1H),1.81–1.69(m,1H).MS(m / z):537.9[MH] - .

[0308] 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)

[0309] N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (38) (0.150 g, 316.267 μmol) 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%). 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),10.05(s,1H),7.69(dd,J=9.6,6.4Hz,1H),7.27–7.15(m,2H),6.11(t,J=55.0Hz,1H) ,2.72–2.56(m,3H),2.40–2.31(m,1H),2.07–2.00(m,1H),1.58(ddd,J=18.0,12.4,6.0Hz,1H).MS(m / z):472.0;474.0[MH] - .

[0310] 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)

[0311] N-(4-bromo-2,5-difluorophenyl)-6-(difluoromethyl)-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (38) (0.150 g, 316.267 μmol) 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%). 1H NMR (400MHz, DMSO-d6) δ11.29(s,1H),10.05(s,1H),7.69(dd,J=9.6,6.5Hz,1H),7.28–7.14(m,2H),6.11(t,J=54 .9Hz,1H),2.71–2.56(m,3H),2.40–2.31(m,1H),2.07–1.99(m,1H),1.63–1.53(m,1H).MS(m / z):472.0;474.0[MH] - .

[0312] 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)

[0313] Step 1: Synthesis of 1-bromo-4-(difluoromethoxy)-2,5-difluorobenzene (43.1)

[0314] 4-Bromo-2,5-difluorophenol (4.000 g, 19.140 mmol) was added to N,N-dimethylformamide (60 mL), followed by cesium carbonate (12.472 g, 38.280 mmol) and sodium difluorochloroacetate (4.377 g, 28.710 mmol). After addition, the reaction was maintained at 100°C for 2 hours. TLC monitoring indicated completion of the reaction. The reaction solution was filtered, and the organic phase was collected. Water (100 mL) was added to the filtrate, followed by extraction with ethyl acetate (3 times, 60 mL each). 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 afforded the product, 1-bromo-4-(difluoromethoxy)-2,5-difluorobenzene (43.1 g) (3.600 g, 72.6% yield).

[0315] Step 2: Synthesis of tert-butyl N-[4-(difluoromethoxy)-2,5-difluorophenyl]carbamate (43.2)

[0316] 1-Bromo-4-(difluoromethoxy)-2,5-difluorobenzene (43.1) (3.600 g, 13.900 mmol) was added to 1,4-dioxane (50 mL), followed by cesium carbonate (13.587 g, 41.700 mmol), Xant-Phos (1.609 g, 2.780 mmol), BocNH2 (2.442 g, 20.850 mmol), and Pd2(DBA)3 (1.273 g, 1.390 mmol). After the addition was complete, the reaction was maintained at 100°C under nitrogen for 12 hours. TLC monitoring indicated the reaction was complete. The 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%).

[0317] Step 3: Synthesis of 4-(difluoromethoxy)-2,5-difluoroaniline (43.3)

[0318] Tert-butyl N-[4-(difluoromethoxy)-2,5-difluorophenyl]carbamate (43.2) (0.260 g, 880.671 μmol) was added to dichloromethane (10 mL), followed by trifluoroacetic acid (800 mg, 7.016 mmol). After addition, the reaction was maintained at 25°C for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was concentrated and purified by flash liquid chromatography to obtain the product, 4-(difluoromethoxy)-2,5-difluoroaniline (43.3) (130 mg, 75.7% yield).

[0319] 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)

[0320] 4-(Difluoromethoxy)-2,5-difluoroaniline (43.3) (68 mg, 348.514 μmol) 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) (80 mg, 168.451 μmol). After the addition, the reaction was maintained at 110°C in a microwave oven for 1.5 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to obtain the product (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) (101 mg, yield 94.6%).

[0321] 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)

[0322] (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) (101 mg, 159.414 μmol) was added to a mixture of methanol (10 mL) and water (1 mL). Potassium carbonate (237 mg, 1.715 mmol) was added. After addition, 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 2N dilute hydrochloric acid was added to adjust the pH to 3-4. The system was extracted by adding 10 mL of ethyl acetate four times. The organic phases were collected and combined, the solvent was dried, and then purified by flash liquid column chromatography. The product (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) (21 mg, yield 27.5%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),9.92(s,1H),7.45–6.99(m,4H),2.82(dd,J=37.1,16.7Hz,2H ),2.69–2.60(m,1H),2.43–2.31(m,1H),2.22–2.09(m,1H),1.83–1.69(m,1H).MS(m / z):480.0[M+H] + .

[0323] 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)

[0324] 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)

[0325] 4-(Difluoromethoxy)-2,5-difluoroaniline (43.3) (62 mg, 317.763 μmol) was added to anhydrous pyridine (0.5 mL), followed by (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) (100 mg, 210.563 μmol). After the addition, the reaction was maintained at 110°C in a microwave oven for 1.5 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to obtain the product (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) (101 mg, yield 75.7%).

[0326] 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)

[0327] (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) (90.000 mg, 142.052 μmol) was added to a mixture of methanol (5 mL) and water (0.5 mL), and potassium carbonate (197 mg, 1.425 mmol) was added. After the addition was complete, the reaction was maintained at 80°C for 1 hour. LCMS monitoring showed that the reaction was complete. The 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. The product (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) (38 mg, yield 55.8%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),9.91(s,1H),7.39(t,J=8.8Hz,1H),7.24–6.84(m,3H),2.82(dd,J=36.3, 16.5Hz,2H),2.70–2.60(m,1H),2.43–2.35(m,1H),2.20–2.12(m,1H),1.80–1.68(m,1H).MS(m / z):480.0[M+H] + .

[0328] 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)

[0329] Step 1: Synthesis of tert-butyl N-[4-(trifluoromethoxy)-2,5-difluorophenyl]carbamate (45.1)

[0330] 1-Bromo-4-(trifluoromethoxy)-2,5-difluorobenzene (2.000 g, 7.221 mmol) was added to 1,4-dioxane (30 mL), followed by cesium carbonate (7.058 g, 21.662 mmol), Xant-Phos (836 mg, 1.445 mmol), BocNH2 (1.269 g, 10.831 mmol), and Pd2(DBA)3 (661 mg, 721.840 μmol). After the addition, the reaction was maintained at 100°C under N2 protection for 12 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was filtered, and the filtrate was collected and concentrated, then purified by flash liquid chromatography to obtain the product, tert-butyl N-[4-(trifluoromethoxy)-2,5-difluorophenyl]carbamate (45.1 g) (2.000 g, 88.4% yield).

[0331] Step 2: Synthesis of 4-(trifluoromethoxy)-2,5-difluoroaniline (45.2)

[0332] Tert-butyl N-[4-(trifluoromethoxy)-2,5-difluorophenyl]carbamate (45.1) (2.000 g, 6.385 mmol) was added to dichloromethane (20 mL), followed by trifluoroacetic acid (7.281 g, 63.853 mmol). After addition, the reaction was maintained at 20°C for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was concentrated and purified by flash liquid chromatography to obtain the product, 4-(trifluoromethoxy)-2,5-difluoroaniline (45.2) (450 mg, 33.1% yield).

[0333] 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)

[0334] 4-(Trifluoromethoxy)-2,5-difluoroaniline (45.2) (84 mg, 394.173 μmol) 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) (110 mg, 231.620 μmol). After the addition, the reaction was maintained at 110°C in a microwave oven for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and then purified by flash liquid column chromatography to obtain the product (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) (80 mg, 122.782 μmol, yield 53.0%).

[0335] 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)

[0336] (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) (80 mg, 122.782 μmol) was added to a mixture of methanol (10 mL) and water (1 mL). Potassium carbonate (170 mg, 1.230 mmol) was added. After addition, the reaction was maintained at 80°C for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction temperature was lowered to 20°C, and 2N dilute hydrochloric acid was then added to adjust the pH to 3-4. The system was extracted by adding 10 mL of ethyl acetate in a total of 5 mL each time. The organic phases were collected and combined, the solvent was dried, and then purified by flash liquid column chromatography. The product (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) (5 mg, yield 8.2%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.25(s,1H),10.17(s,1H),7.60(s,1H),7.28(dd,J=28.9,18.9Hz,2H),2.82(dd,J=36. 2,16.4Hz,2H),2.65–2.59(m,1H),2.42–2.38(m,1H),2.18–2.09(m,1H),1.79–1.70(m,1H).MS(m / z):496.1[MH] - .

[0337] Example 46: 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 (46)

[0338] Step 1: Synthesis of 6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (46.1)

[0339] 1-(p-Toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indol-6-ol (23.7g) (1.000g, 2.783mmol) was dissolved in acetonitrile (30mL). Chlorosulfonic acid (1000mg, 8.582mmol) was added dropwise while maintaining the reaction at -40°C. After addition, the temperature was slowly raised to 20°C and the reaction was allowed to react for a total of 30 minutes. TLC monitoring indicated the reaction was complete. The reaction solution was spin-dried to dryness, and dichloromethane (30mL) was added to the system. Oxalyl chloride (3.533g, 27.832mmol) and N,N-dimethylformamide (203mg, 2.777mmol) were added while maintaining the reaction at 0°C. After addition, the reaction was maintained at 20°C for 1 hour. LCMS monitoring indicated the reaction was complete. The reaction solution was concentrated and purified by flash liquid chromatography. The product 6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (46.1) was obtained (1.100 g, yield 86.3%).

[0340] 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)

[0341] 4-Bromo-2,5-difluoroaniline (900 mg, 4.327 mmol) was added to anhydrous pyridine (7 mL), followed by 6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (46.1) (1.100 g, 2.402 mmol). After the addition, the reaction was maintained at 100°C in a microwave oven for 1 hour. LCMS monitoring indicated the reaction was complete. The 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).

[0342] 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)

[0343] N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (46.2) (1.300 g, 2.065 mmol) was subjected to supercritical fluid chromatography to obtain the product (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) (600 mg, yield 46.2%).

[0344] 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)

[0345] (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) (600 mg, 953.268 μmol) was added to a mixture of methanol (20 mL) and water (10 mL). Potassium carbonate (1.317 g, 9.533 mmol) was added. The reaction was maintained at 80°C for 3 hours. LCMS monitoring indicated the reaction was complete. The reaction temperature was lowered to 20°C, and the pH of the system was adjusted to 4-6 by adding 2N dilute hydrochloric acid. The reaction system was extracted with ethyl acetate three times, 20 mL each. After collecting and combining the organic phases, the organic phases were dried over anhydrous magnesium sulfate. After filtering and drying the filtrate, the product was purified by flash liquid column chromatography. The product (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) (300 mg, yield 66.2%) was obtained. 1H NMR (400MHz, DMSO-d6) δ11.33(s,1H),10.17(s,1H),7.69(dd,J=9.7,6.5Hz,1H),7.33–7.20(m,2H),5.9 6(s,1H),2.83–2.52(m,4H),1.99–1.87(m,1H),1.63(td,J=12.6,5.9Hz,1H).MS(m / z):473.0;475.0[MH] - .

[0346] Example 47: Preparation of N-(4-bromo-2,5-difluorophenyl)-6,6-bis(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (47)

[0347] Step 1: Synthesis of 6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbaldehyde (47.1)

[0348] Dissolve 1-p-Toluenesulfonyl-4,5,6,7-tetrahydro-1H-indole-6-carbaldehyde (25.9 g) (1.000 g, 3.296 mmol) in tetrahydrofuran (20 mL) and add a 1M solution of potassium tert-butoxide in tetrahydrofuran (1M, 9.889 mL). After addition, maintain the reaction under difluorochloromethane at 20°C for 16 hours. LCMS monitoring indicates product formation. Pour the reaction solution into 100 mL of saturated ammonium chloride solution and extract the solution with ethyl acetate four times, 40 mL each. Collect and combine the organic phases. The organic phase was then dried over anhydrous magnesium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated and purified by flash liquid column chromatography to obtain the product 6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbaldehyde (47.1) (200 mg, yield 17.2%).

[0349] Step 2: Synthesis of 6,6-bis(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole (47.2)

[0350] 6-(Difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbaldehyde (47.1) (220 mg, 622.554 μmol) was dissolved in dichloromethane (20 mL). Diethylaminosulfur trifluoride (1.505 g, 9.338 mmol) was added dropwise while maintaining the reaction at 0°C. After addition, the reaction was maintained at 20°C for 72 hours. LCMS monitoring indicated completion of the reaction. The reaction solution was slowly poured into 60 mL of saturated sodium carbonate solution and then extracted with ethyl acetate three times with 30 mL portions. The organic phases were collected and combined. The organic phases were then concentrated and purified by flash liquid chromatography to afford 6,6-bis(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole (47.2) (130 mg, 55.6% yield) as a pale yellow oil.

