HK1233261A1

HK1233261A1 - Piperidine-dione derivatives

Info

Publication number: HK1233261A1
Application number: HK17106977.5A
Authority: HK
Inventors: Jinhua Chen; Charles Z. Ding; Peter Dragovich; Benjamin Fauber; Zhenting GAO; Sharada Labadie; Kwong Wah LAI; Hans Edward Purkey; Kirk Robarge; Binqing Wei; Aihe Zhou
Original assignee: 豪夫迈．罗氏有限公司
Priority date: 2014-03-17
Filing date: 2015-03-17
Publication date: 2018-01-26

Description

Piperidine-dione derivatives

Technical Field

The present application relates to organic compounds that are useful for therapy and/or prophylaxis in mammals and in particular for the inhibition of treatment of cancer.

Background

A number of tumors show altered metabolic characteristics relative to normal untransformed tissue (Ward, p.s.actual.cancer Cell 2012,21,297.Vander Heiden, m.g.nature rev.drug discov.2011,10,671.Zhao, y.et al.frontiers in Bioscience 2011,16,1844.Kaelin, w.g., jr.actual.nature 2010,465,562.Tennant, d.a.et al.nature rev.cancer 2010,10, 267). One example of such altered metabolism involves the use of glucose. Many tumors increase glucose uptake relative to normal cells and metabolize this nutrient mainly by glycolysis (as opposed to the more energy efficient but oxygen dependent mitochondrial oxidative phosphorylation pathway) (Vander Heiden, m.g. et al science 2009,324,1029.Hsu, p.p. et al. cell2008,134, 703). Unlike normal tissues (e.g., actively functioning muscles) that normally employ glycolysis only when oxygen supply limits oxidative phosphorylation, the glycolytic glucose consumption occurs in cancer cells, even in the presence of high levels of oxygen (Vander Heiden, m.g. et al science 2009,324,1029.Hsu, p.p. et al. cell2008,134,703). Originally described by Warburg (Warburg, o.science 1956,123,309.Bensinger, s.j.et.semin.cell dev.biol.2012, doi:10.1016/j.semcdb.2012.02.003.koppenol, w.h.et.c.v.nature rev.cancer 2011,11,325), this "aerobic glycolysis" phenotype is currently considered as an attractive indicator of differentiation between tumor and healthy tissue, which can be studied to develop new anticancer agents (Hamanaka, r.b.et.j.exp.med.2012, 209,211.jones, n.p.et.drug discov.today 2011,17,232.Pelicano, h.et.oncogene, 2006,25, 4633).

Lactate dehydrogenase a (LDHA; also known as LDH-M and LDH-5) is a homotetrameric enzyme that catalyzes the cytosolic conversion of pyruvate to lactate in the final step of glycolysis (Granchi, c.et al. curr. med. chem.2010,17,672.Salaway, j.g. metabolism at a company, 3^rdThe process involves a stereospecific hydride transformation of the ketone part of pyruvate from the reduced form of the relevant nicotinamide adenine dinucleotide cofactor (NADH), a replaceable lactate dehydrogenase isoform (LDHB; also known as LDH-H and LDH-1), although it preferentially catalyzes the reverse reaction in which lactate is converted to pyruvate, LDHA replaceable lactate dehydrogenase isoform (LDHA) is an HIF 32 and Myc target gene induced by hypoxia or mutations in the VHL, FH, RAS/PI3K/ATK signaling pathway, and elevated LDHA levels are common among various cancer indications and related to poor survival (Kolev, y.suetatal. ann. org.2008. 2008. sugar cane 6. sugar cane 7. sugar cane 13. u, sugar cane 13. 7. sugar cane 13. sugar cane, a shows significant inhibition of tumor growth by the Cell growth in vivo growth, Cell inhibition, which is shown by the Cell line of the Cell line growth in response to be more pronounced by the Cell proliferation of the Cell growth in a Cell line growth inhibition by the Cell line of the Cell line, Cell proliferation, Cell line 8, Cell line 8. H, Cell line 8. 9. 7, Cell line 8. 9. c, which is shown by the Cell line, Cell line 8, Cell line, 9. 9, Cell line, 9. 7. 9. c, 9, Cell line 8, 9, Cell line 8, Cell line, 9, Cell line 8, 9, Cell line 8, Cell line 8That is, people lacking LDHA due to genetic defects show a mild phenotype, which indicates that inhibition of the enzyme does not result in significant intolerable side effects. Taken together, these data suggest that LDHA is an attractive target for the development of new anti-cancer agents for hypoxic and/or highly glycolytic tumors.

LDHA inhibitors have been reported in the literature (Le, a.et al proc.natl.acad.sci.2010,107,2037.ward, r.a.et al j.med.chem.2012,55,3285.Granchi, c.et al j.med.chem.2011,54,1599). Recently it was claimed that some of these molecules show uncertain and/or weaker LDHA associations, suggesting that the biochemical activity of the enzyme may be susceptible to non-specific inhibition.

Disclosure of Invention

In one aspect, the present application relates to compounds of formula (I) and stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts thereof:

wherein A is¹、A²、A³、A⁴、R¹、R⁴、R⁵、R⁶、R⁷And R⁸As defined herein. The compounds of formula (I) are useful as LDHA inhibitors.

In one aspect, the application relates to tautomers of compounds of formula (I) such as:

wherein A is¹、A²、A³、A⁴、R¹、R⁴、R⁵、R⁶、R⁷And R⁸As defined herein. Compounds of formula (I) useful as LDHA inhibitorsAnd (4) preparing the preparation.

Another aspect of the present application provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

Another aspect of the present application provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment of cancer.

The application also relates to methods of using the compounds of formula (I) for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, organisms, or associated pathological conditions, such as cancer.

The present application also relates to compounds of formula (I) and the use of the compounds described herein for inhibiting LDHA for the treatment of cancer.

Another aspect of the present application provides a method of treating a disease or disorder comprising administering to a patient having cancer a compound of formula (I).

The method of treating cancer includes a method wherein the cancer is breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, and biliary tract cancer, kidney cancer, pancreatic cancer, myeloid disorders, lymphoma, hairy cell carcinoma, oral cancer, nasopharyngeal cancer, pharyngeal cancer, lip cancer, tongue cancer, mouth cancer, small intestine cancer, colorectal cancer, large intestine cancer, rectal cancer, brain and central nervous system cancer, hodgkin's lymphoma, leukemia, colorectal carcinoma, colon cancer, bronchial carcinoma, thyroid carcinoma, liver and intrahepatic bile duct carcinoma, hepatocellular carcinoma, gastric carcinoma, glioma/glioblastoma, endometrial carcinoma, melanoma, renal and renal pelvis carcinoma, bladder carcinoma, uterine corpus carcinoma, cervical carcinoma, multiple myeloma, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, oral and pharyngeal carcinoma, non-hodgkin's lymphoma, melanoma, or villous colon adenoma.

Another aspect of the present application provides a kit for treating a condition by inhibition comprising: a first pharmaceutical composition comprising a compound of formula (I); and instructions for use.

Other aspects of the present application include: (i) a method for the prevention or treatment of a condition, disorder or disease mediated by activation of LDHA enzyme in a subject in need of such treatment, which method comprises administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in any of the methods described herein in free form or in pharmaceutically acceptable salt form as a medicament; (ii) a compound of formula (I) in free form or in pharmaceutically acceptable salt form for use as a medicament, in particular for use in one or more diseases mediated by LDHA, in any of the methods described herein; (iii) use of a compound of formula (I), in particular in the treatment of one or more diseases mediated by LDHA, in free form or in pharmaceutically acceptable salt form in any of the methods described herein; (iv) use of a compound of formula (I), in free form or in pharmaceutically acceptable salt form, in any of the methods described herein, particularly in the manufacture of a medicament for the treatment of one or more diseases mediated by LDHA.

Detailed Description

Reference will now be made in detail to certain embodiments of the present application, examples of which are illustrated in the accompanying structures and molecular formulae. While the present application is described in conjunction with the enumerated embodiments, it is to be understood that the present application is not limited to those embodiments. On the contrary, the present application is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present application as defined by the appended claims. One skilled in the art will recognize that a variety of methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The present application is in no way limited to the methods and materials described. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terms, usage of terms, described techniques, etc.).

Definition of

The term "alkyl" as used herein means having 1 to 12 carbon atoms (C)₁-C₁₂) Wherein the alkyl group may be optionally substituted independently with one or more substituents described below. In another embodiment, the alkyl group has 1 to 8 carbon atoms (C)₁-C₈) Or 1 to 6 carbon atoms (C)₁-C₆). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl (Et-CH)₂CH₃) 1-propyl (n-Pr, n-propyl, -CH)₂CH₂CH₃) 2-propyl (i-Pr, isopropyl, -CH (CH)₃)₂) 1-butyl (n-Bu, n-butyl, -CH)₂CH₂CH₂CH₃) 2-methyl-1-propyl (i-Bu, isobutyl, -CH)₂CH(CH₃)₂) 2-butyl (s-Bu, sec-butyl, -CH (CH)₃)CH₂CH₃) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH)₃)₃) 1-pentyl (n-pentyl, -CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) 1-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃1-heptyl, 1-octyl, and R exemplified herein²A group.

The term "C₁-C₁₂-alkoxy "means C₁-C₁₂-an alkyl group, wherein the alkyl group is as defined herein, which is attached to the rest of the molecule or to another group via an oxygen atom. Illustrative non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, and the different butoxy isomers and R as exemplified herein¹A group.

Expression "(C)₁-C₁₂Alkylene radicals)_n-C₁-C₁₂By alkoxy is meant (C)₁-C₁₂Alkylene) -C₁-C₁₂-alkoxy or C₁-C₁₂-alkoxy, wherein alkylene and alkoxy are as defined herein.

The term "alkylene" as used herein means having from 1 to 12 carbon atoms (C)₁-C₁₂) Wherein the alkylene group may be optionally substituted independently with one or more substituents described below. In another embodiment, the alkylene group has 1 to 8 carbon atoms (C)₁-C₈) Or 1 to 6 carbon atoms (C)₁-C₆). Examples of alkylene groups include, but are not limited to, methylene (-CH)₂-) ethylene (-CH₂CH₂-) propylene (-CH)₂CH₂CH₂-) and R exemplified herein¹A group.

"aryl" refers to a compound formed by the reaction of the parent compoundHaving 6 to 20 carbon atoms (C) obtained by removing one hydrogen atom from a single carbon atom of an aromatic ring system₆-C₂₀) A monovalent aromatic hydrocarbon group of (2). Some aryl groups are represented in the exemplary structures as "Ar". Aryl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated, or aromatic carbocyclic ring. Typical aryl groups include, but are not limited to, groups derived from benzene (phenyl), substituted benzenes, naphthalenes, anthracenes, biphenyls, indenes, indanes, 1, 2-dihydronaphthalenes, 1,2,3, 4-tetrahydronaphthalenes, and the like. Aryl is optionally independently substituted with one or more substituents described herein. Further non-limiting examples of aryl groups can be found in the present application for R¹The definition of (1).

As used herein, "aryloxy" refers to-O-aryl, wherein aryl is as defined herein. Non-limiting examples of-O-aryl groups are-O-phenyl and-O-naphthyl.

The term "cyanoalkyl" as used herein refers to an alkyl group, as defined herein, substituted with one or more cyano groups, such as one cyano group. In certain embodiments, "cyanoalkyl" is C₁-C₁₂-cyanoalkyl. In other embodiments, "cyanoalkyl" is C₁-C₆Cyanoalkyl groups such as cyanomethyl and cyanoethyl.

The terms "carbocycle", "carbocyclyl", "carbocycle" and "cycloalkyl" refer to a compound having from 3 to 12 carbon atoms (C)₃-C₁₂) Monovalent non-aromatic saturated or partially unsaturated rings in the form of a single ring or in the form of a ring having 7 to 12 carbon atoms. Partially unsaturated rings may also be designated as cycloalkenyl rings. Bicyclic carbocyclic rings having 7 to 12 atoms may be arranged, for example, as bicyclo [4, 5]]、[5,5]、[5,6]Or [6,6 ]]The bicyclic carbocyclic rings having 9 or 10 ring atoms of the system may be arranged as bicyclo [5,6]Or [6,6 ]]Systems or arrangeable bridged ring systems, e.g. bicyclo [2.2.1]Heptane, bicyclo [2.2.2]Octane and bicyclo [3.2.2]Nonane. Examples of monocyclic carbocycles or cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enylCyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantane and R exemplified herein²A group.

The term "halogen" refers to chlorine, iodine, fluorine and bromine. In one embodiment, the halogen is fluorine, chlorine and bromine and in another embodiment fluorine and chlorine.

The term "haloalkyl" refers to an alkyl group as defined above wherein at least one hydrogen atom of the alkyl group is replaced by a halogen atom, preferably fluorine or chlorine, most preferably fluorine. Examples of haloalkyl include C₁-C₁₂Haloalkyl groups, but are not limited to methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-hexyl groups in which one or more hydrogen atoms are replaced by Cl, F, Br or I atoms, and those haloalkyl groups specifically exemplified below by the examples of the present application. Preferred haloalkyl groups are monofluoro-, difluoro-or trifluoro-methyl, monofluoro-, difluoro-or trifluoro-ethyl or monofluoro-, difluoro-or trifluoro-propyl groups such as 3,3, 3-trifluoropropyl, 2-fluoroethyl, 2,2, 2-trifluoroethyl, fluoromethyl, trifluoromethyl. The term "C₁-C₁₂-haloalkyl "refers to a haloalkyl having 1 to 12 carbon atoms, wherein the haloalkyl is as defined herein.

The term "haloalkoxy" refers to an alkoxy group as defined herein, wherein at least one hydrogen atom of the alkoxy group is replaced by a halogen atom, preferably fluorine or chlorine, most preferably fluorine. Examples of haloalkoxy include C₁-C₁₂Haloalkoxy, but not limited to methoxy, ethoxy, propyloxy, isopropyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy or n-hexyloxy in which one or more hydrogen atoms are replaced by Cl, F, Br or I atoms, and those haloalkoxy groups specifically exemplified below by the examples of the present application. Preferred haloalkoxy groups are monofluoro-, difluoro-or trifluoro-methoxy, monofluoro-, difluoro-or trifluoro-ethoxy or monofluoro-, difluoro-or trifluoro-propyloxy, e.g. 3,3, 3-trifluoropropyloxy, 2-fluoroethoxy, 2,2, 2-trifluoro-methoxyEthoxy, fluoromethoxy, trifluoromethoxy. In one embodiment, C₁-C₁₂Haloalkoxy is C₁-C₆-haloalkoxy.

The terms "heterocycle", "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated (i.e., having one or more double and/or triple bonds in the ring) carbocyclic group of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur and the remaining ring atoms are C, wherein one or more ring atoms are optionally independently substituted with one or more substituents described below. Examples of heterocyclyl groups are 4-to 10-membered heterocyclyl groups, i.e. heterocyclyl groups containing 2-9 carbon atoms and 1,2,3 or 4 heteroatoms selected from N, O, P and S. The heterocycle may be a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P and S) or a bicyclic ring having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P and S) such as bicyclo [4, 5] or]、[5,5]、[5,6]Or [6,6 ]]Provided is a system. Heterocycles are described in Paquette, Leo a.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York,1968), in particular chapters 1,3, 4,6, 7 and 9; "The Chemistry of Heterocyclic Compounds, materials of monograms" (John Wiley&Sons, New York,1950 to date), particularly volumes 13, 14, 16, 19 and 28; and j.am.chem.soc. (1960)82: 5566. "Heterocyclyl" also includes groups in which a heterocyclyl group is fused to a saturated ring, a partially unsaturated ring, an aromatic carbocyclic ring, or an aromatic heterocyclic ring. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thietanyl, oxazepanyl, andradical diazaRadical, sulfur nitrogen heteroYl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuryl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 2-oxa-5-azabicyclo [2.2.2]Octane, 3-oxa-8-azabicyclo [3.2.1]Octane, 8-oxa-3-azabicyclo [3.2.1]Octane, 6-oxa-3-azabicyclo [3.1.1]Heptane, 2-oxa-5-azabicyclo [2.2.1]Heptane, 3-azabicyclo [3.1.0]Hexyl, 3-azabicyclo [4.1.0]Heptyl, azabicyclo [2.2.2]Hexyl, 3H-indolyl, quinolizinyl and N-pyridylurea. Spirocyclic moieties are also included within the scope of this definition. Examples of heterocyclyl groups in which the ring atom is partially substituted by oxo (═ O) are pyrimidinone groups and 1, 1-dioxothiomorpholinyl groups. The heterocyclic groups of the present application are optionally independently substituted with one or more substituents described herein.

The term "heteroaryl" refers to monovalent aromatic groups of 5,6 or 7 membered rings and includes fused ring systems (wherein at least one ring is aromatic) having 5 to 20 atoms, the aromatic groups and fused ring systems containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include 5-to 10-membered heteroaryl groups, which refer to monocyclic or bicyclic heteroaryl groups having 2-9 carbon atoms and one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, e.g., 1,2,3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include 5 or 6 membered heteroaryl, which refers to monocyclic or bicyclic heteroaryl groups having 2 to 5 carbon atoms and one or more heteroatoms independently selected from nitrogen, oxygen and sulfur, such as 1,2,3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups are pyridyl (including, e.g., 2-hydroxypyridyl), imidazolyl, imidazopyridyl, pyrimidinyl (including, e.g., 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanylThienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl is optionally independently substituted with one or more substituents described herein, such as alkyl, alkoxy, cyano, halo, oxo, NH₂OH, hydroxyalkyl, amido. Further examples of heteroaryl and possible substituents can be found in R²The definition of (1).

The term "heteroaryloxy" as used herein refers to an-O-heteroaryl group, wherein heteroaryl is as defined herein.

The heterocycle or heteroaryl may be carbon-bonded (attached via carbon) or nitrogen-bonded (attached via nitrogen) where possible. By way of example and not limitation, a carbon-bonded heterocycle or heteroaryl is bonded at: 2,3,4, 5 or 6 position of pyridine; the 3,4, 5 or 6 position of pyridazine; 2,4, 5 or 6 positions of pyrimidine; 2,3, 5 or 6 position of pyrazine; 2,3,4 or 5 positions of furan, tetrahydrofuran, thiophene, pyrrole or tetrahydropyrrole; 2,4 or 5 position of oxazole, imidazole or thiazole; the 3,4 or 5 position of isoxazole, pyrazole or isothiazole; 2 or 3 position of aziridine; the 2,3 or 4 position of azetidine; 2,3,4, 5,6, 7 or 8 positions of quinoline; or 1,3, 4,5, 6,7 or 8 positions of isoquinoline. The ring nitrogen atom of the heterocycle or heteroaryl may be bonded to an oxygen to form an N-oxide.

By way of example and not limitation, nitrogen-bonded heterocycles or heteroaryls are bonded at the following positions: aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, benzimidazole, at the 1-position; position 2 of isoindole or isoindoline; 4-position of morpholine; and the 9-position of carbazole or beta-carboline.

The term "hydroxy" refers to a group having the formula-OH.

The term "hydroxyalkyl" refers to an alkyl group as defined above wherein at least one hydrogen atom of the alkyl group is replaced by a hydroxyl group. Examples of hydroxyalkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, or n-hexyl groups in which one or more hydrogen atoms are replaced with OH, and those hydroxyalkyl groups specifically exemplified below by the examples of the present application. The term "C₁-C₁₂By "hydroxyalkyl" is meant a hydroxyalkyl group having 1 to 12 carbon atoms, wherein hydroxyalkyl is as defined herein.

Oxo refers to a group having the formula ═ O.

The expression "one or more substituents" means substitution by 1,2,3,4, 5,6, 7, 8, 9, 10, 11 or 12 substituents which may be independently selected from the substituents listed after the expression. In one embodiment, one or more substituents refers to 1,2,3,4, or 5 substituents. In one embodiment, one or more substituents refers to 1,2 or 3 substituents.

The term "treatment" refers to both therapeutic treatment and prophylactic measures, the purpose of which is to prevent or slow down (lessen) the development or spread of an undesired physiological change or disorder, such as cancer. For purposes of this application, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of disease extent, stabilization (i.e., not worsening) of the disease state, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "treatment" may also refer to an extended survival time compared to that expected in the absence of treatment. Those in need of treatment include those with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

The phrase "therapeutically effective amount" refers to an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder described herein, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder described herein, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. For cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the size of the tumor; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and/or relieve to some extent one or more symptoms associated with cancer. A drug may be cytostatic and/or cytotoxic if it can prevent growth and/or kill existing cancer cells. For cancer therapy, efficacy can be measured, for example, by assessing time to disease progression (TTP) and/or determining Response Rate (RR).

The term "cancer" refers to or describes a physiological condition in mammals that is typically characterized by unregulated cell growth. A "tumor" includes one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer ("NSCLC"), adenoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or pancreatic cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, head and neck cancer, multiple myeloma, acute myelogenous leukemia, chronic lymphocytic leukemia, myelochronic leukemia, lymphocytic leukemia, myeloid leukemia, oral and pharyngeal cancer, non-hodgkin's lymphoma, melanoma, and villous colon adenoma.

The term "chiral" refers to a molecule having a non-superimposable mirror pair, while the term "achiral" refers to a molecule superimposable with its mirror pair.

The term "stereoisomers" refers to compounds having the same chemical composition but differing arrangements of atoms or groups in space. Stereoisomers include enantiomers and diastereomers.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography. Diastereomers include geometric, cis/trans and E/Z isomers and atropisomers.

"enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

The stereochemical definitions and conventional nomenclature used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present application may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present application, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present application. Many organic compounds exist in optically active form, i.e. they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule about one or more of its chiral centers. The prefixes d and l or (+) and (-) are used as symbols to denote the rotation of plane polarized light by the compound, where (-) or l denotes that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur where the chemical reaction or process is not stereoselective or stereospecific. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, which are not optically active.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted through a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons. As mentioned above, the compounds of formula (I) also encompass tautomers thereof, as depicted by the following formula:

the phrase "pharmaceutically acceptable salt" as used herein refers to pharmaceutically acceptable organic or inorganic salts of the compounds of the present application. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [ i.e., 1' -methylene-bis (2-hydroxy-naphthalene-3-formate) ]. Pharmaceutically acceptable salts can be designed to contain another molecule such as an acetate, succinate, or other counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, pharmaceutically acceptable salts may have more than one charged atom in their structure. Where the plurality of charged atoms are part of a pharmaceutically acceptable salt, there may be a plurality of counterions. Thus, pharmaceutically acceptable salts can have one or more charged atoms and/or one or more counterions.

If the compound of the present application is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, and the like, or with an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosyl acid such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid or cinnamic acid, a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid, and the like.

If the compound of the present application is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, and the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

The phrase "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.

"solvate" refers to an association or complex of one or more solvent molecules with a compound of the present application. Examples of solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

The terms "compound of the present application" and "compound of formula (I)" include compounds of formulae (I), (I-a) and (I-a-1), the specific compounds described herein, and stereoisomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts and prodrugs thereof. As noted above, specific tautomers of compounds of formula (I) are as follows:

any formula or structure given herein, including the compound of formula I, is also intended to represent hydrates, solvates and polymorphs of the compound, or mixtures thereof.

Any formula or structure given herein, including compounds of formula I, is also intended to represent isotopically labeled and unlabeled forms of the compounds. Isotopically labeled compounds have the structure depicted in the structural formulae given herein, but one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine such as, but not limited to²H (deuterium, D),³H (tritium),¹¹C、¹³C、¹⁴C、¹⁵N、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I. various isotopically-labeled compounds of the present application are, for example, those into which a radioactive isotope is introduced, for example³H、¹³C and¹⁴c are those compounds of the present application. The isotopically labeled compounds are useful in metabolic studies, reaction kinetic studies, 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 in radiation therapy of patients. Deuterium labeled or substituted therapeutic compounds of the present application may have improved DMPK (drug metabolism and excretion) with respect to distribution, metabolism and excretion (ADME)Pharmacokinetic) properties. Substitution with heavier isotopes such as deuterium can afford certain therapeutic benefits such as increased in vivo half-life or reduced dosage requirements resulting from greater metabolic stability. Warp beam¹⁸The F-labeled compounds are useful for PET or SPECT studies. Isotopically-labeled compounds of the present application and prodrugs thereof can generally be prepared as follows: the procedures disclosed in the schemes or examples and preparations below are carried out using readily available isotopically labeled reagents in place of non-isotopically labeled reagents. In addition, with heavier isotopes, especially deuterium (i.e. deuterium)²Substitution by H or D) may result in some therapeutic benefit such as an extended in vivo half-life or reduced dosage requirements or improved therapeutic index due to greater metabolic stability. It is to be understood that deuterium in this context is considered as a substituent in the compound of formula (I). The concentration of the heavier isotopes, in particular deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present application, an atom that is not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," the position should be understood as having hydrogen in its natural abundance isotopic composition. Thus, any atom specifically designated as deuterium (D) in the compounds of the present application is intended to represent deuterium.

LDHA inhibitors

In one aspect, the present application relates to compounds of formula (I) and stereoisomers, tautomers, and pharmaceutically acceptable salts thereof:

wherein

A¹Is O, CH₂Or S;

A²is NH or N-C₁-C₃-an alkyl group;

A³is N or CR²；

A⁴Is N or CR³Provided that A is³And A⁴Not N at the same time;

R¹is Cl, NO₂Or CN;

R²and R⁶Independently selected from H, halogen, hydroxy, C₁-C₆-hydroxyalkyl and NH₂；

R³And R⁵Independently selected from:

H；

a hydroxyl group;

halogen;

-C₁-C₆-alkyl-R^f；

-C₁-C₆-alkenyl-R^f；

-C₁-C₆-alkoxy-R^c；

-NR^aR^b；

-NR^a-(C₁-C₆-alkyl) -R^d；

-NR^a-S(O)₂- (4 to 10 membered heterocycloalkyl);

-NR^a-(C₃-C₈-cycloalkyl) which is unsubstituted or substituted by C₁-C₆-alkyl or C₁-C₃-alkylene bridge substitution;

-NR^a-an aryl group, said aryl group being unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, -NH₂、C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₁-C₆-haloalkyl group, C₁-C₆-hydroxyalkyl, C₁-C₆-haloalkoxy and C₃-C₈-a cycloalkyl group;

-NR^a- (4 to 10 membered heterocycloalkyl) which is unsubstituted or substituted by one or more substituents selected from: c₁-C₆Alkyl radical, C₁-C₆-hydroxyalkyl or-CO-alkyl;

-NR^a- (5-or 6-membered heteroaryl), which is unsubstituted or substituted by one or more substituents selected from: halogen, -NR^aR^bAnd C₁-C₆-an alkyl group;

-NR^a(CO)-C₁-C₆-an alkyl group;

-NR^a(CO) -aryl;

-NR^a(CO) - (5 or 6 membered heteroaryl);

-NR^a(CO)O-C₁-C₆-an alkyl group;

-S- (alkyl)_n-R^h；

-S(O)₂-aryl, unsubstituted or substituted by one or more halogens;

-C(O)-R^e；

-C(O)NR^a-(C₁-C₆-alkyl groups)_n-R^g；

-C(O)NR^a-C₁-C₆-an alkoxy group;

-O-C₃-C₈-cycloalkyl, unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆Alkoxyaryl radical, C₁-C₆-haloalkyl group, C₁-C₆Hydroxyalkyl, NR^aR^bAryl, C₁-C₆-alkyl-aryl, 5 or 6 membered heteroaryl and- (C)₁-C₆-alkyl) - (C₁-C₆-alkoxy groups);

-O-aryl, said aryl being unsubstituted or substituted with one or more substituents selected from: halogen, C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₁-C₆-alkyl-C₁-C₆-alkoxy, C₁-C₆-haloalkyl group, C₁-C₆-haloalkoxy, C₁-C₆-hydroxyalkyl, -S-C₁-C₆-alkyl, -C₁-C₆-alkyl-C₃-C₈-cycloalkyl, C₁-C₆-alkoxy-C₃-C₈-cycloalkyl, C₁-C₆-alkyl- (4 to 10 membered heterocycloalkyl), C₁-C₆-alkyl- (5 or 6 membered heterocycloalkyl) or unsubstituted or substituted by one or more groups selected from C₁-C₆Alkyl, - (C)₁-C₆-alkyl) - (C₁-C₆-alkoxy), C₁-C₆-haloalkoxy and C₁-C₆-a 5 or 6 membered heteroaryl substituted with a substituent of an alkylene bridge;

-O- (4 to 10 membered heterocycloalkyl) which is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₆-hydroxyalkyl and-C (O) -C₁-C₆-an alkyl group;

-O- (5-to 10-membered heteroaryl), said heteroaryl being unsubstituted or substituted by halogen, C₁-C₆Alkyl radical, C₁-C₆-hydroxyalkyl or-NR^a(CO)-C₁-C₆-alkyl substitution;

C₃-C₈-a cycloalkyl group, which may be fused with a phenyl group;

aryl, which is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxyRadical, -C (O) OH, C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy, -S (O)₂-NH (alkyl) and-S (O)₂-N (alkyl)₂；

A 4 to 10 membered heterocycloalkyl which is unsubstituted or substituted with one or more substituents selected from: halogen, C₁-C₆Alkyl, -C (O) -C₃-C₈-cycloalkyl, oxo and 5 or 6 membered heterocycloalkyl;

a 5 to 10 membered heteroaryl, which is unsubstituted or substituted with one or more substituents selected from: hydroxy, -NR^aR^b、C₁-C₆Alkyl radical, C₁-C₆-hydroxyalkyl and 4 to 10 membered heterocycloalkyl;

R⁴comprises the following steps:

H；

a cyano group;

halogen;

a hydroxyl group;

NR^aR^b；

C₁-C₆-an alkyl group;

C₁-C₆-a haloalkyl group;

C₁-C₆-a hydroxyalkyl group;

C₁-C₆alkoxy, unsubstituted or substituted by hydroxy, C₁-C₆-alkoxy or NR^aR^bSubstitution;

-(C₁-C₆-alkyl groups)_n-(C₃-C₈-cycloalkyl) which is unsubstituted or substituted by one or more substituents selected from: halogen, hydroxy, -NR^aR^b、C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₁-C₆Alkyl halidesRadical, -C (O) -C₁-C₆Alkyl, -C (O) -C₁-C₆-cycloalkyl and-c (o) - (5 or 6 membered heterocycloalkyl);

-(C₁-C₆-alkyl groups)_n-(C₃-C₈-cycloalkenyl) which is unsubstituted or substituted by one or more substituents selected from: halogen, hydroxy, -NR^aR^b、C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₁-C₆-haloalkyl, -C (O) -C₁-C₆Alkyl, -C (O) -C₁-C₆-cycloalkyl and-c (o) - (5 or 6 membered heterocycloalkyl);

-(C₁-C₆-alkyl groups)_n- (5-or 6-membered heteroaryl), which is unsubstituted or substituted by one or more substituents selected from: halogen, hydroxy, -NR^aR^b、C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₁-C₆-haloalkyl, -C (O) -C₁-C₆Alkyl, -C (O) -C₁-C₆-cycloalkyl and-c (o) - (5 or 6 membered heterocycloalkyl);

