Pyran derivatives as cyp11a1 inhibitors

Abstract

The present invention relates to pyran derivatives as CYP11A1 inhibitors. More specifically, the present invention relates to therapeutically active compounds for the treatment of steroid receptor, in particular androgen receptor (AR), dependent disorders and diseases and pharmaceutical compositions comprising such compounds.

Description

[0001] This application is a divisional application of the parent application with the application number 201780079479.4 and the title "Pyran Derivatives as CYP11A1 (Cytochrome P450 Monooxygenase 11A1) Inhibitors" and the filing date of 21-12-2017. TECHNICAL FIELD

[0002] The present application relates to therapeutically active compounds for the treatment of steroid receptor, in particular androgen receptor (AR) dependent disorders and diseases and pharmaceutical compositions comprising such compounds. BACKGROUND

[0003] Prostate cancer is the most common cancer among men worldwide. Although 5-year survival rates are high for patients with localized prostate cancer, those who develop castration-resistant prostate cancer (CRPC) during the 5-year follow-up period have a poor prognosis.

[0004] The androgen receptor (AR) signalling axis is critical in all stages of prostate cancer. In the CPRC stage, the disease is characterized by high AR expression, AR amplification and persistent activation of the AR signalling axis, caused by residual tissue / tumour androgens and by other steroid hormones and steroid biosynthesis intermediates. Therefore, the treatment of advanced prostate cancer includes androgen deprivation therapy (ADT), such as hormonal treatment with gonadotropin-releasing hormone (GnRH) agonists / antagonists or surgical castration, AR antagonists or CYP17A1 inhibitors (e.g. abiraterone acetate in combination with prednisone).

[0005] Although therapy can initially result in disease regression, eventually most patients develop disease that is refractory to currently available therapies. It has been postulated that increased levels of progesterone in patients treated with abiraterone is one of the mechanisms of resistance. Several non-clinical and clinical studies have shown that enzymes that catalyze steroid biosynthesis are upregulated in advanced stages of CRPC. Recently, it has been published that 11 β-OH androstenedione can be metabolized into 11-keto testosterone (11-K-T) and 11-keto dehydrotestosterone (11-K-DHT), which can bind and activate AR as efficiently as testosterone and dihydrotestosterone. It has been demonstrated that these steroids are found at high levels in the plasma and tissues of prostate cancer patients, which suggests their role as AR agonists in CRPC. In addition, it has been addressed the issue that prostate cancers resistant to CYP17A1 inhibition can still retain steroid dependence and respond to therapies that can further inhibit de novo intratumoral steroid synthesis upstream of CYP17A1, such as CYP11A1 inhibition therapies (Cai, C. et al. Cancer Res., 71(20), 6503-6513, 2011).

[0006] Cytochrome P450 monooxygenase 11A1 (CYP11A1), also known as cholesterol side-chain cleavage enzyme, is a mitochondrial monooxygenase that catalyzes the conversion of cholesterol into pregnenolone, which is the precursor of all steroid hormones. By inhibiting CYP11A1, a key enzyme upstream of steroid biosynthesis of CYP17A1, a complete blockade of the whole steroid biosynthesis can be achieved. Therefore, CYP11A1 inhibitors can have a great potential to treat steroid hormone-dependent cancers such as prostate cancer, even in advanced stages of the disease, especially in those patients that show hormone refractory. It has been recently demonstrated that a compound with CYP11A1 inhibitory action significantly inhibited tumor growth in vivo in a mouse CRPC xenograft model (Oksala, R. et al. Annals of Oncology, (2017) 28(suppl. 5): Abstract / Poster 28P). SUMMARY

[0007] It has been found that compounds of formula (I) are potent CYP11A1 inhibitors. Therefore, the compounds of the present invention are useful as medicaments for the treatment of steroid hormone-dependent conditions and diseases in which the inhibition of CYP11A1 is desirable. Said conditions and diseases include, but are not limited to, endocrine cancers and diseases, such as prostate and breast cancer. In particular, the compounds of the present invention are useful for the treatment of AR-dependent conditions and diseases, including prostate cancer.

[0008] The present invention relates to compounds of formula (I)

[0009]

[0010] wherein

[0011] Ring B is a 4-10 membered monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected from N, O, or S; Ring A is any one of the following

[0012]

[0013] L is absent, -CH2-, -CH2-CH2- or -CH2-CH2-CH2-, or in the case where Ring A is (1), L can also be -C(O)-CH2-;

[0014] R1is hydrogen, C 1-7 alkyl, C 1-7 haloalkyl, halogen, cyano, nitro, C 1-7 haloalkyl, halogen, cyano, nitro, C 1-7 haloalkyl, halogen, cyano, nitro, C 1-7 alkylthio; or R1and R2together with the carbon atom to which they are attached form a fused 1,3-dioxolyl ring;

[0015] R2is hydrogen, C 1-7 alkyl, halogen, cyano, nitro, C 1-7 alkyl, halogen, cyano, nitro, C 1-7 alkyl, halogen, cyano, nitro, C

[0016] or R1and R2together with the carbon atom to which they are attached form a fused 1,3-dioxolyl ring;

[0017] R3is hydrogen, halogen, cyano, nitro, oxo, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, hydroxyC 3-7 alkyl, C 1-7 alkyl, C 1-7 alkyl, C 1-7 alkyl, C 1-7 alkyl, C 1-7 alkyl, C 1-7 alkyl, C 1-7 alkyl, C 2-7 alkyl, C 1-7 alkyl, C 1-7 alkyl, C 1-7 alkyl, C 1-7 alkyl, C 2-7 alkyl, =NSO2R 20 , -S(O)-C 1-7 alkyl, -S(O)(NR 14 )(R 22 ), -S(NR 15 )(C 1-7alkyl), -C(S)NR 18 R 19 , -D-C(O)-NR6R7, -C(O)R8, -D-NR9R 10 , -SO2R 11 , optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered carbocyclylC 1-7 alkyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 4-10 membered heterocyclylC 1-7 alkyl;

[0018] R4is hydrogen, halogen, hydroxyl, C 1-7 alkyl, haloC 1-7 alkyl, or oxo;

[0019] R5is hydrogen, halogen, or C 1-7 alkyl;

[0020] R6is hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, hydroxyC 1-7 alkyl, cyanoC 1-7 alkyl, -C 1-7 alkyl-O-C(O)C 1-7 alkyl, or optionally substituted 4-10 membered heterocyclyl;

[0021] R8is hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 1-7 alkoxy, haloC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, C 1-7 alkylcarbonyl, C 1-7 alkoxycarbonyl, -C 1-7 alkyl-O-C(O)-C 1-7 alkyl, -C 1-7 alkyl-SO2(C 1-7 alkyl), -N=S(O)(C 1-7 alkyl)(C 1-7 alkyl), or optionally substituted 4-10 membered heterocyclyl;

[0022] R9is hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl, C 1-7 alkylcarbonyl, -SO2(C 1-7 alkyl), or -SO2(C 3-7 cycloalkyl);

[0023] R 11is C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, haloC 1-7 alkyl, cyanoC 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkyl, -NR 12 R 13 , optionally substituted 3-10 membered carbocyclyl or optionally substituted 4-10 membered heterocyclyl;

[0024] R 12 is hydrogen, C 1-7 alkyl, hydroxyC 1-7 alkyl, cyanoC 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkoxyC 1-7 alkyl or C 1-7 alkylcarbonyl;

[0025] R7, R 10 , R 13 , R 18 and R 19 are independently hydrogen, C 1-7 alkyl or C 3-7 cycloalkyl;

[0026] R 14 is hydrogen, C 1-7 alkyl, C 1-7 alkylcarbonyl or -SO2R 21 ;

[0027] R 15 is hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl, C 1-7 alkylcarbonyl, -SO2R 17 ;

[0028] R 17 is C 1-7 alkyl or optionally substituted 3-10 membered carbocyclyl;

[0029] R 20 and R 21 are independently C 1-7 alkyl, C 3-7 cycloalkyl or optionally substituted 3-10 membered carbocyclyl;

[0030] R 22 is C 1-7 alkyl or C 3-7 cycloalkyl;

[0031] R 23is hydrogen or oxo;

[0032] R 24 is hydrogen or C 1-7 alkyl;

[0033] D is absent, C 1-7 alkyl or C 2-7 alkenyl;

[0034] wherein the optional substitution is, at each occurrence, selected from 1-3 substituents independently selected from C 1-7 alkyl, halogen, hydroxyl, C 1-7 alkoxy, C 1-7 alkoxy C 1-7 alkyl, C 1-7 alkoxycarbonyl or oxo; and

[0035] wherein the heterocyclyl group has, at each occurrence, 1-4 heteroatoms independently selected from N, O and S;

[0036] or a pharmaceutically acceptable salt thereof;

[0037] provided that the compound is not

[0038] 2-[(3,4-dihydro-2(lH)-isoquinolinyl)methyl]-5-[(2,5-dimethylphenyl)methoxy]- 4H-pyran-4-one;

[0039] 5-[(2,4-dichlorophenyl)methoxy]-2-[(3,4-dihydro-2(lH)-isoquinolinyl)methyl]- 4H-pyran-4-one;

[0040] 5-[(3-chlorophenyl)methoxy]-2-[(3,4-dihydro-2(lH)-isoquinolinyl)methyl]-4H- pyran-4-one;

[0041] 2-[(3,4-dihydro-2(lH)-isoquinolinyl)methyl]-5-[(4-methylphenyl)methoxy]-4H- pyran-4-one;

[0042] 5-[(3,4-dichlorophenyl)methoxy]-2-[(3,4-dihydro-2(lH)-isoquinolinyl)methyl]- 4H-pyran-4-one;

[0043] 2-[(3,4-dihydro-2(lH)-isoquinolinyl)methyl]-5-[(3-fluorophenyl)methoxy]-4H- pyran-4-one;

[0044] 2-[(3,4-dihydro-2(lH)-isoquinolinyl)methyl]-5-(l-naphthalenylmethoxy)-4H- pyran-4-one;

[0045] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[[3-(trifluoromethyl)phenyl]methoxy]- 4H-pyran-4-one;

[0046] 5-[(2-chlorophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-4H-pyran-4- one;

[0047] 5-[(2-chloro-6-fluorophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-4H- pyran-4-one;

[0048] 5-[(4-chlorophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-4H-pyran-4- one;

[0049] 5-[(4-bromophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-4H-pyran-4- one;

[0050] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[(2-fluorophenyl)methoxy]-4H-pyran-4- one;

[0051] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[(2-methylphenyl)methoxy]-4H-pyran-4- one;

[0052] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-(phenylmethoxy)-4H-pyran-4-one;

[0053] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[[4-(trifluoromethyl)phenyl]methoxy]- 4H-pyran-4-one;

[0054] 4-(((6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl) benzoic acid methyl ester;

[0055] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[(4-fluorophenyl)methoxy]-4H-pyran-4- one;

[0056] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[(3,5-dimethoxyphenyl)methoxy]-4H- pyran-4-one;

[0057] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[(3-nitrophenyl)methoxy]-4H-pyran-4- one;

[0058] 5-(((6-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)furan-2-carboxylic acid methyl ester;

[0059] 2-[(3,4-dihydro-2(lH)-isoquinolinyl)methyl]-5-(2-phenylethoxy)-4H-pyran-4-one;

[0060] 2-[(3,4-dihydro-2(lH)-isoquinolinyl)methyl]-5-[(3-methylphenyl)methoxy]-4H-pyran-4-one; or

[0061] 2-[(3,4-dihydro-2(lH)-isoquinolinyl)methyl]-5-[(4-nitrophenyl)methoxy]-4H-pyran-4-one.

[0062] According to one embodiment, the present application provides a method for treating or preventing a steroid receptor, in particular androgen receptor (AR), dependent disorders and diseases, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I)

[0063]

[0064] wherein

[0065] Ring B is a 4-10 membered monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected from N, O, or S;

[0066] Ring A is any one of the following groups

[0067]

[0068] L is absent, -CH2-, -CH2-CH2- or -CH2-CH2-CH2-, or in the case where Ring A is (1), L can also be -C(O)-CH2-;

[0069] R1is hydrogen, C 1-7 alkyl, C 1-7 alkoxy, halogen, cyano, nitro, haloC 1-7 alkyl, haloC 1-7 alkoxy or C 1-7 alkylthio;

[0070] R2is hydrogen, C 1-7 alkyl, halogen, hydroxyl, haloC 1-7 alkyl, nitro, haloC 1-7 alkoxy or mercapto;

[0071] or R1and R2together with the carbon atom to which they are attached form a fused 1,3 dioxolyl ring;

[0072] R3is hydrogen, halogen, nitro, cyano, oxo, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, hydroxyC 3-7 alkyl, C 1-7 alkoxy, hydroxyC 1-7 alkyl, haloC 1-7 alkyl, cyanoC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, C 1-7 alkyl, aminocarbonylC 2-7 alkenyl, haloC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, C 1-7 alkoxyC 2-7 alkenyl, =NSO2R 20 , -S(O)-C 1-7 alkyl, -S(O)(NR 14 )(R 22 ), -S(NR 15 )(C 1-7 alkyl), -C(S)NR 18 R 19 , -D-C(O)-NR6R7, -C(O)R8, -D-NR9R 10 , -SO2R 11 , optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered carbocyclylC 1-7 alkyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 4-10 membered heterocyclylC 1-7 alkyl;

[0073] R4is hydrogen, halogen, hydroxy, C 1-7 alkyl, haloC 1-7 alkyl, or oxo;

[0074] R5is hydrogen, halogen, or C 1-7 alkyl;

[0075] R6is hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, hydroxyC 1-7 alkyl, cyanoC 1-7 alkyl, -C 1-7 alkyl-O-C(O)C 1-7alkyl or optionally substituted 4-10 membered heterocyclyl;

[0076] R8is hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 1-7 alkoxy, haloC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, C 1-7 alkylcarbonyl, C 1-7 alkoxycarbonyl, -C 1-7 alkyl-O-C(O)-C 1-7 alkyl, -C 1-7 alkyl-SO2(C 1-7 alkyl), -N=S(O)(C 1-7 alkyl)(C 1-7 alkyl) or optionally substituted 4-10 membered heterocyclyl;

[0077] R9is hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl, C 1-7 alkylcarbonyl, -SO2(C 1-7 alkyl) or -SO2(C 3-7 cycloalkyl);

[0078] R 11 is C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, haloC 1-7 alkyl, cyanoC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, -NR 12 R 13 , optionally substituted 3-10 membered carbocyclyl or optionally substituted 4-10 membered heterocyclyl;

[0079] R 12 is hydrogen, C 1-7 alkyl, hydroxyC 1-7 alkyl, cyanoC 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkoxyC 1-7 alkyl or C 1-7 alkylcarbonyl;

[0080] R7, R 10 , R 13 , R 18 and R 19 are independently hydrogen, C 1-7 alkyl or C3-7 cycloalkyl;

[0081] R 14 It is hydrogen, C 1-7 Alkyl, C 1-7 Alkyl carbonyl or -SO2R 21 ;

[0082] R 15 It is hydrogen, C 1-7 Alkyl, C 3-7 cycloalkyl, C 1-7 Alkyl carbonyl, -SO2R 17 ;

[0083] R 17 It is C 1-7 Alkyl or optionally substituted 3-10 membered carbon cycloalkanes;

[0084] R 20 and R 21 C is independent 1-7 Alkyl, C 3-7 Cycloalkyl or optionally substituted 3-10 membered carbon cycloalcoside;

[0085] R 22 It is C 1-7 Alkyl or C 3-7 cycloalkyl;

[0086] R 23 It is hydrogen or oxygen;

[0087] R 24 Is it hydrogen or C? 1-7 alkyl;

[0088] D does not exist; it is C. 1-7 Alkyl or C 2-7 alkenyl;

[0089] The optional substitutions mentioned therein are selected from 1 to 3 substituents each time they occur, and the substituents are independently selected from C. 1-7 Alkyl, halogen, hydroxyl, C 1-7 Alkoxy, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 alkoxy carbonyl or oxo; and

[0090] The heterocyclic group described therein has 1-4 heteroatoms independently selected from N, O and S each time it appears;

[0091] Or its pharmaceutically acceptable salt.

[0092] According to one embodiment, the present application provides a pharmaceutical composition comprising a compound of Formula (I) as defined in any one of the above embodiments and a pharmaceutically acceptable carrier.

[0093] According to one embodiment, the present application provides a method for treating or preventing a steroid receptor, in particular androgen receptor (AR), dependent disorder and disease. The disorders and diseases include, but are not limited to, endocrine cancers and diseases, such as prostate cancer and breast cancer. The method comprises administering to an individual in need a therapeutically effective amount of a compound of Formula (I) as defined in any one of the above embodiments. DETAILED DESCRIPTION

[0094] The present application provides novel 4H-pyrran-4-one derivatives of Formula (I) or a pharmaceutically acceptable salt thereof, which are useful as CYP11A1 inhibitors.

[0095] One embodiment of the present application provides a compound of Formula (I)

[0096]

[0097] wherein

[0098] Ring B is a 4-10 membered monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected from N, O, or S; Ring A is any one of the following groups

[0099]

[0100] L is absent, -CH2-, -CH2-CH2- or -CH2-CH2-CH2-, or in the case where Ring A is (1), L can also be -C(O)-CH2-;

[0101] R1is hydrogen, C 1-7 alkyl, C 1-7 alkoxy, halogen, cyano, nitro, haloC 1-7 alkyl, haloC 1-7 alkyl, C 1-7 alkyl, C 1-7 alkyl, halogen, hydroxyl, haloC 1-7 alkyl, nitro, haloC 1-7 alkoxy or mercapto;

[0102] R2is hydrogen, C 1-7 alkyl, halogen, hydroxyl, haloC 1-7 alkyl, nitro, haloC 1-7 alkoxy or mercapto;

[0103] or R1and R2together with the carbon atom to which they are attached form a fused 1,3 dioxole ring;

[0104] R3is hydrogen, halogen, nitro, cyano, oxo, C 1-7 alkyl, C 2-7 alkenyl, C3-7 Cycloalkyl, hydroxy C 3-7 cycloalkyl, C 1-7 Alkoxy, hydroxy C 1-7 Alkyl, Halogenated C 1-7 Alkyl, cyano C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkyl thiols, amino carbonyl groups C 2-7 alkenyl, halogenated C 1-7 Alkylthio, C 1-7 alkoxycarbonyl C 1-7 Alkyl, C 1-7 alkoxycarbonyl C 2-7 alkenyl, =NSO2R 20 -S(O)-C 1-7 Alkyl, -S(O)(NR 14 (R) 22 -S(NR) 15 (C) 1-7 Alkyl), -C(S)NR 18 R 19 , -DC(O)-NR6R7, -C(O)R8, -D-NR9R 10 -SO2R 11 Optional substituted 3-10 membered carbon cyclogroups, Optional substituted 3-10 membered carbon cyclogroups C 1-7 Alkyl group, optionally substituted 4-10 membered heterocyclic group, or optionally substituted 4-10 membered heterocyclic C 1-7 alkyl;

[0105] R4 is hydrogen, halogen, hydroxyl, C 1-7 Alkyl, Halogenated C 1-7 Alkyl or oxo;

[0106] R5 is hydrogen, halogen, or C. 1-7 alkyl;

[0107] R6 is hydrogen, C 1-7 Alkyl, C 2-7 alkenyl, C 3-7 Cycloalkyl, hydroxy C 1-7 Alkyl, cyano C 1-7 Alkyl, -C 1-7 Alkyl-OC(O)C 1-7 Alkyl groups or optionally substituted 4-10 membered heterocyclic groups;

[0108] R8 is hydrogen, C 1-7 Alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 1-7 Alkoxy, halogenated C1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 alkyl carbonyl, C 1-7 alkoxycarbonyl, -C 1-7 Alkyl-OC(O)-C 1-7 Alkyl, -C 1-7 Alkyl-SO2(C 1-7 Alkyl group), -N=S(O)(C 1-7 Alkyl)(C 1-7 Alkyl groups or optionally substituted 4-10 membered heterocyclic groups;

[0109] R9 is hydrogen, C 1-7 Alkyl, C 3-7 cycloalkyl, C 1-7 Alkyl carbonyl, -SO2(C 1-7 alkyl) or -SO2(C 3-7 cycloalkyl);

[0110] R 11 It is C 1-7 Alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, halogenated C 1-7 Alkyl, cyano C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, -NR 12 R 13 Optional substituted 3-10 membered carbocyclic groups or optional substituted 4-10 membered heterocyclic groups;

[0111] R 12 It is hydrogen, C 1-7 Alkyl, hydroxyl C 1-7 Alkyl, cyano C 1-7 Alkyl, C 1-7 Alkoxy, C 1-7 Alkoxy C 1-7 Alkyl or C 1-7 Alkyl carbonyl;

[0112] R7, R 10 R 13 R 18 and R 19 Independently, it is hydrogen and C 1-7 Alkyl or C 3-7 cycloalkyl;

[0113] R 14 It is hydrogen, C 1-7 Alkyl, C 1-7 Alkyl carbonyl or -SO2R 21 ;

[0114] R 15 is hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl, C 1-7 alkylcarbonyl, -SO2R 17 ;

[0115] R 17 is C 1-7 alkyl or optionally substituted 3-10 membered carbocyclyl;

[0116] R 20 and R 21 are independently C 1-7 alkyl, C 3-7 cycloalkyl or optionally substituted 3-10 membered carbocyclyl;

[0117] R 22 is C 1-7 alkyl or C 3-7 cycloalkyl;

[0118] R 23 is hydrogen or oxo;

[0119] R 24 is hydrogen or C 1-7 alkyl;

[0120] D is absent, C 1-7 alkyl or C 2-7 alkenyl;

[0121] wherein said optional substitution is, at each occurrence, selected from 1-3 substituents independently selected from C 1-7 alkyl, halogen, hydroxyl, C 1-7 alkoxy, C 1-7 alkoxy C 1-7 alkyl, C 1-7 alkoxycarbonyl or oxo; and

[0122] wherein said heterocyclyl has, at each occurrence, 1-4 heteroatoms independently selected from N, O and S;

[0123] or a pharmaceutically acceptable salt thereof;

[0124] provided that the compound is not

[0125] 2-[(3,4-dihydro-2(lH)-isoquinolinyl)methyl]-5-[(2,5-dimethylphenyl)methoxy]-4H- pyran-4-one;

[0126] 5-[(2,4-dichlorophenyl)methoxy]-2-[(3,4-dihydro-2(lH)-isoquinolinyl)methyl]-4H- pyran-4-one;

[0127] 5-[(3-chlorophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-4H- pyran-4-one;

[0128] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[(4-methylphenyl)methoxy]-4H- pyran-4-one;

[0129] 5-[(3,4-dichlorophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-4H- pyran-4-one;

[0130] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[(3-fluorophenyl)methoxy]-4H-pyran- 4-one;

[0131] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-(1-naphthylmethoxy)-4H-pyran-4-one;

[0132] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[[3-(trifluoromethyl)phenyl]methoxy]- 4H-pyran-4-one;

[0133] 5-[(2-chlorophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-4H-pyran- 4-one;

[0134] 5-[(2-chloro-6-fluorophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]- 4H-pyran-4-one;

[0135] 5-[(4-chlorophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-4H-pyran- 4-one;

[0136] 5-[(4-bromophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-4H-pyran- 4-one;

[0137] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[(2-fluorophenyl)methoxy]-4H-pyran- 4-one;

[0138] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[(2-methylphenyl)methoxy]-4H-pyran- 4-one;

[0139] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-(phenylmethoxy)-4H-pyran-4-one;

[0140] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[[4-(trifluoromethyl)phenyl]methoxy]- 4H-pyran-4-one;

[0141] 4-(((6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)benzoic acid methyl ester;

[0142] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[(4-fluorophenyl)methoxy]-4H-pyran-4- one;

[0143] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[(3,5-dimethoxyphenyl)methoxy]-4H- pyran-4-one;

[0144] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[(3-nitrophenyl)methoxy]-4H-pyran-4- one;

[0145] 5-(((6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)furan-2-carboxylic acid methyl ester;

[0146] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-(2-phenylethoxy)-4H-pyran-4-one;

[0147] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[(3-methylphenyl)methoxy]-4H-pyran-4- one; or

[0148] 2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-5-[(4-nitrophenyl)methoxy]-4H-pyran-4- one.

[0149] It is understood that the bond to the left of the linker L is to the ring B of formula (I).

[0150] According to one embodiment, the compounds of the application are according to formula (IA):

[0151]

[0152] wherein R1, R2, R3, R4, R5, R 23 , R 24 , L and B are as defined above in any one of the embodiments for formula (I); or a pharmaceutically acceptable salt thereof.

[0153] According to one embodiment, the compounds of the application are of formula (IB):

[0154]

[0155] wherein R1, R2, R3, R4, R5, R 24 , L and B are as defined above for any one of the embodiments of formula (I); or a pharmaceutically acceptable salt thereof.

[0156] According to one embodiment, specifically provided are compounds of formula (I), wherein L is -CH2- or -CH2-CH2-, for example L is -CH2-, or as another example, L is -CH2-CH2-.

[0157] According to one embodiment, specifically provided are compounds of formula (I), wherein ring B is any one of the following groups

[0158]

[0159] wherein R3, R4and R5are as defined above for any one of the embodiments of formula (I) are attached to the B-ring above.

[0160] One sub-class of the above embodiments are compounds wherein ring B is any one of the following groups

[0161] and wherein R3, R4and R5are as defined above for any one of the embodiments of formula (I) are attached to the B-ring above, and wherein the wavy line indicates the point of attachment to L.

[0162] According to yet another embodiment, specifically provided are compounds wherein ring B is a ring (1'), (5'), (7'), (9'), (13') or (14') as defined above.

[0163] One sub-class of the above embodiments are compounds wherein ring B is (1'), (5a'), (7'), (9a'), (13a') or (14a') as defined above.

[0164] According to one embodiment, specifically provided are compounds wherein R3is hydrogen, C 1-7 alkyl, C 2-7 alkenyl, hydroxyC 1-7 alkyl, cyano, C 1-7 alkylthio, C 1-7 alkoxycarbonylC 2-7 alkenyl, -D-C(O)-NR6R7, -C(O)R8, -SO2R 11 , -D-NR9R 10-S(O)(NR 14 )(R 22 ), -S(NR 15 )(C 1-7 alkyl), -C(S)NR 18 R 19 , optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 4-10 membered heterocyclylC 1-7 alkyl; wherein said optional substitution is, at each occurrence, selected from 1-3 substituents independently selected from C 1-7 alkyl, halo, hydroxyl, C 1-7 alkoxy, C 1-7 alkoxyC 1-7 alkyl, C 1-7 alkoxycarbonyl, or oxo, and wherein said heterocyclyl has, at each occurrence, 1-3 heteroatoms independently selected from N, O, and S.

[0165] According to one embodiment, compounds are specifically provided wherein R4and R5are hydrogen.

[0166] According to one embodiment, compounds of the application are of formula (IC):

[0167]

[0168] wherein R1, R2, R3, R4, R5, and R 24 are as defined above in any one of the embodiments for formula (I); or a pharmaceutically acceptable salt thereof.

[0169] According to one embodiment, compounds of the application are of formula (ID):

[0170]

[0171] wherein R1, R2, R3, R4, R5, and R 24 are as defined above in any one of the embodiments for formula (I); or a pharmaceutically acceptable salt thereof.

[0172] According to one embodiment, compounds of the application are of formula (IE):

[0173]

[0174] wherein R1, R2, R3, R4, R5, and R 24 are as defined above in any one of the embodiments for formula (I); or a pharmaceutically acceptable salt thereof.

[0175] According to one embodiment, specifically provided are compounds as defined in any one of the above embodiments, wherein

[0176] R1is hydrogen, C 1-7 alkyl, C 1-7 alkoxy, halogen, cyano, nitro, haloC 1-7 alkyl, haloC 1-7 alkoxy or C 1-7 alkylthio;

[0177] R2is hydrogen or halogen;

[0178] R3is hydrogen, C 1-7 alkyl, C 2-7 alkenyl, hydroxyC 1-7 alkyl, cyano, thio, C 1-7 alkoxycarbonylC 2-7 alkenyl, -D-C(O)-NR6R7, -C(O)R8, -SO2R 11 , -D-NR9R 10 , -S(O)(NR 14 )(R 22 ), -S(NR 15 )(C 1-7 alkyl), -C(S)NR 18 R 19 , 3-6 membered carbocyclyl optionally substituted with 1-2 hydroxy substituents, 4-6 membered heterocyclyl optionally substituted with 1-2 substituents selected from halogen, hydroxy, C 1-7 alkoxycarbonyl or oxo or 4-6 membered heterocyclyl C 1-7 alkyl optionally substituted with 1-2 oxo substituents;

[0179] R4is hydrogen, C 1-7 alkyl, hydroxy or halogen;

[0180] R5is hydrogen or halogen;

[0181] R6is C 1-7 alkyl, C 3-7 cycloalkyl, hydroxyC 1-7 alkyl, -C 1-7 alkyl-O-C(O)C 1-7 alkyl;

[0182] R7is hydrogen or C 1-7 alkyl;

[0183] R8is hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 1-7 alkoxy, haloC 1-7alkyl, C 1-7 alkoxy C 1-7 alkyl, C 1-7 alkylcarbonyl, C 1-7 alkoxycarbonyl, -C 1-7 alkyl-O-C(O)-C 1-7 alkyl, -C 1-7 alkyl-SO2(C 1-7 alkyl), -N=S(O)(C 1-7 alkyl)(C 1-7 alkyl) or 4-6 membered heterocyclyl optionally substituted with 1-2 halo substituents;

[0184] R9is C 1-7 alkylcarbonyl, -SO2(C 1-7 alkyl) or -SO2(C 3-7 cycloalkyl);

[0185] R 10 is hydrogen, C 1-7 alkyl or C 3-7 cycloalkyl;

[0186] R 11 is C 1-7 alkyl, C 3-7 cycloalkyl, halo C 1-7 alkyl, cyano C 1-7 alkyl, C 1-7 alkoxy C 1-7 alkyl, -NR 12 R 13 , 3-6 membered carbocyclyl optionally substituted with 1-2 substituents selected from halo or C 1-7 alkyl or 4-6 membered heterocyclyl optionally substituted with 1-2 substituents selected from halo or C 1-7 alkyl;

[0187] R 12 is C 1-7 alkyl, hydroxy C 1-7 alkyl, cyano C 1-7 alkyl, C 1-7 alkoxy C 1-7 alkyl or C 1-7 alkylcarbonyl;

[0188] R 13 is hydrogen or C 1-7 alkyl;

[0189] R 14 is hydrogen, C 1-7 alkyl, C 1-7 alkylcarbonyl or -SO2R 21 ;

[0190] R15 is hydrogen, C 1-7 alkyl, -SO2R 17 ;

[0191] R 17 is C 1-7 alkyl or 3-6 membered carbocyclyl optionally substituted with 1-2 C 1-7 alkyl substituents;

[0192] R 18 and R 19 are independently hydrogen or C 1-7 alkyl;

[0193] R 21 is 3-6 membered carbocyclyl optionally substituted with 1-2 C 1-7 alkyl substituents;

[0194] R 22 is C 1-7 alkyl or C 3-7 cycloalkyl;

[0195] R 24 is hydrogen or C 1-7 alkyl;

[0196] wherein said heterocyclyl has 1-3 heteroatoms independently selected from N, O and S at each occurrence;

[0197] or a pharmaceutically acceptable salt thereof.

[0198] One subclass is a compound of Formula (IC), wherein

[0199] R1is hydrogen, C 1-7 alkoxy, halogen, nitro, haloC 1-7 alkyl, haloC 1-7 alkoxy or C 1-7 alkylthio;

[0200] R2is hydrogen or halogen;

[0201] R3is C 2-7 alkenyl, hydroxyC 1-7 alkyl, cyano, C 1-7 alkoxycarbonylC 2-7 alkenyl, -D-C(O)-NR6R7, -C(O)R8, -SO2R 11 , -D-NR9R 10 , -S(O)(NR 14 )(R 22 ), -S(NR 15 )(C 1-7R4is hydrogen, hydroxyl, or halogen;

[0202] R4is hydrogen, hydroxyl, or halogen;

[0203] R5is hydrogen or halogen;

[0204] R6is C 1-7 alkyl, hydroxyC 1-7 alkyl or -C 1-7 alkyl-O-C(O)C 1-7 alkyl;

[0205] R7is hydrogen or C 1-7 alkyl;

[0206] R8is C 1-7 alkyl, halogenC 1-7 alkyl, -N=S(O)(C 1-7 alkyl)(C 1-7 alkyl) or 4-6 membered heterocyclyl optionally substituted with 1-2 halogen substituents;

[0207] R9is C 1-7 alkylcarbonyl or -SO2(C 1-7 alkyl);

[0208] R 10 is hydrogen or C 1-7 alkyl;

[0209] R 11 is C 1-7 alkyl, C 3-7 cycloalkyl, halogenC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, -NR 12 R 13 or 4-6 membered heterocyclyl;

[0210] R 12 is C 1-7 alkyl, hydroxyC 1-7 alkyl, cyanoC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl or C 1-7 alkylcarbonyl;

[0211] R 13 is hydrogen or C 1-7 alkyl;

[0212] R 14 is hydrogen, C 1-7 alkyl or C 1-7 alkylcarbonyl;

[0213] R 15 is hydrogen or -SO2R 17 ;

[0214] R 17 is 3-6 membered carbocyclyl optionally substituted with 1-2 C 1-7 alkyl substituents;

[0215] R 22 is C 1-7 alkyl or C 3-7 cycloalkyl;

[0216] R 24 is hydrogen or C 1-7 alkyl;

[0217] D is absent, C 1-7 alkyl or C 2-7 alkenyl;

[0218] wherein said heterocyclyl has 1-3 heteroatoms independently selected from N, O and S at each occurrence;

[0219] or a pharmaceutically acceptable salt thereof.