[0351] Step 3: Synthesis of 6,6-bis(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (47.3)

[0352] 6,6-Bis(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole (47.2) (130 mg, 346.315 μmol) was dissolved in acetonitrile (10 mL). Chlorosulfonic acid (130 mg, 1.116 mmol) was then added while maintaining the temperature at -40°C. After the addition, the reaction was maintained at -40°C for 30 minutes. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated. Thionyl chloride (4 mL) was then added while maintaining the temperature at 0°C. After the addition, the reaction was maintained at 80°C for 1 hour. LCMS monitoring indicated the reaction was complete. The 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%).

[0353] 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)

[0354] 4-Bromo-2,5-difluoroaniline (100 mg, 480.762 μmol) was dissolved in anhydrous pyridine (1 mL), followed by the addition of 6,6-bis(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonyl chloride (47.3) (130 mg, 274.326 μmol). After the addition, the reaction was maintained at 110° in a microwave oven for 1 hour. LCMS monitoring indicated the reaction was complete. The reaction solution was concentrated and purified by flash liquid chromatography. The product, N-(4-bromo-2,5-difluorophenyl)-6,6-bis(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (47.4) (140 mg, 79.1% yield) was obtained.

[0355] Step 5: Synthesis of N-(4-bromo-2,5-difluorophenyl)-6,6-bis(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (47)

[0356] 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 μmol) 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. The reaction system was extracted with ethyl acetate three times, 20 mL each. The organic phases were collected and combined, 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)-6,6-bis(difluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (47) was obtained (65 mg, yield 61.0%). 1 H NMR (400MHz, DMSO-d6) δ11.38(s,1H),10.03(s,1H),7.69(dd,J=9.6,6.4Hz,1H),7.29–7.16(m,2H),6.08 (t,J=54.4Hz,2H),2.67(s,2H),2.56(t,J=5.9Hz,2H),1.85(t,J=6.2Hz,2H).MS(m / z):489.0;491.0[MH] -

[0357] 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)

[0358] Step 1: Synthesis of (S)-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (48.1)

[0359] 2,5-Difluoro-4-(trifluoromethyl)aniline (83 mg, 421.095 μmol) was added to anhydrous pyridine (0.5 mL), followed by (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 mg) (100 mg, 210.563 μmol). After the addition, the reaction was maintained at 110°C in a microwave oven for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to give a yellow oily product (S)-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (48.1) (100 mg, yield 74.7%).

[0360] 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)

[0361] (S)-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (48.1) (60 mg, 94.405 μmol) was added to a mixture of methanol (10 mL) and water (5 mL). Potassium carbonate (140 mg, 1.013 mmol) was added. After addition, the reaction was maintained at 80°C for 2 hours. LCMS monitoring indicated that the reaction was complete. The reaction temperature was lowered to 20°C, and 2N dilute hydrochloric acid was added to adjust the pH of the system to 3-5. The system was extracted by adding 20 mL of ethyl acetate three times. The organic phases were collected and combined, the solvent was dried, and then purified by flash liquid column chromatography. The product (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) (27 mg, yield 59.4%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.27(s,1H),10.66(s,1H),7.59(s,1H),7.33(s,2H),2.77(dt,J=30.2,15.4 Hz,3H),2.47–2.39(m,1H),2.24–2.12(m,1H),1.76(ddd,J=11.4,9.4,4.0Hz,1H).MS(m / z):480.0[MH] - .

[0362] 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)

[0363] 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)

[0364] N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (46.2) (1.300 g, 2.065 mmol) was subjected to supercritical fluid chromatography to obtain the product (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) (600 mg, yield 46.2%).

[0365] 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)

[0366] (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) (600 mg, 953.268 μmol) was added to a mixture of methanol (20 mL) and water (10 mL). Potassium carbonate (1.317 g, 9.533 mmol) was added. The reaction was maintained at 80°C for 3 hours. LCMS monitoring indicated the reaction was complete. The reaction temperature was lowered to 20°C, and the pH of the system was adjusted to 5-6 by adding 2N dilute hydrochloric acid. The reaction system was extracted with ethyl acetate three times, 30 mL each. After collecting and combining the organic phases, the organic phases were dried over anhydrous sodium sulfate. After filtering and drying the filtrate, the product was purified by flash liquid column chromatography. The product (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) (0.210 g, yield 46.4%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.33(s,1H),10.17(s,1H),7.69(dd,J=9.7,6.5Hz,1H),7.30–7.21(m,2H),5.96(s,1H),2.79– 2.61(m,3H),2.59–2.52(m,1H),1.93(dd,J=12.8,4.6Hz,1H),1.63(td,J=12.3,5.8Hz,1H).MS(m / z):473.0;475.0[MH] - .

[0367] Example 50: Preparation of N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (50)

[0368] Step 1: Synthesis of 1-(p-toluenesulfonyl)-6-vinyl-5,7-dihydro-4H-indol-6-ol (50.1)

[0369] 1-(p-Toluenesulfonyl)-1,4,5,7-tetrahydro-6H-indol-6-one (23.6) (10.000 g, 34.560 mmol) was dissolved in tetrahydrofuran (180 mL). The reaction mixture was maintained at -40°C under N2 protection, and a solution of vinylmagnesium bromide in tetrahydrofuran (6.804 g, 51.841 mmol, 1 M) was added dropwise. After addition, the mixture was naturally warmed to 20°C and allowed to react for 16 hours. TLC analysis indicated the formation of the product. The reaction mixture 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).

[0370] Step 2: Synthesis of 1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-vinyl-5,7-dihydro-4H-indole (50.2)

[0371] Dissolve 1-(p-Toluenesulfonyl)-6-vinyl-5,7-dihydro-4H-indol-6-ol (50.1) (3.700 g, 11.657 mmol) in N,N-dimethylformamide (50 mL). Slowly add deuterated iodomethane (4.224 g, 29.143 mmol) and NaH (932 mg, 23.302 mmol, 60% purity) while maintaining the reaction at 0°C. Maintain the reaction at 20°C for 1 hour. TLC monitoring indicates the reaction is complete. Pour the reaction solution into saturated ammonium chloride solution (200 mL), and extract the aqueous phase with ethyl acetate three times, 50 mL each. Combine the organic phases and dry over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by flash liquid column chromatography to obtain the product 1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-vinyl-5,7-dihydro-4H-indole (50.2) (3.600 g, yield 92.339%).

[0372] Step 3: Synthesis of 1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-6-carbaldehyde (50.3)

[0373] Dissolve N-methylmorpholine oxide (700 mg, 5.975 mmol) in water (15 mL) and add K₂OsO₄.2H₂O (22 mg, 59.800 μmol). Maintain the reaction at 20°C for 1 h. Add a solution of 1-(p-toluenesulfonyl)-6-(methoxy-d₃)-6-vinyl-5,7-dihydro-4H-indole (50.2) (1000 mg, 2.990 mmol) in acetone (15 mL). Maintain the reaction at 50°C for 15 h. Lower the temperature to 20°C and add sodium periodate (705 mg, 3.296 mmol). Maintain the reaction at 20°C for 1 h. LCMS monitoring indicates the reaction is complete. Add water (50 mL) to the reaction mixture. Extract the reaction system with three 100 mL portions of dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, and purified by flash liquid column chromatography to obtain the product 1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-6-carbaldehyde (50.3) (800 mg, yield 15.9%).

[0374] Step 4: Synthesis of 1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-6-carbaldehyde oxime (50.4)

[0375] Dissolve 1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-6-carbaldehyde (50.3) (200 mg, 594.495 μmol) in ethanol (10 mL), add hydroxylamine hydrochloride (200 mg, 2.878 mmol) and sodium carbonate (300 mg, 2.830 mmol). After addition, maintain the reaction at 40°C for 1 hour. TLC monitoring indicates the reaction is complete. After filtration, the filtrate is concentrated to obtain the crude product, 1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-6-carbaldehyde oxime (50.4) (200 mg).

[0376] Step 5: Synthesis of 1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-6-carbonitrile (50.5)

[0377] 1-(p-Toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-6-carbaldehyde oxime (50.4) (200 mg, 569.096 μmol) was dissolved in tetrahydrofuran (10 mL) and carbonyldiimidazole (1000 mg, 6.167 mmol) was added. After the addition was complete, the reaction was maintained at 60°C for 2 hours. LCMS monitoring showed that the reaction was complete. The 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).

[0378] Step 6: Synthesis of 6-cyano-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonyl chloride (50.6)

[0379] Dissolve 1-(p-Toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-6-carbonitrile (50.5) (0.030 g, 89.977 μmol) in acetonitrile (5 mL). Add chlorosulfonic acid (30 mg, 257.458 μmol) while maintaining the temperature at -50°C. After addition, maintain the reaction at -50°C for 30 minutes. LCMS monitoring indicates the reaction is complete. The reaction solution is concentrated. Dichloromethane (5 mL), oxalyl chloride (114 mg, 898.160 μmol), and N,N-dimethylformamide (10 mg, 136.810 μmol) are added while maintaining the temperature at 0°C. After addition, maintain the reaction at 20°C for 1 hour. LCMS monitoring indicates the reaction is complete. Add the reaction solution to 20 g of crushed ice and extract the reaction system with three 20 mL portions of dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, and purified by flash liquid column chromatography to obtain the product 6-cyano-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonyl chloride (50.6) (20 mg, yield 51.5%).

[0380] 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)

[0381] 4-Bromo-2,5-difluoroaniline (20 mg, 96.152 μmol) was dissolved in anhydrous pyridine (0.5 mL), and 6-cyano-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonyl chloride (50.6) (20 mg, 46.304 μmol) was added. After the addition, the reaction was maintained at 100° in a microwave oven for 1 hour. LCMS monitoring showed that the reaction was complete. The reaction solution was concentrated and purified by flash liquid column chromatography. The product, N-(4-bromo-2,5-difluorophenyl)-6-cyano-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (50.7) (20 mg, 71.6% yield) was obtained.

[0382] Step 8: Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (50)

[0383] N-(4-bromo-2,5-difluorophenyl)-6-cyano-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (50.7) (20 mg, 33.142 μmol) 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 μmol). 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. The product, N-(4-bromo-2,5-difluorophenyl)-6-cyano-6-(methoxy-d3)-1,4,5,7-tetrahydroindole-3-sulfonamide (50) (8 mg, yield 53.7%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.39(s,1H),10.13(s,1H),7.66(dd,J=9.4,6.5Hz,1H),7.31–7.16(m,2H),3.20(d,J=15.6Hz,1H),2.85(d ,J=15.7Hz,1H),2.74–2.62(m,1H),2.59(dd,J=13.9,7.0Hz,1H),2.27–2.19(m,1H),2.06–1.97(m,1H).MS(m / z):447.0;449.0[MH] -

[0384] 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)

[0385] 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)

[0386] 4-(Trifluoromethoxy)-2,5-difluoroaniline (45.2) (90 mg, 422.328 μmol) was added to anhydrous pyridine (0.5 mL), followed by (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) (100 mg, 210.563 μmol). After the addition, the reaction was maintained at 110°C in a microwave oven for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to obtain the product (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) (100 mg, yield 72.9%).

[0387] 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)

[0388] (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) (100 mg, 153.478 μmol) was added to a mixture of methanol (10 mL) and water (5 mL). Potassium carbonate (220 mg, 1.592 mmol) was added. After addition, the 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 4-5 with saturated citric acid. The system was extracted by adding 20 mL of ethyl acetate three times. The organic phases were collected and combined, the solvent was dried, and then purified by flash liquid column chromatography. The product (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) (26 mg, yield 34.1%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),10.15(s,1H),7.56(s,1H),7.25(d,J=38.8Hz,2H),2.82(dd,J=37.1,17.2H z,2H),2.65–2.61(m,1H),2.44–2.36(m,1H),2.18–2.09(m,1H),1.74(td,J=12.0,6.4Hz,1H).MS(m / z):496.1[MH] - .

[0389] Example 52: Preparation of 6-chloro-N-(6-(3,3-difluorocyclobutyloxy)-5-fluoro-2-methoxypyridin-3-yl)pyrazolo[1,5-a]pyridine-3-sulfonamide (52)

[0390] Step 1: Synthesis of 3-fluoro-6-methoxy-5-nitropyridine-2-ol (52.1)

[0391] 2-Chloro-3-fluoro-6-methoxy-5-nitropyridine (1.8g) (500mg, 2.421mmol) was dissolved in tetrahydrofuran (5mL) and a solution of potassium hydroxide (340mg, 6.060mmol) in water (5mL) was added. After the addition was complete, the reaction was maintained at 20°C for 36 hours. LCMS monitored the reaction completion. 20mL of water was added to the reaction system, followed by extraction with 10mL of ethyl acetate. The aqueous phase was collected. 1N hydrochloric acid was then added to the aqueous phase to adjust the pH of the system to 1-3. The system was extracted with 10mL of dichloromethane five times. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product 3-fluoro-6-methoxy-5-nitropyridine-2-ol (52.1g) (250mg) was obtained.

