N-substituted tetrahydrothiophenepyridine derivatives and their uses

Abstract

A compound of formula (I) is provided, which has been shown to be useful for treating diseases caused by viral infections: (I), wherein R 1 R 2 R 3 A, L, m, n, p, and q are as defined in this paper.

Description

[0001] Cross-referencing of related applications

[0002] This application claims priority to U.S. Serial No. 62 / 687,068, filed June 19, 2018, the contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to N-substituted tetrahydrothiophenepyridine derivatives, pharmaceutical compositions thereof, and their use in the prevention and treatment of viral infections, particularly viral infections caused by dengue virus. Background Technology

[0004] Dengue fever is the most common arthropod-borne viral (arbovirus) disease in humans and remains a global health problem. Dengue fever is a febrile illness caused by one of four dengue virus serotypes—DEN-1, DEN-2, DEN-3, and DEN-4—belonging to the Flaviviridae family. These viruses are primarily transmitted to humans by the Aedes aegypti mosquito, a type of mosquito that feeds on humans.

[0005] From mild, flu-like symptoms to more severe, sometimes fatal, hemorrhagic illnesses, infections produce a range of clinical manifestations. Typical symptoms include fever, severe headache, muscle and joint pain, and rash. The most severe forms of the disease are dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). According to the WHO, DHF has four main clinical manifestations: (1) high fever, (2) bleeding phenomena, (3) thrombocytopenia, and (4) plasma leakage. DSS is defined as DHF with a weak, rapid pulse and narrow pulse pressure or hypotension accompanied by cold, sticky skin, and restlessness. The severity of DHF can be reduced through early detection and intervention, but subjects who develop shock have a higher risk of death.

[0006] It is estimated to affect 390 million people annually, with 96 million showing clinical signs of the disease. According to the WHO, reported cases increased from 2.2 million in 2010 to 3.2 million in 2015. Before 1970, only nine countries experienced severe dengue outbreaks. According to WHO surveillance, dengue is now endemic in more than 100 countries across Africa, the Americas, the Eastern Mediterranean, Southeast Asia, and the Western Pacific. The Americas, Southeast Asia, and the Western Pacific remain the most severely affected regions. One in four infected individuals will require hospitalization, and 3-6% may progress to dengue hemorrhagic fever or shock syndrome, representing the fatal manifestations of the disease. Based on WHO estimates, the current annual death toll in 2012 was approximately 12,500; however, this figure is believed to be a significant underestimation due to the underreporting of most cases. The risk of developing a lethal form of dengue and the social costs of dengue demonstrate that the discovery and commercialization of anti-dengue drugs would offset the costs of hospitalization and inactivity.

[0007] Despite periodic outbreaks, people who have been previously infected remain susceptible to dengue because there are four different serotypes of the dengue virus, one of which provides immunity only to that serotype. DHF is believed to be more likely to occur in subjects with secondary dengue infection. Effective treatments for dengue, DHF, and DSS are being sought.

[0008] Yellow fever virus (YFV), West Nile virus (WNV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis, St. Louis encephalitis, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, and hepatitis C virus (HCV) also belong to the Flaviviridae family.

[0009] WNV may be asymptomatic or cause flu-like symptoms in some individuals. In some cases, it can lead to neurological disorders, encephalitis, and, in severe cases, death. WNV is also transmitted by mosquitoes. YFV is also transmitted by mosquitoes and can cause severe symptoms in infected individuals. JEV is also transmitted by mosquitoes and is both asymptomatic and causes flu-like symptoms, and in some cases can develop into encephalitis. The acute encephalitis phase of the disease is characterized by seizures, neck stiffness, and other symptoms. HCV is a blood-borne virus, transmitted through blood-to-blood contact. In the initial (acute) phase of the disease, most subjects do not experience any symptoms. Even in the chronic phase (i.e., the disease lasts longer than 6 months), the severity of symptoms varies from subject to subject. In the long term, some infected individuals may develop cirrhosis and liver cancer. Current treatment for HCV involves a combination of interferon-alpha and the antiviral drug ribavirin. Effective treatments for infections caused by these Flaviviridae viruses are also being sought.

[0010] This invention relates to N-substituted tetrahydrothiophenepyridine derivatives that can be used to treat viral infections, such as those caused by Flaviviridae viruses, especially dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunzin virus, Murray Valley encephalitis, St. Louis encephalitis, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, and hepatitis C virus, as well as other Flaviviridae viruses described herein. Summary of the Invention

[0011] One aspect of the present invention provides a compound having formula (I) or a pharmaceutically acceptable salt thereof:

[0012]

[0013] in:

[0014] A is a phenyl or a 3-6 membered cycloalkyl group; each is optionally marked with --C 1-6 Alkyl, cyano, -C 1-4 aminoalkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 Haloalkoxy and halogen substitution;

[0015] L is -C 1-6 alkylene-;

[0016] Each R 1 Independently selected from -C 1-6 Alkyl, cyano, -C 1-4 aminoalkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 Haloalkoxy and halogen groups;

[0017] Each R 2 Is it H or -C 1-6 alkyl;

[0018] R 3 Selected from -C 1-6 Alkyl, -CN, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 Halogenated alkoxy groups, halogens, -C(O)R 3a -C(O)OR 3b -C(O)NR 3c R 3d -P(O)R 3e R 3f -P(O)(OR) 3g (OR) 3h -P(O)(OR)3i (R) 3j -S(O)2R 3k -S(O)2NR 3l R 3m -S(O)R 3n -NR 3o R 3p -NR 3q C(O)R 3r -N(R) 3s )C(O)OR 3t and -NR 3u S(O)2R 3v Wherein -C 1-6 Alkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl groups and -C 1-4 The haloalkoxy group can be independently and optionally substituted by: hydroxyl group, -NR group, etc. 3w R 3x -C 1-4 Alkyl group, -S(O)2NR 3y R 3z or -S(O)2R 3a2 ;where R 3w R 3x R 3y and R 3z Each is independently H, -C 1-4 Alkyl or -C 1-6 Halogenated alkyl groups, and R 3a2 It is -C 1-4 Alkyl or -C 1-6 Halogenated alkyl, or

[0019] Any two R 3 It can combine with one atom to form a 5-6 membered fused heterocyclic alkyl group, wherein the heterocyclic alkyl group contains one or two heteroatoms selected from N and S, and wherein the heterocyclic alkyl group is independently optionally substituted by one or two groups selected from: -C 1-6 Alkyl, -C 1-4 Aminoalkyl-CN,-C 1-4 Alkoxy, halogen, -C 1-6 Halogenated alkyl groups and -C 1-4 Halogenated alkoxy groups;

[0020] R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h R 3i R3j R 3k R 3n R 3o R 3p R 3q R 3r R 3s R 3t R 3u R 3v Each is independently selected from H and -C. 1-6 Alkyl and -C 1-6 Halogenated alkyl groups;

[0021] R 3l and R 3m Each is independently selected from H and -C. 1-6 Alkyl, -C 1-6 Halogenated alkyl, aminoalkyl, and hydroxyalkyl, wherein the -C 1-6 The alkyl group is optionally further substituted with a 3-6 membered cycloalkyl group, and wherein the 3-6 membered cycloalkyl substituent is optionally further substituted with 1-2 halogen groups; or R 23 and R 24 It can combine with N to form a 5-6 membered heterocyclic alkyl group, wherein the 5-6 membered heterocyclic alkyl group optionally further comprises a heteroatom selected from S and N; or

[0022] p is 1, 2, or 3; q is 0 or 1; and n and m are each independently selected from 0, 1, and 2.

[0023] The present invention also provides a method for manufacturing the compounds of the present invention and intermediates.

[0024] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to formula (I) or a subformula thereof, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and one or more pharmaceutically acceptable carriers.

[0025] The present invention provides a combination, particularly a pharmaceutical combination, comprising a therapeutically effective amount of a compound according to formula I or a subformula thereof, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and one or more additional therapeutically active agents.

[0026] In another aspect of the invention, a method for treating a disease caused by a viral infection is provided, the method comprising the steps of administering to a subject (particularly a human) a therapeutically effective amount of a compound having formula (I) (including any of the embodiments described herein). In a particularly useful embodiment, the viral infection is caused by a virus selected from the group consisting of: dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunzin virus, Murray Valley encephalitis, St. Louis encephalitis, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, and hepatitis C virus. In an even more particularly useful embodiment, the viral infection is caused by dengue virus. The compound can be administered as a pharmaceutical composition described herein.

[0027] Another aspect of the invention includes compounds having formula (I) (including any of the above embodiments) used as pharmaceuticals (e.g., use of compounds having formula (I) (including any of the above embodiments) in the manufacture of pharmaceuticals for treating diseases caused by viral infections). In a particularly useful embodiment, the viral infection is caused by a virus selected from the group consisting of: dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunzin virus, Murray Valley encephalitis, St. Louis encephalitis, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, and hepatitis C virus. In an even more particularly useful embodiment, the viral infection is caused by dengue virus. Detailed Implementation

[0028] definition

[0029] Unless otherwise stated, the general terms used above and below are preferably meant in the context of this invention, wherein, in any case, more general terms may be replaced or retained by more specific definitions, thereby defining more detailed embodiments of the invention.

[0030] All methods described herein can be performed in any suitable order unless otherwise stated herein or otherwise obviously contradicted by the context. Any and all instances or exemplary language (such as "such as") provided herein are intended only to better illustrate the invention and not to limit the scope of the invention as otherwise claimed.

[0031] The terms “a / an”, “the”, and similar terms used in the context of this invention (particularly in the context of the claims) should be interpreted as encompassing both the singular and the plural, unless otherwise indicated or clearly contradicted by the context.

[0032] As used in this article, the term "heteroatom" refers to a nitrogen (N), oxygen (O), or sulfur (S) atom, especially nitrogen or oxygen.

[0033] Unless otherwise indicated, it is assumed that any heteroatom having an unsaturated valence has hydrogen atoms sufficient to satisfy the valence.

[0034] As used in this article, the term "C" 1-6 "Alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without any unsaturation, having one to six carbon atoms, and attached to the rest of the molecule by single bonds. The term "C" is also used in this context. 1-4 "Alkyl" should be interpreted accordingly. As used herein, the term n-alkyl means a straight-chain (unbranched) alkyl group as defined herein. 1-8 Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl (-CH2CH(CH3)2), sec-butyl (-CH(CH3)CH2CH3), tert-butyl (-C(CH3)3), n-pentyl, isopentyl (-(CH2)2CH(CH3)2), neopentyl (-CH2C(CH3)3), tert-pentyl (-C(CH3)2CH2CH3), 2-pentyl (-CH(CH3)(CH2)2CH3), n-hexyl, etc.

[0035] The term "alkylene" refers to a divalent alkyl group. For example, the terms "C1-C6 alkylene" or "C1 to C6 alkylene" refer to a divalent straight-chain or branched aliphatic group containing 1 to 6 carbon atoms (e.g., methylene (-CH2-), ethylene (-CH2CH2-)).

[0036] Propylene (-CH2CH2CH2-), isopropylene (-CH(CH3)CH2-), butylene, sec-butylene, isobutylene, tert-butylene, pentylene, isopentylene, neopentylene, hexylene, etc.

[0037] The term "alkoxy" refers to an alkyl group bonded to an oxygen atom, and can also be represented as -OR or -OR, where R represents an alkyl group. "C 1-6 "Alkoxy" or "C1 to C6 alkoxy" is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy.

[0038] As used herein, “amino” refers to the group -NH2. When an amino group is described as “substituted” or “optionally substituted”, the term includes NR'R", where R' and R” are each independently H, or alkyl, alkenyl, alkynyl, acyl, aryl, aryl, cycloalkyl, arylalkyl, cycloalkylalkyl groups or isoforms of these groups, each of which may optionally be substituted by a substituent suitable for the respective group as described herein.

[0039] The term "amino" also includes the form in which R' and R" are linked together to form a 3-8 membered ring, which may be saturated, unsaturated or aromatic, and contains 1-3 heteroatoms independently selected from N, O and S as ring members, and is optionally described as suitable for alkyl substituent substitution, or, if NR'R" is an aromatic group, it is optionally described as typical for heteroaryl substituent substitution.

[0040] Unless otherwise stated, compounds of the present invention containing an amino moiety may include their protected derivatives. Suitable protecting groups for the amino moiety include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc.

[0041] As used in this article, the term "C" 1-4 "Aminoalkyl" refers to a group having the formula -RNH2, where R is an alkylene group as defined above.

[0042] The "halogen" or "halogen group" can be fluorine, chlorine, bromine or iodine (fluorine and chlorine are preferred halogens as substituents).

[0043] "Haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl," which is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, substituted with one or more fluorine atoms.

[0044] "Haloalkoxy" refers to a haloalkyl group with a specified number of carbon atoms, as defined above, attached by an oxygen bridge. For example, "C 1-6 "Haloalkoxy" or "C1 to C6 haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy.

[0045] The term "aryl" refers to a 6- to 10-membered aromatic carbon ring moiety having a monocyclic system (e.g., phenyl) or a fused-ring system (e.g., naphthalene). A typical aryl group is a phenyl group.

[0046] "Heterocyclic alkyl" means cycloalkyl as defined in this application, provided that one or more indicated cyclic carbons are partially substituted by a subset of the following: -O-, -N=, -NR-, -C(O)-, -S-, -S(O)-, and -S(O)2-, where R is hydrogen, C is carbon, and C is carbon. 1-4 Alkyl or nitrogen-protected groups (e.g., benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl, 3,4-dimethoxybenzyl, etc.). For example, 3- to 8-membered heterocyclic alkyl groups include epoxy, aziridine, aziridine, imidazolyl, pyrazolidine, tetrahydrofuranyl, tetrahydrothiophene, tetrahydrothiophene 1,1-dioxide, oxazolidine, thiazolyl, pyrrolidinyl, pyrrolidinyl-2-one, morpholinyl, piperazinyl, piperidinyl, piperidinyl ketone, pyrazolidine, hexahydropyrimidinyl, 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, thiomorpholinyl, sulfomorpholinyl, sulfonylmorpholinyl, octahydropyrrolo[3,2-b]pyrrolidinyl, etc.

[0047] The term "heteroaryl" refers to an aromatic moiety containing at least one heteroatom (e.g., oxygen, sulfur, nitrogen, or combinations thereof) within a 5- to 10-membered aromatic ring system (e.g., pyrrole, pyridinyl, pyrazolyl, indolyl, indazole, thiophene, furanyl, benzofuranyl, oxazolyl, isoxazolyl, imidazole, triazolyl, tetrazolyl, triazinyl, pyrimidinyl, pyrazinyl, thiazolyl, purine, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxolinyl, benzopyranyl, benzothiophene, benzimidazolyl, benzooxazolyl, 1H-benzo[d][1,2,3]triazolyl, etc.). Heteroary aromatic moieties can consist of monocyclic or fused ring systems. A typical mono-heteroaryl ring is a 5- to 6-membered ring containing one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen, while a typical fused heteroaryl ring system is a 9- to 10-membered ring system containing one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen. Fused heteroaryl ring systems can consist of two fused heteroaryl rings or a heteroaryl group fused to an aryl group (e.g., phenyl).

[0048] As used herein, "bridged ring" or "bridged ring" refers to a multi-ring system in which the two rings share two ring atoms that are not directly bonded to each other. One or more rings in the ring system may include C 3-6 Cycloalkyl or 4- to 6-membered heterocycles containing a heteroatom selected from N, O, and S as the ring atom. Non-exclusive examples of bridged rings include adamantyl, azabicyclo[3.2.1]oct-3-en-3-yl,

[0049] wait.

[0050] As used in this article, the term "cyano" refers to the group *-C≡N.

[0051] The term "cycloalkyl" refers to a non-aromatic carbon ring that is a fully hydrogenated ring, including monocyclic, bicyclic, or polycyclic, fused, bridged, or spirocyclic systems. 3-10 "Cycloalkyl" or "C3 to C3" 10 "Cycloalkyl" is intended to include C3, C4, C5, C6, C7, C8, C9 and C6 carbon rings having 3 to 10 carbon ring members. 10 Cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1,1,1]pentyl, cyclohexyl, norbornyl, and cubic alkyl.

[0052] As used herein, a "fused ring" refers to a polycyclic assembly containing rings connected such that common ring atoms of the two rings are directly bonded to each other. Fused ring assemblies can be saturated, partially saturated, aromatic, carbocyclic, heterocyclic, etc. Common non-exclusive examples of fused rings include decahydronaphthalene, naphthalene, anthracene, phenanthrene, indole, benzofuran, purine, quinoline, etc.

[0053] As used in this article, the term "hydroxyl group" refers to the -OH group.

[0054] As used herein, the term "substituted" means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that the normal valence is maintained and the substitution produces a stable compound. When the substituent is a ketone group (i.e., =O), two hydrogen atoms on the atom are replaced. Ketone substituents are not present on aromatic moieties. When a ring system (e.g., a carbocyclic or heterocyclic ring) is allegedly substituted with a carbonyl group or double bond, it is intended that the carbonyl group or double bond is part of the ring (i.e., within the ring). As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0055] In the presence of nitrogen atoms (e.g., amines) in the compounds of the present invention, they can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to provide other compounds of the present invention. Therefore, the nitrogen atom shown and claimed is considered to encompass both the nitrogen shown and its N-oxide (N→O) derivatives.

[0056] When any variable appears more than once in any component or chemical formula of a compound, its definition is independent of its definition for each occurrence. Thus, for example, if a group is shown to be substituted with zero to three Rs, the group can be unsubstituted or substituted with at most three Rs, and Rs are chosen independently of their definition.

[0057] As used in this article, It is a symbol representing the attachment point of R to other parts of the molecule.

[0058] When a bond to a substituent is shown to cross a bond between two atoms in the ring, such a substituent can be bonded to any atom in the ring. When a substituent is listed without indicating which atoms in the substituent are bonded to the remainder of a compound having a given formula, such a substituent can be bonded via any atom in that substituent.

[0059] Combinations of substituents and / or variables are permitted only if such combinations produce stable compounds.

[0060] The phrase “pharmaceutically acceptable” indicates a substance or composition that must be chemically and / or toxicologically compatible with other ingredients contained in the preparation and / or with the mammals being treated with it.

[0061] Unless otherwise stated, the term "compound of the present invention" refers to compounds having formula (I), (IA), (IB), or (IC), as well as isomers such as stereoisomers (including diastereomers, enantiomers, and racemates), geometric isomers, conformational isomers (including rotational isomers and throttling isomers), tautomers, isotopically labeled compounds (including deuterium-substituted compounds), and intrinsically formed portions (e.g., polymorphs, solvates, and / or hydrates). Salts, particularly pharmaceutically acceptable salts, are also included where salt-forming portions are present.

[0062] Those skilled in the art will recognize that the compounds of the present invention may contain a chiral center and therefore may exist in different isomeric forms. As used herein, the term "isomer" refers to different compounds having the same molecular formula but different arrangements and configurations of atoms.

[0063] "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to specify racemic mixtures where appropriate. When specifying the stereochemistry of the compounds of the present invention, a single stereoisomer with known relative and absolute configurations having two chiral centers (e.g., (1S,2S)) is specified using the conventional RS system; a single stereoisomer with known relative configurations but unknown absolute configurations is indicated by an asterisk (e.g., (1R*,2R*)); and a racemic mixture with two letters (e.g., (1RS,2RS)) is a racemic mixture of (1R,2R) and (1S,2S); (1RS,2SR) is a racemic mixture of (1R,2S) and (1S,2R).

[0064] A “diastereomer” is a stereoisomer having at least two asymmetric atoms that are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Lngold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon can be represented by R or S. The resolution of a compound with an unknown absolute configuration can be specified (+) or (-) depending on the direction (dextrorotatory or levorotatory) that rotates plane-polarized light at the wavelength of the sodium D line. Alternatively, the resolved compound can be defined by chiral HPLC through the respective retention times of the enantiomer / diastereomer.

[0065] Some of the compounds described herein contain one or more asymmetric centers or axes, and thus can generate enantiomers, diastereomers, and other stereoisomers that can be defined by absolute stereochemistry as (R)- or (S)-.

[0066] Geometric isomers may occur when a compound contains a double bond or other features that impart a certain degree of structural rigidity to the molecule. If the compound contains a double bond, the substituent can be E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have cis or trans configurations.

[0067] A conformational isomer (or conformational isomer) is an isomer that can be rotated around one or more bonds to differ. A rotational isomer is a conformational isomer that differs by rotating around only one bond.

[0068] The term "restricted rotation isomer" refers to structural isomers that exhibit axial or planar chirality based on restricted rotation within the molecule.

[0069] Unless otherwise stated, the compounds of this invention are intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or using conventional techniques (e.g., using suitable solvents or solvent mixtures on chiral SFC or HPLC columns, such as those provided by DAICEL Corp.). and (Separate on top to achieve good separation) split.

[0070] The compounds of this invention can be isolated in either optically active or racemic form. The optically active form can be prepared by resolving the racemic form or by synthesis from optically active starting materials. All methods used to prepare the compounds of this invention and the intermediates prepared therein are considered part of this invention. When preparing enantiomers or diastereomers, they can be separated by conventional methods, such as chromatography or fractional crystallization.

[0071] Depending on the process conditions, the end products of this invention are obtained in free (neutral) or salt form. Both the free form and the salt form of these end products are within the scope of this invention. If necessary, one form of the compound can be converted to another. Free bases or acids can be converted to salts; salts can be converted to free compounds or another salt; and mixtures of isomers of the present invention can be separated into individual isomers.

[0072] Pharmaceutically acceptable salts are preferred. However, other salts may be suitable, for example, for separation or purification steps that may be employed during preparation, and are therefore considered to be within the scope of this invention.

[0073] As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound in which the parent compound is modified by forming its acid salt or base salt. For example, pharmaceutically acceptable salts include, but are not limited to, acetates, ascorbic acid salts, adipates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromoates, bicarbonates / carbonates, bisulfates / sulfates, camphorsulfonates, decanoates, chlorides / hydrochlorides, chlortheophyllonates, citrates, ethanedisulfonates, fumarates, glucohepanoates, glucuronates, glucuronates, glutamates, glutamates, glycolate salts, hippurates, hydroiodates / iodides, and hydroxyethylsulfonates. Lactates, lacturonates, dodecyl sulfates, malates, maleates, malonates / hydroxymalonates, mandelates, methanesulfonates, methyl sulfates, mucilages, naphthates, naphthalenesulfonates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, dihydroxynaphthalates, phenylacetates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonates, propionates, salicylates, stearates, succinates, aminosulfonates, sulfosalicylates, tartrates, toluenesulfonates, trifluoroacetates, or sinetates.

[0074] Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, with hydrochloric acid being preferred. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid.

[0075] Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I through XII of the periodic table. In some embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; basic ion exchange resins, etc. Some organic amines include isopropylamine, benzylamine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0076] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing a basic or acidic moiety. Typically, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both; typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts is found in Allen, LV, Jr., ed., Remington: The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press, London, UK (2012), the contents of which are hereby incorporated by reference.

[0077] Compounds of the present invention containing groups capable of acting as donors and / or acceptors of hydrogen bonds can form cocrystals with suitable cocrystal forgings. These cocrystals can be prepared from the compounds of the present invention using known cocrystal formation procedures. Such procedures involve grinding, heating, co-sublimating, co-melting, or contacting the compounds of the present invention with the cocrystal forgings in solution under crystallization conditions and then separating the resulting cocrystal.

[0078] Any formulas given herein are also intended to represent the unlabeled form and isotopically labeled form of the compound. Isotopically labeled compounds have the structure described by the formulas given herein, except that one or more atoms are replaced by atoms having a chosen atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I. This invention includes various isotope-labeled compounds as defined herein, such as those containing radioactive isotopes (e.g., 3 H, 13 C, and 14 Those compounds in C). These isotopically labeled compounds can be used for metabolic studies (using...) 14 C) Reaction kinetic studies (e.g., using...) 2 H or 3H), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays), or those used for radiation therapy to patients. In particular, 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. The isotopically labeled compounds of the present invention can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents by performing the procedures disclosed in the schemes or examples and preparations described below.

[0079] In addition, heavier isotopes, especially deuterium (i.e., 2 H or D substitution can provide certain therapeutic advantages arising from greater metabolic stability (e.g., prolonged in vivo half-life, reduced dose requirement, or improved therapeutic index). It should be understood that deuterium is considered a substituent in the compounds of this invention herein. The concentration of such a heavier isotope (particularly deuterium) can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotope abundance and the native abundance of the specified isotope. If the substituent in the compound of the present invention specifies deuterium, such a compound has an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doping on each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping).

[0080] The isotopically labeled compounds of the present invention can generally be prepared using conventional techniques known to those skilled in the art or by methods similar to those described herein, using appropriate isotopically labeled reagents instead of unlabeled reagents used in other cases. Such compounds have a variety of potential uses, such as as standards and reagents for determining the ability of potential drug compounds to bind to target proteins or receptors, or for imaging the compounds of the present invention bound to biological receptors in vivo or in vitro.

[0081] "Stable compound" and "stable structure" mean a compound that is robust enough to withstand separation from the reaction mixture to a useful purity and formulation into an effective therapeutic agent. Preferably, the compounds of the present invention do not contain N-halogen, S(O)₂H, or S(O)H groups.

[0082] The term "solvent" refers to the physical association of the compound of the present invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, the solvate can be separable (e.g., when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid). Solvent molecules in a solvate may be present in a regular and / or disordered arrangement. A solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvent" encompasses both a solution phase and a separable solvate. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are generally known in the art.

[0083] As used herein, "one or more polymorphs" refers to one or more crystalline forms having the same chemical structure / composition but with different spatial arrangements of molecules and / or ions forming crystals. The compounds of this invention can be provided in amorphous or crystalline solid form. Lyophilization can be used to provide the compounds of this invention in solid form.

[0084] As used in this article, the term "patient" encompasses all mammal species.

[0085] As used herein, the term "subject" refers to a primate (e.g., a human (male or female), dog, rabbit, guinea pig, pig, rat, and mouse). In some embodiments, the subject is a primate. In still other embodiments, the subject is a human.

[0086] As used herein, a subject is “in need” of treatment if the subject (preferred subject) would benefit from the treatment biologically, medically, or in terms of quality of life.

[0087] As used herein, the term “inhibit (inhibition or inhibiting)” means the reduction or suppression of a given condition, symptom or disorder, or disease, or a significant reduction in baseline activity of a biological activity or process.

[0088] As used herein, the term “treat / treating / treatment” refers to the treatment of a disease / disorder in mammals (particularly humans) and includes: (a) improving the disease / disorder (i.e., slowing or halting or mitigating the development of the disease / disorder, or at least one clinical symptom thereof); (b) alleviating or modulating the disease / disorder (i.e., causing physical regression of the disease / disorder (e.g., stabilizing identifiable symptoms), physiological regression (e.g., stabilizing bodily parameters), or both); (c) alleviating or improving at least one bodily parameter, including those parameters that may not be identifiable by the subject; and / or (d) preventing or delaying the onset or development or progression of a disease or disorder in mammals, specifically, preventing or delaying the occurrence of a disease or disorder in mammals that are susceptible to it but have not yet been diagnosed with it.

[0089] As used herein, “preventing” encompasses preventative treatment (i.e., prevention and / or risk reduction) of subclinical disease states in mammals (particularly humans), aimed at reducing the likelihood of developing a clinical disease state. Patients selected for preventative therapy are chosen based on known factors that increase the risk of developing a clinical disease state compared to the general population. “Preventative” therapy can be categorized into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment of subjects who have not yet developed a clinical disease state, while secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state.

[0090] The term "therapeuticly effective amount" for compounds of the present invention refers to the amount of the compound of the present invention that will cause a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity) or improve symptoms, alleviate symptoms, slow or delay disease progression, or prevent disease, etc.

[0091] The abbreviations used in this article are defined as follows: "1x" means once, "2x" means twice, "3x" means three times, "℃" means degrees Celsius, "aq" means aqueous, "Col" means column, "eq" means equivalent, "g" means gram, "mg" means milligram, "L" means liter, "mL" means milliliter, and "μL" means microliter. ormicroliters), “N” indicates normal, “M” indicates mole, “nM” indicates nanomoles, “mol” indicates mole (mole or moles), “mmol” indicates millimole or millimoles, “min” indicates minute (minute or minutes), “h” indicates hour (hour or hours), “rt” indicates room temperature, “RT” indicates retention time, “ON” indicates overnight, “atm” indicates atmospheric pressure, “psi” indicates pounds per square inch, “conc.” indicates concentration, “aq” indicates aqueous, “sat” or “sat'd” indicates saturation, “MW” indicates molecular weight, “mw” or “μwave” indicates microwave, “mp” indicates melting point, “Wt” indicates weight, “MS” or “Mass Spec” indicates mass spectrometry, “ESI” indicates electrospray mass spectrometry, “HR” indicates high resolution, “HRMS” indicates high resolution mass spectrometry, “LC-MS” indicates liquid chromatography-mass spectrometry, “HPLC” indicates high performance liquid chromatography, “RP” indicates high resolution mass spectrometry. "HPLC" indicates reversed-phase HPLC, "TLC" or "tlc" indicates thin-layer chromatography, "NMR" indicates nuclear magnetic resonance spectroscopy, "nOe" indicates nuclear Overhaus effect spectroscopy, "1H" indicates proton, "δ" indicates δ (delta), "s" indicates singlet, "d" indicates doublet, "t" indicates triplet, "q" indicates quartet, "m" indicates multiplet, "br" indicates broad peak, "Hz" indicates Hertz, "ee" indicates enantiomer excess, and "α", "β", "R", "S", "E" and "Z" are stereochemical designations familiar to those skilled in the art.

[0092] Embodiments of the present invention

[0093] This document describes various embodiments of the invention. It should be understood that the features specified in each embodiment can be combined with other specified features to provide further embodiments. The embodiments listed below are representative of the invention.

[0094] Example 1. A compound having Formula I as described in the invention, or a pharmaceutically acceptable salt thereof:

[0095]

[0096] Examples 2a, b, c, d, e, and f. Compounds having Formula I or pharmaceutically acceptable salts thereof according to Example 1, wherein p is any one of 1, 2, or 3, and q is any one of 0 or 1.

[0097] Examples 3a and 3b. The compounds have formula 1A or formula 1B:

[0098]

[0099] Example 4. A compound having Formula I or a pharmaceutically acceptable salt thereof according to Examples 1-3, wherein ring A is phenyl.