[0220] One subclass of the above embodiments is the compound wherein

[0221] R1is hydrogen, C 1-7 alkoxy, halogen, nitro, haloC 1-7 alkyl or haloC 1-7 alkoxy;

[0222] R2and R 10 are hydrogen;

[0223] R3is C 2-7 alkenyl, hydroxyC 1-7 alkyl, cyano, C 1-7 alkoxycarbonylC 2-7 alkenyl, -D-C(O)-NR6R7, -C(O)R8, -SO2R 11 , -D-NR9R 10 , -S(O)(NR 14 )(R 22 ), -S(NR 15 )(C 1-7 alkyl), oxazolyl, cyclobutyl optionally substituted with a hydroxyl substituent or oxetanyl optionally substituted with a hydroxyl substituent;

[0224] R4and R5are hydrogen or halogen;

[0225] R6is C 1-7 alkyl or hydroxyC 1-7alkyl;

[0226] R7, R 13 , R 14 , and R 24 are hydrogen or C 1-7 alkyl;

[0227] R8is C 1-7 alkyl, pyrrolidinyl, oxetanyl, or azetidinyl optionally substituted with 1-2 halo substituents, -N=S(O)(C 1-7 alkyl)(C 1-7 alkyl);

[0228] R9is -SO2(C 1-7 alkyl);

[0229] R 11 is C 1-7 alkyl, C 3-7 cycloalkyl, haloC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, -NR 12 R 13 , pyrrolidinyl, piperidinyl, azetidinyl, or morpholinyl;

[0230] R 12 is C 1-7 alkyl, hydroxyC 1-7 alkyl, cyanoC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, or C 1-7 alkylcarbonyl;

[0231] R 15 is hydrogen or -SO2R 17 ;

[0232] R 17 is phenyl optionally substituted with a C 1-7 alkyl substituent;

[0233] R 22 is C 1-7 alkyl or C 3-7 cycloalkyl;

[0234] D is absent, C 1-7 alkyl, or C 2-7 alkenyl;

[0235] or a pharmaceutically acceptable salt thereof.

[0236] Another subclass of the above embodiments is the compounds wherein

[0237] R1is hydrogen, C 1-7Alkoxy, halogen, halogenated C 1-7 Alkyl or halogenated C 1-7 Alkoxy;

[0238] R2 and R 10 It is hydrogen;

[0239] R3 is a hydroxyl group C. 1-7 Alkyl, cyano, C 1-7 alkoxycarbonyl C 2-7 Alkenyl, -DC(O)-NR6R7, -C(O)R8, -SO2R 11 -D-NR9R 10 -S(O)(NR) 14 (R) 22 -S(NR) 15 (C) 1-7 Alkyl), oxazolyl, cyclobutyl, optionally substituted with a hydroxyl group, or oxacyclobutyl, optionally substituted with a hydroxyl group;

[0240] R4 and R5 are hydrogen or halogens;

[0241] R6 is C 1-7 alkyl;

[0242] R7, R 13 R 14 and R 24 Is it hydrogen or C? 1-7 alkyl;

[0243] R8 is a pyrroleyl, aziridine, or -N=S(O)(C 1-7 Alkyl)(C 1-7 alkyl);

[0244] R9 is -SO2(C 1-7 alkyl);

[0245] R 11 It is C 1-7 Alkyl, Halogenated C 1-7 Alkyl, -NR 12 R 13 Or pyrroleyl;

[0246] R 12 It is C 1-7 Alkyl, hydroxyl C 1-7 Alkyl, cyano C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl or C 1-7 Alkyl carbonyl;

[0247] R 15 Yes - SO2R 17 ;

[0248] R 17 is phenyl optionally substituted with C 1-7 alkyl substituents;

[0249] R 22 is C 1-7 alkyl or C 3-7 cycloalkyl;

[0250] D is absent, C 1-7 alkyl or C 2-7 alkenyl;

[0251] or a pharmaceutically acceptable salt thereof.

[0252] Another subclass of the above embodiments is the compounds wherein

[0253] R1is hydrogen, halogen, haloC 1-7 alkyl or haloC 1-7 alkoxy;

[0254] R2, R4, R5and R 10 are hydrogen;

[0255] R3is hydroxyC 1-7 alkyl, -D-C(O)-NR6R7, -C(O)R8, -SO2R 11 , -D-NR9R 10 , -S(O)(NR 14 )(R 22 ) or oxetanyl optionally substituted with a hydroxyl substituent;

[0256] R6and R7are C 1-7 alkyl;

[0257] R8is pyrrolidinyl or -N=S(O)(C 1-7 alkyl)(C 1-7 alkyl);

[0258] R9is -SO2(C 1-7 alkyl);

[0259] R 11 is C 1-7 alkyl, -NR 12 R 13 or pyrrolidinyl;

[0260] R 12 is C 1-7 alkyl, hydroxyC 1-7 alkyl or C 1-7 alkoxyC 1-7 alkyl;

[0261] R 13 and R14 is hydrogen or C 1-7 alkyl;

[0262] R 22 is C 1-7 alkyl or C 3-7 cycloalkyl;

[0263] D is C 1-7 alkyl or C 2-7 alkenyl;

[0264] or a pharmaceutically acceptable salt thereof.

[0265] One subclass is the compounds of Formula (ID) wherein

[0266] R1is hydrogen, C 1-7 alkyl, cyano, halo, nitro, haloC 1-7 alkyl, haloC 1-7 alkoxy or C 1-7 alkylthio;

[0267] R2is hydrogen or halo;

[0268] R3is -D-C(O)-NR6R7, -C(O)R8, -SO2R 11 or -C(S)NR 18 R 19 ;

[0269] R4is hydrogen, C 1-7 alkyl, hydroxy or halo;

[0270] R5is hydrogen;

[0271] R6is C 1-7 alkyl or C 3-7 cycloalkyl;

[0272] R7and R 24 are hydrogen or C 1-7 alkyl;

[0273] R8is hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, haloC 1-7 alkyl, C 1-7 alkylcarbonyl, C 1-7 alkoxycarbonyl, C 1-7 alkoxyC 1-7 alkyl, -C 1-7 alkyl-O-C(O)-C 1-7 alkyl, -C 1-7 alkyl-SO2(C 1-7 alkyl) or 4-10 membered heterocyclyl;

[0274] R 11 is C 1-7 alkyl, C 3-7 cycloalkyl, haloC 1-7 alkyl, cyanoC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, -NR 12 R 13 , 3-6 membered carbocyclyl optionally substituted with 1-2 halo substituents or 4-6 membered heterocyclyl optionally substituted with 1-2 substituents selected from halo or C 1-7 alkyl;

[0275] R 12 and R 13 are C 1-7 alkyl;

[0276] R 18 and R 19 are independently hydrogen or C 1-7 alkyl;

[0277] D is absent;

[0278] wherein the heterocyclyl group has 1-3 heteroatoms independently selected from N, O and S at each occurrence,

[0279] or a pharmaceutically acceptable salt thereof.

[0280] One subclass of the above embodiments is the compound wherein

[0281] R1is hydrogen, C 1-7 alkyl, halo, haloC 1-7 alkyl or haloC 1-7 alkoxy;

[0282] R2and R5are hydrogen;

[0283] R3is -D-C(O)-NR6R7, -C(O)R8, -SO2R 11 or -C(S)NR 18 R 19 , or oxetanyl optionally substituted with a hydroxyl substituent;

[0284] R4is hydrogen, C 1-7 alkyl or halo;

[0285] R6is C 1-7 alkyl;

[0286] R7is hydrogen or C 1-7 alkyl;

[0287] R8is C 1-7 alkyl, C2-7 alkenyl, C 3-7 cycloalkyl, halogenated C 1-7 Alkyl, C 1-7 alkyl carbonyl, C 1-7 alkoxycarbonyl, C 1-7 Alkoxy C 1-7 Alkyl, -C 1-7 Alkyl-OC(O)-C 1-7 Alkyl, -C 1-7 Alkyl-SO2(C 1-7 Alkyl), azahexacyclic butyl, morpholinyl, furanyl or pyrrolidinyl;

[0288] R 11 It is C 1-7 Alkyl, C 3-7 cycloalkyl, halogenated C 1-7 Alkyl, cyano C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, -NR 12 R 13 pyrroleyl, phenyl optionally substituted with a halogen group, oxetyl, or optionally substituted with a C- group 1-7 Alkyl-substituted pyrazolyl group;

[0289] R 12 and R 13 It is C 1-7 alkyl;

[0290] R 18 and R 19 Independently hydrogen or C 1-7 alkyl;

[0291] R 24 Is it hydrogen or C? 1-7 alkyl;

[0292] D does not exist;

[0293] Or its pharmaceutically acceptable salt.

[0294] Another subclass of the above-described implementation schemes is compounds, in which...

[0295] R1 is hydrogen, C 1-7 Alkyl, halogen, halogenated C 1-7 Alkyl or halogenated C 1-7 Alkoxy;

[0296] R2, R5, and R7 are hydrogen;

[0297] R3 is -DC(O)-NR6R7, -C(O)R8, or -SO2R 11 ;

[0298] R4is hydrogen or C 1-7 alkyl;

[0299] R6is C 1-7 alkyl;

[0300] R8is C 1-7 alkyl, C 3-7 cycloalkyl, haloC 1-7 alkyl, C 1-7 alkylcarbonyl, -C 1-7 alkyl-O-C(O)-C 1-7 alkyl, -C 1-7 alkyl-SO2(C 1-7 alkyl), morpholinyl or pyrrolidinyl;

[0301] R 11 is C 1-7 alkyl, C 3-7 cycloalkyl, cyanoC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, -NR 12 R 13 , oxetanyl or pyrazolyl optionally substituted with a C 1-7 alkyl substituent;

[0302] R 12 and R 13 are C 1-7 alkyl;

[0303] R 24 is hydrogen or C 1-7 alkyl;

[0304] D is absent;

[0305] or a pharmaceutically acceptable salt thereof.

[0306] Another subclass of the above embodiments is the compounds wherein

[0307] R1is hydrogen, halogen, haloC 1-7 alkyl or haloC 1-7 alkoxy;

[0308] R2, R4, R5and R7are hydrogen;

[0309] R3is -D-C(O)-NR6R7, -C(O)R8or -SO2R 11 ;

[0310] R6, R 12 and R 13 are C 1-7 alkyl;

[0311] R8is C 1-7 alkyl or haloC 1-7 alkyl;

[0312] R 11 is C 1-7 alkyl, C 3-7 cycloalkyl, C 1-7 alkoxyC 1-7 alkyl, -NR 12 R 13 or oxetanyl;

[0313] R 24 is hydrogen;

[0314] D is absent;

[0315] or a pharmaceutically acceptable salt thereof.

[0316] One subclass is compounds of Formula (IE) wherein

[0317] R1, R2, R4, R5, and R 24 is hydrogen;

[0318] R3is hydrogen, -D-C(O)-NR6R7, -C(O)R8, -SO2R 11 , -D-NR9R 10 , -S(O)(NR 14 )(R 22 ), 4-6 membered heterocyclyl optionally substituted with 1-2 oxo substituents, or 4-6 membered heterocyclylC 1-7 alkyl;

[0319] R6, R 11 , and R 22 is C 1-7 alkyl;

[0320] R7is hydrogen or C 1-7 alkyl;

[0321] R8is C 1-7 alkyl, C 1-7 alkoxy, or 4-6 membered heterocyclyl;

[0322] R9is -SO2(C 1-7 alkyl);

[0323] R 10 is hydrogen, C 1-7 alkyl, or C 3-7 cycloalkyl;

[0324] R 14 is hydrogen or -SO2R 21 ;

[0325] R 21 is 3-6 membered carbocyclyl optionally substituted with 1-2 C 1-7 alkyl groups;

[0326] D is absent or C 1-7 alkyl;

[0327] wherein said heterocyclyl has 1-3 heteroatoms independently selected from N, O and S at each occurrence;

[0328] or a pharmaceutically acceptable salt thereof.

[0329] Another subclass of the above embodiments is the compounds wherein

[0330] R1, R2, R4, R5and R 24 are hydrogen;

[0331] R3is -D-C(O)-NR6R7, -C(O)R8, -SO2R 11 , -D-NR9R 10 , -S(O)(NR 14 )(R 22 ), 1,1-dioxidoisothiazolidinyl or 1,1-dioxidoisothiazolidinyl C 1-7 alkyl;

[0332] R6, R 11 and R 22 are C 1-7 alkyl;

[0333] R7is C 1-7 alkyl;

[0334] R8is C 1-7 alkyl or azetidinyl;

[0335] R9is -SO2(C 1-7 alkyl);

[0336] R 10 is hydrogen, C 1-7 alkyl or C 3-7 cycloalkyl;

[0337] R 14 is -SO2R 21 ;

[0338] R 21 is phenyl optionally substituted with a C 1-7 alkyl substituent;

[0339] D is absent or C 1-7 alkyl;

[0340] or a pharmaceutically acceptable salt thereof.

[0341] According to one embodiment, the present application provides a pharmaceutical composition comprising a compound of Formula (I) as defined in any one of the above embodiments, and a pharmaceutically acceptable carrier.

[0342] According to another embodiment, the present application provides a method for treating a steroid receptor, in particular androgen receptor (AR), dependent disorders and diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I)

[0343]

[0344] wherein

[0345] Ring B is a 4-10 membered monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected from N, O, or S;

[0346] Ring A is any one of

[0347]

[0348] L is absent, -CH2-, -CH2-CH2- or -CH2-CH2-CH2-, or in the case where Ring A is (1), L can also be -C(O)-CH2-;

[0349] R1is hydrogen, C 1-7 alkyl, C 1-7 alkoxy, halogen, cyano, nitro, haloC 1-7 alkyl, haloC 1-7 alkyl, C 1-7 alkyl, C 1-7 alkyl, halogen, hydroxyl, haloC 1-7 alkyl, nitro, haloC 1-7 alkoxy or mercapto;

[0350] R2is hydrogen, C 1-7 alkyl, halogen, hydroxyl, haloC 1-7 alkyl, nitro, haloC 1-7 alkoxy or mercapto;

[0351] or R1and R2together with the carbon atom to which they are attached form a fused 1,3 dioxole ring;

[0352] R3is hydrogen, halogen, nitro, cyano, oxo, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, hydroxyC 3-7 alkyl, C 1-7 alkyl, C 1-7 alkyl, haloC 1-7 alkyl, cyanoC 1-7 alkyl, C 1-7 alkoxyC 1-7alkyl, C 1-7 alkyl, C 2-7 alkenyl, haloC 1-7 alkyl, C 1-7 alkyl, C 1-7 alkyl, C 1-7 alkyl, C 2-7 alkyl, C 20 , -S(O)-C 1-7 alkyl, -S(O)(NR 14 )(R 22 ), -S(NR 15 )(C 1-7 alkyl), -C(S)NR 18 R 19 , -D-C(O)NR6R7, -C(O)R8, -D-NR9R 10 , -SO2R 11 , optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered carbocyclylC 1-7 alkyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 4-10 membered heterocyclylC 1-7 alkyl;

[0353] R4 is hydrogen, halogen, hydroxyl, C 1-7 alkyl, haloC 1-7 alkyl or oxo;

[0354] R5 is hydrogen, halogen, or C 1-7 alkyl;

[0355] R6 is hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, hydroxylC 1-7 alkyl, cyanoC 1-7 alkyl, -C 1-7 alkyl-O-C(O)C 1-7 alkyl or optionally substituted 4-10 membered heterocyclyl;

[0356] R8 is hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 1-7 alkoxy, haloC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, C 1-7 alkylcarbonyl, C 1-7 alkoxycarbonyl, -C 1-7 alkyl-O-C(O)-C 1-7 alkyl, -C 1-7alkyl-SO2(C 1-7 alkyl), -N=S(O)(C 1-7 alkyl)(C 1-7 alkyl) or optionally substituted 4-10 membered heterocyclyl;

[0357] R9is hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl, C 1-7 alkylcarbonyl, -SO2(C 1-7 alkyl) or -SO2(C 3-7 cycloalkyl);

[0358] R 11 is C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, haloC 1-7 alkyl, cyanoC 1-7 alkyl, C 1-7 alkoxyC 1-7 alkyl, -NR 12 R 13 , optionally substituted 3-10 membered carbocyclyl or optionally substituted 4-10 membered heterocyclyl;

[0359] R 12 is hydrogen, C 1-7 alkyl, hydroxyC 1-7 alkyl, cyanoC 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkoxyC 1-7 alkyl or C 1-7 alkylcarbonyl;

[0360] R7, R 10 , R 13 , R 18 and R 19 are independently hydrogen, C 1-7 alkyl or C 3-7 cycloalkyl;

[0361] R 14 is hydrogen, C 1-7 alkyl, C 1-7 alkylcarbonyl or -SO2R 21 ;

[0362] R 15 is hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl, C 1-7 alkylcarbonyl, -SO2R 17 ;

[0363] R 17 is C1-7 alkyl or optionally substituted 3-10 membered carbocyclyl;

[0364] R 20 and R 21 independently C 1-7 alkyl, C 3-7 cycloalkyl or optionally substituted 3-10 membered carbocyclyl;

[0365] R 22 is C 1-7 alkyl or C 3-7 cycloalkyl;

[0366] R 23 is hydrogen or oxo;

[0367] R 24 is hydrogen or C 1-7 alkyl;

[0368] D is absent, C 1-7 alkyl or C 2-7 alkenyl;

[0369] wherein said optional substitution is, at each occurrence, selected from 1-3 substituents independently selected from C 1-7 alkyl, halogen, hydroxyl, C 1-7 alkoxy, C 1-7 alkoxy C 1-7 alkyl, C 1-7 alkoxycarbonyl or oxo; and

[0370] wherein said heterocyclyl has, at each occurrence, 1-4 heteroatoms independently selected from N, O and S;

[0371] or a pharmaceutically acceptable salt thereof.

[0372] According to one embodiment, the steroid receptor dependent disease or disorder is an androgen receptor dependent disease or disorder, including endocrine tumors and diseases, such as prostate or breast cancer, in particular castration-resistant prostate cancer (CRPC). According to one embodiment of the application, the CRPC to be treated is refractory to CYP17A1 inhibitor treatment. According to another embodiment, the androgen receptor dependent disease or disorder is an endocrine tumor that is dependent on CYP11A1 activation.

[0373] The compounds of the present application can be prepared by various synthetic routes analogous to the methods known in the literature, using appropriate starting materials. Compounds of formula (I) can be prepared, for example, in an analogous manner or according to the following reaction schemes. Some of the compounds included in formula (I) can be obtained by converting functional groups of other compounds of formula (I) obtained according to the following schemes, by well-known reaction steps such as oxidation, reduction, hydrolysis, acylation, alkylation, amidation, amination, sulfonation, and the like. It should be noted that any appropriate leaving group such as N-protecting groups, for example tert-butoxycarbonyl (t-BOC) or phenylsulfonyl, can be used during the synthesis according to well-known methods in order to improve the selectivity of the reaction steps.

[0374] Compounds of formula (I) can be prepared, for example, according to Scheme 1, wherein R1, R2, R3, R4, R5, R 23 , R 24 , L, A and B are as defined above, and X1is halogen. In the method of Scheme 1, a 5-hydroxy-4H-pyran-4-one derivative [1] is coupled with a ring B derivative [2] in a suitable solvent in the presence of a base at elevated temperature, for example using K2CO3 in DMF, K2CO3 in DMSO, NaOH / KOH in MeOH / EtOH, NaH in DMF or K2CO3 in THF / 1,4-dioxane, to give a compound of formula (I), wherein halogen acts as leaving group.

[0375] Scheme 1

[0376]

[0377] Alternatively, compounds of formula (I) can be prepared according to Scheme 2, wherein R1, R2, R3, R4, R5, R 23 , R 24 , L, A and B are as defined above, and Z is methanesulfonyl or toluenesulfonyl. In the method of Scheme 2, a 5-hydroxy-4H-pyran-4-one derivative [1] is coupled with a ring B derivative [3] in a suitable solvent in the presence of a base at elevated temperature, for example using K2CO3 in DMF, K2CO3 in DMSO, NaOH / KOH in MeOH / EtOH, NaH in DMF or K2CO3 in THF / 1,4-dioxane, to give a compound of formula (I), wherein methanesulfonate or toluenesulfonate acts as leaving group.

[0378] Scheme 2

[0379]

[0380] Compounds of formula (ID) can be prepared, for example, according to Scheme 3, wherein R3is coupled to the piperidine ring via an acyl or sulfonyl group, wherein R1, R2, R3, R4, R5, and R 24 As defined above, and X is halogen. In the method of Scheme 3, a compound of formula (ID) is coupled with a halogen compound [4] in a suitable solvent, such as CH2Cl2, in the presence of a suitable base, such as triethylamine, to give a compound of formula (ID).

[0381] Scheme 3

[0382]

[0383] Compounds of formula (ID) wherein R3is -C(O)-NHR6may be prepared, for example, according to Scheme 4, wherein R1, R2, R4, R5, and R 24 As defined above. In the method of Scheme 4, a compound of formula (ID) is coupled with an isocyanate compound [5] in a suitable solvent, such as CH2Cl2or DMF, in the presence of a suitable base, such as triethylamine or DIPEA, to give a compound of formula (IDa). R 19 -N=C=S as a reagent to prepare compounds of formula (ID) wherein R3is -C(S)NHR 19 .

[0384] Scheme 4

[0385]

[0386] Compounds of formula (I) can also be prepared according to Scheme 5, wherein R1, R2, R3, R4, R5, R 24 , L, A, and B are as defined above, and X is halogen. In the method of Scheme 5, a compound of formula [6] is coupled with a compound of formula [7] in a suitable solvent, such as DMF, in the presence of a base, such as K2CO3, at elevated temperature, to give a compound of formula [8]. A compound of formula [8] can then be reacted with methanesulfonyl chloride in a suitable solvent, such as DCM, under cooling, in the presence of a suitable base, such as triethylamine, to give a compound of formula [9]. A compound of formula (I) can be obtained by coupling a compound of formula [9] with a compound of formula

[10] in a suitable solvent, such as DMSO or DMF, in the presence of a base, such as K2CO3, at elevated temperature.

[0387] Scheme 5

[0388]

[0389] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter pertains. As used herein, the following definitions are provided to facilitate understanding of the invention.

[0390] As used in this article, the term "individual" refers to both humans and animals.

[0391] The term "steroid receptor" refers to a receptor that binds to and is activated by steroid hormones. Examples of steroid receptors include, but are not limited to, androgen receptors, glucocorticoid receptors, and progesterone receptors.

[0392] The term "endocrine tumor" refers to the partial or complete unregulated growth of one or more cellular components of the endocrine system, including but not limited to cancers of one or more adrenal glands.

[0393] As used herein, the term “halogenated” or “halogen” alone or as part of another group refers to chlorine, bromine, fluorine, or iodine.

[0394] As used herein, the term "C" refers to either alone or as part of another group. 1-7 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms. C 1-7 Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and n-hexyl. 1-7 A preferred embodiment of "alkyl" is C 1-3 Alkyl group. The term "C" 1-3 "Alkyl" refers to a compound with 1, 2, or 3 carbon atoms. 1-7 Preferred embodiments of "alkyl".

[0395] As used herein, the term "C" refers to either alone or as part of another group. 2-7 "Alkenyl" refers to an aliphatic hydrocarbon group having 2, 3, 4, 5, 6, or 7 carbon atoms and containing one or more double bonds. Representative examples include, but are not limited to, vinyl, propenyl, and cyclohexenyl.

[0396] As used herein, the term "C" refers to either alone or as part of another group. 3-7 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group containing 3, 4, 5, 6, or 7 carbon atoms. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0397] As used in this article, "C" 3-7 cycloalkyl C 1-7 "alkyl" refers to a C14 group as defined herein. 1-7C 3-7 Cycloalkyl.

[0398] As used herein, the term "hydroxyl," alone or in combination with another group, refers to an -OH group.

[0399] As used herein, the term "cyano," alone or as part of another group, refers to a -CN group.

[0400] As used herein, the term "carboxyl," alone or as part of another group, refers to a -COOH group.

[0401] As used herein, the term "carbonyl," alone or as part of another group, refers to a carbon atom double-bonded to an oxygen atom (C=0).

[0402] As used herein, the term "oxo," alone or as part of another group, refers to an oxygen atom bonded to another atom through a double bond.

[0403] As used herein, the term "C 1-7 alkyl, as defined herein, through an oxygen atom to the parent molecular moiety. Alkoxy 1-7 alkyl. C 1-7 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy, butyloxy, isobutyloxy, sec-butyloxy, and tert-butyloxy.

[0404] As used herein, the term "hydroxyC 1-7 alkyl, as defined herein, through an oxygen atom to the parent molecular moiety. Alkoxy 1-7 at least one hydroxyl group, as defined herein, attached to the parent molecular moiety through a carbon atom of the alkyl group. HydroxyC 1-7 Representative examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl, 1-methyl-1-hydroxyethyl, and 1-methyl-1-hydroxypropyl.

[0405] As used herein, the term "haloC 1-7 alkyl, as defined herein, through an oxygen atom to the parent molecular moiety. Alkoxy 1-7 at least one halogen, as defined herein, attached to the parent molecular moiety through a carbon atom of the alkyl group. HaloC 1-7 Representative examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, and 3-bromopropyl.

[0406] As used herein, the term "cyanoC 1-7 alkyl, as defined herein, through an oxygen atom to the parent molecular moiety. Alkoxy 1-7 at least one cyano group, as defined herein, attached to the parent molecular moiety through a carbon atom of the alkyl group. CyanoC1-7 Representative examples of alkyl groups include, but are not limited to, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, and 2-cyanopropyl.

[0407] As used herein, the term "haloC 1-7 alkyl" means at least one halo group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. 1-7 alkyl group, as defined herein, attached to the parent molecular moiety.

[0408] As used herein, the term "phenylC 1-7 alkyl" means at least one phenyl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. 1-7 alkyl group, as defined herein, attached to the parent molecular moiety.

[0409] As used herein, the term "C 1-7 alkylcarbonyl" means a C 1-7 alkyl group, as defined herein, attached to the parent molecular moiety through a carbonyl group.

[0410] As used herein, the term "C 1-7 alkoxyC 1-7 alkyl" means at least one C 1-7 alkoxy group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. 1-7 alkoxy group.

[0411] As used herein, the term "hydroxyC 1-7 alkoxy" means at least one hydroxy group, as defined herein, attached to the parent molecular moiety through a C 1-7 alkoxy group, as defined herein.

[0412] As used herein, the term "hydroxyC 1-7 alkoxyC 1-7 alkyl" means at least one C 1-7 alkoxy group, as defined herein, attached to the parent molecular moiety through a hydroxyC 1-7 alkoxy group.

[0413] As used herein, the term "4-10 membered heterocyclyl" refers to a saturated, partially saturated, or aromatic ring having 4-10 ring atoms, 1-4 of which are heteroatoms selected from N, O, and S. One embodiment of "4-10 membered heterocyclyl" is "4-6 membered heterocyclyl," which refers to a saturated, partially saturated, or aromatic ring having 4-6 ring atoms, 1-4 of which are heteroatoms selected from N, O, and S. Representative examples of 4-10 membered heterocycles include, but are not limited to, oxetanyl, azetidinyl, pyrazolyl, 1,2,4-triazol-l-yl, 1,2,3-triazol-l-yl, pyrimidinyl, pyridyl, piperidinyl, tetrazolyl, piperazinyl, furanyl, morpholinyl, piperidinyl, pyrrolidinyl, thiazolyl, isoxazolyl, pyrazinyl, tetrahydropyranyl, 1,2,4-oxadiazolyl, oxazolyl, imidazolyl, indolyl, and 4,5-dihydroimidazolyl rings.

[0414] As used herein, the term "3-10 membered carbocyclyl" refers to a saturated, partially saturated, or aromatic ring having 3-10 ring atoms composed solely of carbon atoms. One embodiment of "3-10 membered carbocyclyl" is "3-6 membered carbocyclyl," which refers to a saturated, partially saturated, or aromatic ring having 3-6 ring atoms composed solely of carbon atoms. Representative examples of 3-10 membered carbocyclyl include, but are not limited to, phenyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, and cyclobutyl rings.

[0415] As used herein, the term "4-10 membered heterocyclyl C 1-7 alkyl" means a "4-10 membered heterocyclyl" as defined herein attached through a C 1-7 alkyl group to the parent molecular moiety.

[0416] As used herein, the term "3-10 membered carbocyclyl C 1-7 alkyl" means a "3-10 membered carbocyclyl" as defined herein attached through a C 1-7 alkyl group to the parent molecular moiety.

[0417] The terms "substituted" or "substituted with" as used herein when describing various residues, means halogen substituents such as fluoro, chloro, bromo, iodo, or C 1-7 alkyl, C 3-7 cycloalkyl, hydroxy, amino, nitro, cyano, mercapto C 1-7 alkyl, methylsulfonyl, C 1-7 alkoxy, halo C 1-7 alkyl, hydroxy C 1-7 alkyl, or amino C 1-7 alkyl substituents. Preferred are halogen, C 1-7 alkyl, hydroxy, amino, halo C 1-7 alkyl, C1-7 alkyl or halo substituents, especially methyl, ethyl, chloro, fluoro or bromo substituents. 1-7 alkyl or halo substituents, especially methyl, ethyl, chloro, fluoro or bromo substituents. 1-3 alkyl or halo substituents, especially methyl, ethyl, chloro, fluoro or bromo substituents.

[0418] A "substituted" group can contain 1 to 3, preferably 1 or 2, of the above substituents, unless otherwise defined.

[0419] Optical antipodes or diastereomers of the compounds of formula (I) can be prepared, for example, by resolution of the racemic final product using known methods or by using appropriate optically active starting materials. Similarly, racemic compounds of formula (I) can be prepared by using racemic starting materials. For example, resolution of a racemic compound of formula (I) or its racemic starting materials can be carried out, for example, by converting the racemic compound into a mixture of diastereomeric salts with an optically active acid, followed by separation of the diastereomeric salts by crystallization. Representative examples of optically active acids include, but are not limited to, D-tartaric acid and dibenzoyl-D-tartaric acid. Alternatively, racemic mixtures can be resolved using a preparative chiral chromatographic method.

[0420] Pharmaceutically acceptable salts are well known in the pharmaceutical arts. Non-limiting examples of suitable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Non-limiting examples of metal salts include alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts. Non-limiting examples of salts with inorganic or organic acids include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methanesulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates, acetates, oxalates, fumarates, hemifumarates, and succinates. If applicable, pharmaceutically acceptable esters can be prepared by known methods using pharmaceutically acceptable acids commonly used in the pharmaceutical arts, which are capable of maintaining the pharmacological properties of the free form. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl esters. Phosphate esters and carbonates are also within the scope of the present application.

[0421] The definitions of formula (I) above include all possible isotopes and isomers, such as stereoisomers, including geometric isomers, such as Z and E isomers (cis and trans isomers), and optical isomers, such as diastereomers and enantiomers, as well as prodrug esters, such as phosphate esters and carbonates, of the compounds.

[0422] It will be appreciated by persons skilled in the art that the compounds of the present application can contain at least one chiral center. Thus, the compounds can exist as optically active forms or as racemates. It will be appreciated that formula (I) includes any optically active form or racemic form or mixtures thereof. In one embodiment, the compound is the pure (R)-isomer. In another embodiment, the compound is the pure (S)-isomer. In another embodiment, the compound is a mixture of (R) and (S) isomers. In another embodiment, the compound is a racemic mixture comprising equal amounts of (R) and (S) isomers. The compounds can contain two chiral centers. In this case, according to one embodiment, the compound is a diastereomeric mixture. According to another embodiment, the compound of the present application is an enantiomeric mixture. According to another embodiment, the compound is a pure enantiomer. The individual isomers can be obtained using corresponding isomeric forms of starting materials, or they can be separated by conventional separation methods after preparation of the final compound. For separating optical isomers, such as enantiomers or diastereomers, from mixtures thereof, conventional resolution methods, such as fractional crystallization, can be used.

[0423] The compounds of the present application can also exist in tautomeric forms or in equilibrium mixtures thereof, wherein a proton of the compound is transferred from one atom to another. Examples of tautomeric phenomena include, but are not limited to, amido-imino, keto-enol, phenol-keto, oxime-nitroso, nitro-aci, imine-enamine, cyclic tautomeric phenomena of heterocycles, and the like. The compounds of formula (I) encompass the tautomeric forms, even if only one tautomeric form is described.