[0392] Step 2: Synthesis of 2-(difluoromethoxy)-3-fluoro-6-methoxy-5-nitropyridine (52.2)

[0393] 3-Fluoro-6-methoxy-5-nitropyridine-2-ol (52.1) (150 mg, 797.393 μmol) was dissolved in water (0.5 mL). A solution of potassium hydroxide (450 mg, 8.021 mmol) and diethyl bromofluoromethylphosphonate (2.200 g, 8.240 mmol) in acetonitrile (2 mL) was then added while maintaining the reaction system at 50°C. The reaction was maintained at 50°C for 2 hours. TLC confirmed the reaction was complete. The reaction solution was concentrated, and 10 mL of water was added. Extraction was performed with ethyl acetate three times, 20 mL each time. The organic phases were collected and combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to yield the crude product, 2-(difluoromethoxy)-3-fluoro-6-methoxy-5-nitropyridine (52.2) (1.000 g).

[0394] Step 3: Synthesis of 6-(difluoromethoxy)-5-fluoro-2-methoxypyridin-3-amine (52.3)

[0395] 2-(Difluoromethoxy)-3-fluoro-6-methoxy-5-nitropyridine (52.2) (1.000g) was dissolved in acetic acid (10mL) and iron powder (2.345g, 41.996mmol) was added. After the addition was completed, the reaction was maintained at 20°C for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, 20mL of water was then added thereto, and the system was extracted with 20mL of ethyl acetate for a total of 3 times. The organic phases were collected and combined. After concentrating the organic phase, it was purified by flash liquid column chromatography. The product 6-(difluoromethoxy)-5-fluoro-2-methoxypyridine-3-amine (52.3) (60mg) was obtained.

[0396] 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)

[0397] 6-(Difluoromethoxy)-5-fluoro-2-methoxypyridin-3-amine (52.3) (60 mg, 288.271 μmol) 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 μmol). After the addition, the reaction was maintained at 110°C in a microwave oven for 1.5 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to give the product (S)-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-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-pyridyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (52.4) (60 mg, yield 49.0%).

[0398] 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)

[0399] (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) (60 mg, 92.794 μmol) was added to a mixture of methanol (10 mL) and water (2 mL). Potassium carbonate (150 mg, 1.085 mmol) was added. After the addition was complete, the reaction was maintained at 80°C for 2 hours. LCMS monitoring showed that the reaction was complete. The reaction solution was directly concentrated and then purified by flash liquid column chromatography to obtain the product (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) (27 mg, yield 59.1%). 1 H NMR(400MHz,DMSO-d6)δ11.23(s,1H),9.36(s,1H),7.82-7.46(m,2H),7.13(s,1H) ),3.72(s,3H),2.89–2.64(m,4H),2.19(s,1H),1.76(s,1H).MS(m / z):491.1[MH] - .

[0400] 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)

[0401] 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)

[0402] 2,5-Difluoro-4-(trifluoromethyl)aniline (65 mg, 329.773 μmol) 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 mg) (110 mg, 216.587 μmol). After addition, the reaction was maintained at 110°C in a microwave oven for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was dried by rotary evaporation and purified by flash liquid column chromatography to obtain (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) (70 mg, yield 48.3%).

[0403] Step 2: Synthesis 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)

[0404] (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) (70 mg, 104.708 μmol) was added to a mixture of methanol (10 mL) and water (5 mL). Potassium carbonate (150 mg, 1.085 mmol) was added. After addition, the reaction was maintained at 80°C for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction temperature was lowered to 20°C, and saturated citric acid was then added to adjust the pH to 3-4. The system was then extracted by adding 20 mL of ethyl acetate three times each. The organic phases were collected and combined, and the solvent was then dried and purified by rapid liquid column chromatography. The product (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) (30 mg, yield 55.7%) was obtained. 1 HNMR (400MHz, DMSO-d6) δ11.48(s,1H),10.73(s,1H),7.66(dd,J=9.9,6.8Hz,1H),7.46(d,J=2.4Hz,1H),7.35(dd,J=12.2,6.2Hz, 1H),6.99(t,J=71.8Hz,1H),3.01(q,J=16.8Hz,2H),2.88–2.72(m,1H),2.48–2.32(m,2H),2.05–1.91(m,1H).MS(m / z):513.1[MH] - .

[0405] 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)

[0406] Step 1: Synthesis of 5-fluoro-2-(methoxy-d3)-3-nitropyridine (54.1)

[0407] 5-Fluoro-3-nitropyridin-2(1H)-one (23.9g) (30.000g, 189.769mmol) was added to chloroform (500mL), followed by silver carbonate (100.0g, 362.654mmol) and deuterated iodomethane (275.0g, 1.897mol). The reaction was maintained at 20°C for 16 hours. TLC monitoring indicated the reaction was complete. Aqueous sodium carbonate solution (500mL) was added to the reaction solution, and the reaction was maintained at 20°C for 15 minutes. The reaction solution was filtered and extracted with two 200mL portions of ethyl acetate. The organic phases were combined and concentrated. Purification by flash liquid column chromatography afforded the product, 5-fluoro-2-(methoxy-d3)-3-nitropyridine (54.1g) (15.0g, 45.1% yield).

[0408] Step 2: Synthesis of 5-fluoro-2-(methoxy-d3)pyridin-3-amine (54.2)

[0409] 5-Fluoro-2-(methoxy-d3)-3-nitropyridine (54.1) (15.000 g, 85.650 mmol) was dissolved in methanol (250 mL) and 10% palladium on carbon (3.000 g) was added. The reaction was maintained at 50°C under H2 for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was filtered and the filtrate was dried to give the crude product 5-fluoro-2-(methoxy-d3)pyridin-3-amine (54.2) (12.2 g).

[0410] Step 3: Synthesis of 6-bromo-5-fluoro-2-(methoxy-d3)pyridin-3-amine (54.3)

[0411] 5-Fluoro-2-(methoxy-d3)pyridin-3-amine (54.2) (12.200 g, 84.051 mmol) was dissolved in N,N-dimethylformamide (120 mL), and N-bromosuccinimide (14.960 g, 84.051 mmol) was added portionwise. The reaction was maintained at 40°C for 30 minutes. LCMS monitoring showed that the reaction was complete. The reaction solution was poured into water (400 mL), and the aqueous phase was extracted with ethyl acetate four times with 100 mL each. The organic phases were combined, dried, and purified by flash liquid column chromatography to obtain the product 6-bromo-5-fluoro-2-(methoxy-d3)pyridin-3-amine (54.3) (12.00 g, 63.7% yield).

[0412] Step 4: Synthesis of N,N-bisbenzyl-6-bromo-5-fluoro-2-(methoxy-d3)pyridin-3-amine (54.4)

[0413] 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. The filtrate was concentrated and purified by flash liquid chromatography to obtain the product, N,N-bisbenzyl-6-bromo-5-fluoro-2-(methoxy-d3)pyridin-3-amine (54.4) (8.82 g, 62.7% yield).

[0414] Step 5: Synthesis of N,N-bisbenzyl-5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)pyridin-3-amine (54.5)

[0415] Dissolve N,N-bisbenzyl-6-bromo-5-fluoro-2-(methoxy-d3)pyridin-3-amine (54.4) (2.00 g, 4.947 mmol) in N,N-dimethylformamide (20 mL), and add methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.85 g, 14.835 mmol) and cuprous iodide (1.88 g, 9.871 mmol). After the addition, maintain the reaction at 100°C under nitrogen for 16 hours. LC-MS monitoring indicates the reaction is complete. Pour the reaction solution into water (60 mL), and extract the aqueous phase with three 30 mL portions of ethyl acetate. Combine the organic phases and concentrate. Purification by flash liquid column chromatography gave the product N,N-bisbenzyl-5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)pyridin-3-amine (54.5) (900 mg, yield 46.2%).

[0416] Step 6: Synthesis of 5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)pyridin-3-amine (54.6)

[0417] N,N-bisbenzyl-5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)pyridin-3-amine (54.5) (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%).

[0418] 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)

[0419] 5-Fluoro-2-(methoxy-d3)-6-(trifluoromethyl)pyridin-3-amine (54.6) (100 mg, 469.159 μmol) 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) (100 mg, 196.897 μmol). After the addition, the reaction was maintained at 130°C in a microwave oven for 1 hour. LCMS monitoring indicated the reaction was complete. The reaction solution was spin-dried and purified by flash liquid column chromatography to obtain the product (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) (80 mg, yield 59.4%).

[0420] 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)

[0421] (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) (80 mg, 116.862 μmol) was added to a mixture of methanol (2 mL) and water (1 mL), and potassium carbonate (161 mg, 1.165 mmol) was added. After the addition was complete, the reaction was maintained at 80°C for 1 hour. TLC monitoring showed that the reaction was complete. The reaction mixture was cooled to 20°C and 1N dilute hydrochloric acid was added to adjust the pH of the system to 4-6. The reaction mixture was concentrated and purified by flash liquid column chromatography and reverse phase column chromatography to obtain the product (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) (20 mg, yield 32.3%). 1 H NMR (400MHz, DMSO-d6) δ11.50(s,1H),10.29(s,1H),7.55(dd,J=19.4,7.3Hz,2H),7.00(t,J=71.9Hz,1H ),3.00(q,J=17.0Hz,2H),2.89–2.79(m,1H),2.47–2.39(m,2H),2.05–1.93(m,1H).MS(m / z):529.0[MH] - .

[0422] Example 55: Preparation 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)

[0423] Step 1: Synthesis of 1,4-difluoro-2-nitro-5-vinylbenzene (55.1)

[0424] 1-Bromo-2,5-difluoro-4-nitrobenzene (5.000 g, 21.010 mmol) was added to 1,4-dioxane (80 mL), followed by potassium carbonate (8.711 g, 63.029 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (6.472 g, 42.019 mmol), Pd(dppf)Cl2 (1.537 g, 2.101 mmol), and water (10 mL). After the addition, the reaction was maintained at 100°C under nitrogen for 2 hours. TLC monitoring indicated the reaction was complete. The reaction solution was filtered, and the filtrate was collected and concentrated. The filtrate was then purified by flash liquid chromatography to obtain the product, 1,4-difluoro-2-nitro-5-vinylbenzene (55.1 g) (3.100 g, 79.7% yield).

[0425] Step 2: Synthesis of 1-(2,2-difluorocyclopropyl)-2,5-difluoro-4-nitrobenzene (55.2)

[0426] 1,4-difluoro-2-nitro-5-vinylbenzene (55.1) (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, TMSCF3 (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. After the reaction solution was concentrated, it was 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%).

[0427] Step 3: Synthesis of 4-(2,2-difluorocyclopropyl)-2,5-difluoroaniline (55.3)

[0428] 1-(2,2-difluorocyclopropyl)-2,5-difluoro-4-nitrobenzene (55.2) (250 mg, 1.063 mmol) was dissolved in acetic acid (3 mL) and iron powder (600 mg, 10.744 mmol) was added. After the addition was complete, the reaction was maintained at 20°C for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was poured into 50 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate three times with 20 mL each. The organic phases were collected and combined. The organic phases were then concentrated and purified by flash liquid column chromatography. The product 4-(2,2-difluorocyclopropyl)-2,5-difluoroaniline (55.3) (180 mg, yield 82.5%) was obtained.

[0429] 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)

[0430] 4-(2,2-Difluorocyclopropyl)-2,5-difluoroaniline (55.3) (50 mg, 243.722 μmol) was added to anhydrous pyridine (0.5 mL), followed by (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) (50 mg, 105.282 μmol). After the addition, the reaction was maintained at 100°C in a microwave oven for 1 hour. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to obtain the product (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) (60 mg, yield 88.5%).