[0100] Example 5. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-3, wherein the A ring is a 4-6 membered cycloalkyl group.

[0101] Example 6. A compound having formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-4, wherein L is a -C substituted with a phenyl, a 3-6 membered cycloalkyl or a 5-7 membered bridged cycloalkyl. 1-4 Alkyl group. The phenyl group and the 3-6 membered cycloalkyl substituents are each optionally substituted independently by 1-3 groups selected from the following: halogen, -C 1-4 Alkyl, -C 1-4 Halogenated alkyl groups and -C 1-4 Alkyl group.

[0102] Example 7. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-5, wherein LA is selected from... Furthermore, each of these groups can be independently and optionally substituted by 1-3 groups selected from the following: halogen, -C 1-4 Alkyl, -C 1-4 Halogenated alkyl groups and -C 1-4 Alkyl group.

[0103] Example 8. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-6, wherein LA is selected from... These groups are each independently and optionally substituted by one or two groups selected from the following: halogen, -C 1-4 Alkyl and -C 1-4 Halogenated alkyl groups.

[0104] Example 9. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 7, wherein LA is selected from... Each R occurs at each time A Independently selected from halogen groups, -C 1-4 Alkyl, -C 1-4 Halogenated alkyl groups and -C 1-4 Alkyl group.

[0105] Example 10. A compound having Formula I or a pharmaceutically acceptable salt thereof according to Example 8, wherein each R A It is independently selected from F, Cl, -CH3 and -OCH3.

[0106] Example 11. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-10, wherein LA is selected from...

[0107] Example 12. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-12, wherein each R 1 Independently selected from H, -C 1-4 Alkyl and -C 1-4 Halogenated alkyl groups.

[0108] Example 13. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-12, wherein at least one R 1 It's H.

[0109] Example 14. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-13, wherein two R 1 Both are H.

[0110] Example 15. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-13, wherein at least one R 1 Selected from -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3 and CF3.

[0111] Example 16. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-12, wherein two R 1 Both are -CH3.

[0112] Example 17. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-16, wherein R 3Selected from -S(O)2NH2, -S(O)2N(CH3)2, -S(O)2NHCH3, -S(O)2NH-CH2-cyclobutyl, -S(O)2NH-CH2-cyclopentyl, -S(O)2NH-CH2-cyclohexyl, -S(O)2NH-CH2-difluorocyclobutyl, -S(O)2CH3 and -S(O)2CHF2.

[0113] Example 18. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-17, wherein R 3 Yes-S(O)2R 4 .

[0114] Example 19. A compound having formula IC or a pharmaceutically acceptable salt thereof:

[0115]

[0116] Example 20. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-19, wherein R 3 Selected from -S(O)2NH2, -S(O)2N(CH3)2, -S(O)CH3, -S(O)2CH2CH3, -N(H)S(O)2CH3, -NC(O)CH3, -CH2S(O)NH2, NH2 and -CONH2.

[0117] Example 21. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-19, wherein R 3 It is -S(O)2NH2 or -S(O)2CH3.

[0118] Example 22. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-16, wherein each R 3 Independently selected from halogen groups, CN and -C 1-4 Alkyl group.

[0119] Example 23. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-16, wherein each R 3 Independently is -C 1-4 Alkyl group.

[0120] Example 24. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-16, wherein each R 3 It is independently selected from -OCH3 and -OCH2CH3.

[0121] Example 25. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-24, wherein m is 0.

[0122] Example 26. A compound having formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-24, wherein m is 1.

[0123] Example 27. A compound having formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-24, wherein m is 2.

[0124] Example 28. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-27, wherein n is 0.

[0125] Example 29. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-27, wherein n is 1.

[0126] Example 30. A compound having Formula I or a pharmaceutically acceptable salt thereof according to any one of Examples 1-27, wherein n is 2.

[0127] Example 31. A compound having Formula I according to Example 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Examples 1-127.

[0128] Example 32. A pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I) and a pharmaceutically acceptable carrier or excipient.

[0129] Example 33. A pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I) as described in any one of Examples 1 to 31 as an active ingredient and at least one excipient.

[0130] Example 34. A pharmaceutical composition according to Example 32 or 33, comprising a therapeutically effective amount of a compound having formula (I) and a pharmaceutically acceptable carrier or excipient, and further comprising at least one additional pharmaceutical agent.

[0131] Example 35. The pharmaceutical composition according to Example 32, wherein the at least one additional agent is selected from the group consisting of: interferon, ribavirin and ribavirin analogs, cyclic protein binders, HCV NS3 protease inhibitors, HCV NS5a inhibitors, P7 inhibitors, entry inhibitors, NS4b inhibitors, α-glucosidase inhibitors, host protease inhibitors, immunomodulators, symptomatic relief agents, nucleoside and non-nucleoside NS5b inhibitors.

[0132] Example 36. A method for treating a disease caused by a viral infection, the method comprising the steps of administering to a subject in need a therapeutically effective amount of the compound according to any one of Examples 1-31.

[0133] Example 37. The method according to Example 36, wherein the viral infection is caused by a virus selected from the group consisting of: dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunzin virus, Murray Valley encephalitis, St. Louis encephalitis, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, and hepatitis C virus.

[0134] Example 38. The method according to Example 37, wherein the viral infection is caused by dengue virus.

[0135] Example 39. The compound according to any one of Examples 1-31, used as a drug.

[0136] Example 40. Use of the compound according to any one of Examples 1-31 in the manufacture of a medicament for treating diseases caused by viral infections.

[0137] Example 41. According to the use described in Example 40, the viral infection is caused by a virus selected from the group consisting of: dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunzin virus, Murray Valley encephalitis, St. Louis encephalitis, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, and hepatitis C virus.

[0138] Example 42. The use according to Example 41, wherein the viral infection is caused by dengue virus.

[0139] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In further embodiments, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition can be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also involve inhalation or intranasal application. The pharmaceutical compositions of the present invention can be made in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including but not limited to solutions, suspensions or emulsions). Tablets may be coated with a film or enteric coating according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule comprising one or more of the following:

[0140] a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0141] b) Lubricants, such as silica, talc, stearic acid, their magnesium or calcium salts, and / or polyethylene glycol; also included in tablets.

[0142] c) Adhesives, such as magnesium aluminum silicate, starch paste, gelatin, astragalus gum, methylcellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone; and if desired, also containing

[0143] d) Disintegrants, such as starch, agar, alginate or its sodium salt, or effervescent mixtures; and

[0144] e) Adsorbents, colorants, flavoring agents, and sweeteners.

[0145] Another aspect of the invention includes a pharmaceutical composition comprising a compound having formula (I) (including any of the examples above) and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition may further comprise at least one additional agent described below. Examples of additional agents include, but are not limited to, interferon, ribavirin and ribavirin analogs, cyclic protein binders, HCV NS3 protease inhibitors, HCV NS5a inhibitors, P7 inhibitors, entry inhibitors, NS4b inhibitors, α-glucosidase inhibitors, host protease inhibitors, immunomodulators, kinase inhibitors that induce cytokines or chemokines for severe dengue fever, symptomatic relief agents (e.g., for plasma leakage), surface receptors (e.g., CLEC5A and DC-SIGN), nucleoside and non-nucleoside NS5b inhibitors.

[0146] Pharmacology and efficacy

[0147] Unless otherwise stated, the compounds of this invention are intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. All tautomeric forms are also included.

[0148] The mixture of isomers available according to the invention can be separated into individual isomers in a manner known to those skilled in the art; diastereomers can be separated, for example, by partitioning between multiphase solvent mixtures, recrystallization and / or chromatographic separation, such as silica gel chromatography, or by medium-pressure liquid chromatography, for example, using a reversed-phase column; racemic mixtures can be separated, for example, by forming a salt with an optically pure salting agent and separating (e.g., by fractional crystallization) the diastereomer mixtures thus obtainable, or by chromatographic treatment on an optically active column material.

[0149] Compounds of the present invention containing groups capable of acting as donors and / or acceptors of hydrogen bonds can form cocrystals with suitable cocrystal forgings. These cocrystals can be prepared from compounds of the present invention using known cocrystal formation procedures. Such procedures involve grinding, heating, co-sublimating, co-melting, or contacting the compound of the present invention with the cocrystal forging under crystallization conditions in solution and then separating the resulting cocrystal. Therefore, the present invention further provides cocrystals comprising compounds of the present invention.

[0150] The compounds of the present invention are typically used as pharmaceutical compositions (e.g., the compounds of the present invention and at least one pharmaceutically acceptable carrier). As used herein, the term "pharmaceuticalally acceptable carrier" includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, pharmaceutical stabilizers, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.) and combinations thereof, which are known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990, pp. 1289-1329). Their use in therapeutic or pharmaceutical compositions is considered, except where any conventional carrier is incompatible with the active ingredient. For the purposes of this invention, solvates and hydrates are considered pharmaceutical compositions comprising the compounds of the present invention and a solvent (i.e., a solvate) or water (i.e., a hydrate).

[0151] Formulations can be prepared using conventional dissolution and mixing procedures. For example, the active pharmaceutical ingredient (i.e., the compound of the present invention or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complex)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compounds of the present invention are typically formulated into pharmaceutical dosage forms to provide easily controllable drug dosages and to offer patients an elegant and easy-to-handle product.

[0152] Pharmaceutical compositions (or preparations) for application can be packaged in various ways depending on the method of administration. Generally, the dispensing material includes a container in which the pharmaceutical preparation is stored in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), ampoules, plastic bags, metal cylinders, etc. Containers may also include anti-interference components to prevent accidental contact with the contents. Additionally, the container is labeled with a description of its contents. The label may also include appropriate warnings.

[0153] In some cases, it may be advantageous to administer the compounds of the present invention in combination with at least one other pharmaceutical agent (or therapeutic agent). The compounds of the present invention may be administered simultaneously with, before, or after one or more other therapeutic agents. Alternatively, the compounds of the present invention may be administered separately via the same or different routes of administration as one or more other pharmaceutical agents, or together in the same pharmaceutical composition.

[0154] Other suitable agents include, but are not limited to, interferon, ribavirin and ribavirin analogs, cyclic protein binders, HCV NS3 protease inhibitors, HCV NS5a inhibitors, P7 inhibitors, entry inhibitors, NS4b inhibitors, α-glucosidase inhibitors, host protease inhibitors, immunomodulators, kinase inhibitors that induce cytokines or chemokines for severe dengue fever, symptomatic relief agents (e.g. for plasma leakage), surface receptors (e.g., CLEC5A and DC-SIGN), and nucleoside and non-nucleoside NS5b inhibitors.

[0155] The compounds of the present invention or pharmaceutical compositions thereof are typically administered orally to humans at therapeutic doses.

[0156] It should be understood that the dosage range of the compounds of the present invention used to treat viral infections depends on factors known to those skilled in the art, including the host, the nature and severity of the disease to be treated, the method of administration, and the specific substance to be used.

[0157] The daily dose of the compounds of this invention will vary depending on the compound used, the method of administration, the required treatment and the indicated disease, as well as other factors such as the subject's age, weight, general health condition, illness, medical history, and sex, and similar factors known in the medical field. For example, the compounds of this invention are administered at daily doses ranging from about 0.5 mg / kg body weight to about 15 mg / kg body weight, for example, from about 1 mg / kg body weight to about 10 mg / kg body weight. Typically, for example, for a person weighing 70 kg, satisfactory results can be obtained when the compounds of this invention are administered at a daily dose of about 0.001 g to about 10 g, for example, not exceeding about 1 gram, for example, from about 0.1 g to about 0.5 g, taken up to four times a day.

[0158] Furthermore, several separate doses and intervals can be administered daily or sequentially, or the doses can be infused continuously, or administered by bolus injection. Additionally, the dosage of the compounds of the present invention can be increased or decreased proportionally according to the urgency of the treatment or prevention situation.

[0159] Typically, the therapeutically effective dose of a compound, pharmaceutical composition, or combination thereof depends on the subject's species, weight, age, and individual condition, as well as the disorder or disease being treated or its severity. A physician, pharmacist, clinician, or veterinarian with general skills can readily determine the effective amount of each active ingredient necessary to prevent, treat, or inhibit the progression of a disorder or disease.

[0160] Another aspect of the present invention is a product comprising the compound of the present invention and at least one other therapeutic agent (or pharmaceutical agent) as a combination formulation for use simultaneously, separately or sequentially in a therapy for treating a subject suffering from a disease caused by a viral infection.

[0161] In the combination therapy of the present invention, the compounds of the present invention and other therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compounds of the present invention and another therapeutic agent (or pharmaceutical agent) may be combined as a combination therapy in the following situations: (i) prior to the dispensing of the combination product to a physician (e.g., in the case of a kit or fixed-dose composition containing the compounds of the present invention and other therapeutic agents); (ii) shortly before administration, by the physician himself (or under the guidance of a physician); (iii) in the patient himself, for example during the sequential administration of the compounds of the present invention and other therapeutic agents.

[0162] Pharmaceutical compositions can be formulated, particularly advantageously, in unit dosage forms to facilitate administration and achieve dosage uniformity. As used herein, a unit dosage form refers to a physically discrete unit suitable as a unit dose; each unit contains a predetermined amount of active ingredient calculated to produce the desired therapeutic effect when combined with the desired drug carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions, and their segregated multiples.

[0163] The daily dose relative to other therapeutic agents will vary depending on factors such as the compound used, the host, the route of administration, and the severity of the condition being treated. As mentioned above, the dosage can vary considerably due to the wide variety of other therapeutic agents that can be used, and can be determined through routine experiments.

[0164] The compounds of the present invention and at least one other therapeutic agent (or pharmaceutical agent) may be administered via any conventional route, particularly enteric administration, such as oral administration, for example in the form of a solution, tablet or capsule for drinking, or parenteral administration, such as in the form of an injectable solution or suspension.

[0165] Combinations include those of the compounds of the present invention with non-immunosuppressive cyclophilic protein-binding cyclosporine, with mycophenolic acid, its salts or prodrugs, and / or with S1P receptor agonists (e.g., fingolimod).

[0166] In another aspect, the present invention provides a method comprising administering the compound of the present invention and another antiviral agent, preferably, for example, an antiflaviridae drug, and an antidengue or antihepatitis C virus agent. Such antiviral agents include, but are not limited to, immunomodulators such as α, β, and δ interferon, pegylated derivatized interferon-α compounds, and thymosin; other antiviral agents such as ribavirin, amantadine, and telbivudine; other hepatitis C protease inhibitors (NS2-NS3 inhibitors and NS3-NS4A inhibitors); inhibitors of other targets in the life cycle of flaviviridae (e.g., dengue virus, hepatitis C virus), including helicase, polymerase, and metalloproteinase inhibitors; internal ribosome entry inhibitors; and broad-spectrum viral inhibitors such as IMPDH inhibitors (e.g., US patents 5,807,876, 6,498,178, 6,344,465, 6,054,472, WO 97 / 40028, WO 98 / 40381, WO Compounds of 00 / 56331, and mycophenolic acid and its derivatives, including but not limited to VX-497, VX-148 and / or VX-944; or any combination of the above.

[0167] Each component of the combination according to the invention can be administered separately, together, or in any combination thereof. As will be appreciated by those skilled in the art, the dosage of interferon is typically measured in IU (e.g., about 4 million IU to about 12 million IU). Each component can be administered in one or more dosage forms. Each dosage form can be administered to the subject in any order.

[0168] Preparation of compounds

[0169] In light of the methods, reaction schemes, and examples provided herein, the compounds of this invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. The compounds of this invention can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are carried out in a solvent or solvent mixture suitable for the reagents and materials used and conducive to achieving the transformation. Those skilled in the art of organic synthesis will understand that the functional groups present on the molecule should correspond to the proposed transformation. This will sometimes require judgment to modify the order of synthetic steps or to select a particular process scheme instead of another in order to obtain the desired compounds of this invention.

[0170] General conditions:

[0171] Mass spectra were acquired on an LC-MS system from a range of instruments with the following configurations: SHIMADZU LCMS-2020, Agilent 1200LC / G1956A MSD, Agilent 1200 / G6110A, Agilent 1200LC, and Agilent 6110MSD mass spectrometers [M+H] using electrospray ionization, chemical ionization, and electron impact ionization methods. + It refers to the protonated molecular ions of chemical substances.

[0172] Chiral HPLC spectra were obtained using Chiralpak AS-S and AD-S, and Chiralcel OD-S and OJ-S on an SFC system (Agilent 1260 & Berger).

[0173] NMR spectra were performed on a Bruker 400MHz spectrometer using ICON-NMR under TopSpin program control. Unless otherwise specified, spectra were measured at 298K and referenced to solvent resonances.

[0174] instrument:

[0175] LC-MS method: Using SHIMADZU LCMS-2020, Agilent 1200LC / G1956A MSD and Agilent 1200\G6110A, Agilent 1200LC and Agilent 6110MSD.

[0176] Method 1: 5-95CD_R_220&254

[0177]

[0178]

[0179] Method 2: 10-80CD_4MIN_220&254

[0180]

[0181] Method 3: 5-95AB_R_220&254

[0182]

[0183]

[0184] Method 4: 5-95AB_4MIN_220&254

[0185]

[0186] Method 5: Use the Waters Acquity UPLC PDA wZQ2000 Sys(AI) equipped with Waters Acquity HSS.

[0187]

[0188]

[0189] Method 6: 10-80CD_2MIN_220&254_POS.M

[0190]

[0191] Method 7: Use a Waters Acquity UPLC PDA w ZQ2000Sys(AI) equipped with Waters Acquity CSH.

[0192]

[0193]

[0194] abbreviation:

[0195] AcOH (acetic acid)

[0196] Boc tert-butoxycarbonyl

[0197] Boc2O ditert-butyl dicarbonate

[0198] Bn benzyl

[0199] d Double peak

[0200] dd Double peak

[0201] DCM dichloromethane

[0202] DIPEA (diisopropylethylamine)

[0203] DMAP 4-Dimethylaminopyridine

[0204] TFA (trifluoroacetic acid)

[0205] DMF N,N-dimethylformamide

[0206] DMP Des Martin periodoyl alkane (1,1,1-triacetoxy-1,1-dihydro-1,2-benzoxopyrrolidone 3(1H)-one)

[0207] DMSO (dimethyl sulfoxide)

[0208] Dppf 1,1'-bis(diphenylphosphino)ferrocene

[0209] EtOAc (ethyl acetate)

[0210] h hours

[0211] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0212] HPLC (High-Performance Liquid Chromatography)

[0213] LCMS (Liquid Chromatography and Mass Spectrometry)

[0214] MeOH (methanol)

[0215] MTBE (methyl tert-butyl ether)

[0216] Ms. methanesulfonyl

[0217] MS mass spectrometry

[0218] m multiplet

[0219] mg

[0220] min minutes

[0221] mL

[0222] mmol millimole

[0223] m / z mass-to-charge ratio

[0224] NMR (Nuclear Magnetic Resonance)

[0225] ppm (parts per million)

[0226] PE petroleum ether

[0227] Rt retention time

[0228] s single peak

[0229] t triple peak

[0230] TEA Triethylamine

[0231] TLC (Thin Layer Chromatography)

[0232] Ts(Tos) p-Toluenesulfonyl

[0233] TFA (trifluoroacetic acid)

[0234] Tf2O trifluoromethanesulfonic anhydride

[0235] THF Tetrahydrofuran

[0236] T3P 2,4,6-Tripropyl-1,3,5,2,4,6-Trioxatriphosphacyclohexane-2,4,6-trioxide

[0237] Preparation of intermediates

[0238] Intermediate Core-1a_A:

[0239] 2-Amino-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile

[0240] Step 1: tert-butyl 2-amino-3-cyano-6,7-dihydrothiopheno[3,2-c]pyridine-5(4H)-carboxylate

[0241]

[0242] Sulfur (7.24 g, 225 mmol) and L-proline (3.47 g, 30 mmol) were added to a solution of tert-butyl 3-oxopiperidinium-1-carboxylate core-1a_A1 (30.00 g, 150 mmol) and CH2(CN)2 (19.89 g, 300 mmol) in DMF (300.0 mL). The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with water (1000 mL), followed by brine (1000 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was washed with EtOAc (50 mL) to give 2-amino-3-cyano-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carbamate tert-butyl ester core-1a_A2 (20.50 g, yield 49%); LC-MS Rt 0.92; MS m / z [M+H] + 223.9, Method 1.

[0243] Step 2: 2-Amino-4,5,6,7-Tetrahydrothiopheno[3,2-c]pyridine-3-carboxylonitrile

[0244]

[0245] At 0 °C, TFA (5.0 mL) was added to a solution of tert-butyl 2-amino-3-cyano-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate core-1a_A2 (5.00 g, 17.90 mmol) in DCM (45.0 mL). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was dissolved in water (50 mL) and extracted with DCM (50 mL × 2). The aqueous layer was acidified to pH 8-9 with saturated aqueous Na2CO3 and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated to give 2-amino-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1a_A3 (3.20 g (yield 99%)), which was used directly in the next step. LC-MS Rt 0.43 min; MS m / z [M+H] + 179.9, Method 1.

[0246] Step 3: 2-Amino-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxylonitrile

[0247]

[0248] DIPEA (3.61 g, 27.90 mmol) was added to a stirred solution of 2-amino-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1a_A3 (2.50 g, 13.95 mmol) and 1-(bromomethyl)-3-fluorobenzene core-1a_A4 (2.64 g, 13.95 mmol) in DMF (20.0 mL). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was dissolved in water (50 mL) and extracted with EtOAc (50 mL × 2). The organic layer was washed with a saline solution (100 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by silica column chromatography, eluted with 20 / 1 to 5 / 1 PE / EtOAc, to give 2-amino-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1a_A (1.10 g, yield 39%). 1 H NMR (400MHz, CDCl3) δ7.26-7.20(m,1H),7.10-6.98(m,2H),6.95-6.82(m,1H),4.59(s ,2H),3.62(s,2H),3.38(t,J=1.8Hz,2H),2.72-2.65(m,2H),2.59-2.51(m,2H); LC-MS Rt 1.40min; MS m / z[M+H] +288.1, Method 1.

[0249] Intermediate Core-1a_B:

[0250] 2-Amino-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxylonitrile

[0251] Step 1: 2-Amino-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile

[0252]

[0253] To a solution of 2-amino-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1a_A3 (7.0 g, 39.5 mmol) in DMF (70 mL), (bromomethyl)cyclohexane core-1a_B1 (4.2 g, 23.7 mmol) and DIPEA (10.1 g, 79 mmol) were added, and the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was poured into water (350 mL), and the aqueous layer was extracted with EtOAc (350 mL × 3). The combined organic layers were washed with water (200 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica column chromatography (9%-33% EtOAc in PE) to give 2-amino-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-2a_B as a white solid (2.1 g, yield 19%). 1 H NMR(400MHz,DMSO-d6)δ7.03(s,2H),3.33(s,3H),2.66-2.58(m,2H),2.50-2.44(m,2 H),2.51-2.44(m,2H),1.80-1.46(m,6H),1.32-1.06(m,3H),0.95-0.78(m,2H); LC-MS Rt 1.03min; MS m / z[M+H] + 276.0; Method 1.

[0254] Intermediate Core-1a_C:

[0255] 2-Amino-5-((3,3-difluorocyclobutyl)methyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile

[0256] Step 1: 3,3-Difluorocyclobutane formaldehyde

[0257]

[0258] Add DMP (1.98 g, 4.68 mmol) to a solution of (3,3-difluorocyclobutyl)methanol core-1a_C1 (0.477 g, 3.9 mmol) in DCM (40 mL). Stir the reaction mixture at 20 °C for 2 h. Filter the reaction mixture and use the filtrate directly for the next step.

[0259] Step 2: 2-Amino-5-((3,3-difluorocyclobutyl)methyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile

[0260]

[0261] A mixture of 3,3-difluorocyclobutaneformaldehyde core-1a_C2 (3.9 mmol, crude) and 2-amino-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile core-1a_A3 (1.1 g, 6.5 mmol) in MeOH (1 mL) was stirred at 20 °C for 4 h. After 4 h, NaBH3CN (0.5 g, 7.8 mmol) was added to the mixture. The mixture was stirred at 20 °C for 12 h. The reaction was concentrated to a solid, and the organic layer was concentrated to a solid by dilution with H2O (50 mL) and EtOAc (100 mL). The crude product was purified by reverse-phase column chromatography to give a red oily 2-amino-5-((3,3-difluorocyclobutyl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1a_C (0.4 g, 35% yield) and the byproduct 5-((3,3-difluorocyclobutyl)methyl)-2-(((3,3-difluorocyclobutyl)methyl)amino)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1a_C-byproduct (0.2 g, 11.5% yield). LC-MS Rt 0.89 min; MS m / z [M+H] + 284.0; Method 1.

[0262] Intermediate Core-1a_D:

[0263] 3-Fluorobicyclo[1.1.1]pentane-1-carboxaldehyde

[0264] Step 1: (3-Fluorobicyclo[1.1.1]pent-1-yl)methanol

[0265]

[0266] At 0 °C, LiAlH4 (17 mg, 0.45 mmol) was added to a solution of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid core-1a_D1 (40 mg, 0.3 mmol) in THF (1 mL). The mixture was stirred at 0 °C for 10 min, then heated to 20 °C and stirred for another 50 min. TLC showed that the starting material was consumed and new spots were formed. The reaction was quenched with MeOH (1 mL). The suspension was filtered and the filtrate was concentrated to give the desired core-1a_D2 (45 mg, crude). The crude core-1a_D2 was used directly for the next step without further purification. TLC Rf 0.40 (33% EtOAc in PE).

[0267] Step 2: 3-Fluorobicyclo[1.1.1]pentane-1-carboxaldehyde

[0268]

[0269] Add DMP (191 mg, 0.45 mmol) to a solution of (3-fluorobicyclo[1.1.1]pent-1-yl)methanol core-1a_D2 (35 mg, 0.3 mmol) in DCM (5 mL). Stir the mixture at 20 °C for 2 h. Filter the reaction solution. Concentrate the filtrate to remove most of the solvent. Use the resulting solution directly for the next step. TLC Rf 0.70 (33% EtOAc in PE).

[0270] Intermediate Core-2a_E:

[0271] 2-(3-Methoxy-4-aminosulfonylphenyl)acetic acid

[0272] Step 1: 2-(2-bromo-5-methoxyphenyl)acetic acid

[0273]

[0274] Br2 (8.08 g, 50.55 mmol) was added to a solution of 2-(3-methoxyphenyl)acetic acid core-1a_E1 (7.0 g, 42.12 mmol) in DCM (50 mL) at 0 °C. The reaction mixture was heated to 20 °C and stirred for 4 h. TLC (DCM:MeOH (10:1), Rf 0.30) showed that the reaction was complete. The reaction mixture was diluted with DCM (200 mL) and washed with aqueous Na2SO3 (100 mL). The organic layer was washed with brine and concentrated to give core-1a_E2 (9.0 g, 87.2% yield). 1H NMR (400MHz, CDCl3) δ7.48 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 3.0 Hz, 1H), 6.75 (dd, J = 3.0, 8.8 Hz, 1H), 3.82 (s, 2H), 3.81 (s, 3H).

[0275] Step 2: Methyl 2-(2-bromo-5-methoxyphenyl)acetate

[0276]

[0277] SOCl2 (26.2 g, 220.35 mmol) was added to a solution of 2-(2-bromo-5-methoxyphenyl)acetic acid core-1a_E2 (9.0 g, 36.72 mmol) in MeOH (50 mL). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated, and the residue was dissolved in EtOAc (200 mL), washed with brine, and concentrated to give crude core-1a_E3 (8.0 g, 84.0% yield). The residue was used directly in the next step without further purification.

[0278] Step 3: Methyl 2-(2-bromo-4-(chlorosulfonyl)-5-methoxyphenyl)acetate

[0279]

[0280] A stirred solution of methyl 2-((5-methoxy-2-methylphenyl)(2-oxopropyl)amino)acetate core-1a_E3 (3.00 g, 11.6 mmol) in CH2Cl2 (40 mL) was mixed with ClSO3H (8.11 g, 69.6 mmol) and stirred at 0 °C for 5 h. The reaction mixture was poured into ice-water (500 mL) and extracted with EtOAc (160 mL × 3). The combined organic layers were washed with water (300 mL), followed by brine (200 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl 2-(2-bromo-4-(chlorosulfonyl)-5-methoxyphenyl)acetate core-1a_E4 (3.06 g, 72.3% yield), which was used directly for the next step. 1 H NMR (400MHz, CDCl3) δ8.13(s,1H),7.11(s,1H),4.06(s,3H),3.87(s,2H),3.77(s,3H).

[0281] Step 4: Methyl 2-(2-bromo-5-methoxy-4-aminosulfonylphenyl)acetate

[0282]

[0283] At 0 °C, NH3 (gas) was bubbled into a solution of methyl 2-(2-bromo-4-(chlorosulfonyl)-5-methoxyphenyl)acetate core-1a_E4 (3.00 g, 8.4 mmol) in THF (30 mL) for 0.5 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (10 mL) and dried under vacuum to give methyl 2-(2-bromo-5-methoxy-4-aminosulfonylphenyl)acetate core-1a_E5 (1.60 g, yield 55.9%), which was used directly for the next step. LC-MS Rt 0.76 min; MS m / z [M+H] + 356.9; Method 1.

[0284] Step 5: Methyl 2-(3-methoxy-4-aminosulfonylphenyl)acetate

[0285]

[0286] Anhydrous Pd / C (0.15 g) was added to a solution of methyl 2-(2-bromo-5-methoxy-4-aminosulfonylphenyl)acetate core-1a_E5 (1.57 g, 4.6 mmol) in MeOH (30.0 mL). The suspension was degassed under vacuum and purged several times with H2. The reaction mixture was stirred at 80 °C for 16 h under H2 (50 psi). The reaction mixture was filtered and the filter cake was washed with 30.0 mL of MeOH. The filtrate was dried under vacuum to give methyl 2-(3-methoxy-4-aminosulfonylphenyl)acetate core-1a_E6 (1.10 g, 92.2% yield), which was used directly for the next step. TLC DCM: MeOH (10:1), Rf 0.3; 1 H NMR (400MHz, DMSO-d6) δ7.66-7.65(d,J=7.9Hz,1H),7.13(m,3H),6.96-6.94(d,J=8.0Hz,1H),3.77(s,2H),3.62(s,3H).