-(C₁-C₆-alkyl groups)_n- (4 to 10 membered heterocycloalkyl) which is unsubstituted or substituted by one or more substituents selected from: halogen, hydroxy, cyano, -NR^aR^b、C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₁-C₆-haloalkyl group, C₁-C₆Hydroxyalkyl, -C (O) OH, C₁-C₄Alkylene bridge, -C (O) -C₁-C₆Alkyl, -C (O) -C₃-C₈-cycloalkyl, -c (o) -aryl, -c (o) (4 to 10 membered heterocycloalkyl), and-c (o) - (5 or 6 membered heterocycloalkyl);

R⁷is an aryl, 5 or 6 membered heterocyclyl or 5 or 6 membered heteroaryl group, which aryl, heterocyclyl or heteroaryl group is unsubstituted or substituted by one or more substituents selected from: halogen, C₁-C₆Alkyl radical, C₃-C₈-cycloalkyl, -O-aryl, -S-aryl, -NH-aryl and (C)₁-C₆-alkyl groups)_n-an aryl group;

or R⁶And R⁷Together with the carbon atoms to which they are attached form a 5-membered ring selected from cycloalkyl or heterocycloalkyl having 5 ring members;

R⁸is OH, -NR^aR^b、C₁-C₆Alkoxy or-C (O) O-C₁-C₆-an alkyl group;

or R²And R³Together with the atoms to which they are attached form a naphthyl or 9-or 10-membered heteroaryl group, each of which is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, -NR^aR^b、C₁-C₆Alkyl radical, C₁-C₆-alkoxy and C₁-C₆-a haloalkyl group;

or R³And R⁴Together with the atoms to which they are attached form a naphthyl or 9-or 10-membered heteroaryl group, each of which is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, -NR^aR^b、C₁-C₆Alkyl radical, C₁-C₆-alkoxy and C₁-C₆-a haloalkyl group;

or R⁴And R⁵Together with the atoms to which they are attached form a naphthyl or 9-or 10-membered heteroaryl group, each of which is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, -NR^aR^b、C₁-C₆Alkyl radical, C₁-C₆-alkoxy and C₁-C₆-a haloalkyl group;

or R⁵And R⁶Together with the atoms to which they are attached form a naphthyl or 9-or 10-membered heteroaryl group, each of which is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, -NR^aR^b、C₁-C₆Alkyl radical, C₁-C₆-alkoxy and C₁-C₆-a haloalkyl group;

R^ais H or C₁-C₆-an alkyl group;

R^bis H or C₁-C₆-an alkyl group;

R^cis H, hydroxy, halogen, -NR^aR^b、C₁-C₆-alkoxy, C₁-C₆-alkenyl, unsubstituted or oxo or C₁-C₆-alkyl-substituted 4 to 6 membered heterocycloalkyl, unsubstituted or substituted by C₁-C₆-alkyl-substituted 5 or 6 membered heteroaryl or C unsubstituted or substituted by one or more substituents selected from₃-C₈-a cycloalkyl group: halogen, C₁-C₆Alkyl radical, C₁-C₆Hydroxyalkyl, aryl unsubstituted or substituted by halogen, unsubstituted or by oxo or C₁-C₆-alkyl-substituted 4 to 9 membered heterocycloalkyl and unsubstituted or C₁-C₆-an alkyl-substituted 5 or 6 membered heteroaryl;

R^dis H, hydroxy, C₁-C₆Alkyl radical, C₃-C₈-cycloalkyl or aryl, said groups being unsubstituted or substituted by one or more substituents selected from: halogen and-NR^a-S(O)₂-N(C₁-C₆-alkyl groups)₂；

R^eIs C₁-C₆Alkyl, aryl, C₃-C₈-cycloalkyl, 5-to 9-membered heterocycloalkyl or 5-or 6-membered heteroaryl, wherein said aryl, C₃-C₈-cycloalkyl, 5-to 9-membered heterocycloalkyl or 5-or 6-membered heteroaryl is unsubstituted or substituted by one or more substituents selected from: halogen, C₁-C₆-alkoxy, C₁-C₆-alkyl and C₁-C₆-a haloalkyl group;

R^fis H, C₃-C₈-cycloalkyl, 4-to 10-membered heterocycloalkyl, aryl or 5-or 6-membered heteroaryl, said cycloalkyl, heterocycloalkyl, aryl or heteroaryl being unsubstituted or substituted with one or more substituents selected from: halogen, C₁-C₆-haloalkyl group, C₁-C₆Alkyl radical, C₁-C₆-alkoxy and C₁-C₆-a hydroxyalkyl group;

R^gis C₁-C₆-alkoxy, C₃-C₈-cycloalkyl, aryl, 5 or 6 membered heteroaryl, 5 to 9 membered heterocycloalkyl, wherein said aryl, C₃-C₈-cycloalkyl, 5-to 9-membered heterocycloalkyl or 5-or 6-membered heteroaryl is unsubstituted or substituted by one or more substituents selected from: halogen, C₁-C₆-alkoxy and C₁-C₆-a hydroxyalkyl group;

R^his aryl, 5-or 6-membered heteroaryl, 4-to 10-membered heterocycloalkyl, C₃-C₈-cycloalkyl, each of said groups being unsubstituted or substituted by halogen;

n is 0 or 1.

In one embodiment, the present application relates to compounds of formula (I) and stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts thereof, which compounds can be:

wherein A is¹、A³、A⁴、R¹、R⁴、R⁵、R⁶、R⁸、R⁹And R¹⁰As described herein.

wherein A is³、A⁴、R¹、R⁴、R⁵、R⁶、R⁷And R⁸As described herein.

In one embodiment, the present application relates to compounds of formula (I), which may be:

wherein A is¹、A²、A³、R¹、R³、R⁴、R⁵、R⁶、R⁸、R⁹And R¹⁰As described herein.

wherein A is³、R¹、R³、R⁴、R⁵And R⁶As described herein.

wherein A is³、R¹And R³As described herein.

wherein R is¹And R³As described herein.

wherein R is¹、R²And R³As described herein.

In one embodiment, the present application relates to compounds of formula (I) and stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts thereof, wherein

A¹Is O or S;

A²is NH or N-C₁-C₃-an alkyl group;

A³is N or CR²；

R¹Is Cl, NO₂Or CN;

R²and R⁶Independently selected from H, halogen, hydroxy and NH₂；

R³And R⁵Independently selected from:

H；

a hydroxyl group;

halogen;

-C₁-C₆-alkyl-R^fWherein R is^fIs a 4 to 10 membered heterocycloalkyl, aryl or 5 or 6 membered heteroaryl group, C₃-C₈-cycloalkyl, 5-to 9-membered heterocycloalkyl, aryl or 5-or 6-membered heteroaryl is unsubstituted or substituted with one or more substituents selected from: halogen, C₁-C₆-alkoxy and C₁-C₆-a hydroxyalkyl group;

-C₁-C₆-alkoxy-R^cWherein R is^cIs H, hydroxy, halogen, -NR^aR^b、C₁-C₆-alkoxy, C₁-C₆-alkenyl, C₃-C₈-cycloalkyl, said group being unsubstituted or substituted with one or more substituents selected from: halogen, C₁-C₆Alkyl radical, C₁-C₆Hydroxyalkyl, aryl unsubstituted or substituted by halogen, unsubstituted or by oxo or C₁-C₆-alkyl-substituted 4 to 9 membered heterocycloalkyl and unsubstituted or C₁-C₆-an alkyl-substituted 5 or 6 membered heteroaryl;

-NR^aR^bwherein R is^aAnd R^bIndependently selected from H or C₁-C₆-an alkyl group;

-NR^a-(C₁-C₆-alkyl) -R^dWherein R is^aIs H or C₁-C₆-alkyl, and R^dIs H, hydroxy, C₁-C₆Alkyl radical, C₃-C₈-cycloalkyl or aryl, said groups being unsubstituted or substituted by one or more substituents selected from: halogen and-NR^a-S(O)₂-N(C₁-C₆-alkyl groups)₂；

-NR^a-S(O)₂- (4-to 10-membered heterocycloalkyl) wherein R^aIs H or C₁-C₆-an alkyl group;

-NR^a-(C₃-C₈-cycloalkyl) in which R is^aIs H or C₁-C₆-alkyl, and saidCycloalkyl is unsubstituted;

-NR^a-aryl, wherein R^aIs H or C₁-C₆-an alkyl group, and the aryl group is unsubstituted or substituted with one or more substituents selected from: halogen, C₁-C₆-alkoxy, C₁-C₆-haloalkyl and C₁-C₆-a hydroxyalkyl group;

-NR^a- (4-to 10-membered heterocycloalkyl) wherein R^aIs H or C₁-C₆-an alkyl group;

-NR^a- (5-or 6-membered heteroaryl), wherein R^aIs H or C₁-C₆-an alkyl group, and the heteroaryl group is unsubstituted or substituted with one or more substituents selected from: halogen, -NH₂Or C₁-C₆-an alkyl group;

-NR^a(CO)O-C₁-C₆-alkyl, wherein R^aIs H or C₁-C₆-an alkyl group;

-C(O)-R^ewherein R is^eIs aryl, wherein said aryl is substituted by halogen or C₁-C₆-haloalkyl substitution;

-C(O)NR^a-(C₁-C₆-alkyl groups)_n-R^gWherein R is^aIs H or C₁-C₆-alkyl, and R^gIs C₁-C₆-alkoxy, C₃-C₈-a cycloalkyl group;

-O-C₃-C₈-cycloalkyl, unsubstituted or substituted by halogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₆-alkoxy substituted, said alkoxy being unsubstituted or substituted by C₁-C₆Alkoxyaryl radical, C₁-C₆-haloalkyl substitution;

-O-aryl, said aryl being unsubstituted or substituted by one or more substituents selected from: halogen, C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₁-C₆-haloalkyl group, C₁-C₆-haloalkoxy, C₁-C₆-hydroxyalkyl, -S-C₁-C₆-alkyl, -C₁-C₆-alkyl-C₃-C₈-cycloalkyl, 4-to 10-membered heterocycloalkyl, 5-or 6-membered heteroaryl, said radicals being unsubstituted or substituted by C₁-C₆-alkyl and C₁-C₆-alkylene bridge substitution;

-O- (4 to 10 membered heterocycloalkyl) which is unsubstituted or substituted with one or more substituents selected from: hydroxy, C₁-C₆-hydroxyalkyl, -C (O) -C₁-C₆-an alkyl group;

-O- (5 to 10 membered heteroaryl), said heteroaryl being unsubstituted or substituted by halogen or-NR^a(CO)-C₁-C₆-alkyl substitution;

aryl substituted by one or more-S (O)₂-N (alkyl)₂Substitution;

4 to 10 membered heterocycloalkyl which is unsubstituted or substituted with one or more 5 or 6 membered heterocycloalkyl;

a 5 to 10 membered heteroaryl group which is unsubstituted or substituted with one or more 4 to 10 membered heterocycloalkyl groups;

R⁴comprises the following steps:

H；

a hydroxyl group;

C₁-C₆alkoxy, unsubstituted or substituted by hydroxy or C₁-C₆-alkoxy substitution;

-(C₁-C₆-alkyl groups)_n-(C₃-C₈-cycloalkyl);

-(C₁-C₆-alkyl groups)_n-(C₃-C₈-cycloalkenyl);

-(C₁-C₆-alkyl groups)_n- (4 to 10 membered heterocycloalkyl) which is unsubstituted or substituted by one or more substituents selected from: halogen, C₁-C₆-alkyl or-C (O) -C₁-C₆-an alkyl group;

R⁷is a 5 or 6 membered heteroaryl group, which is unsubstituted or substituted with one or more substituents selected from: halogen, alkyl, -O-aryl, -S-aryl, -NH-aryl, - (C)₁-C₆-alkyl groups)_n-an aryl group;

R⁸is OH, -NH₂、C₁-C₆Alkoxy, -C (O) O-C₁-C₆-an alkyl group;

or R²And R³Together with the atoms to which they are attached form a naphthyl or 9-or 10-membered heteroaryl group, each of which is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, -NH₂、-NH(C₁-C₆-alkyl), -N (C)₁-C₆-alkyl groups)₂、C₁-C₆Alkyl radical, C₁-C₆-alkoxy and C₁-C₆-a haloalkyl group;

or R³And R⁴Together with the atoms to which they are attached form a naphthyl or 9-or 10-membered heteroaryl group, each of which is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, -NH₂、-NH(C₁-C₆-alkyl), -N (C)₁-C₆-alkyl groups)₂、C₁-C₆Alkyl radical, C₁-C₆-alkoxy and C₁-C₆-a haloalkyl group;

or R⁴And R⁵Together with the atoms to which they are attached form a naphthyl or 9-or 10-membered heteroaryl group, each of which is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, -NH₂、-NH(C₁-C₆-alkyl), -N (C)₁-C₆-alkyl groups)₂、C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₁-C₆-a haloalkyl group;

or R⁵And R⁶Together with the atoms to which they are attached form a naphthyl or 9-or 10-membered heteroaryl group, each of which is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, -NH₂、-NH(C₁-C₆-alkyl), -N (C)₁-C₆-alkyl groups)₂、C₁-C₆Alkyl radical, C₁-C₆-alkoxy and C₁-C₆-a haloalkyl group;

n is 0 or 1.

All of the following embodiments may be combined with each other, unless specifically stated otherwise in the present application.

In one embodiment, A is¹Is O. In one embodiment, A is¹Is S. In one embodiment, A is¹Is CH₂。

In one embodiment, A is²Is NH. In one embodiment, A is²Is N-C₁-C₃-an alkyl group.

In one embodiment, A is³Is N. In one embodiment, A is³Is CR²。

In one embodiment, A is⁴Is N. In one embodiment, A is⁴Is CR³。

In one embodiment, A is³Is CR²And A is⁴Is CR³. In one embodiment, A is³Is NH, and A⁴Is CR³. In one embodiment, A is³Is CR²And A is⁴Is NH.

In one embodiment, R¹Is Cl. In one embodiment, R¹Is NO₂. In one embodiment, R¹Is CN.

In one embodiment, R²Is H. In one embodiment, R²Is halogen. In one embodiment, R²Is a hydroxyl group. In one embodiment, R²Is C₁-C₆-hydroxyalkyl. In one embodiment, R²Is NH₂. In one embodiment, R²Is halogen. In one embodiment, R²Is a hydroxyl group. In one embodiment, R²Is C₁-C₆-hydroxyalkyl.

In one embodiment, R³Or R⁵Is H. In one embodiment, R³Or R⁵Is a hydroxyl group. In one embodiment, R³Or R⁵Is halogen. In one embodiment, R³Or R⁵is-C₁-C₆-alkyl-R^fWherein R is^fAs defined herein. In one embodiment, R³Or R⁵is-C₁-C₆-alkenyl-R^fWherein R is^fAs defined herein. In one embodiment, R³Or R⁵is-C₁-C₆-alkoxy-R^cWherein R is^cAs defined herein. In one embodiment, R³Or R⁵is-NR^aR^bWherein R is^aAnd R^bAs defined herein. In one embodiment, R³Or R⁵is-NR^a-(C₁-C₆-alkyl) -R^dWherein R is^aAnd R^dAs defined herein. In one embodiment, R³Or R⁵is-NR^a-S(O)₂- (4-to 10-membered heterocycloalkyl) wherein R^aAs defined herein. In one embodiment, R³Or R⁵is-NR^a-(C₃-C₈-cycloalkyl) in which R is^aAs defined herein, and said cycloalkyl isUnsubstituted or substituted by C₁-C₆-alkyl substitution. In one embodiment, R³Or R⁵is-NR^a-aryl, wherein R^aAs defined herein, and said aryl is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, -NH₂、C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₁-C₆-haloalkyl group, C₁-C₆-hydroxyalkyl, C₁-C₆-haloalkoxy and C₃-C₈-a cycloalkyl group.

In one embodiment, R³Or R⁵is-NR^a- (4-to 10-membered heterocycloalkyl) wherein R^aAs defined herein, and said heterocycloalkyl is unsubstituted or substituted with one or more substituents selected from: c₁-C₆Alkyl radical, C₁-C₆-hydroxyalkyl or-CO-alkyl.

In one embodiment, R³Or R⁵is-NR^a- (5-or 6-membered heteroaryl), wherein R^aAs defined herein, and said heteroaryl is unsubstituted or substituted with one or more substituents selected from: halogen, -NR^aR^bAnd C₁-C₆-an alkyl group.

In one embodiment, R³Or R⁵is-NR^a(CO)-C₁-C₆-alkyl, wherein R^aAs defined herein.

In one embodiment, R³Or R⁵is-NR^a(CO) - (aryl).

In one embodiment, R³Or R⁵is-NR^a(CO) - (5 or 6 membered heteroaryl).

In one embodiment, R³Or R⁵is-NR^a(CO)O-C₁-C₆-alkyl, wherein R^aAs defined herein.

In one embodiment, R³Or R⁵is-S- (alkyl)_n-R^hAnd R is^hAs defined herein.

In one embodiment, R³Or R⁵is-S (O)₂-aryl, which is unsubstituted or substituted by one or more halogens.

In one embodiment, R³Or R⁵is-C (O) -R^eAnd R is^eAs defined herein.

In one embodiment, R³Or R⁵is-C (O) NR^a-(C₁-C₆-alkyl groups)_n-R^gWherein R is^aAnd R^gAs defined herein.

In one embodiment, R³Or R⁵is-O-C₃-C₈-cycloalkyl, unsubstituted or substituted by halogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₆-alkoxy substituted, unsubstituted or by halogen, C₁-C₆Alkoxyaryl radical, C₁-C₆-haloalkyl, aryl, C₁-C₆-alkyl-aryl, 5-or 6-membered heteroaryl, C₁-C₆-haloalkoxy, C₁-C₆Hydroxyalkyl, NR^aR^b、-(C₁-C₆-alkyl) - (C₁-C₆-alkoxy) substitution.

In one embodiment, R³Or R⁵is-O-aryl, said aryl being unsubstituted or substituted with one or more substituents selected from: halogen, C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₁-C₆-haloalkyl group, C₁-C₆-haloalkoxy, C₁-C₆-hydroxyalkyl, -S-C₁-C₆-alkyl, -C₁-C₆-alkyl-C₃-C₈-cycloalkyl, C₁-C₆-alkyl-4 to 10 membered heterocycloalkyl, 5 or 6 membered heteroaryl, said groups being unsubstituted or substituted with one or more substituents selected from: c₁-C₆Alkyl, - (C)₁-C₆-alkyl) - (C₁-C₆-alkoxy), C₁-C₆-haloalkoxy, C₁-C₆An alkylene bridge.

In one embodiment, R³Or R⁵is-O- (4 to 10 membered heterocycloalkyl) which is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, C₁-C₆-hydroxyalkyl and-C (O) -C₁-C₆-an alkyl group.

In one embodiment, R³Or R⁵is-O- (5-to 10-membered heteroaryl), said heteroaryl being unsubstituted or substituted by halogen or-NR^a(CO)-C₁-C₆-alkyl is substituted, and R^aAs defined herein.

In one embodiment, R³Or R⁵Is C₃-C₈-a cycloalkyl group, which may be fused with a phenyl group.

In one embodiment, R³Or R⁵Is an aryl group, which is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, -C (O) OH, C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy, -S (O)₂-NH (alkyl) and-S (O)₂-N (alkyl)₂。

In one embodiment, R³Or R⁵Is a 4 to 10 membered heterocycloalkyl which is unsubstituted or substituted with one or more 5 or 6 membered heterocycloalkyl.

In one embodiment, R³Or R⁵Is a 5 to 10 membered heteroaryl group, which is unsubstituted or substituted with one or more substituents selected from: hydroxy, -NR^aR^b、C₁-C₆Alkyl radical, C₁-C₆-hydroxyalkyl and 4 to 10 membered heterocycloalkyl.

In one embodiment, R³Or R⁵is-NR^a-S(O)₂- (4-to 10-membered heterocycloalkyl) for example:

in one embodiment, R³Or R⁵is-S (O)₂-aryl, unsubstituted or substituted by one or more halogens, for example:

in one embodiment, R³Or R⁵Is C₃-C₈-cycloalkyl, which may be fused with phenyl, or which may be partially unsaturated, for example:

in one embodiment, R³Or R⁵Is NR^a-(C₁-C₆-alkyl) -R^dWherein R is^dIs C₃-C₈Cycloalkyl radicals, such as:

in one embodiment, R³Or R⁵Is C₁-C₆-alkenyl-R^fWherein R is^fIs C₃-C₈Cycloalkyl radicals, such as:

in one embodiment, R³Or R⁵Is aryl, e.g. phenyl, which is unsubstituted or substituted by oneOr a plurality of halogen, hydroxy, -C (O) OH, C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy, -S (O)₂-NH (alkyl) and-S (O)₂-N (alkyl)₂Substitutions, for example:

in one embodiment, R³Or R⁵is-NR^aAryl radicals such as the radical-NR^a-phenyl, said aryl or phenyl being unsubstituted or substituted by one or more halogens, C₁-C₆-alkoxy, C₁-C₆-haloalkyl group, C₁-C₆-hydroxyalkyl, C₃-C₈-cycloalkyl is substituted, and R^aIs H or C₁-C₆-alkyl groups, such as:

in one embodiment, R³Or R⁵is-O-aryl, such as-O-phenyl, said aryl or phenyl being unsubstituted or substituted with one or more of the following substituents: halogen, C₁-C₆-alkyl, -S-C₁-C₆Alkyl radical, C₁-C₆-haloalkyl group, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₃-C₈-cycloalkyl, C₁-C₆-haloalkoxy, C₁-C₆-hydroxyalkyl, C₁-C₆-alkyl-C₁-C₆-alkoxy, C₁-C₆-alkyl- (5 or 6 membered heterocycloalkyl), 5 or 6 membered heterocycloalkyl, said 5 or 6 membered heteroaryl being unsubstituted or substituted by C₁-C₆Alkyl radical, C₁-C₆-haloalkoxy, C₁-C₆Alkylene bridges, partially hydrogenated naphthalene substitutions which are unsubstituted or substituted by halogens, such as:

in one embodiment, R³Or R⁵is-NR^a- (5-or 6-membered heterocycloalkyl) such as:

in one embodiment, R³Or R⁵is-NR^a- (5-or 6-membered heteroaryl), said heteroaryl being unsubstituted or substituted by halogen or C₁-C₆Alkyl substitution, such as:

in one embodiment, R³Or R⁵is-NR^a-(C₃-C₈-cycloalkyl) which is unsubstituted or substituted by C₁-C₆-alkyl or C₁-C₃-alkylene bridge is substituted, and R^aIs H or C₁-C₆-alkyl groups, such as:

in one embodiment, R³Or R⁵Is halogen such as Cl, F or Br.

In one embodiment, R³Or R⁵is-NR^aR^bWherein R is^aAnd R^bIndependently selected from H and C₁-C₆Alkyl radicals, e.g. NH₂-NHMe or-N (Me)₂。

In one embodiment, R³Or R⁵Is a hydroxyl group.

In one embodiment, R³Or R⁵is-NR^a(CO)O-C₁-C₆-alkyl, wherein R^aIs H or C₁-C₆-alkyl groups, such as:

in one embodiment, R³Or R⁵is-O- (5-to 10-membered heteroaryl), said heteroaryl being unsubstituted or substituted by halogen, C₁-C₆Alkyl radical, C₁-C₆-hydroxyalkyl or-NR^aC(O)C₁-C₆Alkyl substitution, such as:

in one embodiment, R³Or R⁵Is C₁-C₆-alkyl-R^fAnd R is^fIs an aryl group. In one embodiment, R^fIs unsubstituted phenyl. In one embodiment, R^fIs phenyl, substituted with one or more substituents selected from: halogen, C₁-C₆-alkoxy, C₁-C₆-haloalkyl and C₁-C₆Hydroxyalkyl, for example:

in one embodiment, R³Or R⁵is-C₁-C₆-alkoxy-R^cWherein R is^cIs hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆Alkenyl, phenyl unsubstituted or substituted by halogen, unsubstituted or by oxo or C₁-C₆-alkyl-substituted 4 to 6 membered heterocycloalkyl, unsubstituted or substituted by C₁-C₆-alkyl-substituted 5 or 6 membered heteroaryl or unsubstituted or substituted by halogen, C₁-C₆-hydroxyalkyl, C₁-C₆-alkyl substituted C₃-C₈Cycloalkyl radicals, such as:

in one embodiment, R³Or R⁵Is C₁-C₆-alkyl-R^fAnd R is^fIs a 5 or 6 membered heterocycloalkyl group, for example:

in one embodiment, R³Or R⁵is-O-C₃-C₆-cycloalkyl, unsubstituted or substituted by halogen, hydroxy, C₁-C₆Alkyl, phenyl, C₁-C₆Alkoxy substitution, such as:

in one embodiment, R³Or R⁵is-O- (5-or 6-membered heterocycloalkyl) which is unsubstituted or substituted by C₁-C₆Alkyl or-C (O) C₁-C₆Alkyl substitution, such as:

in one embodiment, R³Or R⁵is-NR^a-C₁-C₆-alkyl-R^dWherein R is^dIs C₃-C₈Cycloalkyl or phenyl unsubstituted or substituted by halogen, for example:

in one embodiment, R³Or R⁵Is a 5 to 10 membered heteroaryl group, which is unsubstituted or substituted by hydroxy, NH₂、C₁-C₆-alkyl or C₁-C₆Hydroxyalkyl substitution, such as:

in one embodiment, R³Or R⁵Is 5-or 6-membered heterocycloalkyl which is unsubstituted or substituted by halogen, C₁-C₆Alkyl, -C (O) -C₃-C₈-cycloalkyl, oxo, 5 or 6 membered heterocycloalkyl substitution, for example:

in one embodiment, R³Or R⁵is-C (O) NR^a-(C₁-C₆-alkyl groups)_n-R^g. In one embodiment, R³Or R⁵is-C (O) NR^a-(C₁-C₆-alkyl) -R^gAnd R is^gIs C₃-C₆-cycloalkyl or phenyl, said phenyl being unsubstituted or substituted by halogen, or R³Or R⁵is-C (O) NR^a-C₁-C₆Alkoxy groups, such as:

in one embodiment, R³Or R⁵is-S- (alkyl)_n-R^h. In one embodiment, R³Or R⁵is-S-phenyl, unsubstituted or substituted by halogen, for example:

at one isIn embodiments, R³Or R⁵is-C (O) -R^eAnd R is^eIs phenyl, unsubstituted or substituted by halogen, for example:

in one embodiment, R³Or R⁵is-NR^a-S(O)₂- (4-to 6-membered heterocycloalkyl) for example:

in one embodiment, R⁴Is H. In one embodiment, R⁴Is halogen. In one embodiment, R⁴Is a hydroxyl group. In one embodiment, R⁴Is C₁-C₆-an alkyl group. In one embodiment, R⁴Is C₁-C₆-haloalkyl. In one embodiment, R⁴Is C₁-C₆-hydroxyalkyl. In one embodiment, R⁴Is CN. In one embodiment, R⁴Is C₁-C₆Alkoxy, unsubstituted or substituted by hydroxy or C₁-C₆-alkoxy substitution. In one embodiment, R⁴Is- (C)₁-C₆-alkyl groups)_n-(C₃-C₈-cycloalkyl). In one embodiment, R⁴Is- (C)₁-C₆-alkyl groups)_n-(C₃-C₈-cycloalkenyl). In one embodiment, R⁴Is- (C)₁-C₆-alkyl groups)_n- (4 to 10 membered heterocycloalkyl) which is unsubstituted or substituted by one or more substituents selected from: halogen, C₁-C₆-alkyl or-C (O) -C₁-C₆-an alkyl group.

In one embodiment, R⁴is-NR^aR^bAnd R is^aAnd R^bAs defined herein, for example:

in one embodiment, R⁴Is C₁-C₆Alkoxy, unsubstituted or substituted by hydroxy, C₁-C₆-alkoxy or-NR^aR^bIs substituted in which R^aAnd R^bAs defined herein, for example:

in one embodiment, R⁴Is C₃-C₆-cycloalkyl or C₃-C₆Cycloalkenyl such as:

in one embodiment, R⁴Is a 4 to 10 membered heterocycloalkyl which is unsubstituted or substituted with: halogen, hydroxy, cyano, oxo, C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₁-C₆-hydroxyalkyl, -C (O) OH, -C (O) -C₁-C₆Alkyl, -C (O) -C₃-C₈-cycloalkyl, -C (O) -phenyl, 4-to 10-membered heterocycloalkyl, -C (O) (5-or 6-membered heteroaryl), -C (O) (4-to 10-membered heterocycloalkyl), C₁-C₄Alkylene bridges, such as:

in one embodiment of the present application, R⁷Is a 5 or 6 membered heteroaryl group, which is unsubstituted or substituted with one or more substituents selected from: halogen, C₁-C₆Alkyl radical, C₁-C₆-alkoxy, -O-aryl, -S-aryl, -NH-aryl, - (C)₁-C₆-alkyl groups)_nAryl, such as:

in one embodiment of the present application, R⁸Is OH. In one embodiment of the present application, R⁸is-NH₂. In one embodiment of the present application, R⁸Is C₁-C₆-alkoxy groups. In one embodiment of the present application, R⁸is-C (O) O-C₁-C₆-an alkyl group.

In one embodiment of the present application, R⁶And R⁷Together with the carbon atoms to which they are attached form a 5-membered ring selected from cycloalkyl or heterocycloalkyl having 5 ring members, such that the compound of formula (I) is as follows:

in one embodiment of the present application, R²And R³Together with the atoms to which they are attached form a naphthyl or 9-or 10-membered heteroaryl group, each of which is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, -NH₂、-NH(C₁-C₆-alkyl), -N (C)₁-C₆-alkyl groups)₂、C₁-C₆Alkyl radical, C₁-C₆-alkoxy and C₁-C₆-haloalkyl.

In one embodiment of the present application, R³And R⁴Together with the atoms to which they are attached form a naphthyl or 9-or 10-membered heteroaryl group, each of which is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, -NH₂、-NH(C₁-C₆-alkyl), -N (C)₁-C₆-alkyl groups)₂、C₁-C₆Alkyl radical, C₁-C₆-alkoxy and C₁-C₆-haloalkyl.

In one embodiment of the present application, R⁵And R⁶Together with the atoms to which they are attached form a naphthyl or 9-or 10-membered heteroaryl group, each of which is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, -NH₂、-NH(C₁-C₆-alkyl), -N (C)₁-C₆-alkyl groups)₂、C₁-C₆Alkyl radical, C₁-C₆-alkoxy and C₁-C₆-haloalkyl.

In one embodiment of the present application, n is 0. In one embodiment of the present application, n is 1.

In one embodiment, R⁹Is H. In one embodiment, R⁹Is C₁-C₆-an alkyl group. In one embodiment, R⁹Is C₃-C₈-a cycloalkyl group. In one embodiment, R⁹Is halogen. In one embodiment, R⁹is-O-aryl such as-O-phenyl. In one embodiment, R⁹is-S-aryl such as-S-phenyl. In one embodiment, R⁹is-NH-aryl such as-NH-phenyl. In one embodiment, R⁹Is- (C)₁-C₆-alkyl groups)_nAryl radicals such as- (C)₁-C₆-alkyl groups)_n-phenyl.