[0431] 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)

[0432] (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) (60 mg, 93.224 μmol) was added to a mixture of methanol (2 mL) and water (1 mL). Potassium carbonate (129 mg, 933.389 μmol) was added. After the addition was complete, the reaction was maintained at 80°C for 1 hour. LCMS monitoring showed the reaction was complete. The reaction system temperature was lowered to 20°C, 5 mL of water was added, and the pH value of the system was adjusted to 4-6 with 2N dilute hydrochloric acid. The reaction solution was extracted with 10 mL of ethyl acetate three times. After collecting and combining the organic phases, the organic phases were concentrated and purified by flash liquid column chromatography and reverse phase column chromatography. The product (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) (8 mg, yield 17.5%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.27(s,1H),9.92(s,1H),7.27–7.01(m,3H),2.99–2.73(m,3H),2.69–2.61(m,1H),2.45–2.35(m ,1H),2.14(dd,J=13.7,4.9Hz,1H),2.00(ddd,J=18.2,10.0,5.7Hz,2H),1.74(tt,J=11.6,5.7Hz,1H).MS(m / z):488.1[MH] - .

[0433] 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)

[0434] 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)

[0435] 6-(Difluoromethoxy)-5-fluoro-2-methoxypyridin-3-amine (52.3) (43 mg, 206.742 μmol) 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 μmol). After the addition, the reaction was maintained at 110°C in a microwave oven for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to give the product (S)-6-(difluoromethoxy)-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (56.1) (50 mg, yield 53.4%).

[0436] 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)

[0437] (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) (60 mg, 88.293 μmol) was added to a mixture of methanol (10 mL) and water (0.5 mL). Potassium carbonate (200 mg, 1.447 mmol) was added. After the addition was complete, the reaction was maintained at 80°C for 2 hours. LCMS monitoring showed the reaction was complete. The reaction solution was directly concentrated and then purified by flash liquid column chromatography to obtain the product (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) (40 mg, yield 86.2%). 1 H NMR (400MHz, DMSO-d6) δ11.32(s,1H),9.46(s,1H),7.84–6.82(m,4H),3.74(s,3H),3.11–2.92( m,2H),2.85–2.70(m,1H),2.47–2.24(m,2H),1.94(dt,J=22.0,7.1Hz,1H).MS(m / z):524.3[MH] - .

[0438] Example 57: Preparation of N-(2,5-difluoro-4-hydroxyphenyl)-6,6-difluoro-1,4,5,7-tetrahydroindole-3-sulfonamide (57)

[0439] Step 1: Synthesis of 1,4-difluoro-2-(methoxymethoxy)-5-nitrobenzene (57.1)

[0440] 2,5-Difluoro-4-nitrophenol (400 mg, 2.284 mmol) was added to tetrahydrofuran (3 mL), followed by DIPEA (740 mg, 5.725 mmol) and bromo(methoxy)methane (716 mg, 5.729 mmol). After the addition, the reaction was maintained at 23°C for 2 hours. TLC monitoring showed that the reaction was complete. 12 mL of water was added to the reaction solution, and the system was extracted with 5 mL of ethyl acetate three times. The organic phases were collected and combined. The organic phases were then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. Purification by flash liquid column chromatography gave the product 1,4-difluoro-2-(methoxymethoxy)-5-nitrobenzene (57.1) (511 mg).

[0441] Step 2: Synthesis of 2,5-difluoro-4-(methoxymethoxy)aniline (57.2)

[0442] 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.

[0443] 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)

[0444] 2,5-Difluoro-4-(methoxymethoxy)aniline (57.2) (139 mg, 734.832 μmol) 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 μmol). 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. The reaction solution was dried and purified by flash liquid chromatography to obtain the product, N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-6,6-difluoro-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (57.3) (303 mg).

[0445] Step 4: Synthesis of N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-6,6-difluoro-1,4,5,7-tetrahydroindole-3-sulfonamide (57.4)

[0446] N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-6,6-difluoro-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (57.3) (303 mg, 538.616 μmol) 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. 8 mL of water was added, and the system was extracted with 5 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 flash liquid column chromatography. The product N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-6,6-difluoro-1,4,5,7-tetrahydroindole-3-sulfonamide (57.4) (211 mg, yield 95.9%) was obtained.

[0447] Step 5: Synthesis of N-(2,5-difluoro-4-hydroxyphenyl)-6,6-difluoro-1,4,5,7-tetrahydroindole-3-sulfonamide (57)

[0448] N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-6,6-difluoro-1,4,5,7-tetrahydroindole-3-sulfonamide (57.4) (211 mg, 516.692 μmol) 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. The organic phases were collected and combined, concentrated at low temperature, and purified by flash liquid column chromatography and reverse phase column chromatography. The product, N-(2,5-difluoro-4-hydroxyphenyl)-6,6-difluoro-1,4,5,7-tetrahydroindole-3-sulfonamide (57) (46 mg, yield 24.4%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),9.37(s,2H),7.05(d,J=2.7Hz,1H),6.88(dd,J=11.9,7.5Hz,1H),6.69(dd,J=11 .1,8.1Hz,1H),3.10(t,J=14.0Hz,2H),2.58(t,J=6.4Hz,2H),2.11(ddd,J=20.7,13.7,6.9Hz,2H).MS(m / z):363.1[MH] - .

[0449] 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)

[0450] 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)

[0451] 6-(Difluoromethoxy-d)-5-fluoro-2-(methoxy-d3)pyridin-3-amine (2.4) (63 mg, 296.942 μmol) 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 μmol). After the addition, the reaction was maintained at 110°C in a microwave oven for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to give the product (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) (50 mg, yield 52.1%).

[0452] Step 2: Synthesis 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)

[0453] (S)-N-6-(difluoromethoxy-d)-5-fluoro-2-(methoxy-d3)-3-pyridinyl]-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-pyridinyl]-1-(p-toluenesulfonyl)-6-(methoxy-d3)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (58.1) (50 mg, 76.850 μmol) was added to a mixed solution of methanol (5 mL) and water (1 mL), and potassium carbonate (110 mg, 795.913 μmol) was added thereto. After the addition was completed, the reaction was maintained at 80°C for 2 hours. LCMS monitoring showed that the reaction was complete. The reaction temperature was lowered to 20°C, and saturated citric acid was added to adjust the pH 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, concentrated, and purified by flash liquid column chromatography. The product (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) (3 mg, yield 7.9%) was obtained. 1 HNMR (400MHz, DMSO-d6) δ11.24(s,1H),9.38(s,1H),7.62(d,J=10.3Hz,1H),7.14(d,J=2.9Hz,1H) ,2.89–2.65(m,3H),2.47–2.35(m,1H),2.23–2.13(m,1H),1.82–1.69(m,1H).MS(m / z):495.2[MH] - .

[0454] Example 59: Preparation of (S)-N-(2,5-difluoro-4-hydroxyphenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(2,5-difluoro-4-hydroxyphenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (59)

[0455] Step 1: Synthesis of (R)-N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (S)-N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (59.1)

[0456] 2,5-Difluoro-4-(methoxymethoxy)aniline (57.2) (66 mg, 348.913 μmol) 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) (110 mg, 231.620 μmol). After the addition, the reaction was maintained at 110°C in a microwave oven for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to obtain the product (R)-N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (S)-N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (59.1) (90 mg, yield 61.9%).

[0457] Step 2: Synthesis of (R)-N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (S)-N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (59.2)

[0458] (R)-N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (S)-N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (59.1) (70 mg, 111.533 μmol) was added to methanol (3 mL) and 4N aqueous sodium hydroxide solution (3 mL) was added. The reaction was maintained at 60°C for 2 hours. LCMS monitoring indicated that the reaction was complete. The reaction temperature was lowered to 20°C, and saturated citric acid was added to adjust the pH 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, the solvent was dried, and then purified by flash liquid chromatography. The product (R)-N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (S)-N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (59.2) (50 mg, yield 94.7%) was obtained.

[0459] Step 3: Synthesis of (S)-N-(2,5-difluoro-4-hydroxyphenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(2,5-difluoro-4-hydroxyphenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (59)

[0460] (R)-N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (S)-N-[2,5-difluoro-4-(methoxymethoxy)phenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (59.2) (50 mg, 105.613 μmol) was added to tetrahydrofuran (10 mL). A 4M hydrochloric acid solution in 1,4-dioxane (1.1 mL) was slowly added while maintaining the reaction at 0°C. After addition, the reaction was maintained at 25°C for 2 hours. LCMS monitoring indicated the formation of the product. The reaction solution was concentrated under low temperature, 15 mL of water was added, and the solution was extracted with dichloromethane five times in 10 mL increments. The organic phases were collected and combined, concentrated at low temperature, and then purified by flash liquid column chromatography to obtain the product (S)-N-(2,5-difluoro-4-hydroxyphenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-(2,5-difluoro-4-hydroxyphenyl)-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (59) (15 mg, yield 27.6%). 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),6.99(d,J=2.1Hz,1H),6.77(dd,J=12.0,7.6Hz,1H),6.60(dd,J=10.9,8.4Hz,1H),2.83(dd,J=45 .2,16.6Hz,2H),2.59(dd,J=17.1,4.9Hz,1H),2.39–2.30(m,1H),2.12(dd,J=13.5,5.1Hz,1H),1.76–1.66(m,1H).MS(m / z):428.0[MH] - .

[0461] 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)

[0462] Step 1: Synthesis of 2-chloro-5-(difluoromethoxy)-3-fluoro-6-iodopyridine (60.1)

[0463] 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. The organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. Purification by flash liquid column chromatography afforded the product, 2-chloro-5-(difluoromethoxy)-3-fluoro-6-iodopyridine (60.1 g) (11.600 g, 65.4% yield).

[0464] Step 2: Synthesis of 6-chloro-3-(difluoromethoxy)-5-fluoropyridine-2-carbaldehyde (60.2)

[0465] Dissolve 2-chloro-5-(difluoromethoxy)-3-fluoro-6-iodopyridine (60.1) (11.600 g, 35.865 mmol) in tetrahydrofuran (120 mL). Lower the temperature to -80°C and add isopropylmagnesium chloride (2M, 21.519 mL) dropwise over 20 minutes. After completion, warm the mixture to -60°C and allow the reaction to proceed for 40 minutes. Lower the temperature to -80°C and add N,N-dimethylformamide (7.864 g, 107.594 mmol) dropwise over 20 minutes. Allow the mixture to proceed to 0°C and allow the reaction to proceed for 40 minutes. TLC monitoring indicates the reaction is complete. Pour the reaction solution into a mixture of 30 mL of saturated citric acid and 300 mL of saturated brine. Extract the mixture with ethyl acetate three times, 200 mL each. Collect and combine the organic phases. Dry the organic phase over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified by flash liquid column chromatography to obtain the product 6-chloro-3-(difluoromethoxy)-5-fluoropyridine-2-carbaldehyde (60.2) (6.400 g, yield 79.1%).

[0466] Step 3: Synthesis of 2-chloro-5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoropyridine (60.3)

[0467] 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. The organic phases were concentrated and purified by flash liquid column chromatography to obtain the product 2-chloro-5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoropyridine (60.3) (900 mg, 82.0% yield).

[0468] Step 4: Synthesis of tert-butyl N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridinyl]carbamate (60.4)

[0469] 2-Chloro-5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoropyridine (60.3 g) (900 mg, 3.636 mmol) was added to 1,4-dioxane (20 mL), followed by cesium carbonate (3.554 g, 10.907 mmol), X-Phos (346 mg, 725.802 μmol), BocNH2 (638 mg, 5.446 mmol), and Pd2(DBA)3 (332 mg, 362.558 μmol). After the addition was complete, the reaction was maintained at 80°C under nitrogen for 4 hours. LCMS monitoring indicated the reaction was complete. The 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%).

[0470] Step 5: Synthesis of 5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoropyridin-2-amine (60.5)

[0471] Tert-butyl N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridinyl]carbamate (60.4) (670 mg, 2.041 mmol) was added to dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. After the addition was completed, the reaction was maintained at 20°C for 1 hour. TLC monitoring showed that the reaction was complete. After the reaction solution was concentrated, 30 mL of saturated sodium bicarbonate solution 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 concentrating the organic phases, they were purified by flash liquid column chromatography to obtain the product 5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoropyridin-2-amine (60.5) ((350 mg, yield 75.2%)).

[0472] Step 6: Synthesis of (R)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (S)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (60.6)

[0473] 5-(Difluoromethoxy)-6-(difluoromethyl)-3-fluoropyridin-2-amine (60.5 mg) (80 mg, 350.694 μmol) 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 mg, 100 mg, 210.563 μmol). After the addition, the reaction was maintained at 120°C in a microwave oven for 1 hour. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to obtain the product (R)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (S)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (60.6) (40 mg, yield 28.5%).