[0287] Step 6: 2-(3-methoxy-4-aminosulfonylphenyl)acetic acid

[0288]

[0289] NaOH (0.50 g, 12.5 mmol) was added to a solution of methyl 2-(3-methoxy-4-aminosulfonylphenyl)acetic acid core-1a_E6 (1.07 g, 4.13 mmol) in MeOH (5 mL), THF (10.0 mL), and water (1.4 mL). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was acidified to pH 3–4 with 2N HCl and then concentrated. The crude product was purified by preparative HPLC (NH3·H2O) to give 2-(3-methoxy-4-aminosulfonylphenyl)acetic acid core-1a_E1 (0.22 g, 21.8% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ12.49 (s, 1H), 7.67-7.66 (d, J = 8.0Hz, 1H), 7.11 (s, 1H), 7.04(s,2H),6.96-6.93(dd,J=8.0,1.2Hz,1H),3.88(s,3H),3.66(s,2H); LC-MS Rt 0.57min; MS m / z[M+Na] + 268.0.

[0290] Intermediate Core-1a_F:

[0291] N-(3-cyano-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0292] Step 1: 3-Cyano-2-(2-(4-aminosulfonylphenyl)acetamyl)-6,7-dihydrothiopheno[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester

[0293]

[0294] To a stirred solution of tert-butyl 2-amino-3-cyano-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate core-1a_A2 (0.50 g, 1.79 mmol) and 2-(4-aminosulfonylphenyl)acetic acid core-1a_F3 (0.58 g, 2.68 mmol) in DMF (10.0 mL), DIPEA (0.46 g, 3.58 mmol) and T3P (50% in EtOAc, 2.28 g, 3.58 mmol) were added. The reaction mixture was stirred at 120 °C for 45 min in a microwave reactor. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with water (50 mL), followed by brine (50 mL × 4), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (5%-33% EtOAc in PE) to give 3-cyano-2-(2-(4-aminosulfonylphenyl)acetamyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester core-1a_F3 (0.53 g, 62% yield). LC-MS Rt 0.84 min; MS m / z [M+H-100] + 376.9; Method 1.

[0295] Step 2: N-(3-cyano-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0296]

[0297] TFA (0.5 mL) was added to a stirred solution of 3-cyano-2-(2-(4-aminosulfonylphenyl)acetamyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester core-1a_F3 (0.53 g, 1.11 mmol) in anhydrous DCM (4.5 mL). The reaction mixture was stirred at 20 °C for 16 h. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with DCM (50 mL × 2). The aqueous layer was acidified to pH 8-9 with saturated aqueous Na2CO3, and the mixture was extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated to give N-(3-cyano-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide core-1a_F (0.31 g, 76% yield). The crude product was used directly in the next step.

[0298] Intermediate core-1a_G: 2-(3-ethoxy-4-aminosulfonylphenyl)acetic acid

[0299] Step 1: Methyl 2-(2-bromo-5-hydroxyphenyl)acetate

[0300]

[0301] The solution of methyl 2-(3-hydroxyphenyl)acetate core-1a_G1 (20.0 g, 0.12 mol) in AcOH (150 mL) was cooled to 0 °C. Then, a mixture of Br2 in AcOH (50 mL) was added dropwise. The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was evaporated under vacuum. H2O (200 mL) and EtOAc (200 mL) were added. The organic phase was separated, and the aqueous phase was further extracted with EtOAc (200 mL × 3). The combined organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure to give methyl 2-(2-bromo-5-hydroxyphenyl)acetate core-1a_G2 (23.0 g, 78% yield) as a yellow solid. LC-MS Rt 0.70 min; MS m / z [M+H] + 246.9; Method 1.

[0302] Step 2: Methyl 2-(2-bromo-5-ethoxyphenyl)acetate

[0303]

[0304] K₂CO₃ (2.7 g, 19.59 mmol) and EtI (3.1 g, 19.59 mmol) were added to a solution of methyl 2-(2-bromo-5-hydroxyphenyl)acetate core-1a_G₂ (4.0 g, 16.32 mmol) in acetone (50 mL). The reaction mixture was stirred at 50 °C for 16 h and concentrated. The residue was purified by silica gel column chromatography (2% EtOAc in PE) to give methyl 2-(2-bromo-5-ethoxyphenyl)acetate core-1a_G₃ (4.0 g, 89.7% yield).

[0305] Step 3: 2-(2-bromo-4-(chlorosulfonyl)-5-ethoxyphenyl)acetate

[0306]

[0307] At 0 °C, methyl 2-(2-bromo-5-ethoxyphenyl)acetate core-1a_G3 (4.0 g, 14.62 mmol) was added to ClSO3H (30 mL). The reaction mixture was heated to 30 °C and stirred for 2 hours. The reaction mixture was poured into ice-water (150 mL) and extracted with DCM (100 mL × 2). The combined organic layers were washed with brine (80 mL × 2), dried over Na2SO4, and concentrated to give methyl 2-(2-bromo-4-(chlorosulfonyl)-5-ethoxyphenyl)acetate core-1a_G4 (3.0 g, 55.1% yield). The residue was used directly for the next step.

[0308] Step 4: Methyl 2-(2-bromo-5-ethoxy-4-aminosulfonylphenyl)acetate

[0309]

[0310] Core-1a_G5 was prepared using a similar method to that used for core-1a_E5 (1.1 g, yield 38.7%). 1 LC-MS Rt 0.95min;MS m / z[M+H] + 375.6; Method 3.

[0311] Step 5: Methyl 2-(3-ethoxy-4-aminosulfonylphenyl)acetate

[0312]

[0313] Core-1a_G6 (700.0 mg, yield 90.2%) was prepared by a method similar to that used for core-1a_E6. 1 H NMR (400MHz, CDCl3) δ7.83 (d, J = 7.9Hz, 1H), 7.02-6.90 (m, 2H), 5.08 (s, 2H), 4.26(q,J=7.0Hz,2H),3.71(s,3H),3.66(s,2H),1.52(t,J=7.0Hz,3H); LC-MS Rt 0.67min; MS m / z[M+Na] + 295.6; Method 3.

[0314] Step 6: Methyl 2-(3-ethoxy-4-aminosulfonylphenyl)acetate

[0315]

[0316] Core-1a_G was prepared by a method similar to that used for core-1a_E (350.0 mg, yield 40.6%). 1 H NMR(400MHz,DMSO-d6)δ12.45(br s,1H),7.66(d,J=8.0Hz,1H),7.12(s,1H),6.93(d,J=8.0Hz,1H),6.89(s,2H),4.20(q,J=6.9Hz,2H),3.65(s,2H),1.38(t,J=7.0Hz,3H); LC-MSRt 0.64min;MS m / z[M+Na] + 282.0; Method 3.

[0317] Intermediate core-1a_H: 5-(cyclohexylmethyl)-2-(methylamino)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile

[0318] Step 1: (E)-Methyl N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)methylimine ester

[0319]

[0320] Add 2-amino-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1a_B (100 mg, 0.36 mmol) to a flask containing trimethoxymethane (1.5 mL). Stir the reaction mixture at 120 °C for 16 h. Remove residual trimethoxymethane under vacuum. Use the crude core-1a_H1 (115.0 mg) directly for the next step. LC-MS Rt 1.17 min; MS m / z [M+H] + 282.0; Method 1.

[0321] Step 2: 5-(cyclohexylmethyl)-2-(methylamino)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile

[0322]

[0323] NaBH4 (16 mg, 0.084 mmol) was added to a solution of (E)-methyl N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methylimino ester core-1a_H1 (115.0 mg, 0.36 mmol) in MeOH (1.5 mL). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL × 3). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure to give 5-(cyclohexylmethyl)-2-(methylamino)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-3-carboxynitrile core-1a_H (60.0 mg, 57.5% yield) as a yellow solid. LC-MS Rt 1.13min; MS m / z[M+H] + 290.0; Method 1.

[0324] Intermediate Core-1a_I: 2-Amino-5-benzyl-4,4-dimethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxylonitrile C-05469-082-P1

[0325] Step 1: Ethyl 2-(benzylamino)-2-methylpropionate

[0326]

[0327] A mixture of benzylamine core-1a_I1 (6.6 g, 61.4 mmol), ethyl 2-bromo-2-methylpropionate core-1a_I2 (10 g, 51.2 mmol), K2CO3 (8.5 g, 61.4 mmol), and KI (100 mg, 0.6 mmol) was stirred at 90 °C for 16 h. The reaction solution was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (10% EtOAc in PE) to give core-1a_I3 (1.9 g, 17% yield), which was a pale yellow oil.

[0328] Step 2: Ethyl 4-(benzyl(1-ethoxy-2-methyl-1-oxopropyl-2-yl)amino)butyrate

[0329]

[0330] A mixture of ethyl 2-(benzylamino)-2-methylpropionate core-1a_I3 (1.9 g, 8.6 mmol), ethyl 4-bromobutyrate core-1a_I4 (1.9 g, 9.5 mmol), and KI (71 mg, 0.43 mmol) was stirred at 130 °C for 8 h. The reaction mixture was dissolved in water (30 mL) and extracted with EtOAc (15 mL × 3). The organic layer was concentrated. The residue was purified by column chromatography (5% to 6% EtOAc in PE) to give ethyl 4-(benzyl(1-ethoxy-2-methyl-1-oxopropyl-2-yl)amino)butyrate core-1a_I5 (700 mg, 24% yield) as a yellow oil.

[0331] Step 3: Ethyl 1-benzyl-2,2-dimethyl-3-oxoperidin-4-carboxylate

[0332]

[0333] NaH (168 mg, 4.2 mmol) was added to a solution of ethyl 4-(benzyl(1-ethoxy-2-methyl-1-oxoprop-2-yl)amino)butyrate core-1a_I5 (700 mg, 2.1 mmol) in THF (30 mL). The mixture was stirred at 70 °C for 2 h. The reaction solution was concentrated, and the residue was dissolved in saturated NH4Cl (30 mL) and extracted with EtOAc (20 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give ethyl 1-benzyl-2,2-dimethyl-3-oxopiperidin-4-carboxylate core-1a_I6 (550 mg, 90% yield) as a yellow oil. The crude product was used directly in the next step without further purification.

[0334] Step 4: 1-Benzyl-2,2-dimethylpiperidin-3-one

[0335]

[0336] A mixture of ethyl 1-benzyl-2,2-dimethyl-3-oxopiridine-4-carboxylate core-1a_I6 (550 mg, 1.9 mmol) in 6N HCl (15 mL) was stirred at 100 °C for 3 h. The reaction solution was cooled to 20 °C and the pH was adjusted to 7–7.5 with NaHCO3 solid. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 2). The organic layer was concentrated. The residue was purified by preparative TLC (9% EtOAc in PE) to give 1-benzyl-2,2-dimethylpiperidine-3-one core-1a_I7 (390 mg, 94% yield) as a yellow oil.

[0337] Step 5: 2-Amino-5-benzyl-4,4-dimethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile

[0338]

[0339] At 20 °C, sulfur (37 mg, 1.14 mmol) and L-proline (8 mg, 0.07 mmol) were added to a solution of 1-benzyl-2,2-dimethylpiperidin-3-one core-1a_I7 (150 mg, 0.69 mmol) and CH2(CN)2 (50 mg, 0.76 mmol) in DMF (1 mL). The mixture was stirred at 20 °C for 30 min, followed by heating at 60 °C for 15.5 h. The reaction solution was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The organic layer was concentrated. The residue was purified by preparative TLC (33% EtOAc in PE) to give 2-amino-5-benzyl-4,4-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1a_I (70 mg, 33% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.34-7.17 (m, 5H), 4.59 (s, 2H), 3.60 (s, 2H), 2.62 (t, J = 5.4Hz, 2H), 2.37 (t, J = 5.4Hz, 2H), 1.48 (s, 6H); LC-MS Rt 0.54min; MS m / z[M+H] + 298.0; Method 1.

[0340] Intermediate Core-1b_A: tert-butyl 2-amino-3-cyano-6-methyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

[0341] Step 1: 6-Methylpiperidine-3-ol acetate

[0342]

[0343] PtO2 (0.50 g) was added to a solution of 6-methylpyridin-3-ol core-1b_A1 (5.00 g, 45.8 mmol) in MeOH (50.0 mL) and AcOH (50.0 mL). The suspension was degassed under vacuum and purged several times with H2. The reaction mixture was stirred at 70 °C for 16 h under H2 (50 psi). The reaction mixture was concentrated. The crude product, 6-methylpiperidin-3-ol acetate core-1b_A2 (6.78 g, crude), was used directly for the next step.

[0344] Step 2: tert-butyl 5-hydroxy-2-methylpiperidine-1-carboxylate

[0345]

[0346] TEA (10.38 g, 102.6 mmol) and Boc2O (11.20 g, 51.3 mmol) were added to a solution of 6-methylpiperidin-3-ol acetate core-1b_A2 (6.00 g, 34.2 mmol) in THF (50.0 mL), and the reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica column chromatography (9%–33% EtOAc in PE) to give 5-hydroxy-2-methylpiperidin-1-carboxylic acid tert-butyl ester core-1b_A3 (3.82 g, 52% yield); 1 H NMR (400MHz, DMSO-d6) δ4.92-4.49(m,1H),4.23-4.18(m,1H),3.75-3.71(m,1H),3.34-3.26(m,1H),2.90-2.87( m,1H),1.99-1.97(m,1H),1.71-1.68(m,1H),1.55-1.44(m,1H),1.39(s,9H),1.06-1.03(dd,J=6.9,2.6Hz,3H).

[0347] Step 3: tert-butyl 2-methyl-5-oxoperidin-1-carboxylate

[0348]

[0349] Pyridine (3.31 g, 41.8 mmol) and DMP (17.73 g, 41.8 mmol) were added to a solution of tert-butyl 5-hydroxy-2-methylpiperidin-1-carboxylate core-1b_A3 (3.00 g, 13.9 mmol) in DCM (100.0 mL), and the reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into a saturated sodium thiosulfate solution (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with water (100 mL), followed by brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with 10 / 1PE / EtOAc, to give tert-butyl 2-methyl-5-oxopiperidin-1-carboxylate core-1b_A4 (2.05 g, 69% yield). 1H NMR (400MHz, CDCl3) δ4.55-4.30(m,2H),3.61-3.56(d,J=18.8Hz,1H),2.44-2.41(m,2H ),2.24-2.19(m,1H),1.63-1.56(m,1H),1.51-1.46(m,9H),1.25-1.23(d,J=6.5Hz,3H).

[0350] Step 4: tert-butyl 2-amino-3-cyano-6-methyl-6,7-dihydrothiopheno[3,2-c]pyridine-5(4H)-carboxylate

[0351]

[0352] Sulfur (0.67 g, 21.09 mmol) and L-proline (80.6 mg, 0.70 mmol) were added to a solution of tert-butyl 2-methyl-5-oxopiperidinium-1-carboxylate core-1b_A4 (1.50 g, 7.03 mmol) and CH2(CN)2 (1.39 g, 21.09 mmol) in DMF (15.0 mL). The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with water (50 mL), followed by brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (base) to obtain tert-butyl 2-amino-3-cyano-6-methyl-6,7-dihydrothiopheno[3,2-c]pyridine-5(4H)-carboxylate core-1b_A (0.86 g, yield 42%). 1 H NMR (400MHz, CDCl3) δ4.71 (s, 4H), 3.91-3.80 (m, 1H), 2.87-2.78 (m, 1H), 2.27-2.20 (m, 1H), 1.41 (s, 9H), 1.07 (d, J = 7.0Hz, 3H); LC-MS Rt 1.37min, MS m / z[M+Na] + 316.1; Method 2.

[0353] Intermediate Core-1b_B: N-(3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0354] Step 1: tert-butyl 3-cyano-6-methyl-2-(2-(4-aminosulfonylphenyl)acetamyl)-6,7-dihydrothiopheno[3,2-c]pyridine-5(4H)-carboxylate

[0355]

[0356] DIPEA (441 mg, 3.36 mmol) and T3P (1.63 mg, 2.57 mmol) were added to a solution of tert-butyl core-1b_A (500 mg, 1.71 mmol) of 2-amino-3-cyano-6-methyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate in DMF (6 mL). The reaction mixture was stirred in a microwave oven at 120 °C for 0.5 h. The reaction mixture was poured into H2O (150 mL) and extracted with EtOAc (150 mL × 3). The organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was then purified by silica gel chromatography (PE:EtOAc = 20:1-3:1) to obtain 1.28 g (48% yield) of 3-cyano-6-methyl-2-(2-(4-aminosulfonylphenyl)acetamido)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester core-1b_B1, which was a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.99(s,1H),7.78(d,J=8.2Hz,2H),7.49(d,J=8.2Hz,2H),7.32(s,2H),4.62(d,J=17. 1Hz, 2H), 4.09 (d, J = 5.0Hz, 1H), 4.01-3.90 (m, 3H), 2.92-2.77 (m, 1H), 1.43 (s, 9H), 1.03 (d, J = 6.7Hz, 3H); LC-MS Rt 0.89min,MS m / z[M+H-100] + 391.0; Method 1.

[0357] Step 2: N-(3-cyano-6-methyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide 2,2,2-trifluoroacetate

[0358]

[0359] TFA (0.8 mL) was added to a solution of 3-cyano-6-methyl-2-(2-(4-aminosulfonylphenyl)acetamyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester core-1b_B1 (680 mg, 1.43 mmol) in DCM (7.2 mL), and the reaction mixture was stirred at 20 °C for 4 h. The reaction mixture was then evaporated under reduced pressure to give N-(3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)-2-(4-aminosulfonylphenyl)acetamide 2,2,2-trifluoroacetate core-1b_B2 (563 mg, crude) as a deep red solid, which was used directly in the next step.

[0360] Step 3: N-(3-cyano-6-methyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0361]

[0362] Add to a solution of N-(3-cyano-6-methyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide 2,2,2-trifluoroacetate core-1b_B2 (560 mg, 1.15 mmol) in MeOH (3 mL) A-21 ion exchange resin (2 g) was added, and the reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was then filtered and evaporated under reduced pressure to give N-(3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide core-1b_B (220 mg, 0.56 mmol) as a red solid; LC-MSR t 0.68 min, MS m / z [M+Na] + 413.0; Method 3.

[0363] Intermediate core-1b_C: tert-butyl 2-amino-3-cyano-6-ethyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

[0364] Step 1: 6-Vinylpyridine-3-ol

[0365]

[0366] 6-Bromopyridin-3-ol (20.0 g, 114.94 mmol), potassium vinyltrifluoroborate (23.1 g, 174.41 mmol), Pd(PPh3)4 (2.7 g, 2.30 mmol), and K2CO3 (31.8 g, 229.88 mmol) were stirred at 100 °C for 12 h in a suspension of dioxane / H2O (100 / 100 mL). The reaction mixture was adjusted to pH 5-6 with 1 N HCl and extracted with EtOAc (200 mL × 3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 20:1-5:1) to give 10.0 g crude 6-vinylpyridin-3-ol core-1b_C1 as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.17(d,J=2.8Hz,1H),7.34(d,J=8.4Hz,1H),7.23(dd,J=8.4,2.8Hz,1H),6 .77(dd,J=17.6,11.2Hz,1H),5.90(d,J=17.6Hz,1H),5.66-5.47(m,1H),5.34(d,J=11.2Hz,1H).

[0367] Step 2: 6-Ethylpiperidine-3-ol hydrochloride

[0368]

[0369] To a solution of 6-vinylpyridin-3-ol core-1b_C1 (2.5 g, 20.64 mmol) in MeOH (25 mL), HCl (1.7 mL, 20.64 mmol) and PtO2 (250.0 mg) were added. H2 was added to the mixture to 50 psi, and the mixture was stirred at 50 °C for 16 h. The reaction mixture was concentrated to give 6-ethylpiperidine-3-ol hydrochloride core-1b_C2 (2.5 g, crude), which was used directly in the next step.

[0370] Step 3: tert-butyl 2-ethyl-5-hydroxypiperidine-1-carboxylate

[0371]

[0372] Boc₂O (21.7 g, 99.60 mmol) was added to a suspension of 6-ethylpiperidine-3-ol hydrochloride core-1b_C₂ (5.5 g, 33.20 mmol), TEA (10.1 g, 99.60 mmol), and DMAP (405.6 mg, 3.32 mmol) in DCM (50 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with DCM (200 mL) and washed with water (50 mL × 3) and brine (50 mL × 3). The organic layer was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1-2:1) to give tert-butyl 2-ethyl-5-hydroxypiperidine-1-carboxylate core-1b_C₃ (1.0 g, 70% purity) as a colorless oil.

[0373] Step 4: tert-butyl 2-ethyl-5-oxopiperidin-1-carboxylate

[0374]

[0375] DMP (5.5 g, 13.08 mmol) was added to a suspension of tert-butyl 2-ethyl-5-hydroxypiperidine-1-carboxylate core-1b_C3 (1.0 g, 4.36 mmol) and pyridine (1.0 g, 13.08 mmol) in DCM (10 mL). The mixture was stirred at 20 °C for 5 h. The reaction was quenched with saturated aqueous Na2S2O3 (50 mL), and the mixture was extracted with DCM (100 mL × 3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (PE:EtOAc = 10:1–5:1) to give a colorless oily tert-butyl 2-ethyl-5-oxopiridine-1-carboxylate core-1b_C4 (460.0 mg, crude product), which was used directly in the next step.

[0376] Step 5: tert-butyl 2-amino-3-cyano-6-ethyl-6,7-dihydrothiopheno[3,2-c]pyridine-5(4H)-carboxylate

[0377]

[0378] A solution of tert-butyl 2-ethyl-5-oxopiperidin-1-carboxylate (460.0 mg, 2.02 mmol) core-1b_C4, S (97.3 mg, 3.04 mmol), CH2(CN)2 (147.1 mg, 2.23 mmol) and L-proline (23.0 mg, 0.20 mmol) in DMF (5 mL) was stirred at 60 °C for 16 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (10 mL × 3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC (PE:EtOAc = 2:1) to give a yellow solid of tert-butyl 2-amino-3-cyano-6-ethyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate core-1b_C (90.0 mg, 14% yield). 1 H NMR (400MHz, CD3OD) δ4.65-4.47(m,2H),3.81(s,1H),2.80(dd,J=2.4,13.2Hz,1H),2.43(d,J =16.1Hz,1H),1.66-1.55(m,1H),1.50(s,9H),1.47-1.41(m,1H),0.91(t,J=7.4Hz,3H); LC-MS Rt 1.45min,MS m / z[M+Na] + 330.0; Method 2.

[0379] Intermediate Core-1b_D: tert-butyl 3-cyano-2-(2-(3-methoxy-4-aminosulfonylphenyl)acetamyl)-6-methyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

[0380] Step 1: 2-(2-bromo-5-methoxyphenyl)acetic acid

[0381]

[0382] Br2 (4.3 g, 27.08 mmol) was added to a solution of 2-(3-methoxyphenyl)acetic acid (3.0 g, 18.05 mmol) in DCM (30 mL) at 0 °C. After addition, the reaction mixture was warmed to 20 °C and stirred for 4 h. The reaction mixture was diluted with DCM (100 mL) and washed with saturated Na2SO3 (30 mL × 3) and brine (30 mL × 3). The organic layer was dried over anhydrous Na2SO4 and concentrated to give 2-(2-bromo-5-methoxyphenyl)acetic acid core-1b_D1 (4.2 g), which was used directly for the next step; LC-MS Rt 0.64 min, MS m / z [M+H] + 246.9; Method 3.

[0383] Step 2: Methyl 2-(2-bromo-5-methoxyphenyl)acetate

[0384]

[0385] SOCl2 (12.2 g, 102.83 mmol) was added to a solution of 2-(2-bromo-5-methoxyphenyl)acetic acid core-1b_D1 (4.2 g, 17.14 mmol) in MeOH (50 mL) at 0 °C. After addition, the reaction mixture was heated to 80 °C and stirred for 4 h. The reaction mixture was concentrated to dryness. The residue was diluted with EtOAc (100 mL) and washed with brine (30 mL × 3). The organic layer was dried over anhydrous Na2SO4 and concentrated to give 4.5 g of crude product, which was used directly in the next step.

[0386] Step 3: Methyl 2-(2-bromo-4-(chlorosulfonyl)-5-methoxyphenyl)acetate

[0387]

[0388] At 0 °C, methyl 2-(2-bromo-5-methoxyphenyl)acetate core-1b_D2 (7.0 g, 27.02 mmol) was added to ClSO3H (20 mL). After addition, the reaction mixture was warmed to 20 °C and stirred for 16 h. The reaction mixture was poured into ice water (500 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous Na2SO4, and concentrated to give crude product (6.0 g), which was used directly for the next step. 1 H NMR (400MHz, CDCl3) δ8.13(s,1H),7.10(s,1H),4.06(s,3H),3.87(s,2H),3.77(s,3H).

[0389] Step 4: Methyl 2-(2-bromo-5-methoxy-4-aminosulfonylphenyl)acetate

[0390]

[0391] At 0 °C, NH3 was bubbled into a solution of methyl 2-(2-bromo-4-(chlorosulfonyl)-5-methoxyphenyl)acetate core-1b_D3 (6.0 g, 16.78 mmol) in 100 mL of THF for 0.5 h. The reaction mixture was filtered, and the filter cake was washed with 20 mL of THF and dried under vacuum. The crude product was washed with PE:EtOAc = 3:1 (200 mL) to give methyl 2-(2-bromo-5-methoxy-4-aminosulfonylphenyl)acetate core-1b_D4 (2.6 g, 46% yield) as a yellow solid. LC-MSRt 0.78 min, MS m / z [M+Na] + 361.9; Method 1.

[0392] Step 5: Methyl 2-(3-methoxy-4-aminosulfonylphenyl)acetate

[0393]

[0394] Pd / C (300.0 mg) was added to a solution of methyl 2-(2-bromo-5-methoxy-4-aminosulfonylphenyl)acetate core-1b_D4 (2.6 g, 7.69 mmol) and HCOONH4 (533.3 mg, 8.46 mmol) in MeOH (30 mL). The mixture was stirred at 80 °C for 5 h. The reaction mixture was filtered and the filter cake was washed with 20 mL of MeOH and dried under vacuum. The crude product was washed with PE:EtOAc = 3:1 (20 mL) to give methyl 2-(3-methoxy-4-aminosulfonylphenyl)acetate core-1b_D5 (1.8 g, 46% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ7.66 (d, J = 1.6, 8.0 Hz, 1H), 7.19-6.89 (m, 4H), 3.88 (d, J = 1.6 Hz, 3H), 3.77 (s, 2H), 3.63 (d, J = 2.4 Hz, 3H).

[0395] Step 6: 2-(3-methoxy-4-aminosulfonylphenyl)acetic acid

[0396]

[0397] To a solution of methyl 2-(3-methoxy-4-aminosulfonylphenyl)acetic acid core-1b_D5 (1.3 g, 5.01 mmol) in THF / MeOH / H2O (18 / 9 / 9 mL), NaOH (401.1 mg, 10.03 mmol) was added. The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated to remove THF and MeOH, then acidified to pH 1 with 6N HCl and extracted with EtOAc (50 mL × 3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was washed with DCM (20 mL × 3) to give 2-(3-methoxy-4-aminosulfonylphenyl)acetic acid core-1b_D6 (1.1 g, 89% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6), δ7.65 (d, J=8.0Hz, 1H), 7.11 (s, 1H), 7.03 (s, 2H), 6.94 (d, J=8.0Hz, 1H), 3.88 (s, 3H), 3.68-3.62 (m, 2H); LC-MS Rt 0.46min, MS m / z[M+H] + 246.0.

[0398] Step 7: tert-butyl 3-cyano-2-(2-(3-methoxy-4-aminosulfonylphenyl)acetamyl)-6-methyl-6,7-dihydrothiopheno[3,2-c]pyridine-5(4H)-carboxylate

[0399]

[0400] A solution of 2-(3-methoxy-4-aminosulfonylphenyl)acetic acid core-1b_D6 (250.0 mg, 1.02 mmol), 2-amino-3-cyano-6-methyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester core-1b_A (598.2 mg, 2.04 mmol), T3P (486.8 mg, 1.53 mmol), and DIPEA (395.5 mg, 3.06 mmol) in DMF (5 mL) was stirred in a microwave oven at 120 °C for 0.5 h. The reaction mixture was diluted with 50 mL of EtOAc and washed with water (10 mL × 3) and brine (10 mL × 3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by reverse-phase column chromatography (NH3·H2O) to give 3-cyano-2-(2-(3-methoxy-4-aminosulfonylphenyl)acetamyl)-6-methyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester core-1b_D (152.0 mg, yield 29%) as a white solid. 1H NMR(400MHz, DMSO-d6), δ7.66(d,J=8.0Hz,1H),7.18(s,1H),7.03(s,2H),6.97(d,J=8.0Hz,1H),4.60(d,J=17 .2Hz,2H),3.99(s,1H),3.89(s,5H),2.90-2.79(m,1H),2.53(s,1H),1.43(s,9H),1.03(d,J=6.8Hz,3H); LC-MS Rt 0.87min,MS m / z[M+H-100] + 421.1; Method 1.

[0401] Intermediate core-1b_E: tert-butyl 3-cyano-6-methyl-2-(2-(4-(methylsulfinyl)phenyl)acetamyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

[0402] Step 1: 2-(4-(methylsulfinyl)phenyl)acetic acid

[0403]

[0404] At 0 °C, NaIO4 (1.3 g, 6.04 mmol) in H2O (10 mL) was added to a solution of 2-(4-(methylthio)phenyl)acetic acid (1.0 g, 5.49 mmol) in MeOH (10 mL). After addition, the mixture was stirred at 20 °C for 2 h. The reaction mixture was filtered and concentrated to give 2-(4-(methylsulfinyl)phenyl)acetic acid core-1b_E1 (0.9 g, 82% yield) as a white solid, which was used directly for the next step; LC-MS Rt 0.204 min, MS m / z [M+H] + 199.0; Method 3.