In one embodiment, R¹⁰Is H. In one embodiment, R¹⁰Is C₁-C₆-an alkyl group. In one embodiment, R¹⁰Is C₃-C₈-a cycloalkyl group. In thatIn one embodiment, R¹⁰Is halogen. In one embodiment, R¹⁰is-O-aryl such as-O-phenyl. In one embodiment, R¹⁰is-S-aryl such as-S-phenyl. In one embodiment, R¹⁰is-NH-aryl such as-NH-phenyl. In one embodiment, R¹⁰Is- (C)₁-C₆-alkyl groups)_nAryl radicals such as- (C)₁-C₆-alkyl groups)_n-phenyl.

In one embodiment, A is³Is NH. In one embodiment, A is³Is CR²Wherein R is²Selected from H, halogen, hydroxy, C₁-C₆-hydroxyalkyl and NH. In one embodiment, R⁹And R¹⁰Is H. In one embodiment, R¹Is Cl. In one embodiment, R³Is NH-phenyl or NH-pyridyl, said phenyl or pyridyl being substituted by halogen. In one embodiment, R⁴、R⁵、R⁶And R⁸Is H.

In one embodiment, A is¹Is O, A²Is NH, R¹Is Cl, A³Is NH, A⁴Is CR³，R³Is NH-phenyl or NH-pyridyl, said phenyl or pyridyl being substituted by halogen, R⁴、R⁵And R⁶Is H, R⁷Is thienyl.

In one embodiment, A is¹Is S, A²Is NH, R¹Is halogen, A³Is NH, A⁴Is CR³，R³Is NH-phenyl or NH-pyridyl, said phenyl or pyridyl being substituted by halogen, R⁴、R⁵And R⁶Is H, R⁷Is thienyl.

In one embodiment, the compound of formula (I) is selected from the following compounds and stereoisomers, tautomers and pharmaceutically acceptable salts thereof. These compounds can also be prepared as racemates, mixtures of diastereomers or as single stereoisomers, all of which fall within the scope of the present application:

1- [4- [5- (2-chlorophenyl) sulfanyl-4, 6-dioxo-2- (thiophen-3-yl) piperidin-2-yl ] phenyl ] piperidine-4-carbonitrile;

2- [ [6- (6-bromopyridin-2-yl) -2, 4-dioxo-6- (thiophen-3-yl) piperidin-3-yl ] sulfanyl ] benzonitrile;

3- (2-chloro-5-hydroxy-phenyl) sulfanyl-6- [4- (piperidin-1-yl) phenyl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenoxy) -6- (4-morpholinophenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenoxy) -6- [4- (piperidin-1-yl) phenyl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenoxy) -6- [6- (2-cyclopropylethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenoxy) -6- [6- (3, 4-difluorophenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenoxy) -6- [6- (4-fluorophenylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenoxy) -6- [6- (4-fluorophenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-1-methyl-6- (3- (tetrahydropyran-4-yl) oxyphenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-1-methyl-6- [3- (tetrahydropyran-4-ylamino) phenyl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (1H-indol-4-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (2-fluorophenyl) -1-methyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (2-hydroxy-4-morpholino-phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (2-hydroxyphenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (naphthalen-2-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (3-fluoro-4-morpholino-phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (3-hydroxyphenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (3- (tetrahydropyran-4-yl) oxyphenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) -6- (4-thiomorpholinophenyl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) -6- [6- (2,2, 2-trifluoro-1-methyl-ethoxy) pyridin-2-yl ] piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) -6- [6- (2,2, 2-trifluoroethoxy) pyridin-2-yl ] piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) -6- [6- (4,4, 4-trifluorobutoxy) pyridin-2-yl ] piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) -6- [6- [3- (trifluoromethyl) phenoxy ] pyridin-2-yl ] piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) -6- [6- [4- (trifluoromethoxy) phenoxy ] pyridin-2-yl ] piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) -6- [6- [4- (trifluoromethyl) cyclohexyloxy ] pyridin-2-yl ] piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) -6- [6- [4- (trifluoromethyl) phenoxy ] pyridin-2-yl ] piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (4-cyclohexylphenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (4-cyclopropylphenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (4-hydroxyphenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (4-morpholino-3-phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (4-morpholinophenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (4-morpholinophenyl) -6- (5-phenylthiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (4-morpholinophenyl) -6- (6- (tetrahydropyran-4-yl) oxypyridin-2-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (4-morpholinophenyl) -6- (thiazol-4-yl) -piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (4- (piperazin-1-yl) phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (4- (pyrrolidin-1-yl) phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (5-chlorothien-3-yl) -6- [6- (4-fluorophenoxy) pyridin-2-yl ] piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (5-methylthiophen-3-yl) -6- (4-morpholinophenyl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (6- (chroman-4-yl) oxypyridin-2-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (6-ethoxypyridin-2-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (6- (indan-5-yl) oxypyridin-2-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (6-isobutoxypyridin-2-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (6-isopentyloxypyridin-2-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (6-isopropoxypyridin-2-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (6-isopropoxy-5-morpholinopyridin-2-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (6-morpholinopyridin-3-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (6- (pent-2-enyloxy) pyridin-2-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (6-phenoxypyridin-2-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (6-phenylpyridin-2-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (6- (pyrimidin-5-yl) oxypyridin-2-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (6- (tetrahydrofuran-3-yl) oxypyridin-2-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (6- (tetrahydronaphthalen-1-yl) oxypyridin-2-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [3- (4-fluorophenylamino) phenyl ] -1-methyl-6- (3-thienyl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [3- (4-fluorophenylamino) phenyl ] -6- (3-thienyl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [3- (4-fluorophenylamino) phenyl ] -6-phenyl-piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [3- (4-fluoro-N-methyl-phenylamino) phenyl ] -6-phenyl-piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [3- (4-fluorophenoxy) phenyl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [3- (cyclohexylamino) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [3- (tetrahydropyran-4-ylamino) phenyl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [3- [ (6-fluoro-5-methylpyridin-3-yl) amino ] phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (piperidin-1-yl) phenyl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (2, 2-dimethylmorpholin-4-yl) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (2, 6-dimethylmorpholin-4-yl) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (2-ethylmorpholin-4-yl) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (2-hydroxyethoxy) phenyl ] -6- (3-thienyl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (2-methoxyethoxy) phenyl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (2-methylmorpholin-4-yl) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (2-oxa-6-azaspiro [3.3] hept-6-yl) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (2-oxa-7-azaspiro [3.5] non-7-yl) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (3, 3-difluoroazetidin-1-yl) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (3, 3-difluoropyrrolidin-1-yl) phenyl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (3-fluoroazetidin-1-yl) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (3-fluoropyrrolidin-1-yl) phenyl ] -6- (3-thienyl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (3-hydroxypropoxy) phenyl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (3-methoxypropoxy) phenyl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (3-methoxypyrrolidin-1-yl) phenyl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (4, 4-difluoropiperidin-1-yl) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (4-fluoropiperidin-1-yl) phenyl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (4-methoxypiperidin-1-yl) phenyl ] -6- (3-thienyl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (cyclohexen-1-yl) phenyl ] -6- (3-thienyl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (dimethylamino) phenyl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [4- (tetrahydropyran-4-ylamino) phenyl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [5- (4-fluorophenylamino) -2-hydroxy-phenyl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [5- [ (4-fluorophenyl) methyl ] thiophen-3-yl ] -6- (4-morpholinophenyl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (1,2,3, 4-tetrahydroquinolin-8-yloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (1-cyclohexylethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (1-cyclopropylethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (1-cyclopropylethylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (1H-indazol-4-yloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2, 2-difluoroethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2, 2-dimethyl chroman-4-yl) oxypyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2, 2-dimethylpropoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2, 3-difluorophenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2, 4-difluorophenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2-cyclobutylethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2-cyclohexylethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2-cyclohexylethylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2-cyclopentylethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2-cyclopropyl-1-methyl-ethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2-cyclopropylethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2-cyclopropylethylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2-cyclopropylpropoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2-ethoxy-1-methyl-ethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2-ethoxyethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2-fluorophenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2-methoxy-1-methyl-ethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2-methoxyphenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2-methylbutyloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (2-morpholinopyridin-4-yl) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (pyridin-2-yloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (3, 4-difluorophenylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (3, 4-difluorophenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (3, 4-difluorophenoxy) pyridin-2-yl ] -6- (4-morpholinophenyl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (3, 4-difluorophenoxy) pyridin-2-yl ] -6- [4- (piperidin-1-yl) phenyl ] piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (3, 5-difluorophenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (3-fluoro-4-methoxy-phenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (3-fluorophenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (3-hydroxy-3-methyl-butoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (3-hydroxycyclopentyloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (3-methoxy-3-methyl-butoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (3-methoxy-N-methyl-phenylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (3-methoxyphenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (3-methoxypropoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (pyridin-3-yloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (3- (tetrahydropyran-4-yl) azetidin-1-yl) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4, 4-difluorocyclohexyloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-cyclopropyl-2-fluoro-phenylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluoro-2-isopropyl-phenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluoro-2-methoxy-phenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

(6S) -3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluoro-2-methoxy-phenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluoro-2- (tetrahydropyran-4-yl) -phenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluoro-3-methoxy-phenyl) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluoro-3-methyl-phenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenylamino) pyridin-2-yl ] -1-methyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (cyclohexyloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenylamino) pyridin-2-yl ] -6- (4-morpholinophenyl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenylamino) -5-morpholinopyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorobenzoyl) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluoro-N-methyl-phenylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenoxy) pyridin-2-yl ] -1-methyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenoxy) pyridin-2-yl ] -6- (1H-pyrazol-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenoxy) pyridin-2-yl ] -6- (2-hydroxyphenyl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenoxy) pyridin-2-yl ] -6- (4-morpholinophenyl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenoxy) -5-morpholinopyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenyl) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenyl) sulfanylpyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-hydroxy-4-methyl-pentyloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-iodophenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-methoxycyclohexyloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-methoxy-N-methyl-phenylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-methoxyphenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (4-methylsulfanylphenoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (pyridin-4-yl) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (pyridin-4-ylmethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (5-fluorotetrahydronaphthalen-1-yl) oxypyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (isoquinolin-5-yloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (quinolin-5-yloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (6-fluorotetrahydronaphthalen-1-yl) oxypyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (quinolin-6-yloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (7-fluorotetrahydronaphthalen-1-yl) oxypyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (8-fluoro-chroman-4-yl) oxypyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (8-hydroxy-3, 4-dihydro-2H-quinolin-1-yl) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (isoquinolin-8-yloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (quinolin-8-yloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (cyclobutoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (cyclobutylmethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (cycloheptyloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (cyclohexyloxy) pyridin-2-yl ] -6- (4-morpholinophenyl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (cyclohexyloxy) pyridin-2-yl ] -6- [4- (piperidin-1-yl) phenyl ] piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (cyclohexylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (cyclohexylmethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (cyclopentyloxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (cyclopentylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (cyclopentylmethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (cyclopropylmethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (dimethylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (N-ethyl-4-fluoro-phenylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (oxetan-3-ylmethoxy) pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (tetrahydrofuran-2-ylmethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (tetrahydrofuran-3-ylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (tetrahydropyran-4-ylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (tetrahydropyran-4-ylmethoxy) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (tetrahydropyran-4-ylmethyl) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- (thiazol-2-ylamino) pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (1, 5-dimethylpyrazol-3-yl) amino ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (1-methyl-1, 2, 4-triazol-3-yl) amino ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (1-methylcyclopropyl) methoxy ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (1-methylimidazol-2-yl) amino ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (1-methylimidazol-2-yl) methoxy ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (1-methylpyrazol-3-yl) amino ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (2, 4-difluorophenyl) methyl ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (2, 5-dimethylpyrazol-3-yl) amino ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (2-methylcyclopropyl) methoxy ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (2-methylpyrazol-3-yl) amino ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (3, 3-difluorocyclobutyl) methoxy ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (3, 4-difluorophenyl) methyl ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (3, 5-difluorophenyl) methyl ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (3-ethyloxetan-3-yl) methoxy ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

5- (2-chlorophenyl) sulfanyl-4-hydroxy-2- [6- (4-methoxycyclohexyloxy) pyridin-2-yl ] -2- (thiophen-3-yl) -1, 3-dihydropyridin-6-one;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (3-fluoro-5-methoxy-phenyl) methyl ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (3-fluorophenyl) methyl ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (4-fluoro-3-methoxy-phenyl) methyl ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (4-fluorophenyl) methoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (4-fluorophenyl) methyl ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (4-fluorophenyl) methylamino ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (4-methylthiazol-2-yl) amino ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (5-fluoropyridin-3-yl) oxy ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (5-fluoroquinolin-8-yl) oxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (5-methyl-1H-imidazol-2-yl) amino ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (5-methylthiazol-2-yl) amino ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (5-oxotetrahydrofuran-2-yl) methoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (6-fluoropyridin-3-yl) amino ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ (6-fluoro-5-methylpyridin-3-yl) amino ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ [3- (hydroxymethyl) phenyl ] methyl ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ [4- (hydroxymethyl) cyclohexyl ] methoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [1- (3, 4-difluorophenyl) ethoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [1- (3-fluorophenyl) ethoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [1- (4-fluorophenyl) ethoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [1- (4-fluorophenyl) ethylamino ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [1- (4-fluorophenyl) propoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [1- (4-fluorophenyl) propylamino ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [2- (1H-pyrazol-4-yl) phenoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [2- (1-methylcyclopropyl) ethoxy ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [2- (2, 2-difluorocyclopropyl) ethoxy ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [2- (2, 2-dimethyl-1, 3-dioxolan-4-yl) ethoxy ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [2- (2-oxopyrrolidin-1-yl) ethoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [2- (3-methyltriazol-4-yl) phenoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [2- (4-fluorophenyl) ethyl ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [2- (cyclopropylmethoxy) -4-fluoro-phenoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [2- (cyclopropylmethyl) -4-fluoro-phenoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [2- (methoxymethyl) phenoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [2- (oxetan-3-yl) ethoxy ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [3- (1-hydroxyethyl) phenylamino ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [3- (difluoromethyl) -4-fluoro-phenoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [3- (difluoromethyl) phenoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [3- (hydroxymethyl) phenylamino ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [3- (hydroxymethyl) -N-methyl-phenylamino ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ 3-fluoro-5- (hydroxymethyl) phenoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ 4-fluoro-3- (hydroxymethyl) phenylamino ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ 4-fluoro-3- (trifluoromethyl) phenoxy ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [6- (hydroxymethyl) indolin-1-yl ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- [6- [ N-methyl-3- (trifluoromethyl) phenylamino ] pyridin-2-yl ] -6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6-phenyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6-phenyl-6- (thiazol-4-yl) -piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6- (thiazol-4-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione;

4- [3- [5- (2-chlorophenyl) sulfanyl-2- (4-morpholinophenyl) -4, 6-dioxopiperidin-2-yl ] phenyl ] -N, N-dimethyl-benzenesulfonamide;

4- [3- [5- (2-chlorophenyl) sulfanyl-4, 6-dioxo-2- (thiophen-3-yl) piperidin-2-yl ] phenyl ] -N, N-dimethyl-benzenesulfonamide;

4- [6- [5- (2-chlorophenyl) sulfanyl-4, 6-dioxo-2- (thiophen-3-yl) piperidin-2-yl ] pyridin-2-yl ] -N, N-dimethyl-benzenesulfonamide;

6- (3-aminophenyl) -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- (3-phenylaminophenyl) -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- (3-bromo-4-morpholino-phenyl) -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- (3-bromophenyl) -3- (2-chlorophenyl) sulfanyl-1-methyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- (3-bromophenyl) -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- (5-bromo-6-morpholinopyridin-3-yl) -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- (6-benzylpyridin-2-yl) -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- (6-benzyloxypyridin-2-yl) -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- (6-bromopyridin-2-yl) -3- (2-chloro-5-hydroxy-phenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- (6-bromopyridin-2-yl) -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- (6-bromo-5-morpholinopyridin-2-yl) -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [ 3-chloro-5- (4-fluorophenylamino) phenyl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [4- (1,3,3a,4,6,6 a-hexahydrofuro [3,4-c ] pyrrol-5-yl) phenyl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [4- (2-azaspiro [3.3] hept-2-yl) phenyl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [4- (3-azabicyclo [2.1.1] hex-3-yl) phenyl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [4- (4-acetylpiperazin-1-yl) phenyl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [5- (2-chlorophenyl) sulfanyl-4, 6-dioxo-2- (thiophen-3-yl) piperidin-2-yl ] -N- (cyclopropylmethyl) pyridine-2-carboxamide;

6- [6- (2-amino-5-methyl-imidazol-1-yl) pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- (2-bromophenoxy) pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- (2-chloro-3, 4-difluoro-phenylamino) pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- (2-chloro-4-fluoro-phenylamino) pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- (2-chloro-4-fluoro-phenoxy) pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- (2-tert-butoxyethoxy) pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- (3-bromo-4-fluoro-phenoxy) pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- (3-chloro-4-fluoro-phenylamino) pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- (3-chloro-4-fluoro-phenoxy) pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- (3-chlorophenoxy) pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- (4-bromo-2-chloro-phenoxy) pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- (4-bromo-2-fluoro-phenoxy) pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- (4-chloro-N-methyl-phenylamino) pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- (4-chlorophenoxy) pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- (7-bromotetralin-1-yl) oxypyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- [ (2-chloro-6-fluoropyridin-3-yl) oxy ] pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- [ (4-chloro-3-fluoro-phenyl) methyl ] pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- [ [1- (3-chloro-4-fluoro-phenyl) -2-hydroxy-ethyl ] amino ] pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- [1- (3-chloro-4-fluoro-phenyl) propylamino ] pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

6- [6- [1- (4-chlorophenyl) ethoxy ] pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

n- [6- [5- (2-chlorophenyl) sulfanyl-4, 6-dioxo-2- (thiophen-3-yl) piperidin-2-yl ] pyridin-2-yl ] azetidine-1-sulfonamide;

5- (2-chlorophenyl) sulfanyl-4-hydroxy-2- [4- (piperidin-1-yl) phenyl ] -2- (thiophen-3-yl) -1, 3-dihydropyridin-6-one; and

n- [6- [5- (2-chlorophenyl) sulfanyl-4, 6-dioxo-2- (thiophen-3-yl) piperidin-2-yl ] pyridin-2-yl ] carbamic acid tert-butyl ester.

In one embodiment, the present application relates to compounds of the present application for use as therapeutically active substances.

In one embodiment, the present application relates to pharmaceutical compositions comprising a compound of the present application and a therapeutically inert carrier.

In one embodiment, the present application relates to compounds of the present application for use in the treatment or prevention of cancer.

In one embodiment, the present application relates to the use of a compound of the present application for the manufacture of a medicament for the treatment or prevention of cancer.

In one embodiment, the present application relates to a method of treating or preventing cancer comprising administering an effective amount of a compound of the present application.

In one embodiment, the cancer of the present application is selected from the following cancers: breast, ovarian, cervical, prostate, testicular, genitourinary tract, esophageal, laryngeal, glioblastoma, neuroblastoma, gastric, skin, keratoacanthoma, lung, epidermoid, large cell, non-small cell lung cancer (NSCLC), small cell, lung adenocarcinoma, bone, colon, adenoma, pancreatic, adenocarcinoma, thyroid, follicular, undifferentiated, papillary, seminoma, melanoma, sarcoma, bladder, liver and biliary tract, kidney, pancreatic, myeloid disorders, lymphoma, hairy cell, oral, nasopharyngeal, pharyngeal, lip, tongue, mouth, small intestine, colorectal, large intestine, rectal, brain and central nervous system, hodgkin's lymphoma, leukemia, bronchial, thyroid, liver and intrahepatic bile duct, hepatocellular, colon, or rectum, colon cancer, gastric cancer, glioma/glioblastoma, endometrial cancer, melanoma, renal and renal pelvis cancer, bladder cancer, uterine corpus cancer, cervical cancer, multiple myeloma, Acute Myeloid Leukemia (AML), chronic lymphocytic leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, oral and pharyngeal cancer, non-hodgkin's lymphoma, melanoma, or villous colon adenoma.

Pharmaceutical preparation

For use of the compounds of formula (I) for therapeutic treatment (including prophylactic treatment) of mammals, including humans, they are generally formulated as pharmaceutical compositions in accordance with standard pharmaceutical practice. This aspect of the present application provides a pharmaceutical composition comprising a compound of the present application and a pharmaceutically acceptable diluent or carrier.

Typical formulations are prepared by mixing a compound of the present application with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient employed will depend upon the mode and purpose of administration of the compounds of the present application. The solvent is generally selected based on a solvent (GRAS) that one of skill in the art would consider safe for administration to a mammal. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), and the like, and mixtures thereof. The formulations may also include one or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents and other known additives to impart a superior appearance to the drug (i.e., a compound of the present application or a pharmaceutical composition thereof) or to aid in the manufacture of the pharmaceutical product (i.e., a pharmaceutical product).

The formulations may be prepared using conventional dissolution and mixing operations. For example, a bulk drug substance (i.e., a compound of the present application or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above excipients. The compounds of the present application are typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with prescribed regimens.

The pharmaceutical composition (or formulation) for administration may be packaged in a variety of ways depending on the method of administering the drug. Typically, the article of manufacture for dispensing comprises a container in which the pharmaceutical formulation is stored in a suitable form. Suitable containers are known to those skilled in the art and include articles such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, and the like. The container may also include anti-pry means to prevent inadvertent access to the contents of the package. Additionally, the container has a label thereon that describes the contents of the container. The tag may also include suitable warning information.

Pharmaceutical formulations of the compounds of the present application can be prepared for a variety of routes and types of administration. For example, a compound of formula (I) having a desired purity may be optionally mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers in the form of a lyophilized preparation, a milled powder or an aqueous solution (Remington's Pharmaceutical Sciences (1980) 16 th edition, Osol, a.ed.). The formulation can be carried out as follows: mixed at ambient temperature at a suitable pH and in a suitable purity with a physiologically acceptable carrier, i.e. a carrier which is non-toxic to recipients at the dosages and concentrations employed. The pH of the formulation depends primarily on the particular use and compound concentration, but can be from about 3 to about 8. Formulations in acetate buffer at pH 5 are suitable embodiments.

The compounds can generally be stored as solid compositions, lyophilized formulations or as aqueous solutions.

The pharmaceutical compositions of the present application will be formulated, dosed and administered in a manner consistent with good medical practice (i.e., amount, concentration, schedule, course, vehicle and route of administration). Factors to be considered in this context include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of delivery of the drug, the method of administration, the timing of administration and other factors known to medical practitioners. The "therapeutically effective amount" of the compound to be administered will depend on the above factors considered and is the minimum amount required to prevent, ameliorate or treat the hyperproliferative disorder.

As a general proposition, the initial pharmaceutically effective amount of inhibitor per dose administered parenterally will be about 0.01-100mg/kg, i.e., about 0.1-20mg/kg, of patient body weight per day, with a typical initial range of compounds employed being 0.3 to 15 mg/kg/day.

Acceptable diluents, carriers, excipients, and stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (for example octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butanol or benzyl alcohol; alkyl parabens, for example methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants, e.g. TWEEN^TM、PLURONICS^TMOr polyethylene glycol (PEG). The active pharmaceutical ingredient may also be embedded in microcapsules prepared, for example, by coacervation techniques or interfacial polymerization, such as hydroxymethylcellulose or gelatin-microcapsules and poly (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (such as liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions. See Remington 'for the above technology's Pharmaceutical Sciences 16 th edition, Osol, a.ed. (1980).

Sustained release formulations of the compounds of formula (I) may be prepared. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing a compound of formula (I), which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g. poly (2-hydroxyethyl methacrylate) or poly (vinyl alcohol)), polylactide (US3773919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT^TM(microspheres for injection composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly D- (-) -3-hydroxybutyric acid.

Formulations include those suitable for the routes of administration described herein. The formulations may be conveniently presented in unit dosage form and may be prepared by any of the methods known in the art of pharmacy. Techniques and formulations are generally described in Remington's pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). The above method comprises the step of bringing into association the active ingredient with the carrier as one or more accessory ingredients. In general, the formulations are prepared as follows: the active ingredient is combined with a liquid carrier or a finely divided solid carrier or both uniformly and intimately thereafter the product is shaped as required.

Formulations of a compound of formula (I) suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets or tablets each containing a predetermined amount of a compound of formula (I). Compressed tablets may be prepared as follows: the active ingredient in free-flowing form, e.g. powder or granules, optionally mixed with binders, lubricants, inert diluents, preservatives, surfactants or dispersing agents, is compressed in a suitable machine. Molded tablets may be prepared as follows: the mixture of powdered active ingredient moistened with an inert liquid diluent is moulded in a suitable machine. The tablets may optionally be coated or scored and optionally formulated for slow or controlled release of the active ingredient therefrom. Tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules such as gelatin capsules, syrups or elixirs may be prepared for oral administration. Formulations of compounds of formula (I) intended for oral administration may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic physiologically acceptable excipients which are suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

For the treatment of the eye or other external tissues such as the mouth and skin, the formulations may be applied in the form of a topical ointment or cream containing the active ingredient in an amount of, for example, 0.075 to 20% w/w. When formulated in an ointment, the active ingredient may be used with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream together with an oil-in-water cream base. If desired, the aqueous phase of the cream base may comprise polyhydric alcohols, i.e. alcohols having two or more hydroxyl groups such as propylene glycol, butane-1, 3-diol, mannitol, sorbitol, glycerol and polyethylene glycols (including PEG 400) and mixtures thereof. Topical formulations may desirably contain compounds that enhance absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin permeation enhancers include dimethyl sulfoxide and related analogs. The oily phase of the emulsions of the present application may be constituted in a known manner by known ingredients, including mixtures of at least one emulsifier with a fat or an oil or with both a fat and an oil. With a lipophilic emulsifierHydrophilic emulsifiers are included as stabilizers. At the same time, the emulsifier, with or without stabilizer, constitutes the so-called emulsifying wax, and said wax, together with the oil and fat, constitutes the so-called emulsifying cream base, which forms the oily dispersed phase of the cream. Emulsifiers and emulsion stabilizers suitable for use in the formulations herein include60、80. Cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

Aqueous suspensions of the compounds of formula (I) contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, for example, sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing or wetting agents, for example, naturally-occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose or saccharin.

Pharmaceutical compositions of the compounds of formula (I) may be in the form of sterile injectable aqueous or oleaginous suspensions, for example sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to the methods known in the art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol or as a lyophilized powder. Acceptable vehicles and solvents that may be used include water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time release formulation intended for oral administration to humans may contain from about 1 to 1000mg of active substance and a suitable and convenient amount of carrier material which may comprise from about 5 to about 95% by weight of the total composition. Pharmaceutical compositions can be prepared to provide an easily measurable amount of the drug to be administered. For example, aqueous solutions intended for intravenous infusion may contain from about 3 to 500 μ g of active ingredient per mL of solution, thereby enabling an appropriate volume of infusion at a rate of about 30 mL/hr.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in the above formulations at a concentration of about 0.5 to 20% w/w, for example about 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base (usually sucrose and acacia or tragacanth); lozenges comprising the active ingredient in an inert base (e.g. gelatin and glycerol or sucrose and acacia); and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration have a particle size of, for example, 0.1 to 500 microns (including particle sizes between 0.1 and 500 microns and in increments of, for example, 0.5, 1, 30, 35 microns, etc.), which are administered as follows: rapid inhalation is through the nasal passages or inhalation is through the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents, for example, compounds heretofore used for the treatment or prevention of the conditions described below.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules or vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind described above. Preferred unit dosage formulations are those containing the active ingredient in a daily dose or unit daily sub-dose, or suitable fraction thereof, as herein described.

The present application also provides veterinary compositions, which thus contain at least one active ingredient as described above and a veterinary carrier. Veterinary carriers are substances which are useful for the purpose of administering the composition and may be solid, liquid or gaseous substances which are inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

Combination therapy

The compounds of formula (I) may be used alone or in combination with other therapeutic agents for the treatment of diseases or disorders described herein, such as inflammatory or hyperproliferative disorders (e.g., cancer). In some embodiments, the compound of formula (I) is combined in a pharmaceutical combination formulation or dosage regimen as a combination therapy with a second therapeutic compound that has anti-inflammatory or anti-hyperproliferative properties or that is useful for treating inflammation, immune response disorders, or hyperproliferative disorders (e.g., cancer). The second therapeutic agent may be an NSAID anti-inflammatory agent. The second therapeutic agent can be a chemotherapeutic agent. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of formula (I) such that they do not adversely affect each other. The above compounds are suitably present in combination in amounts effective for the intended purpose. In one embodiment, the compositions of the present application comprise a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt or prodrug thereof, in combination with a therapeutic agent, e.g., an NSAID.

The combination therapy may be administered on a simultaneous or sequential schedule. When administered sequentially, the combination may be administered in two or more administrations. Combined administration includes co-administration and sequential administration in any order using separate formulations or a single pharmaceutical formulation, wherein it is preferred that there is a period of time during which both (or all) active agents exert their biological activities simultaneously.

Suitable dosages for any of the above co-administered drugs are those currently used and may be reduced due to the combined effect (synergy) of the newly identified drug and other therapeutic agent or treatment.

Combination therapy may provide a "synergistic effect" and prove to be "synergistic", i.e. the effect achieved when the active ingredients are used together is greater than the sum of the effects achieved with the compounds separately. When the active ingredients are: (1) co-formulated in a combined unit dose formulation and administered or delivered simultaneously; (2) delivered alternately or in parallel in separate formulations; or (3) when administered by some other regimen, a synergistic effect may be achieved. When delivered in alternation therapy, synergy can be achieved when the compounds are administered or delivered sequentially, e.g., by separate injections in different syringes, separate pills or capsules, or separate infusions. Typically, during alternation therapy, an effective dose of each active ingredient is administered sequentially, whereas in combination therapy, an effective dose of two or more active ingredients are administered together.

In a specific embodiment of therapy, the compounds of formula (I) or stereoisomers, tautomers, or pharmaceutically acceptable salts or prodrugs thereof, may be combined with other therapeutic agents, hormonal agents, or antibody agents, such as those described herein, as well as with surgical therapy and radiation therapy. The present combination therapies thus comprise administering at least one compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or prodrug thereof and methods of treatment using at least one other cancer. The amounts of the compound of formula (I) and the other pharmaceutically active chemotherapeutic agent and the associated timing of administration will be selected to achieve the desired combined therapeutic effect.

Metabolites of compounds of formula (I)

The in vivo metabolites of formula (I) as described herein also fall within the scope of the present application. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present application includes metabolites of the compounds of formula (I), including compounds produced by a method comprising contacting a compound of the present application with a mammal for a period of time sufficient to produce a metabolite thereof.