[0474] 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)

[0475] (R)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (S)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (60.6) (40 mg, 60.008 μmol) was added to methanol (2 mL), and an aqueous solution of potassium carbonate (138 mg, 998.509 μmol) (1 mL) was added. After the addition was complete, the reaction was maintained at 80°C for 1 hour. TLC monitoring showed that the reaction was complete. The 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. The product (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) (15 mg, yield 48.8%) was obtained. 1 HNMR(400MHz, DMSO-d6)δ11.37(s,1H),10.87(s,1H),7.95(d,J=10.2Hz,1H),7.19(ddd,J=106.4,47.5,30.8Hz,3H), 2.91–2.72(m,3H),2.49–2.36(m,1H),2.18(dd,J=13.7,5.1Hz,1H),1.78(td,J=12.9,6.0Hz,1H).MS(m / z):511.0[MH] - .

[0476] 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)

[0477] 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)

[0478] 5-(Difluoromethoxy)-6-(difluoromethyl)-3-fluoropyridin-2-amine (60.5) (80 mg, 350.694 μmol) 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) (100 mg, 196.897 μmol). After the addition, the reaction was maintained at 120°C in a microwave oven for 1 hour. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to give the product (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) (80 mg, yield 58.1%).

[0479] 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)

[0480] (S)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-6-(difluoromethyl)-3-fluoro-2-pyridinyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-3-sulfonamide (61.1) (80 mg, 114.361 μmol) was added to a mixture of methanol (2 mL) and water (1 mL). Potassium carbonate (158 mg, 1.143 mmol) was added. After the addition was complete, the reaction was maintained at 80°C for 1 hour. TLC monitoring showed the reaction was complete. The reaction solution was cooled to 20°C, and then saturated citric acid was added to adjust the pH value of the system to 4-6. 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, concentrated, and purified by flash liquid column chromatography and reverse column chromatography. The product (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) (25 mg, yield 40.1%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.44(s,1H),10.94(s,1H),7.93(d,J=10.2Hz,1H),7.45–7.39(m,1H),7.25–6.81(m,3H), 2.94(ddd,J=23.6,21.1,10.6Hz,3H),2.48–2.39(m,2H),1.98(ddd,J=17.6,11.1,6.3Hz,1H).MS(m / z):544.0[MH] - .

[0481] 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 (6S)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (62)

[0482] 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-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (6S)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (62.1)

[0483] (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 3)-5,7-dihydro-4H-indole-3-sulfonamide (55.4) (600 mg, 932.245 μmol) was subjected to supercritical fluid chromatography to obtain the product (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. -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 (6R)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (6S)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (62.1) (250 mg, yield 41.7%).

[0484] 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)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (62)

[0485] (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 (6R)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide To a mixture of methanol (5 mL) and water (2 mL) was added (6S)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (62.1) (250 mg, 388.435 μmol), followed by potassium carbonate (540 mg, 3.907 mmol). The 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. After collecting and combining the organic phases, the organic phases were concentrated and purified by flash liquid column chromatography and reverse phase column chromatography to obtain the product (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 (6R)-N- [4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (6S)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (62) (94 mg, yield 49.4%). 1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),9.92(s,1H),7.16(d,J=42.9Hz,3H),3.05–2.72(m,3H), 2.65(d,J=15.1Hz,1H),2.41(s,1H),2.07(d,J=48.1Hz,3H),1.76(s,1H).MS(m / z):488.1[MH] - .

[0486] 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 (6S)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (63)

[0487] 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-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide or (6S)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (63.1)

[0488] (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 3)-5,7-dihydro-4H-indole-3-sulfonamide (55.4) (600 mg, 932.245 μmol) was subjected to supercritical fluid chromatography to obtain the product (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 (6R)-N-[4-[(1S)-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-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (63.1) (200 mg, yield 33.3%)

[0489] 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)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (63)

[0490] (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 (6R)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide To a mixture of methanol (5 mL) and water (3 mL) was added (6S)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-1-(p-toluenesulfonyl)-6-(trifluoromethyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonamide (63.1) (200 mg, 310.748 μmol), followed by potassium carbonate (420 mg, 3.039 mmol). 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. After collecting and combining the organic phases, the organic phases were concentrated and purified by flash liquid column chromatography and reverse phase column chromatography to obtain the product (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 (6R)-N- [4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (6S)-N-[4-[(1S)-2,2-difluorocyclopropyl]-2,5-difluorophenyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (63) (120 mg, yield 78.9%). 1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),9.92(s,1H),7.16(d,J=42.9Hz,3H),3.05–2.72(m,3H), 2.65(d,J=15.1Hz,1H),2.41(s,1H),2.07(d,J=48.1Hz,3H),1.76(s,1H).MS(m / z):488.1[MH] - .

[0491] 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)

[0492] Step 1: Synthesis of 2-bromo-5-(difluoromethoxy)-3-fluoro-6-methoxypyridine (64.1)

[0493] 6-Bromo-5-fluoro-2-methoxypyridin-3-ol (0.200 g, 900.854 μmol) 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. After filtration, the filtrate was concentrated. Purification by flash liquid column chromatography gave the product, 2-bromo-5-(difluoromethoxy)-3-fluoro-6-methoxypyridine (64.1 g) (150 mg, 61.2% yield).

[0494] Step 2: Synthesis of tert-butyl N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]carbamate (64.2)

[0495] 2-Bromo-5-(difluoromethoxy)-3-fluoro-6-methoxypyridine (64.1) (0.150 g, 551.432 μmol) was added to 1,4-dioxane (10 mL), followed by cesium carbonate (540 mg, 1.657 mmol), Xant-Phos (70 mg, 120.978 μmol), BocNH2 (100 mg, 853.636 μmol), and Pd2(DBA)3 (51 mg, 55.694 μmol). After the addition, the reaction was maintained at 100°C under nitrogen for 12 hours. LCMS monitoring indicated the reaction was complete. The 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%).

[0496] Step 3: Synthesis of 5-(difluoromethoxy)-3-fluoro-6-methoxypyridin-2-amine (64.3)

[0497] Tert-butyl N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]carbamate (64.2) (90 mg, 291.968 μmol) was added to dichloromethane (5 mL), and trifluoroacetic acid (333 mg, 2.920 mmol) was added. After the addition was completed, the reaction was maintained at 25°C for 2 hours. LCMS monitoring showed that the reaction was complete. After the reaction solution was concentrated, 30 mL of saturated sodium bicarbonate solution 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 concentrating the organic phases, they were purified by flash liquid column chromatography to obtain the product 5-(difluoromethoxy)-3-fluoro-6-methoxypyridin-2-amine (64.3) (30 mg, yield 49.4%).

[0498] 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)

[0499] 5-(Difluoromethoxy)-3-fluoro-6-methoxypyridin-2-amine (64.3%) (80 mg, 384.361 μmol) 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%) (120 mg, 252.676 μmol). After addition, the reaction was maintained at 110°C in a microwave oven for 1 hour. LCMS monitoring indicated the reaction was complete. The reaction solution was dried by rotary evaporation and then purified by flash liquid column chromatography to obtain the product (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) (100 mg, yield 61.2%).

[0500] 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)

[0501] (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) (90 mg, 139.191 μmol) was added to methanol (10 mL), and an aqueous solution of potassium carbonate (200 mg, 1.447 mmol) (2 mL) was added. After the addition was complete, the reaction was maintained at 80°C for 2 hours. LCMS monitoring showed that the reaction was complete. The 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. The product (S)-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]-6-(methoxy-d3)-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (64) (20 mg, yield 29.2%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),10.51(s,1H),7.69(d,J=11.5Hz,1H),7.27(d,J=3.0Hz,1H),7.00-6.85(t,J=71.9Hz, 1H),3.72(s,3H),2.90–2.75(m,3H),2.70(d,J=10.5Hz,1H),1.70(d,J=7.4Hz,1H),1.2(d,J=7.4Hz,1H).MS(m / z):490.6[MH] - .

[0502] 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)

[0503] 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)

[0504] 1-(p-Toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-6-ol (23.7) (6.200 g, 22.818 mmol) was subjected to supercritical fluid chromatography to obtain the product (R)-1-(p-Toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-6-ol or (S)-1-(p-Toluenesulfonyl)-6-(trifluoromethyl)-5,7-dihydro-4H-indole-6-ol (65.1) (3.503 g, yield 42.7%).

[0505] 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)

[0506] (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) (1.000 g, 2.783 mmol) was dissolved in dichloromethane (40 mL). Chlorosulfonic acid (1.000 g, 8.584 mmol) was added dropwise while maintaining the reaction at -40°C. After addition, the temperature was slowly raised to 0°C and the reaction was allowed to react for a total of 1 hour. TLC monitoring indicated the formation of the product. The reaction solution was then spin-dried to dryness, and dichloromethane (40 mL) was added to the system. Oxalyl chloride (3.532 g, 27.827 mmol) and N,N-dimethylformamide (205 mg, 2.805 mmol) were then added while maintaining the reaction at 0°C. After the addition is complete, the reaction is maintained at 25°C for 2 hours. LCMS monitoring shows that the reaction is complete. The reaction system is poured into ice water to quench, and the reaction system is extracted with 50 mL of ethyl acetate twice. The organic phases are collected and combined. The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is collected. After concentrating the filtrate, it is purified by flash liquid column chromatography. The product (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) (100 mg, yield 7.8%) is obtained.

[0507] 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)

[0508] 4-(Difluoromethoxy)-2,5-difluoroaniline (43.3) (60 mg, 307.512 μmol) was added to anhydrous pyridine (0.5 mL), followed by (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) (100 mg, 218.402 μmol). After addition, the reaction was maintained at 110°C for 5 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to obtain the product (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) (100 mg, yield 74.3%).

[0509] 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)

[0510] (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) (100 mg, 162.199 μmol) was added to a mixture of methanol (8 mL) and water (2 mL). Potassium carbonate (225 mg, 1.628 mmol) was added. After addition, the reaction was maintained at 80°C for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was concentrated and purified by flash liquid chromatography. The product (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) (30 mg, yield 40.0%) was obtained. 1 H NMR(400MHz,DMSO-d6)δ11.23(s,1H),9.98(s,1H),7.39–6.95(m,4H),5.95(s,1H),2. 78–2.66(m,4H),1.97–1.88(m,1H),1.61(td,J=12.8,6.3Hz,1H).MS(m / z):460.7[MH] - .

[0511] 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)

[0512] 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)

[0513] 5-Fluoro-2-(methoxy-d3)-6-(trifluoromethyl)pyridin-3-amine (54.6) (65 mg, 304.953 μmol) was added to anhydrous pyridine (0.5 mL), followed by (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) (90 mg, 196.562 μmol). After addition, the reaction was maintained at 80°C in a microwave oven for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to obtain the product (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) (60 mg, yield 48.1%).

[0514] 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)

[0515] (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) (60 mg, 94.554 μmol) was added to a mixture of methanol (8 mL) and water (2 mL). Potassium carbonate (131 mg, 947.860 μmol) was added. After the addition was complete, the reaction was maintained at 80°C for 2 hours. LCMS monitoring showed the reaction was complete. The reaction mixture was cooled to 20°C and saturated citric acid was added to adjust the pH of the system to 3-4. The system was extracted with 10 mL of ethyl acetate twice, and the organic phase was concentrated and purified by flash liquid column chromatography. The product (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) (10 mg, yield 22.0%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.43(s,1H),10.25(s,1H),7.62(d,J=11.6Hz,1H),7.48(d,J=2.9Hz,1H),5.96(s,1H),2. 84–2.71(m,2H),2.68–2.54(m,2H),1.94(dd,J=12.7,4.3Hz,1H),1.65(td,J=12.5,5.9Hz,1H).MS(m / z):479.0[MH] - .

[0516] Example 67: Preparation of 6-(difluoromethyl)-N-[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridyl]-6-(hydroxymethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (67)

[0517] Step 1: Synthesis of [6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-yl]methanol (67.1)

[0518] 6-(Difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbaldehyde (47.1) (0.700 g, 1.981 mmol) was dissolved in methanol (10 mL). NaBH4 (100 mg, 2.643 mmol) was added while maintaining the reaction at 0°C. After addition, the reaction was maintained at 20°C for 1 hour. TLC monitoring indicated the reaction was complete. 1 mL of saturated ammonium chloride solution was slowly added to the reaction solution and allowed to react for 10 minutes to quench the reaction. The reaction solution was concentrated and purified by flash liquid column chromatography. The product, [6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-yl]methanol (67.1) (600 mg, 85.2% yield) was obtained.

[0519] Step 2: Synthesis of methyl [6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-yl]acetate (67.2)

[0520] [6-(Difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-yl]methanol (67.1) (600 mg, 1.688 mmol) was dissolved in a mixture of pyridine (4 mL) and N,N-dimethylformamide (4 mL). Acetic anhydride (517 mg, 5.064 mmol) was added while maintaining the reaction at 0°C. After addition, the reaction was maintained at 20°C for 16 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate three times in 50 mL increments. The organic phases were collected, combined, concentrated, and purified by flash liquid chromatography. The product, [6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-yl]acetate (67.2) (600 mg, 89.4% yield), was obtained.