[0405] Step 2: tert-butyl 3-cyano-6-methyl-2-(2-(4-(methylsulfinyl)phenyl)acetamyl)-6,7-dihydrothiopheno[3,2-c]pyridine-5(4H)-carboxylic acid

[0406]

[0407] A solution of tert-butyl 2-amino-3-cyano-6-methyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate core-1b_A (100.0 mg, 0.17 mmol), 2-(4-(methylsulfinyl)phenyl)acetic acid core-1b_E1 (67.6 mg, 0.34 mmol), T3P (81.1 mg, 0.26 mmol), and DIPEA (65.9 mg, 0.51 mmol) in DMF (1 mL) was stirred in a microwave oven for 0.5 h at 120 °C. The reaction mixture was diluted with 20 mL of EtOAc and washed with water (10 mL × 3) and brine (10 mL × 3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by reverse-phase column chromatography (NH3·H2O) to give tert-butyl 3-cyano-6-methyl-2-(2-(4-(methylsulfinyl)phenyl)acetamyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate core-1b_E (47 mg, yield 29%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.65(d,J=8.4Hz,2H),7.52(d,J=8.4Hz,2H),4.61(d,J=17.6Hz,2H),4.06-3.96(m ,1H),3.94(s,2H),2.88-2.79(m,1H),2.73(s,3H),2.55(s,1H),1.43(s,9H),1.03(d,J=6.8Hz,3H); LC-MS Rt 0.91min,MS m / z[M+H-100] + 374.0; Method 1.

[0408] Intermediate core-1b_F: 4-(2-((3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)amino)-2-oxoethyl)benzamide

[0409] Step 1: 2-(4-carbamoylphenyl)acetic acid

[0410]

[0411] 2-(4-cyanophenyl)acetic acid (400 mg, 2.5 mmol) was added to concentrated H₂SO₄ (4 mL). The mixture was stirred at 40 °C for 1 h. The reaction was cooled to 20 °C and then poured into water (8 mL). The suspension was filtered and the filter cake was collected to give 2-(4-carbamoylphenyl)acetic acid core-1b_F1 (300 mg, yield 67%) as a white solid. The product was used directly in the next step without further purification. 1H NMR (400MHz, DMSO-d6) δ7.81 (d, J = 8Hz, 2H), 7.33 (d, J = 8Hz, 2H), 3.64 (s, 2H).

[0412] Step 2: 2-(2-(4-carbamoylphenyl)acetamyl)-3-cyano-6-methyl-6,7-dihydrothiopheno[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester

[0413]

[0414] At 120 °C, 2-amino-3-cyano-6-methyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate core-1b_A (394 mg, 1.34 mmol), 2-(4-carbamoylphenyl)acetic acid core-1b_F1 (200 mg, 1.12 mmol), a solution of T3P in EtOAc (1.43 g, 2.24 mmol, w / w = 50%), and DIPEA (290 mg, 2.24 mmol) were stirred in a microwave oven for 45 min. LC-MS showed the desired mass. The solution was diluted with water (30 mL) and extracted with EtOAc (20 mL × 3). The organic layer was concentrated. The residue was purified by preparative TLC (9% MeOH in DCM) to give a yellow solid, 2-(2-(4-carbamoylphenyl)acetamido)-3-cyano-6-methyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester core-1b_F2 (66 mg, 13% yield); LC-MS Rt 0.85 min, MS m / z [M+H-100]. + 355.0; Method 3.

[0415] Step 3: 4-(2-((3-cyano-6-methyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)amino)-2-oxoethyl)benzamide

[0416]

[0417] TFA (0.5 mL) was added to a solution of 100 mg (0.22 mmol) of 2-(2-(4-carbamoylphenyl)acetamido)-3-cyano-6-methyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester core-1b_F2 in DCM (5 mL). The mixture was stirred at 20 °C for 1 h. The reaction solution was concentrated. The crude product was used directly for the next step without further purification; LC-MS Rt 1.26 min, MS m / z [M+H] + 355.0; Method 5.

[0418] Intermediate core-1b_G: tert-butyl 3-cyano-6-methyl-2-(2-(4-(methanesulfonyl)phenyl)acetamyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

[0419] Step 1: 3-Cyano-6-methyl-2-(2-(4-(methanesulfonyl)phenyl)acetamyl)-6,7-dihydrothiopheno[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester

[0420]

[0421] DIPEA (879.3 mg, 6.82 mmol) and T3P (3.21 g, 5.11 mmol) were added to a solution of tert-butyl 2-amino-3-cyano-6-methyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (1 g, 3.41 mmol) core-1b_A and 2-(4-(methanesulfonyl)phenyl)acetic acid (1.1 g, 5.11 mmol) in DMF (10 mL). The reaction mixture was stirred in a microwave oven at 120 °C for 50 min. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (50 mL × 3). The organic layer was then dried over Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (PE:EtOAc = 10:1-1:1) to give the desired product (612 mg, yield 37%). 1 H NMR (400MHz, CDCl3) δ8.91(s,1H),7.98(d,J=8.0Hz,2H),7.57(d,J=8.4Hz,2H),4.85(s,2H),4.04-4.00(m,1H LC-MS Rt 0.92min,MS m / z[M+H-100] + 390.1; Method 1.

[0422] Intermediates Core-1b_I and Core-1b_J: tert-butyl 2-amino-3-cyano-6-methyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (enantiomer)

[0423] Step 1: tert-butyl 2-amino-3-cyano-6-methyl-6,7-dihydrothienro[3,2-c]pyridine-5(4H)-carboxylate

[0424]

[0425] Chiral SFC was performed on the enantiomer core-1b_A (500 mg) of 2-amino-3-cyano-6-methyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester to give core-1b_I (131 mg, 96% ee) and core-1b_J (156 mg, 98% ee).

[0426] Chiral SFC separation column: OJ-3 100×4.6mm ID, 3um; mobile phase: A is CO2, B is MeOH (0.05% DEA); isocratic: 5% to 40% B phase; total flow rate: 3 mL / min; back pressure: 100 bar; UV: 220 nm; instrument: SFC 80.

[0427] Core-1b_I: 1 H NMR (400MHz, DMSO-d6) δ7.18(s,1H),4.60(s,1H),4.44(d,J=17.2Hz,2H),4.01(s,1H),2.71 -2.51(m,1H),2.25(d,J=16Hz,2H),1.50-1.39(m,9H),1.16-1.05(m,3H); LC-MS: Rt=0.95MS m / z[M+H-56] + 238.0; Method 1.

[0428] Core-1b_J: 1 H NMR(400MHz,DMSO-d6)δ7.17(s,1H),4.60(s,1H),4.44(d,J=17.2Hz,2H),4.01(s,1H),2 .75-2.71(m,1H),2.50-2.30(d,J=16Hz,2H),1.48-1.35(m,9H),1.16-1.05(m,3H); LC-MS Rt 0.95MS m / z[M+H-56] + 238.0; Method 1.

[0429] Intermediate core-1c_A: 2-amino-5-(cyclohexylmethyl)-6,6-dimethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile

[0430] Step 1: (5-oxotetrahydrofuran-2-yl)methyl formate

[0431]

[0432] At 50-55°C, 50 g (500 mmol) of pent-4-enoic acid core-1c_A1 in 85% aqueous formic acid (100 mL) was added to a stirred solution of 30% hydrogen peroxide (74 mL, 650 mmol) in 85% aqueous formic acid (200 mL) for 2.5 h. The solution was maintained at this temperature for 2 h. The reaction was quenched with saturated aqueous Na2SO3 (100 mL). The reaction mixture was concentrated to remove most of the formic acid. The residue was alkalized to pH 6.5-7 with saturated aqueous NaHCO3. The solution was extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give a colorless oily formic acid (5-oxotetrahydrofuran-2-yl)methyl ester core-1c_A2 (28 g, 39% yield). The product was used directly for the next step without further purification.

[0433] Step 2: 5-(hydroxymethyl)dihydrofuran-2(3H)-one

[0434]

[0435] Concentrated HCl (2 mL) was added to a solution of (5-oxotetrahydrofuran-2-yl)methyl formic acid core-1c_A2 (28 g, 194 mmol) in MeOH (100 mL). The mixture was stirred at 20 °C for 1 h. The reaction solution was concentrated to give 5-(hydroxymethyl)dihydrofuran-2(3H)-one core-1c_A3 (23 g, 100% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ4.64-4.60(m,1H),3.87-3.84(d,J=12.4Hz,1H),3.64-3.60(dd,J=1 2.8Hz,4.4Hz,1H),3.25(s,1H),2.60-2.45(m,2H),2.30-2.25(m,1H),2.18-2.06(m,1H).

[0436] Step 3: Methyl (5-oxotetrahydrofuran-2-yl)methanesulfonic acid

[0437]

[0438] At 0 °C, TEA (69 g, 688 mmol) and MsCl (59 g, 516 mmol) were added to a solution of 5-(hydroxymethyl)dihydrofuran-2(3H)-one core-1c_A3 (37.9 g, 344 mmol) in DCM (500 mL). The mixture was stirred at 0 °C for 1 h. The reaction was quenched with water (300 mL) and extracted with DCM (200 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give (5-oxotetrahydrofuran-2-yl)methyl methanesulfonic acid core-1c_A4 (65 g, 100% yield). The crude product was used directly for the next step without further purification.

[0439] Step 4: 5-(azidomethyl)dihydrofuran-2(3H)-one

[0440]

[0441] NaN3 (24.5 g, 378 mmol) was added to a solution of (5-oxotetrahydrofuran-2-yl)methyl methanesulfonic acid core-1c_A4 (65 g, 335 mmol) in DMF (600 mL). The mixture was stirred at 80 °C for 4 h. The reaction solution was diluted with water (1.5 L) and extracted with EtOAc (500 mL × 5). The combined organic layers were concentrated. The residue was purified by silica column chromatography (9% to 25% EtOAc in PE) to give 5-(azidomethyl)dihydrofuran-2(3H)-one core-1c_A5 (32 g, 68% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ4.65-4.61(m,1H),3.59-3.55(m,1H),3.44-3.40(m,1H),2.57-2.45(m,2H),2.31-2.28(m,1H),2.15-1.99(m,1H).

[0442] Step 5: 5-Hydroxypiperidin-2-one

[0443]

[0444] A mixture of 5-(azidomethyl)dihydrofuran-2(3H)-one core-1c_A5 (32 g, 227 mmol) and Pd(OH)2 / C (3 g, catalyst) in MeOH (600 mL) was hydrogenated at 20 °C for 4 h under H2 (15 psi). The reaction solution was filtered, and the filtrate was concentrated. The residue was purified by silica column chromatography (50% EtOAc in PE to 9% MeOH in DCM) to give 5-hydroxypiperidin-2-one core-1c_A6 (0.93 g, 3.5%) as a white solid and an unknown intermediate (37 g, crude). The unknown intermediate was aliquoted into four batches for hydrogenation. Each batch of crude intermediate was dissolved in MeOH (500 mL), and Pd(OH)2 / C (1 g) was added. The mixture was hydrogenated at 20 °C for 4 h under H2 (15 psi). The reaction solution was filtered. The filtrate was concentrated to obtain 25 g of 5-hydroxypiperidin-2-one core-1c_A6 (95% yield) as a white solid. The product was used directly in the next step without further purification.

[0445] Step 6: 1-Benzyl-5-(Benzyloxy)piperidin-2-one

[0446]

[0447] A solution of KOH (48.5 g, 864 mmol) in DMSO (250 mL) was stirred at 20 °C for 30 min under N2. Then, a solution of 5-hydroxypiperidin-2-one core-1c_A6 (12.5 g, 108 mmol) in DMSO (50 mL) was added. After stirring at 20 °C for 1 h, BnBr (74.0 g, 432 mmol) was added. The mixture was stirred for another 2 h. The reaction solution was filtered. The filtrate was diluted with water (1.5 L) and extracted with EtOAc (400 mL × 5). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica column chromatography (9% to 33% EtOAc in PE) to give a pale yellow oily 1-benzyl-5-(benzyloxy)piperidin-2-one core-1c_A7 (21.5 g, 67% yield). 1 H NMR (400MHz, CDCl3) δ7.35-7.27(m,10H),4.68(d,J=14.8Hz,1H),4.56-4.42(m,3H),3.83 -3.80(m,1H),3.34-3.33(m,2H),2.74-2.71(m,1H),2.49-2.44(m,1H),2.08-1.98(m,2H).

[0448] Step 7: 1-Benzyl-5-(benzyloxy)-2,2-dimethylpiperidine

[0449]

[0450] Under N2, Tf2O (5.7 g, 20.3 mmol) was added dropwise to a solution of 1-benzyl-5-(benzyloxy)piperidin-2-one core-1c_A7 (5.0 g, 16.9 mmol) and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) (4.2 g, 20.3 mmol) in DCM (300 mL) at -78 °C. The mixture was stirred at -78 °C for 1 h. Then, a solution of MeMgBr in Et2O (16.9 mL, 50.7 mmol) was added dropwise. The reaction mixture was warmed to 20 °C and stirred for another 2 h. The reaction was quenched with saturated aqueous NH4Cl (50 mL), diluted with water (200 mL), and extracted with DCM (80 mL × 3). The organic layer was concentrated. The residue was purified by column chromatography (9% EtOAc in PE) to obtain 1-benzyl-5-(benzyloxy)-2,2-dimethylpiperidine core-1c_A8 (4.6 g, yield 88%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.42-7.29(m,10H),4.47(s,2H),3.93(d,J=14Hz,1H),3.47-3.45(m,1H),3.22(d,J=14H z,1H),2.80-2.79(m,1H),2.34-2.29(m,1H),1.98-1.96(m,1H),1.66-1.58(m,3H),1.25(s,3H),1.13(s,3H).

[0451] Step 8: tert-butyl 5-(benzyloxy)-2,2-dimethylpiperidine-1-carboxylate

[0452]

[0453] A mixture of 1-benzyl-5-(benzyloxy)-2,2-dimethylpiperidine core-1c_A8 (4.6 g, 14.8 mmol), Boc2O (6.5 g, 29.6 mmol), and Pd(OH)2 / C (1.0 g, catalyst) in MeOH (100 mL) was hydrogenated at 20 °C for 16 h under H2 (50 psi). The reaction solution was filtered, and the filtrate was concentrated to give the desired product (8 g, crude). The crude product was further hydrogenated without purification; LC-MS Rt 0.99 min; MS m / z [M+H] + 320.1; Method 3.

[0454] Step 9: tert-butyl 5-hydroxy-2,2-dimethylpiperidine-1-carboxylate

[0455]

[0456] A mixture of 5-(benzyloxy)-2,2-dimethylpiperidin-1-carboxylic acid tert-butyl ester core-1c_A9 (8 g, crude) and Pd(OH)2 / C (1 g, catalyst) in MeOH (100 mL) was hydrogenated at 20 °C for 16 h under H2 (50 psi). The reaction solution was filtered and the filtrate was concentrated. The residue was purified by column chromatography (9% to 20% EtOAc in PE) to give 5-hydroxy-2,2-dimethylpiperidin-1-carboxylic acid tert-butyl ester core-1c_A10 (3 g, 88% yield, 2 steps) as a white solid. 1 H NMR (400MHz, CDCl3) δ3.93-3.88(m,1H),3.67-3.63(dd,J=13.6,4.4Hz,1H),3.31-3.26( m,1H),1.94-1.92(m,1H),1.75-1.65(m,1H),1.60-1.45(m,11H),1.42(d,J=3.6Hz,6H).

[0457] Step 10: tert-butyl 2,2-dimethyl-5-oxoperidin-1-carboxylate

[0458]

[0459] DMP (8.3 g, 19.5 mmol) was added to a solution of tert-butyl 5-hydroxy-2,2-dimethylpiperidine-1-carboxylate core-1c_A10 (3 g, 13 mmol) in DCM (60 mL). The mixture was stirred at 20 °C for 1 h. The reaction solution was filtered and the filtrate was concentrated. The residue was purified by silica column chromatography (20% EtOAc in PE) to give tert-butyl 2,2-dimethyl-5-oxoperidine-1-carboxylate core-1c_A11 (2.8 g, 95% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.04 (s, 2H), 2.47 (t, J = 6.4Hz, 2H), 1.90 (t, J = 6.4Hz, 2H), 1.53 (s, 6H), 1.47 (s, 9H).

[0460] Step 11: tert-butyl 2-amino-3-cyano-6,6-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

[0461]

[0462] At 20 °C, sulfur (295 mg, 9.2 mmol) and L-proline (70 mg, 0.61 mmol) were added to a solution of tert-butyl 2,2-dimethyl-5-oxopiperidin-1-carboxylate core-1c_A11 (1.4 g, 6.1 mmol) and CH2(CN)2 (443 mg, 6.7 mmol) in DMF (30 mL). The reaction mixture was stirred at 20 °C for 10 min, followed by heating at 60 °C for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL × 3). The organic layer was concentrated. The residue was purified by silica gel column chromatography (9% to 17% EtOAc in PE) to give a yellow solid, tert-butyl 2-amino-3-cyano-6,6-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate core-1c_A12 (0.55 g, 29% yield); LC-MS Rt 0.84 min; MS m / z [M+Na] + 330.0; Method 3; 1 H NMR (400MHz, CDCl3) δ4.71 (s, 2H), 4.37 (d, J = 1.2Hz, 2H), 2.58 (s, 2H), 1.49 (s, 6H), 1.48 (s, 9H).

[0463] Step 12: 2-Amino-6,6-dimethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile

[0464]

[0465] TFA (3 mL) was added to a solution of tert-butyl 2-amino-3-cyano-6,6-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate core-1c_A12 (4 g, 13 mmol) in DCM (30 mL). The reaction solution was concentrated, and the residue was alkalized through an ion exchange resin and filtered. The filtrate was concentrated to give 2-amino-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1c_A13 (3 g, crude). The crude product was used directly for the next step without further purification; LC-MS Rt 0.76 min; MS m / z [M+H] + 330.0; Method 1.

[0466] Step 13: 2-Amino-5-(cyclohexylmethyl)-6,6-dimethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile

[0467]

[0468] DIPEA (3.1 g, 24 mmol) and (bromomethyl)cyclohexane (2.1 g, 12 mmol) were added to a solution of 2-amino-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1c_A12 (2.0 g, 12 mmol) in DMF (20 mL). The mixture was stirred at 80 °C for 16 h. Another batch of (bromomethyl)cyclohexane (2.1 g, 12 mmol) was added, and the mixture was stirred at 80 °C for another 16 h. A third batch of (bromomethyl)cyclohexane (1.1 g, 6 mmol) was added, and the reaction mixture was stirred at 80 °C for another 16 h. The reaction was quenched with water (80 mL) and extracted with EtOAc (40 mL × 3). The organic layer was concentrated. The residue was purified by silica column chromatography (17% EtOAc in PE) to give 2-amino-5-(cyclohexylmethyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1c_A as a yellow solid (418.5 mg, yield 11.5%); LC-MS Rt 1.14 min; MS m / z [M+H] + 304.1; Method 1; 1 H NMR(400MHz,DMSO-d6)δ7.00(s,2H),3.30(s,2H),2.29(s,2H),2.20(d,J=6.8Hz,2H),1 .75-1.60(m,5H),1.40-1.30(m,1H),1.21-1.13(m,3H),1.00(s,6H),0.80-0.77(m,2H).

[0469] Step 14: N-(3-cyano-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(3-methoxy-4-aminosulfonylphenyl)acetamide core-1c_A14

[0470]

[0471] Under argon atmosphere, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphonane 2,4,6-trioxide (50% in DMF) (0.25 mL, 0.423 mmol) was added to a mixture of tert-butyl 2-amino-3-cyano-6,6-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate core-1c_A12 (100 mg, 0.325 mmol), 2-(3-methoxy-4-aminosulfonylphenyl)acetic acid (80 mg, 0.325 mmol), and TEA (91 μL, 0.653 mmol) in DMF (2.5 mL). The reaction was stirred at room temperature for 16 h. The reaction was quenched with water (20 mL), and the product was extracted with EtOAc (3 x 50 mL). The combined organic layers were then washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to a crude product. This crude product was purified by normal-phase chromatography (eluent: cyclohexane / EtOAc) to give tert-butyl 3-cyano-2-(2-(3-methoxy-4-aminosulfonylphenyl)acetamido)-6,6-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (49 mg, yield 28%); LC-MS Rt 1.1 min, MS m / z [M+H]. + 535.2; Method 5.

[0472] TFA (0.1 mL, 1.298 mmol) was added to a solution of tert-butyl 3-cyano-2-(2-(3-methoxy-4-aminosulfonylphenyl)acetamyl)-6,6-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (63 mg, 0.118 mmol) in DCM (1.5 mL). The reaction was stirred at room temperature for 16 h. The reaction was then concentrated under vacuum (co-evaporated several times with DCM) to give N-(3-cyano-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)-2-(3-methoxy-4-aminosulfonylphenyl)acetamide (60 mg, crude) which was used directly in the next step.

[0473] Intermediate core-1c_B: 2-amino-5-((3,3-difluorocyclobutyl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile

[0474] Step 1: 4-Methylbenzenesulfonic acid (3,3-difluorocyclobutyl) methyl ester

[0475]

[0476] TEA (6.6 g, 65.4 mmol) and TsCl (7.5 g, 39.2 mmol) were added to a solution of (3,3-difluorocyclobutyl)methanol core-1c_B1 (4 g, 32.7 mmol) in DCM (60 mL). The mixture was stirred at 20 °C for 16 h. The reaction solution was concentrated. The residue was purified by silica column chromatography (17% EtOAc in PE) to give core-1c_B2 (4.8 g, 53% yield) as a colorless oil.

[0477] Step 2: 2-Amino-5-((3,3-difluorocyclobutyl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile

[0478]

[0479] DIPEA (2.5 g, 19.2 mmol) and methyl 4-methylbenzenesulfonic acid (3,2-c) methyl[3,2-c]pyridine-3-carboxynitrile core-1c_B2 (2.0 g, 9.6 mmol) were added to a solution of 2-amino-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1c_B2 (30 mL) in DMF were added. The mixture was stirred at 80 °C for 16 h. A second batch of methyl 4-methylbenzenesulfonic acid (3,3-difluorocyclobutyl) methyl ester (2.1 g, 7.8 mmol) was added, and the mixture was stirred at 80 °C for 24 h. The reaction was quenched with water (80 mL) and extracted with EtOAc (40 mL × 3). The organic layer was concentrated. The residue was purified by silica column chromatography (17% EtOAc in PE) to give 2-amino-5-((3,3-difluorocyclobutyl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydrothiophene[3,2-c]pyridine-3-carboxynitrile core-1c_B3 (148 mg, 5% yield) as a yellow solid; LC-MS Rt 0.95 min; MS m / z [M+H] + 312.0; Method 1; 1 H NMR (400MHz, DMSO-d6) δ7.03(s,2H),3.34(s,2H),2.66-2.61(m,2H),2.52-2.51(m,2H),2.32-2.18(m,5H),1.05(s,6H).

[0480] Intermediate core-1c_C: 2-amino-5-(3-fluorobenzyl)-6,6-dimethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile

[0481] Step 1: 2-Amino-5-(3-fluorobenzyl)-6,6-dimethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile

[0482]

[0483] DIPEA (623 mg, 4.82 mmol) and 1-(bromomethyl)-3-fluorobenzene (501 mg, 2.65 mmol) were added to a solution of 2-amino-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1c_C1 (500 mg, 2.41 mmol) in DMF (5 mL). The mixture was stirred at 80 °C for 16 h. The reaction solution was diluted with water (30 mL) and extracted with EtOAc (15 mL × 3). The organic layer was concentrated. The residue was purified by column chromatography (PE:EtOAc = 10:1-8:1) to give 2-amino-5-(3-fluorobenzyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1c_C (350 mg, yield 46%) as a yellow solid.

[0484] Preparation of intermediates

[0485] Intermediate Core-2a_A: N-(3-cyano-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0486]

[0487] Step 1: tert-butyl-2-amino-3-cyano-4,5-dihydrothiopheno[2,3-c]pyridine-6(7H)-carboxylate

[0488]

[0489] Sulfur (6.76 g, 210.8 mmol) and L-proline (1.62 g, 14.1 mmol) were added to a solution of tert-butyl 4-oxopiperidinium-1-carboxylate core-2a_1 (14.00 g, 70.3 mmol) and CH2(CN)2 (13.93 g, 210.8 mmol) in DMF (150 mL). The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was then poured into water (500 mL) and extracted with EA (500 mL × 2). The combined organic layers were washed with water (700 mL) and brine (700 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel chromatography, eluting with 10 / 1 to 2 / 1 PE / EtOAc to give tert-butyl-2-amino-3-cyano-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carbamate core-2a₂ (17.52 g, 89% yield); LC-MS Rt 0.905 min; MS m / z [M+H-56] + 221.9; Method 1.

[0490] Step 2: tert-butyl-3-cyano-2-(2-(4-aminosulfonylphenyl)acetamyl)-4,5-dihydrothiopheno[2,3-c]pyridine-6-(7H)-carboxylate 4

[0491]

[0492] DIPEA (0.83 g, 6.44 mmol) and T3P (50% EtOAc, 4.10 g, 6.44 mmol) were added to a stirred solution of tert-butyl-2-amino-3-cyano-4,5-dihydrothieno-[2,3-c]pyridine-6(7H)-carboxylate core-2a_2 (0.90 g, 3.22 mmol) and 2-(4-aminosulfonylphenyl)acetic acid core-2a_3 (1.04 g, 4.83 mmol) in DMF (10 mL). The reaction mixture was stirred at 120 °C for 45 min in a microwave reactor. The reaction mixture was poured into water (200 mL) and extracted with EA (200 mL × 2). The combined organic layers were washed with water (500 mL), followed by brine (500 mL x 4), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel chromatography, eluting with 10 / 1 to 1 / 1 PE / EA to give tert-butyl-3-cyano-2-(2-(4-aminosulfonylphenyl)acetamyl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate core-2a₄ (3.21 g, 75% yield); LC-MS Rt 0.84 min; MS m / z [M+H-100] +377.0, Method 1.

[0493] Step 3: N-(3-cyano-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0494]

[0495] TFA (3 mL) was added to a stirred solution of tert-butyl-cyano-3-cyano-2-(2-(4-aminosulfonylphenyl)acetamyl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate core-2a_4 (2.21 g, 4.64 mmol) in anhydrous DCM (27 mL). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, giving a crude product (1.60 g, 91% yield), which was used directly for the next step. 1 H NMR(400MHz,DMSO-d6)δ11.96(1H,s),7.22(4H,m),7.09(4H,m),5.95(1H,s),4.12(2H,m),4.10( 3H,s),2.29(3H,s),2.29(3H,s),2.15(2H,t),1.75(2H,m),1.46(2H,m),1.35-1.23(4H,m); LC-MS Rt 0.584min;MS m / z[M+H] + 377.0; Method 1.

[0496] Intermediate core-2a_B: (2,5-dichloropyridin-4-yl)methyl-4-methylbenzenesulfonate

[0497]

[0498] TsCl (128 mg, 0.67 mmol) and Et3N (113 mg, 1.18 mmol) were added to a solution of (2,5-dichloropyridin-4-yl)methanol core-2a_1a (100 mg, 0.56 mmol) in DCM (2 mL). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was then directly purified by preparative TLC (PE / EtOAc = 10 / 1) to give (2,5-dichloropyridin-4-yl)-methyl-4-methylbenzenesulfonate core-2a_B (70 mg, 37% yield) as a white solid; LC-MS Rt 0.919 min; MS m / z [M+H] + 332.0; Method 3.

[0499] Intermediate core-2a_C: Methyl-5-chloro-4-((toluenesulfonyloxy)methyl)pyridinecarboxylate

[0500] Step 1: Methyl-5-chloro-4-(hydroxymethyl)pyridine carboxylate

[0501]

[0502] A mixture of (2,5-dichloropyridin-4-yl)methanol core-2a_1a (200 mg, 1.12 mmol), Pd(dppf)Cl2 (80 mg, 0.11 mmol), and Et3N (227 mg, 2.24 mmol) in MeOH (30 mL) was stirred at 80 °C for 16 h under CO (50 psi). The reaction solution was filtered and the filtrate was concentrated to give the residue. The residue was purified by preparative TLC (PE:EtOAc = 2:1) to give methyl-5-chloro-4-(hydroxymethyl)pyridinecarboxylate core-2a_2r (200 mg, yield: 88%) as a white solid. 1 H NMR (400MHz, CDCl3) δ8.62(s,1H),8.38(s,1H),4.88(s,2H),4.02(s,3H).

[0503] Step 2: Methyl-5-chloro-4-((toluenesulfonyloxy)methyl)pyridinecarboxylate

[0504]

[0505] Et3N (101 mg, 1.00 mmol) and TsCl (143 mg, 0.75 mmol) were added to a solution of methyl-5-chloro-4-((toluenesulfonyloxy)methyl)pyridinecarboxylate core-2a_2r (100 mg, 0.50 mmol) in DCM (10 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (PE:EtOAc = 4:1) to give methyl-5-chloro-4-((toluenesulfonyloxy)methyl)pyridinecarboxylate core-2a_C (50 mg, yield 28%) as a white solid; LC-MS: Rt = 0.841 min; MS m / z [M+H] + 355.9; Method 3.

[0506] Intermediate core-2a_D: 2-amino-6-(2,2,2-trifluoro-1-phenylethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxynitrile

[0507] Step 1: 8-(2,2,2-trifluoro-1-phenylethyl)-1,4-dioxa-8-azaspiro[4.5]decane

[0508]

[0509] TsCl (128 mg, 0.67 mmol) and Et3N (113 mg, 1.18 mmol) were added to a solution of (2,5-dichloropyridin-4-yl)methanol core-2a_1d (100 mg, 0.56 mmol) in DCM (2 mL). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was then directly purified by preparative TLC (PE / EtOAc = 10 / 1) to give (2,5-dichloropyridin-4-yl)-methyl-4-methylbenzenesulfonate core-2a_3d (70 mg, 37% yield) as a white solid; LC-MS Rt 0.849 min; MS m / z [M+H] + 302.1; Method 3.

[0510] Step 2: 1-(2,2,2-trifluoro-1-phenylethyl)piperidin-4-one

[0511]

[0512] Aqueous HCl (4N, 9 mL, 36 mmol) was added to a solution of 8-(2,2,2-trifluoro-1-phenylethyl)-1,4-dioxa-8-azaspiro[4.5]decane core-2a_3d (270 mg, 0.89 mmol) in THF (1 mL). The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with water (5 mL) and washed with MTBE (2 × 10 mL). The aqueous layer was alkalized to pH 9–10 with aqueous NaOH (2N). The mixture was extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated to give an oily 1-(2,2,2-trifluoro-1-phenylethyl)piperidin-4-one core-2a_4d (130 mg, yield: 56%); LC-MS Rt 0.956 min; MS m / z [M+H] + 258.0; Method 1.