[0424] Examples of a group of preferred compounds of formula (I) include:

[0425] (E)-3-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)phenyl)acrylic acid methyl ester (Compound 2);

[0426] 2-(isoindolin-2-ylmethyl)-5-((4-(pyrrolidin-1-ylsulfonyl)benzyl)oxy)-4H-pyran-4-one (Compound 5);

[0427] 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N-methylbenzenesulfonamide (Compound 8);

[0428] 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N-dimethylbenzenesulfonamide (Compound 10);

[0429] 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N-(2- methoxyethyl)benzenesulfonamide (Compound 11);

[0430] N-(2-hydroxyethyl)-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)-N-methylbenzenesulfonamide (Compound 12);

[0431] N-(2-hydroxyethyl)-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)benzenesulfonamide (Compound 15);

[0432] N-ethyl-N-(2-hydroxyethyl)-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)benzenesulfonamide (Compound 21);

[0433] 5-((4-((difluoromethyl)sulfonyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4- one (Compound 22);

[0434] N-(2-cyanoethyl)-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)- N-methylbenzenesulfonamide (Compound 23);

[0435] 2-(isoindolin-2-ylmethyl)-5-((1-(oxetan-3-ylsulfonyl)piperidin-4-yl)methoxy)-4H- pyran-4-one (Compound 36);

[0436] 5-((4-(methylsulfonyl)benzyl)oxy)-2-((5-(trifluoromethoxy)isoindolin-2-yl)methyl)- 4H-pyran-4-one (Compound 37);

[0437] 2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-((4-(2-hydroxypropan-2-yl)benzyl)oxy)- 4H-pyran-4-one (Compound 44);

[0438] 2-isoindolin-2-ylmethyl)-5-((4-(prop-1-en-2-yl)benzyl)oxy)-4H-pyran-4-one (Compound 47);

[0439] 5-((4-(2-hydroxypropan-2-yl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 49);

[0440] 5-(Cyclohexylmethoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 65);

[0441] 5-((1-(Oxetan-3-ylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-4-one (Compound 69a);

[0442] N-((4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)phenyl)sulfonyl)-N- methylacetamide (Compound 70);

[0443] 5-((4-(Cyclobutanesulfonimidoyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 71);

[0444] 5-((4-(Cyclopropylsulfonyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 72);

[0445] 5-((4-(Isobutylsulfonyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 73);

[0446] 5-((4-(S-Methylsulfinimidoyl)benzyl)oxy)-2-((5-(trifluoromethyl)isoindolin-2-yl)methyl)- 4H-pyran-4-one (Compound 74);

[0447] 4-({[6-(1,3-Dihydro-2H-isoindol-2-ylmethyl)-4-oxo-4H-pyran-3-yl]oxy}methyl)-N- [dimethyl(oxido)-λ 6 -sulfanylidene]benzamide (Compound 83);

[0448] N-[dimethyl(oxido)-λ 6 -sulfanylidene]-4-[({6-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-oxo-4H-pyran- 3-yl}oxy)methyl]benzamide (Compound 84);

[0449] 5-((4-(S-Methylsulfinimidoyl)benzyl)oxy)-2-((5-(trifluoromethyl)isoindolin-2-yl)methyl)- 4H-pyran-4-one (Compound 89);

[0450] 5-((4-(S-methylsulfonimidoyl)benzyl)oxy)-2-((5-(trifluoromethoxy)isoindolin-2- yl)methyl)-4H-pyran-4-one (Compound 90);

[0451] 2-(1-(Isoindolin-2-yl)ethyl)-5-((4-(S-methylsulfonimidoyl)benzyl)oxy)-4H-pyran-4- one (Compound 91);

[0452] 5-((4-(N,S-dimethylsulfonimidoyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4- one (Compound 92);

[0453] N-{[4-({[6-(1,3-dihydro-2H-isoindol-2-ylmethyl)-4-oxo-4H-pyran-3-yl]oxy}methyl)phenyl](methyl)- lambda 4 -sulfanilyl}-4-methylbenzenesulfonamide (Compound 93);

[0454] 5-((4-(azetidine-1-carbonyl)-2-fluorobenzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4- one (Compound 95);

[0455] 2-(Isoindolin-2-ylmethyl)-5-((4-(propan-2-ylsulfonimidoyl)benzyl)oxy)-4H-pyran-4-one (Compound 103);

[0456] 5-((5-fluoro-1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-2-(isoindolin-2- ylmethyl)-4H-pyran-4-one (Compound 104);

[0457] 2-(Isoindolin-2-ylmethyl)-5-((4-(oxazol-2-yl)benzyl)oxy)-4H-pyran-4-one (Compound 109);

[0458] 5-((4-(1-hydroxycyclobutyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 111);

[0459] N-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)benzyl)methanesulfonamide (Compound 113);

[0460] 5-((4-(3-hydroxyoxetan-3-yl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 114);

[0461] 2-((5-fluoroisoindolin-2-yl)methyl)-5-((4-(3-hydroxyoxetan-3-yl)benzyl)oxy)- 4H-pyran-4-one (Compound 115);

[0462] 5-((4-(3-hydroxyoxetan-3-yl)benzyl)oxy)-2-((5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-4-one (Compound 116);

[0463] 2-(isoindolin-2-ylmethyl)-5-((4-(pyrrolidine-1-carbonyl)benzyl)oxy)-4H-pyran-4- one (Compound 122);

[0464] 5-((4-(azetidine-1-carbonyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 129);

[0465] 2-((5-bromoisoindolin-2-yl)methyl)-5-((4-(pyrrolidine-1-carbonyl)benzyl)oxy)-4H- pyran-4-one (Compound 130);

[0466] N-(tert-butyl)-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl) benzamide (Compound 131);

[0467] 4-(((6-isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N-diisopropyl benzamide (Compound 134);

[0468] 4-(((6-((5-chloroisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N- dimethyl benzamide (Compound 137);

[0469] 4-(((6-((5-methoxyisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N- dimethyl benzamide (Compound 138);

[0470] N,N-dimethyl-4-(((4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3- yl)oxy)methyl)benzamide (Compound 139);

[0471] (E)-3-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)phenyl)-N,N- dimethyl acrylamide (Compound 146);

[0472] 5-((4-(3,3-difluoroazetidine-l-carbonyl)benzyl)oxy)-2-((5-methoxyisoindolin-2- yl)methyl)-4H-pyran-4-one (Compound 162);

[0473] 3,5-difluoro-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N- dimethylbenzamide (Compound 172);

[0474] N-((4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)cyclohexyl)methyl) methanesulfonamide (Compound 173);

[0475] 5-((4-((l,l-dioxidoisothiazolidin-2-yl)methyl)cyclohexyl)methoxy)-2-(isoindolin-2- ylmethyl)-4H-pyran-4-one (Compound 176);

[0476] 5-((l-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-4-one (Compound 184);

[0477] 2-(isoindolin-2-ylmethyl)-5-((l-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4- one (Compound 185);

[0478] 2-((5-fluoroisoindolin-2-yl)methyl)-5-((l-(methylsulfonyl)piperidin-4-yl)methoxy)-4H- pyran-4-one (Compound 186);

[0479] 5-((l-(cyclopropylsulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran- 4-one (Compound 187);

[0480] 5-((l-(ethylsulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 188);

[0481] 5-((l-(ethylsulfonyl)piperidin-4-yl)methoxy)-2-((5-fluoroisoindolin-2-yl)methyl)-4H- pyran-4-one (Compound 189);

[0482] 5-((l-(cyclopropylsulfonyl)piperidin-4-yl)methoxy)-2-((5-fluoroisoindolin-2-yl)methyl)- 4H-pyran-4-one (Compound 190);

[0483] 5-((1-(ethylsulfonyl)-4-methylpiperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)- 4H-pyran-4-one (Compound 192);

[0484] 2-(1 -isoindolin-2-yl)ethyl)-5-((1 -(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran- 4-one (Compound 195);

[0485] 2-(isoindolin-2-ylmethyl)-5-((tetrahydro-2H-thiopyran-4-yl)methoxy)-4H-pyran-4- one (Compound 196);

[0486] 5-((1 -(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethoxy)-isoindolin-2- yl)methyl)-4H-pyran-4-one (Compound 205);

[0487] 2-((5-methylisoindolin-2-yl)methyl)-5-((1 -(methylsulfonyl)piperidin-4-yl)methoxy)- 4H-pyran-4-one (Compound 211);

[0488] 2-(isoindolin-2-ylmethyl)-5-(3-(1 -(methylsulfonyl)piperidin-4-yl)propoxy)-4H-pyran- 4-one (Compound 213);

[0489] 2-(isoindolin-2-ylmethyl)-5-((1 -(pyrrolidine-1 -carbonyl)piperidin-4-yl)methoxy)-4H- pyran-4-one (Compound 215);

[0490] 5-(((1 r,4r)-4-(1,1 -dioxidoisothiazinan-2-yl)cyclohexyl)methoxy)-2-(isoindolin-2- ylmethyl)-4H-pyran-4-one (Compound 216);

[0491] 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N-dimethylcyclo- hexan-1 -carboxamide (Compound 217);

[0492] N-cyclopropyl-N-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)- cyclohexyl)methanesulfonamide (Compound 219);

[0493] 5-((1 -butanoylpiperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 221);

[0494] 5-((1-(2,2-difluoropropanoyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)- 4H-pyrrol-4-one (Compound 222);

[0495] 2-((5-fluoroisoindolin-2-yl)methyl)-5-((1-propionylpiperidin-4-yl)methoxy)-4H- pyrrol-4-one (Compound 224);

[0496] 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyrrol-3-yl)oxy)methyl)-N,N-dimethylpiperidine- 1 -sulfonamide (Compound 225);

[0497] 5-((1-(cyclopropanecarbonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H- pyrrol-4-one (Compound 226);

[0498] 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyrrol-3-yl)oxy)methyl)-N-isopropyl-piperidine- 1 -carboxamide (Compound 229);

[0499] 4-(((6-((5-fluoroisoindolin-2-yl)methyl)-4-oxo-4H-pyrrol-3-yl)oxy)methyl)-N,N- dimethylpiperidine-1 -sulfonamide (Compound 230);

[0500] 2-(isoindolin-2-ylmethyl)-5-((1-(morpholine-4-carbonyl)piperidin-4-yl)methoxy)-4H- pyrrol-4-one (Compound 232);

[0501] 5-((4-(azetidine-1-carbonyl)cyclohexyl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyrrol-4- one (Compound 234);

[0502] 2-(isoindolin-2-ylmethyl)-5-((1-(2-(methylsulfonyl)acetyl)piperidin-4-yl)methoxy)-4H- pyrrol-4-one (Compound 238);

[0503] 5-(((1r,4r)-4-acetylcyclohexyl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyrrol-4-one (Compound 244);

[0504] 5-((1-propionylpiperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)isoindolin-2-yl)methyl)- 4H-pyrrol-4-one (Compound 244a);

[0505] 2-((5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)methyl)isoindoline-5- carbonitrile (Compound 245a);

[0506] 1 -(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidin-1 -yl)-4- methylpentane-1,2-dione (Compound 249);

[0507] 2-(isoindolin-2-ylmethyl)-5-((1 -neopentanoylpiperidin-4-yl)methoxy)-4H-pyran-4-one (Compound 251 );

[0508] 2-((4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidin-1 -yl)sulfonyl)acetonitrile (Compound 254);

[0509] 2-(isoindolin-2-ylmethyl)-5-((1 -((1 -methyl-1 H-pyrazol-5-yl)sulfonyl)piperidin-4-yl)methoxy)-4H- pyran-4-one (Compound 255);

[0510] Acetic acid 2-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidin-1 -yl)-2- oxoethyl ester (Compound 257);

[0511] 2-(isoindolin-2-ylmethyl)-5-((1 -neopentanoylpiperidin-4-yl)methoxy)-4H-pyran-4-one (Compound 251 );

[0512] 2-(isoindolin-2-ylmethyl)-5-((1 -neopentanoylpiperidin-4-yl)methoxy)-4H-pyran-4-one (Compound 251 );

[0513] 5-((1 -(isobutylsulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 271 );

[0514] 5-((1 -isobutyrylpiperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 272);

[0515] 4-((6-((5-bromoisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3-yloxy)methyl)benzonitrile (Compound 278);

[0516] 5-((4-(S-methylsulfonimidoyl)benzyl)oxy)-2-((5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-4-one (Compound 285);

[0517] 5-((4-(S-methylsulfonimidoyl)benzyl)oxy)-2-((5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-4-one (Compound 285);

[0518] and tautomers and pharmaceutically acceptable salts thereof.

[0519] Another group of examples of preferred compounds of Formula (I) includes:

[0520] 2-(Isoindolin-2-ylmethyl)-5-((4-(methylsulfonyl)benzyl)oxy)-4H-pyran-4-one (Compound 1);

[0521] N,N-diethyl-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)benzenesulfonamide (Compound 4);

[0522] 2-(Isoindolin-2-ylmethyl)-5-((4-(morpholinosulfonyl)benzyl)oxy)-4H-pyran-4-one (Compound 6);

[0523] 2-(Isoindolin-2-ylmethyl)-5-((4-(morpholinosulfonyl)benzyl)oxy)-4H-pyran-4-one (Compound 6);

[0524] 5-((4-(Ethylsulfonyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 24);

[0525] 4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N-(2- methoxyethyl)-N-methylbenzenesulfonamide (Compound 20);

[0526] 5-((4-(Ethylsulfonyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 24);

[0527] 2-(Isoindolin-2-ylmethyl)-5-((4-(morpholinosulfonyl)benzyl)oxy)-4H-pyran-4-one (Compound 6);

[0528] 2-((5,6-Difluoroisoindolin-2-yl)methyl)-5-((4-(methylsulfonyl)benzyl)oxy)-4H-pyran-4- one (Compound 26);

[0529] 2-(Isoindolin-2-ylmethyl)-5-((4-((2-methoxyethyl)sulfonyl)benzyl)oxy)-4H-pyran-4- one (Compound 28);

[0530] 2-((5-Fluoroisoindolin-2-yl)methyl)-5-((4-((2-methoxyethyl)sulfonyl)benzyl)oxy)-4H- pyran-4-one (Compound 29);

[0531] 5-((1-((5-Chlorothiophen-3-yl)sulfonyl)azetidin-3-yl)methoxy)-2-(isoindolin-2- ylmethyl)-4H-pyran-4-one (Compound 30);

[0532] 5-((4-Acetylb enzy l)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 31);

[0533] 5-((2-Fluoro-4-(methylsulfonyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 34);

[0534] 5-((4-(4-Bromo-1H-pyrazol-1-yl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 39);

[0535] 2-((3,4-Dihydroisoquinolin-2(1H)-yl)methyl)-5-((4-(2-hydroxy-2-methylpropyl)benzyl)oxy)- 4H-pyran-4-one (Compound 46);

[0536] 4-(((6-((6-Methoxy-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)benzonitrile (Compound 53);

[0537] 3-Fluoro-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)benzamide (Compound 56);

[0538] 3-Fluoro-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N- dimethylbenzamide (Compound 61);

[0539] 2-((5-Fluoroisoindolin-2-yl)methyl)-5-((4-(methylsulfonyl)benzyl)oxy)-4H-pyran-4-one (Compound 63);

[0540] 2-((5-chloroisoindolin-2-yl)methyl)-5-((4-(methylsulfonyl)benzyl)oxy)-4H- pyran-4-one (Compound 64);

[0541] 2-(isoindolin-2-ylmethyl)-5-((tetrahydro-2H-pyran-4-yl)methoxy)-4H-pyran-4- one (Compound 67);

[0542] 5-((4-(methylsulfonyl)benzyl)oxy)-2-((5-nitroisoindolin-2-yl)methyl)-4H-pyran-4- one (Compound 68);

[0543] N-(2-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)phenyl)propan- 2-yl)acetamide (Compound 69);

[0544] 2-(isoindolin-2-ylmethyl)-5-((4-(methylsulfinyl)benzyl)oxy)-4H-pyran-4-one (Compound 81);

[0545] 2-(isoindolin-2-ylmethyl)-5-((4-(methylthio)benzyl)oxy)-4H-pyran-4-one (Compound 82);

[0546] 4-(((6-((5,6-difluoroisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N- dimethylbenzamide (Compound 82a);

[0547] 2-(isoindolin-2-ylmethyl)-5-((4-(S-methylsulfinamyl)benzyl)oxy)-4H-pyran-4-one (Compound 85);

[0548] 2-(isoindolin-2-ylmethyl)-5-((4-(S-methylsulfinamyl)benzyl)oxy)-4H-pyran-4-one (Compound 86);

[0549] 2-((5-fluoroisoindolin-2-yl)methyl)-5-((4-(S-methylsulfinamyl)benzyl)oxy)-4H-pyran- 4-one (Compound 88);

[0550] N-{[4-({[6-(1,3-dihydro-2H-isoindol-2-ylmethyl)-4-oxo-4H-pyran-3-yl]oxy}methyl)phenyl] (methyl)oxido-λ 6 sulfanyl}(Compound 94);

[0551] 5-((4-(N-ethyl-S-methylsulfonimidoyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)- 4H-pyran-4-one (Compound 97);

[0552] 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4- yl)methoxy)-4H-pyran-4-one (Compound 98);

[0553] 5-((1-(ethylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-2-(isoindolin-2- ylmethyl)-4H-pyran-4-one (Compound 99);

[0554] 2-(isoindolin-2-ylmethyl)-5-((1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4- yl)methoxy)-4H-pyran-4-one (Compound 100);

[0555] 5-((4-(ethylsulfonimidoyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 101);

[0556] 5-((4-(ethylsulfonimidoyl)benzyl)oxy)-2-((5-fluoroisoindolin-2-yl)methyl)-4H- pyran-4-one (Compound 102);

[0557] 5-((4-(1H-1,2,3-triazol-1-yl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 107);

[0558] 5-((4-(1H-pyrazol-1-yl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 108);

[0559] 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N-dimethyl- benzamide (Compound 120);

[0560] 2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-((4-methoxybenzyl)oxy)-4H-pyran- 4-one (Compound 121);

[0561] 4-(((6-((6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)-N,N-dimethylbenzamide (Compound 124);

[0562] N,N-diethyl-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)benzamide (Compound 126);

[0563] 4-(((6-((5-fluoroisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N- dimethylbenzamide (Compound 127);

[0564] 2-(isoindolin-2-ylmethyl)-5-((4-(piperidin-1 -carbonyl)benzyl)oxy)-4H-pyran-4-one (Compound 128);

[0565] N-(tert-butyl)-4-(((6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)benzamide (Compound 135);

[0566] 2-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)phenyl)-N,N- dimethylacetamide (Compound 136);

[0567] 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N-isopropylbenzamide (Compound 140);

[0568] N-hexyl-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)benzamide (Compound 142);

[0569] 2-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)benzamido)-2- methylpropyl acetate (Compound 143);

[0570] N-(2-hydroxyethyl)-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N- methylbenzamide (Compound 147);

[0571] 5-((4-(3,3-difluoroazetidine-1 -carbonyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran- 4-one (Compound 158);

[0572] 5-((4-(3,3-difluoroazetidine-1 -carbonyl)benzyl)oxy)-2-((5-fluoroisoindolin-2-yl)methyl)- 4H-pyran-4-one (Compound 161);

[0573] 2-((5-chloroisoindolin-2-yl)methyl)-5-((4-(3,3-difluoroazetidine-1-carbonyl)benzyl)oxy)- 4H-pyran-4-one (Compound 163);

[0574] 5-([1,1'-biphenyl]-4-ylmethoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 164);

[0575] 2-(isoindolin-2-ylmethyl)-5-((4-(pyridin-2-yl)benzyl)oxy)-4H-pyran-4-one (Compound 165);

[0576] 5-((4-(ethylsulfonimidoyl)benzyl)oxy)-2-((5-nitroisoindolin-2-yl)methyl)-4H-pyran-4-one (Compound 168);

[0577] N-butyl-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)benzamide (Compound 169);

[0578] 2,6-difluoro-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N- dimethylbenzamide (Compound 174);

[0579] 2-(isoindolin-2-ylmethyl)-5-(((1R,5S)-8-(methylsulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)methoxy)-4H-pyran-4-one (Compound 177);

[0580] 5-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)isoindolin-1-one (Compound 180);

[0581] 4-(((6-((5-fluoroisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N- dimethylpiperidine-1-carboxamide (Compound 181);

[0582] 2-(isoindolin-2-ylmethyl)-5-((4-methyl-1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H- pyran-4-one (Compound 191);

[0583] N-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-1-oxido- tetrahydro-2H-thiopyran-1-ylidene)-4-methylbenzenesulfonamide (Compound 194);

[0584] 2-(Isoindolin-2-ylmethyl)-5-(2-(1-(methylsulfonyl)piperidin-4-yl)ethoxy)-4H-pyran-4- one (Compound 198);

[0585] (R)-3-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)pyrrolidine-1- carboxylic acid tert-butyl ester (Compound 199);

[0586] (S)-3-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)pyrrolidine-1- carboxylic acid tert-butyl ester (Compound 200);

[0587] 5-((1-(Methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(methylthio)isoindolin-2-yl)methyl)- 4H-pyran-4-one (Compound 208);

[0588] 2-((5,7-Dihydro-6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin- 4-yl)methoxy)-4H-pyran-4-one (Compound 209);

[0589] 2-((5,6-Difluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H- pyran-4-one (Compound 210);

[0590] 2-(Isoindolin-2-ylmethyl)-5-(3-(pyridin-4-yl)propoxy)-4H-pyran-4-one (Compound 214);

[0591] N-(4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)cyclohexyl)-N- methylmethanesulfonamide (Compound 218);

[0592] 2-(Isoindolin-2-ylmethyl)-5-((4-(methylsulfonyl)cyclohexyl)methoxy)-4H-pyran-4-one (Compound 220);

[0593] 5-((1-(2,2-Difluoropropanoyl)piperidin-4-yl)methoxy)-2-((5-fluoroisoindolin-2-yl)methyl)- 4H-pyran-4-one (Compound 223);

[0594] 4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N-methylcyclohexanecarbox amide (Compound 227);

[0595] 4-(((6-(isindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N- methylpiperidine-1-carboxamide (Compound 228);

[0596] 5-((1-(azetidine-1-carbonyl)piperidin-4-yl)methoxy)-2-(isindolin-2- ylmethyl)-4H-pyran-4-one (Compound 231);

[0597] 2-(isindolin-2-ylmethyl)-5-((4-(oxetan-3-ylsulfonyl)benzyl)oxy)-4H- pyran-4-one (Compound 233);

[0598] 5-((4-fluoro-1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-(isindolin-2- ylmethyl)-4H-pyran-4-one (Compound 235);

[0599] 5-((4-fluoro-1-(isopropylsulfonyl)piperidin-4-yl)methoxy)-2-(isindolin-2- ylmethyl)-4H-pyran-4-one (Compound 236);

[0600] 5-((4-fluoro-1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-fluoroisindolin- 2-yl)methyl)-4H-pyran-4-one (Compound 237);

[0601] N-{[4-({[6-(1,3-dihydro-2H-indolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl]oxy}methyl) cyclohexyl](methyl)oxido-λ 6 sulfanyl} -4-methylbenzenesulfonamide (Compound 239);

[0602] 2-((5-chloroisindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)-4H-pyran-4-one (Compound 241);

[0603] N-cyclopropyl-4-(((6-(isindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl) piperidine-1-carboxamide (Compound 247);

[0604] N-(tert-butyl)-4-(((6-(isindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl) piperidine-1-carboxamide (Compound 248);

[0605] 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N- methylpiperidine-1-carbothioamide (Compound 250);

[0606] 5-((1 -acetylpiperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4- one (Compound 252);

[0607] 5-((1 -((4-fluorophenyl)sulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2- ylmethyl)-4H-pyran-4-one (Compound 256);

[0608] 5-((1 -acetylpiperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4- one (Compound 252);

[0609] 5-((1 -(furan-2-carbonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)- 4H-pyran-4-one (Compound 260);

[0610] 2-(isoindolin-2-ylmethyl)-5-((1 -(pyrrolidin-1 -ylsulfonyl)piperidin-4- yl)methoxy)-4H-pyran-4-one (Compound 267);

[0611] 5-((1 -(azetidin-1 -ylsulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2- ylmethyl)-4H-pyran-4-one (Compound 268);

[0612] 2-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidin- 1 -yl)-2-oxoacetic acid ethyl ester (Compound 269);

[0613] 2-(isoindolin-2-ylmethyl)-5-((1 -(isopropylsulfonyl)piperidin-4- yl)methoxy)-4H-pyran-4-one (Compound 270);

[0614] 2-(isoindolin-2-ylmethyl)-5-((1 -(2,2,2-trifluoroacetyl)piperidin-4- yl)methoxy)-4H-pyran-4-one (Compound 273);

[0615] cis-N-(3-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)- cyclopentyl)methanesulfonamide (Compound 276);

[0616] 2-((5-methylisoindolin-2-yl)methyl)-5-((4-(methylsulfonyl)benzyl)oxy)-4H- pyran-4-one (Compound 279);

[0617] 5-((4-(methylsulfonyl)benzyl)oxy)-2-((5-(methylthio)isoindolin-2-yl)methyl)-4H- pyran-4-one (Compound 280);

[0618] N-(1-hydroxy-2-methylpropan-2-yl)-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)benzamide (Compound 283);

[0619] 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1- carbaldehyde (Compound 284);

[0620] 5-((1-(methylsulfonyl)-1,2,3,4-tetrahydropyridin-4-yl)methoxy)-2-((5- (trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-4-one (Compound 291);

[0621] and tautomers and pharmaceutically acceptable salts thereof.

[0622] Another group of preferred examples of compounds of Formula (I) includes:

[0623] 2-(isoindolin-2-ylmethyl)-5-((4-((trifluoromethyl)thio)benzyl)oxy)-4H-pyran-4- one (Compound 3);

[0624] 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)benzenesulfonamide (Compound 13);

[0625] 2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-((4-(methylsulfonyl)benzyl)oxy)-4H- pyran-4-one (Compound 14);

[0626] 5-((2-chloro-4-(methylsulfonyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4- one (Compound 16);

[0627] 5-((3-fluoro-4-(methylsulfonyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4- one (Compound 17);

[0628] 5-((2-chloro-4-(methylsulfonyl)benzyl)oxy)-2-((3,4-dihydroisoquinolin-2(lH)- yl)methyl)-4H-pyran-4-one (Compound 18);

[0629] 2-(Isoindolin-2-ylmethyl)-5-((4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)oxy)- 4H-pyran-4-one (Compound 19);

[0630] 2-((4-Fluoroisoindolin-2-yl)methyl)-5-((4-(methylsulfonyl)benzyl)oxy)-4H-pyran-4- one (Compound 27);

[0631] 4-(((6-((4-Fluoroisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N- dimethylbenzamide (Compound 32);

[0632] 2-((4-Fluoroisoindolin-2-yl)methyl)-5-((4-(2-hydroxypropan-2-yl)benzyl)oxy)-4H- pyran-4-one (Compound 33);

[0633] 5-((l,l-Dioxotetrahydro-2H-thiopyran-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H- pyran-4-one (Compound 35);

[0634] 2-(Isoindolin-2-ylmethyl)-5-((4-nitrobenzyl)oxy)-4H-pyran-4-one (Compound 38);

[0635] l-(4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)phenyl)-lH- pyrazole-4-carboxylic acid ethyl ester (Compound 40);

[0636] 4-(((6-((3,4-Dihydroisoquinolin-2(lH)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl) benzonitrile (Compound 41);

[0637] 2-((3,4-Dihydroisoquinolin-2(lH)-yl)methyl)-5-((4-methylbenzyl)oxy)-4H-pyran-4- one (Compound 42);

[0638] 4-(((6-((3,4-Dihydroisoquinolin-2(lH)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl) benzamide (Compound 43);

[0639] 4-(((6-(isoxazol-3-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-3- fluorobenzonitrile (Compound 49);

[0640] 4-(((6-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)-N-methylbenzamide (Compound 48);

[0641] 3-(((6-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)benzonitrile (Compound 50);

[0642] 4-(((6-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)-3-fluorobenzonitrile (Compound 51);

[0643] 5-((4-(2-hydroxypropan-2-yl)benzyl)oxy)-2-((6-methoxy-3,4- dihydroisoquinolin-2(lH)-yl)methyl)-4H-pyran-4-one (Compound 52);

[0644] 4-(((6-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)-3-fluorobenzamide (Compound 55);

[0645] 4-(((6-(isoxazol-3-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)benzamide (Compound 57);

[0646] 5-((4-bromobenzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 58);

[0647] 5-((4-(2-hydroxypropan-2-yl)benzyl)oxy)-2-((l-methyl-3,4- dihydroisoquinolin-2(lH)-yl)methyl)-4H-pyran-4-one (Compound 59);

[0648] 4-(((6-(isoxazol-3-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)benzoic acid methyl ester (Compound 60);

[0649] 4-(((6-(isoxazol-3-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N- methylbenzamide (Compound 62);

[0650] 2-((5,7-dihydro-6H-[1,3]dioxepino[4,5-f]isoindol-6-yl)methyl)-5-((4- (methylsulfonyl)benzyl)oxy)-4H-pyran-4-one (Compound 66);

[0651] 2-(Isoindolin-2-ylmethyl)-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)-4H- pyran-4-one (Compound 75);

[0652] 2-(Isoindolin-2-ylmethyl)-5-((6-methoxypyridin-3-yl)methoxy)-4H-pyran-4-one (Compound 76);

[0653] N,N-Dimethyl-4-(((6-((1-methylisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)benzamide (Compound 77);

[0654] 4-(((6-((3,4-Dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)- 2-fluoro-N,N-dimethylbenzamide (Compound 78);

[0655] 2-Fluoro-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N- methylbenzamide (Compound 79);

[0656] 4-(((6-((3,4-Dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)- 2-fluoro-N-methylbenzamide (Compound 80);

[0657] 2-((3,4-Dihydroisoquinolin-2(1H)-yl)methyl)-5-((4-(S-methylsulfonimidoyl)benzyl)oxy)- 4H-pyran-4-one (Compound 87);

[0658] 4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N-(2-oxotetrahydrothiophen- 3-yl)benzamide (Compound 96);

[0659] 2-(Isoindolin-2-ylmethyl)-5-((3-nitrobenzyl)oxy)-4H-pyran-4-one (Compound 105);

[0660] 5-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-2-methylisoindolin-1- one (Compound 106);

[0661] 2-(Isoindolin-2-ylmethyl)-5-((2-methoxypyridin-4-yl)methoxy)-4H-pyran-4- one (Compound 110);

[0662] 4-(2-((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)ethyl)-N,N- dimethylbenzamide (Compound 112);

[0663] 2-((3,4-Dihydroisoquinolin-2(lH)-yl)methyl)-5-((4-(3-hydroxyoxetan-3- yl)benzyl)oxy)-4H-pyran-4-one (Compound 117);

[0664] 2-Chloro-4-(((6-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)benzonitrile (Compound 118);

[0665] 4-(((6-((3,4-Dihydroisoquinolin-2(lH)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy) methyl)-N,N-dimethylbenzamide (Compound 119);

[0666] 5-((4-(Hydroxymethyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 123);

[0667] 2-((l-Methyl-3,4-dihydroisoquinolin-2(lH)-yl)methyl)-5-((4-(pyrrolidine- 1-carbonyl)benzyl)oxy)-4H-pyran-4-one (Compound 125);

[0668] (S)-N,N-Dimethyl-4-(((6-((l-methylisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)benzamide (Compound 132);

[0669] (R)-N,N-Dimethyl-4-(((6-((l-methylisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)benzamide (Compound 133);

[0670] 4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N-(prop-2- yn-l-yl)benzamide (Compound 141);

[0671] 2-(Isoindolin-2-ylmethyl)-5-((4-vinylbenzyl)oxy)-4H-pyran-4-one (Compound 144);

[0672] N-(4-(((6-(isoxazol-3-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-2- methoxyphenyl)-4-oxo-4H-pyran-4-yl acetate (Compound 143); and

[0673] (E)-3-(4-(((6-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)phenyl)-N-methylacrylamide (Compound 148);

[0674] 2-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)-5-((4-(3-hydroxypiperidine- 1 -carbonyl)benzyl)oxy)-4H-pyran-4-one (Compound 149);

[0675] 5-((4-(azetidine-l-carbonyl)benzyl)oxy)-2-((5-fluoroisoindolin-2-yl)methyl)- 4H-pyran-4-one (Compound 150);

[0676] N-(3-hydroxy-2,2-dimethylpropyl)-4-(((6-(isoxazol-3-ylmethyl)-4-oxo-4H- pyran-3-yl)oxy)methyl)benzamide (Compound 151);

[0677] 5-((4-(4-hydroxypiperidine-l-carbonyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)- 4H-pyran-4-one (Compound 152);

[0678] 5-(2-(4-benzylpiperazin-l-yl)-2-oxoethoxy)-2-(isoindolin-2-ylmethyl)-4H- pyran-4-one (Compound 153);

[0679] 5-(2-(4-(4-chlorophenyl)piperazin-l-yl)-2-oxoethoxy)-2-(isoindolin-2- ylmethyl)-4H-pyran-4-one (Compound 154);

[0680] 5-(2-(4-benzylpiperidin-l-yl)-2-oxoethoxy)-2-(isoindolin-2-ylmethyl)-4H- pyran-4-one (Compound 155);

[0681] 2-(isoindolin-2-ylmethyl)-5-(2-oxo-2-(4-(phenylsulfonyl)piperazin-l- yl)ethoxy)-4H-pyran-4-one (Compound 156);

[0682] 2-(isoindolin-2-ylmethyl)-5-(2-oxo-2-(4-m-tolylsulfonylpiperazin-l- yl)ethoxy)-4H-pyran-4-one (Compound 157);

[0683] 2-(Isoindolin-2-ylmethyl)-5-(2-(4-(3-(methyloxyrnethyl)pyridin-2-yl)piperazin-l-yl)-2- oxoethoxy)-4H-pyran-4-one (Compound 159);

[0684] 5-((4-(3-Hydroxypiperidine-l-carbonyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4- one (Compound 160);

[0685] 2-((3,4-Dihydroisoquinolin-2(lH)-yl)methyl)-5-((4-(ethylsulfonimidoyl)benzyl)oxy)-4H- pyran-4-one (Compound 166);

[0686] 6-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N-dimethylnicotinamide (Compound 170);

[0687] 2-Fluoro-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)benzamide (Compound 171);

[0688] (Methyl)(l r,4r)-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)cyclohexane- 1-carboxylate (Compound 178);

[0689] 2-((3,4-Dihydroisoquinolin-2(lH)-yl)methyl)-5-((l-(methylsulfonyl)piperidin-4-yl)methoxy)- 4H-pyran-4-one (Compound 179);

[0690] 3-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)pyrrolidine-l-carboxylic acid tert-butyl ester (Compound 182);

[0691] 3-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N-dimethylpyrrolidine-l- carboxamide (Compound 183);

[0692] 5-((3-Hydroxy-l-(methylsulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H- pyran-4-one (Compound 193);

[0693] 4-(2-((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)ethyl)piperidine-l-carboxylic acid tert-butyl ester (Compound 197);

[0694] (S)-3-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1- carboxylic acid tert-butyl ester (Compound 201);

[0695] (R)-3-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1- carboxylic acid tert-butyl ester (Compound 202);

[0696] 4-((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (Compound 203);

[0697] 5-(2-(1-acetylpiperidin-4-yl)ethoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 206);

[0698] 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-nitroisoindolin-2-yl)methyl)-4H- pyran-4-one (Compound 207);

[0699] 2-((1,1-dimethylisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)- 4H-pyran-4-one (Compound 212);

[0700] 2-(isoindolin-2-ylmethyl)-5-((4-(S-methylsulfonimidoyl)cyclohexyl)methoxy)-4H- pyran-4-one (Compound 240);

[0701] 5-((1-imino-1-oxohexahydro-1 lambda 6 -thiopyran-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 242);

[0702] N-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-1-oxotetrahydro- 2H-1 lambda 6 -thiopyran-1-ylidene)acetamide (Compound 243);

[0703] 2-((4,5-difluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)- 4H-pyran-4-one (Compound 245);

[0704] 2-(Isoindolin-2-ylmethyl)-5-((1-((2,2,2-trifluoroethyl)sulfonyl)piperidin-4-yl)methoxy)- 4H-pyran-4-one (Compound 253);

[0705] 5-((3-Aminobenzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 263);

[0706] 4 / 5-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N-dimethyl-1H-1,2,3- triazol-1 -carboxamide (Compound 264);

[0707] 4 / 5-(((6-((3,4-Dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N- dimethyl-1H-1,2,3-triazol-1-carboxamide (Compound 265);

[0708] Cis-N-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)cyclopent-2-en-1- yl)cyclopropane sulfamide (Compound 274);

[0709] Cis-N-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)cyclopent-2-en-1- yl)-3-methylbutanamide (Compound 275);

[0710] (R)-2-(Isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)pyrrolidin-3-yl)methoxy)-4H-pyran-4- one (Compound 277);

[0711] 2-((4-Chloroisoindolin-2-yl)methyl)-5-((4-(methylsulfonyl)benzyl)oxy)-4H-pyran-4-one (Compound 281);

[0712] N-(3-Hydroxypropyl)-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)benzamide (Compound 282);

[0713] 5-((1-(Methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)-2H-indolin-2-yl)methyl)- 4H-pyran-4-one (Compound 287);

[0714] 2-((5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)methyl)isoindoline-2-oxide (Compound 289);

[0715] 2-((5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)methyl)isoindoline-2-oxide (Compound 289);

[0716] and tautomers and pharmaceutically acceptable salts thereof.