[0521] Step 3: Synthesis of methyl [3-chlorosulfonyl-6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-yl]acetate (67.3)

[0522] Methyl [6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-yl]acetate (67.2 g) (600 mg, 1.510 mmol) was dissolved in dichloromethane (40 mL). Chlorosulfonic acid (439 mg, 3.767 mmol) was added while maintaining the temperature at -40°C. After addition, the reaction was maintained at 0°C for 1 hour. LCMS monitoring indicated the reaction was complete. Oxalyl chloride (1.916 g, 15.097 mmol) and N,N-dimethylformamide (110 mg, 1.505 mmol) were added while maintaining the temperature at 0°C. After addition, the reaction was maintained at 20°C for 1 hour. LCMS monitoring indicated the reaction was complete. The 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).

[0523] 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)

[0524] 5-Fluoro-2-(methoxy-d3)-6-(trifluoromethyl)pyridin-3-amine (54.6) (450 mg, 2.111 mmol) was dissolved in anhydrous pyridine (3 mL) and methyl [3-chlorosulfonyl-6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-yl]acetate (67.3) (600 mg, 1.210 mmol) was added. After addition, the reaction was maintained at 120° in a microwave for 1 hour. LCMS monitoring showed that the reaction was complete. The reaction solution was concentrated and purified by flash liquid chromatography. The product was obtained: [6-(difluoromethyl)-3-[[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridinyl]sulfamoyl]-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indol-6-yl]acetic acid methyl ester (67.4) (600 mg, yield 73.7%).

[0525] 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)

[0526] 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%) (100 mg, 148.670 μmol) was added to methanol (2 mL), followed by a 2 mL aqueous solution of lithium hydroxide monohydrate (37 mg, 881.708 μmol). After addition, 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 3 mL of saturated ammonium chloride solution was added. The reaction system was concentrated and purified by reverse-phase column chromatography. The product 6-(difluoromethyl)-N-[5-fluoro-2-(methoxy-d3)-6-(trifluoromethyl)-3-pyridinyl]-6-(hydroxymethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (67) was obtained (35 mg, yield 49.4%). 1 H NMR (400MHz, DMSO-d6) δ11.36(s,1H),10.16(s,1H),7.60(d,J=11.6Hz,1H),7.41(d,J=3.0Hz,1H),5.95(t,J=56.7Hz,1H),4.95(t,J=5.1Hz,1H),3 .31(d,J=5.0Hz,2H),2.73–2.60(m,1H),2.48–2.30(m,3H),1.81(dt,J=1 2.2,4.4Hz,1H),1.52(ddd,J=12.8,10.4,5.9Hz,1H).MS(m / z):474.9[MH] -

[0527] Example 68: N-(4-Bromo-2,5-difluorophenyl)-6-methoxyimino-1,4,5,7-tetrahydroindole-3-sulfonamide (68)

[0528] Step 1: Synthesis of 1-(p-toluenesulfonyl)-4,5,6,7-tetrahydroindole-6-ol (68.1)

[0529] 1-(p-Toluenesulfonyl)-5,7-dihydro-4H-indol-6-one (23.6) (5.000 g, 17.280 mmol) was dissolved in methanol (50 mL). NaBH4 (600 mg, 15.860 mmol) was added while maintaining the reaction at 0°C. After addition, the reaction was maintained at 20°C for 1 hour. TLC monitoring indicated the reaction was complete. The reaction solution was poured into 150 mL of saturated ammonium chloride solution and extracted with ethyl acetate three times, 100 mL each. The organic phases were collected, combined, and concentrated to obtain the crude product, 1-(p-Toluenesulfonyl)-4,5,6,7-tetrahydroindol-6-ol (68.1) (5.500 g).

[0530] Step 2: Synthesis of [1-(p-Toluenesulfonyl)-4,5,6,7-tetrahydroindol-6-yl]acetate (68.2)

[0531] 1-(p-Toluenesulfonyl)-4,5,6,7-tetrahydroindole-6-ol (68.1) (5.000 g, 17.161 mmol) was dissolved in a mixture of pyridine (30 mL) and N,N-dimethylformamide (30 mL). Acetic anhydride (5.256 g, 51.482 mmol) was added while maintaining the reaction at 0°C. The reaction was then maintained at 20°C for 16 hours. LCMS monitoring indicated the reaction was complete. After removing pyridine by rotary evaporation, the reaction solution was poured into 200 mL of water and extracted with ethyl acetate three times in 100 mL increments. The organic phases were collected, combined, concentrated, and purified by flash liquid chromatography. This afforded the product, [1-(p-Toluenesulfonyl)-4,5,6,7-tetrahydroindole-6-yl] acetate (68.2) (5.300 g, 92.6% yield).

[0532] Step 3: Synthesis of [3-chlorosulfonyl-1-(p-toluenesulfonyl)-4,5,6,7-tetrahydroindol-6-yl]acetate (68.3)

[0533] Dissolve [1-(p-Toluenesulfonyl)-4,5,6,7-tetrahydroindol-6-yl]acetate (68.2) (5.300 g, 15.897 mmol) in dichloromethane (100 mL). Add chlorosulfonic acid (5.187 g, 44.511 mmol) while maintaining the temperature at -40°C. After addition, maintain the reaction at 0°C for 1 hour. LCMS monitoring indicates the reaction is complete. Add oxalyl chloride (20.177 g, 158.968 mmol) and N,N-dimethylformamide (1.162 g, 15.897 mmol) while maintaining the temperature at 0°C. After addition, maintain the reaction at 20°C for 1 hour. LCMS monitoring indicates the reaction is complete. Cool the reaction solution to 20°C, add 100 g of crushed ice, and extract the reaction system 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-1-(p-toluenesulfonyl)-4,5,6,7-tetrahydroindol-6-yl] acetate (68.3 g) (6.200 g, yield 90.3%).

[0534] Step 4: Synthesis of [3-[(4-bromo-2,5-difluorophenyl)sulfamoyl]-1-(p-toluenesulfonyl)-4,5,6,7-tetrahydroindol-6-yl]acetate (68.4)

[0535] 4-Bromo-2,5-difluoroaniline (3.882 g, 18.661 mmol) was dissolved in anhydrous pyridine (10 mL), and [3-chlorosulfonyl-1-(p-toluenesulfonyl)-4,5,6,7-tetrahydroindol-6-yl] acetate (68.3) (6.200 g, 14.355 mmol) was added. After the addition, the reaction was maintained at 100° for 6 hours. LCMS monitoring indicated the reaction was complete. The 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).

[0536] Step 5: Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-1-(p-toluenesulfonyl)-4,5,6,7-tetrahydroindole-3-sulfonamide (68.5)

[0537] [3-[(4-bromo-2,5-difluorophenyl)sulfamoyl]-1-(p-toluenesulfonyl)-4,5,6,7-tetrahydroindole-6-yl]acetate (68.4) (6.000 g, 9.943 mmol) was added to methanol (60 mL), followed by a 30 mL solution of lithium hydroxide monohydrate (835 mg, 19.898 mmol). After addition, the reaction was maintained at 20°C for 1 hour. 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. The mixture was then filtered and the filter cake collected. This afforded the crude product, N-(4-bromo-2,5-difluorophenyl)-6-hydroxy-1-(p-toluenesulfonyl)-4,5,6,7-tetrahydroindole-3-sulfonamide (68.5) (5.200 g).

[0538] Step 6: Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-oxo-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (68.6)

[0539] 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. The organic phases were collected and combined. The organic phases were then concentrated and purified by flash liquid chromatography. The product N-(4-bromo-2,5-difluorophenyl)-6-oxo-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (68.6) was obtained (1.200 g, yield 48.2%).

[0540] Step 7: Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-methoxyimino-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (68.7)

[0541] 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. 50 mL of water was added to the mixture, and the mixture was extracted with 30 mL of ethyl acetate each time for a total of three times. The organic phases were collected and combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated to give a crude product of N-(4-bromo-2,5-difluorophenyl)-6-methoxyimino-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-3-sulfonamide (68.7 g) (1.000 g).

[0542] Step 8: Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-methoxyimino-1,4,5,7-tetrahydroindole-3-sulfonamide (68)

[0543] 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. The mixture was extracted with ethyl acetate three times, 30 mL each. The organic phases were collected and combined, concentrated, and purified by flash liquid chromatography and reverse phase column chromatography. The product N-(4-bromo-2,5-difluorophenyl)-6-methoxyimino-1,4,5,7-tetrahydroindole-3-sulfonamide (68) was obtained (0.016 g, 36.845 μmol, yield 2.2%). 1 H NMR (400MHz, DMSO-d6) δ11.40 (s, 1H), 10.15 (s, 1H), 7.69 (dd, J = 9.7, 6.4Hz, 1H), 7.34 –7.18(m,2H),3.76(s,3H),3.30(s,2H),2.69–2.57(m,4H).MS(m / z):431.9;433.9[MH] -

[0544] 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)

[0545] Step 1: Synthesis of 5-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (69.1)

[0546] 3-Bromo-5-methoxy-2-methylpyridine (69.1) (5.000 g, 24.747 mmol) was added to 1,4-dioxane (50 mL), followed by potassium acetate (6.063 g, 61.866 mmol), Pd(dppf)Cl2 (1.811 g, 2.475 mmol), and pinacol diboronate (18.85 g, 74.213 mmol). After the addition, the reaction was maintained at 100°C under nitrogen for 12 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was filtered, and the filtrate was collected and concentrated. The filtrate was then purified by flash liquid chromatography to yield the product, 5-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (69.1) (6.000 g, 97.3% yield).

[0547] Step 2: Synthesis of 5-methoxy-2-methylpyridin-3-ol (69.2)

[0548] 5-Methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (69.1) (5.000 g, 20.071 mmol) was added to tetrahydrofuran (5 mL). Hydrogen peroxide (4.750 g, 41.912 mmol, 30% purity) was added while maintaining the reaction at 0°C. After addition, the reaction was maintained at 25°C for 2 hours. LCMS monitoring indicated completion of the reaction. The reaction temperature was lowered to 0°C, and saturated sodium sulfite solution was added to the reaction mixture until starch-potassium iodide paper did not change color. The mixture was extracted with ethyl acetate three times, 50 mL each. The organic phases were collected and combined. After concentration, the organic phases were purified by flash liquid chromatography. The product, 5-methoxy-2-methylpyridin-3-ol (69.2), was obtained (1.450 g, 51.9% yield).

[0549] Step 3: Synthesis of 6-bromo-5-methoxy-2-methylpyridin-3-ol (69.3)

[0550] 5-Methoxy-2-methylpyridin-3-ol (69.2) (300 mg, 2.156 mmol) was added to N,N-dimethylformamide (5 mL). N-bromosuccinimide (500 mg, 2.809 mmol) was added while maintaining the system at 0°C. After the addition, the reaction was maintained at 0°C for 3 hours. LCMS monitoring showed that the reaction was complete. The temperature of the reaction system was lowered to 0°C, and 20 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction. The system was extracted with ethyl acetate three times with 50 mL each. The organic phases were collected and combined. After the organic phases were concentrated, they were purified by flash liquid column chromatography. The product 6-bromo-5-methoxy-2-methylpyridin-3-ol (69.3) (400 mg, yield 85.1%) was obtained.

[0551] Step 4: Synthesis of 2-bromo-5-(difluoromethoxy)-3-methoxy-6-methylpyridine (69.4)

[0552] 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%).

[0553] Step 5: Synthesis of tert-butyl N-[5-(difluoromethoxy)-3-methoxy-6-methyl-2-pyridyl]carbamate (69.5)

[0554] 2-Bromo-5-(difluoromethoxy)-3-methoxy-6-methylpyridine (69.4) (200 mg, 746.115 μmol) was added to 1,4-dioxane (10 mL), followed by cesium carbonate (490 mg, 1.504 mmol), Xant-Phos (64 mg, 110.609 μmol), BocNH2 (220 mg, 1.878 mmol), and Pd2(DBA)3 (68 mg, 74.259 μmol). After the addition, the reaction was maintained at 50°C under N2 protection for 1 hour. LCMS monitoring indicated the formation of the product. The reaction solution was filtered, and the filtrate was collected and concentrated, and then purified by flash liquid chromatography to obtain tert-butyl N-[5-(difluoromethoxy)-3-methoxy-6-methyl-2-pyridyl]carbamate (69.5) (200 mg, 88.1% yield).