[0513] Step 3: 2-Amino-6-(2,2,2-trifluoro-1-phenylethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxynitrile

[0514]

[0515] At 20 °C, sulfur (24 mg, 0.75 mmol) and L-proline (10 mg, 0.087 mmol) were added to a solution of 1-(2,2,2-trifluoro-1-phenylethyl)piperidin-4-one core-2a_4d (130 mg, 0.5 mmol) and CH2(CN)2 (40 mg, 0.6 mmol) in DMF (10 mL). The mixture was heated at 60 °C for 6 h. The reaction was concentrated, diluted with water (10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine and concentrated. The residue was purified by preparative TLC to give 2-amino-6-(2,2,2-trifluoro-1-phenylethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxynitrile core-2a_D as a yellow solid (100 mg, 60% yield); LC-MS Rt 0.854 min MS m / z [M+H] + 338.0; Method 3.

[0516] Intermediate core-2b_A:(R)-tert-butyl-2-amino-3-cyano-5-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate

[0517] Step 1: (E)-N-methoxy-N-methylbut-2-eneamide

[0518]

[0519] At 0 °C, a solution of Et3N (11.1 g, 110 mmol) and DMAP (584 mg, 4.78 mmol) in DCM (200 mL) was added to a solution of N,O-dimethylhydroxylamine hydrochloride core-2b_A2 (4.7 g, 47.8 mmol) in DCM (30 mL). After 30 min, a solution of crotonyl chloride core-2b_A1 (5.0 g, 47.8 mmol) in DCM (20 mL) was added at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction was quenched with water (200 mL) and extracted with DCM (100 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (9% ethyl acetate / petroleum ether) to give (E)-N-methoxy-N-methylbut-2-enamide core-2b_A3 (4.1 g, yield 66%), which was a light yellow oil. 1 H NMR (400MHz, CDCl3) δ6.97-6.88 (m, 1H), 6.37 (d, J = 16Hz, 1H), 3.65 (s, 3H), 3.18 (s, 3H), 1.86 (d, J = 8Hz, 3H).

[0520] Step 2: (R)-2-methyl-1-((S)-1-phenylethyl)piperidin-4-one 6a and (S)-2-methyl-1-((S)-1-phenylethyl)piperidin-4-one

[0521]

[0522] Under N2, vinyl magnesium bromide (17 mL, 17.0 mmol, 1N in THF) was added dropwise to a 0°C solution of core-2b_A3 (2.0 g, 15.5 mmol) in THF (40 mL). The reaction was heated to 20°C. After stirring for 1 h, (S)-1-phenylethylamine (3.8 g, 31.0 mmol) and water (4 mL) were added. The system was stirred for another 1 h. The reaction solution was diluted with water (60 mL), concentrated to remove THF, and extracted with DCM (50 mL × 3). The organic layer was layered and concentrated. The residue was purified by silica column chromatography (PE:EtOAc = 10:1) to give core-2b_A4a (450 mg, yield 13.5%) and core-2b_A4b (200 mg, yield 5.9%) as yellow solids; core-2b_A4a, 1 H NMR (400MHz, CDCl3) δ7.47-7.45(m,2H),7.37-7.33(m,2H),7.28-7.26(m,1H),4.05-4.00(m,1H),3.42-3.39(m,1H) ,2.77-2.67(m,3H),2.28-2.27(m,1H),2.25-2.23(m,2H),1.35(d,J=6.8Hz,3H),1.15(d,J=6.8Hz,3H); Core-2b_A4b, 1 H NMR (400MHz, CDCl3) δ7.38-7.31(m,4H),7.28-7.27(m,1H),3.96-3.93(m,1H),3.19-3.17(m,1H),2.99-2.95( m,2H),2.60-2.55(m,2H),2.36-2.30(m,1H),2.15-2.10(m,1H),1.44(d,J=6.8Hz,3H),1.06(d,J=6.8Hz,3H).

[0523] Step 3: (R)-tert-butyl-2-methyl-4-oxopiperidin-1-carboxylate

[0524]

[0525] A mixture of core-2b_A4a (450 mg, 2.1 mmol), Boc2O (698 mg, 3.2 mmol), and Pd(OH)2 / C (50 mg, catalyst) in THF (40 mL) was hydrogenated at 20 °C for 16 h under H2 (50 psi). The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica column chromatography (20% EtOAc / PE) to give core-2b_A5a (180 mg, 40% yield) as a white solid. 1 H NMR(400MHz, CDCl3)δ4.72(brs,1H),4.27-4.22(m,1H),3.36-3.32(m,1H),2.72-2 .66(m,1H),2.58-2.42(m,1H),2.37-2.25(m,2H),1.50(s,9H),1.19(d,J=8Hz,3H).

[0526] Step 4: (R)-tert-butyl2-amino-3-cyano-5-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate and (R)-tert-butyl2-amino-3-cyano-7-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate

[0527]

[0528] At 20 °C, sulfur (40 mg, 1.26 mmol) and L-proline (10 mg, 0.084 mmol) were added to a solution of (R)-tert-butyl-2-methyl-4-oxopiperidin-1-carboxylate core-2b_A5a (180 mg, 0.84 mmol) and CH2(CN)2 (61 mg, 0.93 mmol) in DMF (6 mL). The mixture was stirred at 20 °C for 10 min, followed by heating at 60 °C for 3 h. The reaction solution was diluted with water (20 mL) and extracted with EtOAc (15 mL × 3). The organic layer was concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 4:1) to give a mixture (190 mg) of (R)-tert-butyl-2-amino-3-cyano-5-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate and (R)-tert-butyl-2-amino-3-cyano-7-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate as a yellow solid; LC-MS Rt 0.81 min; MS m / z [M+H] + 294.10; Method 3.

[0529]

[0530] Procedure: A mixture of regioisomers (190 mg) was submitted for chiral SFC to yield (R)-tert-butyl2-amino-3-cyano-5-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (86.9 mg, 96% ee) and (R)-tert-butyl2-amino-3-cyano-7-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (44.6 mg, 100% ee).

[0531] Chiral SFC separation (conditions a: column: OJ-10um, 250mm*30mm, ID, 5um; mobile phase: A is CO2, B is EtOH (0.1% ammonia); isocratic: 25% B phase; total flow rate: 55mL / min; back pressure: 100 bar; UV: 220nm; instrument: SFC 80).

[0532] (R)-tert-butyl-2-amino-3-cyano-5-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate: 1 H NMR(400MHz,DMSO-d6)δ7.16(s,2H),4.56-4.52(m,2H),3.87-3.83(m,1H) ,2.65-2.61(m,1H),2.27-2.22(m,1H),1.42(s,9H),1.06(d,J=6.4Hz,3H).

[0533] (R)-tert-butyl-2-amino-3-cyano-7-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate: 1 H NMR(400MHz,DMSO-d6)δ7.17(s,2H),4.90-4.84(m,1H),4.11-4.08(m,1H) ,3.03-2.92(m,1H),2.40-2.36(m,2H),1.42(s,9H),1.26(d,J=6.4Hz,3H).

[0534] Intermediate core-2b_B:(R)-tert-butyl-2-amino-3-cyano-5-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate

[0535] Step 1: (S)-tert-butyl-2-methyl-4-oxopiperidin-1-carboxylate

[0536]

[0537] A mixture of core-2b_A4b (200 mg, 0.92 mmol), Boc2O (301 mg, 1.38 mmol), and Pd(OH)2 / C (50 mg, catalyst) in THF (30 mL) was hydrogenated at 20 °C for 16 h under H2 (50 psi). The reaction was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (PE:EtOAc = 4:1) to give core-2b_B1 (110 mg, 55% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.64(brs,1H),4.19-4.14(m,1H),3.28-3.25(m,1H),2.63-2.58(m,1H ),2.41-2.39(m,1H),2.29-2.25(m,1H),2.20-2.16(m,1H),1.48(s,9H),1.11(d,J=8Hz,3H).

[0538] Step 2: (S)-tert-butyl-2-amino-3-cyano-5-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate and (S)-tert-butyl-2-amino-3-cyano-7-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate

[0539]

[0540] Sulfur (25 mg, 0.78 mmol) and L-proline (6 mg, 0.052 mmol) were added to a solution of core-2b_B1 (110 mg, 0.52 mmol) and CH2(CN)2 (38 mg, 0.57 mmol) in DMF (3 mL) at 20 °C. The mixture was stirred at 20 °C for 10 min, followed by heating at 60 °C for 3 h. The reaction solution was diluted with water (20 mL) and extracted with EtOAc (15 mL × 3). The organic layer was concentrated. The residue was purified by silica column chromatography (20% ethyl acetate / petroleum ether) to give a mixture (130 mg) of (S)-tert-butyl-2-amino-3-cyano-5-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate and (S)-tert-butyl-2-amino-3-cyano-7-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (130 mg), as a yellow solid; LC-MS Rt 0.81 min; MS m / z [M+H] + 294.10; Method 3.

[0541]

[0542] Procedure: A mixture (130 mg) of (S)-tert-butyl-2-amino-3-cyano-5-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate and (S)-tert-butyl-2-amino-3-cyano-7-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate was submitted for chiral SFC to give (S)-tert-butyl-2-amino-3-cyano-5-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (57.2 mg, 100% ee) and (S)-tert-butyl-2-amino-3-cyano-7-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (32.2 mg, 100% ee); LC-MS Rt 0.84 min; MS m / z [M-55] + 238.0; Method 3.

[0543] Chiral SFC separation (Conditions a: Column: OJ-10um, 250mm*30mm, ID, 5um; Mobile phase: A is CO2, B is EtOH (0.1% ammonia); Isocratic: 20% B phase; Total flow rate: 55mL / min; Back pressure: 100 bar; UV: 220nm; Instrument: SFC 80).

[0544] (S)-tert-butyl-2-amino-3-cyano-5-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate: 1 H NMR(400MHz,DMSO-d6)δ7.16(s,2H),4.59-4.52(m,2H),3.87-3.83(m,1H) ,2.66-2.61(m,1H),2.27-2.22(m,1H),1.42(s,9H),1.06(d,J=6.4Hz,3H).

[0545] (S)-tert-butyl-2-amino-3-cyano-7-methyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate: 1 H NMR(400MHz,DMSO-d6)δ7.18(s,2H),4.89-4.84(m,1H),4.11-4.08(m,1H) ,3.03-2.92(m,1H),2.40-2.36(m,2H),1.42(s,9H),1.26(d,J=6.4Hz,3H).

[0546] Intermediates core-8_A and core-9_B: 2-amino-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azacycloheptane-3-carboxylonitrile and 2-amino-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azacycloheptane-3-carboxylonitrile

[0547] Step 1: tert-butyl-2-amino-3-cyano-7,8-dihydro-4H-thieno[2,3-d]azacycloheptane-6(5H)-carboxylate and tert-butyl-2-amino-3-cyano-5,6-dihydro-4H-thieno[2,3-c]azacycloheptane-7(8H)-carboxylate

[0548]

[0549] Sulfur (1.50 g, 23.4 mmol) and morpholine (1.02 g, 11.7 mmol) were added to a solution of tert-butyl-4-oxazacycloheptan-1-carboxylate core-8&9_1 (5.00 g, 23.4 mmol) and CH2(CN)2 (3.10 g, 46.8 mmol) in DMF (50 mL). The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with water (300 mL) and brine (300 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 2:1) to give a mixture of tert-butyl-2-amino-3-cyano-7,8-dihydro-4H-thieno[2,3-d]azacycloheptane-6(5H)-formate core-8_2a and tert-butyl-2-amino-3-cyano-5,6-dihydro-4H-thieno[2,3-c]azacycloheptane-7(8H)-formate core-9_2a (3.02 g, yield 44%); LC-MS Rt 0.93 min; MS m / z [M+H-56] + 237.9; Method 1.

[0550] Step 2: 2-Amino-5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azacycloheptane-3-carboxylonitrile and 2-Amino-5,6,7,8-Tetrahydro-4H-thieno[2,3-c]azacycloheptane-3-carboxylonitrile

[0551]

[0552] At 0 °C, TFA (3.0 mL) was added to a solution of tert-butyl-2-amino-3-cyano-7,8-dihydro-4H-thieno[2,3-d]azacycloheptane-6(5H)-carbamate core-8_2 and tert-butyl-2-amino-3-cyano-5,6-dihydro-4H-thieno[2,3-c]azacycloheptane-7(8H)-carbamate core-9_2a (3.00 g, 10.23 mmol) in DCM (27 mL). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was dissolved in water (50 mL) and extracted with DCM (50 mL × 2). The pH of the aqueous layer was adjusted to 8–9 with saturated Na₂CO₃ and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated to give a mixture of 2-amino-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azacycloheptane-3-carboxynitrile core-8_A and 2-amino-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azacycloheptane-3-carboxynitrile core-8_B (2.23 g, crude), which was used directly for the next step; LC-MS Rt 0.66 & 0.71 min; MS m / z [M+H] + 193.9 & [M+H-17] + 176.9, Method 1.

[0553] 2-Amino-6-(3-fluorobenzyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azacycloheptane-3-carboxylonitrile and 2-Amino-7-(3-fluorobenzyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azacycloheptane-3-carboxylonitrile

[0554]

[0555] To a solution of 2-amino-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azacycloheptane-3-carboxynitrile core-8_A and 2-amino-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azacycloheptane-3-carboxynitrile core-9_B (400.0 mg, 2.07 mmol) in DMF (10 mL), 1-(bromomethyl)-3-fluorobenzene core-8&9_3 (470 mg, 2.48 mmol) and DIPEA (535 mg, 4.14 mmol) were added. The reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1) to give a crude product (400 mg), which was further purified by preparative TLC (PE:EtOAc = 5:1) to give a product mixture (350 mg, yield 56.11%). The mixture was then purified by SFC to give 2-amino-6-(3-fluorobenzyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azacycloheptane-3-carboxynitrile (125 mg, peak 2; 1 H NMR (400MHz, CDCl3) δ7.31-7.27(m,1H),7.12(d,J=7.6Hz,2H),6.98-6.94(m,1H),4.54(br s,2H),3.73(s,2H),2.79-2.63(m,8H).;LC-MS: Rt=0.98min,MS m / z[M+H] + 302.0; Method 1) and 2-amino-7-(3-fluorobenzyl)-5,6,7,8-tetrahydro-4H-thiopheno[2,3-c]azacycloheptane-3-carboxynitrile (105 mg, peak 1); 1 H NMR (400MHz, CDCl3) δ7.31-7.27(m,1H),7.09-7.05(m,2H),6.96(dt,J=8.4,1.9Hz,1H),4.59(br s,2H),3.66(s,2H),3.63(s,2H),3.20-3.17(m,2H),2.78-2.75(m,2H),1.78-1.73(m,2H); LC-MS Rt 0.979min,MS m / z[M+H] + 302.0; Method 1.

[0556] 2-Amino-6-(cyclohexylmethyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azacycloheptane-3-carboxylonitrile and 2-Amino-7-(cyclohexylmethyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azacycloheptane-3-carboxylonitrile

[0557]

[0558] The title compound was prepared by means of a method similar to that in Example 1, by replacing 1-(bromomethyl)-3-fluorobenzene 5 (Step 3 of Example 1) with a mixture of 2-amino-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azacycloheptane-3-carboxylonitrile (intermediate core-8_A) and 2-amino-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azacycloheptane-3-carboxylonitrile (intermediate core-9_B) in DMF for 16 h; 2-amino-6-(cyclohexylmethyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azacycloheptane-3-carboxylonitrile (145.0 mg, yield 7%; (400 MHz, CDCl3) δ 4.54 (br) s,2H), 2.81-2.70(m,8H), 2.38(d,J=6.8Hz,2H), 1.82-1.71(m,5H), 1.61-1.48(m,1H), 1.28-1.19(m,3H), 0.94-0.87(m,2H); LC-MS Rt 1.08min, MS m / z[M+H]+290.0; Method 1) and 2-amino-7-(cyclohexylmethyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azacycloheptane-3-carboxylonitrile (110.0 mg, yield 6%); 1 H NMR((400MHz,CDCl3)δ4.49(br s,2H),3.62(s,2H),3.04-2.99(m,2H),2.65-2.62(m,2H),2.17(d,J=7.2Hz,2H), 1.65-1.57(m,7H),1.41-1.24(m,1H),1.17-1.09(m,3H),0.79-0.74(m,2H); LC-MS Rt 0.61min, MS m / z[M+H]+290.2; method 2).

[0559] Preparation of instances

[0560] Example 1: N-(3-cyano-5-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0561]

[0562] To a solution of N-(3-cyano-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide core-1a_F (20 mg, 0.05 mmol) in MeOH (2 mL), AcOH (0.02 mL, catalyst) and a solution of 3-fluorobicyclo[1.1.1]pentane-1-carboxaldehyde core-1a_D (crude) in DCM (1 mL) were added. The mixture was stirred at 20 °C for 1 h. NaBH3CN (10 mg, 0.15 mmol) was added. The mixture was stirred at 20 °C for another 1 h. The reaction mixture was purified by preparative TLC (11% MeOH in DCM) to give the desired product (10 mg, crude) as a white solid. The crude product was mixed with another batch and further purified by preparative TLC (11% MeOH in DCM) to give the title compound (5.6 mg) as a white solid. 1 H NMR(400MHz,CD3OD)δ7.89(d,J=8.4Hz,2H),7.53(d,J=8.4Hz,2H),3.97(s,2H),3.6 0(s,2H),2.95(s,2H),2.90-2.88(m,2H),2.80-2.78(m,2H),2.08(d,J=2.4Hz,6H). LC-MS Rt1.51min; MS m / z[M+H] + 475.1; Method 1.

[0563] Example 2: N-(3-cyano-5-((3,3-difluorocyclobutyl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0564]

[0565] Example 2 was prepared by a method similar to that of Example 1, using N-(3-cyano-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide with a suitable aldehyde derivative (commercially available or prepared as described above). 1H NMR (400MHz, DMSO-d6) δ11.89(s,1H),7.77(d,J=8.3Hz,2H),7.48(d,J=8.4Hz,2H),7.31(s,2H LC-MS Rt 0.85min; MS m / z[M+H] + 481.0; Method 1.

[0566] Example 3: N-(3-cyano-5-(1-cyclohexylethyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0567]

[0568] Example 3 was prepared by a method similar to that of Example 1, using N-(3-cyano-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (core-1a_F) with a suitable aldehyde derivative (commercially available or prepared as described above). 1 H NMR (400MHz, DMSO-d6) δ8.36(s,1H),7.75(d,J=8.4Hz,2H),7.47(d,J=8.4Hz,2H),7.28(s,2H),3.83(s,2H),3.50(d,J=14.6Hz,2H),2.82(d,J= 5.2Hz, 1H), 2.42 (d, J = 8.6Hz, 1H), 2.04-1.92 (m, 3H), 1.76-1.57 (m, 4H), 1.12 (d, J = 23.3Hz, 3H), 0.95 (d, J = 6.6Hz, 3H), 0.92-0.82 (m, 3H); LC-MS Rt 0.66min,MS m / z[M+H] + 487.1; Method 5.

[0569] Example 4: N-(3-cyano-5-(cyclopentylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0570]

[0571] DIPEA (68.7 mg, 0.52 mmol) was added to a stirred solution of N-(3-cyano-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide core-1a_F (100.0 mg, 0.26 mmol) and (bromomethyl)cyclopentane 5 (52.0 mg, 0.32 mmol) in DMF (2.0 mL). The reaction mixture was stirred at 70 °C for 4 h. The reaction mixture was purified by preparative HPLC (NH3·H2O) to give N-(3-cyano-5-(cyclopentylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (24.0 mg, 20% yield). 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),7.78(d,J=8.2Hz,2H),7.49(d,J=8.2Hz,2H),7.33(s,2H),3.95(s,2H),3.40(s,2H),2. 75-2.61(m,4H),2.40(d,J=7.4Hz,2H),2.21-2.06(m,1H),1.71(d,J=6.7Hz,2H),1.61-1.44(m,4H),1.26-1.16(m,2H); LC-MS Rt 0.93min; MS m / z[M+H] + 459.1; Method 1.

[0572] Example 5: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0573]

[0574] Example 5 was prepared by a method similar to that of Core 2a (K2CO3, room temperature, 16 h) using N-(3-cyano-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (Core-1a_F) with a suitable halide derivative (commercially available or prepared as described above). 1H NMR (400MHz, DMSO-d6) δ11.89(s,1H),7.79-7.75(m,2H),7.50-7.45(m,2H),7.43-7.36(m,1H),7.31(s,2H),7.19(t,J=9 .4Hz,2H),7.10(td,J=8.7,8.3,2.7Hz,1H),3.95(s,2H),3.72(s,2H),3.42(s,2H),2.77-2.69(m,3H),2.67(s,2H); LC-MS Rt 0.61min,MS m / z[M+H] + 485.1; Method 5.

[0575] Example 6: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0576]

[0577] 1 H NMR(400MHz,DMSO-d6)δ7.80-7.75(m,2H),7.48(d,J=8.4Hz,2H),7.31(s,2H),3.95(s,2H),3.36(s,2H),2 .66(d,J=3.7Hz,4H),2.30(d,J=7.2Hz,2H),1.79-1.50(m,6H),1.29-1.11(m,3H),0.93-0.80(m,2H); LC-MS Rt 0.62min,MS m / z[M+H] + 473.0: Method 5.

[0578] Example 7: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3-methoxy-4-aminosulfonylphenyl)acetamide

[0579]

[0580] DIPEA (568 mg, 4.4 mmol) and T3P (2.1 g, 3.3 mmol) were added to a solution of 2-amino-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1a_B (600 mg, 2.2 mmol) and 2-(3-methoxy-4-aminosulfonylphenyl)acetic acid core-1a_E (809 mg, 3.3 mmol) in DMF (6 mL). The reaction mixture was stirred in a microwave at 120 °C for 45 min. The reaction mixture was then poured into water (60 mL) and Na2CO3 was added to adjust the pH to 8–9. The mixture was extracted with EtOAc (60 mL × 3), the organic layers were combined, dried over Na2SO4, and concentrated. The crude product was washed with MeOH to obtain N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(3-methoxy-4-aminosulfonylphenyl)acetamide (315.0 mg, 16%) as a white solid. The mother liquor was purified by preparative HPLC (NH3·H2O) to obtain another batch (232.0 mg, 12%). 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),7.67(d,J=8.0Hz,1H),7.16(s,1H),7.03(s,2H),6.97(d,J=8.0Hz,1H),3.93(s,2H),3 .89(s,3H),3.34(s,2H),2.65(s,4H),2.29(d,J=7.0Hz,2H),1.75-1.72(m,6H),1.27-1.09(m,3H),0.90-0.81(m,2H); LC-MS Rt 0.67min; MS m / z[M+H] + 503.1; Method 3.

[0581] Examples 8 to 20 were prepared by a method similar to that of Example 3, using 2-amino-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile core-1a_B with a suitable acid derivative (commercially available or prepared as described above).

[0582] Example 8: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-(1,1,1-trifluoro-2-hydroxypropyl-2-yl)phenyl)acetamide

[0583]

[0584] 1H NMR (400MHz, DMSO-d6) δ11.84 (s, 1H), 7.54 (d, J = 8.3Hz, 2H), 7.35-7.27 (m, 2 H),6.54(s,1H),3.86(s,2H),3.36-3.35(m,2H),2.66(q,J=4.5,3.6Hz,4H), 2.30(d,J=7.2Hz,2H),1.74(d,J=13.3Hz,2H),1.65(d,J=9.8Hz,6H),1.55(t t,J=7.3,3.6Hz,1H),1.29-1.11(m,3H),0.86(q,J=13.4,12.7Hz,2H); LC-MS Rt 0.79min,MS m / z[M+H] + 506.2; Method 5.

[0585] Example 9: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(3-fluoro-4-aminosulfonylphenyl)acetamide

[0586]

[0587] 1 H NMR (400MHz, DMSO-d6) δ7.74(t,J=7.9Hz,1H),7.61(s,2H),7.36(d,J=11.3Hz,1H),7.27(dd,J=8.1,1.3Hz,1H),3.94(s,2H),3.35(s,2H) ,2.65(d,J=3.9Hz,4H),2.30(d,J=7.2Hz,2H),1.80-1.50(m,6H),1.20(dq,J=23.6,11.5,10.9Hz,3H),0.86(q,J=13.5,12.6Hz,2H); LC-MS Rt 0.60min,MS m / z[M+H] + 491.1; Method 5.

[0588] Example 10: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(3-methoxy-4-(methylsulfonyl)phenyl)acetamide

[0589]

[0590] 1H NMR (400MHz, DMSO-d6) δ7.75(d,J=8.0Hz,1H),7.27(d,J=1.4Hz,1H),7.08(dd,J=8. 1,1.5Hz,1H),3.96(d,J=6.4Hz,5H),3.36(s,2H),3.22(s,3H),2.66(d,J=4.1Hz,4H ),2.30(d,J=7.2Hz,2H),1.74(d,J=13.0Hz,2H),1.66(d,J=12.8Hz,3H),1.55(tt,J =7.2, 3.5Hz, 1H), 1.19 (dq, J = 23.7, 11.7, 11.2Hz, 3H), 0.86 (q, J = 11.8Hz, 2H); LC-MS Rt0.65min,MS m / z[M+H] + 502.1; Method 5.

[0591] Example 11: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-((difluoromethyl)sulfonyl)phenyl)acetamide

[0592]

[0593] 1 H NMR (400MHz, DMSO-d6) δ7.98-7.90(m,2H),7.75-7.66(m,2H),7.29(t,J=52.1Hz,1H),4.03(s,2H),3.34(s,2H),2.64(dt,J=9 .7,4.0Hz,4H),2.29(d,J=7.2Hz,2H),1.74(d,J=12.7Hz,2H),1.70-1.50(m,4H),1.26-1.11(m,3H),0.93-0.79(m,2H); LC-MS Rt 0.77min,MS m / z[M+H] + 508.1; Method 5.

[0594] Example 12: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(3-ethoxy-4-aminosulfonylphenyl)acetamide

[0595]

[0596] 1H NMR (400MHz, DMSO-d6) δ7.67(d,J=8.0Hz,1H),7.17(d,J=1.2Hz,1H),6.96(dd,J=8.0,1.3Hz,1H),6.88(s,2H),4.20(q,J=7.0Hz,2H),3.91(s,2H),3 .36(s,2H),2.66(d,J=3.5Hz,4H),2.30(d,J=7.2Hz,2H),1.79-1.51(m,6H ),1.38(t,J=7.0Hz,3H),1.29-1.08(m,3H),0.86(q,J=11.6Hz,2H); LC-MS Rt 0.65min,MS m / z[M+H] + 517.2; Method 5.

[0597] Example 13: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-(methylsulfonamido)phenyl)acetamide

[0598]

[0599] 1 H NMR (400MHz, DMSO-d6) δ9.68(s,1H),7.27(d,J=8.6Hz,2H),7.21-7.12(m,2H),3.80(s,2H),3.35(s,2H),2.96(s,3H),2.65(d,J=3 .6Hz, 4H), 2.29 (d, J = 7.2Hz, 2H), 1.74 (d, J = 12.5Hz, 2H), 1.70-1.50 (m, 4H), 1.30-1.07 (m, 3H), 0.86 (q, J = 11.0, 9.9Hz, 2H); LC-MS Rt 0.65min,MS m / z[M+H] + 487.2; Method 5.

[0600] Example 14: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-(N,N-dimethylaminosulfonyl)phenyl)acetamide

[0601]

[0602] 1H NMR (400MHz, DMSO-d6) δ11.91(s,1H),7.77-7.68(m,2H),7.58(d,J=8.4Hz,2H),4.01(s,2H),3.37(s,2H),2.66(s ,4H),2.61(s,6H),2.30(d,J=7.1Hz,2H),1.79-1.50(m,6H),1.30-1.08(m,3H),0.86(q,J=10.7,9.7Hz,2H); LC-MS Rt 0.71min,MS m / z[M+H] + 501.2; Method 5.

[0603] Example 15: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3-(2-methoxyethoxy)phenyl)acetamide

[0604]

[0605] 1 H NMR(400MHz, DMSO-d6)δ7.22(t,J=7.9Hz,1H),6.93-6.80(m,3H),4.06(dd,J=5.4,3.8Hz,2H),3.80(s,2H),3.65(dd,J=5.4,3.8Hz,2H), 3.35(s,2H),3.30(s,3H),2.64(s,4H),2.29(d,J=7.2Hz,2H),1.80-1.47(m,6H),1.31-1.07(m,3H),0.85(q,J=10.9,10.3Hz,2H); LC-MS Rt0.70min,MS m / z[M+H] + 468.2; Method 5.

[0606] Example 16: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(1,1-dioxy-2,3-dihydrobenzo[d]isothiazo-5-yl)acetamide

[0607]

[0608] 1H NMR (400MHz, DMSO-d6) δ7.80-7.73(m,2H),7.52-7.45(m,2H),4.39(d,J=4.7Hz,2H),4.00(s,2H),3.36(s,2H),2.66(d,J=3. 7Hz, 4H), 2.30 (d, J = 7.2Hz, 2H), 1.80-1.49 (m, 6H), 1.20 (dq, J = 23.4, 12.0, 11.5Hz, 3H), 0.86 (q, J = 10.8, 10.0Hz, 2H); LC-MS Rt0.59min,MS m / z[M+H] + 485.2; Method 5.

[0609] Example 17: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-(aminosulfonylmethyl)phenyl)acetamide

[0610]

[0611] 1 H NMR (400MHz, DMSO-d6) δ7.36-7.22(m,4H),6.84(s,2H),4.24(s,2H),3.85(s,2H),3.35(s,2H),2.69-2.60(m,4H),2.30(d,J=7. 2Hz, 2H), 1.74 (d, J = 13.0Hz, 2H), 1.66 (d, J = 12.9Hz, 3H), 1.56 (d, J = 3.9Hz, 1H), 1.27-1.11 (m, 3H), 0.86 (q, J = 11.9Hz, 2H); LC-MS Rt 0.63min,MS m / z[M+H] + 487.1; Method 5.