[0717] In one particularly preferred group of compounds of formula (I), examples of compounds include:

[0718] N-ethyl-N-(2-hydroxyethyl)-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)benzenesulfonamide (Compound 21);

[0719] 5-((4-(2-hydroxypropan-2-yl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 49);

[0720] 4-({[6-(1,3-dihydro-2H-isoindol-2-ylmethyl)-4-oxo-4H-pyran-3-yl]oxy}methyl)-N-[dimethyl(oxido)-lambda 6 -sulfanediyl]benzamide (Compound 83);

[0721] 5-((4-(S-methylsulfonimidoyl)benzyl)oxy)-2-((5-(trifluoromethoxy)isoindolin-2-yl)methyl)-4H-pyran-4-one (Compound 90);

[0722] 2-(1-(isoindolin-2-yl)ethyl)-5-((4-(S-methylsulfonimidoyl)benzyl)oxy)-4H-pyran-4-one (Compound 91);

[0723] 2-(isoindolin-2-ylmethyl)-5-((4-(pyrrolidine-1-carbonyl)benzyl)oxy)-4H-pyran-4-one (Compound 122);

[0724] 5-((4-((1,1-dioxidoisothiazolidin-2-yl)methyl)cyclohexyl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 176);

[0725] 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-4-one (Compound 184);

[0726] 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4- one (Compound 185);

[0727] 5-((1-(cyclopropylsulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran- 4-one (Compound 187);

[0728] 5-((1-(ethylsulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 188);

[0729] 5-((1-(ethylsulfonyl)piperidin-4-yl)methoxy)-2-((5-fluoroisoindolin-2-yl)methyl)-4H-pyran- 4-one (Compound 189);

[0730] 2-(1-isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4- one (Compound 195);

[0731] 2-(isoindolin-2-ylmethyl)-5-(3-(1-(methylsulfonyl)piperidin-4-yl)propoxy)-4H-pyran-4- one (Compound 213);

[0732] 5-(((1r,4r)-4-(1,1-dioxidoisothiazinan-2-yl)cyclohexyl)methoxy)-2-(isoindolin-2- ylmethyl)-4H-pyran-4-one (Compound 216);

[0733] 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N-dimethylcyclohexane- 1-carboxamide (Compound 217);

[0734] 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N-dimethylpiperidine-1- sulfonamide (Compound 225);

[0735] 5-(((1r,4r)-4-acetylcyclohexyl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 244);

[0736] 5-((1-acetylpiperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-4-one (Compound 244a);

[0737] 2-(Isoindolin-2-ylmethyl)-5-((1-acetylpiperidin-4-yl)methoxy)-4H-pyran-4-one (Compound 261);

[0738] 4-((6-((5-Bromoisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3-yloxy)methyl)benzonitrile (Compound 278);

[0739] and tautomers and pharmaceutically acceptable salts thereof.

[0740] The compounds of the application can be administered to a patient in a therapeutically effective amount, generally ranging from about 1 mg to about 2000 mg, more typically about 10 mg to about 1500 mg per day, depending upon the age, sex, weight, race, condition, the disorder to be treated, the route of administration and the active ingredient employed. The compounds of the application can be formulated into dosage forms using principles known in the art. The compounds can be administered to a patient as they are, or in combination with suitable pharmaceutical excipients, in the form of tablets, granules, capsules, suppositories, emulsions, suspensions or solutions. The selection of suitable ingredients for the compositions is routine for those skilled in the art. Suitable vehicles, solvents, gel-forming excipients, dispersing agents, antioxidants, coloring agents, sweetening agents, wetting compounds and other ingredients commonly used in the art can also be used. The compositions containing the active compounds can be administered enterally or parenterally, the oral route being the preferred mode. The active compounds are present in the compositions in an amount of about 0.5-100%, preferably about 0.5% to about 20% by weight of the total composition.

[0741] The compounds of the application can be administered to an individual as the sole active ingredient or in combination with one or more additional active ingredients useful in the treatment of the particular disease.

[0742] In the treatment of steroid receptor-dependent diseases or conditions, such as endocrine tumors and disorders, including prostate and breast cancer, it is often advantageous to combine the therapeutic agent and / or additional therapy, such as radiation therapy. The second (or third) active agent administered can have the same or a different mechanism of action as the primary therapeutic agent.

[0743] Thus, the compounds of the application can be administered in combination with additional anti-cancer treatments for the treatment of cancer, for example prostate cancer or breast cancer. For example, the compounds of the application can be packaged together with instructions for the use of the compounds of the application in combination with additional anti-cancer agents and treatments for cancer. The application also includes combination products of a compound of the application and one or more additional active agents in the form of a kit, for example where they are packaged together or in separate packages for sale as a kit, or where they are packaged for formulation together.

[0744] According to one embodiment of the application, a therapeutically effective amount of a compound of formula (I) is co-administered with a glucocorticoid and / or a mineralocorticoid and, optionally, with one or more anti-cancer agents.

[0745] Examples of suitable glucocorticoids include, but are not limited to, hydrocortisone, prednisone, prednisolone, methylprednisolone and dexamethasone. Examples of suitable mineralocorticoids include, but are not limited to, fludrocortisone, deoxycorticosterone, 11-deoxycortisone and deoxycorticosterone acetate.

[0746] The optional additional anti-cancer agents that can be administered in addition to the compounds of formula (I) include, but are not limited to:

[0747] - non-steroidal androgen receptor antagonists (for example enzalutamide, apalutamide

[0748] (apalutamide) and darolutamide);

[0749] - inhibitors of steroidogenesis (for example CYP17A1 inhibitors, for example abiraterone acetate and

[0750] seviteronel);

[0751] - chemotherapeutic agents (for example docetaxel and paclitaxel);

[0752] - anti-estrogens (for example tamoxifen and fulvestrant);

[0753] - epigenetic modulators (for example BET inhibitors and HDAC inhibitors);

[0754] - mTOR inhibitors (for example everolimus);

[0755] - AKT inhibitors (for example AZ5363);

[0756] - radiopharmaceuticals (for example alpharadin);

[0757] - GnRH / LHRH analogues (e.g. leuprolide);

[0758] - PI3K inhibitors (e.g. idelalisib); and

[0759] - CDK4 / 6 inhibitors (e.g. ribocyclib).

[0760] According to one embodiment of the application, a therapeutically effective amount of a compound of formula (I) is administered to a patient in need thereof in addition to a therapeutically effective amount of one or more anticancer agents selected from:

[0761] - non-steroidal androgen receptor antagonists (e.g. enzalutamide, apalutamide and darolutamide);

[0762] - inhibitors of steroidogenesis (e.g. CYP17A1 inhibitors such as abiraterone acetate and

[0763] seviteronel);

[0764] - chemotherapeutic agents (e.g. docetaxel and paclitaxel);

[0765] - anti-estrogens (e.g. tamoxifen and fulvestrant);

[0766] - epigenetic modulators (e.g. BET inhibitors and HDAC inhibitors);

[0767] - mTOR inhibitors (e.g. everolimus);

[0768] - AKT inhibitors (e.g. AZ5363);

[0769] - radiopharmaceuticals (e.g. alpharadin);

[0770] - GnRH / LHRH analogues (e.g. leuprolide);

[0771] - PI3K inhibitors (e.g. idelalisib); and

[0772] - CDK4 / 6 inhibitors (e.g. ribocyclib).

[0773] According to one embodiment of the application, a therapeutically effective amount of a compound of formula (I) is administered to an individual in need thereof in addition to a therapeutically effective amount of an inhibitor of steroidogenesis (e.g. a CYP17A1 inhibitor). Examples of suitable CYP17A1 inhibitors include, but are not limited to, abiraterone acetate and seviteronel.

[0774] According to another embodiment of the application, a therapeutically effective amount of a compound of formula (I) is administered to an individual in need thereof in addition to a therapeutically effective amount of a non-steroidal androgen receptor antagonist. Examples of suitable non-steroidal androgen receptor (AR) antagonists include, but are not limited to, enzalutamide, apalutamide, and darolutamide.

[0775] According to another embodiment, the present application provides a pharmaceutical combination comprising a compound of formula (I) and at least one additional active ingredient selected from:

[0776] - a glucocorticoid;

[0777] - a mineralocorticoid;

[0778] - a steroidogenesis inhibitor (e.g. CYP17A1 inhibitor);

[0779] - a non-steroidal androgen receptor antagonist;

[0780] - a chemotherapeutic agent (e.g. docetaxel and paclitaxel);

[0781] - an anti-estrogen (e.g. tamoxifen and fulvestrant);

[0782] - an epigenetic modulator (e.g. BET inhibitor and HDAC inhibitor);

[0783] - an mTOR inhibitor (e.g. everolimus);

[0784] - an AKT inhibitor (e.g. AZ5363);

[0785] - a radiopharmaceutical (e.g. alpharadin);

[0786] - a GnRH / LHRH analogue (e.g. leuprolide);

[0787] - a PI3K inhibitor (e.g. idelalisib); and

[0788] - a CDK4 / 6 inhibitor (e.g. ribocyclib),

[0789] for simultaneous, separate or sequential administration.

[0790] The above additional therapeutic agents can be used in amounts as given in the Physicians’ Desk Reference (PDR) or in amounts determined by those skilled in the art when used in combination with the compounds of the present application.

[0791] The compounds of the present application can be prepared by a variety of synthetic routes analogous to the methods known in the literature, employing appropriate starting materials. The present application is explained in greater detail by the following experiments and examples. These experiments and examples are for illustrative purposes only and do not limit the scope of the application as defined in the claims. Examples

[0792] Intermediate-1 : Methyl 4-((2-methoxyethyl)thio)benzoate

[0793]

[0794] To a solution of methyl 4-mercaptobenzoate (2 g, 10.98 mmol) in MeOH (35 ml) was added K2CO3(2.27 g, 16.48 mmol) followed by 1-bromo-2-methoxyethane (1.54 g, 16.48 mmol) at room temperature. The mixture was refluxed for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2.19 g of the title compound as colorless oil. 1 H-NMR (400 MHz; CDC13): δ 7.95 (d, 2H), 7.33 (d, 2H), 3.89 (s, 3H), 3.64 (t, 2H), 3.37 (s, 3H), 3.18 (t, 2H).

[0795] Intermediate-2: Methyl 4-((2-methoxyethyl)sulfonyl)benzoate

[0796]

[0797] To a solution of methyl 4-((2-methoxyethyl)thio)benzoate (2.19 g, 9.15 mmol) in DCM (30 ml) was added m-CPBA (~ 70% assay, 7.89 g, 32.1 mmol) at 0 °C followed by stirring at room temperature for 16 h. The reaction mixture was quenched with 10% aqueous NaOH solution and extracted with DCM. The organic layer was washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 1.86 g of the title compound as white solid. 1 H-NMR (400 MHz; CDC13): δ 7.95 (d, 2H), 7.33 (d, 2H), 3.89 (s, 3H), 3.64 (t, 2H), 3.37 (s, 3H), 3.18 (t, 2H).

[0798] Intermediate-3: 4-(Cyclopropylsulfonyl)benzaldehyde

[0799]

[0800] To a solution of 4-fluorobenzaldehyde (0.09 ml, 0.8 mmol) in DMSO (5 ml) was added sodium cyclopropane sulfinate (0.13 g, 1.0 mmol). The reaction mixture was heated in a microwave oven at 140 °C for 1 h. To this mixture was added water and the product was extracted with EtOAc. The organic layer was washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 0.15 g of the title compound. LC-MS: m / z 211.1 [M+H] + .

[0801] The following intermediates were prepared according to the procedure described for Intermediate-3 using the starting materials given in the table.

[0802]

[0803]

[0804] Intermediate-6: Methyl 4-(dimethylcarbamoyl)cyclohexane-1-carboxylate

[0805]

[0806] To a solution of 4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (2.0 g, 10.7 mmol) in DCM (25 ml) at 0 °C was added DMF (1 drop) and oxalyl chloride (2.32 ml, 26.8 mmol) followed by stirring at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in DCM (25 ml) and cooled to 0 °C. Dimethylamine (30 ml) was added to the above solution followed by stirring at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound. MS: m / z 213 [M+H] + .

[0807] The following intermediates were prepared according to the procedure described for Intermediate-6 using the starting materials given in the table.

[0808]

[0809] Intermediate-9: (4-((2-methoxyethyl)sulfonyl)phenyl)methanol

[0810]

[0811] To a solution of methyl 4-((2-methoxyethyl)sulfonyl)benzoate (1.86 g, 6.84 mmol) in EtOH (20 ml) was added NaBH4(1.3 g, 34.24 mmol) at 0 °C followed by stirring at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to afford 1.18 g of the title compound as colorless oil. 1 H-NMR (400 MHz; CDC13): δ 8.91 (d, 2H), 8.55 (d, 2H), 5.0 (t, 1H), 4.82 (s, 2H), 3.74 (t, 2H), 3.38 (t, 2H), 3.24 (s, 3H).

[0812] Following the procedure described for Intermediate 9, the following intermediates were prepared using the starting materials given in the table.

[0813]

[0814]

[0815] Intermediate-26: 4-(Bromomethyl)-2-fluoro-l-(ethylsulfonyl)benzene

[0816]

[0817] To a solution of (3-fluoro-4-(ethylsulfonyl)phenyl)methanol (3.90 g, 19.11 mmol) in dry DCM (50 ml) was added PBr3(3.63 ml, 38.23 mmol) at 0 °C followed by stirring at room temperature for 16 h. The reaction mixture was quenched with cold water, neutralized with aqueous NaHC03and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to afford 1.72 g of the title compound as white solid. 1 H-NMR (400 MHz; DMSO-d6): δ 7.84-7.88 (t, 1H), 7.62-7.65 (d, 1H), 7.53-7.55 (d, 1H), 4.77 (s, 2H), 3.32 (s, 3H). MS: m / z 268 [M+H] + .

[0818] Following the procedure described for Intermediate 26, the following intermediates were prepared using the starting materials given in the table.

[0819]

[0820] Intermediate-31: 4-(Bromomethyl)-N,N-diethylbenzenesulfonamide

[0821]

[0822] To a solution of diethylamine (0.05 g, 0.74 mmol) in DCM (5 ml) at 0 °C was added 4-(bromomethyl)benzenesulfonyl chloride (0.2 g, 0.74 mmol) and TEA (0.1 ml, 0.74 mmol) at room temperature followed by stirring for 1 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water, dried over Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to get 0.10 g of the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (t, J=7.12 Hz, 6 H) 3.16 (q, J=7.11 Hz, 4 H) 4.77 (s, 2 H) 7.57 - 7.68 (m, 2 H) 7.78 (d, J=8.60 Hz, 2 H).

[0823] The following intermediates were prepared according to the procedure described for Intermediate 31 using the starting materials given in the table.

[0824]

[0825] Intermediate-35: l-(chloromethyl)-4-(cyclopropylsulfonyl)benzene

[0826]

[0827] To a solution of (4-(cyclopropylsulfonyl)phenyl)methanol (0.18 g, 0.848 mmol) in DCM (5.0 ml) and DMF (0.1 ml) was added SOCl2(1.0 ml, 1.5 mmol) dropwise at 0 °C followed by refluxing for 2 h. Water was added and the reaction mixture was extracted with DCM. The organic layer was washed with water and saturated NaHC03solution. After drying over Na2S04, the solvent was evaporated and the residue was purified by column chromatography to get 0.17 g of the title compound. LC-MS: m / z 213.2 (M+H) +

[0828] The following intermediates were prepared according to the procedure described for Intermediate 35 using the starting materials given in the table.

[0829]

[0830] Intermediate-38: Methanesulfonic acid (4-((l,l-dioxidoisothiazolidin-2-yl)methyl)cyclohexyl)methyl ester

[0831]

[0832] To a solution of 2-((4-(hydroxymethyl)cyclohexyl)methyl)isothiazolidine 1,1-dioxide (1.6 g, 6.47 mmol) in DCM (10 ml) was added Et3N (3.0 ml, 19.0 mmol), DMAP (0.07 g, 0.6 mmol) at 0 °C followed by MsCl (1.4 ml, 17.5 mmol). The mixture was stirred at room temperature for 16 h, quenched with water, extracted with DCM. The organic layer was washed with water, dried over Na2S04, filtered, concentrated under reduced pressure. The crude product was purified by column chromatography to afford the title compound. LC-MS: m / z 326.2 (M+H) +

[0833] The following intermediates were prepared according to the procedure described for Intermediate 38 using the starting materials given in the table.

[0834]

[0835] Intermediate-42: 4-Methylbenzenesulfonic acid ((1 r,4r)-4-(N- methylmethanesulfonamido)cyclohexyl)methyl ester

[0836]

[0837] To a solution of N-((1 r,4r)-4-(hydroxymethyl)cyclohexyl)-N- methylmethanesulfonamide (0.302 g, 1.365 mmol) in pyridine (3 ml) was added TsCl (0.31 g, 1.6 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h, then quenched with saturated aqueous NaHC03solution, extracted with DCM. The organic layer was washed with water, dried over Na2S04, filtered, concentrated under reduced pressure. The crude product was purified by column chromatography to afford the title compound. LC-MS: m / z 375.5 (M+H) +

[0838] The following intermediates were prepared according to the procedure described for Intermediate 42 using the starting materials given in the table.

[0839]

[0840]

[0841] Intermediate-52: S-(oxetan-3-yl)hydroxythioacetate

[0842]

[0843] To a solution of ethanethioic S-acid (10.0 g, 54 mmol) in DMF (100 ml) was added 3- iodo oxetane (6.82 g, 59 mmol) followed by stirring at room temperature for 16 h. The reaction was quenched with cold water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2S04and concentrated under reduced pressure to get 2.52 g of the title compound as a yellow oil. 1 H-NMR (400 MHz; DMSO-d6): δ 4.94 (t, 2H), 4.56 (m, 1H), 4.42 (t, 2H), 2.33 (s, 3H).

[0844] Intermediate-53: Oxetane-3-sulfonyl chloride

[0845]

[0846] To a solution of N-chlorosuccinimide (10.0 g, 75 mmol) in MeCN (50 ml) was added 2N HC1 (5 ml) and S-(oxetan-3-yl)ethanethioate (2.5 g, 18 mmol) followed by stirring at room temperature for 16 h. The reaction was concentrated, quenched with saturated aqueous NaHC03solution and extracted with Et20. The organic layer was dried over anhydrous Na2S04and concentrated under reduced pressure to get 2.8 g of the title compound as a crude.

[0847] Intermediate-54: 4-(bromomethyl)piperidine hydrobromide

[0848]

[0849] A mixture of piperidin-4-ylmethanol (0.5 g, 4.3 mmol) and aqueous HBr (10 ml) was heated at 140 °C for 3 h. The reaction mixture was concentrated under reduced pressure to get 0.5 g of the title compound as a yellow solid. 1 H-NMR (400 MHz; DMSO-d6): δ 3.70 (s, 1H), 3.50 (d, 2H), 3.25 (d, 2H), 2.84-2.93 (m, 2H), 1.86-1.97 (m, 3H), 1.36-1.46 (m, 2H).

[0850] Intermediate-55: 4-(bromomethyl)-1-(oxetan-3-ylsulfonyl)piperidine

[0851]

[0852] To a solution of 4-(bromomethyl)piperidine hydrobromide (4.16 g, 16 mmol) in DCM (200 ml) was added Et3N (3.23 ml, 44 mmol) and oxetane-3-sulfonyl chloride (2.3 g, 14 mmol) followed by stirring at room temperature for 16 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was dried over anhydrous Na2S04and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using 30% EtOAc in hexane as eluent to get 0.780 g of the title compound as a white solid. 1 H-NMR (400 MHz; DMSO): δ 4.76-4.80 (m, 1H), 4.67-4.74 (m, 3H), 3.6 (d, 2H), 3.46 (d, 2H), 2.75 (t, 1H), 1.72-1.81 (m, 3H), 1.08-1.23 (m, 2H).

[0853] Intermediate-56: 4-(Bromomethyl)-3-fluorobenzoic acid

[0854]

[0855] To a solution of 3-fluoro-4-methylbenzoic acid (5.0 g, 34.67 mmol) in benzene (50 ml) was added benzoyl peroxide (0.8 g, 3.46 mmol) and NBS (6.0 g, 34.6 mmol) followed by heating at 85 °C for 4 h. The reaction mixture was cooled to room temperature, the precipitated solid was filtered, washed with water followed by hexane and then dried to get 4.6 g of the title compound. 1 H-NMR (400 MHz; CDCl3): δ 7.8 (d, 1H), 7.76 (d, 1H), 7.51 (t, 1H), 1.79 (s, 2H). MS: m / z 231 [M-H] + .

[0856] Intermediate 57: Azetidin-1-yl (4-(chloromethyl)-3-fluorophenyl)methanone

[0857]

[0858] To a solution of 4-(bromomethyl)-3-fluorobenzoic acid (4.5 g, 19.4 mmol) in DCM (60 ml) at 0 °C was added azetidine hydrochloride (2.17 g, 23.3 mmol), DIPEA (17 ml, 97.4 mmol) and T3P (17.5 ml, 58.4 mmol) at room temperature and stirred for 16 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 30% EtOAc in hexane as eluent to afford 1.2 g of the title compound as a white solid. 1 H-NMR (400 MHz; CDC13): δ 7.49-7.35 (m, 4H), 4.64 (s, 2H), 4.29-4.24 (m, 4H), 2.09 (m, 2H). MS: m / z 228 [M+H] + .

[0859] Intermediate 58: 5-Hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one

[0860]

[0861] To a stirred solution of 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one (2.0 g, 12.5 mmol) in acetonitrile (50 mL) was added DIPEA (3.22 mL, 25.0 mmol) and isoindoline (1.78 g, 25.0 mmol) at room temperature. When the reaction was complete, the precipitated solid was filtered and washed with EtOAc. The title compound was collected as a light brown solid (1.1 g). LC-MS: m / z 244.1 (M+H) + .

[0862] Intermediate 59: 5-Hydroxy-2-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-4-one

[0863]

[0864] To a stirred solution of 2-(aminomethyl)-5-hydroxy-4H-pyran-4-one (5.6 g, 17.0 mmol) in acetonitrile (40 mL) was added 1,2-bis(bromomethyl)-4-(trifluoromethyl)-benzene (2.4 g, 17.0 mmol) and DIPEA (23.78 mL, 136.2 mmol) at room temperature. The reaction mixture was heated to 90 °C until the reaction was complete. The reaction mixture was concentrated under reduced pressure and the resulting residue was stirred in EtOAc. The mixture was filtered and the filtrate was concentrated. The crude compound was further purified by semi-preparative HPLC to give the title compound (0.85 g). LC-MS m / z: 312.1 (M+H) + .

[0865] Intermediate 60: 2-((5-Fluoroisoindolin-2-yl)methyl)-5-hydroxy-4H-pyran-4-one

[0866]

[0867] To a stirred solution of 2-(aminomethyl)-5-hydroxy-4H-pyran-4-one (14.2 g, 63.8 mmol) in toluene (100 mL) was added 1,2-bis-(bromomethyl)-4-fluorobenzene (19.7 g, 70.2 mmol) and Et3N (35.8 mL, 255 mmol) at room temperature. The mixture was stirred at 100 °C until the reaction was complete. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography to give the title compound as a beige solid (4.60 g). LC-MS: m / z 262.2 (M+H) + .

[0868] Intermediate 61: 5-(Hydroxymethyl)isoindolin-1-one

[0869]

[0870] To a stirred solution of methyl 1-oxoisoindoline-5-carboxylate (4.0 g, 20.9 mmol) in THF (120 mL) was added DIBAL-H (1.2 M, 87.2 mL, 104.6 mmol) at -70 °C. After 2 h at -70 °C, the mixture was warmed to 0 °C and stirred for 1 h. The reaction was quenched with MeOH and the emulsion was filtered through a pad of Celite. The filtrate was concentrated under vacuum and the crude product was purified by column chromatography to give the title compound as a light brown solid (0.8 g). LC-MS: m / z 164.1 (M+H) +

[0871] Intermediate 62: 5-(Hydroxymethyl)-2-methylisoindolin-1-one ​

[0872]

[0873] a) 2-methyl-l-oxoisoindoline-5-carboxylic acid methyl ester

[0874] To a stirred solution of methyl 2-methyl-l-oxoisoindoline-5-carboxylate (3.4 g, 16.6 mmol) in THF (150 mL) at 0 °C was added MeOH (0.53 mL, 13.1 mmol) and LiBH4(2.0 M solution, 16.6 mL, 33.2 mmol). After 3 h at 0 °C, the solution was allowed to warm to room temperature and stirred until the reaction was complete. The reaction was quenched with MeOH:H2O (1 : 1) and the mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography to give the title compound as a light brown solid (2.0 g). LC-MS m / z 178.1 (M+H) + .

[0875] b) 5-(hydroxymethyl)-2-methylisoindolin-l-one

[0876] To a stirred solution of methyl 2-methyl-l-oxoisoindoline-5-carboxylate (3.4 g, 16.6 mmol) in THF (150 mL) at 0 °C was added MeOH (0.53 mL, 13.1 mmol) and LiBH4(2.0 M solution, 16.6 mL, 33.2 mmol). After 3 h at 0 °C, the solution was allowed to warm to room temperature and stirred until the reaction was complete. The reaction was quenched with MeOH:H2O (1 : 1) and the mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography to give the title compound as a light brown solid (2.0 g). LC-MS m / z 178.1 (M+H) + .

[0877] Intermediate 63: 4-bromo-l-(4-(bromomethyl)phenyl)-lH-pyrazole

[0878]

[0879] a) l-(p-tolyl)-lH-pyrazole

[0880] To a microwave reactor was added ketone (II) monohydrate (0.02 g, 0.1 mmol), DMF (5 mL), pyrazole (0.177 g, 2.60 mmol), 4-iodotoluene (0.436 g, 2.0 mmol), and Cs2CO3(1.30 g, 4 mmol). The solution was purged with nitrogen and then heated at 120 °C under microwave irradiation. When the reaction was complete (LC-MS), the reaction mixture was diluted with H2O and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with H2O, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (0.26 g). LC-MS: m / z 159.1 (M+H) + .

[0881] b) 4-Bromo-1-(p-tolyl)-1H-pyrazole

[0882] To a round bottom flask was added 1-(p-tolyl)-1H-pyrazole (0.26 g, 1.64 mmol), chloroform (10 mL), N-bromosuccinimide (0.336 g, 1.89 mmol), and benzoyl peroxide (0.04 g, 0.16 mmol). The solution was purged with nitrogen and heated to reflux. When the reaction was complete (LC-MS), it was quenched with water. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated to dryness to give the title compound (0.409 g, crude yield). LC-MS: m / z 237.1 (M+H) + .

[0883] c) 4-Bromo-1-(4-(bromomethyl)phenyl)-1H-pyrazole

[0884] To a round bottom flask was added the crude bromide compound from above (0.40 g), chloroform (10 mL), N-bromosuccinimide (0.345 g, 1.94 mmol), and benzoyl peroxide (0.041 g, 0.17 mmol). The solution was purged with nitrogen and heated to reflux. When the reaction was complete (LC-MS), it was quenched with water. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated to dryness to give the title compound (0.569 g, crude yield). This material was used as is in the next step. LC-MS: m / z 315.1 (M+H) + .

[0885] Intermediate 64: 1-(4-(Bromomethyl)phenyl)-1H-pyrazole-4-carboxylate

[0886]

[0887] a) 1-(p-Tolyl)-1H-pyrazole-4-carboxylate

[0888] The title compound was prepared from 4-iodotoluene (0.436 g, 2.0 mmol), ketone (II) monohydrate (0.02 g, 0.1 mmol), 4-ethoxycarbonylpyrazole (0.392 g, 2.80 mmol) and Cs2CO3(1.30 g, 4 mmol) in DMF (5 mL) as described in step (a) for Intermediate 66. The title compound was purified by column chromatography (0.11 g). LC-MS: m / z 231.3 (M+H) + .

[0889] b) 1 -(4-(bromomethyl)phenyl)- 1 H-pyrazole-4-carboxylic acid ethyl ester

[0890] To a round bottom flask was added 1 -(p-tolyl)- 1 H-pyrazole-4-carboxylic acid ethyl ester (0.11 g, 0.48 mmol), acetonitrile (4 mL), N-bromosuccinimide (0.102 g, 0.57 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.016 g, 0.1 mmol). The solution was refluxed until the reaction was complete (LC-MS). The reaction was quenched with saturated NaHC03and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The crude material was purified by column chromatography to afford the title compound (0.12 g). LC-MS: m / z 309.3 (M+H) + .

[0891] Intermediate 65: 1 -(4-(chloromethyl)phenyl)- 1 H- 1,2,3-triazole

[0892]

[0893] a) (4-( 1 H- 1,2,3-triazol- 1 -yl)phenyl)methanol

[0894] To a vial was added p-iodobenzyl alcohol (0.234 g, 1 mmol), DMSO (4 mL), L-proline (0.023 g, 0.200 mmol), copper(I) iodide (0.019 g, 0.100 mmol), sodium L-ascorbate (0.040 g, 0.200 mmol), sodium azide (0.098 g, 1.500 mmol), trimethylsilyl acetylene (0.285 mL, 2.000 mmol), H2O (0.5 ml), and potassium carbonate (0.207 g, 1.500 mmol). Nitrogen was passed through the solution and the mixture was heated to 80 °C. When the reaction was complete (LC-MS), 10% ammonia solution was added followed by EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude material was purified by column chromatography to give the title compound (0.055 g). LC-MS: m / z 176.2 (M+H) + .

[0895] b) 1 -(4-(chloromethyl)phenyl)- 1 H- 1,2,3-triazole

[0896] To an oven-dried round bottom flask was added (4-(lH-l,2,3-triazol-l-yl)phenyl)methanol (0.11 g, 0.628 mmol) and CH2Cl2(3 mL). One drop of DMF (~0.05 mL) was added at 0 °C followed by SOCl2(0.069 mL, 0.94 mmol). The solution was kept at 0 °C for 10 min and then warmed to room temperature. When the reaction was complete (LC-MS), the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to give the title compound (0.049 g). LC-MS: m / z 194.2 (M+H) + .