Metabolites are typically identified as follows: preparation of a Compound of the application radiolabeled (e.g.¹⁴C or³H) Isotopes, which are administered parenterally to animals such as rats, mice, guinea pigs, monkeys, or to humans in detectable doses (e.g., greater than about 0.5mg/kg), allowed a time sufficient for metabolism to occur (typically about 30 seconds to 30 hours) and their conversion products isolated from urine, blood, or other biological samples. These products are easy to isolate because they are labeled (others are isolated by using antibodies that are capable of binding to epitopes that survive in the metabolite). The metabolite structure is determined in a conventional manner, for example by MS, LC/MS or NMR analysis. Typically, the metabolites are analyzed for conventional drug metabolism known to those skilled in the artThe study was performed in the same manner. The metabolites may be used in diagnostic assays for therapeutic dosages of the compounds of the present application, provided that they are not otherwise present in the body.

Article of manufacture

Another embodiment of the present application provides articles of manufacture and "kits" containing materials useful for treating the above-described diseases and conditions. In one embodiment, the kit comprises a container containing a compound of formula (I). The kit may further comprise a label or package insert on or associated with the container. The term "package insert" is used to refer to instructions typically contained in commercial packages of therapeutic products that contain information regarding the indications, usage, dosage, administration, contraindications and/or precautions involved in using the above-described therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container may be formed from a variety of materials, such as glass or plastic. The container may contain a compound of formula (I) or a formulation thereof effective in treating the condition and may have a sterile interface (e.g. the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound of formula (I). The label or package insert indicates that the composition is used to treat the selected condition, e.g., cancer. In addition, the label or package insert may indicate that the patient to be treated is a patient suffering from a condition such as a hyperproliferative condition, neurodegeneration, cardiac hypertrophy, pain, migraine or a neurotrauma disease or event. In one embodiment, the label or package insert indicates that compositions comprising a compound of formula (I) are useful for treating conditions resulting from abnormal cell growth. The label or package insert may also indicate that the composition can be used to treat other conditions. Alternatively or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution, and dextrose solution. The kit may also contain other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.

The kit may also contain instructions for administering the compound of formula (I) and the second pharmaceutical formulation, if present. For example, if the kit comprises a first composition comprising a compound of formula (I) and a second pharmaceutical formulation, the kit may further comprise instructions for administering the first and second pharmaceutical compositions simultaneously, sequentially or separately to a patient in need thereof.

In another embodiment, the kit is suitable for delivering a solid oral form of the compound of formula (I) such as a tablet or capsule. The kit preferably comprises a plurality of unit doses. The kit may comprise a card having the dosages arranged in the order of their intended use. An example of such a kit is a "blister pack". Blister packs are known in the packaging industry and are widely used for packaging pharmaceutical unit dose forms. Memory aids, for example in the form of numbers, letters or other indicia or with calendar instructions indicating those days on which dosing may be performed in the treatment schedule, may be provided as desired.

According to one embodiment, a kit may comprise (a) a first container having a compound of formula (I) therein; and optionally (b) a second container having a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a second compound having anti-hyperproliferative activity. Alternatively or additionally, the kit may further comprise a third container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution, and dextrose solution. It may also contain other substances desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.

In certain other embodiments where the kit comprises a composition of formula (I) and a second therapeutic agent, the kit may comprise containers for holding separate compositions, such as separate bottles or separate foil packets, although separate compositions may also be contained in a single, undivided container. Typically, the kit contains instructions for administering the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g. oral and parenteral) or at different dosage intervals or when the attending physician requires titration of the individual components combined.

Biological evaluation

Within the scope of the present application, the inventors have identified LDHA inhibitors.

The relative potency of the compounds of formula (I) as inhibitors of enzymatic activity (or other biological activity) can be demonstrated as follows: the concentration at which each compound inhibits the activity to a predetermined degree is determined, and the results are compared. Typically, the preferred determination is the concentration that inhibits 50% of activity in a biochemical assay, i.e., the 50% inhibitory concentration or "IC₅₀”。IC₅₀Values may be determined using conventional techniques known in the art. In general, ICs₅₀Can be determined as follows: the activity of a given enzyme is measured in the presence of a range of concentrations of the inhibitor under investigation. The experimentally obtained enzyme activity values were then plotted against the inhibitor concentration used. The concentration of inhibitor showing 50% enzyme activity (compared to the activity in the absence of any inhibitor) was taken as IC₅₀The value is obtained. Similarly, other inhibitory concentrations may be defined by appropriate activity determinations. For example, in some cases, it is desirable to determine the 90% inhibitory concentration, i.e., IC₉₀And the like.

Thus, a "selective LDHA inhibitor" is understood to mean a compound that exhibits a 50% Inhibitory Concentration (IC) against LDHA₅₀) At most IC for any or all other LDHA family members₅₀One tenth of the value.

The activity of the compounds of formula (I) on LDHA kinase activity can be determined by a variety of direct and indirect detection methods. LDHA-inhibiting IC₅₀Values range from less than 1nM (nanomolar) to about 10. mu.M (micromolar). LDHA inhibitory IC of certain exemplary Compounds of the present application₅₀Values were less than 10 nM. Certain compounds of formula (I) may have antiproliferative properties and may be useful in the treatment of disorders such as cancer. The compounds of formula (I) inhibit LDHA in mammals and are useful for treating human cancer patients.

The examples section herein shows compounds of formula (I) prepared, characterized, and tested for LDHA inhibition and selectivity according to the methods of the present application and having the corresponding structures and names (ChemBioDraw Ultra, Version 11.0, Cambridge softcorp.

Preparation of Compounds of formula (I)

Compounds of formula (I) can be synthesized by synthetic routes including methods analogous to those known in the chemical arts and particularly referring to the specification of the application and to those used for other heterocycles, see: comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier,1997, e.g., Vol.3; liebigs Annalen der Chemie, (9):1910-16, (1985); helvetica Chimica Acta,41:1052-60, (1958); Arzneimittel-Forschung,40(12):1328-31, (1990), each of which is expressly incorporated by reference. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using methods known to those skilled in the art (e.g., by the methods outlined in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-23, Wiley, N.Y. (1967. d. 2006.) or Beilsteins Handbuch der organischen Chemie,4, autofl. ed. Springer-Verlag, Berlin (including supplements) (also available from the Beilstein online database)).

Synthetic chemical transformations and protecting group methodologies (protection and deprotection) and necessary reagents and intermediates useful in the synthesis of compounds of formula (I) are known in the art and are described, for example, in r.larock, Comprehensive organic transformations, VCH Publishers (1989); T.W.Greene and P.G.M.Wuts, protective groups in Organic Synthesis,3^rdEd, John Wiley and Sons (1999); and L.Patquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and its successors.

The compounds of formula (I) may be prepared individually or in the form of compound libraries comprising at least 2, for example 5 to 1,000 or 10 to 100 compounds. Libraries of compounds of formula (I) can be prepared by procedures known to those skilled in the art by combined "split and mix" measures or by multiple parallel syntheses using solution phase or solid phase chemistry. Accordingly, another aspect of the present application provides a library of compounds comprising at least 2 compounds or pharmaceutically acceptable salts thereof.

When preparing compounds of formula (I), it may be desirable to protect remote functional groups (e.g., primary or secondary amines) of the intermediates. The need for such protection will vary with the nature of the remote functional group and the conditions of the preparation process. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting Groups and their use see t.w. greene, Protective Groups in Organic Synthesis, john wiley & Sons, New York, 1991.

For purposes of illustration, the following scheme shows a general method for preparing the compounds of formula (I) and key intermediates of the present application. See the examples section for a more detailed description of the individual reaction steps. One skilled in the art will recognize that other synthetic routes may be used to synthesize the claimed compounds. Although specific starting materials and reagents are described and discussed in the general procedures, examples and schemes, other starting materials and reagents can be readily substituted to provide a variety of derivatives and/or reaction conditions. In addition, the various exemplary compounds prepared by the methods described can be further modified based on the present disclosure using conventional chemical methods known to those skilled in the art.

Examples

The present application will be more fully understood by reference to the following examples. However, it should not be construed as limiting the scope of the application.

The chemical reactions described in the examples can be readily adapted to prepare a variety of other LDHA inhibitors of the present application and alternative methods of preparing the compounds of the present application are considered to be within the scope of the present application. For example, the synthesis of non-exemplified compounds herein can be successfully carried out by modifications apparent to those skilled in the art, e.g., by appropriate protection of reactive functional groups, by use of other suitable reagents known to those skilled in the art in addition to those described herein, and/or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability to the preparation of other compounds herein.

¹H NMR spectra were recorded at ambient temperature using an NMR spectrometer, including a varian unity Inova (400MHz) spectrometer with a triple resonance 5mm probe. Chemical shifts are expressed in ppm relative to tetramethylsilane. The following abbreviations are used: br is broad singlet, s is singlet, d is doublet, dd is doublet, t is triplet, q is quartet, and m is multiplet.

High pressure liquid chromatography/mass spectrometry (LCMS) experiments can be performed to determine retention time (R)_T) And the associated mass ions. The spectrometer may have an electrospray source operating in both the cation and anion modes. An evaporative light scattering detector was used for additional detection.

All reactions were carried out under an inert, i.e., argon or nitrogen, atmosphere unless otherwise indicated.

Abbreviations

AcOH: acetic acid; BOC: di-tert-butyl dicarbonate; DCM: dichloromethane; DIPEA: diisopropylethylamine; DMAP: 4-dimethylaminopyridine; EtOAc: ethyl acetate; HATU: 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate; HCl: hydrochloric acid; MeOH: methanol; NaBH₄: sodium borohydride; NBS: n-bromosuccinimide; NH (NH)₄Cl: ammonium chloride; NMR: nuclear magnetic resonance; pd (dppf) Cl₂: [1, 1' -bis (diphenylphosphino) ferrocene]A complex of palladium (II) dichloride and dichloromethane; RT: room temperature; TFA: trifluoroacetic acid; THF: tetrahydrofuran.

Example 1

6- (6-bromopyridin-2-yl) -3- (2-chlorophenyl) sulfanyl-6- (thien-3-yl) piperidine-2, 4-dione

Scheme 1

Step A: n, O-dimethylhydroxylamine hydrochloride (39g,0.40mol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b ] pyridin-3-yloxy) -methylammonium hexafluorophosphate (152g,0.40mol) and N, N-diisopropylethylamine (130.3g,1.01mol) were added to a solution of 6-bromopyridine-2-carboxylic acid (68g,0.34mol) in DCM (1L). The mixture was stirred at ambient temperature for 3 hours. The reaction mixture was washed with 1N HCl (600mL × 2), dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by silica gel chromatography (eluting with a gradient of 10% to 30% EtOAc/hexanes) to give 6-bromo-N-methoxy-N-methylpyridine-2-carboxamide (80g,0.33mol, 97% yield) as a light colored oil.

And B: n-BuLi (158mL,0.4mol) was slowly added to a solution of 3-bromothiophene (65.2g,0.4mol) in isopropyl ether (1L) at-78 ℃. After stirring at-78 ℃ for 30min, the reaction mixture was then slowly treated with 6-bromo-N-methoxy-N-methylpyridine-2-carboxamide (80g,0.33mol) and stirred at-78 ℃ for 3 h. The reaction mixture was washed with saturated NH₄The mixture was diluted with EtOAc (400mL), washed with water (500mL × 2), dried over anhydrous sodium sulfate and concentrated the crude residue was purified by silica gel chromatography eluting with a 0% -10% EtOAc/hexanes gradient to give (6-bromopyridin-2-yl) (thiophen-3-yl) methanone (75g,0.28mol, 86% yield) as a yellow solid.

And C: reacting (6-bromopyridin-2-yl) (thiophen-3-yl) methanone (75g,0.28mol) with Ti (OEt)₄(191.5g,0.84mol) was added to a solution of 2-methylpropane-2-sulfinamide (67.8g,0.56mol) in THF (1L). The mixture was heated at 70 ℃ for 16 hours. Mixing the suspensionThe mixture was poured into ice water, filtered, washed with EtOAc the filtrate was extracted with EtOAc (500mL × 2), dried over anhydrous sodium sulfate and concentrated the crude material was chromatographed on silica gel (eluting with a 10% to 30% EtOAc/hexanes gradient) to give N- ((6-bromopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide (80g,215.6mmol, 77% yield) as an orange oil.

Step D: methyl 3-oxobutyrate (50.0g,431.2mmol) was added to a suspension of NaH (10.35g,431.2mmol) in THF (1L) at 0 deg.C. The reaction mixture was then slowly treated with N-BuLi (172mL,431.2mmol) and stirred at 0 ℃ for 30 minutes, N- ((6-bromopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide (80g,215.6mmol) was added to the mixture and stirred at 0 ℃ for an additional 2 hours. The reaction mixture was washed with saturated NH₄The mixture was diluted with EtOAc (400mL), washed with water (500mL × 2), dried over anhydrous sodium sulfate and concentrated to give methyl 5- (6-bromopyridin-2-yl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoate (95g,194.9mol, 90% yield) as a yellow oil.

Step E: HCl/MeOH (150mL) was added slowly to a solution of methyl 5- (6-bromopyridin-2-yl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoate (95g,194.9mol) in MeOH (1L) at 0 ℃. The mixture was stirred at ambient temperature for 1 hour and then slowly basified to pH 7 at 0 ℃ using 2N NaOH. The solvent was removed in vacuo. The crude product was extracted with EtOAc (800mL × 2), dried over anhydrous sodium sulfate and concentrated to give methyl 5-amino-5- (6-bromopyridin-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoate (62g,161.9mmol, 83% yield) as a dark oil.

Step F: potassium carbonate (67.1g,485.7mmol) was added to a solution of methyl 5-amino-5- (6-bromopyridin-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoate (62g,161.9mmol) in MeOH (800 mL). The mixture was heated at 80 ℃ for 2 hours. The suspension was cooled to ambient temperature. The solvent was removed in vacuo and the crude product was dissolved in water (1L) and washed with EtOAc (1L × 2). The aqueous layer was acidified to pH 4 using 3N HCl. The mixture was extracted with EtOAc (800 mL. times.2). The organic layer was dried over anhydrous sodium sulfate and concentrated to give 6 '-bromo-4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridin ] -6(1H) -one (31g,88.3mmol, 55% yield) as a yellow solid.

Step G: potassium carbonate (36.6g,264.9mmol) and 1, 2-bis (2-chlorophenyl) disulfane (15.2g,53.0mmol) were added to a solution of 6 '-bromo-4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridin ] -6(1H) -one (31g,88.3mmol) in MeOH (800 mL). The mixture was heated at 80 ℃ for 2 hours. The suspension was cooled to ambient temperature. The solvent was removed in vacuo and the crude product was dissolved in water (800mL) and washed with EtOAc (800 mL. times.2). The aqueous layer was acidified to pH 4 using 3N HCl. The mixture was extracted with EtOAc (800 mL. times.2). The organic layer was dried over anhydrous sodium sulfate and concentrated to give 6 '-bromo-5- (2-chloro-phenylsulfanyl) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridin ] -6(1H) -one (38g,76.9mmol, 87% yield) as a light colored solid.

Example 2

3- (2-chlorophenyl) sulfanyl-6- (6-isopropoxypyridin-2-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione

Step A: NaH (73mg,3.04mmol) was added to a solution of propan-2-ol (182mg,3.04mmol) in THF (10mL) at 0 deg.C. After stirring for 30 minutes, 6 '-bromo-5- (2-chloro-phenylsulfanyl) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine at 0 ℃]-6(1H) -one (300mg,0.61mmol) was added to the mixture, and the mixture was refluxed for 12 hours. The suspension was cooled to 0 ℃, quenched with water (10mL), diluted with EtOAc (20mL), acidified to pH 7 with 1N HCl, washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by preparative HPLC (formic acid) to give 3- ((2-chlorophenyl) thio) -6- (6-isopropoxy-pyridin-2-yl) -6- (thiophen-3-yl) piperidine-2, 4-diKetone (112mg,0.24mmol, 39% yield) as a white solid. Mixture of diastereomers:¹H NMR(400MHz,CD₃OD)7.68(dd, J ═ 8.4,3.6Hz,1H),7.43(dd, J ═ 5.2,2.8Hz,1H),7.26 to 7.11(m,4H),6.92(dd, J ═ 8.0,8.0Hz,1H),6.76 to 6.67(m,2H),5.97(dd, J ═ 8.0,1.2Hz,1H),5.39 to 5.32(m,1H),3.88(d, J ═ 16.4Hz,1H),3.45(d, J ═ 16.4Hz,1H),1.31(d, J ═ 6.4Hz,3H),1.26(d, J ═ 6.4Hz, 3H). LCMSM +1 ═ 472.8. Stereoisomer 1:¹H NMR(400MHz,CD₃OD)7.68(dd, J ═ 8.4,3.6Hz,1H),7.43(dd, J ═ 5.2,2.8Hz,1H),7.26 to 7.11(m,4H),6.92(dd, J ═ 8.0,8.0Hz,1H),6.76 to 6.67(m,2H),5.97(dd, J ═ 8.0,1.2Hz,1H),5.39 to 5.32(m,1H),3.89(d, J ═ 16.4Hz,1H),3.45(d, J ═ 16.4Hz,1H),1.31(d, J ═ 6.4Hz,3H),1.26(d, J ═ 6.4Hz, 3H). LCMSM +1 ═ 472.8. Stereoisomer 2:¹H NMR(400MHz,CD₃OD)7.68(dd,J＝8.4,3.6Hz,1H),7.43(dd,J＝5.2,2.8Hz,1H),7.26-7.11(m,4H),6.92(dd,J＝8.0,8.0Hz,1H),6.76-6.67(m,2H),5.97(dd,J＝8.0,1.2Hz,1H),5.39-5.32(m,1H),3.89(d,J＝16.4Hz,1H),3.45(d,J＝16.4Hz,1H),1.31(d,J＝6.4Hz,3H),1.26(d,J＝6.4Hz,3H)。LCMS M+1＝472.9。

example 3

6- [6- (2-chloro-4-fluoro-phenoxy) pyridin-2-yl ] -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione

Step A: mixing 6 '-bromo-5- (2-chloro-phenylsulfanyl) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro-1H- [2, 2']Bipyridin-6-one (500mg,1mmol), 2-chloro-4-fluoro-phenol (178mg,1.2mmol), 2- (dimethylamino) acetate (28mg,0.2mmol), CuI (39mg,0.2mmol), and Cs₂CO₃(0.99g,3mmol) were mixed. Dioxane (5ml) was added and the mixture was stirred at 120 ℃ under a nitrogen atmosphere for 3 h. After cooling the suspension to ambient temperature, EtOAc (20mL) was added and the mixture was filtered through celite. Subjecting the obtained solution toWashed three times with brine, dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure. The crude residue was purified by preparative HPLC (formic acid) to give the product (mixture of diastereomers, 230mg, 41%, delivery 10mg) as a white solid. The mixture of diastereomers (220mg) was purified (neutral) by SFC to give the isomers (80mg of stereoisomer 1 and 128mg of stereoisomer 2) as a white solid. Mixture of diastereomers:¹H NMR(400MHz,(CD₃)₂SO)7.93(dd, J ═ 8.0,8.0Hz,1H),7.60 to 7.53(m,1H),7.44(dd, J ═ 4.8,2.1Hz,1H),7.37(d, J ═ 7.6Hz,1H),7.30 to 7.23(m,3H),7.18(dd, J ═ 2.8,1.2Hz,1H),7.04(d, J ═ 8.4Hz,1H),6.98 to 6.93(m,1H),6.91(dd, J ═ 4.2,1.2Hz,1H),6.78 to 6.74(m,1H),5.88(dd, J ═ 7.6,1.2Hz,1H),3.37(d, J ═ 16.4, 1H), 3.13.13H, 13H, 1H). LCMS M +1 ═ 558.7. Stereoisomer 1:¹H NMR(400MHz,CD₃OD)7.88(dd, J ═ 8.0,8.0Hz,1H),7.36(dd, J ═ 3.9,2.4Hz,1H),7.35-7.32(m,2H),7.22(dd, J ═ 8.0,1.2Hz,1H),7.19-7.09(m,3H),7.07(d, J ═ 8.2Hz,1H),6.96(dd, J ═ 3.9,0.9Hz,1H),6.94(dd, J ═ 8.0,1.2Hz,1H),6.81-6.74(m,1H),5.88(dd, J ═ 8.4,1.2Hz,1H),3.48(d, J ═ 16.4, 1H),3.20(d, 1H), 16.4, 1H). LCMS M +1 ═ 558.7. Stereoisomer 2:¹H NMR(400MHz,CD₃OD)7.89(dd,J＝8.0,8.0Hz,1H),7.36(dd,J＝3.9,2.4Hz,1H),7.35-7.32(m,2H),7.22(dd,J＝8.0,1.2Hz,1H),7.19-7.09(m,3H),7.07(d,J＝8.2Hz,1H),6.96(dd,J＝3.9,0.9Hz,1H),6.94(dd,J＝8.0,1.2Hz,1H),6.81-6.74(m,1H),5.97(dd,J＝8.4,1.2Hz,1H),3.48(d,J＝16.4Hz,1H),3.20(d,J＝16.4Hz,1H)。LCMS M+1＝558.8。

example 4

3- (2-chlorophenyl) sulfanyl-6- [6- (cyclohexylamino) pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: reacting 6- (6-bromopyridin-2-yl) -3- ((2-chloro)Phenyl) thio) -6- (thien-3-yl) -piperidine-2, 4-dione (300mg, 607.5. mu. mol), cyclohexylamine (90.4mg, 911.3. mu. mol), Brettphos (65.2mg, 121.5. mu. mol), Pd₂(dba)₃(55.6mg, 60.8. mu. mol) and NaOtBu (116.8mg,1.2mmol) were mixed and dioxane (5ml) was added. The mixture was stirred at 120 ℃ for 8 hours under a nitrogen atmosphere. After cooling the suspension to room temperature, ethyl acetate (15mL) was added and the mixture was filtered through celite. The resulting solution was washed three times with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (formic acid) to give the expected product (mixture of diastereomers, 75.4mg, 24%, delivery 7.4mg) as a yellow solid. The mixture of diastereomers (68.0mg) was purified (neutral) by SFC to give the expected product (10mg of stereoisomer 1 and 5.8mg of stereoisomer 2) as a yellow solid. Mixture of diastereomers:¹HNMR(400MHz,CD₃OD)7.88(dd, J ═ 7.6,7.6Hz,1H),7.69(d, J ═ 2.8Hz,1H),7.63(d, J ═ 2.8Hz,1H),7.28-7.26(m,2H),7.19(d, J ═ 7.6Hz,1H),7.10(d, J ═ 7.4Hz,1H),6.85(d, J ═ 7.6Hz,1H),6.47(d, J ═ 7.2Hz,1H),6.03(d, J ═ 8.0Hz,1H),3.70-3.66(m,1H),3.88-3.67(m,5H),3.59(d, J ═ 16.0Hz,2H),1.93-1.91(m, 1.70H), 1.70-1H, 1.73(m, 1H), 1.4-1H, 1(m, 22H). LCMS M +1 ═ 511.9. Stereoisomer 1:¹H NMR(400MHz,CD₃OD)7.40(dd, J ═ 7.6,7.6Hz,1H),7.28(d, J ═ 2.8Hz,1H),7.18(d, J ═ 2.8Hz,1H),7.15(d, J ═ 2.8Hz,1H),6.91(d, J ═ 7.6Hz,1H),6.77(d, J ═ 7.4Hz,1H),6.64(d, J ═ 7.6Hz,1H),6.40(d, J ═ 7.2Hz,1H),6.06(d, J ═ 8.0Hz,1H),3.81-3.77(m,1H),3.76(d, J ═ 16.0Hz,1H),3.41(d, J ═ 16.0, 1H), 2.01-1H, 1.95(m, 1H), 1.73-1H, 1H), 1.73 (d, J ═ 16.0Hz,1H), 1.1H, 1H, 1.73 (d, 1H), 1.73-1H), 1H, 1. LCMS M +1 ═ 511.8. Stereoisomer 2:¹H NMR(400MHz,CD₃OD)7.40(dd,J＝7.6,7.6Hz,1H),7.28(d,J＝2.8Hz,1H),7.18(d,J＝2.8Hz,1H),7.15(d,J＝2.8Hz,1H),6.91(d,J＝7.6Hz,1H),6.77(d,J＝7.4Hz,1H),6.62(d,J＝7.6Hz,1H),6.40(d,J＝7.2Hz,1H),6.06(d,J＝8.0Hz,1H),3.80-3.78(m,1H),3.76(d,J＝16.0Hz,1H),3.42(d,J＝16.0Hz,1H),2.01-1.95(m,2H),1.74-1.71(m,2H),1.62-1.40(m,2H),1.27-1.17(m,4H)。LCMS M+1＝511.9。

example 5

3- (2-chlorophenyl) sulfanyl-6- [6- [ (3-fluorophenyl) methyl ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: 1, 2-dibromoethane (100mg,0.53mmol) and 1- (bromomethyl) -3-fluorobenzene (1g,5.3mmol) were added to a suspension of zinc powder (345mg,5.3mmol) in anhydrous THF (10 mL). The reaction mixture was stirred at room temperature for 8 hours. The resulting solution was used directly in the next step.

And B: (3-Fluorobenzyl) Zinc (II) bromide (5.7mL,3.04mmol) was added to Pd (PPh)₃)₄(69mg,0.06mmol) and 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one (300mg,0.61mmol) in dry THF (5 mL). The suspension was stirred at room temperature for 12 hours, then quenched with water and filtered through celite. The resulting solution was dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by preparative HPLC (formic acid) to give 3- (2-chlorophenyl) sulfanyl-6- [6- [ (3-fluorophenyl) methyl group]Pyridin-2-yl]-6- (thiophen-3-yl) piperidine-2, 4-dione (61mg,0.12mmol, 20% yield) as a white solid. The mixture of diastereomers was purified (neutral) by SFC to give the isolated stereoisomers. Mixture of diastereomers:¹H NMR(400MHz,CD₃OD)7.75(dd, J ═ 8.0,8.0Hz,1H),7.41 to 7.39(m,2H),7.22 to 7.17(m,4H),7.10 to 7.09(m,2H),7.08(d, J ═ 8.0Hz,1H),6.87 to 6.86(m,2H),6.55(dd, J ═ 8.0,0.8Hz,1H),5.82(dd, J ═ 8.0,1.6Hz,1H),4.17(s,2H),3.97(d, J ═ 16.8Hz,1H),3.47(d, J ═ 16.4Hz, 1H). LCMS M +1 ═ 522.9. Stereoisomer 1:¹H NMR(400MHz,CD₃OD)7.74(dd,J＝8.0,8.0Hz,1H),7.43-7.41(m,2H),7.24-7.17(m,4H),7.15-7.09(m,2H),7.07(d, J ═ 8.0Hz,1H),6.84-6.82(m,2H),6.55(dd, J ═ 8.0,0.8Hz,1H),5.87(d, J ═ 8.4Hz,1H),4.16(s,2H),3.85(d, J ═ 16.0Hz,1H),3.45(d, J ═ 16.4Hz, 1H). LCMS M +1 ═ 522.9. Stereoisomer 2:¹H NMR(400MHz,CD₃OD)7.73(dd,J＝8.0,8.0Hz,1H),7.42-7.36(m,2H),7.24-7.21(m,4H),7.09-7.08(m,2H),7.07(d,J＝8.0Hz,1H),6.84-6.82(m,2H),6.57(dd,J＝8.0,0.8Hz,1H),5.90(dd,J＝8.0,1.6Hz,1H),4.16(s,2H),3.78(d,J＝16.0Hz,1H),3.44(d,J＝16.4Hz,1H)。LCMS M+1＝522.9。

example 6

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorobenzoyl) pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: reacting 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one (300mg,0.61mmol) and (4-fluorophenyl) boronic acid (94mg,0.67mmol) were added to K₂CO₃(253mg,0.83mmol) and PdCl₂(PPh₃)₂(21mg,0.02mmol) in THF (6 mL). The mixture was heated at 100 ℃ for 20 hours under a carbon monoxide atmosphere (0.5 MPa). After cooling to room temperature, the reaction mixture was filtered through celite. The resulting solution was dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by preparative HPLC (formic acid) to give 3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorobenzoyl) pyridin-2-yl]-6- (thiophen-3-yl) piperidine-2, 4-dione (78mg,0.15mmol, 24% yield) as a white solid. The mixture of diastereomers was purified (neutral) by SFC to give the isolated stereoisomers. Mixture of diastereomers:¹H NMR(400MHz,CD₃OD)7.68(dd, J ═ 8.4,3.6Hz,1H),7.43(dd, J ═ 5.2,2.8Hz,1H),7.26 to 7.11(m,4H),6.92(dd, J ═ 8.0,8.0Hz,1H),6.76 to 6.67(m,2H),5.97(dd, J ═ 8.0,1.2Hz,1H),5.39 to 5.32(m,1H),3.88(d, J ═ 16.4Hz,1H),3.45(d, J ═ 16.4Hz,1H),1.31(d, J ═ 6.4Hz,3H),1.26(d, J ═ 6.4Hz, 3H). LCMS M +1 ═ 472.8. Stereoisomer 1:¹H NMR(400MHz,CD₃OD)7.68(dd, J ═ 8.4,3.6Hz,1H),7.43(dd, J ═ 5.2,2.8Hz,1H),7.26 to 7.11(m,4H),6.92(dd, J ═ 8.0,8.0Hz,1H),6.76 to 6.67(m,2H),5.97(dd, J ═ 8.0,1.2Hz,1H),5.39 to 5.32(m,1H),3.89(d, J ═ 16.4Hz,1H),3.45(d, J ═ 16.4Hz,1H),1.31(d, J ═ 6.4Hz,3H),1.26(d, J ═ 6.4Hz, 3H). Stereoisomer 2:¹H NMR(400MHz,CD₃OD)7.68(dd,J＝8.4,3.6Hz,1H),7.43(dd,J＝5.2,2.8Hz,1H),7.26-7.11(m,4H),6.92(dd,J＝8.0,8.0Hz,1H),6.76-6.67(m,2H),5.97(dd,J＝8.0,1.2Hz,1H),5.39-5.32(m,1H),3.89(d,J＝16.4Hz,1H),3.45(d,J＝16.4Hz,1H),1.31(d,J＝6.4Hz,3H),1.26(d,J＝6.4Hz,3H)。

example 7

3- (2-chlorophenyl) sulfanyl-6- [4- (2-methylmorpholin-4-yl) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione

Scheme 2

Step A: to a solution of 3-bromothiophene (14.43g,220.74mmol) in anhydrous isopropyl ether (500mL) was added n-BuLi (88.2mL,220.74mmol) at-78 deg.C under a nitrogen atmosphere. The reaction mixture was stirred for 1 hour. 4-bromobenzaldehyde (100g,183.95mmol) was added and the reaction mixture was stirred at-78 ℃ for 2 hours. The reaction mixture was quenched with MeOH and acidified to pH 4 with 1N HCl and extracted with DCM (100mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by silica gel chromatography (petroleum ether: EtOAc ═ 3:1) to give (4-bromophenyl) (thiophen-3-yl) methanol (100g, 69%) as a yellow solid.