[0612] Example 18: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(1,1-dioxy-2,3-dihydrobenzo[b]thiophenyl-5-yl)acetamide

[0613]

[0614] 1H NMR(400MHz,DMSO-d6)δ7.72-7.67(m,1H),7.46(d,J=7.0Hz,2H),3.97(s,2 H),3.57(dd,J=7.5,6.3Hz,2H),3.36(s,2H),3.34(s,2H),2.69-2.61(m,4H ),2.30(d,J=7.2Hz,2H),1.74(d,J=13.0Hz,2H),1.66(d,J=12.7Hz,3H),1. 55(tt,J=7.2,3.5Hz,1H),1.29-1.11(m,3H),0.86(q,J=11.6Hz,2H); LC-MS Rt 0.63min,MS m / z[M+H] + 484.1

[0615] Example 19: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(2-methoxy-4-aminosulfonylphenyl)acetamide

[0616]

[0617] 1 H NMR (400MHz, DMSO-d6) δ11.80(s,1H),7.42-7.36(m,3H),7.32(s,2H),3.89(s,2H),3.81(s,3H),3.37(s,2H),2.66(d,J=6.0Hz,4H),2. 30(d,J=7.1Hz,2H),1.75(d,J=13.1Hz,2H),1.66(d,J=12.9Hz,3H),1.59-1.51(m,1H),1.26-1.15(m,3H),0.87(q,J=11.5Hz,2H); LC-MS Rt 0.63min,MS m / z[M+H] + 503.2; Method 5.

[0618] Example 20: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(isoindoline-5-yl)acetamide

[0619]

[0620] 1H NMR(400MHz, DMSO-d6)δ7.30(d,J=11.4Hz,2H),7.23(d,J=7.6Hz,1H),4.33(s,2H),3.86(s,2H),2.69-2.57(m,4H) ,2.30(d,J=7.2Hz,2H),1.79-1.60(m,5H),1.50(d,J=41.0Hz,3H),1.28-1.09(m,4H),0.89(d,J=9.9Hz,4H); LC-MS Rt 0.46min,MS m / z[M+H] + 435.2; Method 5.

[0621] Examples 21 to 49 were prepared by a similar method, by replacing 2-amino-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile core-1a_A with a suitable acid derivative (commercially available or prepared above).

[0622] Example 21: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3-ethoxy-4-aminosulfonylphenyl)acetamide

[0623]

[0624] Yield 30%; 1 H NMR (400MHz, DMSO-d6) δ7.67(d,J=8.0Hz,1H),7.44-7.35(m,1H),7.23-7.15(m,3H),7.14-7.06(m,1H),6.96(d,J=7.9 LC-MS Rt0.94min; MS m / z[M+H] + 529.1; Method 3.

[0625] Example 22: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3-methoxy-4-aminosulfonylphenyl)acetamide

[0626]

[0627] Yield 76%; 1H NMR (400MHz, DMSO-d6) δ11.86 (s, 1H) 7.69-7.66 (d, J = 8.03Hz, 1H) 7.44-7.34 (m, 1H) 7.25-7.23 (m, 1H) 7.2 4-6.92(m,6H)3.97-3.86(m,5H)3.72(s,2H)3.46-3.40(m,2H)3.47-3.37(m,1H)2.65-2.80(m,4H); LC-MS Rt 0.90min; MS m / z[M+H] + 515.1; Method 1.

[0628] Example 23: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(1,1-dioxy-2,3-dihydrobenzo[d]isothiazo-5-yl)acetamide

[0629]

[0630] Yield 16%; 1 H NMR(400MHz,DMSO-d6)δ7.73(d,J=8.0Hz,2H),7.48-7.38(m,3H),7.20-7.10(m,2H), 4.38(s,2H),3.86(s,2H),3.70(s,2H),3.48(s,2H),2.71(m,2H),2.61(m,2H); LC-MS Rt 0.91min; MS m / z[M+H] + 497.13; Method 1.

[0631] Example 24: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(2-methoxy-4-aminosulfonylphenyl)acetamide

[0632]

[0633] Yield 24%; 1 LC-MS Rt 0.95min;MSm / z[M+H] + 515.1; Method 1.

[0634] Example 25: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(1,1-dioxy-2,3-dihydrobenzo[d]isothiazo-6-yl)acetamide

[0635]

[0636] Yield 24%; 1 H LC-MS Rt0.63min; MS m / z[M+H] + 497.0; Method 3.

[0637] Example 26: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(isoindoline-5-yl)acetamide

[0638]

[0639] Yield 11%; 1 H NMR(400MHz,CD3OD)δ7.35-7.24(m,1H)7.23-7.10(m,5H)7.02-6.98(m,1H)4.15-4.14(d,J =3.42Hz,4H)3.80(s,2H)3.74(s,2H)3.48(s,2H)3.35-3.34(m,2H)2.82-2.72(m,4H); LC-MS Rt 1.01min; m / z[M+H] + 447.1; Method 1.

[0640] Example 27: 2-(3-cyano-4-(methylsulfonyl)phenyl)-N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)acetamide

[0641]

[0642] Yield 31%; 1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),11.39(s,1H),8.13-8.09(m,2H),7.91-7.89(m,1H),7. 39-7.10(m,4H),4.07(s,2H),3.72(s,2H),3.41(s,2H),3.38(s,3H),2.67-2.66(m,4H); LC-MS Rt0.94min; MS m / z[M+H] + 509.2; Method 1.

[0643] Example 28: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(2-(N-methylaminosulfonyl)phenyl)acetamide

[0644]

[0645] Yield: 7.8%; 1 H NMR: (400MHz, DMSO-d6) δ11.91(s,1H),7.76(s,1H),7.75-7.64(m,1H),7.60-7.54(m,2H),7.49-7.35(m,2H),7.24-7. 15(m,2H),7.14-7.07(m,1H),3.99(s,2H),3.73(s,2H),3.43(s,2H),2.80-2.64(m,4H),2.43(d,J=5.01Hz,3H); LC-MS Rt1.38min; MS m / z[M+H] + 499.1; Method 6.

[0646] Example 29: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-(N-methylaminosulfonyl)phenyl)acetamide

[0647]

[0648] Yield: 9.2%; 1H NMR (400MHz, DMSO-d6) δ11.92(s,1H),7.74(d,J=8.19Hz,2H),7.53(d,J=8.31Hz,2H),7.46-7.35(m,2H),7.23-7.15(m,2H),7.11(td,J= 8.56,2.32Hz,1H),3.98(s,2H),3.73(s,2H),3.43(s,1H),2.73(d,J=5.01Hz,2H),2.41(d,J=5.01Hz,3H),2.68(d,J=4.89Hz,2H); LC-MS Rt 0.94min; MS m / z[M+H] + 499.1; Method 1.

[0649] Example 30: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3-methoxy-4-(methylsulfonyl)phenyl)acetamide

[0650]

[0651] Yield: 20.6%; 1 H NMR (400MHz, DMSO-d6) δ12.60-11.22(m,1H),7.73(d,J=8.03Hz,1H),7.45-7.34(m,1H),7.30-7.23(m,1H),7.22-7.14(m,2H),7. 13-7.05(m,2H),3.98-3.87(m,5H),3.71(s,2H),3.50-3.48(m,2H),3.21(s,3H),2.76-2.69(m,2H),2.66(d,J=4.64Hz,2H); LC-MS Rt 0.93min,MS m / z[M+H] + 514.1; Method 1.

[0652] Example 31: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3-(2-methoxyethoxy)phenyl)acetamide

[0653]

[0654] Yield: 17.6%; 1H NMR(400MHz,DMSO-d6)δ11.81(s,1H),7.44-7.35(m,1H),7.26-7.15(m,3H),7.13-7.04(m,1H),6.91-6.81(m,3H),4.11-4.0 3(m,2H),3.80(s,2H),3.72(s,2H),3.67-3.61(m,2H),3.42(s,2H),3.30(s,3H),2.72(d,J=4.89Hz,2H),2.67(s,2H); LC-MS Rt 1.04min; MS m / z[M+H] + 480.2; Method 1.

[0655] Example 32: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-((methanesulfonyl)methyl)phenyl)acetamide

[0656]

[0657] Yield: 6.4%; 1 H NMR: (400MHz, DMSO-d6) δ11.83(s,1H),7.42-7.37(m,1H),7.37-7.30(m,4H),7.22-7.14(m,2H),7.13-7.05 (m,1H),4.44(s,2H),3.80(s,2H),3.71(s,2H),2.88(s,3H),2.74-2.69(m,2H),2.64(d,J=4.8Hz,2H); LC-MS Rt 0.94min; MS m / z[M+H] + 498.1; Method 1.

[0658] Example 33: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(1,1-dioxy-2,3-dihydrobenzo[b]thiophenyl-5-yl)acetamide

[0659]

[0660] Yield: 6.4%; 1H NMR (400MHz, CDCl3) δ9.12-8.68(m,1H),7.74(d,J=7.9Hz,1H),7.49-7.37(m,2H),7.33-7.28(m,1H),7.18-7.05(m,2H),6 .97(dt,J=2.2,8.3Hz,1H),3.88(s,2H),3.72(s,2H),3.58-3.47(m,4H),3.44-3.34(m,2H),2.78(dd,J=4.5,11.5Hz,4H). LC-MS Rt 0.93min,MS m / z[M+H] + 496.1; Method 1.

[0661] Example 34: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(2,3-dimethoxyphenyl)acetamide

[0662]

[0663] Yield: 61%; 1 H NMR(400MHz,DMSO-d6)δ11.81(s,1H),7.44-7.36(m,1H),7.21-7.10(m,3H),7.01-6.97(m,2H),6.83-6.81(dd, J=7.15,1.65Hz,1H),3.82(s,2H),3.79(s,3H),3.72(s,2H),3.65(s,3H)3.42(s,2H),2.73-2.60(m,4H); LC-MS Rt 1.07min; MS m / z[M+H] + 466.1; Method 1.

[0664] Example 35: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3-fluoro-5-methoxyphenyl)acetamide

[0665]

[0666] Yield 24%; 1H NMR (400MHz, DMSO-d6) δ11.83 (s, 1H), 7.45-7.35 (m, 1H), 7.23-7.16 (m, 2H), 7.11 (dt, J = 2.4, 8.4Hz, 1H), 6.77-6. 70(m,3H),3.84(s,2H),3.76(s,3H),3.73(s,2H),3.43(s,2H),2.73(d,J=4.8Hz,2H),2.69(d,J=4.5Hz,2H); LC-MS Rt 1.06min,MS m / z[M+1] + 454.1; Method 1.

[0667] Example 36: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(1-(methanesulfonyl)-1H-pyrrolo-3-yl)acetamide

[0668]

[0669] Yield 22%; 1 H NMR (400MHz, DMSO-d6) δ11.84-11.62(m,1H),7.44-7.35(m,1H),7.24-7.04(m,5H),6.34(br s,1H),3.78-3.64(m,4H),3.44(s,2H),3.42(s,3H),2.79-2.64(m,4H); LC-MS Rt 0.97min; MS m / z[M+H] + 473.1; Method 1.

[0670] Example 37: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3-ethoxy-4-(methylsulfonyl)phenyl)acetamide

[0671]

[0672] Yield 23%; 1H NMR (400MHz, DMSO-d6) δ11.93 (s, 1H), 7.75-7.73 (d, J = 8.0Hz, 1H), 7.39-7.38 (m, 1H), 7.25 (s, 1H), 7.21-7.19 (m, 2H), 7.14-7.10 (m, 1H), 7.09-7. 04(m,1H),4.28-4.19(q,J=6.9Hz,2H),3.96(s,2H),3.72(s,2H),3.42(s ,2H),3.24(s,3H),2.73-2.67(m,4H),1.42-1.38(t,J=7.0Hz,3H); LC-MS Rt 0.95min; MS m / z[M+H] + 528.2; Method 1.

[0673] Example 38: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3-cyano-5-methoxyphenyl)acetamide

[0674]

[0675] Yield: 10.86%; 1 H NMR(400MHz, CDCl3)δ8.60(s,1H),7.33-7.28(m,1H),7.23(s,1H),7.17-7.06(m,4H),7.02-6.9 3(m,1H),3.86(s,3H),3.81(s,2H),3.72(s,2H),3.54(s,2H),2.78(d,J=4.3,10.2Hz,4H); LC-MS Rt 1.01min; MS m / z[M+1] + 461.1; Method 1.

[0676] Example 39: 2-(2-chloro-5-methoxyphenyl)-N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)acetamide

[0677]

[0678] Yield 18%; 1H NMR (400MHz, DMSO-d6) δ11.92(s,1H),7.38-7.33(m,2H),7.21-7.19(m,2H),7.10(dt,J=2.1,8.6Hz,1H),7.02(d,J=3.0Hz,1H) ,6.89(dd,J=3.0,8.8Hz,1H),3.98(s,2H),3.75(s,3H),3.73(s,2H),3.43(s,2H),2.73(d,J=5.0Hz,2H),2.68(d,J=4.9Hz,2H). LC-MS Rt 1.07min; MS m / z[M+1] + 470.1; Method 1.

[0679] Example 40: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(2-fluoro-3-methoxyphenyl)acetamide

[0680]

[0681] Yield: 10.4%; 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),7.42-7.35(m,1H),7.22-7.15(m,2H),7.14-7.03(m,3H),6.94-6.84( LC-MS Rt 1.03min; MS m / z[M+H] + 454.1; Method 1.

[0682] Example 41: 2-(2-chloro-3-methoxyphenyl)-N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)acetamide

[0683]

[0684] Yield: 22.9%; 1H NMR(400MHz,DMSO-d6)δ11.93(s,1H),7.43-7.35(m,1H),7.31-7.24(m,1H),7.23-7.15(m,2H),7.14-7.05( LC-MS Rt 1.05min; MS m / z[M+H] + 470.0; Method 1.

[0685] Example 42: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3,3-dimethyl-1,1-dioxy-2,3-dihydrobenzo[b]thiophenyl-5-yl)acetamide

[0686]

[0687] Yield 31%; 1 H NMR(400MHz,DMSO-d6)δ7.65-7.59(m,2H),7.47-7.38(m,2H),7.21-7.08(m,3H),3.94 (s,2H),3.72(s,2H),3.49(s,2H),3.33(m,2H),2.72-2.65(m,4H),1.46(s,6H); LC-MS Rt 0.96min; MS m / z[M+H] + 524.2; Method 1.

[0688] Example 43: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3-fluoro-4-aminosulfonylphenyl)acetamide

[0689]

[0690] 1H NMR (400MHz, DMSO-d6) δ11.91(s,1H),7.75(t,J=7.9Hz,1H),7.63(s,2H),7.37(dd,J=11.2,1.3Hz,3H),7.28(dd,J=8.1,1.5Hz,1H) ,7.20(s,2H),4.40(d,J=90.5Hz,1H),3.99(s,2H),3.75(d,J=20.8Hz,2H),3.42(s,1H),3.10-2.89(m,1H),2.81-2.63(m,3H); LC-MS Rt 0.62min,MS m / z[M+H] + 503.1; Method 7.

[0691] Example 44: (4-(2-((3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)amino)-2-oxoethyl)phenyl)(methyl)phosphonite

[0692]

[0693] 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),7.71(dd,J=11.7,8.2Hz,2H),7.48(dd,J=8.2,2.9Hz,6H),4.39(d,J=88.4H LC-MS Rt 0.62min,MS m / z[M+H] + 498.1; Method 7.

[0694] Example 45: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-((difluoromethyl)sulfonyl)phenyl)acetamide

[0695]

[0696] 1H NMR(400MHz,DMSO-d6)δ7.96-7.91(m,2H),7.73-7.68(m,2H),7.43-7.35(m,1H),7.29(s,1H),7.22-7.15(m,2H),7 .13-7.06(m,1H),4.01(s,2H),3.72(s,2H),3.41(d,J=1.9Hz,2H),2.73(t,J=5.6Hz,2H),2.69-2.62(m,2H); LC-MS Rt 0.81min,MS m / z[M+H] + 520.1; Method 5.

[0697] Example 46: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-(methylsulfonamido)phenyl)acetamide

[0698]

[0699] 1 H NMR (400MHz, DMSO-d6) δ9.67 (s, 1H), 7.43-7.35 (m, 1H), 7.26 (d, J = 8.5Hz, 2H), 7.22-7.14 (m, 4H), 7.10 (td, J = 8.6, 2.2Hz, 1H), 3.80 (s, 2H), 3.72 (s, 2H), 3.42 (s, 2H), 2.96 (s, 3H), 2.73 (t, J = 5.3Hz, 2H), 2.67 (d, J = 4.6Hz, 2H); LC-MS Rt 0.66min,MS m / z[M+H] + 499.1; Method 5.

[0700] Example 47: N-(3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-(N,N-dimethylaminosulfonyl)phenyl)acetamide

[0701]

[0702] 1H NMR (400MHz, DMSO-d6) δ11.92 (s, 1H), 7.76-7.68 (m, 2H), 7.57 (d, J = 8.4Hz, 2H), 7.43-7.35 (m, 1H), 7.23-7.15 (m, 2H), 7. 13-7.07(m,1H),4.00(s,2H),3.73(s,2H),3.43(s,2H),2.73(d,J=5.0Hz,2H),2.68(d,J=4.5Hz,2H),2.61(s,6H); LC-MS Rt0.76min,MS m / z[M+H] + 513.2; Method 5.

[0703] Example 48: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3-methoxy-4-aminosulfonylphenyl)-N-methylacetamide

[0704]

[0705] The title compound (18.2 mg, 16.7%) was prepared by a similar method by substituting 5-(cyclohexylmethyl)-2-(methylamino)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1a_H and core-1a_E. 1 HNMR(400MHz,DMSO-d6)δ7.63(d,J=7.5Hz,1H),7.11-6.73(m,4H),3.86(s,3H),3.52-3.39(m,3H),3.23(s,3 LC-MS Rt 1.06min; MS m / z[M+H] + 517.2; Method 1.

[0706] Example 49: N-(5-benzyl-3-cyano-4,4-dimethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3-methoxy-4-aminosulfonylphenyl)acetamide

[0707]

[0708] The title compound (18.2 mg, 16.7%) was prepared by a similar method by substituting 2-amino-5-benzyl-4,4-dimethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile core-1a_I and core-1a_E. 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),7.68-7.66(m,1H),7.39-7.37(m,2H),7.34-7.33(m,2H),7.30-7.24(m,1H),7.19(s ,1H),7.03-6.92(m,3H),3.94(s,2H),3.91(s,3H),3.68(s,2H),2.68-2.61(m,2H),2.45-2.40(m,2H),1.52(s,6H); LC-MS Rt 1.01min; MS m / z[M+H] + 525.2; Method 1.

[0709] Examples 50 to 52 were prepared by a similar method using 2-amino-5-((3,3-difluorocyclobutyl)methyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile core-1a_C with a suitable acid derivative (commercially available or prepared as described above).

[0710] Example 50: N-(3-cyano-5-((3,3-difluorocyclobutyl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(3-methoxy-4-aminosulfonylphenyl)acetamide

[0711]

[0712] 1 H NMR (400MHz, DMSO-d6) δ11.86(s,1H),7.67(d,J=7.91Hz,1H),7.17(s,1H),7.03(s,2H),6.98(d,J=7.91Hz,1H),3.87-3.9 6(m,5H),3.43(s,1H),2.69-2.76(m,2H),2.60-2.68(m,6H),2.41(d,J=7.03Hz,1H),2.18-2.35(m,2H),2.09(s,1H); LC-MS Rt0.85min; MS m / z[M+H] + 511.1; Method 1.

[0713] Example 51: N-(3-cyano-5-((3,3-difluorocyclobutyl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(3-methoxy-4-(methylsulfonyl)phenyl)acetamide

[0714]

[0715] 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),7.74(d,J=8.0Hz,1H),7.27(d,J=1.1Hz,1H),7.08(dd,J=8.0,1.3Hz,1H),3 .95(d,J=5.3Hz,5H),3.42(s,2H),3.22(s,3H),2.75-2.60(m,8H),2.40(d,J=7.0Hz,1H),2.35-2.18(m,2H); LC-MS Rt 0.55min,MS m / z[M+H] + 510.1; Method 5.

[0716] Example 52: N-(3-cyano-5-((3,3-difluorocyclobutyl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(1,1-dioxy-2,3-dihydrobenzo[d]isothiazo-5-yl)acetamide

[0717]

[0718] 1 H NMR (400MHz, DMSO-d6) δ11.92(s,1H),7.77(d,J=7.8Hz,2H),7.52-7.44(m,2H),4.39(d,J=4.6Hz, 2H), 4.00 (s, 2H), 3.42 (s, 2H), 2.75-2.60 (m, 8H), 2.40 (d, J = 7.3Hz, 1H), 2.34-2.19 (m, 2H); LC-MS Rt0.52min,MS m / z[M+H] + 493.1; Method 5.

[0719] Example 53: N-(3-cyano-5-(3-fluorobenzyl)-6-methyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0720]

[0721] To a solution of N-(3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide core-1b_B (318 mg, 0.815 mmol) in DMF (3 mL), 1-(bromomethyl)-3-fluorobenzene (154.0 mg, 0.815 mmol) and DIPEA (210.6 mg, 1.63 mmol) were added. The resulting mixture was heated to 50 °C and stirred at this temperature for 3 h. The reaction mixture was poured into H2O (15 mL) and extracted with EtOAc (15 mL × 3). The organic layer was then dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (DCM:MeOH = 100:1-10:1), and then by reversed-phase chromatography to obtain N-(3-cyano-5-(3-fluorobenzyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (95 mg, yield 24%). 1 H NMR (400MHz, DMSO-d6) δ11.9(s,1H),7.98(d,J=8.4Hz,2H),7.49(d,J=8.4Hz,2H),7.38-7.09(m,6H),3.95(s,2H),3.70 LC-MS Rt 0.93min; MS m / z[M+H] + 499.1; Method 1.

[0722] Examples 54 and 55: N-(3-cyano-6-methyl-5-(1-phenylethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (enantiomer)

[0723]

[0724] DIPEA (0.1 g, 0.75 mmol) was added to a solution of (1-bromoethyl)benzene (0.14 g, 0.75 mmol) and N-(3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide core-1b_B (0.1 g, 0.25 mmol) in DMF (5 mL). The reaction was stirred at 60 °C for 16 h. The reaction mixture was concentrated. The residue was diluted with water and extracted with EtOAc (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to a solid. The solids were purified by preparative HPLC (NH3·H2O) to give N-(3-cyano-6-methyl-5-(1-phenylethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide, Examples 54 (8.7 mg) and 55 (13.6 mg), as white solids.

[0725] Example 54: 1 H NMR(400MHz,DMSO-d6)δ12.02-11.73(m,1H),7.77(d,J=8.28Hz,2H),7.48 (d,J=8.41Hz,2H),7.37-7.28(m,6H),7.28-7.21(m,1H),4.01-3.86(m,2H) ,3.83-3.66(m,2H),3.46-3.38(m,1H),3.22-3.10(m,1H),2.78-2.65(m,1H ),2.36-2.21(m,1H),1.31(d,J=6.53Hz,3H),0.85(d,J=6.53Hz,3H); LC-MS Rt 0.65min,MS m / z[M+H] + 495.1; Method 3

[0726] Example 55: 1H NMR (400MHz, DMSO-d6) δ12.15-11.55(m,1H),7.77(d,J=8.41Hz,2H),7.47(d,J=8 .41Hz,2H),7.41-7.28(m,6H),7.27-7.22(m,1H),3.90(s,2H),3.75(q,J=6.44Hz, 1H),3.55(d,J=6.40Hz,1H),3.31(s,1H),3.23-3.14(m,1H),2.90(d,J=10.92Hz,1 H), 2.43 (d, J=16.31Hz, 1H), 1.31 (d, J=6.53Hz, 3H), 0.98 (d, J=6.53Hz, 3H); LC-MS Rt0.65min,MS m / z[M+H] + 495.1; Method 3.

[0727] Examples 56 and 57: N-(3-cyano-5-((3,3-difluorocyclobutyl)methyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide and N-(3-cyano-5-((3,3-difluorocyclobutyl)methyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-(N-((3,3-difluorocyclobutyl)methyl)aminosulfonyl)phenyl)acetamide

[0728]

[0729] A mixture of 3,3-difluorocyclobutaneformaldehyde (4.1 mmol, crude), N-(3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide core-1b_B (1.6 g, 4.1 mmol), and AcOH (10 mg) in MeOH (50 mL) was stirred at 20 °C for 4 h. NaBH3CN (0.516 g, 8.2 mmol) was added. The mixture was stirred at 20 °C for 12 h and then concentrated. The residue was diluted with H2O (20 mL) and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine and concentrated. The crude product was purified by preparative HPLC (NH3·H2O) to obtain N-(3-cyano-5-((3,3-difluorocyclobutyl)methyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (238.7 mg, 11%) and the byproduct N-(3-cyano-5-((3,3-difluorocyclobutyl)methyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-(N-((3,3-difluorocyclobutyl)methyl)aminosulfonyl)phenyl)acetamide (34.4 mg).

[0730] Example 56: 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),7.78(d,J=8.41Hz,2H),7.48(d,J=8.41Hz,2H),7.32(s,2H),3.96(s,2H),3.59-3.43(m,2 LC-MS Rt 0.85min; MS m / z[M+H] + 495.1; Method 1.

[0731] Example 57: 1H NMR(400MHz,DMSO-d6)δ11.90(s,1H),7.86-7.73(m,3H),7.58-7.49(m,2H),4.01-3.95(m,2H),3.58-3.44(m,2H),3.17-3.06(m, 1H),2.85(t,J=6.21Hz,2H),2.80-2.71(m,1H),2.69-2.56(m,5H),2.43-2.13(m,7H),1.10(s,1H),0.98(d,J=6.53Hz,3H); LC-MS Rt0.71min; MS m / z[M+H] + 599.1; Method 3.

[0732] Example 58: 4-(2-((3-cyano-5-(3-fluorobenzyl)-6-methyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)amino)-2-oxoethyl)benzamide

[0733]

[0734] DIPEA (57 mg, 0.44 mmol) and 1-(bromomethyl)-3-fluorobenzene (62 mg, 0.33 mmol) were added to a solution of 4-(2-((3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)amino)-2-oxoethyl)benzamide core-1b_F (78 mg, 0.22 mmol) in DMF. The mixture was stirred at 50 °C for 2 h. The reaction solution was diluted with water (10 mL) and extracted with EtOAc (10 mL × 4). The organic layer was concentrated. The residue was purified by preparative TLC (9% MeOH in DCM) to give 4-(2-((3-cyano-5-(3-fluorobenzyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)amino)-2-oxoethyl)benzamide (47.5 mg, 45% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.9(s,1H),7.93(s,1H),7.84-7.82(m,2H),7.40-7.32(m,4H),7.19-7.15(m,2H),7.10-7.08(m,1H),3. 91(s,2H),3.69(s,2H),3.45-3.40(m,2H),3.19-3.17(m,1H),2.84-2.81(m,1H),2.44-2.39(m,1H),1.04(d,J=6.4Hz,3H); LC-MS Rt 0.66min;MSm / z[M+H]+ 463.0; Method 3.

[0735] Examples 59-60 were prepared by a similar method, by replacing the appropriate halide derivative with N-(3-cyano-6-methyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide core-1b_B.

[0736] Example 59: N-(3-cyano-5-(cyclopentylmethyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide hydrochloride

[0737]

[0738] Yield 29%; 1 H NMR (400MHz, DMSO-d6) δ12.15 (s, 1H), 10.62-10.02 (m, 1H), 7.79 (d, J = 8.19Hz, 2H) ,7.49(d,J=8.31Hz,2H),7.33(s,2H),4.51-4.33(m,1H),4.28-4.13(m,1H),4.00( s,2H),3.97-3.80(m,1H),3.18-2.99(m,3H),2.89-2.74(m,1H),2.36-2.22(m,1H) ,2.01-1.77(m,2H),1.69-1.48(m,4H),1.43-1.33(m,1H),1.32-1.18(m,4H); LC-MS Rt0.95min; MS m / z[M+H] + 473.1; Method 1.

[0739] Example 60: N-(3-cyano-5-(cyclobutylmethyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0740]

[0741] Yield 15%; 1H NMR (400MHz, DMSO-d6) δ12.20-11.66(m,1H),7.77(d,J=8.3Hz,2H),7.48(d,J=8 .2Hz,2H),7.32(s,2H),3.93(s,2H),3.44(d,J=6.9Hz,2H),3.30-3.26(m,2H),3 .12-3.00(m,1H),2.77-2.66(m,1H),2.47-2.41(m,1H),2.39-2.30(m,1H),2.08 -1.94(m,2H),1.94-1.72(m,2H),1.70-1.54(m,2H),0.97(d,J=6.6Hz,3H); LC-MS Rt 0.86 min, MS m / z [M+H] + 459.1; Method 1.

[0742] Examples 61 to 63 were prepared by a method similar to that of Example 1.2, by replacing a suitable aldehyde derivative with N-(3-cyano-6-methyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide core-1b_B.

[0743] Example 61: N-(3-cyano-5-(cyclopentylmethyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-(N-(cyclopentylmethyl)aminosulfonyl)phenyl)acetamide

[0744]

[0745] Example 61: 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),7.74(d,J=8.41Hz,2H),7.58(t,J=6.02Hz,1H) ,7.51(d,J=8.28Hz,2H),3.96(s,2H),3.50(q,J=15.73Hz,2H),3.20-3.06(m,1H),2. 76-2.72(m,1H),2.63(t,J=6.65Hz,2H),2.43-2.30(m,3H),2.09-2.05(m,1H),1.96- 1.84(m,1H),1.69-1.39(m,12H),1.26-1.09(m,4H),0.96(d,J=6.53Hz,3H); LC-MSRt 0.75min;MS m / z[M+H] + 555.2; Method 3.

[0746] Examples 62 and 63: N-(3-cyano-5-(cyclohexylmethyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide and N-(3-cyano-5-(cyclohexylmethyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-(N-(cyclohexylmethyl)aminosulfonyl)phenyl)acetamide

[0747]

[0748] Yield 17%; 1 H NMR (400MHz, DMSO-d6) δ12.14 (s, 1H), 11.06-9.20 (m, 1H), 7.79 (d, J = 8.31 Hz,2H),7.49(d,J=8.31Hz,2H),7.33(s,2H),4.34-4.55(m,1H),4.10-4.3 0(m,1H),4.00(s,2H),3.95-3.77(m,1H),3.19-3.00(m,2H),2.81(d,J=16 .87Hz,2H),2.03-1.56(m,6H),1.42-1.06(m,6H),1.05-0.84(m,2H); LC-MS Rt 0.70min; MS m / z[M+H] + 487.1; Method 3.