[0555] Step 6: Synthesis of 5-(difluoromethoxy)-3-methoxy-6-methylpyridin-2-amine (69.6)

[0556] Tert-butyl N-[5-(difluoromethoxy)-3-methoxy-6-methyl-2-pyridinyl]carbamate (69.5) (120 mg, 394.362 μmol) was added to dichloromethane (5 mL), followed by trifluoroacetic acid (600 mg, 5.262 mmol). After the addition was complete, the reaction was maintained at 25°C for 3 hours. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated, 5 mL of water was added to the system, and saturated sodium bicarbonate solution was added to adjust the pH value of the system to 7-8. The system was extracted with ethyl acetate 3 times with 20 mL each. The organic phases were collected and combined, and after concentrating the organic phases, the crude product 5-(difluoromethoxy)-3-methoxy-6-methylpyridin-2-amine (69.6) (50 mg) was obtained.

[0557] 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)

[0558] 5-(Difluoromethoxy)-3-methoxy-6-methylpyridin-2-amine (69.6) (48 mg, 235.094 μmol) 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) (90 mg, 177.208 μmol). After the addition, the reaction was maintained at 110°C in a microwave oven for 1 hour. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to give the product (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) (80 mg, yield 66.8%).

[0559] 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)

[0560] (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) (80 mg, 118.415 μmol) was added to methanol (10 mL), and an aqueous solution of potassium carbonate (200 mg, 1.447 mmol) (2 mL) was added. After the addition was complete, the reaction was maintained at 80°C for 1 hour. LCMS monitoring showed the reaction was complete. The 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. The product (S)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-3-methoxy-6-methyl-2-pyridyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide or (R)-6-(difluoromethoxy)-N-[5-(difluoromethoxy)-3-methoxy-6-methyl-2-pyridyl]-6-(trifluoromethyl)-1,4,5,7-tetrahydroindole-3-sulfonamide (69) (6 mg, yield 9.7%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),9.55(s,1H),7.44–6.81(m,4H),3.78(s,3H),3.01(dd,J=30.2,16.5H z,3H),2.61(dd,J=6.1,4.1Hz,1H),2.46–2.38(m,1H),2.23(s,3H),2.03–1.86(m,1H).MS(m / z):520.1[MH] - .

[0561] Example 70: N-(4-bromo-2,5-difluorophenyl)-6,6-dioxo-1,4,5,7-tetrahydrothiopyrano[3,4-b]pyrrole-3-sulfonamide (70)

[0562] Step 1: Synthesis of methyl 3-bromo-1-(p-toluenesulfonyl)pyrrole-2-carboxylate (70.1)

[0563] 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. The 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.

[0564] Step 2: Synthesis of methyl 1-(p-toluenesulfonyl)-3-vinylpyrrole-2-carboxylate (70.2)

[0565] Methyl 3-bromo-1-(p-toluenesulfonyl)pyrrole-2-carboxylate (70.1) (17.000 g, 47.459 mmol) was added to 1,4-dioxane (200 mL), followed by potassium carbonate (16.398 g, 118.646 mmol), Pd(dppf)Cl2 (1.736 g, 2.373 mmol), vinylboronic acid pinacol ester (14.619 g, 94.917 mmol), and water (20 mL). After the addition, the reaction was maintained at 100°C under N2 protection for 16 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was filtered, and the filtrate was collected and concentrated, then purified by flash liquid chromatography to obtain the product, methyl 1-(p-toluenesulfonyl)-3-vinylpyrrole-2-carboxylate (70.2) (13.500 g, 93.2% yield).

[0566] Step 3: Synthesis of methyl 3-(2-hydroxyethyl)-1-(p-toluenesulfonyl)pyrrole-2-carboxylate (70.3)

[0567] 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. Over 1 hour, a solution of NaOH (70.7g, 1.768mol) in water (1L) was added dropwise. After the addition, the reaction mixture was maintained at 20°C for 2 hours. TLC monitoring indicated the reaction was complete. Saturated sodium sulfite solution was added to the reaction mixture until the starch potassium iodide test paper did not change color. The reaction mixture was rotary evaporated to remove tetrahydrofuran, and the system was extracted with ethyl acetate three times with 500 mL each. The organic phases were collected and combined. After concentration, the organic phases were purified by flash liquid column chromatography to obtain the product, methyl 3-(2-hydroxyethyl)-1-(tosyl)pyrrole-2-carboxylate (70.3 g) (8.000 g, 56.0% yield).

[0568] Step 4: Synthesis of 2-[2-(hydroxymethyl)-1-(p-toluenesulfonyl)pyrrol-3-yl]ethanol (70.4)

[0569] Methyl 3-(2-hydroxyethyl)-1-(p-toluenesulfonyl)pyrrole-2-carboxylate (70.3) (1.000 g, 3.092 mmol) was added to tetrahydrofuran (20 mL). The reaction was maintained under N2 protection and at 0°C. Lithium aluminum hydride (200 mg, 5.270 mmol) was added to the reaction solution. After addition, the reaction was maintained at 20°C for 3 hours. TLC monitoring showed that the reaction was complete. 0.2 mL of water, 0.2 mL of 15% sodium hydroxide solution, and 0.6 mL of water were added to the reaction solution to quench the reaction. The reaction solution was concentrated and purified by flash liquid column chromatography to obtain 2-[2-(hydroxymethyl)-1-(p-toluenesulfonyl)pyrrol-3-yl]ethanol (70.4) as a red solid (700 mg, 76.6% yield).

[0570] Step 5: Synthesis of 3-(2-bromoethyl)-2-(bromomethyl)-1-(p-toluenesulfonyl)pyrrole (70.5)

[0571] 2-[2-(Hydroxymethyl)-1-(p-toluenesulfonyl)pyrrol-3-yl]ethanol (70.4) (500 mg, 1.693 mmol) was added to N,N-dimethylformamide (20 mL). The reaction was maintained at 0°C, and phosphorus tribromide (1.375 g, 5.079 mmol) was added to the reaction solution. After the addition, the reaction was maintained at 20°C for 16 hours. LCMS monitoring showed that the reaction was complete. The product, 3-(2-bromoethyl)-2-(bromomethyl)-1-(p-toluenesulfonyl)pyrrole (70.5) (700 mg, yield 100%), was obtained as a solution in N,N-dimethylformamide.

[0572] Step 6: Synthesis of 1-(p-Toluenesulfonyl)-5,7-dihydro-4H-thiopyrano[3,4-b]pyrrole (70.6)

[0573] To a solution of 3-(2-bromoethyl)-2-(bromomethyl)-1-(p-toluenesulfonyl)pyrrole (70.5) (700 mg, 1.662 mmol) in N,N-dimethylformamide (20 mL) were added cesium carbonate (8.123 g, 24.932 mmol) and sodium sulfide (1.946 g, 24.932 mmol), and the reaction was maintained at 20°C for 4 hours. LCMS monitoring showed that the reaction was complete. The reaction solution was poured into 100 mL of water and extracted with 30 mL of ethyl acetate three times. The organic phases were collected and combined. The organic phases were then concentrated and purified by flash liquid column chromatography to obtain the product 1-(p-toluenesulfonyl)-5,7-dihydro-4H-thiopyrano[3,4-b]pyrrole (70.6) (200 mg, yield 41.0%).

[0574] Step 7: Synthesis of 1-(p-Toluenesulfonyl)-5,7-dihydro-4H-thiopyrano[3,4-b]pyrrole-3-sulfonyl chloride (70.7)

[0575] 1-(p-Toluenesulfonyl)-5,7-dihydro-4H-thiopyrano[3,4-b]pyrrole (70.6) (50 mg, 170.414 μmol) was dissolved in acetonitrile (10 mL), and chlorosulfonic acid (60 mg, 514.915 μmol) was added while maintaining the temperature at -40°C. After the addition, the reaction was maintained at 20°C for 1 hour. LCMS monitoring indicated that the reaction was complete. The reaction solution was spin-dried, and 10 mL of dichloromethane was added to the reaction system. Oxalyl chloride (441 mg, 3.474 mmol) and N,N-dimethylformamide (39 mg, 533.560 μmol) were added while maintaining the temperature at 0°C. After the addition, the reaction was maintained at 20°C for 1 hour. LCMS monitoring indicated that the reaction was complete. The reaction solution was concentrated and purified by flash liquid column chromatography. The product 1-(p-toluenesulfonyl)-5,7-dihydro-4H-thiopyrano[3,4-b]pyrrole-3-sulfonyl chloride (70.7) (50 mg, yield 73.3%) was obtained.

[0576] 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)

[0577] 4-Bromo-2,5-difluoroaniline (50 mg, 240.381 μmol) was dissolved in anhydrous pyridine (10 mL), and 1-(p-toluenesulfonyl)-5,7-dihydro-4H-thiopyrano[3,4-b]pyrrole-3-sulfonyl chloride (70.7) (50 mg, 127.579 μmol) was added. After the addition was complete, the reaction was maintained at 110° in a microwave oven for 1 hour. LCMS monitoring showed that the reaction was complete. The reaction solution was concentrated and purified by flash liquid column chromatography. The product N-(4-bromo-2,5-difluorophenyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-thiopyrano[3,4-b]pyrrole-3-sulfonamide (70.8) (40 mg, yield 55.6%) was obtained.

[0578] 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)

[0579] 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 μmol) was added to dichloromethane (5 mL). The reaction was maintained at 0°C. mCPBA (30 mg, 173.847 μmol) 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. 10 mL of water was added to the reaction mixture, and the system was extracted with 20 mL of dichloromethane three times. The organic phases were collected and combined. The organic phase was concentrated to give a crude product 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 g) (40 mg).

[0580] 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)

[0581] N-(4-bromo-2,5-difluorophenyl)-6,6-dioxo-1-(toluenesulfonyl)-5,7-dihydro-4H-thiopyrano[3,4-b]pyrrole-3-sulfonamide (70.9) (40 mg, 67.176 μmol) 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. 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 reverse phase column chromatography. The product N-(4-bromo-2,5-difluorophenyl)-6,6-dioxo-1,4,5,7-tetrahydrothiopyrano[3,4-b]pyrrole-3-sulfonamide (70) was obtained (1 mg, yield 3.4%). 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),7.43(s,1H),7.21(s,2H),4.27(s,2H),3.30(s,2H),3.01(s,2H).MS(m / z):438.9;440.9[MH] - .

[0582] 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)

[0583] 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)

[0584] 6-(Difluoromethyl)-1-(p-toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole (38.2) (8.000 g, 22.320 mmol) was subjected to supercritical fluid chromatography to obtain the product (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) (2.900 g, yield 36.3%).

[0585] 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)

[0586] Dissolve (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) (1.500 g, 4.185 mmol) in acetonitrile (20 mL). Add chlorosulfonic acid (1.463 g, 12.555 mmol) dropwise while maintaining the reaction at -40°C. After addition, maintain the reaction at -40°C for 2 hours. 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. The product (S)-6-(difluoromethyl)-1-(toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonyl chloride or (R)-6-(difluoromethyl)-1-(toluenesulfonyl)-6-(methoxy-d3)-5,7-dihydro-4H-indole-3-sulfonyl chloride (71.2) (1.500 g, yield 78.4%) was obtained.

[0587] 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)

[0588] 4-(Difluoromethoxy)-2,5-difluoroaniline (43.3) (84 mg, 430.517 μmol) was added to anhydrous pyridine (0.5 mL), followed by (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) (150 mg, 328.281 μmol). After the addition, the reaction was maintained at 100°C in a microwave oven for 1 hour. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to obtain the product (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) (0.150 g, yield 74.2%).

[0589] Step 4: Synthesis 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)

[0590] (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) (0.150 g, 243.673 μmol) was added to a mixture of methanol (9 mL) and water (3 mL). Potassium carbonate (169 mg, 1.223 mmol) was added. After the addition was complete, the reaction was maintained at 80°C for 2 hours. LCMS monitoring showed the reaction was complete. The reaction solution temperature was lowered to 20°C, and then 1N dilute hydrochloric acid was added to adjust the pH value of the system to 5-6. The reaction system was extracted with 30 mL of ethyl acetate for a total of 3 times. After collecting and combining the organic phases, the organic phase was dried over anhydrous sodium sulfate. After filtering and drying the filtrate, it was purified by fast liquid column chromatography and reverse phase column chromatography. The product (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) (0.050 g, yield 44.5%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.27(s,1H),9.88(s,1H),7.42–7.01(m,4H),6.11(t,J=55.0Hz,1H),2.62(dt,J=18.9 ,9.9Hz,3H),2.41–2.32(m,1H),2.03(dd,J=13.2,2.1Hz,1H),1.58(td,J=13.5,6.0Hz,1H).MS(m / z):460.0[MH] - .