And B: to (4-bromophenyl) (thiophen-3-yl) methanol (100g,371.5mmol) in CHCl₃MnO was added to the solution (200ml)₂(322.9g,3715 mmol). The reaction mixture was stirred at 60 ℃ for 12 hours. After cooling to room temperature, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The crude residue (86g, 86% yield) was used in the next step without further purification.

And C: (E) -N- ((4-bromophenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide was prepared according to example 1, step C, in 86% yield replacing (6-bromopyridin-2-yl) (thiophen-3-yl) methanone with (4-bromophenyl) (thiophen-3-yl) methanone.

Step D: prepared according to example 1, step D, methyl 5- (4-bromophenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoate in 85% yield by replacing (Z) -N- ((6-bromopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with (E) -N- ((4-bromophenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide.

Step E: prepared according to example 1, step E, 5-amino-5- (4-bromophenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester in 90% yield by replacing 5-amino-5- (6-bromopyridin-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5- (4-bromophenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.

Step F: 6- (4-bromophenyl) -4-hydroxy-6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one prepared in 75% yield according to example 1, step F, substituting 6 '-bromo-4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one with methyl 5-amino-5- (4-bromophenyl) -3-oxo-5- (thiophen-3-yl) pentanoate.

Step G: prepared according to example 1, step G, 6- (4-bromophenyl) -3- ((2-chlorophenyl) thio) -4-hydroxy-6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one in 90% yield, the 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one was replaced with 6- (4-bromophenyl) -4-hydroxy-6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one.

Step H: to a solution of 6- (4-bromophenyl) -3- ((2-chlorophenyl) thio) -4-hydroxy-6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one (0.25g,0.5mmol) in dioxane (6mL) was added 2-methylmorpholine (500mg,5mmol), Brettphos (25mg,0.05mmol), Pd₂(dba)₃(45mg,0.05mmol) and t-BuONa (0.5g,5 mmol). The reaction mixture was stirred at 110 ℃ under a nitrogen atmosphere for 16 hours. After cooling to room temperature, the reaction mixture was filtered through a short pad of silica gel. The filtrate was concentrated in vacuo. The crude residue was purified by preparative HPLC (formic acid) to give the product (10mg, 3.8% yield) as a white solid.¹H NMR(400MHz,(CD₃)₂SO)8.35(s,1H),7.57(d,J＝5.2Hz,1H),7.32(m,4H),7.16(m,1H),6.98(m,3H),6.73(m,1H),5.92(m,1H),3.93(m,1H),3.64(m,3H),3.58(m,1H),3.37(m,2H),2.69(m,1H),2.34(m,1H),1.15(d,J＝6.4Hz,3H)。LCMS M+1＝512.9。

Example 8

3- (2-chlorophenyl) sulfanyl-6- [4- (cyclohexen-1-yl) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: to a solution of 6- (4-bromophenyl) -3- ((2-chlorophenyl) thio) -6- (thiophen-3-yl) piperidine-2, 4-dione (0.25g,0.5mmol) in dioxane (6mL) and water (2mL) was added cyclohex-1-en-1-ylboronic acid (126mg,1mmol), pd (dppf) Cl₂(36mg,0.05mmol) and K₂CO₃(0.27g,2 mmol). The reaction mixture was subjected to microwave irradiation at 100 ℃ for 1 hour under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered through a short pad of silica gel. Will be provided withThe filtrate was concentrated in vacuo and the crude residue was purified by preparative HPLC (formic acid) to give the product (11.7mg, 5% yield).¹H NMR(400MHz,(CD₃)₂SO)8.47(s,1H),7.56-7.55(m,1H),7.54-7.39(m,2H),7.32-7.20(m,3H),7.27(d,J＝8Hz,1H),7.14(dd,J＝5.2,4.8Hz,1H),6.93(dd,J＝7.6,4.8Hz,1H),6.15(s,1H),5.85(d,J＝8.0Hz,1H),3.39(s,2H),2.47(s,2H),2.33(s,2H),1.71-1.68(m,2H),1.58-1.56(m,2H)。LCMS M+1＝493.9；495.9。

Example 9

3- (2-chlorophenyl) sulfanyl-6- (4-cyclohexylphenyl) -6- (thien-3-yl) piperidine-2, 4-dione

Step A: to a solution of GNT _ C349_986(0.8g,1.6mmol) in acetic acid (20mL) was added Pd/C (0.1 g). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (60Psi) for 24 hours. After the pressure was released, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The crude residue was purified by preparative HPLC (formic acid) to give the product (10mg, 1.2% yield) as a white solid.¹H NMR(400MHz,(CD₃)₂SO)7.49(s,1H),7.35-7.32(m,2H),7.26-7.25(m,4H),7.19(d,J＝8.0Hz,1H),6.93(dd,J＝6.8,6.8Hz,1H),6.72(dd,J＝6.8,6.8Hz,1H),5.98(d,J＝6.8Hz,1H),3.45(s,2H),1.96-1.74(m,5H),1.48-1.27(m,5H)。LCMSM+1＝495.8。

Example 10

3- (2-chlorophenyl) sulfanyl-6- [6- [2- (1-methylcyclopropyl) ethoxy ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: diethyl zinc (40.6mL,40.6mmol) and diiodomethane (9.3g,34.8mmol) were added to a solution of 3-methylbut-3-en-1-ol (1g,11.6mmol) in DCM (80mL) at-10 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour, then at room temperature for another 12 hours. The reaction mixture was washed with saturated NH₄Quenched with Cl, extracted with DCM (50mL × 2), dried over anhydrous sodium sulfate and concentrated to give 2- (1-methylcyclopropyl) ethanol (600mg,6mmol, 52% yield) as a light colored oil.

And B: prepared according to example 2, step a, 5- ((2-chlorophenyl) thio) -4-hydroxy-6 '- (2- (1-methylcyclopropyl) ethoxy) -2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridinyl ] -6(1H) -one in 39% yield replacing propan-2-ol with 2- (1-methylcyclopropyl) ethanol.

Mixture of diastereomers:¹H NMR(400MHz,CD₃OD)7.74(dd, J ═ 8.0,8.0Hz,1H),7.47(dd, J ═ 5.2,3.2Hz,1H),7.30-7.15(m,4H),6.96(dd, J ═ 8.0,8.0Hz,1H),6.77-6.75(m,2H),6.01(dd, J ═ 8.4,1.6Hz,1H),4.49(t, J ═ 7.2Hz,2H),3.93(d, J ═ 16.0Hz,1H),3.48(d, J ═ 16.4Hz,1H),1.70(t, J ═ 6.8Hz,2H),1.09(s,3H),0.34-0.23(m, 4H). Stereoisomer 1:¹H NMR(400MHz,CD₃OD)7.50(dd, J ═ 8.0,8.0Hz,1H),7.48(dd, J ═ 5.2,3.2Hz,1H),7.30-7.22(m,2H),7.06-7.00(m,2H),6.93(dd, J ═ 8.0,8.0Hz,1H),6.54-6.52(m,2H),5.79(dd, J ═ 8.0,1.6Hz,1H),4.26(t, J ═ 6.8Hz,2H),3.70(d, J ═ 16.0Hz,1H),3.25(d, J ═ 16.4Hz,1H),1.46(t, J ═ 6.8Hz,2H),0.86(s,3H),0.11-0.00(m, 4H). Stereoisomer 2:¹H NMR(400MHz,CD₃OD)7.48(dd,J＝8.0,8.0Hz,1H),7.46(dd,J＝5.2,3.2Hz,1H),7.21-7.20(m,2H),7.05-7.03(m,2H),6.93(dd,J＝8.0,8.0Hz,1H),6.53-6.50(m,2H),5.77(dd,J＝8.0,1.6Hz,1H),4.24(t,J＝6.8Hz,2H),3.68(d,J＝16.0Hz,1H),3.23(d,J＝16.4Hz,1H),1.45(t,J＝6.8Hz,2H),0.85(s,3H),0.10-0.01(m,4H)。

examples 11 and 12

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenylamino) pyridin-2-yl ] -1-methyl-6- (thien-3-yl) piperidine-2, 4-dione and 3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenoxy) pyridin-2-yl ] -1-methyl-6- (thien-3-yl) piperidine-2, 4-dione

Step A: to a stirred solution of 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one (1g,2mmol) in anhydrous THF (20mL) at 0 ℃ was added NaH (288mg,12 mmol). The reaction mixture was stirred at the same temperature for 0.5 hour, and then methyl iodide (1.65g,12mmol) was added to the reaction mixture and stirred at room temperature for 12 hours. The reaction mixture was quenched with water, dried and concentrated. The crude residue was purified by silica gel chromatography (eluting with a 10% -50% EtOAc/hexanes gradient) to give 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-1-methyl-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one (475mg,0.94mol, 46% yield) as a yellow solid.

And B: prepared according to example 4, step a, 5- ((2-chlorophenyl) thio) -6 '- ((4-fluorophenyl) amino) -4-hydroxy-1-methyl-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridin ] -6(1H) -one in 8% yield replacing cyclohexylamine with 4-fluoroaniline.

And C: 5- ((2-chlorophenyl) thio) -6 ' - (4-fluorophenoxy) -4-hydroxy-1-methyl-2- (thiophen-3-yl) -2, 3-dihydro- [2,2 ' -bipyridin ] -6(1H) -one was prepared in 4% yield according to example 3, step A, substituting 2-chloro-4-fluoro-phenol with 4-fluorophenol and 6 ' -bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2,2 ' -bipyridin ] -6(1H) -one with 6 ' -bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-1H) -one -1-methyl-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one.

Example 11:¹H NMR(400MHz,CD₃OD)7.59-7.46(m,4H),7.20(dd,J＝8.0,1.2Hz,1H),7.15(dd,J＝5.2,1.6Hz,1H),7.07(dd,J＝2.8,1.6Hz,1H),6.94-6.84(m,4H),6.78(dd,J＝8.4,0.8Hz,1H),6.63(dd,J＝7.6,0.4Hz,1H),6.23(dd,J＝7.0,1.6Hz,1H),3.88(d,J＝16.8Hz,1H),3.56(d,J＝16.8Hz,1H),2.86(s,3H)。LCMS M+1＝537.8。

example 12:¹H NMR(400MHz,CD₃OD)7.88(dd,J＝8.4,7.6Hz,1H),7.49(dd,J＝5.2,2.8Hz,1H),7.23(dd,J＝8.0,1.6Hz,1H),7.09-6.95(m,8H),6.89-6.83(m,2H),6.04(dd,J＝8.0,1.2Hz,1H),3.57-3.46(m,2H),2.65(s,3H)。LCMS M+1＝538.8。

example 13

3- (2-chlorophenyl) sulfanyl-6- (2-fluorophenyl) -1-methyl-6- (thien-3-yl) piperidine-2, 4-dione

Step A: 2-fluoro-N-methoxy-N-methylbenzamide was prepared according to example 1, step a, in 73% yield, substituting 6-bromopyridine-2-carboxylic acid with 2-fluorobenzoic acid.

And B: (2-fluorophenyl) (thiophen-3-yl) methanone prepared according to example 1, step B, in 99% yield, 6-bromo-N-methoxy-N-methylpyridine-2-carboxamide was replaced with 2-fluoro-N-methoxy-N-methylbenzamide.

And C: (Z) -N- ((2-fluorophenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide was prepared according to example 1, step C, in 46% yield, replacing (6-bromopyridin-2-yl) (thiophen-3-yl) methanone with (2-fluorophenyl) (thiophen-3-yl) methanone.

Step D: prepared according to example 1, step D, methyl 5- (1, 1-dimethylethylsulfonamido) -5- (2-fluorophenyl) -3-oxo-5- (thiophen-3-yl) pentanoate in 91% yield by replacing N- ((6-bromopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with (Z) -N- ((2-fluorophenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide.

Step E: prepared according to example 1, step E, with 33% yield of methyl 5-amino-5- (2-fluorophenyl) -3-oxo-5- (thiophen-3-yl) pentanoate, methyl 5- (6-bromopyridin-2-yl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoate was replaced with methyl 5- (1, 1-dimethylethylsulfonamido) -5- (2-fluorophenyl) -3-oxo-5- (thiophen-3-yl) pentanoate.

Step F: 6- (2-fluorophenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione was prepared according to example 1, step F, in 89% yield, replacing 5-amino-5- (6-bromopyridin-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5-amino-5- (2-fluorophenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.

Step G: 3- ((2-chlorophenyl) thio) -6- (2-fluorophenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione was prepared according to example 1, step G, in 83% yield, replacing 6 '-bromo-4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one with 6- (2-fluorophenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione.

Step H: 3- (2-chlorophenyl) sulfanyl-6- (2-fluorophenyl) -1-methyl-6- (thiophen-3-yl) piperidine-2, 4-dione was prepared in 30% yield according to example 11, step B, from 6 '-bromo-4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one is replaced with 3- ((2-chlorophenyl) thio) -6- (2-fluorophenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione.¹H NMR(400MHz,CD₃OD)7.57(d,J＝4.0Hz,1H),7.50-7.47(m,1H),7.28-7.16(m,5H),6.99-6.85(m,3H),6.26(dd,J＝8.0,4.0Hz,1H),3.76-3.67(m,2H),2.82(s,3H)。LCMSM+1＝445.9。

Example 14

3- (2-chlorophenyl) sulfanyl-6- [5- (4-fluorophenylamino) -2-hydroxy-phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: chloro (methoxy) methane (19.1g,0.23mol) was added to a solution of 5-bromo-2-hydroxybenzaldehyde (30g,0.15mol) and diisopropyl-ethylamine (38.5g,0.30mol) in DCM at 0 ℃. The mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was quenched with water, dried over anhydrous sodium sulfate and concentrated to give 5-bromo-2- (methoxymethoxy) benzaldehyde (30g,0.12mol, 82% yield) as a light colored oil.

And B: (5-bromo-2- (methoxymethoxy) phenyl) (thiophen-3-yl) methanol was prepared according to example 7, step a, in 77% yield replacing 4-bromobenzaldehyde with 5-bromo-2- (methoxymethoxy) benzaldehyde.

And C: prepared according to example 7, step B, in 91% yield, of (5-bromo-2- (methoxymethoxy) phenyl) (thiophen-3-yl) methanone by substituting (4-bromophenyl) (thiophen-3-yl) methanol with (5-bromo-2- (methoxymethoxy) phenyl) (thiophen-3-yl) methanol.

Step D: the reaction solution was prepared by dissolving (5-bromo-2- (methoxymethoxy) phenyl) (thiophen-3-yl) methanone (10g,27.0mmol), 4-fluoroaniline (10g,53.9mmol), Xantphos (3.85g,5.39mmol), Pd₂(dba)₃(3.72g,2.7mmol)、Cs₂CO₃A mixture of (39.5g,80.9mmol) and 1, 4-dioxane (200mL) was stirred at 110 ℃ for 16 h. The reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluting with a gradient of 10% to 50% EtOAc/hexanes) to give (5- ((4-fluorophenyl) amino) -2- (methoxymethoxy) phenyl) (thiophen-3-yl) methanone (14g,39.2mmol, 85% yield) as a yellow solid.

Step E: a mixture of (5- ((4-fluorophenyl) amino) -2- (methoxymethoxy) phenyl) (thiophen-3-yl) methanone (14g,39.2mol), di-tert-butyl dicarbonate (16.9g,78.3mmol), 4-dimethylaminopyridine (2.37g,19.6mmol) and DCM (200mL) was stirred at room temperature for 12 h. The mixture was diluted with DCM (200mL), washed with water (300mL × 2), brine, dried over sodium sulfate and concentrated. The crude material was purified by silica gel chromatography (eluting with a 10% -50% EtOAc/hexanes gradient) to give tert-butyl (4-fluorophenyl) (4- (methoxymethoxy) -3- (thiophene-3-carbonyl) phenyl) carbamate (11.8g,25.8mol, 91% yield) as a yellow solid.

Step F: tert-butyl (Z) - (3- (((tert-butylsulfinyl) imino) (thiophen-3-yl) methyl) -4- (methoxymethoxy) phenyl) (4-fluorophenyl) carbamate was prepared in 56% yield according to example 1, step C, replacing (6-bromopyridin-2-yl) (thiophen-3-yl) methanone with tert-butyl (4-fluorophenyl) (4- (methoxymethoxy) -3- (thiophene-3-carbonyl) phenyl) carbamate.

Step G: prepared according to example 1, step D, methyl 5- (5- ((tert-butoxycarbonyl) (4-fluorophenyl) amino) -2- (methoxymethoxy) phenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoate in 78% yield, replacement of N- ((6-bromopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with tert-butyl (Z) - (3- (((tert-butylsulfinyl) imino) (thiophen-3-yl) methyl) -4- (methoxymethoxy) phenyl) (4-fluorophenyl) carbamate.

Step H: prepared according to example 1, step E, methyl 5-amino-5- (5- ((tert-butoxycarbonyl) (4-fluorophenyl) amino) -2- (methoxymethoxy) phenyl) -3-oxo-5- (thien-3-yl) pentanoate in 86% yield by replacing 5- (6-bromopyridin-2-yl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thien-3-yl) pentanoic acid methyl ester with 5- (5- ((tert-butoxycarbonyl) (4-fluorophenyl) amino) -2- (methoxymethoxy) phenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thien-3-yl) And (3) methyl valerate.

Step I: tert-butyl (3- (4, 6-dioxo-2- (thiophen-3-yl) piperidin-2-yl) -4- (methoxymethoxy) phenyl) (4-fluorophenyl) carbamate prepared according to example 1, step F, in 93% yield, methyl 5-amino-5- (6-bromopyridin-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoate was replaced with methyl 5-amino-5- (5- ((tert-butoxycarbonyl) (4-fluorophenyl) amino) -2- (methoxymethoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoate.

Step J: tert-butyl (3- (5- ((2-chlorophenyl) thio) -4, 6-dioxo-2- (thiophen-3-yl) piperidin-2-yl) -4- (methoxymethoxy) phenyl) (4-fluorophenyl) carbamate prepared in 70% yield according to example 1 step G,6 '-bromo-4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one was replaced with tert-butyl (3- (4, 6-dioxo-2- (thiophen-3-yl) piperidin-2-yl) -4- (methoxymethoxy) phenyl) (4-fluorophenyl) carbamate.

Step K: to a stirred solution of tert-butyl (3- (5- ((2-chlorophenyl) thio) -4, 6-dioxo-2- (thiophen-3-yl) piperidin-2-yl) -4- (methoxymethoxy) phenyl) (4-fluorophenyl) carbamate (600mg,0.88mmol) in methanol (10mL) in ice bath was added HCl-MeOH (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was neutralized by adding 1N NaOH. The mixture was then extracted with EtOAc and water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude material was purified by preparative HPLC (formic acid) to give 3- ((2-chlorophenyl) thio) -6- (5- ((4-fluorophenyl) amino) -2-hydroxyphenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione (150mg,0.28mmol, 32% yield) as a white solid.¹HNMR(400MHz,CD₃OD)7.41(dd,J＝5.2,5.2Hz,1H),7.27-7.26(m,2H),7.13-7.10(m,2H),6.96-6.81(m,8H),6.25(dd,J＝8.0,1.6Hz,1H),4.79-4.73(m,1H),3.79(d,J＝17.2Hz,1H),3.43(d,J＝16.8Hz,1H)。LCMS M+1＝538.8。

Example 15

3- (2-chlorophenyl) sulfanyl-6- (1H-indol-4-yl) -6- (thien-3-yl) piperidine-2, 4-dione

Step A: 1H-indole-4-carbaldehyde (10g,69.0mmol) was added to a suspension of NaH (2.0g,82.6mmol) in anhydrous THF (150mL) at 0 deg.C. The resulting suspension was stirred at 0 ℃ for 30 minutes, followed by the addition of 2- (trimethylsilyl) ethoxymethyl chloride (13.8g,82.6 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water, dried over anhydrous sodium sulfate and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluting with a 10% -30% EtOAc/hexanes gradient) to give 1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indole-4-carbaldehyde (817g,61.4mmol, 89% yield) as a dark yellow solid.

And B: thiophen-3-yl (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-4-yl) methanol was prepared according to example 7, step a in 68% yield replacing 4-bromobenzaldehyde with 1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indole-4-carbaldehyde.

And C: thiophen-3-yl (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-4-yl) methanone was prepared according to example 7, step B, in 94% yield replacing (4-bromophenyl) (thiophen-3-yl) methanol with thiophen-3-yl (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-4-yl) methanol.

Step D: (E) -2-methyl-N- (thien-3-yl (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-4-yl) methylene) propane-2-sulfinamide was prepared according to example 1, step C, in 64% yield replacing (6-bromopyridin-2-yl) (thien-3-yl) methanone with thien-3-yl (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-4-yl) methanone.

Step E: methyl 5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) -5- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-4-yl) pentanoate was prepared according to example 1 step D in 88% yield, (ii) substituting N- ((6-bromopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with (E) -2-methyl-N- (thiophen-3-yl (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-4-yl) methylene) propane-2-sulfinamide.

Step F: 5-amino-3-oxo-5- (thiophen-3-yl) -5- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-4-yl) pentanoic acid methyl ester prepared according to example 1 step E in 65% yield by replacing 5- (6-bromopyridin-2-yl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) -5- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-4-yl) pentanoic acid methyl ester -yl) pentanoic acid methyl ester.

Step G: 6- (thien-3-yl) -6- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-4-yl) piperidine-2, 4-dione was prepared according to example 1, step F, in 43% yield by replacing 5-amino-5- (6-bromopyridin-2-yl) -3-oxo-5- (thien-3-yl) pentanoic acid methyl ester with 5-amino-3-oxo-5- (thien-3-yl) -5- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-4-yl) pentanoic acid methyl ester.

Step H: 3- ((2-chlorophenyl) thio) -6- (thiophen-3-yl) -6- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-4-yl) piperidine-2, 4-dione was prepared according to example 1, step G, in 59% yield, replacing 6 '-bromo-4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one with 6- (thiophen-3-yl) -6- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-4-yl) piperidine-2, 4-diketones.

Step I: to a stirred solution of 3- ((2-chlorophenyl) thio) -6- (thiophen-3-yl) -6- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-4-yl) piperidine-2, 4-dione (250mg,0.43mmol) in THF (4mL) was added TBAF (4mL,1M in THF). The reaction mixture was heated at 80 ℃ for 12 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20mL), washed with water and concentrated in vacuo. The crude material was purified by preparative HPLC (formic acid) to give 3- ((2-chlorophenyl) thio) -6- (1H-indol-4-yl) -6- (thiophen-3-yl) piperidine-2, 4-dione (24mg,0.05mmol, 12% yield), which wasAs a white solid.¹H NMR(400MHz,CD₃OD)7.58(dd,J＝8.0,8.0Hz,1H),7.43-7.41(m,2H),7.27-7.19(m,3H),7.05(dd,J＝8.0,8.0Hz,1H),6.91-6.88(m,1H),6.77-6.75(m,2H),6.53(d,J＝8.4Hz,1H),6.08(dd,J＝8.0,4.0Hz,1H),3.88(d,J＝16.0Hz,1H),3.50(d,J＝16.0Hz,1H)。LCMS M+1＝452.8。

Example 16

3- (2-chlorophenyl) sulfanyl-6- [6- [2- (oxetan-3-yl) ethoxy ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: to a suspension of NaH (688mg,27.8mmol) in THF (80mL) was added diethyl malonate (7.45g,46.5mmol) dropwise. ((2-bromoethoxy) methyl) benzene (5g,23.2mmol) was then added. The reaction mixture was heated to 90 ℃ and held for 5 hours. After cooling to room temperature, the mixture was diluted with EtOAc (50mL), washed with water (50 mL. times.2), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluting with a gradient of 10% to 30% EtOAc/hexanes) to give diethyl 2- (2- (benzyloxy) ethyl) malonate (6.6g,22.5mmol, 81% yield) as a colorless oil.

And B: to LiAlH in an ice bath₄(1.71g,45.0mmol) to a suspension in anhydrous THF (80mL) was added diethyl 2- (2- (benzyloxy) ethyl) malonate (6.6g,22.5mmol) dropwise, the reaction mixture was warmed to room temperature and stirred for 12 h, the reaction mixture was quenched with water, diluted with EtOAc (50mL), washed with water (50mL × 2), dried over anhydrous sodium sulfate and concentrated in vacuo, the crude residue was purified by silica gel chromatography (eluting with a 10% -30% EtOAc/hexanes gradient) to give 2- (2- (benzyloxy) ethyl) propane-1, 3-diol (2.2g,10.6mmol, 47% yield) as a colorless oil.

And C: to a solution of 2- (2- (benzyloxy) ethyl) propane-1, 3-diol (2.2g,10.6mmol) in THF (20mL) was added n-BuLi (4.2mL,10.6mmol) in an ice bath. The mixture was stirred at 0 ℃ for 30min, then TsCl (404mg,2.12mmol) was added. The reaction mixture was stirred at 0 ℃ for 1h, then n-BuLi (4.2mL,10.6mmol) was added. The reaction mixture was stirred at 60 ℃ for 6 hours and then cooled to room temperature. The mixture was diluted with EtOAc (30mL), washed with water (50 mL. times.2), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluting with a gradient of 0% to 15% EtOAc/hexanes) to give 3- (2- (benzyloxy) ethyl) oxetane (550mg,2.86mmol, 27% yield) as a colorless oil.

Step D: a mixture of 3- (2- (benzyloxy) ethyl) oxetane (550mg,2.86mmol), Pd/C (350mg), and ethanol (5mL) was stirred at room temperature under a hydrogen atmosphere for 2 days. The mixture was filtered and the filtrate was concentrated to give 2- (oxetan-3-yl) ethanol (200mg,1.96mmol, 66% yield) as a colorless oil.

Step E:

5- ((2-chlorophenyl) thio) -4-hydroxy-6 '- (2- (oxetan-3-yl) ethoxy) -2- (thien-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one was prepared according to example 2, step a, in 35% yield, replacing propan-2-ol with 2- (oxetan-3-yl) ethanol.¹H NMR(400MHz,CD₃OD)7.70(dd,J＝8.0,8.0Hz,1H),7.40(dd,J＝2.8,2.8Hz,1H),7.27(d,J＝2.8Hz,1H),7.17-7.14(m,3H),6.88(dd,J＝8.0,8.0Hz,1H),6.75-6.73(m,2H),6.00(dd,J＝9.6,1.6Hz,1H),4.38-4.28(m,2H),3.83-3.69(m,5H),3.43-3.41(m,1H),2.71-2.67(m,1H),2.06-2.02(m,1H),1.75-1.71(m,1H)。LCMS M+1＝514.9。

Example 17

3- (2-chlorophenyl) sulfanyl-6- [6- [ [3- (hydroxymethyl) phenyl ] methyl ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: to a stirred solution of methyl 3- (bromomethyl) benzoate (5g,21.8mmol) in toluene (50mL) in an ice bath was added DABAL-H (43.6mL,43.6 mmol). The reaction mixture was stirred at 0 ℃ for 2 hours. The mixture was quenched with 1n hcl and extracted with EtOAc and water. The organic layer was dried over anhydrous sodium sulfate and concentrated to give (3- (bromomethyl) phenyl) methanol (4.0g,19.9mmol, 91% yield) as a colorless oil.

And B: a mixture of (3- (bromomethyl) phenyl) methanol (2.0g,10.0mmol), 2, 6-lutidine (2.13g,19.9mmol), tert-butyldimethylsilyl trifluoromethanesulfonate (3.1g,14.9mmol) and DCM (30mL) was stirred at room temperature for 2 h. The reaction mixture was quenched with water (20mL) and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc ═ 20/1) to give ((3- (bromomethyl) benzyl) oxy) (tert-butyl) dimethylsilane (2.8g,8.9mmol, 89% yield) as a colorless oil.

And C: to a mixture of zinc powder (408mg,6.3mol) in anhydrous THF (30mL) was added 1, 2-dibromoethane (107mg,0.57mmol) and ((3- (bromomethyl) benzyl) oxy) (tert-butyl) dimethylsilane (1.8g.5.7mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 8 hours. The reaction solution was used directly in the next step.

Step D: to 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one (example 1,300mg,0.61mmol) and Pd (PPh)₃)₄(69mg,0.06mmol) to a stirred solution in THF (1mL) was added (3- (((tert-butyldimethylsilyl) oxy) methyl) benzyl) zinc (II) bromide (5.3mL,3.04 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water and then filtered through celite. The filtrate was concentrated in vacuo and the crude residue was purified by preparative HPLC (formic acid) to give 6 '- (3- (((tert-butyldimethylsilyl) oxy) methyl) benzyl) -5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one (80mg,0.12mmol, 20% yield) as a white solid.

Step E: to 6 '- (3- (((tert-butyldimethylsilyl) oxy) methyl) benzyl) -5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thien-3-yl) -2, 3-dihydro- [2, 2' -bipyridine in an ice bath]To a stirred solution of-6 (1H) -one (80mg,0.12mmol) in MeOH (5mL) was added HCl-MeOH (5 mL). The mixture was stirred at 0 ℃ for 1 hour. Water was added to the reaction mixture, which was then filtered and washed with water. Drying the solid to obtain 5- ((2-chlorophenyl) thio) -4-hydroxy-6 '- (3- (hydroxymethyl) benzyl) -2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one (50mg,0.09mmol, 76% yield) as a white solid. Mixture of diastereomers:¹H NMR(400MHz,CD₃OD)7.74(dd, J ═ 8.0,8.0Hz,1H),7.42-7.40(m,2H),7.22-7.17(m,6H),7.11-7.09(m,2H),6.85(dd, J ═ 8.0,8.0Hz,1H),6.51(dd, J ═ 8.0,8.0Hz,1H),5.78(dd, J ═ 8.4,1.6Hz,1H),4.47(s,2H),4.17(s,2H),4.00(d, J ═ 16.4Hz,1H),3.47(d, J ═ 16.4Hz, 1H). LCMS M +1 ═ 534.9. Stereoisomer 1:¹H NMR(400MHz,CD₃OD)7.75(dd, J ═ 8.0,8.0Hz,1H),7.44-7.42(m,2H),7.31-7.14(m,8H),6.85(dd, J ═ 8.0,8.0Hz,1H),6.56(dd, J ═ 8.0,8.0Hz,1H),5.87(d, J ═ 8.0Hz,1H),4.51(s,2H),4.20(s,2H),3.92(d, J ═ 16.4Hz,1H),3.49(d, J ═ 16.4Hz, 1H). Stereoisomer 2:¹H NMR(400MHz,CD₃OD)7.74(dd,J＝8.0,8.0Hz,1H),7.44-7.41(m,2H),7.16-7.13(m,8H),6.87(dd,J＝8.0,8.0Hz,1H),6.56(dd,J＝8.0,8.0Hz,1H),5.87(d,J＝8.0Hz,1H),4.51(s,2H),4.20(s,2H),3.91(d,J＝16.4Hz,1H),3.49(d,J＝16.0Hz,1H)。

example 18

3- (2-chlorophenyl) sulfanyl-6- [6- [2- (1H-pyrazol-4-yl) phenoxy ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: to 2- (2-hydroxyethyl) phenol (5g,36.2mmol) and Cs in an ice bath₂CO₃(38.9g,108.7mmol) to a stirred suspension in acetone (100mL) was added methyl iodide (6.2g,43.4 mmol). The reaction mixture was stirred at 0 ℃ for 50 minutes. The mixture was filtered and the filtrate was concentrated in vacuo. The crude material was extracted with EtOAc and water. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 2- (2-methoxyphenyl) ethanol (4.5g,29.6mmol, 82% yield) as a yellow solid.