[0749] Yield 26%; 1 H NMR (400MHz, CD3OD) δ7.81(d,J=7.78Hz,2H),7.54(d,J=7.78Hz,2H),4.01-3.86(m,1H),3.56(s,2H),2.83(d,J=14.9 3Hz, 1H), 2.66 (d, J = 6.40Hz, 2H), 2.53-2.27 (m, 3H), 1.91-1.47 (m, 10H), 1.44-1.01 (m, 13H), 0.99-0.68 (m, 4H); LC-MS Rt1.22min; MS m / z[M+H] + 583.3; Method 1.

[0750] Examples 64 to 69 were prepared by a method similar to that of Core 2a (K2CO3, room temperature, 16 h) using N-(3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (Core-1b_B) with a suitable halide derivative (commercially available or prepared as described above).

[0751] Example 64: N-(3-cyano-5-(2,5-dichlorobenzyl)-6-methyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0752]

[0753] 1 H NMR (400MHz, DMSO-d6) δ7.76(d,J=8.4Hz,2H),7.57(d,J=2.6Hz,1H),7.48(d,J=8.6Hz,2H),7.37(dd,J=8.5,2.7Hz,1H),7.29(s,1H),3.89(s,2 LC-MS Rt 0.94min,MS m / z[M+2H] + 552.9; Method 5.

[0754] Example 65: N-(3-cyano-5-(3-fluorobenzyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (enantiomer)

[0755]

[0756] 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),7.78(d,J=8.1Hz,2H),7.48(d,J=8.1Hz,2H),7.41-7.28(m,3H),7.17(t,J=8.9Hz,2H),7.08(t,J=8.2Hz,1H ),3.94(s,2H),3.69(s,2H),3.44(d,J=6.9Hz,2H),3.21-3.15(m,1H),2. 83(d,J=16.2Hz,1H),2.42(d,J=15.6Hz,1H),1.05(d,J=6.5Hz,3H); LC-MS Rt 0.62min,MS m / z[M+H] + 499.0; Method 5.

[0757] Example 66: N-(3-cyano-5-(3-fluorobenzyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (enantiomer)

[0758]

[0759] 1 H NMR (400MHz, DMSO-d6) δ7.77(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),7.41-7.34(m,1H),7.31(s,2H),7.22-7.14(m,2H),7.08(t,J=8.2Hz,1H LC-MS Rt 0.62min,MS m / z[M+H] + 499.0; Method 5.

[0760] Example 67: N-(3-cyano-6-methyl-5-phenylethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0761]

[0762] 1 H NMR (400MHz, DMSO-d6) δ7.77(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),7.32-7.23(m,6H),7.20-7.15(m,1H),3.93(s,2H), 3.69-3.49(m,2H),3.21-3.15(m,1H),2.75(dt,J=11.2,5.3Hz,5H),2.35(d,J=21.6Hz,1H),0.99(d,J=6.5Hz,3H); LC-MS Rt0.60min,MS m / z[M+H] + 495.0; Method 5.

[0763] Example 68: N-(3-cyano-5-(2-cyclohexylethyl)-6-methyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0764]

[0765] 1 H NMR (400MHz, DMSO-d6) δ7.77(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),7.31(s,2H),3.92(s,2H),3.51(d,J=15.8Hz,2H),3.43(s,1H),3.1 2-3.06(m,1H),2.74(d,J=16.2Hz,1H),2.34(dd,J=14.7,3.2Hz,1H),1.67(t,J=14.7Hz,5H),1.39-1.12(m,7H),0.98-0.84(m,5H); LC-MS Rt 0.58min,MS m / z[M+H] + 501.1; Method 7.

[0766] Examples 69 to 70 were prepared by a method similar to that of Example 4 Core 2a (K2CO3, room temperature, 16 h) using N-(3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-(methanesulfonyl)phenyl)acetamide with a suitable halide derivative (commercially available or prepared as described above).

[0767] Example 69: N-(3-cyano-5-(3-fluorobenzyl)-6-methyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-(methylsulfonyl)phenyl)acetamide

[0768]

[0769] 1 H NMR (400MHz, DMSO-d6) δ11.92(s,1H),7.92-7.85(m,2H),7.58(d,J=8.4Hz,2H),7.42-7.32(m,1H),7.21-7.12(m,2H),7.11-7.05(m,1H),3.9 9(s,2H),3.69(s,2H),3.44(d,J=6.7Hz,2H),3.20(s,4H),2.83(d,J=16.1Hz,1H),2.41(dd,J=16.1,4.3Hz,1H),1.05(d,J=6.6Hz,3H); LC-MS Rt 0.69min,MS m / z[M+H] + 498.0; Method 5.

[0770] Example 70: N-(3-cyano-5-(2,5-dichlorobenzyl)-6-methyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-(methylsulfonyl)phenyl)acetamide

[0771]

[0772] 1 H NMR (400MHz, DMSO-d6) δ7.87(d,J=8.3Hz,2H),7.57(dd,J=5.5,2.8Hz,3H),7.48(d,J=8.5Hz,1H),7.37(dd,J=8.5,2.6Hz,1H),3.92( s,2H),3.74(d,J=2.5Hz,2H),3.49(s,2H),3.19(s,4H),2.81(d,J=16.2Hz,1H),2.41(d,J=15.5Hz,1H),1.07(d,J=6.6Hz,3H); LC-MS Rt1.02min,MS m / z[M+H] + 548.0; Method 5.

[0773] Example 71: N-(3-cyano-5-(cyclohexylmethyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0774]

[0775] To a solution of 2-amino-5-(cyclohexylmethyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1c_A (1.15 g, 3.8 mmol) in DMF (12 mL), 2-(4-aminosulfonylphenyl)acetic acid (1.23 g, 5.7 mmol), DIPEA (982 mg, 7.6 mmol), and T3P from EtOAc (4.84 g, 50% w / w, 7.6 mmol) were added. The mixture was stirred at 65 °C for 1 h. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (15 mL × 4). The organic layer was concentrated. The residue was purified by silica column chromatography (PE:EtOAc = 10:1-2:1) to give the desired product (1.15 g, 60% yield) as a light yellow solid; LC-MS Rt 1.08 min, MS m / z [M+H] + 501.3; Method 1; 1H NMR (400MHz, DMSO-d6) δ11.9(s,1H),7.78(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),7.33(s,2H),3.96(s,2H),3.49(s,2H),2.46(s,2H ), 2.24(d,J=6.8Hz,2H),1.76-1.73(m,2H),1.67-1.64(m,3H),1.39-1.33(m,1H),1.25-1.15(m,3H),1.02(s,6H),0.88-0.75(m,2H).

[0776] Example 72: N-(3-cyano-5-(cyclohexylmethyl)-6,6-dimethyl-4,5,6,7-tetrahydrothiophene[3,2-c]pyridin-2-yl)-2-(3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[b]thiophenyl-5-yl)acetamide

[0777]

[0778] The title compound was prepared by a method similar to that in Example 1.0, by substituting 2-(4-aminosulfonylphenyl)acetic acid core-1c_1 with 2-(3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[b]thiophene-5-yl)acetic acid core-1c_2; yield 56%; LC-MS Rt 0.76 min, MS m / z [M+H] + 540.1; Method 3; 1 H NMR (400MHz, CD3OD) δ7.64-7.49(m,3H),4.31(s,2H),4.03(s,3H),3.43(s,2H),2.99(s,2H),1.89-0.89(m,25H).

[0779] Examples 73 to 77 were prepared by a method similar to that of Example 1c.1, by replacing the 2-(4-aminosulfonylphenyl)acetic acid core-1c_1 with a suitable acid derivative.

[0780] Example 73: N-(3-cyano-5-(cyclohexylmethyl)-6,6-dimethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-phenylacetamide

[0781]

[0782] 1H NMR (400MHz, DMSO-d6) δ11.8(s,1H),7.33-7.25(m,5H),3.85(s,2H),3.48(s,2H),2.49(s,2H),2.23(d,J= 6.8Hz,2H),1.80-1.60(m,5H),1.45-1.35(m,1H),1.20-1.10(m,3H),1.02(s,6H),0.90-0.75(m,2H); LC-MS Rt 0.74min,MS m / z[M+H] + 422.2; Method 3.

[0783] Example 74: 2-(3-(aminomethyl)-1,1-dioxy-2,3-dihydrobenzo[b]thiophene-5-yl)-N-(3-cyano-5-(cyclohexylmethyl)-6,6-dimethyl-4,5,6,7-tetrahydrothiophene[3,2-c]pyridin-2-yl)acetamide

[0784]

[0785] LC-MS Rt 1.03 min, MS m / z [M+H] + 541.3; Method 3; 1 H NMR(CD3OD)δ7.68(d,J=8.0Hz,1H),7.56(s,1H),7.53(d,J=7.9Hz,1H),3.99(s,2 H),3.74-3.64(m,2H),3.62-3.48(m,3H),3.21-3.11(m,1H),3.06-2.92(m,1H),2. 53(s,2H),2.32(d,J=6.8Hz,2H),1.82(d,J=13.2Hz,2H),1.77-1.64(m,3H),1.46 (ddd,J=3.9,7.1,14.1Hz,1H),1.37-1.16(m,4H),1.11(s,6H),0.94-0.83(m,2H).

[0786] Example 75: N-(3-cyano-5-(cyclohexylmethyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-N-methyl-2-(4-aminosulfonylphenyl)acetamide

[0787]

[0788] LC-MS Rt 1.13 min, MS m / z [M+H] + 515.4; Method 3; 1H NMR (400MHz, CDCl3) δ7.93-7.79(m,2H),7.37-7.29(m,1H),7.37-7.28(m, 1H),4.92(s,2H),3.73(d,J=1.9Hz,2H),3.63(s,2H),3.34(s,3H),2.62(s, 2H),2.32(d,J=6.8Hz,2H),1.82(d,J=12.4Hz,2H),1.77-1.66(m,3H),1.46 (dd,J=6.8Hz,3.6,1H),1.35-1.19(m,3H),1.16(s,6H),0.91-0.78(m,2H).

[0789] Example 76: N-(3-cyano-5-(cyclohexylmethyl)-6,6-diethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0790]

[0791] Yield 45%; LC-MS Rt 1.17 min, MS m / z [M+H] + 529.2; Method 3; 1 H NMR (400MHz, DMSO-d6) δ11.86(s,1H),7.78(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),7.32(s,2H),3.95(s,2H),3.55(s ,2H),2.38(s,2H),2.21(d,J=6.8Hz,2H),1.57-1.85(m,5H),1.31-1.50(m,5H),1.04-1.27(m,3H),0.55-0.97(m,8H).

[0792] Example 77: N-(3-cyano-5-((3,3-difluorocyclobutyl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide,

[0793]

[0794] Add 2-(4-amino-5-((3,3-difluorocyclobutyl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1c_B (200 mg, 0.64 mmol) to 2-amino-5-((3,3-difluorocyclobutyl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1c_B (200 mg, 0.64 mmol), 2-(4-aminosulfonylphenyl)acetic acid (207 mg, 0.96 mmol), DIPEA (165 mg, 1.28 mmol), and a solution of T3P in EtOAc (815 mg, 1.28 mmol, w / w 50%) to DMF (2 mL). Stir the mixture at 65 °C for 1 h. Dilute the reaction solution with water (10 mL) and extract with EtOAc (10 mL × 4). Concentrate the organic layer. The residue was purified by preparative TLC (PE:EtOAc = 1:1) to give N-(3-cyano-5-((3,3-difluorocyclobutyl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (141.5 mg, yield 43%) as a grayish-white solid. LC-MS Rt 0.90 min, MS m / z [M+H] + 509.2; Method 1; 1 H NMR (400MHz, DMSO-d6) δ11.9(s,1H),7.77(d,J=8.0Hz,2H),7.47(d,J=8.4Hz,2H),7.3 2(s,2H),3.95(s,2H),3.50(s,2H),2.70-2.40(m,6H),2.30-2.10(m,3H),1.04(s,6H).

[0795] Example 78: N-(3-cyano-5-((3,3-difluorocyclobutyl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3-ethoxy-4-aminosulfonylphenyl)acetamide

[0796]

[0797] Example 78 was prepared using 2-(3-ethoxy-4-aminosulfonylphenyl)acetic acid by a method similar to step 3 of 2-amino-5-((3,3-difluorocyclobutyl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxynitrile core-1c_B. 1H NMR (400MHz, DMSO-d6) δ7.67(d,J=8.0Hz,1H),7.17(s,1H),6.96(d,J=7.7Hz,1H),6.89(s,2H),4.20(q,J=7.0Hz,2H), 3.91(s,2H),3.51(s,2H),2.61-2.54(m,3H),2.29-2.13(m,2H),1.38(t,J=6.9Hz,3H),1.24(s,4H),1.05(s,6H); LC-MS Rt0.61min,MS m / z[M+H] + 553.1; Method 5.

[0798] Example 79: N-(3-cyano-5-((3,3-difluorocyclobutyl)methyl)-6,6-diethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0799]

[0800] Example 79 was prepared by a method similar to step 3 of intermediate core-1c_B, by replacing 2-amino-5-(cyclohexylmethyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxylonitrile core-1c_B with 2-amino-5-(cyclohexylmethyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxylonitrile core-1c_B. Yield 12%; LC-MS Rt 1.02 min, MS m / z [M+H] + 537.2; 1 H NMR (400MHz, CD3OD) δ7.89(d,J=8.4Hz,2H),7.53(d,J=8.4Hz,2H),3.95(s,2H),3.68(s,2H),2. 63-2.66(m,3H),2.45-2.54(m,3H),2.20-2.31(m,3H),1.51-1.66(m,4H),0.91(t,J=7.6Hz,6H).

[0801] Example 80: N-(3-cyano-5-(3-fluorobenzyl)-6,6-dimethyl-4,5,6,7-tetrahydrothiopheneno[3,2-c]pyridin-2-yl)-2-(3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[b]thiophenyl-5-yl)acetamide

[0802]

[0803] Example 80 was prepared by a method similar to that of Example 1c.1, by replacing the 2-amino-5-(3-fluorobenzyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1c_C with 2-(3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[b]thiophene-5-yl)acetic acid core-1c_2. Yield 41%; LC-MS Rt 1.05 min, MS m / z [M+H] + 552.3; Method 3; 1 H NMR(400MHz,DMSO-d6)δ11.9(s,1H),7.69-7.67(m,1H),7.62(s,1H),7.48-7.45(m,1H),7.38-7.32(m,1H),7.18-7.13(m,2H ),7.08-7.05(m,1H),3.99(s,2H),3.69(s,2H),3.50(s,2H),3.34-3.32(m,2H),2.59-2.54(m,2H),1.46(s,6H),1.16(s,6H).

[0804] Example 81: N-(3-cyano-5-(3-fluorobenzyl)-6,6-dimethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0805]

[0806] Example 81 was prepared by a similar method using N-(3-cyano-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide with a suitable halide derivative (commercially available or prepared as described above). 1 H NMR (400MHz, DMSO-d6) δ7.81-7.74(m,2H),7.48(d,J=8.4Hz,2H),7.40-7.29(m,3H),7.22-7.13(m,2H LC-MS Rt 0.65min,MS m / z[M+H] + 513.7; Method 5.

[0807] Example 82: N-(3-cyano-5-(cyclohexylmethyl)-6,6-dimethyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3-methoxy-4-aminosulfonylphenyl)acetamide

[0808]

[0809] Example 82 was prepared by a method similar to that of Core 2a (K2CO3, room temperature, 16 h) using N-(3-cyano-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(3-methoxy-4-aminosulfonylphenyl)acetamide (Core-1c_A14) with a suitable halide derivative (commercially available or prepared as described above). 1 H NMR (400MHz, DMSO-d6) δ7.65(d,J=8.0Hz,1H),7.17(d,J=1.2Hz,1H),7.04-6.93(m,3H),3.88(d,J=8.4Hz,5H),3.47(s,2H),2.44(s,2H),2.24(d ,J=7.0Hz,2H),1.74(d,J=11.3Hz,2H),1.65(d,J=13.3Hz,3H),1.39(s,1H),1.27-1.10(m,3H),1.02(s,6H),0.81(q,J=12.0,10.0Hz,2H); LC-MS Rt 0.64min,MS m / z[M+H] + 531.2; Method 5.

[0810] Example 83: N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3-methoxy-4-aminosulfonylphenyl)acetamide

[0811]

[0812] DIPEA (568 mg, 4.4 mmol) and T3P (2.1 g, 3.3 mmol) were added to a solution of 2-amino-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxynitrile core-1a_B (600 mg, 2.2 mmol) and 2-(3-methoxy-4-aminosulfonylphenyl)acetic acid core-1a_E (809 mg, 3.3 mmol) in DMF (6 mL). The reaction mixture was stirred in a microwave at 120 °C for 45 min. The reaction mixture was then poured into water (60 mL) and Na2CO3 was added to adjust the pH to 8–9. The mixture was extracted with EtOAc (60 mL × 3), the organic layers were combined, dried over Na2SO4, and concentrated. The crude product was washed with MeOH to give N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(3-methoxy-4-carbamoylphenyl)acetamide Example 83 (315.0 mg, yield 16%) as a white solid. The mother liquor was purified by preparative HPLC (NH3·H2O) to give another batch of Example 83 (232.0 mg, yield 12%). 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),7.67(d,J=8.0Hz,1H),7.16(s,1H),7.03(s,2H),6.97(d,J=8.0Hz,1H),3.93(s,2H),3 .89(s,3H),3.34(s,2H),2.65(s,4H),2.29(d,J=7.0Hz,2H),1.75-1.72(m,6H),1.27-1.09(m,3H),0.90-0.81(m,2H); LC-MS Rt0.67min; MS m / z[M+H] + 503.1; Method 3.

[0813] Example 84N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(5-aminosulfonylthiophenyl-2-yl)acetamide

[0814]

[0815] Example 84 was prepared by a method similar to that of Example 83, by substituting a suitable acid derivative. 1H NMR (400MHz, DMSO-d6) δ8.13(s,1H),7.60(s,2H),7.40(d,J=3.7Hz,1H),6.99(d,J=3.7Hz,1H),4.17(s,2H),2.67 LC-MS Rt 0.62min; MS m / z[M+H] + 479.0; Method 5.

[0816] Example 85N-(3-cyano-5-(3,5-difluorobenzyl)-6-methyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0817]

[0818] Example 85 was prepared by a method similar to that of Core 2a (K2CO3, room temperature, 15 h) using N-(3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (Core-1b_B) with a suitable halide derivative (commercially available or prepared as described above). 1 H NMR (400MHz, DMSO-d6) δ11.90(s,1H),7.77(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),7.31(s,2H),7.09-7.07(m,3H),3.94(s,2H) ,3.70(s,2H),3.46(ABq,J=16.0Hz,2H),3.20-3.16(m,1H),2.86-2.84(m,1H),2.41(dd,J=16.4,4.0Hz,1H),1.05(s,3H); LC-MS Rt 0.75min;MS m / z[M+H] + 517.0; Method 5.

[0819] Example 86N-(3-cyano-5-(3-fluorobenzyl)-6-methyl-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(3-(2-methoxyethoxy)-4-aminosulfonylphenyl)acetamide

[0820]

[0821] Example 86 was prepared by a method similar to that of core 2a (K2CO3, room temperature, 18 h) using N-(3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(3-(2-methoxyethoxy)-4-aminosulfonylphenyl)acetamide with a suitable halide derivative (commercially available or prepared as described above). 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),7.67(d,J=6.8Hz,2H),7.40(m,2H),7.18(m,2H),7.01(d,J=6.8Hz,2H),6.83(s,2H),4.27(d,J=4.4Hz,2H),3. 93(s,3H),3.75(d,J=4.4Hz,2H),3.73(s,2H),3.50-3.30(m,2H),3.44(s, 3H),3.20(m,1H),2.89-2.86(m,1H),2.40-2.50(m,1H),1.05(s,3H); LC-MS Rt0.68min; MS m / z[M+H] + 573.1; Method 5.

[0822] Example 87: N-(3-cyano-6-ethyl-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0823]

[0824] Example 87 was prepared by a method similar to that of core 2a (K2CO3, room temperature, 15 h) using N-(3-cyano-6-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide with a suitable halide derivative (commercially available or prepared as described above). 1H NMR (400MHz, DMSO-d6) δ11.90(s,1H),7.77(d,J=8.4Hz,2H),7.48(d,J=8.8Hz ,2H),7.39-7.36(m,1H),7.31(s,2H),7.19-7.14(m,2H),7.10-7.06(m,1H),3 .95(s,2H),3.66(ABq,J=14.0Hz,2H),3.50(s,2H),2.96-2.92(m,1H),2.78-2 .73(m,1H),1.63-1.59(m,1H),1.37-1.31(m,1H),0.92(t,J=7.6Hz,3H); LC-MS Rt 0.72min; MS m / z[M+H] + 513.0; Method 5.

[0825] Example 88N-(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(1-methyl-4-aminosulfonyl-1H-pyrrolo-2-yl)acetamide

[0826]

[0827] Example 88 was prepared by a method similar to that of Example 83, by substituting a suitable acid derivative. 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),7.19(d,J=2.0Hz,1H),6.86(s,2H),6.23(d,J=2.0Hz,1H),3.91(s,2H),3.57(s,3H),2.67( d,J=3.4Hz,4H),2.31(d,J=7.1Hz,2H),1.81-1.47(m,7H),1.20(dtd,J=20.7,14.9,13.5,10.0Hz,4H),0.95-0.77(m,2H); LC-MS Rt0.56min; MS m / z[M+H] + 476.1; Method 5.

[0828] Example 89 4-(2-((3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)amino)-2-oxoethyl)-2-ethoxybenzamide

[0829]

[0830] Step 1: 3-Cyano-2-(2-(3-ethoxy-4-(ethoxycarbonyl)phenyl)acetamyl)-6,7-dihydrothiopheno[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester

[0831] Under argon atmosphere, TEA (138 μL, 0.991 mmol) and T3P (354 μL, 0.595 mmol) were added to a mixture of core-1a_A2 (111 mg, 0.396 mmol) and 2-(2-oxoindol-6-yl)acetic acid (100 mg, 0.396 mmol) in DMF (1.5 mL). The reaction was stirred at room temperature for 2 h. The crude mixture was partitioned between EtOAc and water. The organic layer was recovered, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with water (x3) and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by normal-phase chromatography using silica gel (solvent: cyclohexane / EtOAc = 1:0 to 0:1) to give the product (143 mg, 56% yield). LC-MS Rt 1.26 min; MS m / z [MH] - 512.4; Method 5.

[0832] Step 2: 4-(2-((3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)amino)-2-oxoethyl)-2-ethoxybenzoate

[0833] TFA (343 μL, 4.45 mmol) was added to a solution of tert-butyl 3-cyano-2-(2-(3-ethoxy-4-(ethoxycarbonyl)phenyl)acetamyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (143 mg, 0.223 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was then concentrated under vacuum, redissolved in DMF, and 1-(bromomethyl)-3-fluorobenzene (41.0 μL, 0.334 mmol) and Cs₂CO₃ (218 mg, 0.668 mmol) were added. The reaction was stirred at room temperature for 2 h. The crude mixture was partitioned between EtOAc and water. The organic layer was recovered, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with water (x³) and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by normal-phase chromatography using silica gel (solvent: cyclohexane / EtOAc = 1:0 to 0:1), yielding the product (95 mg, 79% yield). LC-MSRt 0.89 min; MS m / z [M+H] + 522.2; Method 5.

[0834] Step 3: 4-(2-((3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)amino)-2-oxoethyl)-2-ethoxybenzoic acid

[0835] LiOH (13.22 mg, 0.552 mmol) was added to a solution of ethyl 4-(2-((3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)amino)-2-oxoethyl)-2-ethoxybenzoate (72 mg, 0.138 mmol) in THF (1.5 mL) - water (1.5 mL). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum. It was redissolved in EtOAc, and the solution was washed with aqueous 1 M HCl. The organic layer was recovered, concentrated, and the product was given (42 mg, 60% yield). LC-MS Rt 0.72 min; MS m / z [M+H] + 494.1; Method 5.

[0836] Step 4: 4-(2-((3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)amino)-2-oxoethyl)-2-ethoxybenzamide

[0837] 4-(2-((3-cyano-5-(3-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)amino)-2-oxoethyl)-2-ethoxybenzoic acid (36 mg, 0.073 mmol) and HATU (36.1 mg, 0.095 mmol) were dissolved in DMF (1 mL). Ammonium chloride (19.51 mg, 0.365 mmol) and DIPEA (0.025 mL, 0.146 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. The crude mixture was partitioned between EtOAc and water. The organic layer was recovered, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with water (x3) and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the product (6 mg, 16% yield). 1H NMR (400MHz, DMSO-d6) δ7.77(s,1H),7.75(s,1H),7.54(s,1H),7.50(s,1H),7.42-7.36(m,1H),7.21-7.16(m,2H),7.12-7.08(m,2H),6. 94(d,J=8.0Hz,1H),4.17(q,J=8.0Hz,2H),3.86(s,2H),3.72(s,2H),3.42(s,2H),2.73(m,2H),2.66(m,2H),1.39(t,J=8.0Hz,3H); LC-MS Rt 0.68min; MS m / z[M+H] + 493.1; Method 5.

[0838] Example 90: N-(3-cyano-6-(1-phenylethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)-acetamide hydrochloride

[0839]

[0840] N-(3-cyano-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (intermediate core-2a_A) (100 mg, 0.26 mol) and DIPEA (100 mg, 0.78 mmol) were added to a solution of (1-bromoethyl)benzene core-2a_6a (63 mg, 0.34 mol) in DMF (10 mL). The reaction was stirred at 60 °C for 4 h. The mixture was quenched with water (20 mL), extracted with EtOAc (20 mL × 3), washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (HCl) to give N-(3-cyano-6-(1-phenylethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide hydrochloride (31 mg, yield: 17%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ12.15 (s, 1H), 11.55 (s, 1H), 7.34-7.79 (m, 11H), 2.82-4.68 (m, 9H), 1.73 (d, J = 2Hz, 3H); LC-MS Rt 0.907min, MS m / z [M+H] + 481.1; Method 1.

[0841] Example 91: Methyl-2-((3-cyano-2-(2-(4-aminosulfonylphenyl)acetamyl)-4,5-dihydrothiopheno[2,3-c]pyridin-6-(7H)-yl)methyl)benzoate hydrochloride

[0842]

[0843] 1 H NMR: (400MHz, DMSO-d6)δ12.21(br s,1H),10.19(br s,1H),8.12-8.11(br d,J=6.7Hz,1H),7.80-7.67(m,6H),7.51-7.49(d,J=8.4Hz,2H),7.36(s,2H),4.81-4.71(m,2H),4.38(br s,2H),4.01(s,2H),3.89(s,3H),3.76-3.49(m,2H),3.00(m,2H); LC-MS Rt0.886min,MS m / z[M+H] + 525.1, Method 1.

[0844] Example 92: N-(3-cyano-6-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0845]

[0846] 1 H NMR: (400MHz, MeOD) δ7.88-7.87(d,J=8.5Hz,2H),7.52-7.50(d,J=8.4Hz,2H),3.95(s,2H),3.51(s,2H),2.80-2.77(m,2H),2.70-2.69(br d,J=5.4Hz,2H),2.37-2.36(d,J=7.0Hz,2H),1.83-1.80(br d,J=14.1Hz,2H),1.75-1.71(br d,J=15.1Hz,2H),1.64-1.56(m,2H),1.32-1.29(br d, J=11.8Hz, 3H), 0.98-0.89 (m, 2H); LC-MS: Rt0.987min, MS m / z[M+H] + 473.2. Method 1.

[0847] Example 93: N-(3-cyano-6-(3,5-difluorobenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0848]

[0849] 1 H NMR (400MHz, DMSO-d6) δ11.91(s,1H),7.77(d,J=8.0Hz,2H),7.48(d,J=8.0Hz,2H),7.32(s,2H),7. 13-7.06(m,3H),3.96(s,2H),3.70(s,2H),3.51(s,2H),2.76-2.73(m,2H),2.60-2.58(m,2H); LC-MS Rt 0.686min,MS m / z[M+H] + 503.0. Method 3.

[0850] Example 94: N-(3-cyano-6-(2-methoxybenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0851]

[0852] The title compound was prepared by a similar method, by replacing the 2,5-dichloronicotinaldehyde core-2a_6g with N-(3-cyano-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (intermediate core-2a_A) (Example 2, step 4); 1 H NMR (400MHz, DMSO-d6) δ12.17(s,1H),7.79(d,J=8.4Hz,2H),7.53-7.48(m,4H),7.35(s,2H),7.14(d,J=8.4Hz,1 LC-MS Rt0.883min,MS m / z[M+H] + 497.2, Method 1.

[0853] Examples 95 to 97 were prepared by a method similar to that of Example 2, by replacing N-(3-cyano-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (intermediate A) with a suitable aldehyde derivative (commercially available or prepared as described above).

[0854] Example 95: N-(3-cyano-6-(2,3-dimethylbenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0855]

[0856] 1 H NMR (400MHz, DMSO-d6) δ12.18(s,1H),10.77(br,s,1H),7.79(d,J=8.4Hz,2H),7.49(d,J=8.4Hz,2H),7.47-7.42(m,1H LC-MS Rt 0.961min,MS m / z[M+H] + 495.2, Method 1.

[0857] Example 96: N-(3-cyano-6-((2-methylpyridin-4-yl)methyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0858]

[0859] At 20 °C, T3P (50% of EtOAc) (170 mg, 0.267 mmol) was added to a solution of 2-amino-6-(2,2,2-trifluoro-1-phenylethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxynitrile (intermediate core-2a_D) (60 mg, 0.178 mmol), 2-(4-aminosulfonylphenyl)acetic acid core-2a_6d (60 mg, 0.267 mmol), and DIPEA (46 mg, 0.356 mmol) in DMF (10 mL). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated to an oil, diluted with EtOAc (10 mL), washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated into a yellow oil, which was then purified by preparative HPLC (alkaline) to obtain N-(3-cyano-6-(2,2,2-trifluoro-1-phenylethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (18 mg, yield: 18%), which was a yellow solid. 1 H NMR(400MHz,CD3OD)δ7.88(d,J=8.41Hz,2H),7.37-7.59(m,7H),4.51-4.58(m,1H),3.94( s,2H),3.66-3.84(m,2H),3.06-3.19(m,1H),2.78-2.92(m,1H),2.56-2.72(m,2H); LC-MS Rt 0.945min,MS m / z[M+H] + 535.1, Method 1.