[0897] Intermediate 66: 2-(4-(chloromethyl)phenyl)oxazole

[0898]

[0899] The title compound was prepared according to the procedure described in step (b) of Intermediate 65 from (4-(oxazol-2-yl)phenyl)methanol (0.13 g, 0.74 mmol), SOCl2(0.081 mL, 1.11 mmol), and 1 drop of DMF (~0.05 mL) in CH2Cl2(3 mL) (0.122 g). LC-MS: m / z 194.2 (M+H) + .

[0900] Intermediate 67: Azetidin-1-yl(4-(hydroxymethyl)piperidin-1-yl)methanone

[0901]

[0902] To a round bottom flask was added piperidin-4-ylmethanol (0.230 g, 2 mmol), acetonitrile (10 mL), and N,N'-carbonyldiimidazole (0.357 g, 2.200 mmol). The mixture was allowed to react at room temperature for 2 hours. DIPEA (0.35 mL, 2.0 mmol) was added, followed by azetidine (0.270 mL, 4.00 mmol), and the mixture was heated to 60 °C until the reaction was complete (LC-MS). A 1:1 mixture of saturated NaHCO3, brine, and EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated to dryness to give the title compound (0.41 g). LC-MS: m / z 199.2 (M+H) + .

[0903] Intermediate 68: (4-(Hydroxymethyl)piperidin-1-yl)(morpholino)methanone

[0904]

[0905] To a round bottom flask was added piperidin-4-ylmethanol (0.230 g, 2 mmol), dichloromethane (10 mL), Et3N (0.5 mL, 3.6 mmol), and 4-morpholine carbonyl chloride (0.257 mL, 2.20 mmol), and the mixture was allowed to react at room temperature until the reaction was complete (NMR). The mixture was evaporated to dryness, then saturated NaHCO3 and EtOAc were added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (0.2 g). LC-MS: m / z 229.3 (M+H) + .

[0906] Intermediate 69: 4-(Hydroxymethyl)-N,N-dimethylpiperidine-1-sulfonamide

[0907]

[0908] To an oven dried round bottom flask was added piperidin-4-ylmethanol (0.346 g, 3 mmol), CH2Cl2(10 mL) and Et3N (1.67 ml, 12 mmol). Cyclopropanecarbonyl chloride (0.28 mL, 3.9 mmol) was added at 0 °C. The solution was allowed to react at room temperature. When amide formation was complete (TLC), p-toluenesulfonyl chloride (0.858 g, 4.50 mmol) was added at room temperature. When the reaction was complete (LC-MS), the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was purified by column chromatography to give the title compound (0.548 g). LC-MS: m / z 338.4 (M+H) + .

[0909] Intermediate 70: 4-Methylbenzenesulfonic acid (l-(cyclopropanecarbonyl)piperidin-4-yl)methyl ester

[0910]

[0911] To an oven dried round bottom flask was added piperidin-4-ylmethanol (0.346 g, 3 mmol), CH2Cl2(10 mL) and Et3N (1.67 ml, 12 mmol). Cyclopropanecarbonyl chloride (0.28 mL, 3.9 mmol) was added at 0 °C. The solution was allowed to react at room temperature. When amide formation was complete (TLC), p-toluenesulfonyl chloride (0.858 g, 4.50 mmol) was added at room temperature. When the reaction was complete (LC-MS), the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was purified by column chromatography to give the title compound (0.548 g). LC-MS: m / z 338.4 (M+H) + .

[0912] Intermediate 71: 4-(Hydroxymethyl)-N-methylcyclohexane-1-carboxamide

[0913]

[0914] a) 4-(Methylcarbamoyl)cyclohexane-1 -carboxylic acid methyl ester

[0915] To a solution of 4-(methoxycarbonyl)cyclohexane-1 -carboxylic acid (1.2 g, 6.4 mmol) in CH2CI2(25 mL) was added DMF (1 drop) followed by (COCl)2(1.4 mL, 16.1 mmol) at 0 °C, after which the mixture was stirred at room temperature. The reaction mixture was concentrated under reduced pressure to remove excess (COCl)2. The residue was dissolved in CH2CI2(25 ml) and cooled to 0 °C. MeNH2(17 ml) was added to the above solution, which was then stirred at room temperature until the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound as a colorless oil (0.5 g). LC-MS: m / z 200 (M+H) + .

[0916] b) 4-(hydroxymethyl)-N-methylcyclohexane-1-carboxamide

[0917] To a solution of methyl 4-(methylcarbamoyl)cyclohexane-1 -carboxylate (0.4 g, 2.0 mmol) in EtOH (10 mL) was added NaBH4(0.57 g, 20.1 mmol) at 0 °C, which was then stirred at room temperature until the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound as a colorless liquid (0.3 g). LC-MS: m / z 172 (M+H) + .

[0918] Intermediate 72: 4-(hydroxymethyl)-N-methylpiperidine-1-carboxamide

[0919]

[0920] a) ethyl 1-(methylcarbamoyl)piperidine-4-carboxylate

[0921] To a solution of ethyl piperidine-4-carboxylate (10.6 g, 68.0 mmol) in THF (25 mL) was added Et3N (13.7 mL, 136.1 mmol) and phenyl methylcarbamate (10.4 g, 68.0 mmol), which was then heated at 80 °C. When the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound as a yellow solid (9.8 g). LC-MS: m / z 215 (M+H) + .

[0922] b) 4-(hydroxymethyl)-N-methylpiperidine-1-carboxamide

[0923] To a solution of ethyl 1-(methylcarbamoyl)piperidine-4-carboxylate (3.0 g, 14.0 mmol) in MeOH (100 ml) was added NaBH4(4.2 g, 112.0 mmol) at 0 °C, then stirred at room temperature until the reaction was complete. The reaction mixture was quenched with cold water and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound as a sticky mass (1.21 g). MS: m / z 173 (M+H) + .

[0924] Intermediate 73: 5-(Chloromethyl)-2-methylisoindolin-1-one

[0925]

[0926] To a stirred solution of 5-(hydroxymethyl)-2-methylisoindolin-1-one (2.5 g, 14.1 mmol) in CH2Cl2(150 mL) was added Et3N (8.86 mL, 63.5 mmol) at 0 °C. MsCl (1.64 mL, 21.2 mmol) was added and the solution was stirred at 0 °C for 2 h after which it was allowed to warm to room temperature. The reaction mixture was quenched with water and extracted with CH2Cl2. The combined organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure in vacuo. The crude compound was purified by column chromatography to give the title compound as an off-white solid (500 mg). LC-MS: m / z 196.1 (M+H) + .

[0927] The following intermediates were prepared as described for Intermediate 73 from the starting materials shown in the table.

[0928]

[0929] Intermediate 76: 4-Methylbenzenesulfonic acid (1-(N,N-dimethylsulfamoyl)piperidin-4- yl)methyl ester

[0930]

[0931] The title compound was prepared as described for Intermediate 73 from 4-(hydroxymethyl)-N,N-dimethylpiperidine-1-sulfonamide (0.58 g, 2.6 mmol), p-toluenesulfonyl chloride (0.572 g, 3.0 mmol) and Et3N (0.545 mL, 3.91 mmol) in CH2Cl2(10 mL). The crude material was purified by column chromatography to give the title compound as an off-white solid (0.44 g). LC-MS: m / z 377.5 (M+H) + .

[0932] The following intermediates were prepared as described for Intermediate 76 from the starting materials shown in the table.

[0933]

[0934] The following intermediates were prepared as described for Intermediate 38 from the starting materials shown in the table.

[0935]

[0936] The following intermediates were prepared as described for Intermediate 42 from the starting materials shown in the table.

[0937]

[0938] Intermediate 83. 5-Hydroxy-2-((l-methylisoindolin-2-yl)methyl)-4H-pyran-4- one

[0939]

[0940] To a stirred solution of 2,3-dihydro-l-methyl-lH-isoindole hydrochloride (480 mg, 2.83 mmol) in CH3CN (10 mL) at room temperature was added DIPEA (1.77 mL, 9.91 mmol) and 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one (453 mg, 2.83 mmol). When the reaction was complete, the solid was filtered and washed with cold CH3CN. The title compound was collected as a pink solid (235 mg). LC-MS: m / z: 258 (M+H)+.

[0941] Intermediate 84: 2-((4-Fluoroisoindolin-2-yl)methyl)-5-hydroxy-4H-pyran-4-one

[0942]

[0943] This compound was prepared using the method described for Intermediate 83 using 4-fluoro-2,3-dihydro-lH-isoindole hydrochloride (2.90 g, 16.8 mmol), 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one (2.24 g, 14.0 mmol), DIPEA (5.2 ml, 29.4 mmol) and acetonitrile (50 mL). Yield 1.0 g. LC-MS: m / z 288.6 (M+H) + .

[0944] Intermediate 85: 2-((5,6-difluoroisoindolin-2-yl)methyl)-5-hydroxy-4H-pyran-4-one

[0945]

[0946] To a stirred solution of 2-(aminomethyl)-5-hydroxy-4H-pyran-4-one (2.35 g, 16.7 mmol) in CH3CN (100 mL) at room temperature was added DIPEA (23.8 mL, 136 mmol) and 1,2-bis(bromomethyl)-4,5-difluoro-benzene (5.0 g, 16.7 mmol). The reaction mixture was heated at 90 °C. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was stirred in EtOAc (100 mL). A white solid precipitated and was filtered to give the title compound (1.10 g). LC-MS: m / z 280 (M+H)+.

[0947] Intermediate 86: Methanesulfonic acid (4-methylpiperidin-4-yl)methyl ester trifluoroacetate salt

[0948]

[0949] To a solution of tert-butyl 4-methyl-4-(((methylsulfonyl)oxy)methyl)piperidine-1- carboxylate (1.37 g, 4.46 mmol) in DCM (17 ml) at 0 °C was added trifluoroacetic acid (17.2 ml, 0.22 mol). The mixture was stirred for 30 min and then evaporated to dryness. The residue was triturated twice with Et2O to give the title compound as a white solid (1.2 g). LC-MS: m / z 208.2 (M+H) + .

[0950] Intermediate 87: 4-(chloromethyl)-1,2,3,6-tetrahydropyridine trifluoroacetate salt

[0951]

[0952] a) tert-Butyl 4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)- carboxylate

[0953] To a solution of tert-butyl 4-oxopiperidine-l-carboxylate (5 g, 25.1 mmol) in THF (50 ml) was added LiHMDS (1.0 M in THF, 27.5 ml, 27.5 mmol) at -78 °C and stirred for 30 min. To this was added a solution of l,l,l-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (9.7 g, 27.6 mmol) in THF (15 ml) at -78 °C and the reaction mixture was stirred at -78 °C for 3 h. The reaction mixture was quenched with ice water and extracted with EtOAc. The organic layer was dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to get 6.6 g of the title compound as off-white liquid. 1H-NMR (400 MHz; DMSO-d6): δ 6.01 (d, 1H), 3.98 (t, 2H), 3.55 (d, 2H), 2.38 (t, 2H), 1.40 (s, 9H).

[0954] b) tert-butyl 4-methyl 3,6-dihydropyridine-l-carboxylate 4-carboxylate

[0955] To a mixture of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-3,6- dihydropyridine-l(2H)-carboxylate (5.6 g, 16.8 mmol), Et3N (4.7 ml, 33.0 mmol) in DMF (69 ml) and MeOH (52 ml) was added PPh3 (0.2 g, 1.0 mmol) and Pd(OAc)2 (0.1 g, 0.5 mmol) at room temperature under nitrogen and stirred for 12 h under CO atmosphere. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography to get 2.0 g of the title compound as light green liquid. 1H-NMR (400 MHz; DMSO-d6): δ 6.85 (d, 1H), 4.00 (t, 2H), 3.67 (s, 3H), 3.42 (d, 2H), 2.25 (t, 2H), 1.41 (s, 9H).

[0956] c) tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-l(2H)-carboxylate

[0957] To a solution of tert-butyl 4-methyl 3,6-dihydropyridine-l-carboxylate 4- carboxylate (1.7 g, 7.3 mmol) in DCM (20 ml) was added DIBAL-H (1.0 M in toluene, 10.5 ml, 10.5 mmol) at -78 °C followed by stirring at room temperature for 16 h. The reaction was cooled to 0 °C and quenched with water and extracted with DCM. The organic layer was dried, filtered and concentrated under reduced pressure to get 1.5 g of the title compound as light green viscous liquid. LC-MS: m / z 214 (M+H)+.

[0958] d) 4-(chloromethyl)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester

[0959] To a solution of 4-(hydroxymethyl)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (1.3 g, 6.3 mmol) in DCM (20 ml) at 0 °C was added Et3N (1.9 ml, 18.0 mmol) and TsCl (1.8 g, 9.5 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured on crushed ice and extracted with DCM. The organic layer was washed with brine, dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 1.1 g of the title compound.1H-NMR (400 MHz; DMSO-d6): δ 5.85 (d, 1H), 4.19 (s, 2H), 3.79-3.81 (m, 2H), 3.42 (t, 2H), 2.05-2.15 (m, 2H), 1.40 (s, 9H).

[0960] e) 4-(chloromethyl)-1,2,3,6-tetrahydropyridine trifluoroacetate

[0961] The title compound was prepared by the method described for Intermediate 86 using 4-(chloromethyl)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (0.10 g, 0.43 mmol), TFA (1.7 ml, 22 mmol) and DCM (1.6 ml). Yield 0.076 g. LC-MS: m / z 132.0 (M+H) + .

[0962] Intermediate 88: 4-methylbenzenesulfonic acid (4-fluoropiperidin-4-yl) methyl ester trifluoroacetate

[0963]

[0964] The title compound was prepared by the method described for Intermediate 86 using 4-fluoro-4-((tosyloxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (0.30 g, 0.77 mmol), TFA (3 ml, 39 mmol) and DCM (4.5 ml). Yield 0.264 g. LC-MS: m / z 288.6 (M+H) + .

[0965] Intermediate 89: 4-(chloromethyl)-5-fluoro-1,2,3,6-tetrahydropyridine trifluoroacetate

[0966]

[0967] a) 1-benzyl-5-fluoro-1,2,3,6-tetrahydropyridine-4-carboxylic acid ethyl ester

[0968] To a solution of ethyl 1 -benzyl-5-hydroxy-1,2,3,6-tetrahydropyridine-4- carboxylate (25.0 g, 84.0 mmol) in DCM (500 ml) was added DAST (33.3 ml, 252 mmol) at 0 °C, followed by stirring at room temperature for 3 h. The reaction mixture was quenched with cold saturated NaHC03solution and extracted with DCM. The organic layer was dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 9.8 g of the title compound as a yellow oil. LC-MS: m / z 264 (M+H)+.

[0969] b) Methyl 5-fluoro-1,2,3,6-tetrahydropyridine-4-carboxylate

[0970] To a solution of ethyl 1 -benzyl-5-fluoro-1,2,3,6-tetrahydropyridine-4-carboxylate (9.8 g, 37.0 mmol) in DCE (200 ml) was added 1 -chloroethyl chloroformate (20.0 ml, 186 mmol) at 0 °C. The reaction mixture was stirred at 60 °C for 4 h. The mixture was cooled to 0 °C, MeOH (200 ml) was added and then refluxed for 1 h. The residue was neutralized to pH 7 with Et3N and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 4.5 g of the title compound as a brown solid. LC-MS: m / z 174 (M+H)+.

[0971] c) 1 -tert-Butoxy-4-methoxy-5-fluoro-3,6-dihydropyridine-1,4(2H)-dicarboxylate

[0972] To a solution of ethyl 5-fluoro-1,2,3,6-tetrahydropyridine-4-carboxylate (4.5 g, 26.0 mmol) in DCM (100 ml) was added Et3N (10.8 ml, 78.0 mmol) and Boc20 (11.3 ml, 52.0 mmol) at 0 °C and stirred at room temperature for 16 h. The reaction was quenched with water and extracted with DCM. The organic layer was washed with brine, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 3.5 g of the title compound as a yellow liquid.1H-NMR (400 MHz; CDC13): d 4.27 (q, 2H), 4.12 (d, 2H), 3.48 (d, 2H), 2.43 (s, 2H), 1.47 (s, 9H), 1.32 (t, 3H).

[0973] d) tert-Butyl 5-fluoro-4-(hydroxymethyl)-3,6-dihydropyridine-1 (2H)-carboxylate

[0974] To a solution of 5-fluoro-3,6-dihydropyridine-l,4(2H)-dipercarboxylic acid 1-tert- butyl ester 4-methyl ester (3.5 g, 12.8 mmol) in THF (60 ml) was added LAH (1.0 M in THF, 12.8 ml, 12.8 mmol) at -20 °C, followed by stirring at room temperature for 16 h. The reaction mixture was quenched with ice and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 1.2 g of the title compound as a colorless oil.1H-NMR (400 MHz; DMSO-d6): δ 4.76 (t, 1H), 4.02 (d, 2H), 3.87 (s, 2H), 3.38 (d, 2H), 2.13 (d, 2H), 1.40 (s, 9H).

[0975] e) 4-(Chloromethyl)-5-fluoro-3,6-dihydropyridine-l(2H)-carboxylic acid tert-butyl ester

[0976] To a solution of 5-fluoro-4-(hydroxymethyl)-3,6-dihydropyridine-l(2H)-carboxylic acid tert-butyl ester (1.2 g, 5.1 mmol) in DCM (25 ml) was added Et3N (2.1 ml, 15.0 mmol) and TsCl (1.4 g, 7.7 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water and extracted with DCM. The organic layer was washed with brine, dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 0.4 g of the title compound as a white solid.1H-NMR (400 MHz; CDCl3): δ 4.29 (s, 2H), 3.96 (s, 2H), 3.43 (t, 2H), 2.20 (d, 2H), 1.41 (s, 9H).

[0977] f) 4-(Chloromethyl)-5-fluoro-l,2,3,6-tetrahydropyridine trifluoroacetate

[0978] The title compound was prepared by the method described for Intermediate 86 using 4-(chloromethyl)-5-fluoro-3,6-dihydropyridine-l(2H)-carboxylic acid tert-butyl ester (0.15 g, 0.60 mmol), TFA (2.3 ml, 30 mmol) and DCM (2.5 ml). Yield 0.147 g. LC-MS: m / z 150.0 (M+H) + .

[0979] Intermediate 90: 4-(Chloromethyl)-N-(dimethyloxido-λ 4 -sulfanylidenyl)-benzamide

[0980]

[0981] To a mixture of NaH (60% dispersion, 0.063 g, 1.6 mmol) in DCM (10 ml) was added S,S-dimethyl-sulfoximine (0.15 g, 1.6 mmol) at room temperature under nitrogen and the mixture was stirred for 1 h. The mixture was cooled to 0 °C and 4-(chloromethyl)benzoyl chloride (0.30 g, 1.6 mmol) was added and stirring was continued for 1 h. Ice water was added and the product was extracted with DCM. The organic phase was washed with NaOH and brine, dried, evaporated to give the title compound (0.236 g, crude yield). LC-MS: m / z 246.1 (M+H) + .

[0982] Intermediate 91 : 4-(Chloromethyl)-N-(2-oxotetrahydrothiophen-3-yl)benzamide

[0983]

[0984] To a solution of 4-(chloromethyl)benzoyl chloride (0.60 g, 3.17 mmol) in THF (8 ml) was added DL-homocysteine thiolactone hydrochloride (0.49 g, 3.17 mmol) under nitrogen atmosphere and the mixture was cooled in an ice water bath. Et3N (1.1 ml, 7.9 mmol) was added and mixing was continued for 2 h. THF was evaporated and water was added to the residue and the mixture was extracted with EtOAc. The organic layer was washed with 1 M HCI, 1 M NaOH and brine, dried, evaporated to give the title compound (0.66 g, crude yield). LC-MS: m / z 270.2 (M+H) + .

[0985] Intermediate 92: 4-Methylbenzenesulfonic acid (1-(2-(methylsulfonyl)acetyl)piperidin-4- yl)methyl ester

[0986]

[0987] To a solution of phosphorus pentachloride (0.232 g, 1.11 mmol) in DCM (6 ml) was added methanesulfonylacetic acid (0.154 g, 1.11 mmol) and the mixture was refluxed for 30 min. Pivaloyl chloride (0.1 ml, 0.743 mmol) was added in DCM (2 ml) and then the mixture was refluxed for 1 h. Water was added and the product was extracted with EtOAc. The organic phase was washed with 0.5 M NaOH, 1 M HCI and brine, dried, evaporated to give the title compound (0.122 g, crude yield). LC-MS: m / z 390.4 (M+H) + .

[0988] Intermediate 93: (3-Hydroxy-l-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate

[0989]

[0990] To a solution of 4-(hydroxymethyl)piperidin-3-ol (0.070 g, 0.53 mmol) in ACN (10 ml) at 0 °C was added K2CO3(0.15 g, 1.07 mmol) and methanesulfonyl chloride (0.122 g, 1.07 mmol) in ACN (1 ml). 1 ml of DMF was added for better solubility. The reaction mixture was stirred at room temperature for 1 h and then evaporated to dryness to give the title compound (0.10 g, crude yield). LC-MS: m / z 288.1 (M+l) + .

[0991] Intermediate 94: l-(Chloromethyl)-4-(propan-2-ylsulfonimidoyl)benzenesulfonyl

[0992]

[0993] a) 4-(Isopropylthio)benzaldehyde

[0994] To a solution of propan-2-thiol (3.3 g, 44.9 mmol) in DMSO (100 ml) at 0 °C was added K2CO3(11.0 g, 80.0 mmol) and 4-fluorobenzaldehyde (5.0 g, 40.0 mmol) and then heated at 100 °C for 16 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried and concentrated under reduced pressure to give the title compound (6.4 g). LC-MS: m / z 181 (M+l) + .

[0995] b) (4-(Isopropylthio)phenyl)methanol

[0996] To a solution of 4-(isopropylthio)benzaldehyde (6.4 g, 35.0 mmol) in MeOH (120 ml) at 0 °C was added NaBH4(2.0 g, 53.0 mmol) followed by stirring at room temperature for 2 h. The reaction was quenched with ice-cold water and extracted with EtOAc. The organic layer was dried and concentrated under reduced pressure to give the title compound (5.5 g). LC-MS: m / z 183 (M+l) + .

[0997] c) (4-(Chloromethyl)phenyl)(isopropyl)sulfane

[0998] To a solution of (4-(isopropylthio)phenyl)methanol (5.5 g, 30.0 mmol) in dry DCM (100 ml) was added SOCl2(3.8 g, 33.0 mmol) at 0 °C followed by stirring at room temperature for 1 h. The reaction was quenched with aqueous NaHCO3solution and extracted with DCM. The organic layer was washed with water, dried and concentrated under reduced pressure to obtain the title compound (5.7 g).1H-NMR (400 MHz; DMSO-d6): 7.36 (d, 2H), 7.30 (d, 2H), 4.56 (s, 2H), 3.38-3.41 (m, 1H), 1.30 (d, 6H).

[0999] d) N-((4-(chloromethyl)phenyl)isopropyl)-λ4-sulfenyl)-4-methylbenzenesulfonamide

[1000] To a solution of (4-(chloromethyl)phenyl)(isopropyl)sulfane (5.7 g, 28.0 mmol) in ACN (100 ml) was added 4-methylbenzenesulfonamide (4.8 g, 28.0 mmol), phenyliodine diacetate (14.4 g, 44.0 mmol) and acetylacetone Fe(III) (0.7 g, 1.9 mmol) at room temperature followed by stirring for 16 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography to obtain the title compound (8.5 g). LC-MS: m / z 370 (M+1) + .

[1001] e) 1-(chloromethyl)-4-(propan-2-ylsulfonimidoyl)benzene sulfonamide

[1002] To a solution of N-((4-(chloromethyl)phenyl)isopropyl)-λ4-sulfenyl)-4-methylbenzenesulfonamide (8.0 g, 21.0 mmol) in DCM (150 ml) was added m-CPBA (70% in water, 11.1 g, 65.0 mmol), K2CO3(11.5 g, 84.0 mmol) followed by stirring at room temperature for 2 days. The reaction mixture was quenched with aqueous NaHCO3solution and extracted with DCM. The organic layer was washed with water, dried and concentrated under reduced pressure. The crude residue was purified by column chromatography to obtain the title compound (1.1 g). LC-MS: m / z 384 (M+1) + .

[1003] Intermediate 95: N-((4-(chloromethyl)phenyl)(ethyl)(oxo)-λ4-sulfenyl)-4-methylbenzenesulfonamide

[1004]

[1005] a) N-((4-(chloromethyl)phenyl)(ethyl)-λ4-sulfanylidene)-4- methylbenzenesulfonamide

[1006] The title compound was prepared by the method described in step (d) of Intermediate 94, starting from (4-(chloromethyl)phenyl)-(ethyl)sulfane (11.0 g, 59.1 mmol) and 4-methylbenzenesulfonamide (10.0 g, 59.1 mmol). Yield 14.8 g. LC-MS: m / z 356 (M+1) + .

[1007] b) N-((4-(chloromethyl)phenyl)(ethyl)(oxo)-λ4-sulfanylidene)-4- methylbenzenesulfonamide

[1008] The title compound was prepared by the method described in step (e) of Intermediate 94, starting from N-((4-(chloromethyl)phenyl)(ethyl)-λ4-sulfanylidene)-4- methylbenzenesulfonamide (14.5 g, 40.0 mmol) and m-CPBA (70% in water, 14.0 g, 80.0 mmol). Yield: 7.1 g. LC-MS: m / z 372 (M+H)+.

[1009] Intermediate 96: Methanesulfonic acid 1-oxido-1-(toluene- sulfonimidoyl-tetrahydro-2H-thiopyran-4-yl)methyl ester

[1010]

[1011] a) Methanesulfonic acid [1-({[(4-methylphenyl)sulfonyl]oxy}imino)hexahydro-1λ 4 - thiopyran-4-yl]methyl ester

[1012] The title compound was prepared by the method described in step (d) of Intermediate 94, starting from methanesulfonic acid (tetrahydro-2H-thiopyran-4-yl)methyl ester (2.1 g, 10.0 mmol), 4-methylbenzenesulfonamide (2.56 g, 15.0 mmol), phenyliodine diacetate (5.12 g, 16.0 mmol) and acetylacetone Fe(III) (0.25 g, 0.7 mmol). Yield 0.94 g. LCMS: m / z 380.1 (M+1) + .

[1013] b) Methanesulfonic acid (1-oxido-1-(toluene-sulfonimidoyl-tetrahydro-2H- thiopyran-4-yl)methyl ester

[1014] The title compound was prepared by the method described in step (e) of Intermediate 94, starting from methanesulfonic acid [1-({[(4-methylphenyl)sulfonyl]oxy}imino)hexahydro-1λ 4The title compound was prepared from 4-((S)-methyl-N- tosylsulfimide) cyclohexyl)methyl-4-methyl benzenesulfonate (0.86 g, 2.27 mmol), m-CPBA (77% in water, 1.0 g, 4.5 mmol) and K2CO3(0.94 g, 6.8 mmol) as starting materials. Yield: 0.31 g. LC-MS: m / z 396.1 [M+H]+.

[1015] Intermediate 97: 4-methyl benzenesulfonic acid (4-(S-methyl-N- tosylsulfimide) cyclohexyl)methyl ester

[1016]

[1017] a) (4-(methylthio)cyclohexyl)methanol

[1018] To a solution of methyl 4-(methylthio)cyclohexane-l-carboxylate (6.0 g, 31.9 mmol) in THF (100 ml) was added LiBH4(2.0 M in THF, 40 ml, 95.7 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with aqueous NH4CI solution and extracted with EtOAc. The organic layer was dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give the title compound. Yield 4.0 g. MS: m / z 161 (M+H)+.

[1019] b) 4-methyl benzenesulfonic acid (4-(methylthio)cyclohexyl)methyl ester

[1020] To a solution of (4-(methylthio)cyclohexyl)methanol (4.0 g, 29.3 mmol) in DCM (50 ml) was added Et3N (12 ml, 87.9 mmol) and TsCI (8.4 g, 44.0 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with ice water and extracted with DCM. The organic layer was dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give the title compound. Yield 7.5 g.1H-NMR (400 MHz; DMSO-d6): δ 7.78 (d, 2H), 7.48 (d, 2H), 3.83 (d, 2H), 2.89-2.90 (m, 1H), 2.44 (s, 3H), 1.99 (s, 3H), 1.60 (q, 4H), 1.58 (s, 1H), 1.41 (q, 2H), 1.33 (q, 2H).

[1021] c) 4-methyl benzenesulfonic acid (4-(S-methyl-N-tosylsulfimide) cyclohexyl)methyl ester

[1022] The title compound was prepared by the method described in step (d) of Intermediate 94, starting from 4-(methylthio)benzyl chloride (2.5 g, 14.5 mmol), 4- methylbenzenesulfonamide (3.7 g, 21.7 mmol), phenylhydrazidiodoacetate (7.5 g, 23.1 mmol) and acetylacetone Fe(lll) (0.36 g, 1.0 mmol). Yield 3.3 g. LC-MS: m / z 342.1 (M+1).

[1023] d) 4-Methylbenzenesulfonic acid (4-(S-methyl-N-tosylsulfonimidoyl)cyclohexyl)methyl ester

[1024] To a solution of 4-methylbenzenesulfonic acid (4-(S-methyl-N-tosylsulfonimidoyl)cyclohexyl)methyl ester (1.5 g, 3.1 mmol) in ethanol: ACN (1 :3) (20 ml) at 0 °C was added H2O2 (30% aqueous solution, 0.8 ml, 6.8 mmol) and K2CO3 (2.5 g, 18.8 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography to give the title compound. LC-MS: m / z 498 (M+H)+.

[1025] Intermediate 98: N-((4-(chloromethyl)phenyl)(methyl)(oxo)-λ4-sulfanylidene)-4- methylbenzenesulfonamide

[1026]

[1027] a) N-((4-(chloromethyl)phenyl)methyl)-λ4-sulfanylidene)-4-methylbenzenesulfonamide

[1028] The title compound was prepared by the method described in step (d) of Intermediate 94, starting from 4-(methylthio)benzyl chloride (2.5 g, 14.5 mmol), 4- methylbenzenesulfonamide (3.7 g, 21.7 mmol), phenylhydrazidiodoacetate (7.5 g, 23.1 mmol) and acetylacetone Fe(lll) (0.36 g, 1.0 mmol). Yield 3.3 g. LC-MS: m / z 342.1 (M+1) + .

[1029] b) N-((4-(chloromethyl)phenyl)(methyl)(oxo)-λ4-sulfanylidene)-4-methylbenzenesulfonamide

[1030] The title compound was prepared by the method described in step (e) of Intermediate 94, starting from N-((4-(chloromethyl)phenyl)methyl)-λ4-sulfanylidene)-4- methylbenzenesulfonamide (3.3 g, 9.7 mmol), m-CPBA (77% in water, 4.37 g, 19.5 mmol) and K2CO3(4.0 g, 29 mmol). Yield 3.0 g (white solid). LC-MS: m / z 358.1 (M+H)+.

[1031] Intermediate-99: l-(chloromethyl)-4-(S-methylsulfmimidoyl)benzene

[1032]

[1033] A solution of l-(chloromethyl)-4-(methylsulfmimidoyl)benzene phenylsulfonate (0.70 g, 1.95 mmol) in sulfuric acid (3.0 ml) was stirred at room temperature for 1 h. The reaction mixture was poured into water, basified with 2M NaOH solution and extracted with DCM. The organic layer was washed with water, dried over Na2SO4and evaporated to give the title compound. LC-MS: m / z 205.9 (M+H) +

[1034] The following intermediates were prepared according to the procedure described for Intermediate 99, starting from the materials indicated in the table.

[1035]

[1036] Intermediate 107: l-(chloromethyl)-4-(N,S-dimethylsulfmimidoyl)benzene

[1037]

[1038] To a solution of l-(chloromethyl)-4-(S-methylsulfmimidoyl)benzene (Intermediate 107) (0.038 g, 0.18 mmol) in DCM (4 ml) was added trimethyloxonium tetrafluoroborate (0.041 g, 0.28 mmol) under nitrogen atmosphere. The mixture was stirred at room temperature for 5 h. The reaction was quenched with saturated NaHCO3solution and the mixture was extracted with DCM. The organic phase was dried, filtered and evaporated to dryness to give the title compound (yield 0.025 g). LC-MS: m / z 218.2 (M+1) + .

[1039] Intermediate 108: l-(chloromethyl)-4-(N-acetyl-S-methylsulfmimidoyl)benzene

[1040]

[1041] To a solution of 1-(chloromethyl)-4-(S-methylsulfmylimino)benzene (Intermediate 106) (0.097 g, 0.47 mmol) in DCM (5 ml) under nitrogen was added Et3N (0.072 g, 0.71 mmol) and then cooled to 0 °C. Acetyl chloride (0.037 g, 0.47 mmol) was added and then stirred at 0 °C for 3 h. The reaction was quenched with ice water and the aqueous layer was extracted with EtOAc. The organic layer was washed with 0.5 M HCl, saturated NaHCO3and brine, dried, filtered and evaporated to dryness to give the title compound (yield 0.162 g). LC-MS: m / z 246.1 (M+1) + .

[1042] Intermediate 109: 1-(Chloromethyl)-4-(N-ethyl-S-methylsulfmylimino)benzene

[1043]

[1044] To a solution of Intermediate 108 (0.109 g, 0.44 mmol) in DCM (3 ml) at 0 °C under nitrogen was added borane-dimethylsulfide complex (0.067 g, 0.89 mmol) and then stirred for 4 h. MeOH (1 ml) and water (2 ml) were added and the product was extracted with EtOAc. The organic phase was dried, filtered and evaporated to dryness to give the title compound (yield 0.055 g). LC-MS: m / z 232.1 (M+1) + .