And B: to a stirred solution of 2- (2-methoxyphenyl) ethanol (4.5g,29.6mmol) in DCM (80mL) was added Dess-Martin reagent (51.1g,35.5mmol) in an ice bath. The reaction mixture was stirred at 0 ℃ for 1 hour. The mixture was diluted with DCM (100mL) and saturated NaHCO₃(100mL × 2), washed with brine, dried over anhydrous sodium sulfate and concentrated the crude residue was purified by silica gel chromatography eluting with a 10% -50% EtOAc/hexanes gradient to give 2- (2-methoxyphenyl) acetaldehyde (2.5g,16.7mmol, 56% yield) as a yellow oil.

And C: a mixture of 2- (2-methoxyphenyl) acetaldehyde (2.5g,16.7mmol) and 1, 1-dimethoxy-N, N-dimethylmethylamine (5mL) was stirred at room temperature for 5 h. The mixture was diluted with DCM (30mL) and saturated NaHCO₃(20mL × 2), washed with brine, dried over anhydrous sodium sulfate and concentrated the crude residue was purified by silica gel chromatography eluting with a 10% -50% EtOAc/hexanes gradient to give (E) -3- (dimethylamino) -2- (2-methoxyphenyl) propenal (350mg,1.7mmol, 12% yield) as a yellow solid.

Step D: a mixture of (E) -3- (dimethylamino) -2- (2-methoxyphenyl) propenal (350mg,1.7mmol), hydrazine hydrate (2mL) and ethanol (5mL) was heated to 80 ℃ and held for 30 minutes. The mixture was diluted with DCM (10mL) and saturated NaHCO₃(10mL × 2), washed with brine, dried over anhydrous sodium sulfate and concentrated to give 4- (2-methoxyphenyl) -1H-pyrazole (260mg,1.5mmol, 88% yield) as a yellow solid.

Step E: to a stirred solution of 4- (2-methoxyphenyl) -1H-pyrazole (260mg,1.5mmol) in DCM (5mL) in an ice bathBoron tribromide (750mg,3.0mmol) was added to the solution. The reaction mixture was stirred at 0 ℃ for 12 hours. The mixture was diluted with DCM (20mL) and saturated NaHCO₃(20mL × 2), washed with brine, dried over anhydrous sodium sulfate and concentrated to give 2- (1H-pyrazol-4-yl) phenol (200mg,1.25mmol, 84% yield) as a yellow oil.

Step F: 6 '- (2- (1H-pyrazol-4-yl) phenoxy) -5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one was prepared according to example 3 step a in 3% yield replacing 2-chloro-4-fluoro-phenol with 2- (1H-pyrazol-4-yl) phenol.¹H NMR(400MHz,(CD₃)₂SO)11.75(s,1H),9.92(s,1H),9.08(s,1H),9.64(s,1H),8.30(s,1H),8.07(dd,J＝8.0,8.0Hz,1H),7.90(d,J＝8.4Hz,1H),7.59-7.53(m,3H),7.40(s,1H),7.23-7.21(m,2H),7.08(dd,J＝8.0,4.0Hz,1H),6.93-6.84(m,3H),6.60(dd,J＝8.0,8.0Hz,1H),5.85(d,J＝8.4Hz,1H),4.04(d,J＝16.0Hz,1H),3.43(d,J＝16.4Hz,1H)。LCMS M+1＝573.1。

Example 19

3- (2-chlorophenyl) sulfanyl-6- (5-chlorothien-3-yl) -6- [6- (4-fluorophenoxy) pyridin-2-yl ] piperidine-2, 4-dione

Step A: a solution of thiophene-3-carbaldehyde (20.0g,178.3mmol) and N-chlorosuccinimide (23.8g,178.3mmol) in AcOH (180mL) was stirred at 110 ℃ for 4 hours. After completion of the reaction, the solution was cooled to room temperature, then diluted with EtOAc (120mL) and washed with H₂O (100mL × 3), saturated NaHCO₃(50mL × 2), washed with brine, dried over anhydrous sodium sulfate and concentrated to give 5-chlorothiophene-3-carbaldehyde (8.0g,5 g)4.6mmol, 31% yield) as a yellow solid and used directly in the next step without further purification.

And B: (5-chlorothien-3-yl) (6- (4-fluorophenoxy) pyridin-2-yl) methanol was prepared in 50% yield according to example 7, step a, substituting 4-bromobenzaldehyde with 5-chlorothien-3-carbaldehyde and 3-bromothiophene with 2-bromo-6- (4-fluorophenoxy) pyridine.

And C: prepared according to example 7, step B, in 79% yield from (5-chlorothien-3-yl) (6- (4-fluorophenoxy) pyridin-2-yl) methanone by substituting (4-bromophenyl) (thien-3-yl) methanone with (5-chlorothien-3-yl) (6- (4-fluorophenoxy) pyridin-2-yl) methanone.

Step D: (E) -N- ((5-chlorothien-3-yl) (6- (4-fluorophenoxy) pyridin-2-yl) methylene) -2-methylpropane-2-sulfinamide was prepared according to example 7, step C, in 74% yield replacing (E) -N- ((4-bromophenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with (E) -N- ((5-chlorothien-3-yl) (6- (4-fluorophenoxy) pyridin-2-yl) methylene) -2-methylpropane-2-sulfinamide.

Step E: prepared according to example 7, step D, methyl 5- (5-chlorothien-3-yl) -5- (1, 1-dimethylethylsulfonamido) -5- (6- (4-fluorophenoxy) pyridin-2-yl) -3-oxopentanoate in 86% yield, 5- (4-bromophenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester was replaced with 5- (5-chlorothien-3-yl) -5- (1, 1-dimethylethylsulfonamido) -5- (6- (4-fluorophenoxy) pyridin-2-yl) -3-oxopentanoic acid methyl ester.

Step F: prepared according to example 7, step E, methyl 5-amino-5- (5-chlorothien-3-yl) -5- (6- (4-fluorophenoxy) pyridin-2-yl) -3-oxopentanoate in 49% yield, methyl 5-amino-5- (4-bromophenyl) -3-oxo-5- (thien-3-yl) pentanoate was replaced with methyl 5-amino-5- (5-chlorothien-3-yl) -5- (6- (4-fluorophenoxy) pyridin-2-yl) -3-oxopentanoate.

Step G: 6- (5-chlorothien-3-yl) -6- (6- (4-fluorophenoxy) pyridin-2-yl) piperidine-2, 4-dione was prepared in 57% yield according to example 7, step F, substituting 6- (4-bromophenyl) -4-hydroxy-6- (thien-3-yl) -5, 6-dihydropyridin-2 (1H) -one with 6- (5-chlorothien-3-yl) -6- (6- (4-fluorophenoxy) pyridin-2-yl) piperidine-2, 4-dione.

Step H: 5- ((2-chlorophenyl) thio) -2- (5-chlorothien-3-yl) -6 '- (4-fluorophenoxy) -4-hydroxy-2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one was prepared according to example 7, step G, in 5.4% yield by substituting 6- (4-bromophenyl) -3- ((2-chlorophenyl) thio) -4-hydroxy-6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one with 5- ((2-chlorophenyl) thio) -2- (5-chlorothien-3-yl) -6 '- (4-fluorophenoxy) -4-hydroxy-2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one. Mixture of diastereomers:¹H NMR(400MHz,CD₃OD)7.89(dd, J ═ 7.6,7.6Hz,1H),7.31(d, J ═ 8.0Hz,1H),7.21(d, J ═ 7.8Hz,1H),7.12-7.08(m,4H),7.01-6.89(m,3H),6.98-6.89(m,2H),6.07(dd, J ═ 8.0,1.2Hz,1H),3.54(d, J ═ 16.0Hz,1H),3.25(d, J ═ 16.0Hz, 1H). LCMS M +1 ═ 558.9. Stereoisomer 1:¹H NMR(400MHz,CD₃OD)7.89(dd, J ═ 7.6,7.6Hz,1H),7.33(d, J ═ 8.0Hz,1H),7.22(d, J ═ 7.8Hz,1H),7.10-7.07(m,4H),7.01-6.89(m,3H),6.89-6.81(m,2H),6.07(d, J ═ 6.8Hz,1H),3.55(d, J ═ 16.0Hz,1H),3.28(d, J ═ 16.0Hz, 1H). Stereoisomer 2:¹H NMR(400MHz,CD₃OD)7.89(dd,J＝7.6,7.6Hz,1H),7.33(d,J＝8.0Hz,1H),7.12(d,J＝7.8Hz,1H),7.10-7.08(m,4H),7.01-6.99(m,3H),6.89-6.81(m,2H),6.08(d,J＝6.8Hz,1H),3.54(d,J＝16.0Hz,1H),3.28(d,J＝16.0Hz,1H)。

example 20

3- (2-chlorophenyl) sulfanyl-6- [6- [2- (2, 2-difluorocyclopropyl) ethoxy ] pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: benzoyl chloride (2.0g,14.2mmol) was added dropwise to but-3-en-1-ol (1.2g,17.1mmol) and Et at 0 deg.C₃A solution of N (2.9g,28.5mmol) in DCM (35 mL). The reaction mixture was then warmed to ambient temperature and stirred for 3 hours. The reaction mixture was washed with saturated NH₄Aqueous Cl (10mL) quench. The organic layer was washed with saturated NaHCO₃The solution (5mL × 2), washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel chromatography (eluting with 20% EtOAc in hexanes) to give but-3-enyl benzoate (2.3g,13.1mmol, 91% yield) as a yellow oil.

And B: a mixture of but-3-enyl benzoate (500mg,2.8mmol), trimethylsilyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (1.4g,5.7mmol) and NaF (5.9mg, 141.8. mu. mmol) was heated at 110 ℃ for 2 hours under anhydrous conditions. After cooling to room temperature, DCM (10mL) and H were added₂O (5mL), separate. The DCM extract was concentrated. The crude residue was purified by silica gel chromatography (eluting with 10% EtOAc/hexanes) to give 2- (2, 2-difluorocyclopropyl) ethyl benzoate (330mg,1.5mmol, 51% yield) as a yellow oil.

And C: to potassium hydroxide (409mg,7.3mmol) in MeOH/H at 0 deg.C₂To the suspension in O (3:2,5mL) was added 2- (2, 2-difluorocyclopropyl) ethyl benzoate (330mg,1.5mmol) followed by stirring at room temperature for 1h the reaction mixture was quenched with saturated aqueous brine solution (5mL) and extracted with EtOAc (10mL × 4) the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give crude 2- (2, 2-difluorocyclopropyl) ethanol (150mg, 84%) as a colorless oil which was used directly in the next step.

Step D: 5- ((2-chlorophenyl) thio) -6 '- (2- (2, 2-difluorocyclopropyl) ethoxy) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one was prepared according to example 2, step a, in 21% yield, replacing propan-2-ol with 2- (2, 2-difluorocyclopropyl) ethanol.¹H NMR(400MHz,CD₃OD)7.73(dd,J＝7.6,7.6Hz,1H),7.43(d,J＝2.8Hz,1H),7.27-7.14(m,4H),7.14(d,J＝2.8Hz,1H),6.93-6.74(m,2H),5.96(d,J＝8.0Hz,1H),4.43(t,J＝3.6Hz,2H),3.88(d,J＝16.0Hz,1H),3.47(d,J＝16.0Hz,1H),1.95-1.67(m,3H),1.36-1.34(m,1H),1.00-0.96(m,1H)。LCMS M+1＝534.9。

Example 21

3- (2-chlorophenyl) sulfanyl-6- [6- [2- (3-methyltriazol-4-yl) phenoxy ] benzene]Pyridin-2-yl]-6- (thien-3-yl) piperidine-2, 4-dione

Step A: 1H-1,2, 3-triazole (1.0g,14.5mmol), methyl iodide (3.1g,21.7mmol) and K₂CO₃A solution of (4.0g,28.9mmol) in THF (15mL) was stirred at room temperature for 3 hours. EtOAc (20mL) and H were added₂O (10mL), isolated. The solvent was concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluting with 10% MeOH in DCM) to give 1-methyl-1H-1, 2, 3-triazole (860mg,10.4mmol, 71% yield) as a yellow oil.

And B: to a solution of 1-methyl-1H-1, 2, 3-triazole (860mg,10.4mmol) in THF (10mL) at-78 deg.C was added n-BuLi (5.0mL,12.4mmol,2.5M) dropwise. The mixture was stirred at-78 ℃ for 2 hours, then Bu was added₃SnCl (3.7g,11.4 mmol). The mixture was stirred at-78 ℃ for 1 hour, then at room temperature for 1 hour. The mixture was concentrated in vacuo and hexane was added. The insoluble material was filtered and the filtrate was concentrated in vacuo to give 1-methyl-5- (tributylstannyl) -1H-1,2, 3-triazole (3.1g, 80%) as a yellow oil and used directly in the next step.

And C: 1-methyl-5- (tributylstannyl) -1H-1,2, 3-triazole (3.1g,8.3mmol), 2-bromophenol (1.7g,10.0mmol), Et₃N (1.7g,16.7mmol) and PdCl₂(PPh₃)₂A solution of (1.1g,1.7mmol) in PhMe (16mL) was stirred at 110 ℃ for 14 h. After cooling to room temperature, DCM (25mL) and H were added₂O (10mL), isolated. The DCM was concentrated in vacuo. Subjecting the crude residue to silica gelSpectral purification (gradient elution with 20% EtOAc/hexanes to 10% MeOH/DCM) afforded 2- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenol (110mg, 8.0% yield) as a white solid.

Step D: 5- ((2-chlorophenyl) thio) -4-hydroxy-6 '- (2- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenoxy) -2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one was prepared according to example 3, step a, in 8.3% yield, replacing 2-chloro-4-fluoro-phenol with 2- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenol.¹H NMR(400MHz,CD₃OD)7.80(dd,J＝7.6,7.6Hz,1H),7.47(d,J＝2.8Hz,1H),7.41-7.39(m,4H),7.30(d,J＝2.8Hz,1H),7.21(d,J＝7.6Hz,2H),7.08(s,1H),6.94-6.92(m,3H),6.73(dd,J＝7.2,7.2Hz,1H),5.94(d,J＝8.0Hz,1H),3.87(s,3H),3.50(d,J＝16.0Hz,1H),3.31(d,J＝16.0Hz,1H)。LCMS M+1＝587.8。

Example 22

3- (2-chlorophenyl) sulfanyl-6- (3- (tetrahydropyran-4-yl) oxyphenyl) -6- (thien-3-yl) piperidine-2, 4-dione

Step A: methyl 3-hydroxybenzoate (22.0g,144.6mmol), tetrahydro-2H-pyran-4-ol (22.2g,216.9mmol) and PPh₃A suspension of (3.8g,14.5mmol) and DEAD (28.0g,159.1mmol) in THF (150ml) was refluxed for 8 hours. The reaction mixture was then cooled to room temperature and diluted with water (60mL) and EtOAc (120 mL). The organic layer was separated and concentrated. The crude residue was purified by silica gel column chromatography (using petroleum ether: EtOAc ═ 3:1 as eluent) to give methyl 3- (tetrahydro-2H-pyran-4-yloxy) benzoate (18.1g, 53% yield) as a brown oil.

And B: methyl 3- (tetrahydro-2H-pyran-4-yloxy) benzoate (18.1g,76.6mmol) and LiOH (9.2g,383mmol) in methanol/H₂The solution in O (80mL/5mL) was stirred at room temperature for 3 hours. Mixing the reaction mixtureThe filtrate was filtered and the filtrate was adjusted to pH 2-3 with aqueous HCl (1M) the resulting solution was extracted with EtOAc (80mL × 2) and concentrated the crude residue 3- (tetrahydro-2H-pyran-4-yloxy) benzoic acid as a yellow solid (14.3g, 84% yield) was used directly in the next step without further purification.

And C: N-methoxy-N-methyl-3- (tetrahydro-2H-pyran-4-yloxy) benzamide was prepared according to example 1, step a, in 85% yield replacing 6-bromopyridine-2-carboxylic acid with 3- ((tetrahydro-2H-pyran-4-yl) oxy) benzoic acid.

Step D: prepared according to example 1, step B, in 67% yield from (3- (tetrahydro-2H-pyran-4-yloxy) phenyl) (thiophen-3-yl) methanone, 6-bromo-N-methoxy-N-methylpyridine-2-carboxamide was replaced with (3- (tetrahydro-2H-pyran-4-yloxy) phenyl) (thiophen-3-yl) methanone.

Step E: (E) -2-methyl-N- ((3- (tetrahydro-2H-pyran-4-yloxy) phenyl) (thiophen-3-yl) methylene) propane-2-sulfinamide prepared according to example 1, step C, in 63% yield by replacing (Z) -N- ((6-bromopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with (E) -2-methyl-N- ((3- (tetrahydro-2H-pyran-4-yloxy) phenyl) (thiophen-3-yl) methylene) propane-2-sulfinamide.

Step F: prepared according to example 1, step D, methyl 5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (3- (tetrahydro-2H-pyran-4-yloxy) phenyl) -5- (thiophen-3-yl) pentanoate in 58% yield, the methyl 5- (6-bromopyridin-2-yl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thien-3-yl) pentanoate was replaced by methyl 5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (3- (tetrahydro-2H-pyran-4-yloxy) phenyl) -5- (thien-3-yl) pentanoate.

Step G: prepared according to example 1, step E, 5-amino-3-oxo-5- (3- (tetrahydro-2H-pyran-4-yloxy) phenyl) -5- (thiophen-3-yl) pentanoic acid methyl ester in 74% yield by replacing 5-amino-5- (6-bromopyridin-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5-amino-3-oxo-5- (3- (tetrahydro-2H-pyran-4-yloxy) phenyl) -5- (thiophen-3-yl) pentanoic acid methyl ester.

Step H: 4-hydroxy-6- (3- (tetrahydro-2H-pyran-4-yloxy) phenyl) -6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one was prepared according to example 1, step F, in 87% yield, the 6 '-bromo-4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridin ] -6(1H) -one was replaced with 4-hydroxy-6- (3- (tetrahydro-2H-pyran-4-yloxy) phenyl) -6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one.

Step I: 3- (2-Chlorophenylthio) -4-hydroxy-6- (3- (tetrahydro-2H-pyran-4-yloxy) phenyl) -6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one prepared in 5.0% yield according to example 1, step G,6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one was replaced with 3- (2-chlorophenylthio) -4-hydroxy-6- (3- (tetrahydro-2H-pyran-4-yloxy) phenyl) -6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one.¹H NMR(400MHz,CD₃OD)7.48(dd,J＝8.0,8.0Hz,1H),7.32(dd,J＝2.0,2.0Hz,1H),7.22(d,J＝8.0Hz,1H),7.21(d,J＝8.0Hz,1H),7.18(d,J＝8.0Hz,1H),7.16-7.14(m,2H),7.15-7.03(m,2H),6.69(d,J＝3.2Hz,1H),5.92(dd,J＝7.6,2.4Hz,1H),4.54-4.50(m,1H),3.89(t,J＝5.6Hz,2H),3.56(d,J＝16.0Hz,1H),3.54(t,J＝5.6Hz,2H),3.51(d,J＝16.0Hz,1H),1.98-1.92(m,2H),1.70-1.60(m,2H)。LCMS M+1＝513.9。

Example 23

3- (2-chlorophenyl) sulfanyl-1-methyl-6- (3- (tetrahydropyran-4-yl) oxyphenyl) -6- (thien-3-yl) piperidine-2, 4-dione

Step A: to a suspension of NaH (60 wt%, 47mg,1.2mmol) in dry THF (5mL) was added methyl iodide (166mg,1.2mmol) dropwise at 0 deg.C under a nitrogen atmosphere, and the reaction mixture was stirred for 30 minutes. A solution of the compound from example 22 (200mg, 389. mu. mol) in THF (3mL)Dropwise added to the reaction mixture and the reaction mixture was stirred at 0 ℃ for 1 hour, followed by stirring at room temperature for another 1 hour. The reaction mixture was quenched with HCl solution (1M) and separated. The solvent was removed. The crude residue was purified by preparative HPLC (formic acid) to give the expected product (5.5mg, 3% yield) as a white solid.¹H NMR(400MHz,CD₃OD)7.58(dd,J＝8.0,8.0Hz,1H),7.57(dd,J＝2.0,2.0Hz,1H),7.37(d,J＝8.0Hz,1H),7.23(d,J＝8.0Hz,1H),7.21(d,J＝8.0Hz,1H),7.16(d,J＝7.2Hz,1H),7.15-7.02(m,2H),6.97-6.79(m,2H),6.10(dd,J＝8.0,1.2Hz,1H),4.51-4.49(m,1H),3.90(t,J＝5.6Hz,2H),3.66(d,J＝16.0Hz,1H),3.55(t,J＝5.6Hz,2H),3.51(d,J＝16.0Hz,1H),2.84(s,3H),1.96-1.92(m,2H),1.69-1.63(m,2H)。LCMS M+1＝527.9。

Example 24

3- (2-chlorophenyl) sulfanyl-6- [3- (4-fluorophenoxy) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: (3-bromophenyl) (thiophen-3-yl) methanol was prepared according to example 7, step A, in 95% yield, replacing 4-bromobenzaldehyde with 3-bromobenzaldehyde.

And B: prepared according to example 7, step B, in 95% yield from (3-bromophenyl) (thiophen-3-yl) methanone by replacing (4-bromophenyl) (thiophen-3-yl) methanol with (3-bromophenyl) (thiophen-3-yl) methanol.

And C: (E) -N- ((3-bromophenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide was prepared according to example 1, step C, in 97% yield replacing (6-bromopyridin-2-yl) (thiophen-3-yl) methanone with (3-bromophenyl) (thiophen-3-yl) methanone.

Step D: prepared according to example 1, step D, methyl 5- (3-bromophenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoate in 68% yield by replacing (Z) -N- ((6-bromopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with (E) -N- ((3-bromophenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide.

Step E: prepared according to example 1, step E, 5-amino-5- (3-bromophenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester in 74% yield by replacing 5-amino-5- (6-bromopyridin-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5- (3-bromophenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.

Step F: 6- (3-bromophenyl) -4-hydroxy-6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one prepared in 80% yield according to example 1, step F, substituting 6 '-bromo-4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one with methyl 5-amino-5- (3-bromophenyl) -3-oxo-5- (thiophen-3-yl) pentanoate.

Step G: prepared according to example 1, step G, in 92% yield from 6- (3-bromophenyl) -3- ((2-chlorophenyl) thio) -4-hydroxy-6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one, the 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one was replaced with 6- (3-bromophenyl) -4-hydroxy-6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one.

Step H: 3- ((2-chlorophenyl) thio) -6- (3- (4-fluorophenoxy) phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione was prepared according to example 3, step a, in 6.6% yield, replacing 2-chloro-4-fluoro-phenol with 4-fluorophenol and substituting 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one was replaced with 6- (3-bromophenyl) -3- ((2-chlorophenyl) thio) -4-hydroxy-6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one.¹H NMR(400MHz,CD₃OD)7.49(dd,J＝4.8,2.8Hz,1H),7.29(dd,J＝8.0,8.0Hz,1H),7.30-7.26(m,1H),7.23-7.21(m,2H),7.14(d,J＝4.8Hz,1H),7.06-7.02(m,3H),6.96-6.92(m,4H),6.80-6.75(m,1H),5.98(dd,J＝7.6,1.2Hz,1H),3.47-3.45(m,2H)。LCMS M+1＝523.8。

Example 25

6- (6-bromo-5-morpholinopyridin-2-yl) -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione

Step A: methyl 5-bromopyridine-2-carboxylate (60.0g,277mmol), morpholine (72g,833mmol) and Pd₂(dba)₃(5.0g,5.55mmol), 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (6.9g,11.1mmol) and Cs₂CO₃(135g,417mmol) were combined in a flask (2L.) dioxane (1L) was added and the mixture was stirred at 120 ℃ under nitrogen atmosphere for 18h the reaction mixture was cooled to room temperature, filtered and washed with EtOAc (300ml × 3.) the filtrate was dried over anhydrous magnesium sulfate and concentrated silica gel chromatography (eluting with 50% EtOAc/hexanes) afforded methyl 5-morpholinopyridine-2-carboxylate (25g,112.6mmol, 40% yield) as a yellow solid.

And B: to a solution of methyl 5-morpholinopyridine-2-carboxylate (25.0g,113mmol) in DCM (500mL) was added N-bromosuccinimide (22g,123 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated. The residue was purified by silica gel chromatography to give methyl 6-bromo-5-morpholinopyridine-2-carboxylate (23g,69.6mmol, 62% yield) as a yellow solid.

And C: to a solution of methyl 6-bromo-5-morpholinopyridine-2-carboxylate (23.0g,69.6mmol) in THF (200mL) was added LiOH (9.62g,229.1mmol) in H₂Solution in O (100 ml). The reaction mixture is placed in a chamberStir for 8 hours at room temperature. The mixture was concentrated and the resulting aqueous solution was adjusted to pH with HCl solution (1M)<4, extracted with DCM (100ml × 3), dried over anhydrous sodium sulfate and concentrated to give 6-bromo-5-morpholinopyridine-2-carboxylic acid (21.0g,73.1mmol, 96%) as a yellow solid.

Step D: 6-bromo-N-methoxy-N-methyl-5-morpholinopyridine-2-carboxamide was prepared according to example 1, step A, in 75% yield, substituting 6-bromopyridine-2-carboxylic acid with 6-bromo-5-morpholinopyridine-2-carboxylic acid.

Step E: (6-bromo-5-morpholinopyridin-2-yl) (thiophen-3-yl) methanone was prepared according to example 1, step B, in 22% yield replacing 6-bromo-N-methoxy-N-methyl-5-morpholinopyridine-2-carboxamide with 6-bromo-N-methoxy-N-methyl-2-carboxamide.

Step F: (Z) -N- ((6-bromo-5-morpholinopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide was prepared according to example 1, step C, in 82% yield replacing (6-bromopyridin-2-yl) (thiophen-3-yl) methanone with (6-bromo-5-morpholinopyridin-2-yl) (thiophen-3-yl) methanone.

Step G: prepared according to example 1, step D, methyl 5- (6-bromo-5-morpholinopyridin-2-yl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoate in 84% yield by replacing (Z) -N- ((6-bromopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with (Z) -N- ((6-bromo-5-morpholinopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide.

Step H: prepared according to example 1, step E, 5-amino-5- (6-bromo-5-morpholinopyridin-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester in 88% yield by replacing 5-amino-5- (6-bromopyridin-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5- (6-bromo-5-morpholinopyridin-2-yl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.

Step I: 6 ' -bromo-4-hydroxy-5 ' -morpholino-2- (thiophen-3-yl) -2, 3-dihydro- [2,2 ' -bipyridin ] -6(1H) -one was prepared according to example 1, step F in 89% yield, 6 '-bromo-4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridin ] -6(1H) -one was replaced with 5- (6-bromo-5-morpholinopyridin-2-yl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.

Step J: 6 ' -bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-5 ' -morpholino-2- (thiophen-3-yl) -2, 3-dihydro- [2,2 ' -bipyridine]-6(1H) -one was prepared according to example 1, step G, in 36% yield from 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one is replaced by 5-amino-5- (6-bromo-5-morpholinopyridin-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.¹H NMR(400MHz,(CD₃)₂SO)11.70(br s,1H),8.47(s,1H),7.65(d,J＝8.0Hz,1H),7.63(d,J＝8.0Hz,1H),7.53-7.51(m,1H),7.31-7.27(m,2H),7.12(dd,J＝5.2,1.6Hz,1H),6.96(d,J＝8.0Hz,1H),6.81-6.78(m,1H),5.95(dd,J＝8.0,1.2Hz,1H),3.80-3.72(m,5H),3.36(d,J＝16.4Hz,1H),3.01-2.99(m,4H)。LCMS M+1＝579.8。

Example 26

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenylamino) -5-morpholinopyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: 5- ((2-chlorophenyl) thio) -6 ' - ((4-fluorophenyl) amino) -4-hydroxy-5 ' -morpholino-2- (thiophen-3-yl) -2, 3-dihydro- [2,2 ' -bipyridine]-6(1H) -one was prepared according to example 4 step a in 6% yield, substituting cyclohexylamine with 4-fluoroaniline and substituting 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one was replaced with 6 ' -bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-5 ' -morpholino-2- (thiophen-3-yl) -2, 3-dihydro- [2,2 ' -bipyridine]-6(1H) -one.¹H NMR(400MHz,CD₃OD)7.61-7.58(m,2H),7.50(d,J＝8.0Hz,1H),7.49-7.48(m,1H),7.33(s,1H),7.28-7.22(m,1H),7.17-7.12(m,1H),7.06-7.01(m,4H),6.86-6.82(m,1H),6.25(d,J＝8.0Hz,1H),3.93(m,4H),3.82(d,J＝16.4Hz,1H),3.49(d,J＝16.4Hz,1H),2.98-2.96(m,4H)。LCMS M+1＝608.8。

Example 27

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenoxy) -5-morpholinopyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione

5- ((2-chlorophenyl) thio) -6 ' - (4-fluorophenoxy) -4-hydroxy-5 ' -morpholino-2- (thiophen-3-yl) -2, 3-dihydro- [2,2 ' -bipyridine]-6(1H) -one was prepared according to example 2, step a, in 3% yield, replacing propan-2-ol with 4-fluorophenol and substituting 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one was replaced with 6 ' -bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-5 ' -morpholino-2- (thiophen-3-yl) -2, 3-dihydro- [2,2 ' -bipyridine]-6(1H) -one.¹H NMR(400MHz,CD₃OD)7.42(d,J＝8.4Hz,1H),7.37-7.36(m,1H),7.26-7.22(m,2H),7.12-7.01(m,5H),6.98-6.94(m,2H),6.82-6.78(m,1H),6.02(dd,J＝8.0,1.2Hz,1H),3.87-3.84(m,4H),3.52(d,J＝16.8Hz,1H),3.24-3.17(m,5H)。LCMS M+1＝609.8。

Example 28

3- (2-chlorophenyl) sulfanyl-6- [4- (3-hydroxypropoxy) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: to a solution of 4-hydroxybenzaldehyde (25g,205mmol) and (3-bromopropoxy) (tert-butyl) dimethylsilane (57g,225mmol) in MeCN (200mL) was added K₂CO₃(85g,614 mmol). The reaction mixture was heated at 80 ℃ for 12 hours. After cooling to room temperature, DCM (50mL) was added and the mixture was filtered through celite. The filtrate was then concentrated and purified by silica gel column (petroleum ether/EtOAc ═ 20/1) to give 4- (3- ((tert-butyldimethylsilyl) oxy) propoxy) benzaldehyde (36g, 60% yield) as a white solid.

And B: (4- (3- ((tert-butyldimethylsilyl) oxy) propoxy) phenyl) (thiophen-3-yl) methanol was prepared according to example 7, step a, in 84% yield replacing 4-bromobenzaldehyde with 4- (3- ((tert-butyldimethylsilyl) oxy) propoxy) benzaldehyde.