[0591] Example 72: Preparation of N-(4-bromo-2,5-difluorophenyl)-6-methylsulfonyl-1,4,5,7-tetrahydropyrrolo[2,3-c]pyridine-3-sulfonamide (72)

[0592] Step 1: Synthesis of 6-benzyl-1H-pyrrolo[2,3-c]pyridin-6-ium (72.1)

[0593] 1H-pyrrolo[2,3-c]pyridine (5.000 g, 42.324 mmol) was added to acetonitrile (100 mL). Benzyl bromide (18.097 g, 105.811 mmol) was added to the reaction mixture. After addition, the reaction was maintained at 100°C for 16 hours. LCMS monitoring indicated the reaction was complete. The reaction mixture was concentrated, and 100 mL of ethyl acetate was added to the mixture, followed by beating. The mixture was filtered and the filter cake was collected. The crude product, 6-benzyl-1H-pyrrolo[2,3-c]pyridin-6-ium (72.1 g) (12.200 g), was obtained.

[0594] Step 2: Synthesis of 6-benzyl-1,4,5,7-tetrahydropyrrolo[2,3-c]pyridine (72.2)

[0595] 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 showed that 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.

[0596] Step 3: Synthesis of 6-benzyl-1-(p-toluenesulfonyl)-5,7-dihydro-4H-pyrrolo[2,3-c]pyridine (72.3)

[0597] 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. The reaction solution was poured into 500 mL of saturated ammonium chloride solution and extracted with ethyl acetate three times in 200 mL increments. The organic phases were collected and combined, the solvent was evaporated, and then purified by flash liquid chromatography. The product 6-benzyl-1-(p-toluenesulfonyl)-5,7-dihydro-4H-pyrrolo[2,3-c]pyridine (72.3) was obtained (6.500 g, yield 47.1%).

[0598] Step 4: Synthesis of 1-(p-toluenesulfonyl)-4,5,6,7-tetrahydropyrrolo[2,3-c]pyridine (72.4)

[0599] 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. The reaction solution was concentrated and purified by flash liquid chromatography to obtain the product, 1-(p-toluenesulfonyl)-4,5,6,7-tetrahydropyrrolo[2,3-c]pyridine (72.4) (2.700 g, 55.1% yield).

[0600] Step 5: Synthesis of 6-methylsulfonyl-1-(p-toluenesulfonyl)-5,7-dihydro-4H-pyrrolo[2,3-c]pyridine (72.5)

[0601] 1-(p-Toluenesulfonyl)-4,5,6,7-tetrahydropyrrolo[2,3-c]pyridine (72.4) (1.000 g, 3.619 mmol) was added to dichloromethane (30 mL), followed by triethylamine (1.098 g, 10.856 mmol). After the addition was complete, methanesulfonic anhydride (1.261 g, 7.237 mmol) was added to the reaction system while maintaining the reaction at 0°C. The reaction system was maintained at 20°C for 6 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was concentrated and purified by flash liquid chromatography to obtain the product, 6-methylsulfonyl-1-(p-Toluenesulfonyl)-5,7-dihydro-4H-pyrrolo[2,3-c]pyridine (72.5) (0.500 g, 39.0% yield).

[0602] Step 6: Synthesis of 6-methylsulfonyl-1-(p-toluenesulfonyl)-5,7-dihydro-4H-pyrrolo[2,3-c]pyridine-3-sulfonyl chloride (72.6)

[0603] Dissolve 6-methylsulfonyl-1-(p-toluenesulfonyl)-5,7-dihydro-4H-pyrrolo[2,3-c]pyridine (72.5 g) (0.400 g, 1.129 mmol) in dichloromethane (10 mL). Add chlorosulfonic acid (658 mg, 5.647 mmol) dropwise while maintaining the reaction at -40°C. Maintain the reaction at -40°C for 1 hour. LCMS monitoring indicates the reaction is complete. Add oxalyl chloride (2 mL) while maintaining the reaction at -40°C. Raise the reaction temperature to 0°C and slowly add N,N-dimethylformamide (2 mL) dropwise in portions. After the addition, slowly warm the reaction system to 25°C and allow to react for 11 hours. TLC monitoring indicates the reaction is complete. Cool the reaction mixture to 20°C and slowly add dropwise to 50 g of crushed ice. Extract the aqueous phase with 20 mL of ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, and then spin-dried to dryness. The organic phase was then purified by flash liquid column chromatography to obtain the product 6-methylsulfonyl-1-(p-toluenesulfonyl)-5,7-dihydro-4H-pyrrolo[2,3-c]pyridine-3-sulfonyl chloride (72.6 g) (0.450 g, 88.0% yield).

[0604] 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)

[0605] 4-(Difluoromethoxy)-2,5-difluoroaniline (43.3) (119 mg, 572.106 μmol) was added to anhydrous pyridine (2 mL), followed by 6-methylsulfonyl-1-(p-toluenesulfonyl)-5,7-dihydro-4H-pyrrolo[2,3-c]pyridine-3-sulfonyl chloride (72.6) (0.200 g, 441.547 μmol). After the addition, the reaction was maintained at 100°C in a microwave oven for 1 hour. LCMS monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid chromatography to obtain the product, N-(4-bromo-2,5-difluorophenyl)-6-methylsulfonyl-1-(p-toluenesulfonyl)-5,7-dihydro-4H-pyrrolo[2,3-c]pyridine-3-sulfonamide (72.7) (0.270 g, 97.9% yield).

[0606] Step 8: Synthesis of N-(4-bromo-2,5-difluorophenyl)-6-methylsulfonyl-1,4,5,7-tetrahydropyrrolo[2,3-c]pyridine-3-sulfonamide (72)

[0607] 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 μmol) 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. The 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) was obtained (0.116 g, yield 57.0%). 1 H NMR (400MHz, DMSO-d6) δ11.45(s,1H),10.19(s,1H),7.69(dd,J=9.7,6.4Hz,1H),7.35–7.22(m,2H) ,4.19(s,2H),3.37(t,J=5.7Hz,2H),2.91(s,3H),2.65(t,J=5.6Hz,2H).MS(m / z):467.8;469.8[MH] - .

[0608] 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)

[0609] 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)

[0610] 4-(Difluoromethoxy)-2,5-difluoroaniline (43.3) (60 mg, 307.512 μmol) 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) (80 mg, 157.518 μmol). After addition, the reaction was maintained at 110°C in a microwave oven for 1 hour. TLC monitoring indicated the reaction was complete. The reaction solution was dried and purified by flash liquid column chromatography to obtain the product (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) (100 mg, yield 95.2%).

[0611] 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)

[0612] (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) (100 mg, 150.030 μmol) was added to methanol (2 mL), and an aqueous solution of potassium carbonate (270 mg, 1.954 mmol) (2 mL) was added. After the addition was complete, the reaction was maintained at 80°C for 1 hour. TLC monitoring showed that the reaction was complete. The 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. The product (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) (30 mg, yield 39.0%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.40(s,1H),9.98(s,1H),7.45–6.80(m,5H),3.02(q,J=17.2 Hz,2H),2.80–2.64(m,1H),2.46–2.30(m,2H),2.05–1.86(m,1H).MS(m / z):511.0[MH] - .

[0613] 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)

[0614] Step 1: Synthesis of 6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbaldehyde oxime (74.1)

[0615] Dissolve 6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbaldehyde (47.1 g) (1.800 g, 5.094 mmol) in ethanol (50 mL), add hydroxylamine hydrochloride (1.661 g, 23.909 mmol) and sodium carbonate (2.558 g, 24.139 mmol). After addition, maintain the reaction at 40°C for 1 hour. TLC monitoring indicates the reaction is complete. After filtration, the filtrate is concentrated to obtain the crude product, 6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbaldehyde oxime (74.1 g) (1.000 g).

[0616] Step 2: Synthesis of 6-(difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbonitrile (74.2)

[0617] 6-(Difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbaldehyde oxime (74.1) (1.000 g, 2.714 mmol) was dissolved in tetrahydrofuran (20 mL), followed by the addition of carbonyldiimidazole (4.181 g, 25.787 mmol). After the addition was complete, the reaction was maintained at 60°C for 4 hours. LCMS monitoring showed that the reaction was complete. The 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).

[0618] 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)

[0619] 6-(Difluoromethyl)-1-(p-toluenesulfonyl)-5,7-dihydro-4H-indole-6-carbonitrile (74.2) (0.660 g, 217.171 μmol) was subjected to supercritical fluid chromatography to obtain the product (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) (263 mg, yield 39.8%).

[0620] 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)

[0621] (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 mg, 570.805 μmol) was dissolved in acetonitrile (2 mL) and chlorosulfonic acid (200 mg, 1.716 mmol) was added while maintaining the temperature at -40°C. After the addition, the reaction was maintained at 20°C for 1 hour. TLC monitoring indicated that the reaction was complete. The reaction solution was concentrated. 3 mL of dichloromethane was added to the reaction solution, and oxalyl chloride (732 mg, 5.767 mmol) and N,N-dimethylformamide (41 mg, 560.922 μmol) were 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 chromatography. The product (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) (160 mg, yield 62.4%) was obtained.

[0622] Step 5: Synthesis of (S)-N-(4-bromo-2,5-difluorophenyl)-6-cyano-1-p-toluenesulfonyl-...

Claims

1. A compound represented by the following formula I: or a tautomer, mesomer, racemate, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof; in, W is selected from Ring A is selected from a 4- to 7-membered saturated cycloalkyl or heterocyclic group; T, V, X, Y, and Z are independently selected from C or N; R is selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo 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)2Ra, or 3-10 membered cycloalkyl containing 0-3 heteroatoms, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, 3-10 membered cycloalkyl containing 0-3 heteroatoms, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 Ra; R is selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo 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)2Ra, or 3-10 membered cycloalkyl containing 0-3 heteroatoms, heterocyclyl, aryl, and heteroaryl, said alkyl, alkenyl, alkynyl, 3-10 membered cycloalkyl containing 0-3 heteroatoms, heterocyclyl, aryl, and heteroaryl being optionally substituted with 1-3 Ra; or for 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 optionally substituted with 1-3 Rc; Each Rc and Rd is independently selected from hydrogen, halogen, carbonyl, hydroxyl, cyano, nitro, phenyl, benzyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C6 cycloalkyl or halo C3-C6 cycloalkyl; n is selected from 0, 1, 2, 3, 4 or 5; m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; and m' is selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1, wherein W is selected from 3. The compound according to claim 1, wherein The formula I is formula Ia: Wherein, T and Z are selected from C or -N=; R1, R2, Ra, Rb, Rc, Rd, m', and n are as defined in claim 1.

4. The compound according to claim 1, wherein Formula I is Formula Ib: Wherein, X, Z are selected from C or -N=; R1, R2, Ra, Rb, Rc, Rd, m, and n are as defined in claim 1.

5. The compound of formula (I) according to claim 1, wherein R1 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, hydroxyl, 6. The compound of formula (I) according to claim 1, wherein R1 is selected from hydrogen, methyl, methoxy, chlorine, fluorine, bromine, iodine, trifluoromethyl, Hydroxyl, 7. The compound of formula (I) according to claim 1, wherein R2 is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, carbonyl, C1-C6 alkyl, C1-C6 alkylhydroxyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocyclyl, halogenated C3-C6 cycloalkyl, 8. The compound of formula (I) according to claim 1, wherein R2 is selected from hydrogen, deuterium, fluorine, chlorine, cyclopropyl, hydroxy, trifluoromethyl, methoxy, cyano, carbonyl, -CH2OH, 9. The compound of formula (I) according to claim 1, wherein The compound is selected from:

10. The compound of formula (I) according to claim 1, wherein The compound is selected from:

11. Use of the compound according to any one of claims 1 to 10, its isomer or pharmaceutically acceptable salt thereof in the preparation of a GPR17 receptor inhibitor.

12. Use of the compound according to any one of claims 1 to 10, its isomer or pharmaceutically acceptable salt thereof for preparing a medicament for treating and / or preventing neurodegenerative diseases.

13. The use according to claim 12, wherein The neurodegenerative disease is caused by damage to inhibitory neurons and includes multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis or Parkinson's syndrome.

14. Use of the compound according to any one of claims 1 to 10, its isomer or pharmaceutically acceptable salt thereof for preparing a medicament for treating and / or preventing diseases related to GPR17-mediated dysmyelination.

15. The use according to claim 14, wherein The GPR17-mediated myelin formation disorder-related diseases include multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis or Parkinson's syndrome.

16. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 10, its isomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

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