[1045] Intermediate 110: Methanesulfonic acid (4-methyl-1-(methylsulfonyl)piperidin-4- yl)methyl ester

[1046]

[1047] To a suspension of methanesulfonic acid (4-methylpiperidin-4-yl)methyl ester trifluoroacetate salt (Intermediate 86) (0.40 g, 1.24 mmol) in DCM (25 ml) was added Et3N (0.52 ml, 3.73 mmol) and methanesulfonyl chloride (0.096 ml, 1.24 mmol). The reaction mixture was stirred at room temperature. When the reaction was complete, EtOAc was added and the mixture was washed with saturated NaHCO3, 0.5 M HCl and brine. The organic layer was dried and evaporated to dryness to give the title compound (0.25 g). LC-MS: m / z 286.2 (M+1) + .

[1048] The following intermediates were prepared according to the procedure described for Intermediate 110 from the starting materials shown in the table.

[1049]

[1050]

[1051] Intermediate 121: 1-(4-(chloromethyl)phenyl)cyclobutanol

[1052]

[1053] To a stirred solution of 4-bromobenzyl chloride (5.0 g, 24.3 mmol) in THF (50 mL) was added n-BuLi (18 ml, 29.2 mmol) and cyclobutanone (2.2 ml, 29.2 mmol) at -78 °C and stirred for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to get the crude compound. Purification by column chromatography afforded the title compound (1.2 g). 1 H NMR (chloroform-d): δ 7.50 (d, 2H), 7.40 (d, 2H), 4.59 (s, 2H), 2.52-2.59 (m, 2H), 2.33-2.41 (m, 2H), 1.98-2.05 (m, 1H), 1.66-1.77 (m, 1H). LC-MS: m / z 179 [(M-H2O)+H] +

[1054] Intermediate 122: 4-(2-chloroethyl)-N,N-dimethylbenzamide

[1055]

[1056] To an ice-cold mixture of p-(b-chloroethyl)benzoic acid (0.554 g, 3 mmol), dimethylamine hydrochloride (0.306 g, 3.75 mmol) and triethylamine (2.4 ml, 17.22 mmol) in DMF (6 ml) was added 1-propanephosphonic acid cyclic anhydride (50% in EtOAc, 2.4 mL, 4.07 mmol) dropwise. The mixture was stirred at room temperature until the reaction was complete (by LC-MS analysis). The mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (0.583 g). 1HNMR (400 MHz, chloroform-d): δ 7.36-7.41 (m, 2H), 7.23-7.27 (m, 2H), 3.72 (t, 2H), 3.11 (br s, 3H), 3.09 (t, 2H), 2.99 (br s, 3H); LC-MS: m / z 212.1 (M+H) + .

[1057] Intermediate 123: 3-(4-(chloromethyl)phenyl)oxetan-3-ol

[1058]

[1059] To a stirred solution of 4-bromobenzyl chloride (7 g, 34.06 mmol) in THF (110 mL) was added n-BuLi (2.2 M, 18.60 mL, 40.87 mmol) and 3-oxetanone (2.94 g, 40.87 mmol) at -78 °C and stirred for 1.5 h. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to get the crude compound. Purification by column chromatography afforded the title compound (1.21 g). 1 H NMR (DMSO-d6): δ 7.68 (d, 2H), 7.45 (d, 2H), 6.36 (bs, 1H), 4.75-4.77 (m, 4H), 4.66 (d, 2H); LC-MS m / z 181 [(M-H20)+H] +

[1060] Intermediate 124: cis-methanesulfonic acid (4-((tert-butoxycarbonyl)- amino)cyclopent-2-en-l-yl)methyl ester

[1061]

[1062] To a stirred solution of cis-(4-(hydroxymethyl)cyclopent-2-en-l-yl)carbamic acid tert-butyl ester (1.0 g, 4.69 mmol) and triethylamine (1.0 ml, 7.17 mmol) in DCM (20 ml) was added methanesulfonyl chloride (0.5 ml, 6.46 mmol) in DCM (2 ml). The mixture was stirred at 5-20 °C till the reaction was complete (by LC-MS analysis). The mixture was diluted with water and saturated NH4C1 solution, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to get the title compound (1.36 g). 1HNMR (400 MHz, chloroform-d): δ 5.77-5.86 (m, 2H), 4.50-4.85 (m, 2H), 4.12-4.23 (m, 2H), 3.02 (s, 3H), 2.98-3.07 (m, 1H), 2.59 (dt, 1H), 1.45 (s, 9H), 1.35 (dt, 1H).

[1063] Intermediate 125: 2-(l-(methylsulfonyl)piperidin-4-yl)ethyl methanesulfonate

[1064]

[1065] To a stirred solution of 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one (5.0 g, 158.0 mmol) in acetonitrile (50 mL) was added DIPEA (15.0 mL, 94.92 mmol) and 1,2,3,4-tetrahydroisoquinoline (5.05 g, 37.96 mmol) at room temperature and stirred for 16 h. The precipitated solid was filtered, washed with EtOAc and dried under reduced pressure to get the title compound (2.6 g). 1 H NMR (chloroform-d): δ 4.30 (t, 2H), 3.78-3.86 (m, 2H), 3.02 (s, 3H), 2.77 (s, 3H), 2.66 (td, 2H), 1.81-1.88 (m, 2H), 1.74 (q, 2H), 1.56-1.68 (m, 1H), 1.30-1.42 (m, 2H).

[1066] Intermediate 126: 2-{[3,4-dihydroisoquinolin-2(lH)-yl]methyl}-5-hydroxy-4H- pyran-4-one

[1067]

[1068] To a stirred solution of 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one (5.0 g, 158.0 mmol) in acetonitrile (50 mL) was added DIPEA (15.0 mL, 94.92 mmol) and 1,2,3,4-tetrahydroisoquinoline (5.05 g, 37.96 mmol) at room temperature and stirred for 16 h. The precipitated solid was filtered, washed with EtOAc and dried under reduced pressure to get the title compound (2.6 g). 1H NMR (DMSO-d6): δ 9.06 (s, 1H), 8.05 (s, 1H), 7.0-7.11 (m, 4H), 6.40 (s, 1H), 3.62 (s, 1H), 3.58 (s, 2H), 2.81-2.84 (m, 1H), 2.74-2.76 (m, 2H). LC-MS m / z 258.2 (M+H) +

[1069] Intermediate 127: 5-Hydroxy-2-((5-(trifluoromethoxy)isoindolin-2-yl)methyl)-4H- pyran-4-one

[1070]

[1071] a) tert-Butyl 5-(((methylthio)thiocarbamoyl)oxy)isoindoline-2-carboxylate

[1072] To a solution of tert-butyl 5-hydroxyisoindoline-2-carboxylate (3.0 g, 12.7 mmol) in DMF (60 ml) was added NaH (60% in mineral oil, 0.8 g, 19.1 mmol) at 0 °C and stirred for 30 min. To this reaction mixture was added CS2 (1.0 ml, 16.5 mmol) and stirred for 1 h. To this mixture was added Mel (1.1 ml, 16.5 mmol) and stirred at room temperature for 16 h. The reaction was quenched with ice cold water and extracted with EtOAc. The organic layer was washed with water, dried, filtered and concentrated under reduced pressure to get the title compound (4.4 g). 1 H-NMR (400 MHz; CDC13): δ 7.39 (d, 1H), 7.16 (s, 1H), 7.08 (d, 1H), 4.5 (d, 4H), 2.68 (s, 3H), 1.45 (s, 9H); LC-MS: m / z 324 (M-H) + .

[1073] b) 5-(trifluoromethoxy)isoindoline

[1074] To a solution of tert-butyl 5-(((methylthio)thiocarbamoyl)oxy)isoindoline-2-carboxylate (4.4 g, 13.5 mmol) in hydrogen fluoride-pyridine complex (31.0 ml, 108.0 mmol) was added 1,3-dibromo-5,5-dimethylhydantoin (11.6 g, 40.6 mmol) at 0 °C and stirred at room temperature for 16 h. The reaction was quenched with ice cold water and extracted with EtOAc. The organic layer was washed with water, dried, filtered and concentrated under reduced pressure to get the crude product. Purification by column chromatography afforded the title compound (1.3 g). 1H-NMR (400 MHz; DMSO-d6): δ 9.36 (s, 1H), 7.55 (d, 1H), 7.47 (s, 1H), 7.38 (d, 1H), 4.53 (d, 4H); LC-MS: m / z 204 (M+H) + .

[1075] c) 5-Hydroxy-2-((5-(trifluoromethoxy)isoindolin-2-yl)methyl)-4H-pyran-4-one

[1076] To a solution of 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one (0.788 g, 4.9 mmol) in dioxane (20 ml) was added 5-(trifluoromethoxy)isoindoline (1.0 g, 4.9 mmol) and DIPEA (4.5 ml, 24.5 mmol) at room temperature and then stirred at 80 °C for 16 h. The reaction was concentrated under reduced pressure to get crude product. Purification by column chromatography gave the title compound (0.4 g). 1 H-NMR (400 MHz; DMSO-d6): δ 9.36 (s, 1H), 7.55 (d, 1H), 7.47 (s, 1H), 7.38 (d, 1H), 4.53 (d, 4H); LC-MS: m / z 204 (M+H) + .

[1077] Intermediate 128: 2-Chloro-4-(hydroxymethyl)benzonitrile

[1078]

[1079] To a solution of 2-chloro-4-formylbenzonitrile (0.25 g, 1.510 mmol) in THF (15 ml) was added sodium borohydride (0.228 g, 6.04 mmol) in 5 batches over 15 min. The reaction mixture was heated at reflux for 15 min. The mixture was cooled with an ice bath and to this solution was added saturated NH4Cl solution (5 ml) followed by EtOAc (10 ml). The resulting mixture was filtered through a 5 mm The combined organic layers were washed with NH4Cl solution, dried over Na2SO4, filtered and evaporated to give the title compound (0.12 g). The combined organic layers were washed with NH4Cl solution, dried over Na2SO4, filtered and evaporated to give the title compound (0.12 g). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.66 (d, 1H), 7.54-7.56 (m, 1H), 7.36 (d, 1H), 4.78 (s, 2H).

[1080] Intermediate 129: 3-chloro-4-cyanobenzyl methanesulfonate

[1081]

[1082] To a solution of 2-chloro-4-(hydroxymethyl)benzonitrile (0.119 g, 0.710 mmol) and triethylamine (0.109 ml, 0.781 mmol) in DCM (2 ml) was added dropwise methanesulfonyl chloride (0.060 ml, 0.781 mmol) in DCM (2 ml) at 0-5 °C. The reaction mixture was stirred at room temperature for 1 h. Water (15 ml) was added and the aqueous layer was extracted with DCM. The organic layers were combined, washed with saturated NaHC03solution, water and brine, dried over Na2S04, filtered and evaporated to give the title compound (0.12 g). 1 H NMR (400 MHz, Chloroform-d) δ ppm 7.72 (d, 1 H), 7.51 - 7.64 (m, 1 H), 7.33 - 7.49 (m, 1 H), 3.08 (s, 3 H).

[1083] Intermediate 130: 1 -(4-(bromomethyl)phenyl)-2-methylpropan-2-ol

[1084]

[1085] To a solution of methyl 2-(4-(bromomethyl)phenyl)acetate (1 g, 4.11 mmol) in THF (10 ml) was added dropwise a 3 M solution of methylmagnesium bromide (3.93 ml, 11.79 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 2 h, at 0 °C for 4 h and at room temperature for 16 h. Saturated NH4CI solution was added and the aqueous layer was extracted with Et20. The organic layers were combined, washed with water and brine, dried over Na2S04, filtered and evaporated to give the title compound (0.81 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.29 - 7.35 (m, 2 H), 7.15 - 7.23 (m, 2 H), 4.67 - 4.75 (m, 2 H), 2.63 - 2.65 (m, 2 H), 1.05 (s, 6 H).

[1086] Intermediate 131 : 4-(bromomethyl)-3-fluorobenzamide

[1087]

[1088] To a suspension of 4-(bromomethyl)-3-fluorobenzonitrile (1 g, 4.67 mmol) and water (0.185 ml, 10.28 mmol) was added sulfuric acid (4.58 ml, 93 mmol) and then stirred at 100 °C for 1 h, cooled to 50 °C, poured onto ice. The mixture was stirred, the precipitated material was filtered, washed with water, dried in a vacuum oven at 40 °C for 16 h to give the title compound (0.94 g). LC-MS: m / z 232.0 (M+H) + .

[1089] Intermediate 132: 2-((6-fluoro-3,4-dihydroisoquinolin-2(lH)-yl)methyl)-5-hydroxy- 4H-pyran-4-one

[1090]

[1091] To a solution of 6-fluoro-l,2,3,4-tetrahydroisoquinoline (0.301 g, 1.993 mmol) and 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one (0.32 g, 1.993 mmol) in 1,2-dichloroethane (5 ml) was added TEA (0.972 ml, 6.98 mmol) dropwise at 0 °C. The solution was stirred at 60 °C for 3 h, washed with saturated NaHC03solution. The aqueous layer was extracted with DCM. The combined organic layers were washed with water and brine, dried over Na2S04, filtered and evaporated. The crude product was purified by column chromatography to give the title compound (70 mg). LC-MS: m / z 276.2 (M+H) + .

[1092] Intermediate 133: 4-(chloromethyl)-N,N-diethylbenzamide

[1093]

[1094] To a suspension of sodium hydride (0.099 g, 2.476 mmol) and 4- (chloromethyl)benzamide (0.14 g, 0.825 mmol) in DMF (3 ml) was added iodoethane (0.664 ml, 8.25 mmol) in DMF (2 ml) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 3 h, quenched with water to form a precipitate. The precipitate was filtered, washed with water and dried to give the title compound (0.14 g) 1 H NMR (400 MHz, Chloroform-d) δ ppm 7.28 - 7.44 (m, 4H), 4.42 - 4.64 (m, 2H), 3.38 - 3.62 (m, 2H), 3.15 - 3.38 (m, 2H), 1.05 - 1.30 (m, 6H).

[1095] Intermediate 134: 4-(bromomethyl)-3-fluoro-N,N-dimethylbenzamide

[1096]

[1097] To a solution of 4-(bromomethyl)-3-fluorobenzamide (0.2 g, 0.862 mmol) and NaH (0.103 g, 2.59 mmol) in DMF (1 ml) was added iodomethane (0.537 ml, 8.62 mmol) in DMF (2 ml) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, poured on ice. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with water and brine, dried over Na2S04, filtered, evaporated. The crude product was purified by column chromatography to give the title compound (0.10 g). 1 H NMR (400 MHz, Chloroform-d) δ ppm 7.39 (t, 1 H), 7.08-7.17 (m, 2 H), 4.38-4.51 (m, 2 H), 3.10 (br s, 3 H), 2.99 (br s, 3 H).

[1098] Intermediate 135: (4-(chloromethyl)phenyl)(piperidin-l-yl)methanone

[1099]

[1100] To a suspension of 4-(chloromethyl)benzoyl chloride (0.88 g, 4.66 mmol) and piperidine hydrochloride (0.566 g, 4.66 mmol) in DCM (10 ml) was added triethylamine (1.363 ml, 9.78 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, at 20 °C for 1 h, washed with 1 M NaOH, 1 M HC1, brine and water. The organic layer was dried over Na2S04, filtered, evaporated to give the title compound (0.98 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.48-7.52 (m, 2 H), 7.35-7.41 (m, 2 H), 4.80 (s, 2 H), 3.25 (br s, 2 H), 1.37-1.65 (m, 8 H).

[1101] Intermediate 136: azetidin-l-yl(4-(chloromethyl)phenyl)methanone

[1102]

[1103] Triethylamine (2.70 mL, 19.36 mmol) was added dropwise to a suspension of 4-(chloromethyl)benzoyl chloride (2.1 g, 9.22 mmol) and azacyclobutane hydrochloride (0.863 g, 9.22 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and washed with 1 M NaOH, 1 M HCl, brine, and water. The organic layer was dried over Na₂SO₄, filtered, and evaporated to give the title compound (1.52 g). LC-MS: m / z 210.1 (M+H) + .

[1104] Intermediate 137: 2-((5-bromoisoindoline-2-yl)methyl)-5-hydroxy-4H-pyran-4-one

[1105]

[1106] DIPEA (2.66 mL, 15.27 mmol) was added dropwise to a solution of 5-bromoisoindoline (1.21 g, 6.11 mmol) and 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one (0.981 g, 6.11 mmol) in 10 mL of DMF at 0 °C. The reaction mixture was stirred at 50 °C for 2.5 h and poured onto ice. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with water and brine, dried over Na₂SO₄, filtered, and evaporated. The crude product was purified by column chromatography to give the title compound (0.22 g). LC-MS: m / z 322.2 (M+H) + .

[1107] Intermediate 138: N-(tert-butyl)-4-(chloromethyl)benzamide

[1108]

[1109] One drop of DMF was added to a suspension of 4-(bromomethyl)phenylacetic acid (0.82 g, 3.72 mmol) and oxaloyl chloride (1.351 mL, 18.60 mmol). The reaction mixture was stirred at 20 °C for 16 h. Excess oxaloyl chloride was evaporated. DCM (15 mL) and 2-methylpropane-2-amine hydrochloride (0.408 g, 3.72 mmol) were added, followed by DIPEA (1.620 mL, 9.30 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Water was added, and the layers were separated. The aqueous layer was extracted with DCM. The organic layers were combined, washed with 1 M NaOH, 1 M HCl, and brine, dried over Na₂SO₄, filtered, and evaporated to give the title compound (0.85 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.76-7.78 (m, 2 H), 7.47-7.50 (m, 2 H), 4.80 (s, 2 H), 1.37 (s, 9 H).

[1110] Intermediate 139: 2-(4-(Chloromethyl)phenyl)-N,N-dimethylacetamide

[1111]

[1112] To a suspension of 4-(bromomethyl)phenylacetic acid (2 g, 8.73 mmol) and oxalyl chloride (3 ml, 34.9 mmol) was added 1 drop of DMF. The reaction mixture was stirred at 20 °C for 16 h. The excess oxalyl chloride was evaporated. DCM (20 ml) and dimethylamine hydrochloride (0.783 g, 9.60 mmol) were added followed by the addition of triethylamine (2.74 ml, 19.64 mmol) in DCM (5 ml) at 0 °C. The reaction mixture was stirred at 0 °C for 3.5 h. Water (20 ml) was added and the layers were separated. The aqueous layer was extracted with DCM. The organic layers were combined, washed with 1 M NaOH, 1 M HCl and brine, dried over Na2SO4, filtered and evaporated to give the title compound (0.64 g). LC-MS: m / z 212.2 (M+H) + .

[1113] Intermediate 140: 2-(4-(Chloromethyl)-N-methylbenzamido)ethyl acetate

[1114]

[1115] To a suspension of a-bromo-p-toluic acid (1 g, 4.65 mmol) and oxalyl chloride (1.35 ml, 18.60 mmol) was added 1 drop of DMF. The reaction mixture was stirred at 20 °C for 16 h. The excess oxalyl chloride was evaporated. DCM (40 ml) and ethyl sarcosine hydrochloride (0.714 g, 4.65 mmol) were added. The mixture was cooled to 0 °C and DIPEA (2.03 ml, 11.63 mmol) was added dropwise at 0 °C. The reaction mixture was stirred for 1 h. The organic layer was washed with water and brine, dried over Na2SO4, filtered and evaporated to give the title compound (0.14 g). LC-MS: m / z 270.2 (M+H) + .

[1116] Intermediate 141 : 4-(Chloromethyl)-N-isopropylbenzamide

[1117]

[1118] To a suspension of propan-2-amine hydrochloride (0.531 g, 5.55 mmol) and 4- (chloromethyl)benzamide (1 g, 5.29 mmol) in DCM (20 ml) at 5 °C was added TEA (1.659 ml, 11.90 mmol) dropwise. The reaction mixture was stirred at 0 °C for 30 min. To the mixture was added water, the layers were separated, and the aqueous layer was extracted with DCM. The organic layers were combined, washed with 1 M NaOH, 1 M HCl and brine, dried over Na2SO4, filtered, and evaporated to give the title compound (1.05 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (br d, J=7.5 Hz, 1 H), 7.81 - 7.87 (m, 2 H), 7.48 - 7.53 (m, 2 H), 4.80 (s, 2 H), 4.09 (dt, J=7.7, 6.6 Hz, 1 H), 1.16 (d, J=6.6 Hz, 6 H).

[1119] Intermediate 142: 4-(Chloromethyl)-N-(prop-2-yn-1-yl)benzamide

[1120]

[1121] To a suspension of propan-2-amine hydrochloride (0.531 g, 5.55 mmol) and 4- (chloromethyl)benzamide (1 g, 5.29 mmol) in DCM (20 ml) at 5 °C was added TEA (1.659 ml, 11.90 mmol) dropwise. The reaction mixture was stirred at 0 °C for 30 min. To the mixture was added water, the layers were separated, and the aqueous layer was extracted with DCM. The organic layers were combined, washed with 1 M NaOH, 1 M HCl and brine, dried over Na2SO4, filtered, and evaporated to give the title compound (1.05 g). + .

[1122] Intermediate 143: N-Butyl-4-(chloromethyl)benzamide

[1123]

[1124] To a suspension of butane-1 -amine hydrochloride (0.609 g, 5.55 mmol) and 4- (chloromethyl)benzoyl chloride (1 g, 5.29 mmol) in DCM (20 ml) was added TEA (1.659 ml, 11.90 mmol) dropwise at 5 °C and then stirred at 0 °C for 45 min. To this mixture was added water and the layers were separated, the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with 1 M NaOH, 1 M HC1 and brine, dried over Na2S04, filtered and evaporated. The crude product was triturated with heptane:MTBE to give the title compound (1.01 g). LC-MS: m / z 226.2 (M+H)+.

[1125] Intermediate 144: 4-(chloromethyl)-N-hexylbenzamide

[1126]

[1127] To a suspension of 4-(chloromethyl)benzoyl chloride (1 g, 5.29 mmol) and hexan-1 - amine hydrochloride (0.765 g, 5.55 mmol) in DCM (20 ml) was added TEA (1.659 ml, 11.90 mmol) dropwise at 5 °C. The reaction mixture was stirred at 0 °C for 45 min. To this mixture was added water and the layers were separated, the aqueous layer was extracted with DCM. The organic layers were combined, washed with 1 M NaOH, 1 M HC1 and brine, dried over Na2S04, filtered and evaporated to give the title compound (1.24 g). LC-MS: m / z 254.2 (M+H) + .

[1128] Intermediate 145: 4-(chloromethyl)-N-(1 -hydroxy-2-methylpropan-2-yl)benzamide

[1129]

[1130] To a suspension of 4-(chloromethyl)benzoyl chloride (0.92 g, 4.87 mmol) and 2-amino- 2-methylpropan-1 -ol hydrochloride (0.64 g, 5.11 mmol) in DCM (20 ml) was added TEA (1.526 ml, 10.95 mmol) dropwise at 5 °C. The reaction mixture was stirred at 0 °C for 30 min. To this mixture was added water and the layers were separated, the aqueous layer was extracted with DCM. The organic layers were combined, washed with 1 M NaOH, 1 M HC1 and brine, dried over Na2S04, filtered and evaporated to give the title compound (0.80 g). LC-MS: m / z 242.2 (M+H) + .

[1131] Intermediate 146: Acetic acid 2-(4-(chloromethyl)benzamido)-2-methylpropyl ester

[1132]

[1133] To a solution of 4-(chloromethyl)-N-(l-hydroxy-2-methylpropan-2-yl)benzamide (0.367 g, 1.518 mmol) in pyridine (5 ml) at 0 °C was added acetic anhydride (0.215 ml, 2.277 mmol) dropwise. The reaction mixture was stirred at 0 °C for 15 min, then at 20 °C for 2 h. The volatiles were removed in vacuo and the residue was dissolved in DCM. The solution was washed with 1 M HCl, 5% NaHCO3and brine, dried over Na2SO4, filtered and evaporated to give the title compound (0.26 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.84 (s, 1 H), 7.76 - 7.81 (m, 2 H), 7.47 - 7.53 (m, 2 H), 4.80 (s, 2 H), 4.25 (s, 2 H), 3.86 (s, 1 H), 2.02 (s, 3 H), 1.36 (s, 6 H).

[1134] Intermediate 147: 4-(chloromethyl)-N-(4-hydroxybutyl)benzamide

[1135]

[1136] To a suspension of 4-(chloromethyl)benzoyl chloride (1 g, 5.29 mmol) and 4- aminobutane-1-ol hydrochloride (0.664 g, 5.29 mmol) in DCM (20 ml) at 0 °C was added TEA (1.659 ml, 11.90 mmol) dropwise. The reaction mixture was stirred at 0 °C for 30 min. Water was added to the mixture and the layers were separated. The aqueous layer was extracted with DCM. The organic layers were combined and washed with 1 M NaOH, 1 M HCl and brine, dried over Na2SO4, filtered and evaporated. Ethyl ether was added to the residue. The mixture was stirred, filtered and dried to give the title compound (0.44 g). LC-MS: m / z 242.2 (M+H) + .

[1137] Intermediate 148 and 149: (E)-3-(4-(chloromethyl)phenyl)-N,N-dimethylacrylamide and (E)-3-(4-(bromomethyl)phenyl)-N,N-dimethylacrylamide

[1138]

[1139] To a suspension of (E)-3-(4-(bromomethyl)phenyl)acrylic acid (0.76 g, 3.15 mmol) and oxalyl chloride (1.083 ml, 12.6 mmol) was added 1 drop of DMF. The mixture was stirred at 20 °C for 16 h. The excess oxalyl chloride was evaporated. DCM (20 ml) and dimethylamine hydrochloride (0.27 g, 3.31 mmol) were added at 0 °C followed by the addition of triethylamine (0.989 ml, 7.09 mmol). The mixture was stirred at 0 °C for 1 h. Water (20 ml) was added and the layers were separated. The aqueous layer was extracted with DCM. The organic layers were combined, washed with 1 M NaOH, 1 M HCl and brine, dried over Na2S04, filtered and evaporated to give the title compound as a mixture of (E)-3-(4-(chloromethyl)phenyl)-N,N-dimethylacrylamide and (E)-3-(4-(bromomethyl)phenyl)-N,N-dimethylacrylamide (0.33 g). LC-MS: m / z 224.2 (M+H) + .LC-MS: m / z 270.1 (M+H). + .

[1140] Intermediate 150: 2-(4-(chloromethyl)phenyl)-N-(2-hydroxyethyl)-N-methylacetamide

[1141]

[1142] To a suspension of 4-(bromomethyl)phenylacetic acid (2 g, 8.73 mmol) and oxalyl chloride (3 ml, 34.9 mmol) was added 1 drop of DMF. The mixture was stirred at 20 °C for 16 h. The excess oxalyl chloride was evaporated. DCM (15 ml) and N-methylethanolamine HC1 (0.974 g, 8.73 mmol) were added at 0 °C followed by the addition of TEA (2.738 ml, 19.64 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Water was added and the layers were separated. The aqueous layer was extracted with DCM. The organic layers were combined, washed with 1 M NaOH, 1 M HCl and brine, dried over Na2S04, filtered and evaporated to give the title compound (0.23 g). LC-MS: m / z 242.2 (M+H) + .

[1143] Intermediate 151 : 4-(chloromethyl)-N-(3-hydroxypropyl)benzamide

[1144]

[1145] To a solution of 4-(chloromethyl)benzoyl chloride (2.97 g, 15.71 mmol) in DCM (10 ml) was added 3-amino-1-propanol (1.180 g, 15.71 mmol) in DCM (20 ml) followed by TEA (2.409 ml, 17.28 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 45 min. To the mixture was added water, the layers were separated and the aqueous layer was extracted with DCM. The organic layers were combined and washed with 1 M NaOH, 1 M HCl and brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography and then triturated with ether to give the title compound (1.79 g). LC-MS: m / z 228.2 (M+H) + .

[1146] Intermediate 152: Acetic acid 3-(4-(chloromethyl)benzoylamino)propyl ester

[1147]

[1148] To a solution of 4-(chloromethyl)-N-(3-hydroxypropyl)benzamide (1.79 g, 7.86 mmol) in pyridine (15 ml) was added acetic anhydride (1.115 ml, 11.79 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min and at 20 °C for 30 min. The solvent was evaporated and water was added to the residue. The aqueous layer was extracted with EtOAc, the organic layers were combined and washed with 1 M HCl, water, 5% NaHCO3 and brine, dried over Na2SO4, filtered and evaporated to give the title compound (1.29 g). LC-MS: m / z 270.2 (M+H) + .

[1149] Intermediate 155: (E)-3-(4-(chloromethyl)phenyl)-N-methylacrylamide

[1150]

[1151] To a suspension of (E)-3-(4-(bromomethyl)phenyl)acrylic acid (1.0 g, 4.15 mmol) and oxalyl chloride (1.424 ml, 16.59 mmol) was added 1 drop of DMF and then stirred at 20 °C for 16 h. The excess oxalyl chloride was evaporated, DCM (20 ml) and methylamine hydrochloride (0.28 g, 4.15 mmol) were added at 0 °C followed by the addition of triethylamine (1.301 ml, 9.33 mmol). The reaction mixture was stirred at 0 °C for 1 h. Water (20 ml) was added, the layers were separated and the aqueous layer was extracted with DCM. The organic layers were combined and washed with 1 M NaOH, 1 M HCl and brine, dried over Na2SO4, filtered and evaporated, triturated with diethyl ether to give the title compound (0.42 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.01 - 8.11 (m, 1 H), 7.51 - 7.58 (m, 2 H), 7.44 - 7.50 (m, 2 H), 7.37 - 7.44 (m, 1 H), 6.52 - 6.69 (m, 1 H), 4.71 - 4.79 (m, 2 H), 2.68 - 2.75 (m, 3 H).

[1152] Intermediate 156: (4-(chloromethyl)phenyl)(3-hydroxypiperidin-l- yl)methanone

[1153]

[1154] To a suspension of 4-(chloromethyl)benzoyl chloride (1 g, 5.29 mmol) and piperidin-3-ol hydrochloride (0.728 g, 5.29 mmol) in DCM (20 ml) was added TEA (0.811 ml, 5.82 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Water was added to the mixture, the layers were separated and the aqueous layer was extracted with DCM. The organic layers were combined and washed with 1 M NaOH, 1 M HCl and brine, dried over Na2SO4, filtered and evaporated. Heptane was added to the residue which was then stirred, filtered and dried to give the title compound (0.62 g). LC-MS: m / z 254.2 (M+H) + .

[1155] Intermediate 157: 4-(chloromethyl)-N-(3-hydroxy-2,2-dimethylpropyl)benzamide

[1156]

[1157] TEA (1.669 ml, 11.98 mmol) was added dropwise to a suspension of 4-(chloromethyl)benzoyl chloride (2.058 g, 10.89 mmol) and 3-amino-2,2-dimethylpropane-1-ol hydrochloride (1.520 g, 10.89 mmol) in DCM (25 ml) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Water was added to the mixture, and the layers were separated. The aqueous layer was extracted with DCM. The organic layers were combined, washed with 1 M NaOH, 1 M HCl, and brine, dried over Na₂SO₄, filtered, and evaporated. The residue was purified by column chromatography to give the title compound (0.67 g). LC-MS: m / z 256.2 (M+H) + .

[1158] Intermediate 158: (4-(chloromethyl)phenyl)(4-hydroxypiperidin-1-yl)methyl ketone

[1159]

[1160] TEA (5.41 ml, 38.9 mmol) was added dropwise to a suspension of 4-(chloromethyl)benzoyl chloride (3.3 g, 17.46 mmol) and piperidine-4-ol hydrochloride (2.376 g, 17.27 mmol) in DCM (35 ml) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Water was added to the mixture, and the layers were separated. The aqueous layer was extracted with DCM. The organic layers were combined, washed with 1 M NaOH, 1 M HCl, and brine, dried over Na₂SO₄, filtered, and evaporated to give the title compound (3.62 g). LC-MS: m / z 254.3 (M+H) + .

[1161] Intermediate 159: 2-chloro-1-(4-(phenylsulfonyl)piperazin-1-yl)ethyl ketone

[1162]

[1163] Chloroacetyl chloride (0.422 ml, 5.30 mmol) in DCM (5 ml) was added to a solution of 1-(phenylsulfonyl)piperazine (1 g, 4.42 mmol) and TEA (1.355 ml, 9.72 mmol) in DCM (15 ml) at 0 °C. The reaction mixture was stirred at 20 °C for 50 min and washed with water and brine. The organic layer was dried over Na₂SO₄, filtered, and evaporated to give the title compound (1.12 g). LC-MS: m / z 303.3 (M+H) + .

[1164] Intermediate 160: 2-chloro-1-(4-toluenesulfonylpiperazin-1-yl)ethyl ketone

[1165]

[1166] To a solution of 1-tosylpiperazine (1 g, 4.16 mmol) and TEA (0.696 ml, 4.99 mmol) in DCM (15 ml) at 0 °C was added chloroacetyl chloride (0.397 ml, 4.99 mmol) in DCM (5 ml). The mixture was stirred at 20 °C for 50 min, washed with water and brine. The organic layer was dried over Na2SO4, filtered, evaporated to give the title compound (1.30 g). 1 HNMR (400 MHz, DMSO-d6) δ ppm 7.59-7.66 (m, 2H), 7.44-7.49 (m, 2H), 4.34 (s, 2H), 3.47-3.59 (m, 4H), 2.80-3.00 (m, 4H), 2.41 (s, 3H).