And C: prepared according to example 7, step B, in 56% yield, of (4- (3- ((tert-butyldimethylsilyl) oxy) propoxy) phenyl) (thiophen-3-yl) methanone by substituting (4- (3- ((tert-butyldimethylsilyl) oxy) propoxy) phenyl) (thiophen-3-yl) methanol for (4- (3- ((tert-butyldimethylsilyl) oxy) propoxy) methanone.

Step D: (Z) -N- ((4- (3- ((tert-butyldimethylsilyl) oxy) propoxy) phenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide prepared according to example 7, step C in 71% yield by replacing (E) -N- ((4-bromophenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with (4- (3- ((tert-butyldimethylsilyl) oxy) propoxy) phenyl) (thiophen-3-yl) methanone.

Step E: prepared according to example 7, step D, methyl 5- (4- (3- ((tert-butyldimethylsilyl) oxy) propoxy) phenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoate in 82% yield, (E) -N- ((4-bromophenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide was replaced with (Z) -N- ((4- (3- ((tert-butyldimethylsilyl) oxy) propoxy) phenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide.

Step F: prepared according to example 7, step E, 82% yield of methyl 5-amino-5- (4- (3-hydroxypropoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoate by replacing 5- (4- (3- ((tert-butyldimethylsilyl) oxy) propoxy) phenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoate with methyl 5- (4- (3- ((tert-butyldimethylsilyl) oxy) propoxy) phenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoate.

Step G: 6- (4- (3-Hydroxypropoxy) phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione was prepared according to example 7, step F, in 90% yield by replacing 5-amino-5- (4- (3-hydroxypropoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5-amino-5- (4- (3-hydroxypropoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.

Step H: 3- ((2-chlorophenyl) thio) -4-hydroxy-6- (4- (3-hydroxypropoxy) phenyl) -6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one prepared in 29% yield according to example 7, step G, substituting 6- (4-bromophenyl) -4-hydroxy-6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one with 6- (4- (3-hydroxypropoxy) phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione.¹H NMR(400MHz,(CD₃)₂SO)11.41(s,1H),8.41(s,1H),7.55(dd,J＝5.0,3.0Hz,1H),7.25-7.30(m,4H),7.12(d,J＝5.1Hz,1H),6.88-6.96(m,3H),6.72(dd,J＝7.6,7.6Hz,1H),5.84(dd,J＝6.0,1.2Hz,1H),4.45(s,1H),4.00(t,J＝6.3Hz,2H),3.52(t,J＝6.2Hz,2H),3.39-3.46(m,2H),1.85-1.79(m,2H)。LCMS M+1＝487.9。

Example 29

3- (2-chlorophenyl) sulfanyl-6- [4- (2-hydroxyethoxy) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: 4- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) benzaldehyde was prepared according to example 28, step a, in 90% yield replacing (3-bromopropoxy) (tert-butyl) dimethylsilane with (2-bromoethoxy) (tert-butyl) dimethylsilane.

And B: (4- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) (thiophen-3-yl) methanol was prepared according to example 7, step a, in 26% yield replacing 4-bromobenzaldehyde with 4- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) benzaldehyde.

And C: prepared according to example 7, step B, in 97% yield from (4- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) (thiophen-3-yl) methanone by substituting (4- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) (thiophen-3-yl) methanol for (4- ((tert-butyldimethylsilyl) oxy) ethoxy).

Step D: (Z) -N- ((4- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) (thiophen-3-yl) methylene) -2-methylpropan-2-sulfinamide prepared according to example 7, step C, in 48% yield by replacing (E) -N- ((4-bromophenyl) (thiophen-3-yl) methylene) -2-methylpropan-2-sulfinamide with (4- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) (thiophen-3-yl) methanone.

Step E: methyl 5- (4- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoate was prepared according to example 7 step D in 66% yield, (E) -N- ((4-bromophenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide was replaced with (Z) -N- ((4- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide.

Step F: prepared according to example 7, step E, 5- (4-bromophenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester was replaced with 5- (4- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester by 5- (4-bromophenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester in 79% yield.

Step G: 6- (4- (2-hydroxyethoxy) phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione was prepared according to example 7, step F, in 93% yield, replacing 5-amino-5- (4- (2-hydroxyethoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5-amino-5- (4- (2-hydroxyethoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.

Step H: 3- ((2-chlorophenyl) thio) -6- (4- (2-hydroxyethoxy) phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione was prepared in 35% yield according to example 7, step G, substituting 6- (4-bromophenyl) -4-hydroxy-6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one with 6- (4- (2-hydroxyethoxy) phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione.¹H NMR(400MHz,CD₃OD)8.38(s,1H),7.54(dd,J＝4.8,2.8Hz,1H),7.29-7.25(m,4H),7.13(dd,J＝5.2,1.2Hz,1H),6.95-6.89(m,3H),6.74-6.69(m,1H),5.85(dd,J＝8.0,1.2Hz,1H),4.84(s,1H),3.96(t,J＝4.8Hz,2H),3.66(d,J＝4.4Hz,2H),3.34(d,J＝4.4Hz,2H)。LCMS M+1＝473.8。

Example 30

3- (2-chlorophenyl) sulfanyl-6- [4- (2-methoxyethoxy) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: 4- (2-methoxyethoxy) benzaldehyde was prepared according to example 28, step A, in 81% yield, replacing (3-bromopropoxy) (tert-butyl) dimethylsilane with 1-bromo-2-methoxyethane.

And B: prepared according to example 7, step a, in 91% yield from (4- (2-methoxyethoxy) phenyl) (thiophen-3-yl) methanol, replacing 4-bromobenzaldehyde with 4- (2-methoxyethoxy) benzaldehyde.

And C: prepared according to example 7, step B, in 50% yield, of (4- (2-methoxyethoxy) phenyl) (thiophen-3-yl) methanone by replacing (4-bromophenyl) (thiophen-3-yl) methanone with (4- (2-methoxyethoxy) phenyl) (thiophen-3-yl) methanol.

Step D: (Z) -N- ((4- (2-methoxyethoxy) phenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide prepared according to example 7, step C, in 58% yield by replacing (E) -N- ((4-bromophenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with (4- (2-methoxyethoxy) phenyl) (thiophen-3-yl) methanone.

Step E: prepared according to example 7, step D, methyl 5- (1, 1-dimethylethylsulfonamido) -5- (4- (2-methoxyethoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoate in 78% yield by replacing (E) -N- ((4-bromophenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with (Z) -N- ((4- (2-methoxyethoxy) phenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide.

Step F: prepared according to example 7, step E, 5-amino-5- (4- (2-methoxyethoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester in 90% yield by replacing 5- (4-bromophenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5- (1, 1-dimethylethylsulfonamido) -5- (4- (2-methoxyethoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.

Step G: 6- (4- (2-methoxyethoxy) phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione was prepared according to example 7, step F, in 26% yield by replacing 5-amino-5- (4- (2-methoxyethoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5-amino-5- (4- (2-methoxyethoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.

Step H: 3- ((2-chlorophenyl) thio) -6- (4- (2-methoxyethoxy) phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione was prepared in 30% yield according to example 7, step G, substituting 6- (4-bromophenyl) -4-hydroxy-6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one with 6- (4- (2-methoxyethoxy) phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione.¹H NMR(400MHz,(CD₃)₂SO)8.45(s,1H),7.58(dd,J＝5.0,3.0Hz,1H),7.28-7.33(m,4H),7.16(dd,J＝5.1,1.1Hz,1H),6.93-6.98(m,3H),6.72-6.76(m,1H),5.87(dd,J＝8.0,1.2Hz,1H),4.09-4.11(m,2H),3.65-3.67(m,2H),3.42(s,2H),3.31(s,3H)。LCMS M+1＝487.9。

Example 31

3- (2-chlorophenyl) sulfanyl-6- [4- (3-methoxypropoxy) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: 4- (3-Methoxypropoxy) benzaldehyde was prepared according to example 28, step A, in 96% yield, replacing (3-bromopropoxy) (tert-butyl) dimethylsilane with 1-bromo-3-methoxypropane.

And B: prepared according to example 7, step a, in 97% yield from (4- (3-methoxypropoxy) phenyl) (thiophen-3-yl) methanol, replacing 4-bromobenzaldehyde with 4- (3-methoxypropoxy) benzaldehyde.

And C: prepared according to example 7, step B, in 68% yield, of (4- (3-methoxypropoxy) phenyl) (thiophen-3-yl) methanone by substituting (4- (3-methoxypropoxy) phenyl) (thiophen-3-yl) methanol for (4- (3-methoxypropoxy) phenyl) (thiophen-3-yl) methanone.

Step D: (Z) -N- ((4- (3-methoxypropoxy) phenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide prepared in 51% yield according to example 7, step C, replacing (E) -N- ((4-bromophenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with (4- (3-methoxypropoxy) phenyl) (thiophen-3-yl) methanone.

Step E: prepared according to example 7, step D, methyl 5- (1, 1-dimethylethylsulfonamido) -5- (4- (3-methoxypropoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoate in 93% yield by replacing (E) -N- ((4-bromophenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with (Z) -N- ((4- (3-methoxypropoxy) phenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide.

Step F: prepared according to example 7, step E, 5-amino-5- (4- (3-methoxypropoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester in 90% yield by replacing 5- (4-bromophenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5- (1, 1-dimethylethylsulfonamido) -5- (4- (3-methoxypropoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.

Step G: 6- (4- (3-Methoxypropoxy) phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione was prepared according to example 7, step F, in 33% yield, replacing 5-amino-5- (4-bromophenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5-amino-5- (4- (3-methoxypropoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.

Step H: 3- ((2-chlorophenyl) thio) -6- (4- (3-methoxypropoxy) phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione was prepared in 33% yield according to example 7, step G, substituting 6- (4-bromophenyl) -4-hydroxy-6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one with 6- (4- (3-methoxypropoxy) phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione.¹H NMR(400MHz,(CD₃)₂SO)8.41(s,1H),7.54(dd,J＝5.1,2.9Hz,1H),7.25-7.30(m,4H),7.13(dd,J＝5.1,1.1Hz,1H),6.88-6.95(m,3H),6.68-6.72(m,1H),5.83(dd,J＝7.9,1.1Hz,1H),4.00(t,J＝6.4Hz,2H),3.44(t,J＝6.3Hz,2H),3.21(s,2H),3.25(s,3H),1.90(t,J＝6.3Hz,2H)。LCMS M+1＝501.9。

Example 32

3- (2-chlorophenyl) sulfanyl-6- (naphthalen-2-yl) -6- (thien-3-yl) piperidine-2, 4-dione

Step A: N-methoxy-N-methylnaphthalene-2-carboxamide was prepared in 90% yield according to example 1, step a, substituting 6-bromopyridine-2-carboxylic acid with naphthalene-2-carboxylic acid.

And B: naphthalen-2-yl (thiophen-3-yl) methanone prepared according to example 1, step B, in 25% yield, 6-bromo-N-methoxy-N-methylpyridine-2-carboxamide was replaced with N-methoxy-N-methylnaphthalene-2-carboxamide.

And C: (E) -2-methyl-N- (naphthalen-2-yl (thiophen-3-yl) methylene) propane-2-sulfinamide prepared according to example 1, step C, in 78% yield, replacing (6-bromopyridin-2-yl) (thiophen-3-yl) methanone with naphthalen-2-yl (thiophen-3-yl) methanone.

Step D: prepared according to example 1, step D, methyl 5- (1, 1-dimethylethylsulfonamido) -5- (naphthalen-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoate in 80% yield by replacing (Z) -N- ((6-bromopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with (E) -2-methyl-N- (naphthalen-2-yl (thiophen-3-yl) methylene) propane-2-sulfinamide.

Step E: 5-amino-5- (naphthalen-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester prepared according to example 1 step E in 80% yield by replacing 5-amino-5- (6-bromopyridin-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5- (1, 1-dimethylethylsulfonamido) -5- (naphthalen-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.

Step F: 4-hydroxy-6- (naphthalen-2-yl) -6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one prepared in 92% yield according to example 1, step F, replacing 6 '-bromo-4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one with methyl 5-amino-5- (naphthalen-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoate.

Step G: 3- ((2-chlorophenyl) thio) -4-hydroxy-6- (naphthalen-2-yl) -6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one prepared according to example 1, step G, in 9% yield from 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -ketone is replaced by 4-hydroxy-6- (naphthalen-2-yl) -6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one.¹H NMR(400MHz,(CD₃)₂SO)11.53(s,1H),8.65(s,1H),7.69-7.62(m,4H),7.61-7.52(m,4H),7.41(dd,J＝2.8,1.2Hz,1H),7.26-7.22(m,2H),6.88-6.84(m,1H),6.30-5.79(m,1H),5.77(d,J＝8.0Hz,1H),3.61(d,J＝16.8Hz,1H),3.61(d,J＝16.8Hz,1H)。LCMS 463.8。

Example 33

3- (2-chlorophenyl) sulfanyl-6- (4-cyclopropylphenyl) -6- (thien-3-yl) piperidine-2, 4-dione

Step A: 4-Cyclopropylbenzaldehyde was prepared according to example 8, step A, in 80% yield by substituting cyclohex-1-en-1-ylboronic acid with cyclopropylboronic acid and 6- (4-bromophenyl) -3- ((2-chlorophenyl) thio) -6- (thiophen-3-yl) piperidine-2, 4-dione with 4-bromobenzaldehyde.

And B: (4-cyclopropylphenyl) (thiophen-3-yl) methanol was prepared according to example 7, step a, in 91% yield, replacing 4-bromobenzaldehyde with 4-cyclopropylbenzaldehyde.

And C: prepared according to example 7, step B, in 88% yield from (4-cyclopropylphenyl) (thiophen-3-yl) methanone by replacing (4-bromophenyl) (thiophen-3-yl) methanol with (4-cyclopropylphenyl) (thiophen-3-yl) methanol.

Step D: (Z) -N- ((4-cyclopropylphenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide was prepared according to example 1, step C, in 71% yield, replacing (6-bromopyridin-2-yl) (thiophen-3-yl) methanone with (4-cyclopropylphenyl) (thiophen-3-yl) methanone.

Step E: prepared according to example 1, step D, methyl 5- (4-cyclopropylphenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoate in 98% yield by replacing (Z) -N- ((6-bromopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with (Z) -N- ((4-cyclopropylphenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide.

Step F: prepared according to example 1, step E, 5-amino-5- (4-cyclopropylphenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester in 72% yield by replacing 5-amino-5- (6-bromopyridin-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5- (4-cyclopropylphenyl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.

Step G: 6- (4-cyclopropylphenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione was prepared according to example 1, step F, in 55% yield by substituting 6 '-bromo-4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one with methyl 5-amino-5- (4-cyclopropylphenyl) -3-oxo-5- (thiophen-3-yl) pentanoate.

Step H: 3- ((2-chlorophenyl) thio) -6- (4-cyclopropylphenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione was prepared according to example 1, step G, in 38% yield from 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one is replaced by 6- (4-cyclopropylphenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione.¹H NMR(400MHz,(CD₃)₂SO)7.47(dd,J＝8.0,8.0Hz,1H),7.31-7.27(m,3H),7.18(dd,J＝4.0,4.0Hz,1H),7.11(dd,J＝8.0,4.0Hz,1H),7.02(d,J＝8.0Hz,2H),6.84(dd,J＝8.0,8.0Hz,1H),6.67(dd,J＝8.0,8.0Hz,1H),5.98(d,J＝8.0Hz,1H),3.24(d,J＝5.2Hz,2H),1.92-1.86(m,1H),0.96-0.91(m,2H),0.67-0.63(m,2H)。LCMS M+1＝453.8。

Example 34

3- (2-chlorophenyl) sulfanyl-1-methyl-6- [3- (tetrahydropyran-4-ylamino) phenyl ] -6- (thien-3-yl) piperidine-2, 4-dione

Step A: prepared from 6- (3-bromophenyl) -3- ((2-chlorophenyl) thio) -4-hydroxy-1-methyl-6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one by example 11 step a in 15% yield by substituting 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one with 6- (3-bromophenyl) -3- ((2-chlorophenyl) thio) -4-hydroxy-6- (thiophen-3-yl) -5, 6-dihydropyridin-2 (1H) -one.

And B: 3- (2-chlorophenyl) sulfanyl-1-methyl-6- [3- (tetrahydropyran-4-ylamino) phenyl]-6- (thien-3-yl) piperidine-2, 4-dione was prepared according to example 7, step H, in 6% yield, replacing 2-methylmorpholine with tetrahydro-2H-pyran-4-amine.¹H NMR(400MHz,(CD₃)₂SO)11.3(s,1H),7.67(dd,J＝5.2,3.2Hz,1H),7.31(dd,J＝8.0,1.6Hz,1H),7.15-7.10(m,3H),6.98(dd,J＝7.6,1.2Hz,1H),6.88(dd,J＝7.6,1.2Hz,1H),6.61(dd,J＝8.4,1.6Hz,1H),6.43(m,2H),6.15(d,J＝8.4Hz,1H),3.85(m,2H),3.60(d,J＝16.8Hz,1H),3.48(d,J＝16.8Hz,1H),3.44(m,3H),2.69(s,3H),1.82(m,2H),1.34(m,2H)。LCMS M+1＝527.0。

Example 35

3- (2-chlorophenyl) sulfanyl-6- (2-hydroxy-4-morpholino-phenyl) -6- (thien-3-yl) piperidine-2, 4-dione

Step A: 4-fluoro-2-hydroxy-N-methoxy-N-methylbenzamide was prepared according to example 1, step a, in 75% yield, replacing 6-bromopyridine-2-carboxylic acid with 4-fluoro-2-hydroxybenzoic acid.

And B: 4-fluoro-N-methoxy-2- (methoxymethoxy) -N-methylbenzamide prepared according to example 13, step a, in 62% yield, substituting 5-bromo-2-hydroxybenzaldehyde with 4-fluoro-2-hydroxy-N-methoxy-N-methylbenzamide.

And C: prepared according to example 1, step B, in 41% yield from (4-fluoro-2- (methoxymethoxy) phenyl) (thiophen-3-yl) methanone, 6-bromo-N-methoxy-N-methylpyridine-2-carboxamide was replaced with 4-fluoro-N-methoxy-2- (methoxymethoxy) -N-methylbenzamide.

Step D: to a solution of (4-fluoro-2- (methoxymethoxy) phenyl) (thiophen-3-yl) methanone (10g,38mmol) in NMP (50mL) was added morpholine (16.4g,188mmol) and K₂CO₃(10.4g,75 mmol). The solution was stirred at 120 ℃ for 8 hours. The reaction mixture was quenched with water, adjusted to pH 5 with HCl solution, extracted with DCM and concentrated in vacuo. The crude residue was purified by silica gel column to give (6- (4-fluorophenoxy) pyridin-2-yl) (2- (methoxymethoxy) phenyl) methanone (7.2g, 60% yield).

Step E: prepared according to example 1, step C, N- ((2-hydroxy-4-morpholinophenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide in 10% yield, replacing (6-bromopyridin-2-yl) (thiophen-3-yl) methanone with (6- (4-fluorophenoxy) pyridin-2-yl) (2- (methoxymethoxy) phenyl) methanone.

Step F: prepared according to example 1, step D, methyl 5- (1, 1-dimethylethylsulfonamido) -5- (2-hydroxy-4-morpholinophenyl) -3-oxo-5- (thiophen-3-yl) pentanoate in 36% yield by replacing N- ((6-bromopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with N- ((2-hydroxy-4-morpholinophenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide.

Step G: prepared according to example 1, step E, 5-amino-5- (2-hydroxy-4-morpholinophenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester in 40% yield by replacing 5- (6-bromopyridin-2-yl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5- (1, 1-dimethylethylsulfonamido) -5- (2-hydroxy-4-morpholinophenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.

Step H: 3- (2-chlorophenyl) sulfanyl-6- (2-hydroxy-4-morpholino-phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione was prepared in 2% yield according to example 1, step G, by reacting 6 '-bromo-4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one is replaced by 5-amino-5- (2-hydroxy-4-morpholinophenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.¹H NMR(400MHz,(CD₃)₂SO)7.36(d,J＝5.2Hz,1H),7.20-7.15(m,3H),7.06(d,J＝5.2Hz,1H),6.92(dd,J＝7.6,1.6Hz,1H),6.77(dd,J＝7.6,1.6Hz,1H),6.50(m,2H),6.19(d,J＝8.0Hz,1H),3.83(dd,J＝4.8,4.8Hz,4H),3.68(d,J＝16.4Hz,1H),3.36(d,J＝16.4Hz,1H),3.13(dd,J＝4.8,4.8Hz,4H)。LCMS M+1＝514.9。

Example 36

3- (2-chlorophenyl) sulfanyl-6- (2-hydroxyphenyl) -6- (thien-3-yl) piperidine-2, 4-dione

Step A: 2- (methoxymethoxy) benzaldehyde was prepared according to example 13, step A, at 82% replacing 5-bromo-2-hydroxybenzaldehyde with 2-hydroxybenzaldehyde.

And B: prepared according to example 7, step a, in 60% yield from (2- (methoxymethoxy) phenyl) (thiophen-3-yl) methanol, substituting 4-bromobenzaldehyde with 2- (methoxymethoxy) benzaldehyde.

And C: prepared according to example 7, step B, in 71% yield from (2- (methoxymethoxy) phenyl) (thiophen-3-yl) methanone by substituting (4-bromophenyl) (thiophen-3-yl) methanol with (2- (methoxymethoxy) phenyl) (thiophen-3-yl) methanol.

Step D: n- ((2- (methoxymethoxy) phenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide was prepared according to example 1, step C, in 50% yield replacing (6-bromopyridin-2-yl) (thiophen-3-yl) methanone with (2- (methoxymethoxy) phenyl) (thiophen-3-yl) methanone.

Step E: prepared according to example 1, step D, methyl 5- (1, 1-dimethylethylsulfonamido) -5- (2- (methoxymethoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoate in 47% yield by replacing N- ((6-bromopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with N- ((2- (methoxymethoxy) phenyl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide.

Step F: prepared according to example 1, step E, 5-amino-5- (2-hydroxyphenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester in 51% yield by replacing 5- (6-bromopyridin-2-yl) -5- (1, 1-dimethylethylsulfonamido) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5- (1, 1-dimethylethylsulfonamido) -5- (2- (methoxymethoxy) phenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.

Step G: 6- (2-hydroxyphenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione was prepared according to example 1, step F, in 60% yield, replacing 5-amino-5- (6-bromopyridin-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5-amino-5- (2-hydroxyphenyl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester.

Step H: 3- ((2-chlorophenyl) thio) -4-hydroxy-6- (2-hydroxyphenyl) -6- (thiophen-3-yl) -5, 6-dihydropirPyridin-2 (1H) -one was prepared in 7% yield according to example 1, step G starting from 6 '-bromo-4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine]-6(1H) -one is replaced by 6- (2-hydroxyphenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione.¹HNMR(400MHz,(CD₃)₂SO)9.81(s,1H),7.69(s,1H),7.46(d,J＝5.2Hz,1H),7.29(m,3H),7.26(m,1H),7.17(m,1H),6.96(m,1H),6.86(m,2H),6.74(m,1H),6.10(d,J＝8.0Hz,1H),3.74(d,J＝16.4Hz,1H),3.42(d,J＝16.4Hz,1H)。LCMS M+1＝429.8。

Example 37

Step A: to a stirred solution of 6- (4-bromophenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione (5g,14.3mmol) in DMF (50mL) in an ice bath was added NBS (3.05g,17.8 mol). The reaction mixture was stirred at 0 ℃ for 30 min. The reaction mixture was used directly in the next step.

And B: to a solution of 3-bromo-6- (4-bromophenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione (14.3mmol) in DMF (50mL) was added 2-chlorophenol (2.8g,21.5mmol) and potassium carbonate (5.9g,42.9 mmol). The reaction mixture was stirred at 80 ℃ for 12 hours. The reaction mixture was extracted with EtOAc and brine. The organic layer was dried and concentrated. The crude material was purified by silica gel chromatography (PE/EA ═ 2/1) to give 6- (4-bromophenyl) -3- (2-chlorophenoxy) -6- (thiophen-3-yl) piperidine-2, 4-dione (2g,4.2mmol, 29%) as a light colored solid.

And C: to a solution of 6- (4-bromophenyl) -3- (2-chlorophenoxy) -6- (thiophen-3-yl) piperidine-2, 4-dione (600mg,1.26mmol) in dioxane (10mL) was added morpholine (328mg,3.77mmol), Brettphos (65mg,0.13mmol), Pd₂(dba)₃(64mg,0.07mmol) and t-BuONa (362mg,3.77 mmol). The solution was stirred at 110 ℃ under nitrogen for 8 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (FA) and SFC to give (6S) -3- (2-chlorophenoxy) -6- (4-morpholino)Phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione (35mg, 6%) as a white solid.

Step D: prepared according to example 37, step C, in 8% yield from (6S) -3- (2-chlorophenoxy) -6- (4- (piperidin-1-yl) phenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione substituting morpholine for piperidine.

Example 38

6- (6-Bromopyridin-2-yl) -3- ((2-chlorophenyl) thio) -6- (4-morpholinophenyl) piperidine-2, 4-dione

Step A: to a solution of 2, 6-dibromopyridine (8.39g,31.4mmol) in isopropyl ether (500mL) was added n-BuLi (12.6mL,31.4mmol) at-78 deg.C under nitrogen. The mixture was then stirred for 1 h. 4-Morpholinobenzaldehyde (5g,26.2mmol) was added to the above solution and the mixture was stirred at-78 ℃ for 2 h. TLC showed the reaction was complete. The mixture was quenched with MeOH and acidified to pH 4 with 1N HCl and extracted with DCM (100mL × 2). The combined organic layers were dried over sodium sulfate and the crude product was purified by silica gel chromatography (PE: EA ═ 3:1) to give the expected product (6.8g, 79%) as a yellow oil.

And B: prepared in 69% yield according to example 7, step B, using (6-bromopyridin-2-yl) (4-morpholinophenyl) methanone to replace (4-bromophenyl) (thiophen-3-yl) methanol with (6-bromopyridin-2-yl) (4-morpholinophenyl) methanol.

And C: (Z) -N- ((6-bromopyridin-2-yl) (4-morpholinophenyl) methylene) -2-methylpropane-2-sulfinamide was prepared according to example 1, step C, in 58% yield by replacing (6-bromopyridin-2-yl) (thiophen-3-yl) methanone with (6-bromopyridin-2-yl) (4-morpholinophenyl) methanone.

Step D: prepared according to example 1, step D, methyl 5- (6-bromopyridin-2-yl) -5- (1, 1-dimethylethylsulfonamido) -5- (4-morpholinophenyl) -3-oxopentanoate in 79% yield from (Z) -N- ((6-bromopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide to (Z) -N- ((6-bromopyridin-2-yl) (4-morpholinophenyl) methylene) -2-methylpropane-2-sulfinamide.

Step E: prepared according to example 1, step E, 5-amino-5- (6-bromopyridin-2-yl) -5- (4-morpholinophenyl) -3-oxopentanoic acid methyl ester in 67% yield by replacing 5-amino-5- (6-bromopyridin-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5- (6-bromopyridin-2-yl) -5- (1, 1-dimethylethylsulfonamido) -5- (4-morpholinophenyl) -3-oxopentanoic acid methyl ester.

Step F: prepared according to example 1, step F, 6 '-bromo-4-hydroxy-2- (4-morpholinophenyl) -2, 3-dihydro- [2, 2' -bipyridin ] -6(1H) -one in 47% yield by replacing 6 '-bromo-4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridin ] -6(1H) -one with methyl 5-amino-5- (6-bromopyridin-2-yl) -5- (4-morpholinophenyl) -3-oxopentanoate.

Step G: prepared according to example 1, step G, in 96% yield from 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (4-morpholinophenyl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one, the 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one was replaced with 6 '-bromo-4-hydroxy-2- (4-morpholinophenyl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one.

Example 39

Step A: 3- ((2-chlorophenyl) thio) -6- (6- ((4-fluorophenyl) amino) pyridin-2-yl) -6- (4-morpholinophenyl) piperidine-2, 4-dione was prepared according to example 4, step a, in 42% yield by substituting 6- (6-bromopyridin-2-yl) -3- ((2-chlorophenyl) thio) -6- (thiophen-3-yl) piperidine-2, 4-dione with 6- (6-bromopyridin-2-yl) -3- ((2-chlorophenyl) thio-6- (4-morpholinophenyl) piperidine-2, 4-dione and cyclohexylamine is replaced by 4-fluoroaniline.¹H NMR (400MHz, methanol-d)₄) 7.57(dd, J ═ 8.0,8.0Hz,1H),7.54 to 7.50(m,2H),7.36(d, J ═ 9.2,2H),7.20 to 6.92(m,6H),6.73 to 6.67(m,2H),6.12(d, J ═ 7.2Hz,1H),3.84(dd, J ═ 9.2,4.4Hz,4H),3.75(d, J ═ 16.4Hz,1H),3.49(d, J ═ 16.4Hz,1H),3.16(dd, J ═ 9.2,4.4Hz,4H), single stereoisomers.¹HNMR (400MHz, methanol-d)₄)7.51 (dd, J ═ 8.0,8.0Hz,1H),7.49-7.47(m,2H),7.33(d, J ═ 8.8,2H),7.18(d, J ═ 8.0,1H),6.99-6.89(m,6H),6.71-6.69(m,2H),6.07(dd, J ═ 6.4,1.6Hz,1H),3.81(dd, J ═ 4.8,4.8Hz,4H),3.78(d, J ═ 16.8Hz,1H),3.47(d, J ═ 16.8Hz,1H),3.15(dd, J ═ 4.8,4.8Hz,4H), mixtures of diastereomers.

Example 40

Step A: 3- (2-chlorophenyl) sulfanyl-6- [6- (3, 4-difluorophenoxy) pyridin-2-yl]-6- (4-morpholinophenyl) piperidine-2, 4-dione was prepared according to example 3, step a, in 47% yield by substituting 6- (6-bromopyridin-2-yl) -3- ((2-chlorophenyl) thio) -6- (thiophen-3-yl) piperidine-2, 4-dione with 6- (6-bromopyridin-2-yl) -3- ((2-chlorophenyl) thio) -6- (4-morpholinophenyl) piperidine-2, 4-dione and 2-chloro-4-fluoro-phenol with 3, 4-difluorophenol.¹H NMR (400MHz, methanol-d)₄) 7.88(dd, J ═ 8.0,8.0Hz,1H),7.33(d, J ═ 7.2,1H),7.20-7.16(m,4H),7.02-6.92(m,5H),6.85(d, J ═ 7.2,1H),6.72(dd, J ═ 8.0,8.0,1H),5.91(dd, J ═ 8.0,1.2Hz,1H),3.81(dd, J ═ 4.8,4.8Hz,4H),3.55(d, J ═ 16.8Hz,1H),3.31(d, J ═ 16.8Hz,1H),3.12(dd, J ═ 4.8, 4H), mixtures of diastereomers.¹H NMR (400MHz, methanol-d)₄)d＝7.91(dd,J＝7.6,7.6Hz,1H),7.37(d,J＝7.6,1H),7.36-7.21(m,4H),7.04-6.96(m,2H),6.93-6.85(m,4H),6.75(dd,J＝7.6,7.6,1H),3.84(dd,J＝4.8,4.8Hz,4H),3.55(d,J＝16.8Hz,1H),3.33(d,J＝16.8Hz,1H),3.16(dd,J＝4.8,4.8Hz,4H), single stereoisomers.