[0860] Example 97: N-(3-cyano-6-(2-methylbenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0861]

[0862] N-(3-cyano-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (intermediate A) (50 mg, 0.106 mmol) and K₂CO₃ (58.4 mg, 0.422 mmol) were added to a solution of 1-(bromomethyl)-2-methylbenzene (23.5 mg, 0.127 mmol) in DMF (2 mL). The reaction was stirred at room temperature for 16 h. The mixture was quenched with water (2 x 10 mL), extracted with EtOAc (20 mL × 3), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to a crude solid, and purified by preparative HPLC to obtain N-(3-cyano-6-(2-methylbenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (20.9 mg, yield: 40%). 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),7.78(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),7.31(s,2H),7.25(d,J=6.1Hz ,1H),7.18-7.11(m,3H),3.96(s,2H),3.62(s,2H),3.48(s,2H),2.75(t,J=5.7Hz,2H),2.58(s,2H),2.31(s,3H). LC-MS Rt 0.60min,MS m / z[M+H] + 481.1

[0863] Examples 98 to 116 were prepared by a method similar to that of Example 4.0, using N-(3-cyano-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide (core-2a_A) with a suitable halide derivative (commercially available or prepared as described above).

[0864] Example 98: N-(3-cyano-6-(4-methylbenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0865]

[0866] 1H NMR (400MHz, DMSO-d6) δ8.35(s,1H),7.75(d,J=8.4Hz,2H),7.47(d,J=8.4Hz,2H),7.28(s,2H),7.21(d,J=8.0Hz,2H LC-MS Rt 0.68min,MS m / z[M+H] + 481.1.

[0867] Example 99: N-(3-cyano-6-(2-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0868]

[0869] 1 H NMR (400MHz, DMSO-d6) δ11.89 (s, 1H), 7.78 (d, J = 8.4Hz, 2H), 7.54-7.40 (m, 3H), 7.31 (s, 3H) ,7.25-7.10(m,2H),3.96(s,2H),3.72(s,2H),3.51(s,2H),2.76(s,2H),2.59(s,2H); LC-MS Rt 0.56min,MS m / z[M+H] + 485.1

[0870] Example 100: N-(3-cyano-6-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0871]

[0872] 1 H NMR (400MHz, DMSO-d6) δ11.89 (s, 1H), 7.84-7.71 (m, 2H), 7.48 (d, J = 8.4Hz, 2H), 7.42-7.26 (m, 3H), 7. 13(dt,J=30.6,7.7Hz,3H),3.96(s,2H),3.69(s,2H),3.50(s,2H),2.75(s,2H),2.60(s,2H);); LC-MS Rt 0.57min,MS m / z[M+H] + 485.1.

[0873] Example 101: N-(3-cyano-6-(4-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0874]

[0875] 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),7.82-7.74(m,2H),7.48(d,J=8.5Hz,2H),7.42-7.26(m,4H),7.15(t ,J=8.9Hz,2H),3.96(s,2H),3.66(s,2H),3.47(s,2H),2.73(d,J=5.3Hz,2H),2.59(d,J=5.2Hz,2H); LC-MS Rt 0.54min,MS m / z[M+H] + 485.1.

[0876] Example 102: N-(3-cyano-6-(3-methylbenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0877]

[0878] 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),7.78(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),7.31(s,2H),7.2 5-7.03(m,4H),3.96(s,2H),3.62(s,2H),3.46(s,2H),2.73(s,2H),2.58(s,2H),2.29(s,3H); LC-MS Rt0.60min,MS m / z[M+H] + 481.1.

[0879] Example 103: N-(3-cyano-6-(2-methylbenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-(methylsulfonyl)phenyl)acetamide

[0880]

[0881] 1H NMR(400MHz,DMSO-d6)δ7.91-7.86(m,2H),7.61-7.54(m,2H),7.27-7.23(m,1H),7.19-7.10(m,3H),3.98(s,2H), 3.62(s,2H),3.47(d,J=1.8Hz,2H),3.19(s,3H),2.75(t,J=5.7Hz,2H),2.57(t,J=5.8Hz,2H),2.31(s,3H); LC-MS Rt 0.64min,MS m / z[M+H] + 481.1.

[0882] Example 104: N-(3-cyano-6-(3-methylbenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-(methylsulfonyl)phenyl)acetamide

[0883]

[0884] 1 H NMR (400MHz, DMSO-d6) δ7.91-7.86(m,2H),7.60-7.55(m,2H),7.21(t,J=7.5Hz,1H),7.15-7.05(m,3H),3 .99(s,2H),3.62(s,2H),3.45(s,2H),3.19(s,3H),2.73(t,J=5.7Hz,2H),2.58(s,2H),2.29(s,3H); LC-MS Rt 0.64min,MS m / z[M+H] + 481.1.

[0885] Example 105: N-(3-cyano-6-(3,4-difluorobenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0886]

[0887] LC-MS Rt 0.67 min, MS m / z [M+H] + 503.0.

[0888] Example 106: N-(3-cyano-6-(2,3-difluorobenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0889]

[0890] LC-MS Rt 0.67 min, MS m / z [M+H] + 503.0.

[0891] Example 107: N-(6-(2-chloro-4-fluorobenzyl)-3-cyano-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0892]

[0893] LC-MS Rt 0.73 min, MS m / z [M+H] + 520.1.

[0894] Example 108: Methyl 3-((3-cyano-2-(2-(4-aminosulfonylphenyl)acetamyl)-4,7-dihydrothiopheno[2,3-c]pyridin-6(5H)-yl)methyl)benzoate

[0895]

[0896] 1 H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.87(s,1H),7.81-7.74(m,2H),7.62(s,1H),7.55-7.42(m,3H),7 .31(s,2H),3.97(s,2H),3.86(s,3H),3.74(s,1H),3.49(s,1H),2.76(s,1H),2.60(s,1H),1.24(s,2H). LC-MS Rt 0.58min,MS m / z[M+H] + 525.1.

[0897] Example 109: N-(3-cyano-6-(2,5-dichlorobenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0898]

[0899] LC-MS Rt 0.91 min, MS m / z [M+H] + 536.9.

[0900] Example 110: N-(3-cyano-6-(3,5-dimethylbenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0901]

[0902] LC-MS Rt 0.66 min, MS m / z [M+H] + 595.1.

[0903] Example 111: N-(6-(2-chloro-6-fluorobenzyl)-3-cyano-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0904]

[0905] LC-MS Rt 0.75 min, MS m / z [M+H] + 520.1.

[0906] Example 112: N-(3-cyano-6-(2,6-dichlorobenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0907]

[0908] LC-MS Rt 0.86 min, MS m / z [M+H] + 537.1.

[0909] Example 113: N-(3-cyano-6-(2,5-difluorobenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0910]

[0911] LC-MS Rt 0.66 min, MS m / z [M+H] + 503.1.

[0912] Example 114: N-(6-(2-chlorobenzyl)-3-cyano-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0913]

[0914] LC-MS Rt 0.67 min, MS m / z [M+H] + 501.1.

[0915] Example 115: N-(3-cyano-6-(2-fluoro-3-methylbenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0916]

[0917] LC-MS Rt 0.62 min, MS m / z [M+H] + 499.1.

[0918] Example 116: N-(3-cyano-6-(2,6-difluorobenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0919]

[0920] 1 H NMR(400MHz,DMSO-d6)δ11.96(s,1H),7.82-7.73(m,2H),7.56-7.43(m,3H), 7.31(s,2H),7.16(s,2H),3.97(s,2H),3.38(s,6H),2.75-2.60(m,2H); LC-MS Rt 0.64min,MS m / z[M+H] + 503.1.

[0921] Examples 117 to 121 were prepared by a method similar to that of Example 4, using N-(3-cyano-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-(methanesulfonyl)phenyl)acetamide with a suitable halide derivative (commercially available or prepared as described above).

[0922] Example 117: N-(3-cyano-6-(3,4-difluorobenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-(methylsulfonyl)phenyl)acetamide

[0923]

[0924] 1 H NMR (400MHz, DMSO-d6) δ11.96(s,1H),7.89(d,J=8.3Hz,2H),7.58(d,J=8.3Hz,2H),7.44-7.32(m,2H),7. 19(s,1H),4.00(s,2H),3.66(s,2H),3.49(s,2H),3.20(s,3H),2.74(t,J=5.6Hz,2H),2.59(s,2H); LC-MS Rt 0.69min,MS m / z[M+H] + 502.0.

[0925] Example 118: N-(3-cyano-6-(3,5-dimethylbenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-(methylsulfonyl)phenyl)acetamide

[0926]

[0927] 1 H NMR (400MHz, DMSO-d6) δ7.92-7.84(m,2H),7.58(d,J=8.4Hz,2H),6.90(d,J=17.4Hz,3H),3.99(s,2H), 3.57(s,2H),3.44(s,2H),3.19(s,3H),2.72(t,J=5.7Hz,2H),2.57(t,J=6.9Hz,2H),2.25(s,6H); LC-MS Rt 0.71min,MS m / z[M+H] + 494.0.

[0928] Example 119: N-(3-cyano-6-(3-fluorobenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-(methylsulfonyl)phenyl)acetamide

[0929]

[0930] 1 H NMR(400MHz, DMSO-d6)δ7.92-7.85(m,2H),7.58(d,J=8.4Hz,2H),7.41-7.31(m,1H),7.21-6.98(m,3H), 3.99(s,2H),3.69(s,2H),3.49(s,2H),3.19(s,3H),2.74(t,J=5.7Hz,2H),2.59(d,J=5.3Hz,2H); LC-MS Rt 0.65min,MS m / z[M+H] + 484.0.

[0931] Example 120: Methyl 3-((3-cyano-2-(2-(4-(methanesulfonyl)phenyl)acetamyl)-4,7-dihydrothiopheno[2,3-c]pyridin-6(5H)-yl)methyl)benzoate

[0932]

[0933] 1H NMR (400MHz, DMSO-d6) δ7.94(s,1H),7.87(td,J=6.2,1.6Hz,3H),7.59(dd,J=15.9,8.1Hz,3H),7.49(t,J=7.7Hz,1H) ,3.98(s,2H),3.85(s,3H),3.74(s,2H),3.48(s,2H),3.19(s,3H),2.75(t,J=5.7Hz,2H),2.59(d,J=5.3Hz,2H); LC-MS Rt 0.64min,MS m / z[M+H] + 524.1.

[0934] Example 121: N-(3-cyano-6-(2,5-dichlorobenzyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-(methylsulfonyl)phenyl)acetamide

[0935]

[0936] 1 H NMR (400MHz, DMSO-d6) δ7.92-7.85(m,2H),7.62-7.54(m,3H),7.48(d,J=8.5Hz,1H),7.38(dd,J=8.5,2.6Hz, 1H), 3.99 (s, 2H), 3.75 (s, 2H), 3.57 (s, 2H), 3.19 (s, 3H), 2.81 (t, J = 5.7Hz, 2H), 2.62 (d, J = 5.3Hz, 2H); LC-MS Rt 0.98min,MS m / z[M+H] + 535.8

[0937] Examples 122 to 123 were prepared by a method similar to that of Example 4.0 Core 2a (K2CO3, room temperature, 16 h) using N-(3-cyano-5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide with a suitable halide derivative (commercially available or prepared as described above).

[0938] Example 122: N-(3-cyano-6-(3-fluorobenzyl)-5-methyl-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0939]

[0940] 1H NMR (400MHz, DMSO-d6) δ11.89(s,1H),7.78(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),7.31(s,3H),7.21-6.99(m,3H),3.96(s, 2H),3.71-3.51(m,4H),3.18(d,J=5.3Hz,1H),2.74(d,J=13.8Hz,1H),2.34(d,J=14.7Hz,1H),1.10(d,J=6.2Hz,3H); LC-MSRt 0.62min,MS m / z[M+H] + 499.0.

[0941] Example 123: N-(3-cyano-6-(3-fluorobenzyl)-5-methyl-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0942]

[0943] 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),7.81-7.73(m,2H),7.48(d,J=8.4Hz,2H),7.40-7.28(m,3H),7.14(t,J=8.2Hz,2H),7.06(t,J =8.3Hz,1H),3.96(s,2H),3.71-3.53(m,4H),3.23-3.12(m,1H),2.79-2.70(m,1H),2.38-2.29(m,1H),1.10(d,J=6.6Hz,3H); LC-MS Rt 0.62min,MS m / z[M+H] + 499.0.

[0944] Example 124: N-(3-cyano-6-(3-fluorobenzyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azacycloheptane-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0945]

[0946] 1H NMR(400MHz, DMSO-d6)δ7.80-7.74(m,2H),7.48(d,J=8.4Hz,2H),7.41-7.29(m,3H),7.22-7 .15(m,2H),7.07(td,J=8.3,1.8Hz,1H),3.95(s,2H),3.75(s,2H),2.81-2.64(m,8H); LC-MS Rt 0.53min,MS m / z[M+H] + 499.4

[0947] Example 125: N-(3-cyano-6-(cyclohexylmethyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azacycloheptane-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0948]

[0949] 1 H NMR (400MHz, DMSO-d6) δ7.81-7.74(m,2H),7.51-7.45(m,2H),7.31(s,2H),3.93(s,2H),2.77-2.64(m,8H),2.33(d,J=7.1H LC-MS Rt0.62min,MS m / z[M+H] + 487.1.

[0950] Example 126: N-(3-cyano-7-(3-fluorobenzyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azacycloheptane-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0951]

[0952] Example 126 was prepared by a similar method using 2-amino-7-(3-fluorobenzyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azacycloheptane-3-carboxynitrile with a suitable acid derivative (commercially available or prepared as described above). 1H NMR (400MHz, DMSO-d6) δ7.78(d,J=8.3Hz,2H),7.49(d,J=8.3Hz,2H),7.38-7.28(m,3H),7.13-7.00(m ,3H),3.96(s,2H),3.75(s,2H),3.57(s,2H),3.11-3.03(m,2H),2.83-2.70(m,2H),1.67(s,2H); LC-MS Rt 0.58min,MS m / z[M+H] + 499.6.

[0953] Example 127: N-(3-cyano-7-(cyclohexylmethyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azacycloheptane-2-yl)-2-(4-aminosulfonylphenyl)acetamide

[0954]

[0955] Example 127 was prepared by a similar method using 2-amino-7-(cyclohexylmethyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azacycloheptane-3-carboxynitrile with a suitable acid derivative (commercially available or prepared as described above). 1 H NMR(400MHz,DMSO-d6)δ7.79-7.74(m,2H),7.51-7.44(m,2H),7.30(s,2H),3.90(s,2H),3.72(s,2H),3.04-3.01(m,2 LC-MS Rt 0.63min,MS m / z[M+H] + 487.1.

[0956] High-content cell imaging-based flavivirus immunoassay (HCI-CFI) assay

[0957] A549 cells in 384-well plates were infected with DENV-2 (MY97-10340) at an MOI of 0.3 (7 x 10⁶ cells per well). 3 (cells). Cells were then treated with a 3-fold 10-point serial dilution of the test compound. After 48 h, cells were fixed with paraformaldehyde and treated with Dylight. TMViral E protein was detected using a 4G2 antibody labeled with 488 (GenScript). Cell nuclei were stained with Draq5 (Pierce / Thermo) and images were acquired on an Opera imaging system (PerkinElmer). Dose-response curves were plotted to calculate the effective concentration (EC50) of the compound required to reduce E protein expression by 50% using GraphPad Prism. 50 The following table 1 summarizes the obtained EC. 50 Values: +≥1μM; 1μM>++≥0.1μM; 0.1μM>+++

[0958] Table 1 Dengue Fever IC 50 data

[0959]

[0960]

[0961]

[0962]

[0963] In vivo antiviral efficacy in a mouse model of dengue fever

[0964] AG129 mice (lacking IFN-α / β and IFN-γ receptors (Schul, W. et al. 2007. J. Infect. Dis. [Journal of Infectious Diseases], 195, 665-74)) were obtained from the Singapore Bioresource Centre (BRC). Male and female AG129 mice aged 8 to 14 weeks (weighing 20–30 g, n = 6 per group) were used. DENV-2 (TSV01 strain) infection (500 μL, 1.4 x 10⁷ pfu / mL) was performed intraperitoneally. The DENV-2TSVO1 strain was used in the mouse model and propagated in C6 / 36 mosquito cells. Compounds (% w / w) were formulated in 0.5% methylcellulose, 0.5% Tween and 99.0% deionized water or 20% polyethylene glycol (PEG300), 10% lemovorite RH40 and 70% 100 mM pH 3 citrate buffer (% v / v). The compound was administered orally via tube feeding for three consecutive days post-infection. Viremia readouts of terminal blood samples (anticoagulant: K2EDTA) were obtained by qRT-PCR as previously described (Santiago, GA et al. 2013. PLoS Negl. Trop. Dis. [PLoS Neglected Tropical Diseases], 7, e2311).

[0965] Table 2. In vivo antiviral efficacy of N-substituted tetrahydrothiophenepyridine derivatives in a mouse model of dengue fever.

[0966] Instance number Dosage / Regimen DENV-2 viremia logarithmosis 53 100mg / kg once daily 1.06 53 100 mg / kg twice daily 1.78 53 30 mg / kg twice daily 0.80 71 10 mg / kg twice daily 0.51 71 30 mg / kg twice daily 1.45 71 60mg / kg once daily 1.54 71 180mg / kg single dose 1.49 71 100 mg / kg twice daily 3.0 77 30 mg / kg twice daily 0.62 83 30 mg / kg twice daily 0.60 83 100mg / kg once daily 0.94 100 100 mg / kg twice daily 1.50 109 100 mg / kg twice daily 1.60

Claims

1. A compound having formula (I) or a pharmaceutically acceptable salt thereof: (I) in: A is a phenyl or a 3-6 membered cycloalkyl group; wherein the 3-6 membered cycloalkyl group is optionally -C 1-6 Alkyl, cyano, -C 1-4 aminoalkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 The alkyl halogen and halogen groups are substituted, and the phenyl group is substituted with -C. 1-6 Alkyl, cyano, -C 1-4 aminoalkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 Halogenated alkoxy groups and halogen substitutions; L is -C 1-6 alkylene-; Each R 1 Independently selected from -C 1-6 Alkyl, cyano, -C 1-4 aminoalkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 Halogenated alkoxy groups and halogens; Each R 2 Is it H or -C 1-6 alkyl; R 3 Selected from -C 1-6 Alkyl, -CN, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 Halogenated alkoxy groups, halogens, -C(O)R 3a -C(O)OR 3b -C(O)NR 3c R 3d -P(O)R 3e R 3f -P(O)(OR) 3g (OR) 3h -P(O)(OR) 3i (R) 3j -S(O)2R 3k -S(O)2NR 3l R 3m -S(O)R 3n -NR 3o R 3p -NR 3q C(O)R 3r -N(R) 3s )C(O)OR 3t and -NR 3u S(O)2R 3v Wherein -C 1-6 Alkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl groups and -C 1-4 Each haloalkoxy group may be independently substituted by one of the following: hydroxyl group, -NR group, etc. 3w R 3x -C 1-4 Alkyl group, -S(O)2NR 3y R 3z or -S(O)2R 3a2 ;where R 3w R 3x R 3y and R 3z Each is independently H, -C 1-4 Alkyl or -C 1-6 Halogenated alkyl groups, and R 3a2 It is -C 1-4 Alkyl or -C 1-6 Halogenated alkyl, or Any two R 3 It can combine with one atom to form a 5-6 membered fused heterocyclic alkyl group, wherein the heterocyclic alkyl group contains one or two heteroatoms selected from N and S, and wherein the heterocyclic alkyl group is independently optionally substituted by one or two groups selected from: -C 1-6 Alkyl, -C 1-4 aminoalkyl, -CN, -C 1-4 Alkoxy, halogen, -C 1-6 Halogenated alkyl groups and -C 1-4 Halogenated alkoxy groups; R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h R 3i R 3j R 3k R 3n R 3o R 3p R 3q R 3r R 3s R 3t R 3u R 3v Each is independently selected from H and -C. 1-6 Alkyl and -C 1-6 Halogenated alkyl groups; R 3l and R 3m Each is independently selected from H and -C. 1-6 Alkyl and -C 1-6 Halogenated alkyl groups, wherein the -C 1-6 The alkyl group is optionally further substituted with a 3-6 membered cycloalkyl group, and wherein the 3-6 membered cycloalkyl substituent is optionally further substituted with 1-2 halogens; p is 1, 2, or 3; q is 0 or 1; m is 0, 1, or 2, and n is 0, 1, or 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 1.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 2.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 3.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein q is 0.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein q is 1.

7. A compound having formula (IA) or a pharmaceutically acceptable salt thereof: (IA) in: A is a phenyl or a 3-6 membered cycloalkyl group; wherein the 3-6 membered cycloalkyl group is optionally -C 1-6 Alkyl, cyano, -C 1-4 aminoalkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 The alkyl halogen and halogen groups are substituted, and the phenyl group is substituted with -C. 1-6 Alkyl, cyano, -C 1-4 aminoalkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 Halogenated alkoxy groups and halogen substitutions; L is -C 1-6 alkylene-; Each R 1 Independently selected from -C 1-6 Alkyl, cyano, -C 1-4 aminoalkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 Halogenated alkoxy groups and halogens; Each R 2 Is it H or -C 1-6 alkyl; R 3 Selected from -C 1-6 Alkyl, -CN, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 Halogenated alkoxy groups, halogens, -C(O)R 3a -C(O)OR 3b -C(O)NR 3c R 3d -P(O)R 3e R 3f -P(O)(OR) 3g (OR) 3h -P(O)(OR) 3i (R) 3j -S(O)2R 3k -S(O)2NR 3l R 3m -S(O)R 3n -NR 3o R 3p -NR 3q C(O)R 3r -N(R) 3s )C(O)OR 3t and -NR 3u S(O)2R 3v Wherein -C 1-6 Alkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl groups and -C 1-4 Each haloalkoxy group may be independently substituted by one of the following: hydroxyl group, -NR group, etc. 3w R 3x -C 1-4 Alkyl group, -S(O)2NR 3y R 3z or -S(O)2R 3a2 ;where R 3w R 3x R 3y and R 3z Each is independently H, -C 1-4 Alkyl or -C 1-6 Halogenated alkyl groups, and R 3a2 It is -C 1-4 Alkyl or -C 1-6 Halogenated alkyl, or Any two R 3 It can combine with one atom to form a 5-6 membered fused heterocyclic alkyl group, wherein the heterocyclic alkyl group contains one or two heteroatoms selected from N and S, and wherein the heterocyclic alkyl group is independently optionally substituted by one or two groups selected from: -C 1-6 Alkyl, -C 1-4 aminoalkyl, -CN, -C 1-4 Alkoxy, halogen, -C 1-6 Halogenated alkyl groups and -C 1-4 Halogenated alkoxy groups; R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h R 3i R 3j R 3k R 3n R 3o R 3p R 3q R 3r R 3s R 3t R 3u R 3v Each is independently selected from H and -C. 1-6 Alkyl and -C 1-6 Halogenated alkyl groups; R 3l and R 3m Each is independently selected from H and -C. 1-6 Alkyl and -C 1-6 Halogenated alkyl groups, wherein the -C 1-6 The alkyl group is optionally further substituted with a 3-6 membered cycloalkyl group, and wherein the 3-6 membered cycloalkyl substituent is optionally further substituted with 1-2 halogens; m is 0, 1, or 2, and n is 0, 1, or 2.

8. A compound having formula (IB) or a pharmaceutically acceptable salt thereof: (ONE) in: A is a phenyl or a 3-6 membered cycloalkyl group; wherein the 3-6 membered cycloalkyl group is optionally -C 1-6 Alkyl, cyano, -C 1-4 aminoalkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 The alkyl halogen and halogen groups are substituted, and the phenyl group is substituted with -C. 1-6 Alkyl, cyano, -C 1-4 aminoalkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 Halogenated alkoxy groups and halogen substitutions; L is -C 1-6 alkylene-; Each R 1 Independently selected from -C 1-6 Alkyl, cyano, -C 1-4 aminoalkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 Halogenated alkoxy groups and halogens; Each R 2 Is it H or -C 1-6 alkyl; R 3 Selected from -C 1-6 Alkyl, -CN, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 Halogenated alkoxy groups, halogens, -C(O)R 3a -C(O)OR 3b -C(O)NR 3c R 3d -P(O)R 3e R 3f -P(O)(OR) 3g (OR) 3h -P(O)(OR) 3i (R) 3j -S(O)2R 3k -S(O)2NR 3l R 3m -S(O)R 3n -NR 3o R 3p -NR 3q C(O)R 3r -N(R) 3s )C(O)OR 3t and -NR 3u S(O)2R 3v Wherein -C 1-6 Alkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl groups and -C 1-4 Each haloalkoxy group may be independently substituted by one of the following: hydroxyl group, -NR group, etc. 3w R 3x -C 1-4 Alkyl group, -S(O)2NR 3y R 3z or -S(O)2R 3a2 ;where R 3w R 3x R 3y and R 3z Each is independently H, -C 1-4 Alkyl or -C 1-6 Halogenated alkyl groups, and R 3a2 It is -C 1-4 Alkyl or -C 1-6 Halogenated alkyl, or Any two R 3 It can combine with one atom to form a 5-6 membered fused heterocyclic alkyl group, wherein the heterocyclic alkyl group contains one or two heteroatoms selected from N and S, and wherein the heterocyclic alkyl group is independently optionally substituted by one or two groups selected from: -C 1-6 Alkyl, -C 1-4 aminoalkyl, -CN, -C 1-4 Alkoxy, halogen, -C 1-6 Halogenated alkyl groups and -C 1-4 Halogenated alkoxy groups; R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h R 3i R 3j R 3k R 3n R 3o R 3p R 3q R 3r R 3s R 3t R 3u R 3v Each is independently selected from H and -C. 1-6 Alkyl and -C 1-6 Halogenated alkyl groups; R 3l and R 3m Each is independently selected from H and -C. 1-6 Alkyl and -C 1-6 Halogenated alkyl groups, wherein the -C 1-6 The alkyl group is optionally further substituted with a 3-6 membered cycloalkyl group, and wherein the 3-6 membered cycloalkyl substituent is optionally further substituted with 1-2 halogens; m is 0, 1, or 2, and n is 0, 1, or 2.

9. The compound of any one of claims 1, 7, or 8, or a pharmaceutically acceptable salt thereof, wherein R 2 It is H or CH3.

10. The compound of any one of claims 1, 7 or 8, or a pharmaceutically acceptable salt thereof, wherein L is selected from -CH2-, -CH(CH3)-, -CH2-CH2- and -CH2CH2CH2-.

11. The compound of any one of claims 1, 7, or 8, or a pharmaceutically acceptable salt thereof, wherein at least one R 3 They are -S(O)2NH2, -S(O)2N(CH3)2, -S(O)2NHCH3, -S(O)2NH-CH2-cyclobutyl, -S(O)2NH-CH2-cyclopentyl, -S(O)2NH-CH2-cyclohexyl, -S(O)2NH-CH2-difluorocyclobutyl, -S(O)2CH3 and -S(O)2CHF2.

12. Compounds of formula (IC) or pharmaceutically acceptable salts thereof: (IC) in A is a phenyl or a 3-6 membered cycloalkyl group; wherein the 3-6 membered cycloalkyl group is optionally -C 1-6 Alkyl, cyano, -C 1-4 aminoalkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 The alkyl halogen and halogen groups are substituted, and the phenyl group is substituted with -C. 1-6 Alkyl, cyano, -C 1-4 aminoalkyl, -C 1-4 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-4 Halogenated alkoxy groups and halogen substitutions; R 1a and R 1b Independently selected from -H, -CH3, and -CH2CH3; R 3 It is H, -OCH3, or -OCH2CH3; and R 4 Selected from -NH2, -N(CH3)2, -NHCH3, -NH-CH2-cyclobutyl, -NH-CH2-cyclopentyl, -NH-CH2-cyclohexyl, -NH-CH2-difluorocyclobutyl, -CH3 and -CHF2, or with R 3 They combine to form a 1,1-dioxide-2,3-dihydrothiophene group or a 1,1-dioxide-2,3-dihydroisothiazolyl ring.

13. The compound of any one of claims 1, 7, 8 or 12, or a pharmaceutically acceptable salt thereof, wherein A is phenyl and is substituted with F or Cl.

14. The compound of any one of claims 1, 7, 8 or 12, or a pharmaceutically acceptable salt thereof, wherein A is selected from cyclobutyl, cyclopentyl, cyclohexyl and bicyclo[1.1.1]pentyl, each optionally substituted with F or Cl.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from... Or its pharmaceutically acceptable salt.

16. The compound of claim 1, wherein the compound is N -(3-cyano-5-(cyclohexylmethyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide, or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1, wherein the compound is N -(3-cyano-5-((3,3-difluorocyclobutyl)methyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide, or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, wherein the compound is N -(3-cyano-5-(cyclohexylmethyl)-6,6-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(3-methoxy-4-aminosulfonylphenyl)acetamide, or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, wherein the compound is N -(3-cyano-5-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(3-methoxy-4-aminosulfonylphenyl)acetamide, or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, wherein the compound is N -(3-cyano-6-(3-fluorobenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide, or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, wherein the compound is N -(3-cyano-6-(2,5-dichlorobenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide, or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1, wherein the compound is N -(3-cyano-5-(3-fluorobenzyl)-6-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-(4-aminosulfonylphenyl)acetamide, or a pharmaceutically acceptable salt thereof.

23. Compounds, selected from Or its pharmaceutically acceptable salt.

24. A pharmaceutical composition comprising a therapeutically effective amount of the compound as described in any one of claims 1 to 23, and a pharmaceutically acceptable carrier or excipient.

25. The pharmaceutical composition of claim 24, further comprising at least one additional pharmaceutical agent.

26. The pharmaceutical composition of claim 25, wherein the at least one additional agent is selected from the group consisting of: interferon, ribavirin, ribavirin analogs, cyclic protein binders, HCV NS3 protease inhibitors, HCV NS5a inhibitors, P7 inhibitors, entry inhibitors, NS4b inhibitors, α-glucosidase inhibitors, host protease inhibitors, immunomodulators, symptomatic relief agents, nucleoside NS5b inhibitors, and non-nucleoside NS5b inhibitors.

27. Use of the compound of any one of claims 1 to 23 in the manufacture of a medicament for treating a disease caused by a viral infection, wherein the viral infection is caused by dengue virus.

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