[1167] Intermediate 161 : (4-(chloromethyl)phenyl)(3,3-difluoroazetidin-1-yl)methanone

[1168]

[1169] To a suspension of 4-(chloromethyl)benzoyl chloride (1.0 g, 5.29 mmol) and 3,3-difluoroazetidine hydrochloride (0.685 g, 5.29 mmol) in tert-butyl methyl ether (15 ml) at 0 °C was added triethylamine (1.659 ml, 11.90 mmol) dropwise. The reaction mixture was stirred at 0 °C for 1 h. To the reaction mixture was added water and the organic phase was extracted with EtOAc. The combined organic layers were washed with 1 M NaOH, 1 M HC1, brine and who. The organic layer was dried over Na2SO4, filtered, evaporated to dryness. Ethyl ether and heptane were added and the precipitate was filtered, washed with heptane and dried to give the title compound (0.9 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.67-7.73 (m, 2H), 7.51-7.57 (m, 2H), 4.82 (s, 2H), 4.61-4.81 (m, 2H), 4.38-4.58 (m, 2H).

[1170] Intermediate 162: 2-chloro-1-(4-(3-(methoxymethyl)pyridin-2-yl)piperazin-1-yl)ethanone

[1171]

[1172] To a solution of 1-(3-(methoxymethyl)pyridin-2-yl)piperazine hydrochloride (0.75 g, 3.08 mmol) and TEA (0.944 ml, 6.77 mmol) in DCM (15 ml) was added chloroacetyl chloride (0.294 ml, 3.69 mmol) in DCM (5 ml) at 0 °C. The reaction mixture was stirred at 20 °C for 50 min, washed with water and brine. The organic layer was dried over Na2SO4, filtered, evaporated to give the title compound (0.59 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.21 (dd, J=4.8, 1.9 Hz, 1 H), 7.72 (dd, J=7.4, 1.9 Hz, 1 H), 7.05 (dd, J=7.5, 4.8 Hz, 1 H), 4.43 (s, 2 H), 4.42 (s, 2 H), 4.27 (s, 2 H), 3.57 - 3.64 (m, 4 H), 3.11 - 3.18 (m, 2 H), 3.03 - 3.11 (m, 2 H)

[1173] Intermediate 163: 5-Hydroxy-2-((5-(methylthio)isoindolin-2-yl)methyl)-4H-pyran- 4-one

[1174]

[1175] To a solution of 5-(methylthio)isoindoline HCl (0.1 g, 0.496 mmol) and 2- (chloromethyl)-5-hydroxy-4H-pyran-4-one (0.080 g, 0.496 mmol) in DMSO (1 ml) was added dropwise DIPEA (0.181 ml, 1.041 mmol) at 60 °C. The reaction mixture was stirred at 60 °C for 35 min, poured on ice. The aqueous layer was extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered, evaporated. The crude product was triturated with diethyl ether to give the title compound (0.12 g). 1 H NMR (400 MHz, Chloroform-d) δ ppm 7.85 (s, 1 H), 7.11 - 7.18 (m, 3 H), 6.56 (s, 1 H), 4.17 - 4.24 (m, 1 H), 3.98 - 4.04 (m, 4 H), 3.79 (s, 2 H), 2.47 (s, 3 H).

[1176] Intermediate 164: 5-Hydroxy-2-((5-methylisoindolin-2-yl)methyl)-4H-pyran-4-one

[1177]

[1178] A solution of 5-methylisoindoline (0.207 g, 1.557 mmol), 2-(chloromethyl)-5- hydroxy-4H-pyran-4-one (0.25 g, 1.557 mmol) and DIPEA (0.298 ml, 1.713 mmol) in DMSO (2 ml) was stirred at 75 °C for 1 h, poured on ice. The precipitate was filtered, washed with water and dried to give the title compound (0.28 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.98-9.12 (m, 1 H), 8.06 (s, 1 H), 7.10-7.13 (m, 1 H), 7.05 (s, 1 H), 6.97-7.02 (m, 1 H), 6.41 (s, 1 H), 3.90 (s, 4 H), 3.77 (s, 2 H), 2.28 (s, 3 H).

[1179] Intermediate 165: 3-(piperidin-4-yl)propan-1-ol, HC1

[1180]

[1181] A suspension of 4-pyridinylpropanol (3.29 g, 24 mmol), platinum (IV) oxide (0.545 g, 2.400 mmol), 37% HC1 (6.00 ml, 24 mmol) and ethanol (35 ml) was shaken in a Parr apparatus under 8 kPa hydrogen pressure for 3.5 h. The reaction mixture was filtered and the filtrate was evaporated to dryness to give the title compound (5.80 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.98-9.12 (m, 1 H), 8.06 (s, 1 H), 7.10-7.13 (m, 1 H), 7.05 (s, 1 H), 6.97-7.02 (m, 1 H), 6.41 (s, 1 H), 3.90 (s, 4 H), 3.77 (s, 2 H), 2.28 (s, 3 H).

[1182] Intermediate 166: methanesulfonic acid 3-(1-(methylsulfonyl)piperidin-4-yl)propyl ester

[1183]

[1184] To a suspension of 3-(piperidin-4-yl)propan-1 -ol hydrochloride (1 g, 5.57 mmol) and K2CO3(3.31 g, 23.93 mmol) in ACN (10 ml) was added dropwise methanesulfonyl chloride (12.92 ml, 16.70 mmol) at 0 °C. The reaction mixture was stirred at 30 °C for 1.5 h. The reaction mixture was filtered, the filtrate was evaporated to dryness. The residue was stirred in brine, filtered, washed with brine and water, dried to give the title compound (0.68 g). 1 HNMR (400 MHz, CHLOROFORM-d) δ ppm 4.19-4.26 (m, 2H), 3.76-3.83 (m, 2H), 3.02 (s, 3H), 2.77 (s, 3H), 2.59-2.69 (m, 2H), 1.74-1.85 (m, 4H), 1.26-1.45 (m, 5H).

[1185] Intermediate 167: 4-Methylbenzenesulfonic acid (1-imino-1-oxotetrahydro-2H- thiopyran-4-yl)methyl ester

[1186]

[1187] A mixture of 4-methylbenzenesulfonic acid (1-oxo-1-(toluenesulfonylimino)tetrahydro- 2H-thiopyran-4-yl)methyl ester (0.4 g, 0.848 mmol) and sulfuric acid (1.260 ml, 25.4 mmol) was stirred at 20 °C for 2 h. To the reaction mixture was added ice, then the pH was adjusted to 10 with NaOH. The aqueous layer was extracted with DCM, the organic layer was washed with brine, dried over Na2SO4, filtered, evaporated to give the title compound (0.23 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.77-7.81 (m, 2H), 7.47-7.51 (m, 2H), 3.90-3.97 (m, 2H), 3.66 (s, 1H), 2.87-3.05 (m, 4H), 2.43 (s, 3H), 1.80-1.99 (m, 3H), 1.49-1.64 (m, 2H).

[1188] Intermediate 168: 4-Methylbenzenesulfonic acid (1-(acetylimino)-1-oxotetrahydro-2H- thiopyran-4-yl)methyl ester

[1189]

[1190] To a solution of 4-methylbenzenesulfonic acid (l-imino-l-oxido-tetrahydro-2H- thiopyran-4-yl)methyl ester (0.28 g, 0.882 mmol) and TEA (0.307 ml, 2.205 mmol) in DCM (10 ml) was added acetyl chloride (0.069 ml, 0.970 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h, washed with 1 M HC1, 1 M NaOH and brine. The organic layer was dried over Na2S04, filtered and evaporated to give the title compound (0.31 g). LC-MS: m / z 360.2 (M+H) + .

[1191] Intermediate 169: 2-((5-Hydroxy-4-oxo-4H-pyran-2-yl)methyl)-5- (trifluoromethyl)isoindoline-1,3-dione

[1192]

[1193] A solution of 2-(aminomethyl)-5-hydroxy-4H-pyran-4-one (1.1 g, 7.91 mmol) and 5-(trifluoromethyl)isobenzofuran-1,3-dione (1.7 g, 7.91 mmol) in acetic acid (12 ml) was stirred under heating for 1 h. The reaction mixture was poured into water. The resulting precipitate was filtered and dried to give 2.45 g of the title compound. LC-MS: m / z 340.1 (M+H) + .

[1194] Intermediate 170: Mixture of 3-hydroxy-2-((5-hydroxy-4-oxo-4H-pyran-2- yl)methyl)-5-(trifluoromethyl)isoindolin-1-one and 3-hydroxy-2-((5-hydroxy-4- oxo-4H-pyran-2-yl)methyl)-6-(trifluoromethyl)isoindolin-1-one

[1195]

[1196] A solution of 2-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-5- (trifluoromethyl)isoindoline-1,3-dione (2.82 g, 8.31 mmol) in methanol (50 ml) was treated with NaBH4(0.94 g, 24.94 mmol) at 0 °C for 1 h. After evaporation of the solvent, water (20 ml) was added. The product was extracted with EtOAc. The organic layer was washed with water, dried over Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give 1.2 g of the title mixture. LC-MS: m / z 342.1 (M+H) + .

[1197] Intermediate 171 : Mixture of 2-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-5- (trifluoromethyl)isoindolin-1 -one and 2-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-6- (trifluoromethyl)isoindolin-1 -one

[1198]

[1199] To a mixture of 3-hydroxy-2-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-5- (trifluoromethyl)isoindolin-1 -one and 3-hydroxy-2-((5-hydroxy-4-oxo-4H-pyran-2- yl)methyl)-6-(trifluoromethyl)isoindolin-1 -one (230 mg, 0.67 mmol) at 0 °C was added TFAA (5 ml) and triethylsilane (0.60 ml, 3.81 mmol). The mixture was stirred at room temperature for 2 h, then poured into water (10 ml) and basified with 2M NaOH. The product was extracted with DCM. The organic layer was washed with water, dried over Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give 0.20 g of the title mixture. LC-MS: m / z 326.1 (M+H) + .

[1200] Example 1.

[1201] 2-(Isoindolin-2-ylmethyl)-5-((4-(methylsulfonyl)benzyl)oxy)-4H-pyran-4-one (Compound 1)

[1202]

[1203] To a solution of 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (0.20 g, 0.82 mmol) in DMF (5 ml) was added 4-methylsulfonylbenzyl bromide (0.20 g, 0.82 mmol) and K2C03(0.23 g, 1.6 mmol). The reaction mixture was heated at 60 °C for 1 h. The mixture was cooled to room temperature, water (10 ml) was added and the product was extracted with EtOAc. The combined extracts were washed with water, dried over Na2S04, filtered and evaporated. The crude product was purified by column chromatography to give 0.21 g of the title compound. 1 H NMR (Chloroform-d) δ: 7.95-7.98 (m, 2H), 7.62-7.65 (m, 3H), 7.21 (d, 4H), 6.52 (s, 1H), 5.18 (s, 2H), 4.04 (s, 4H), 3.77 (s, 2H), 3.06 (s, 3H). LC-MS: m / z 413.4 (M+H) + .

[1204] The following compounds were prepared according to the procedure described for compound 1 of example 1 using 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one or 5-hydroxy-2-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)-4H-pyran-4-one or a derivative thereof as starting material and another appropriate starting material. Characterization data, starting materials and possible changes in reaction conditions (solvent, base, reaction temperature, reaction time, purification method) if any, are indicated in the table.

[1205] Purification method used:

[1206] A = crystallization

[1207] B = column chromatography

[1208] C = precipitation in aqueous medium

[1209] D = semi-preparative HPLC

[1210] E = trituration

[1211] F = salification

[1212] G = as is

[1213]

[1214]

[1215]

[1216]

[1217]

[1218]

[1219]

[1220]

[1221]

[1222]

[1223]

[1224]

[1225]

[1226]

[1227]

[1228]

[1229] Example 2.

[1230] N-((4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)phenyl)sulfonyl)- N-methylacetamide (Compound 70)

[1231]

[1232] To a solution of 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (0.36 g, 1.5 mmol) in DMF (5 ml) was added 4-methylsulfonylbenzyl bromide (0.40 g, 1.5 mmol) and K2CO3(0.41 g, 2.9 mmol). The reaction mixture was heated at 60 °C for 1 h. The mixture was cooled to room temperature, water (10 ml) was added and the product was extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4, filtered and evaporated to give 0.14 g of 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N- methylbenzenesulfonamide.

[1233] To a solution of 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N- methylbenzenesulfonamide (0.02 g, 0.05 mmol) in DCM (20 ml) was added acetic anhydride (0.24 g, 2,4 mmol) and zinc chloride (6.1 mg, 0.05 mmol). The reaction mixture was heated at 60 °C for 0.5 h. Water (5 ml) was added. The product was extracted with DCM. The combined extracts were washed with water, dried over Na2SO4, filtered and evaporated to give crude product which was purified by column chromatography to give 0.002 g of N-((4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)phenyl)sulfonyl)-N- methylacetamide. 1 H NMR (Chloroform-d) δ: 7.88-7.92 (m, 2H), 7.66 (s, 1H), 7.63 (d, 2H), 7.20-7.23 (m, 4H), 6.54 (s, 1H), 5.17 (s, 2H), 4.05 (s, 4H), 3.78 (s, 2H), 3.30 (s, 3H), 2.39 (s, 3H). LC-MS: m / z 469.5 (M+H) + .

[1234] Example 3.

[1235] 5-((4-(cyclobutanesulfonimidoyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H- pyran-4-one (Compound 71)

[1236]

[1237] To a solution of 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (0.11 g, 0.46 mmol) in DMSO (4 ml) was added l-(chloromethyl)-4- (cyclobutanesulfonimidoyl)benzene (0.14 g, 0.55 mmol) and K2CO3(0.14 g, 1.0 mmol). The reaction mixture was heated at 80 °C for 2 h. The mixture was cooled to room temperature, water (10 ml) was added and the product was extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography to give (0.02 g) 5-((4- (cyclobutanesulfonimidoyl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one. 1 H NMR (Chloroform-d) δ: 7.94 (d, 2H), 7.64 (s, 1H), 7.59 (d, 2H), 7.18-7.24 (m, 4H), 6.54 (s, 1H), 5.14 (s, 2H), 4.07 (s, 4H), 3.87-3.95 (m, 1H), 3.80 (s, 2H), 2.58-2.68 (m, 1H), 2.39-2.51 (m, 1H), 2.21-2.33 (m, 1H), 1.89-2.07 (m, 3H)

[1238] The following compounds were prepared following the procedure described for compound 71 of example 3, using 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one or 5-hydroxy-2-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)-4H-pyran-4-one or a derivative thereof as starting material and another appropriate starting material. Characterization data, starting materials and possible changes in reaction conditions (solvent, reaction temperature, reaction time, purification method) if any, are indicated in the table.

[1239] Purification method used:

[1240] A = crystallization

[1241] B = column chromatography

[1242] C = precipitation in aqueous medium

[1243] D = semi-preparative HPLC

[1244] E = ground

[1245] F = salt formation

[1246] G = as is

[1247] Alternative preparation method: NaOH / KOH in MeOH / EtOH, NaH in DMF, K2CO3 in THF / 1,4-dioxane

[1248]

[1249]

[1250]

[1251]

[1252]

[1253]

[1254]

[1255]

[1256]

[1257]

[1258]

[1259]

[1260]

[1261]

[1262]

[1263]

[1264]

[1265]

[1266]

[1267]

[1268]

[1269]

[1270]

[1271]

[1272]

[1273]

[1274]

[1275] Example 4.

[1276] N-((4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)cyclohexyl)methyl)methanesulfonamide (Compound 173)

[1277]

[1278] To a solution of 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (0.10 g, 0.41 mmol) in DMF (2 ml) was added methylsulfonic acid (4-(methylsulfonamidomethyl)cyclohexyl)methyl ester (0.14 g, 0.45 mmol) and K2CO3(0.12 g, 0.8 mmol). The reaction mixture was heated at 80 °C for 2 h. The mixture was cooled to room temperature, water (10 ml) was added and the product was extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography to give the title compound (0.06 g). 1 H NMR (400 MHz, Chloroform-d) δ ppm 0.92 - 1.11 (m, 4 H) 1.40 - 1.63 (m, 2 H) 1.78 - 2.00 (m, 4 H) 2.91 - 2.99 (m, 5 H) 3.65 (d, J=6.46 Hz, 2 H) 3.77 (s, 2 H) 4.03 (s, 4 H) 5.04 (br t, J=6.31 Hz, 1 H) 6.49 (s, 1 H) 7.20 (s, 4 H) 7.59 (s, 1 H).

[1279] The following compounds were prepared according to the procedure described for compound 173 of example 4, using 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one or 5-hydroxy-2-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)-4H-pyran-4-one or a derivative thereof as starting material and another appropriate starting material. Characterization data, starting materials and possible changes in reaction conditions (solvent, reaction temperature, reaction time, purification method) if any, are indicated in the table.

[1280] Purification method used:

[1281] A = crystallization

[1282] B = column chromatography

[1283] C = precipitation in aqueous medium

[1284] D = semi-preparative HPLC

[1285] E = trituration

[1286] F = salification

[1287] G = as is

[1288]

[1289]

[1290]

[1291]

[1292]

[1293]

[1294]

[1295]

[1296]

[1297]

[1298]

[1299]

[1300] Example 5.

[1301] 2-(Isoindolin-2-ylmethyl)-5-((1-(pyrrolidine-1-carbonyl)piperidin-4-yl)methoxy)- 4H-pyran-4-one (Compound 215)

[1302]

[1303] To a solution of 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (0.20 g, 0.82 mmol) in DMF (4 ml) was added 4-methylbenzenesulfonic acid (1-(pyrrolidine-1- carbonyl)piperidin-4-yl)methyl ester (0.30 g, 0.82 mmol) and K2CO3(0.25 g, 1.8 mmol). The reaction mixture was heated at 80 °C for 2 h. The mixture was cooled to room temperature. Water (10 ml) was added and the product was extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography to give the title compound (0.084 g). 1 H NMR (Chloroform-d) δ: 7.60 (s, 1H), 7.17-7.22 (m, 4H), 6.48 (s, 1H), 4.04 (s, 4H), 3.75-3.84 (m, 4H), 3.72 (d, 2H), 3.32-3.38 (m, 4H), 2.76 (m, 2H), 2.00-2.11 (m, 1H), 1.77-1.90 (m, 6H), 1.22-1.36 (m, 2H). LCMS: m / z 438.5 (M+H) + .

[1304] The following compounds were prepared according to the method described for Compound 215 of Example 5, using 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one as starting material and another appropriate starting material. Characterization data, starting materials and possible changes in reaction conditions (solvents, reaction temperature, reaction time, purification method) if any, are indicated in the table.

[1305] Purification method used:

[1306] A = crystallization

[1307] B = column chromatography

[1308] C = precipitation in aqueous medium

[1309] D = semi-preparative HPLC

[1310] E = trituration

[1311] F = salification

[1312] G = as is

[1313]

[1314]

[1315]

[1316]

[1317]

[1318]

[1319]

[1320]

[1321]

[1322] Example 6.

[1323] 2-((4,5-difluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)- 4H-pyran-4-one (Compound 245)

[1324]

[1325] To a solution of 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H- pyran-4-one (0.15 g, 0.45 mmol) in ACN (10 ml) was added 4,5-difluoroisoindoline HC1 (0.08 g, 0.45 mmol), K2CO3(0.15 g, 1.12 mmol) and KI (0.07 g, 0.45 mmol). The reaction mixture was heated at 90 °C for 2 h. The mixture was cooled to room temperature, water (10 ml) was added and the product was extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography to give the title product. 1 H NMR (Chloroform-d) δ: 7.60 (s, 1H), 7.00-7.07 (m, 1H), 6.87-6.92 (m, 1H), 6.48 (s, 1H), 4.11-4.15 (m, 4H), 4.02 (s, 2H), 3.86 (br d, 2H), 3.77 (s, 2H), 3.74 (d, 2H), 2.79 (s, 3H), 2.65-2.73 (m, 1H), 1.97-2.03 (m, 4H).

[1326] The following compounds were prepared according to the procedure described for compound 245 of example 6, using 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)- 4H-pyran-4-one as starting material and another appropriate starting material. Characterization data, starting materials and possible reaction conditions variations (solvents, reaction temperature, reaction time, purification method) if any, are indicated in the table.

[1327]

[1328] Example 7.

[1329] 4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N- dimethylpiperidine-1-carboxamide (compound 246)

[1330]

[1331] To a round bottom flask was added 2-(isoindolin-2-ylmethyl)-5-(piperidin-4- ylmethoxy)-4H-pyran-4-one trifluoroacetate salt (0.36 g), CH2Cl2(3 mL), dimethylcarbamoyl chloride (0.10 mL, 1.1 mmol) and Et3N (0.4 mL, 2.9 mmol). After 3 h at room temperature, the reaction was incomplete (LC-MS), so dimethylcarbamoyl chloride (0.10 mL, 1.1 mmol) and Et3N (0.4 mL, 2.9 mmol) were added again. The solution was concentrated, then saturated NaHCO3was added. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was purified by column chromatography to give the title compound (0.07 g). 1 H NMR (Chloroform-d) δ: 7.59 (s, 1H), 7.16-7.24 (m, 4H), 6.49 (s, 1H), 4.04 (s, 4H), 3.77 (s, 2H), 3.65-3.75 (m, 4H), 2.82 (s, 6H), 2.73-2.81 (m, 2H), 1.97-2.12 (m, 1H), 1.79-1.93 (m, 2H), 1.30 (m, 2H). LC-MS: m / z 412.6 (M+H) + .

[1332] The following compounds were prepared according to the procedure described for compound 246 of example 7, using 2-(isoindolin-2-ylmethyl)-5-(piperidin-4-ylmethoxy)-4H-pyran-4- one trifluoroacetate salt as starting material and another appropriate starting material. Characterization data and starting materials are indicated in the table.

[1333]

[1334]

[1335]

[1336]

[1337] Example 8.

[1338] 5-((3-aminobenzyl)oxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (Compound 263)

[1339]

[1340] To a round bottom flask was added 2-(isoindolin-2-ylmethyl)-5-((3- nitrobenzyl)oxy)-4H-pyran-4-one (0.640 g, 1.69 mmol), MeOH (17 mL), ammonium chloride (0.226 g, 4.23 mmol), and zinc powder (1.10 g, 16.9 mmol). The mixture was refluxed until the reaction was complete. The mixture was filtered through Celite, and the filtrate was concentrated. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated to give the title compound (0.48 g). The residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated to give the title compound (0.48 g). 1 H NMR (DMSO-d6) δ: 8.14 (s, 1H), 7.17-7.27 (m, 4H), 7.01 (m, 1H), 6.60 (s, 1H), 6.52 (m, 2H), 6.40 (s, 1H), 5.13 (s, 2H), 4.78 (s, 2H), 3.95 (s, 4H), 3.79 (s, 2H). LC-MS: m / z 349.4 (M+H) + .

[1341] Example 9.

[1342] 4 / 5-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N- dimethyl-1H-1,2,3-triazole-1-carboxamide (Compound 264)

[1343]

[1344] a) 2-(isoindolin-2-ylmethyl)-5-(prop-2-yn-1-yloxy)-4H-pyran-4-one

[1345]

[1346] The title compound was prepared as follows: following the procedure of Example 1, compound 1, from 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (0.487 g, 2.0 mmol), propargyl chloride (0.6 mL, 8.3 mmol), and K2CO3(0.553 g, 4.0 mmol) in DMF (5 mL) at 50 °C. After quenching the reaction with water, the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (350 mg). LC-MS: m / z 282.2 (M+H) + .

[1347] b) 5-((lH-l,2,3-triazol-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one

[1348]

[1349] To a flask was added 2-(isoindolin-2-ylmethyl)-5-(prop-2-yn-l-yloxy)-4H-pyran-4-one (0.35 g, 1.244 mmol) and DMSO (3 mL). Then azidotrimethylsilane (0.165 mL, 1.244 mmol), H2O (3 mL), sodium L-ascorbate (0.049 g, 0.249 mmol), and copper (II) sulfate pentahydrate (0.031 g, 0.124 mmol) were added. The mixture was heated to 70 °C until the reaction was complete (LC-MS). The mixture was diluted with H2O and the solids were filtered off. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was treated with EtOAc, then EtOAc / Et2O to give the title compound as a precipitate (0.056 g). LC-MS: m / z 325.3.

[1350] c) 4 / 5-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N- dimethyl- lH-l,2,3-triazole- 1 -carboxamide (Compound 264)

[1351] To a round bottom flask was added 5-((lH-l,2,3-triazol-4-yl)methoxy)-2-(isoindolin-2- ylmethyl)-4H-pyran-4-one (0.058 g, 0.179 mmol), acetonitrile (3 mL), Et3N (0.087 ml, 0.626 mmol), dimethylcarbamoyl chloride (0.028 ml, 0.304 mmol), and DMAP (4.37 mg, 0.036 mmol). The solution was allowed to react at room temperature to completion (LC-MS). The reaction was quenched with saturated NaHC03solution, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated. The crude material was purified by column chromatography to give the title compound (40 mg).

[1352] Isomer 1 (Compound 264a): 1 H NMR (CHLOROFORM-d) δ: 7.93 (s, 1H), 7.77 (s, 1H), 7.16-7.24 (m, 4H), 6.51 (s, 1H), 5.27 (s, 2H), 4.04 (s, 4H), 3.77 (s, 2H), 3.22 (br s, 3H), 3.19 (br s, 3H). LC-MS: m / z 396.4 (M+H) + .

[1353] Isomer 2 (Compound 264b): 1 H NMR (CHLOROFORM-d) δ: 8.26 (s, 1H), 7.84 (s, 1H), 7.16-7.24 (m, 4H), 6.52 (s, 1H), 5.27 (s, 2H), 4.04 (s, 4H), 3.77 (s, 2H), 3.34 (br s, 3H), 3.19 (br s, 3H). LC-MS: m / z 396.4 (M+H) + .

[1354] Example 10. 4 / 5-(((6-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N-dimethyl-lH-l,2,3-triazole-l-carboxamide (Compound 265)

[1355]

[1356] a) 2-((3,4-Dihydroisoquinolin-2(lH)-yl)methyl)-5-(prop-2-yn-l-yloxy)-4H-pyran-4-one

[1357]

[1358] The title compound was prepared as follows: following the procedure of Example 1, compound 1, from 2-{[3,4-dihydroisoquinolin-2(lH)-yl]methyl}-5-hydroxy-4H-pyran-4- one (0.515 g, 2.0 mmol), propargyl chloride (0.15 mL, 2.07 mmol), K2CO3(0.553 g, 4.0 mmol) in DMF (5 mL) at 50 °C. The reaction was quenched with water after which the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound (0.45 g). LC-MS: m / z 296.3 (M+H) + .

[1359] b) 5-((lH-l,2,3-triazol-4-yl)methoxy)-2-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)- 4H-pyran-4-one

[1360]

[1361] The title compound was prepared as follows: as described in step (c) of Example 9, from 2-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)-5-(prop-2-yn-l-yloxy)-4H-pyran-4- one (0.15 g, 0.51 mmol), azidotrimethylsilane (0.067 mL, 0.51 mmol), sodium L- ascorbate (0.020 g, 0.10 mmol), and copper(II) sulfate pentahydrate (0.013 g, 0.05 mmol) in DMSO / H2O (1: 1, 4 mL). The reaction was quenched with water and extracted with EtOAc. The aqueous layer was adjusted to pH 7 and extracted with EtOAc. The combined second extracts were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound. 1 H NMR (CHLOROFORM-d) δ: 13.35 (br s, 1H), 7.81 (s, 1H), 7.58 (s, 1H), 7.10-7.18 (m, 3H), 7.01 (m, 1H), 6.59 (s, 1H), 5.12 (s, 2H), 3.73 (s, 2H), 3.59 (s, 2H), 2.91-2.97 (m, 2H), 2.80-2.91 (m, 2H). LC-MS: m / z 339.3 (M+H) + .

[1362] c) 4-(((6-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)- N,N-dimethyl-lH-l,2,3-triazole-l-carboxamide (Compound 265)

[1363] The title compound was prepared as described in step (c) of example 9 from 5-((lH-l,2,3-triazol-4-yl)methoxy)-2-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)- 4H-pyran-4-one (0.08 g, 0.236 mmol), triethylamine (0.1 mL, 0.72 mmol), dimethylcarbamoyl chloride (0.033 mL, 0.36 mmol) and DMAP (5.8 mg, 0.05 mmol) in acetonitrile (3 mL). The crude material was purified by column chromatography to afford the title compound (0.033 g). Major isomer (compound 265a): 1 H NMR (Chloroform-d) δ: 7.91-7.94 (m, 1H), 7.77 (s, 1H), 7.08-7.17 (m, 3H), 6.99 (m, 1H), 6.52 (s, 1H), 5.26 (s, 2H), 3.71 (s, 2H), 3.55 (s, 2H), 3.33 (br s, 3H), 3.21 (br s, 3H), 2.90-2.97 (m, 2H), 2.80-2.86 (m, 2H). LC-MS: m / z 410.4 (M+H) + .

[1364] Example 11.

[1365] 4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N- dimethylpiperidine-1-carboxamide (Compound 266)

[1366]

[1367] a) 4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1- carboxylic acid tert-butyl ester

[1368]

[1369] The compound was prepared according to the method of example 1 from 5-hydroxy- 2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (0.73 g, 3.0 mmol), 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (1.056 g, 3.6 mmol) and K2CO3(0.871 g, 6.3 mmol) in DMF (6 mL) at 80 °C. The crude material was purified by column chromatography to afford the title compound (0.28 g). LC-MS: m / z 441.5 (M+H) + .

[1370] b) 2-(Isoindolin-2-ylmethyl)-5-(piperidin-4-ylmethoxy)-4H-pyran-4-one hydrochloride

[1371]

[1372] To a round bottom flask was added 2-(isoindolin-2-ylmethyl)-5-(piperidin-4- ylmethoxy)-4H-pyran-4-one trifluoroacetate (0.36 g), DCM (3 mL), dimethylcarbamoyl chloride (0.10 mL, 1.1 mmol), and Et3N (0.4 mL, 2.9 mmol). After 3 h at room temperature, the reaction was incomplete (LC-MS), so dimethylcarbamoyl chloride (0.10 mL, 1.1 mmol) and Et3N (0.4 mL, 2.9 mmol) were added. The solution was concentrated, then saturated NaHCO3was added. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was purified by column chromatography to give the title compound (0.07 g). + The HC1 salt of the title compound can be prepared from 4-(((6-(isoindolin-2- ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1 -carboxylic acid tert-butyl ester in a pre-mixed solution of acetyl chloride (6-7 equivalents) and methanol following a similar procedure. Evaporation to dryness gave the title compound as the HC1 salt.

[1373] c) 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N- dimethylpiperidine-1 -carboxamide (Compound 267)

[1374] To a round bottom flask was added 2-(isoindolin-2-ylmethyl)-5-(piperidin-4- ylmethoxy)-4H-pyran-4-one trifluoroacetate (0.36 g), DCM (3 mL), dimethylcarbamoyl chloride (0.10 mL, 1.1 mmol), and Et3N (0.4 mL, 2.9 mmol). After 3 h at room temperature, the reaction was incomplete (LC-MS), so dimethylcarbamoyl chloride (0.10 mL, 1.1 mmol) and Et3N (0.4 mL, 2.9 mmol) were added. The solution was concentrated, then saturated NaHCO3was added. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was purified by column chromatography to give the title compound (0.07 g). 1 H NMR (CHLOROFORM-d) δ: 7.59 (s, 1H), 7.16-7.24 (m, 4H), 6.49 (s, 1H), 4.04 (s, 4H), 3.77 (s, 2H), 3.65-3.75 (m, 4H), 2.82 (s, 6H), 2.73-2.81 (m, 2H), 1.97-2.12 (m, 1H), 1.79-1.93 (m, 2H), 1.30 (m, 2H). LC-MS: m / z 412.6 (M+H) + .

[1375] The following compounds were prepared according to the procedure of Example 11, Step (c) using 2-(isoindolin-2-ylmethyl)-5-(piperidin-4-ylmethoxy)-4H-pyran-4-one hydrochloride and another appropriate starting material. Characterization data, starting materials, and possible reaction condition variations (solvents, reaction temperatures, reaction times, purification methods) are indicated in the table, if any.

[1376]

[1377]

[1378] Example 12.

[1379] 5-((1 -isobutyrylpiperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4- one (Compound 272) and 2-(isoindolin-2-ylmethyl)-5-((1 -(2,2,2- trifluoroacetyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (Compound 273)

[1380]

[1381] To a round bottom flask was added tert-butyl 4-(((6-(isoindolin-2-ylmethyl)-4-oxo- 4H-pyran-3-yl)oxy)methyl)piperidine-1 -carboxylate (0.16 g, 0.36 mmol), CH2Cl2(4 mL) and trifluoroacetic acid (0.32 mL, 4.3 mmol). The solution was allowed to react at room temperature. When the reaction was complete (LC-MS), the solvent was evaporated in vacuo. The residue was dissolved in CH2Cl2(4 mL) and Et3N (0.25 mL, 4.9 mmol). Isobutyryl chloride (0.057 mL, 0.55 mmol) was then added at room temperature. When the reaction reached completion (LC-MS), the solvent was evaporated. The residue was partitioned between saturated NaHCO3and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude material was purified by column chromatography, then by semi-preparative HPLC to give the title compound.