EXAMPLE 41

Step A: 3- ((2-chlorophenyl) thio) -6- (6- (cyclohexyloxy) pyridin-2-yl) -6- (4-morpholinophenyl) piperidine-2, 4-dione was prepared according to example 4, step A in 11% yield, 6- (6-bromopyridin-2-yl) -3- ((2-chlorophenyl) thio) -6- (thiophen-3-yl) piperidine-2, 4-dione was replaced with 6- (6-bromopyridin-2-yl) -3- ((2-chlorophenyl) thio) -6- (4-morpholinophenyl) piperidine-2, 4-dione and propan-2-ol was replaced with cyclohexanol.

Example 42

Step A: N-methoxy-N-methylthiazole-4-carboxamide was prepared according to example 1, step a, in 67% yield, replacing 6-bromopyridine-2-carboxylic acid with thiazole-4-carboxylic acid.

And B: (4-fluorophenyl) (thiazol-4-yl) methanone was prepared according to example 36, step a, in 72% yield, substituting 4-bromothiophene-2-carbaldehyde with N-methoxy-N-methylthiazole-4-carboxamide.

And C: prepared according to example 34, step D, in 56% yield, of (4-morpholinophenyl) (thiazol-4-yl) methanone by replacing (4-fluoro-2- (methoxymethoxy) phenyl) (thiophen-3-yl) methanone with (4-fluorophenyl) (thiazol-4-yl) methanone.

Step D: (Z) -2-methyl-N- ((4-morpholinophenyl) (thiazol-4-yl) methylene) propane-2-sulfinamide was prepared according to example 1, step C, in 56% yield replacing (6-bromopyridin-2-yl) (thiophen-3-yl) methanone with (4-morpholinophenyl) (thiazol-4-yl) methanone.

Step E: 5- (1, 1-Dimethylethylsulfonamido) -5- (4-morpholinophenyl) -3-oxo-5- (thiazol-4-yl) pentanoic acid methyl ester was prepared according to example 1, step D, substituting (Z) -N- ((6-bromopyridin-2-yl) (thiophen-3-yl) methylene) -2-methylpropane-2-sulfinamide with (Z) -2-methyl-N- ((4-morpholinophenyl) (thiazol-4-yl) methylene) propane-2-sulfinamide.

Step F: 5-amino-5- (4-morpholinophenyl) -3-oxo-5- (thiazol-4-yl) pentanoic acid methyl ester prepared according to example 1, step E, 5-amino-5- (6-bromopyridin-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester was replaced with 5- (1, 1-dimethylethylsulfonamido) -5- (4-morpholinophenyl) -3-oxo-5- (thiazol-4-yl) pentanoic acid methyl ester.

Step G: prepared according to example 1, step F, 4-hydroxy-6- (4-morpholinophenyl) -6- (thiazol-4-yl) -5, 6-dihydropyridin-2 (1H) -one in 18% yield (over three steps) by replacing 5-amino-5- (6-bromopyridin-2-yl) -3-oxo-5- (thiophen-3-yl) pentanoic acid methyl ester with 5-amino-5- (4-morpholinophenyl) -3-oxo-5- (thiazol-4-yl) pentanoic acid methyl ester.

Step H: 3- ((2-chlorophenyl) thio) -6- (4-morpholinophenyl) -6- (thiazol-4-yl) piperidine-2, 4-dione was prepared according to example 1, step G, in 3% yield by replacing 6 '-bromo-5- ((2-chlorophenyl) thio) -4-hydroxy-2- (thiophen-3-yl) -2, 3-dihydro- [2, 2' -bipyridine ] -6(1H) -one with 4-hydroxy-6- (4-morpholinophenyl) -6- (thiazol-4-yl) -5, 6-dihydropyridin-2 (1H) -one.

Example 43

Step A: 6- (4-bromophenyl) -3- ((2-chloro-5-hydroxyphenyl) thio) -6- (thiophen-3-yl) piperidine-2, 4-dione was prepared according to example 7, step B, in 68% yield, replacing 1, 2-bis (2-chlorophenyl) disulfane with 4-chloro-3-mercaptophenol.

And B: to a solution of 6- (4-bromophenyl) -3- ((2-chloro-5-hydroxyphenyl) thio) -6- (thiophen-3-yl) piperidine-2, 4-dione (200mg,0.4mmol) in dioxane (4mL) was added piperidine (136mg,1.6mmol), Brettphos (20mg,0.04mmol), Pd₂(dba)₃(18mg,0.02mmol) and t-BuONa (154mg,1.6 mmol). The solution was stirred at 110 ℃ under nitrogen atmosphere for 8 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (FA) to give compound 43(12mg, 6%) as a white solid.

The following compounds were prepared as shown in the tables and were prepared according to the methods described herein unless otherwise indicated.

ST: stereochemistry; SS is a single stereoisomer; mixture of MD ═ diastereomers

Example 417

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenylamino) pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione (racemate)

To a solution of 2, 6-dibromopyridine (5.0g,21mmol) in anhydrous THF (50mL) cooled in a dry ice-acetone bath was added 2.5M butyllithium (8.4mL,21mmol) and the resulting mixture was stirred for 10 min. To this solution was added thiophene-3-carbaldehyde (2.4g,21mmol) and the resulting mixture was stirred at-78 ℃ for 10 min. The reaction mixture was quenched with water and warmed to room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc/heptane) to give (6-bromopyridin-2-yl) - (thiophen-3-yl) -methanol (2.6g, 46%). Ms (esi): m + H272.¹H NMR (400MHz, chloroform-d) 7.51(t, J ═ 7.7Hz,1H),7.40(d, J ═ 7.8Hz,1H),7.29(dd, J ═ 5.0,3.0Hz,1H),7.05-7.01(m,1H),7.26(s,1H),7.20(d, J ═ 7.6Hz,1H),7.03(dd, J ═ 5.0,1.2Hz,1H),5.84(d, J ═ 4.0Hz,1H),4.17(d, J ═ 4.9Hz, 1H).

A mixture of (6-bromopyridin-2-yl) - (thiophen-3-yl) -methanol (2.6g,9.6mmol) and Des-Martin iodophor (6.3g,14mmol) in DCM (50mL) was stirred at ambient temperature for 2 h. The solid was removed by filtration through celite and washed thoroughly with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate, water, brine and dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc/heptane) to give (6-bromo-pyridin-2-yl) - (thiophen-3-yl) -methanone (1.8g, 70%). Ms (esi): m + H270.¹H NMR (400MHz, chloroform-d) 8.92(dd, J ═ 3.0,1.1Hz,1H),8.14-8.08(m,1H),7.88(dd, J ═ 5.1,1.2Hz,1H),7.75(t, J ═ 7.7Hz,1H),7.67(d, J ═ 7.8Hz,1H),7.34(dd,J＝5.1,3.0Hz,1H)。

a mixture of (6-bromo-pyridin-2-yl) - (thiophen-3-yl) -methanone (2.5g,9.3mmol), 2-methylpropane-2-sulfinamide (1.7g,14mmol) and titanium tetraethoxide (4.3g,19mmol) in THF was heated at reflux for 20 h. The reaction mixture was cooled, diluted with water and stirred with ethyl acetate. The solids were removed by filtration through celite. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (silica gel, 0-100% EtOAc/heptane) to give 2-methylpropane-2-sulfinic acid 1- (6-bromo-pyridin-2-yl) -1- (thiophen-3-yl) -meth- (Z) -ylideneamide (2.1g, 61%). Ms (esi): m + H373.

To a solution of ethyl acetate in anhydrous THF (0.47g,5.4mmol) cooled in a dry ice-acetone bath was added 2M LDA/heptane/ethylbenzene (2.7mL,5.4mmol) and the mixture was stirred for 10min and a solution of 2-methylpropane-2-sulfinic acid 1- (6-bromo-pyridin-2-yl) -1- (thiophen-3-yl) -methyl- (Z) -ylideneamide (1.0g,2.7mmol) in THF (3mL) was added slowly. The resulting mixture was stirred for 10min, quenched with saturated ammonium chloride, warmed to ambient temperature and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. It was purified by flash chromatography (silica gel, 0-100% EtOAc/heptane) to give ethyl 3- (6-bromo-pyridin-2-yl) -3- (2-methylpropan-2-sulfinylamino) -3- (thiophen-3-yl) -propionate (1.1 g). Ms (esi): m + H461.

Ethyl 3- (6-bromo-pyridin-2-yl) -3- (2-methylpropane-2-sulfinylamino) -3- (thiophen-3-yl) -propionate (1.1g,2.0mmol) was dissolved in DCM (5mL) and 4N HCl-1, 4-dioxane (4mL,16mmol) was added and the mixture was stirred for 15 min. The solvent was removed and to the residue was added (2-chloro-phenylsulfanyl) -acetic acid (0.52g,2.6mmol), HATU (1.1g,2.8mmol) and DMF (5mL), followed by DIPEA (1.4mL,7.8 mmol). The resulting mixture was stirred for 1h, then diluted with water and extracted with ethyl acetate. The organic layer was washed several times with brine, dried over sodium sulfate and concentrated. The residue was dissolved in toluene (5mL) and 25% sodium methoxide/methanol (1.5mL,6.5mmol) was added and the resulting dark solution was heated at 80 ℃ for 15 min. The reaction mixture was cooled, acidified with 1N HCl and extracted with ethyl acetate.The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 0-100% EtOAc/heptane) to give 6- (6-bromopyridin-2-yl) -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione (0.56 g). Ms (esi): m + H566.¹HNMR(400MHz,DMSO-d6)11.62(s,1H),8.68(s,1H),7.73-7.61(m,2H),7.61-7.53(m,2H),7.43-7.33(m,4H),7.30(dd,J＝8.0,1.3Hz,1H),7.03-6.93(m,1H),6.77-6.69(m,1H),5.84(dd,J＝8.0,1.5Hz,1H),3.49(s,2H)。

A mixture of 6- (6-bromopyridin-2-yl) -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione (0.50g,1mmol), 4-fluoroaniline (0.22g,2mmol), Brettphos-Admix (0.13g,0.1mmol) and sodium tert-butoxide (0.3g,3mmol) in a mixture of tert-butanol and 1, 4-dioxane (1:1 mixture, 10ml) was heated in a sealed tube at 105 ℃ for 1 h. The reaction mixture was cooled and the solid was collected by filtration. The solid was acidified with 1N HCl and then dissolved in ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography (silica gel, 20-100% EtOAc/heptane) afforded 3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenylamino) pyridin-2-yl]-6- (thien-3-yl) piperidine-2, 4-dione (racemate) (0.30g, 56%). Ms (esi): m + H524.¹H NMR(400MHz,DMSO-d6)11.48(s,1H),9.12(s,1H),8.37(s,1H),7.66-7.57(m,3H),7.53(dd,J＝5.1,3.0Hz,1H),7.39(dd,J＝3.0,1.4Hz,1H),7.30(dd,J＝7.9,1.3Hz,1H),7.18(dd,J＝5.1,1.4Hz,1H),7.11-7.03(m,3H),6.99-6.92(m,1H),6.81(ddd,J＝8.5,7.3,1.3Hz,1H),6.72(dd,J＝8.3,0.7Hz,1H),6.06(dd,J＝8.0,1.5Hz,1H),3.77(d,J＝16.4Hz,1H),3.45(d,J＝16.5Hz,1H)。

Enantiomer 1: chiral SFC (column: AS, EtOH w/0.1% FA) RT 0.892 min.¹H NMR(400MHz,DMSO-d6)11.49(s,1H),9.12(s,1H),7.67-7.57(m,3H),7.52(dd,J＝5.1,2.9Hz,1H),7.39(dd,J＝3.0,1.4Hz,1H),7.30(dd,J＝7.9,1.3Hz,1H),7.18(dd,J＝5.1,1.4Hz,1H),7.12-7.00(m,3H),6.99-6.92(m,1H),6.85-6.78(m,1H),6.72(d,J＝8.3Hz,1H),6.06(dd,J＝8.0,1.5Hz,1H),3.76(d,J＝16.5Hz,1H),3.44(d,J＝16.5Hz,1H)。

Enantiomer 2: chiral SFC (column: AS, EtOH w >0.1％FA):RT＝1.276min。¹H NMR(400MHz,DMSO-d6)11.48(s,1H),9.12(s,1H),8.36(s,1H),7.67-7.55(m,3H),7.53(dd,J＝5.0,3.0Hz,1H),7.39(dd,J＝3.0,1.4Hz,1H),7.30(dd,J＝7.9,1.3Hz,1H),7.18(dd,J＝5.1,1.4Hz,1H),7.11-7.02(m,3H),7.00-6.93(m,1H),6.86-6.78(m,1H),6.72(d,J＝8.3Hz,1H),6.06(dd,J＝7.9,1.5Hz,1H),3.77(d,J＝16.4Hz,1H),3.45(d,J＝16.4Hz,1H)。

Example 418

4- [6- [5- (2-chlorophenyl) sulfanyl-4, 6-dioxo-2- (thiophen-3-yl) piperidin-2-yl ] pyridin-2-yl ] -N, N-dimethyl-benzenesulfonamide (racemate)

6- (6-Bromopyridin-2-yl) -3- (2-chlorophenyl) sulfanyl-6- (thien-3-yl) piperidine-2, 4-dione (0.50g,1mmol), 4-fluoroaniline (0.06g,0.10mmol), N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (0.05g,0.12mmol), PdCl₂(PPh₃)₂A mixture of (0.015g,0.014mmol) and sodium carbonate (0.05g,0.47mmol) in 1, 4-dioxane was heated in a microwave reactor at 110 ℃ for 20 min. The reaction mixture was cooled, acidified with 1N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography (silica gel, 0-100% EtOAc/heptane) afforded 4- [6- [5- (2-chlorophenyl) sulfanyl-4, 6-dioxo-2- (thiophen-3-yl) piperidin-2-yl]Pyridin-2-yl]-N, N-dimethyl-benzenesulfonamide (0.04 g). Ms (esi): m + H598.¹H NMR(400MHz,DMSO-d6)11.69(s,1H),8.65(s,1H),8.51-8.43(m,2H),8.16-8.03(m,2H),7.88-7.81(m,2H),7.74(d,J＝7.7Hz,1H),7.54(dd,J＝5.1,3.0Hz,1H),7.38(dd,J＝3.0,1.4Hz,1H),7.26(dd,J＝7.9,1.2Hz,1H),7.19(dd,J＝5.0,1.3Hz,1H),6.89(td,J＝7.7,1.5Hz,1H),6.56(td,J＝7.7,1.3Hz,1H),5.81(dd,J＝8.0,1.5Hz,1H),4.14(d,J＝16.3Hz,1H),3.45(d,J＝16.2Hz,1H),2.65(s,6H)。

Example 419

3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenoxy) pyridin-2-yl ] -6- (thien-3-yl) piperidine-2, 4-dione

Mixing 6- (6-bromopyridin-2-yl) -3- ((2-chlorophenyl) thio) -6- (thiophen-3-yl) piperidine-2, 4-dione (0.50g,1mmol), 4-fluorophenol (0.34g,3mmol), Pd₂(dba)₃A mixture of (0.10g,0.1mmol), tert-BuX-phos (0.10g,0.24mmol) and sodium tert-butoxide (0.3g,3mmol) in 1, 4-dioxane (10ml) was heated in a microwave reactor at 110 ℃ for 30 min. The reaction mixture was cooled and the solid was collected by filtration. The solid was acidified with 1N HCl and then dissolved in ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography (silica gel, 20-100% EtOAc/heptane) afforded 3- (2-chlorophenyl) sulfanyl-6- [6- (4-fluorophenoxy) pyridin-2-yl]-6- (thien-3-yl) piperidine-2, 4-dione racemate (0.30g, 56%). LC/MS, m + H525.¹H NMR(400MHz,DMSO-d6)11.44(s,1H),8.43(s,1H),7.98-7.87(m,1H),7.50(dd,J＝5.1,3.0Hz,1H),7.41(d,J＝7.5Hz,1H),7.32-7.22(m,3H),7.16-7.08(m,2H),7.08-6.91(m,3H),6.84-6.75(m,1H),5.95(dd,J＝8.0,1.5Hz,1H),3.57(d,J＝16.5Hz,1H),3.25(s,1H)。

Enantiomer 1: chiral SFC (column: AD; MeOH/0.1% NH)₄OH):RT＝0.521

Enantiomer 2: chiral SFC (column: AD; MeOH/0.1% NH)₄OH):RT＝0.775

Example 420

2- [ [6- (6-bromopyridin-2-yl) -2, 4-dioxo-6- (thiophen-3-yl) piperidin-3-yl ] sulfanyl ] benzonitrile (MD)

6- (6-Bromopyridin-2-yl) -6- (thien-3-yl) piperidine-2, 4-dione (0.14g,0.40mmol), 2- [ (2-cyanophenyl) dithio-alkyl]A mixture of benzonitrile (0.21g,0.80mmol) and potassium carbonate (0.17g,1.20mmol) was heated in acetonitrile (5mL) for 1 h. The reaction mixture was cooled, acidified with dilute HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 0-100% EtOAc/heptane) to give 2- [ [6- (6-bromopyridin-2-yl) -2, 4-dioxo-6- (thiophen-3-yl) piperidin-3-yl]Sulfanyl radical]Benzonitrile (0.04g, 20%). Ms (esi): m + H484.¹H NMR(400MHz,DMSO-d6)11.94(s,1H),8.58(s,1H),7.86(t,J＝7.8Hz,1H),7.72-7.62(m,3H),7.56(dd,J＝5.1,3.0Hz,1H),7.37-7.30(m,1H),7.15(td,J＝5.2,4.6,1.7Hz,3H),6.16-6.00(m,1H),3.84(d,J＝16.4Hz,1H),3.43(d,J＝16.4Hz,1H)。

Example 421

6- (3-bromophenyl) -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione (0.50g,1mmol), 4-fluorophenol (0.34g,3mmol), and Pd₂(dba)₃A mixture of (0.10g,0.1mmol), tert-BuX-phos (0.10g,0.24mmol) and sodium tert-butoxide (0.3g,3mmol) in 1, 4-dioxane (10ml) was heated at 110 ℃ for 30 min. The reaction mixture was cooled, acidified with 1N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography (silica gel, 0-100% EtOAc/heptane) afforded 3- (2-chlorophenyl) sulfanyl-6- (3-hydroxyphenyl) -6- (thiophen-3-yl) piperidine-2, 4-dione (25 mg). Ms (esi): m + H430.¹H NMR(400MHz,DMSO-d6)11.44(s,1H),9.43(s,1H),8.33(s,1H),7.56(dd,J＝5.1,2.9Hz,1H),7.35(dd,J＝3.0,1.4Hz,1H),7.28(dd,J＝8.0,1.3Hz,1H),7.20-7.13(m,2H),7.02-6.92(m,1H),6.87-6.67(m,4H),5.94(dd,J＝8.0,1.5Hz,1H),3.44-3.36(m,2H)。

Example 422

To a solution of 1-7(0.21g,0.60mmol) in DCM (10mL) was added NBS (0.10g,0.60mmol) and the resulting mixture was stirred for 1 h. The reaction mixture was washed with water, brine, dried over sodium sulfate and concentrated. The resulting residue was dissolved in acetonitrile (5ml) and 2-chlorophenol (0.15g,1.2mmol) and potassium carbonate (0.16g,1.2mmol) were added and the mixture was heated at 85 ℃ for 20 h. The reaction mixture was cooled, acidified with dilute HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography (silica gel, 0-100% EtOAc/heptane) afforded 6- (6-bromopyridin-2-yl) -3- (2-chlorophenoxy) -6- (thiophen-3-yl) piperidine-2, 4-dione (0.20g, 70%). Ms (esi): m + H479.¹H NMR(400MHz,DMSO-d6)10.74(s,1H),8.33(s,1H),7.89-7.81(m,1H),7.70-7.61(m,2H),7.58-7.51(m,1H),7.43-7.29(m,2H),7.15(dd,J＝5.1,1.4Hz,1H),6.99-6.83(m,2H),6.13(dd,J＝8.2,1.5Hz,1H),3.74-3.66(m,1H),3.36(d,J＝16.2Hz,1H)。

6- (6-Bromopyridin-2-yl) -3- (2-chlorophenoxy) -6- (thiophen-3-yl) piperidine-2, 4-dione (0.05g,0.10mmol) was converted to 3- (2-chlorophenoxy) -6- [6- (4-fluorophenylamino) pyridin-2-yl as described above]-6- (thien-3-yl) piperidine-2, 4-dione (0.42mg, 80%). Ms (esi): m + H508.¹H NMR(400MHz,DMSO-d6)9.10(s,1H),8.04(s,1H),7.66-7.57(m,3H),10.87-10.41(m,1H),7.49(dd,J＝5.1,3.0Hz,1H),7.40(dd,J＝3.0,1.4Hz,1H),7.34(dd,J＝7.8,1.7Hz,1H),7.17(dd,J＝5.1,1.4Hz,1H),7.10-6.97(m,3H),6.97-6.83(m,2H),6.70(d,J＝8.2Hz,1H),6.17(dd,J＝8.2,1.6Hz,1H),3.63(d,J＝16.2Hz,1H),3.36(s,1H)。

Example 423

A mixture of 6- (3-bromophenyl) -3- (2-chlorophenyl) sulfanyl-6- (thien-3-yl) piperidine-2, 4-dione (0.07g,0.14mmol), tert-butyl carbamate (0.05g,0.43mmol), Brettphos-Admix (0.02g,0.02mmol) and sodium tert-butoxide (0.04mg,0.43mmol) in tert-butanol was heated at 120 ℃ for 1 h. The reaction mixture was cooled, acidified with dilute HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was dissolved in DCM (2mL) and 4N HCl-1, 4-dioxane was added and stirred for 30 min. The reaction mixture was concentrated, treated with sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Purification by column chromatography (silica gel, 0-100% iPRAC/heptane) gave 6- (3-aminophenyl) -3- (2-chlorophenyl) sulfanyl-6- (thiophen-3-yl) piperidine-2, 4-dione (0.02g, 32%). Ms (esi): m + H429.¹H NMR(400MHz,DMSO-d6)8.29(s,1H),7.56(dd,J＝5.0,3.0Hz,1H),7.34(dd,J＝2.9,1.4Hz,1H),7.29(dd,J＝7.9,1.3Hz,1H),7.16(dd,J＝5.1,1.4Hz,1H),7.05-6.95(m,2H),6.85-6.75(m,1H),6.61(t,J＝2.0Hz,1H),6.56-6.48(m,2H),5.96(dd,J＝7.9,1.5Hz,1H),3.42-3.33(m,2H)。

Example 424

All steps and conditions are described in the above examples of the present application.

Example 425

LDHA enzyme inhibition assay procedure

Human recombinant carboxy-terminal his-labeled LDHA (amino acids 2-332) was expressed and purified by e. Enzyme assays were performed in a uClear low volume 384 well plate (Greiner #788092) with 10 μ L volumes having the following final enzyme and buffer conditions: 50mM Hepes (pH 7.2), 0.01% (v/v) TritonX-100, 0.01% (0.1mg/mL) bovine gamma-globulin, 2mM DTT, 1nM LDHA, 50. mu.M NADH and 50. mu.M pyruvate. Test compounds were diluted in 100% DMSO at 1:3 serial dilutions. Oxamate (Sigma # O2751) was used as a positive control and diluted in H₂O (10 point 1:3 serial dilutions, final DMSO 1%). For the enzymatic reaction, the serially diluted compounds are added to the mixture of enzyme and NADH. The assay plate was then incubated at room temperature for 10 minutes and baseline readings were taken on FDSS700(Hamamatsu) with an excitation wavelength of 340nm and an emission wavelength of 480nm for 12.5 seconds to identify any compounds that interfere with NADH fluorescence. After the baseline reading, pyruvate was added to the assay plate and the plate was read with an excitation wavelength of 340nm and an emission wavelength of 480nm for 10 minutes, once every 2.5 seconds. An appropriate linear time frame (150-. The raw data were fitted to a 4-parameter dose response curve using the following equation:

fit＝(A+((B-A)/(1+((C/x)^D))))

inv＝(C/((((B-A)/(y-A))-1)^(1/D)))

res＝(y-fit)

where a is the smallest y, B is the largest y, C is 50% y max, and D is the slope factor.

The bottom of the curve was set to the background rate (recorded the initial 5 seconds before pyruvate addition) and the top of the curve was set to the no inhibitor (DMSO only) control well rate. Oxamate was used as a positive control and showed an average IC₅₀The value was 57.2 μ M ± 13.1 μ M (n 202). For a previous description of LDH enzyme assays see Rossmann, m.g. et al. evolution and structural relationships, ammonia, products, in: Boyer, p.d. ed., The Enzymes, vol.xi. new York: Academic Press, 1975; pp 61-102. See also Moorhouse, a.d.actual.chem.commun.2011, 47,230 for "SuChapter pplementary Material ".

The compounds of the present application were tested for their ability to inhibit LDHA activity and activation as described in the enzyme inhibition assays described above. The following table summarizes the results of this assay involving exemplary compounds of the present application:

the above description is only illustrative of the subject matter of the present application. In addition, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the application to the exact construction and process shown above. Accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the application as defined by the appended claims.

The terms "comprises" and "comprising," when used in this specification and the appended claims, are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

Claims

1. A compound of formula (I) and stereoisomers, tautomers, and pharmaceutically acceptable salts thereof:

wherein

A¹Is O, CH₂Or S;

A²is NH or N-C₁-C₃-an alkyl group;

A³is N or CR²；

A⁴Is N or CR³Provided that A is³And A⁴Not N at the same time;

R¹is Cl, NO₂Or CN;

R³And R⁵Independently selected from:

H；

a hydroxyl group;

halogen;

-C₁-C₆-alkyl-R^f；

-C₁-C₆-alkenyl-R^f；

-C₁-C₆-alkoxy-R^c；

-NR^aR^b；

-NR^a-(C₁-C₆-alkyl) -R^d；

-NR^a-S(O)₂- (4 to 10 membered heterocycloalkyl);

-NR^a- (5-or 6-membered heteroaryl), which is unsubstituted or substitutedSubstituted with one or more substituents selected from: halogen, -NR^aR^bAnd C₁-C₆-an alkyl group;

-NR^a(CO)-C₁-C₆-an alkyl group;

-NR^a(CO) -aryl;

-NR^a(CO) - (5 or 6 membered heteroaryl);

-NR^a(CO)O-C₁-C₆-an alkyl group;

-S- (alkyl)_n-R^h；

-S(O)₂-aryl, unsubstituted or substituted by one or more halogens;

-C(O)-R^e；

-C(O)NR^a-(C₁-C₆-alkyl groups)_n-R^g；

-C(O)NR^a-C₁-C₆-an alkoxy group;

C₃-C₈-a cycloalkyl group, which may be fused with a phenyl group;

aryl, which is unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, -C (O) OH, C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy, -S (O)₂-NH (alkyl) and-S (O)₂-N (alkyl)₂；

R⁴comprises the following steps:

H；

a cyano group;

halogen;

a hydroxyl group;

NR^aR^b；

C₁-C₆-an alkyl group;

C₁-C₆-a haloalkyl group;

C₁-C₆-a hydroxyalkyl group;

-(C₁-C₆-alkyl groups)_n-(C₃-C₈-cycloalkyl) which is unsubstituted or substituted by one or more substituents selected from: halogen, hydroxy, -NR^aR^b、C₁-C₆Alkyl radical, C₁-C₆-alkoxy, C₁-C₆-haloalkyl, -C (O) -C₁-C₆Alkyl, -C (O) -C₁-C₆-cycloalkyl and-c (o) - (5 or 6 membered heterocycloalkyl);

R⁷is an aryl, 5 or 6 membered heterocyclyl or 5 or 6 membered heteroaryl group, which aryl, heterocyclyl or heteroaryl group is unsubstituted or substituted by one or more substituents selected from: halogen, C₁-C₆Alkyl radical, C₃-C₈-cycloalkyl, -O-aryl, -S-aryl, -NH-aryl and- (C)₁-C₆-alkyl groups)_n-an aryl group;

R⁸is OH, -NR^aR^b、C₁-C₆Alkoxy or-C (O) O-C₁-C₆-an alkyl group;

R^ais H or C₁-C₆-an alkyl group;

R^bis H or C₁-C₆-an alkyl group;

n is 0 or 1.

2. The compound of claim 1, wherein it has the following general formula:

wherein A is¹、A²、A³、R¹、R³、R⁴、R⁵、R⁶、R⁸、R⁹And R¹⁰As defined in claim 1 or 2.

3. The compound of claim 1 or 2, wherein it has the following general formula:

wherein A is³、R¹、R³、R⁴、R⁵、R⁶、R⁸、R⁹And R¹⁰As defined in claim 1 or 2.

4. The compound of claim 1 or 2, wherein it has the following general formula:

5. The compound of any one of claims 1-4, wherein A³Is NH.

6. The compound of any one of claims 1-7, wherein A³Is CR²Wherein R is²Selected from H, halogen, hydroxy, C₁-C₆-hydroxyalkyl and NH.

7. The compound of any one of claims 1-6, wherein R⁹And R¹⁰Is H.

8. The compound of any one of claims 1-7, wherein R¹Is Cl.

9. The compound of any one of claims 1-8, wherein R³Is NH-phenyl or NH-pyridyl, said phenyl or pyridyl being substituted by halogen.

10. The compound of any one of claims 1-9, wherein R⁴、R⁵、R⁶And R⁸Is H.

11. A compound according to any one of claims 1 to 10, wherein it is selected from the following compounds in the form of their racemates, single stereoisomers, tautomers and pharmaceutically acceptable salts:

3- (2-chlorophenyl) sulfanyl-6-phenyl-6- (thiophen-3-yl) piperidine-2, 4-dione;

3- (2-chlorophenyl) sulfanyl-6-phenyl-6- (thiazol-4-yl) -piperidine-2, 4-dione;

12. A pharmaceutical composition comprising a compound of any one of claims 1-11 and a therapeutically inert carrier.

13. Use of a compound according to any one of claims 1 to 11 for the treatment or prophylaxis of cancer.

14. Use of a compound of any one of claims 1-11 as an LDHA inhibitor.

15. Use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment or prophylaxis of cancer.

16. A compound of any one of claims 1-11 for use in inhibiting LDHA.

17. A compound according to any one of claims 1 to 11 for use against hypoxic and/or highly glycolytic tumours.

18. A compound according to any one of claims 1 to 11 for use in inhibiting cell survival.

19. A compound according to any one of claims 1 to 11 for use in the treatment or prevention of cancer.

20. A method of treating or preventing cancer, comprising administering an effective amount of a compound of any one of claims 1-11.

21. The invention as described in the present application.