[1382] 5-((1 -isobutyrylpiperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4- one (Compound 272) (0.004 g): 1H NMR (Chloroform-d) δ: 7.60 (s, 1H), 7.16-7.25 (m, 4H), 6.49 (s, 1H), 4.65-4.74 (m, 1H), 4.04 (s, 4H), 3.91-4.01 (m, 1H), 3.77 (s, 2H), 3.64-3.75 (m, 2H), 3.05 (br m, 1H), 2.75-2.85 (m, 1H), 2.50-2.64 (m, 1H), 1.79-1.89 (m, 2H), 1.17-1.25 (m, 2H), 1.08-1.15 (m, 6H). LC-MS: m / z 411.5 (M+H) + .

[1383] 2-(Isoindolin-2-ylmethyl)-5-((1-(2,2,2-trifluoroacetyl)piperidin-4-yl)methoxy)- 4H-pyran-4-one (Compound 273) (0.079 g): 1 H NMR (Chloroform-d) δ: 7.61 (s, 1H), 7.16-7.24 (m, 4H), 6.49 (s, 1H), 4.54-4.63 (m, 1H), 4.01-4.11 (m, 1H), 4.04 (s, 4H), 3.71-3.81 (m, 4H), 3.09-3.23 (m, 1H), 2.74-2.87 (m, 1H), 2.14-2.30 (m, 1H), 1.95-2.11 (m, 2H), 1.26-1.49 (m, 2H). LC-MS: m / z 437.5 (M+H) + .

[1384] Example 13.

[1385] Cis-N-(4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)cyclopent-2- en-1-yl)cyclopropane sulfonamide, formate salt (Compound 274)

[1386]

[1387] a) Cis 5-((4-aminocyclopent-2-en-1-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H- pyran-4-one dihydrochloride

[1388]

[1389] To a suspension of cis-tert-buty\ ((4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)cyclopent-2-en-1-yl)carbamate (0.250 g, 0.57 mmol) in 2-propanol (2.5 ml) was added hydrogen chloride (3M in CPME, 0.653 ml, 1.96 mmol). The mixture was stirred at 50 °C until the reaction was complete (by LC-MS analysis). The mixture was cooled and the precipitated product was isolated by suction filtration. Drying under vacuum gave the title compound (0.128 g). 1 HNMR (400 MHz, DMSO-d6): δ 12.4 (br s, 1H), 8.34 (s, 1H), 8.07 (s, 3H), 7.37 (br, 4H), 6.80 (br s, 1H), 6.07-6.12 (m, 1H), 5.86-5.90 (m, 1H), 4.60 (br, 4H), 4.16-4.27 (br, 1H), 3.84-3.96 (m, 2H), 3.15-3.22 (m, 1H), 2.4-2.54 (m, 3H, partially overlapped with DMSO), 1.67-1.75 (m, 1H).

[1390] b) cis-N-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)cyclopent-2- en-1-yl)cyclopropane sulfonamide, formate salt

[1391] To a suspension of cis 5-((4-aminocyclopent-2-en-1-yl)methoxy)-2-(isoindolin-2- ylmethyl)-4H-pyran-4-one dihydrochloride (0.128 g, 0.311 mmol) and triethylamine (0.167 ml, 1.195 mmol) in dry DCM (2 ml) was added cyclopropane sulfonyl chloride (35 μl, 0.341 mmol). The mixture was stirred at room temperature until the reaction was complete (by LC-MS analysis). The mixture was diluted with DCM and saturated NaHC03solution, washed with water and brine, dried over sodium sulfate, concentrated under reduced pressure to give the crude product. Purification by column chromatography and semi-preparative HPLC gave the title compound (18.6 mg). 1 HNMR (400 MHz, DMSO-d6): δ 12.4 (br s, 1H), 8.34 (s, 1H), 8.07 (s, 3H), 7.37 (br, 4H), 6.80 (br s, 1H), 6.07-6.12 (m, 1H), 5.86-5.90 (m, 1H), 4.60 (br, 4H), 4.16-4.27 (br, 1H), 3.84-3.96 (m, 2H), 3.15-3.22 (m, 1H), 2.4-2.54 (m, 3H, partially overlapped with DMSO), 1.67-1.75 (m, 1H). LC-MS: m / z 419.4 (M+H)+

[1392] Example 14.

[1393] Cis-N-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)cyclopent-2-en-1- yl)-3-methylbutanamide, formate salt (Compound 275)

[1394]

[1395] To a suspension of cis 5-((4-aminocyclopent-2-en-1-yl)methoxy)-2-(isoindolin-2- ylmethyl)-4H-pyran-4-one dihydrochloride (0.187 g, 0.455 mmol), triethylamine (0.209 ml, 1.50 mmol) and 4-dimethylaminopyridine (6.1 mg, 0.05 mmol) in dry THF (1.5 ml) was added 3-methylbutanoyl chloride (91 μl, 0.75 mmol) in dry THF (0.5 ml). The mixture was stirred at room temperature until the reaction was complete (by LC-MS analysis). The mixture was diluted with EtOAc and 5% aqueous Na2CO3 solution and stirred for 10 min. The phases were separated and the organic phase was washed with 5% aqueous NaOH, water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography and semi-preparative HPLC gave the title compound (39.5 mg). 1 H NMR (chloroform-d): δ 8.11 (s, 1H), 7.92 (br d, 1H), 7.53 (s, 1H), 7.18-7.25 (m, 4H), 6.51 (s, 1H), 5.81-5.84 (m, 1H), 5.71-5.75 (m, 1H), 5.21-5.29 (m, 1H), 4.08 (s, 4H), 3.81 (s, 2H), 3.81 (dd, 1H), 3.72 (dd, 1H), 3.01-3.08 (m, 1H), 2.49-2.60 (m, 1H), 2.24-2.34 (m, 2H), 2.12 (sept, 1H), 1.55-1.63 (m, 1H), 0.96 (d, 3H), 0.92 (d, 3H); LC-MS: m / z 423.9 (M+H) +

[1396] Example 15.

[1397] Cis-N-(3-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-cyclopentyl)- methanesulfonamide (Compound 276)

[1398]

[1399] a) cis-tert-butyl (3-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)cyclopentyl)carbamate

[1400]

[1401] To a mixture of Pd on activated charcoal (10% Pd, 0.102 g, 0.096 mmol) in methanol (15 ml) was added a solution of cis-tert-butyl (4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)cyclopent-2-en-1-yl)carbamate (0.84 g, 1.916 mmol) in methanol (15 ml). The mixture was stirred at room temperature under hydrogen until the reaction was complete (by LC-MS analysis). The reaction mixture was filtered through a short column and the filtrate was evaporated to give the crude product. Purification by column chromatography gave the title compound (0.378 g). The reaction mixture was filtered through a short column and the filtrate was evaporated to give the crude product. Purification by column chromatography gave the title compound (0.378 g). 1 H NMR (chloroform-d): δ 7.59 (s, 1H), 7.17-7.24 (m, 4H), 6.48 (m, 1H), 5.07 (br, 1H), 3.98-4.08 (m, 1H), 4.04 (s, 4H), 3.82 (d, 2H), 3.77 (d, 2H), 2.36-2.48 (m, 1H), 2.22-2.32 (m, 1H), 1.90-1.99 (m, 1H), 1.78-1.89 (m, 1H), 1.49-1.65 (m, 3H), 1.45 (s, 9H).

[1402] b) cis-5-((3-aminocyclopentyl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one

[1403]

[1404] To a suspension of cis-tert-buty\ oxycarbamate (0.350 g, 0.794 mmol) in 2-propanol (4 ml) was added hydrogen chloride (3M in CPME, 0.927 ml, 2.78 mmol). The mixture was stirred at 60 °C until the reaction was complete (by LC-MS analysis). The reaction mixture was diluted with water, basified with saturated aqueous NaHC03, extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate, concentrated under reduced pressure to give the title compound (0.16 g) which was used as such in the next step. LC-MS: m / z 341.3 (M+H) +

[1405] c) cis-N-(3-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)- cyclopentyl)-methanesulfonamide

[1406] To a solution of cis-5-((3-aminocyclopentyl)methoxy)-2-(isoindolin-2- ylmethyl)-4H-pyran-4-one (0.16 g, 0.47 mmol) and triethylamine (0.131 ml, 0.94 mmol) in dry DCM (2.5 ml) was added methanesulfonyl chloride (36 μl, 0.47 mmol). The mixture was stirred at room temperature until the reaction was complete (by LC-MS analysis). The mixture was diluted with DCM and saturated NaHC03solution, washed with water and brine, dried over sodium sulfate, concentrated under reduced pressure to give the crude product. Purification by column chromatography gave the title compound (39 mg). 1 H NMR (Chloroform-d): δ 7.56 (s, 1H), 7.18-7.24 (m, 4H), 6.53 (br d, 1H), 6.52 (s, 1H), 4.05-4.13 (m, 1H), 4.04 (s, 4H), 3.79-3.85 (m, 2H), 3.78 (d, 2H), 3.04 (s, 3H), 2.43-2.52 (m, 1H), 2.23-2.33 (m, 1H), 1.73-2.01 (m, 4H), 1.69 (td, 1H); LC-MS: m / z 463.2 (M-H) +

[1407] Example 16.

[1408] (R)-2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)pyrrolidin-3-yl)methoxy)- 4H-pyran-4-one (Compound 277)

[1409]

[1410] a) (R)-2-(Isoindolin-2-ylmethyl)-5-(pyrrolidin-3-ylmethoxy)-4H-pyran-4-one

[1411]

[1412] This compound was prepared according to the procedure described in Example 15, step (b) from (R)-3-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)pyrrolidine-1 -carboxylate (0.834 g, 1.955 mmol) and hydrogen chloride (3M in CPME, 2.28 ml, 6.84 mmol) in 2-propanol (10 ml). The title compound (0.175 g) was used as such in the next step. LC-MS: m / z 327.2 (M+H) +

[1413] b) (R)-2-(Isoindolin-2-ylmethyl)-5-((1 -(methylsulfonyl)pyrrolidin-3-yl)methoxy)- 4H-pyran-4-one

[1414] This compound was prepared according to the procedure described in Example 15, step (c) from (R)-2-(Isoindolin-2-ylmethyl)-5-(pyrrolidin-3-ylmethoxy)-4H-pyran-4- one (0.175 g, 0.536 mmol), triethylamine (0.149 ml, 1.072 mmol) and methanesulfonyl chloride (41 μΙ, 0.536 mmol) in dry DCM (3 ml). Purification by column chromatography afforded the title compound (50 mg). 1 H NMR (Chloroform-d): δ 7.66 (s, 1 H), 7.18-7.24 (m, 4H), 6.49 (m, 1 H), 4.06 (s, 4H), 3.95 (dd, 1 H), 3.88 (dd, 1 H), 3.79 (d, 2H), 3.56 (dd, 1 H), 3.45-3.53 (m, 1 H), 3.34-3.40 (m, 1 H), 3.31 (dd, 1 H), 2.88 (s, 3H), 2.74-2.85 (m, 1 H), 2.12-2.23 (m, 1 H), 1.83-1.94 (m, 1 H); LC-MS: m / z 405.2 (M+H) +

[1415] Example 17.

[1416] 4-((6-((5-Bromoisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3-yloxy)methyl)benzonitrile (Compound 278)

[1417]

[1418] a) 4-((6-(hydroxymethyl)-4-oxo-4H-pyran-3-yloxy)methyl)benzonitrile

[1419]

[1420] A solution of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (500 mg, 3.52 mmol), a-bromo-p-tolunitrile (690 mg, 3.52 mmol) and potassium carbonate (973 mg, 7.04 mmol) in DMF (10 ml) was heated at 80 °C in a microwave reactor for 15 min. The reaction mixture was poured into water. The precipitate was filtered, washed with water and dried to give the title compound (0.75 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.21 (s, 1 H), 7.89 (s, 1 H), 7.87 (s, 1 H), 7.60-7.64 (m, 2 H), 6.33-6.35 (m, 1 H), 5.07 (s, 2 H), 4.30 (s, 2 H).

[1421] b) Methanesulfonic acid (5-(4-cyanobenzyloxy)-4-oxo-4H-pyran-2-yl)methyl ester

[1422]

[1423] To a solution of 4-((6-(hydroxymethyl)-4-oxo-4H-pyran-3-yloxy)methyl)benzonitrile (0.2 g, 0.777 mmol) and TEA (0.325 ml, 2.332 mmol) in DCM (5 ml) was added dropwise methanesulfonyl chloride (0.075 ml, 0.972 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 3 h, washed with saturated NaHC03, 0.1 M HC1 and brine. The organic layer was dried over Na2S04, filtered and evaporated to give the title compound (0.14 g). 1 H NMR (400 MHz, Chloroform-d) δ ppm 7.66-7.70 (m, 2 H), 7.64-7.66 (m, 1 H), 7.51-7.56 (m, 2 H), 6.43-6.55 (m, 1 H), 5.14 (s, 2 H), 4.30-5.05 (m, 2 H), 3.11-3.15 (m, 3 H).

[1424] c) 4-((6-((5-bromoisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3-yloxy)methyl)benzonitrile

[1425] A solution of 5-bromoisoindoline (0.07 g, 0.353 mmol) and 5-(5- cyanobenzyloxy)-4-oxo-4H-pyran-2-yl)methyl methanesulfonate (0.119 g, 0.353 mmol) and potassium carbonate (0.098 g, 0.707 mmol) in DMSO (2 ml) was stirred at 60 °C for 30 min. Water was added and the aqueous layer was extracted with DCM. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, evaporated and purified with semi-preparative HPLC to give the title compound (9 mg).1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.66-7.70 (m, 1 H), 7.63 (s, 1 H), 7.52-7.56 (m, 2 H), 7.33-7.37 (m, 2 H), 7.05-7.17 (m, 1 H), 6.50 (s, 1 H), 5.13-5.16 (m, 1 H), 3.95-4.04 (m, 4 H), 3.74-3.76 (m, 2 H), 1.54-1.83 (m, 2 H); LC-MS: m / z 437.3 (M+H)+.

[1426] The following compounds were prepared according to the procedure of Example 17, step (c), using isoindoline or a derivative thereof as the starting material and another appropriate starting material. Characterization data, starting materials and possible changes in reaction conditions (solvent, reaction temperature, reaction time, purification method) (if any) are indicated in the table.

[1427] Purification methods used:

[1428] A = crystallization

[1429] B = column chromatography

[1430] C = precipitation in aqueous medium

[1431] D = semi-preparative HPLC

[1432] E = trituration

[1433] F = salt formation

[1434] G = as is

[1435]

[1436] Example 18.

[1437] N-(3-hydroxypropyl)-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)benzamide (Compound 282)

[1438]

[1439] a) 4-(Chloromethyl)-N-(3-hydroxypropyl)benzamide

[1440] To a solution of 4-(chloromethyl)benzoyl chloride (2.97 g, 15.71 mmol) in DCM (10 ml) was added 3-amino-1-propanol (1.180 g, 15.71 mmol) in DCM (20 ml) followed by TEA (2.409 ml, 17.28 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 45 min. To this mixture was added water and the layers were separated. The aqueous layer was extracted with DCM. The organic layers were combined and washed with 1 M NaOH, 1 M HCl and brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography and then triturated with ether to give the title compound. LC-MS: m / z 228.2 (M+H) + .

[1441] b) Acetic acid 3-(4-(chloromethyl)benzamido)propyl ester

[1442] To a solution of 4-(chloromethyl)-N-(3-hydroxypropyl)benzamide (1.79 g, 7.86 mmol) in pyridine (15 ml) was added acetic anhydride (1.115 ml, 11.79 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min and at 20 °C for 30 min. The solvent was evaporated and water was added to the residue. The aqueous layer was extracted with EtOAc. The organic layers were combined and washed with 1 M HCl, water, 5% NaHCO3 and brine, dried over Na2SO4, filtered and evaporated to give the title compound. LC-MS: m / z 270.2 (M+H) + .

[1443] c) Acetic acid 3-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)benzamido)propyl ester

[1444] A suspension of acetic acid 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (0.2 g, 0.822 mmol), 3-(4-(chloromethyl)benzamido)propyl ester (0.222 g, 0.822 mmol) and K2CO3(0.199 g, 1.439 mmol) in DMF (2 ml) was heated at 80 °C for 30 min. To this mixture was added water and the aqueous layer was extracted with DCM. The organic layers were combined and washed with water and brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography to give the title compound. LC-MS: m / z 477.5 (M+H) + .

[1445] d) N-(3-hydroxypropyl)-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)benzamide

[1446] A suspension of acetic acid 3-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)benzamido)propyl ester (0.195 g, 0.409 mmol), K2CO3(0.071 g, 0.512 mmol) and methanol (5 ml) in DCM (5 ml) was stirred at 20 °C for 1 h, then filtered. The filtrate was evaporated to dryness, the residue was purified by column chromatography, then triturated with a mixture of heptane and ethyl ether to give the title compound (0.04 g).1H NMR (400 MHz, chloroform-d) δ ppm 7.74-7.79 (m, 2H), 7.58 (s, 1H), 7.42-7.47 (m, 2H), 7.18-7.24 (m, 4H), 6.91-6.98 (m, 1H), 6.51 (s, 1H), 5.09 (s, 2H), 4.03 (s, 4H), 3.75 (s, 2H), 3.70-3.73 (m, 2H), 3.58-3.64 (m, 3H), 1.75-1.83 (m, 3H), 1.21 (t, J = 7.0 Hz, 1H); LC-MS: m / z 435.5 (M+H)+.

[1447] Example 19.

[1448] N-(1-hydroxy-2-methylpropan-2-yl)-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)benzamide (Compound 283)

[1449]

[1450] A suspension of acetic acid 2-(4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3- yl)oxy)methyl)benzamido)-2-methylpropyl ester (0.284 g, 0.579 mmol), K2CO3(0.100 g, 0.724 mmol) and methanol (5 ml) in DCM (5 ml) was stirred at 20 °C for 1 h, then filtered. The filtrate was evaporated to dryness, the residue was purified by column chromatography to give the title compound (0.12 g).1H NMR (400 MHz, DMSO-d6) δ ppm 8.21 (s, 1H), 7.78-7.84 (m, 2H), 7.51-7.58 (m, 1H), 7.48 (s, 2H), 7.17-7.26 (m, 4H), 6.42 (s, 1H), 5.02 (s, 2H), 4.91 (t, J = 6.0 Hz, 1H), 3.95 (s, 4H), 3.79 (s, 2H), 3.50 (d, J = 6.0 Hz, 2H), 1.31 (s, 6H); LC-MS: m / z 449.5 (M+H)+.

[1451] Example 20.

[1452] 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1- carbaldehyde HC1 (Compound 284)

[1453]

[1454] A solution of 2-(isoindolin-2-ylmethyl)-5-(piperidin-4-ylmethoxy)-4H-pyran-4- one (0.13 g, 0.382 mmol) and methyl formate (0.030 ml, 0.496 mmol) was stirred at 0 °C for 30 min. The mixture was then allowed to reach 20 °C and stirred for 90 min. Sodium hydroxide (0.04 g, 0.095 mmol) was added to the mixture. The mixture was stirred for 16 h. 10 ml of DCM was added and the solid was removed by filtration. 1 M HC1 in ether (1 ml) was added to the mixture. The mixture was stirred for 30 min. The solid was removed by filtration. The filtrate was evaporated to dryness and the residue was purified by column chromatography to give the title compound (0.12 g).1H NMR (400 MHz, DMSO-d6) δ ppm 8.21 (s, 1H), 7.78-7.84 (m, 2H), 7.51-7.58 (m, 1H), 7.48 (s, 2H), 7.17-7.26 (m, 4H), 6.42 (s, 1H), 5.02 (s, 2H), 4.91 (t, J = 6.0 Hz, 1H), 3.95 (s, 4H), 3.79 (s, 2H), 3.50 (d, J = 6.0 Hz, 2H), 1.31 (s, 6H); LC-MS: m / z 449.5 (M+H)+. The mixture was filtered, and the solvent was removed under reduced pressure. The residue was treated with diethyl ether, filtered, and dried to give the title compound (0.1 g).1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (s, 1H), 7.99 (s, 1H), 7.34 - 7.44 (m, 5H), 6.75 (s, 1H), 6.75 (s, 1H), 4.72 - 4.85 (m, 2H), 4.61 (s, 2H), 4.15 - 4.23 (m, 1H), 3.70 - 3.74 (m, 3H), 3.01 - 3.11 (m, 1H), 2.59 - 2.72 (m, 1H), 1.95 - 2.09 (m, 1H), 1.72 - 1.85 (m, 2H), 1.01 - 1.22 (m, 3H); LC-MS: m / z 369.2.

[1455] Example 21.

[1456] 5-((4-(S-methylsulfonimidoyl)benzyl)oxy)-2-((5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-4-one (Compound 285) and 5-((4-(R-methylsulfonimidoyl)benzyl)oxy)-2-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-4-one (Compound 286)

[1457]

[1458] A racemic resolution of 5-((4-(R,S-methylsulfonimidoyl)benzyl)oxy)-2-((5- (trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-4-one (0.1 g, 0.21 mmol) was performed using Chiralpak IF, 5 μm, 20*250 mm column and using n-hexane, EtOH and DEA as eluents.

[1459] S-isomer (39.3 mg): 1 H NMR (chloroform-d) δ: 8.02 (d, 2H), 7.64 (s, 1H), 7.61 (d, 2H), 7.50 (d, 1H), 7.46 (s, 1H), 7.31 (d, 1H), 6.52 (s, 1H), 5.17 (s, 2H), 4.09 (s, 4H), 3.79 (s, 2H), 3.11 (s, 3H).

[1460] R-isomer (43.9 mg): 1H NMR (chloroform-d) δ: 7.99-8.08 (m, 1H), 7.99-8.08 (m, 1H), 7.64 (s, 1H), 7.61 (d, 2H), 7.50 (d, 1H), 7.46 (s, 1H), 7.31 (d, 1H), 7.27 (s, 1H), 7.26-7.27 (m, 1H), 6.52 (s, 1H), 5.17 (s, 2H), 4.09 (s, 4H), 3.79 (s, 2H), 3.11 (s, 3H).

[1461] Example 22.

[1462] 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)-2H- indolizin-2-yl)methyl)-4H-pyran-4-one (Compound 287)

[1463]

[1464] To a solution of 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5- (trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-4-one (0.40 g, 0.82 mmol) in dry dioxane (10 ml) was added palladium (II) acetate (0.18 g, 0.82 mmol) and cyclohexene (0.41 ml, 4.11 mmol). The reaction mixture was heated at 130 °C for 4 h. The catalyst was filtered off. The solvent was evaporated. The crude product was purified by column chromatography to give 0.35 g of the title compound. 1 H NMR (methanol-d4) δ: 8.01 (s, 1H), 7.87 (s, 1H), 7.62 (m, 1H), 7.50 (d, 1H), 7.37-7.41 (m, 1H), 7.00 (m, 1H), 6.24 (s, 1H), 5.45 (s, 2H), 3.68-3.78 (m, 4H), 2.81 (s, 3H), 2.71-2.80 (m, 2H), 1.88-2.01 (m, 3H), 1.24-1.49 (m, 2H). LC-MS: m / z 487.3 (M+H) + .

[1465] Example 23.

[1466] 2-((2H-isoindol-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H- pyran-4-one (Compound 288)

[1467]

[1468] To a solution of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)-4H-pyran-4-one (0.20 g, 0.48 mmol) in dry dioxane (15 ml) was added palladium (II) acetate (107 mg, 0.48 mmol) and cyclohexene (0.48 ml, 4.78 mmol). The reaction mixture was heated at 130 °C for 4 h. The catalyst was filtered off. The solvent was evaporated. The crude product was purified by column chromatography to give 24.7 mg of the title compound. 1 H NMR (DMSO-d6) δ: 8.12-8.17 (m, 1H), 7.47 (d, 2H), 6.84 (d, 2H), 6.22 (s, 1H), 5.42 (s, 2H), 3.68 (d, 2H), 3.55 (br d, 3H), 2.84 (s, 3H), 2.65-2.74 (m, 2H), 1.75-1.85 (m, 3H), 1.20-1.30 (m, 2H). LC-MS: m / z 416.5 (M+H) + .

[1469] Example 24.

[1470] 2-((5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)methyl)isoindoline 2-oxide (Compound 289)

[1471]

[1472] To a solution of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)-4H-pyran-4-one (0.10 g, 0.24 mmol) in methanol (1 ml) was added formic acid (11.0 mg, 0.24 mmol) and hydrogen peroxide 35% aqueous solution (8.13 mg, 0.24 mmol). The mixture was stirred at room temperature for 6 h. The solvent was evaporated. The crude product was purified by column chromatography to give 70 mg of the title compound. 1 H NMR (DMSO-d6) δ: 10.44 (s, 1H), 7.96 (d, 1H), 7.85 (d, 2H), 7.61 (d, 2H), 7.41 (m, 1H), 7.20 (d, 1H), 6.95 (m, 1H), 6.84 (d, 1H), 6.59 (d, 1H), 3.36 (s, 1H), 3.27 (m, 2H), 2.77 (m, 1H), 2.14 (s, 3H), 1.05-1.13 (m, 8H). LC-MS: m / z 435.2 (M+H) + .

[1473] Example 25.

[1474] 2-((5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)methyl)-5- (trifluoromethyl)isoindoline 2-oxide (Compound 290)

[1475]

[1476] To a solution of 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5- (trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-4-one (0.10 g, 0.20 mmol) in methanol (2 ml) was added formic acid (47.0 mg, 1.02 mmol) and hydrogen peroxide 35% in water (0.20 g, 2.05 mmol). The mixture was stirred at room temperature for 6 h. The solvent was evaporated. The crude product was purified by column chromatography to give 43 mg of the title compound. 1 H NMR (DMSO-d6) δ: 8.24 (br s, 1H), 7.77 (br s, 1H), 7.70 (br d, 1H), 7.59 (br d, 1H), 6.68 (s, 1H), 5.15-5.27 (m, 2H), 4.76 (br s, 2H), 4.62 (br d, 2H), 3.75 (br d, 2H), 3.38 (m, 2H), 2.86 (s, 3H), 2.73 (br m, 2H), 1.86 (br d, 3H), 1.24-1.36 (m, 2H). LC-MS: m / z 435.2 (M+H) + .

[1477] Example 26.

[1478] 5-((1-(methylsulfonyl)-1,2,3,4-tetrahydropyridin-4-yl)methoxy)-2-((5- (trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-4-one (Compound 291)

[1479]

[1480] a) Ethyl piperidine-4-carboxylate trifluoroacetate salt

[1481] To a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (20 g, 77.8 mmol) in DCM (400 ml) was added TFA (200 ml) dropwise at 0 °C, followed by stirring at room temperature for 2 h. The mixture was concentrated under reduced pressure to give 44 g of the crude title compound as a brown oil. It was used directly in the next reaction step without further purification.

[1482] b) Ethyl 1-(methylsulfonyl)piperidine-4-carboxylate

[1483] To a solution of ethyl piperidine-4-carboxylate trifluoroacetate salt (44 g, 162.3 mmol) in ACN (400 ml) was added DIPEA (106 ml, 649.4 mmol) and MsCI (25 ml, 327.4 mmol) at 0 °C, followed by stirring at room temperature for 2-3 h. The reaction mixture was quenched with water (500 ml) and extracted with EtOAc (3 x 500 ml). The organic layer was washed with brine, dried (anhydrous Na2S04), filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using 25% EtOAc in hexane as eluent to afford 5.6 g of the title compound as a white solid. MS: m / z 158 [M+H] + .

[1484] c) Ethyl 1-(methylsulfonyl)-2-oxopiperidine-4-carboxylate

[1485] To a solution of ethyl 1-(methylsulfonyl)piperidine-4-carboxylate (3.6 g, 15.3 mmol) in ACN:H20 (2:5) (14 mL) was added ruthenium (IV) oxide hydrate (0.2 g, 1.5 mmol) in a water bath. After 5 min, sodium periodate (6.8 g, 32.1 mmol) was added in portions at a temperature between 18 °C to 22 °C (the temperature should not exceed 30 °C during addition). The mixture was stirred at room temperature for 7 h. The reaction mixture was quenched with water followed by addition of DCM (50 mL). The mixture was filtered through celite. The organic layer was separated, dried (anhydrous Na2S04) and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using 20-40% EtOAc in hexane as eluent to afford 2.3 g of the title compound as a light yellow solid. MS: m / z 250 [M+H] + .

[1486] d) Ethyl 2-hydroxy-1-(methylsulfonyl)piperidine-4-carboxylate

[1487] To a solution of ethyl 1-(methylsulfonyl)-2-oxopiperidine-4-carboxylate (2.26 g, 9.0 mmol) in dry THF (100 ml) was added DIBAL-H in toluene (1.5 M in toluene, 15.1 ml, 22.6 mmol) dropwise at -78 °C, followed by stirring for 5 h. The mixture was cooled to room temperature, quenched with saturated NH4CI solution and extracted with EtOAc (3 x 50 mL). The organic layer was dried (anhydrous Na2S04), filtered and concentrated under reduced pressure to afford 2.1 g of the crude title compound as a light yellow oil. It was used directly in the next reaction step without further purification.​

[1488] e) Ethyl 1-(methylsulfonyl)-1,2,3,4-tetrahydropyridine-4-carboxylate

[1489] To a solution of ethyl 2-hydroxy-1-(methylsulfonyl)piperidine-4-carboxylate (2.1 g, 8.3 mmol) in DCM (40 ml) was added TFAA (2.9 ml, 20.9 mmol) dropwise at -78 °C followed by stirring for 6 h. After this, TEA (24 ml, 167.3 mmol) was added at -78 °C followed by stirring at room temperature for 2.5 h. The reaction mixture was quenched with aqueous NaHC03solution and extracted with DCM (3 x 50 mL). The organic layer was washed with water, dried (anhydrous Na2S04), filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using 10-20% EtOAc in hexane as eluent to afford 1.1 g of the title compound as a pale yellow solid. MS: m / z 234 [M+H] + .

[1490] f) (1-(methylsulfonyl)-1,2,3,4-tetrahydropyridin-4-yl)methanol

[1491] To a solution of ethyl 1-(methylsulfonyl)-1,2,3,4-tetrahydropyridine-4-carboxylate (0.95 g, 4.0 mmol) in dry THF (100 ml) was added LiBH4(3.0 M in THF, 2.7 ml, 8.1 mmol) dropwise at -40 °C followed by stirring at room temperature for 16 h. The reaction mixture was quenched with ice and extracted with EtOAc (3 x 50 mL). The organic layer was dried (anhydrous Na2S04), filtered and concentrated under reduced pressure to afford 0.77 g of the title compound as a clear oil. MS: m / z 192 [M+H] + .

[1492] g) Methylsulfonic acid (1-(methylsulfonyl)-1,2,3,4-tetrahydropyridin-4-yl)methyl ester

[1493] To a solution of (1-(methylsulfonyl)-1,2,3,4-tetrahydropyridin-4-yl)methanol (0.76 g, 3.97 mmol) in ACN (10 ml) was added DIPEA (2.9 ml, 15.91 mmol) and MsCI (0.6 ml, 7.95 mmol) at 0 °C followed by stirring for 10 min. The reaction mixture was quenched with brine (50 ml) and extracted with EtOAc (3 x 25 mL). The organic layer was dried (anhydrous Na2S04), filtered and concentrated under reduced pressure to afford 1.2 g of the crude title compound. This was used as such in the next reaction step without further purification. MS: m / z 270 [M+H] + .

[1494] h) 5-((1-(methylsulfonyl)-1,2,3,4-tetrahydropyridin-4-yl)methoxy)-2-((5- (trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-4-one

[1495] To a solution of 5-hydroxy-2-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran- 4-one (0.5 g, 1.6 mmol) and methylsulfonic acid (1-(methylsulfonyl)-1,2,3,4- tetrahydropyridin-4-yl)methyl ester (0.4 g, 1.6 mmol) in ACN (10 ml) was added Cs2CO3 (1.3 g, 4.0 mmol) followed by stirring at 70 °C for 16 h. The mixture was diluted with EtOAc (50 ml), filtered, concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC using Agilent, X Select Hexyl Phenyl (19 x 250) mm, 5 pm, 30% - 70% ACN in water with 5 mM ammonium acetate aqueous solution gradient, RT, 13.5 min to give 13.7 mg of the title compound as a brown solid. 1 H-NMR (400 MHz; DMSO-d6): δ 8.17 (s, 1H), 7.63 (s, 1H), 7.57 (d, 1H), 7.47 (d, 1H), 6.52 (d, 1H), 6.41 (s, 1H), 4.96 (q, 1H), 4.07 (s, 4H), 3.81 (s, 2H), 3.63-3.66 (m, 2H), 3.53-3.57 (m, 1H), 3.40-3.45 (m, 1H), 2.99 (s, 3H), 2.59-2.68 (m, 2H), 1.90-1.95 (m, 1H), 1.71-1.72 (m, 1H); MS: m / z 485 [M+H] + .

[1496] Experiment

[1497] CYP11A1 inhibition

[1498] The ability of test compounds to inhibit the conversion of cholesterol to progesterone and isocaproic acid was determined by a modified version of the isocaproic acid release assay (IARA) described by Ruangwises et al. (Biology of Reproduction 1991; 45(1): 143-50) with the difference that the human H295R adrenocortical carcinoma cell line was used as enzyme source and extraction was performed using a dextran-coated charcoal suspension (Isomaa, V. et al. Endocrinology 1982; 111(3): 833-843). The H295R cell line has been shown to express all key steroidogenic enzymes. To determine the half maximal inhibitory concentration (IC 50 ) of test compounds for CYP11A1 inhibition, cells were treated for 3 days with increasing concentrations of test compounds in the presence of 3 nM [24,25-3H]-labelled cholesterol (American Radiolabelled Chemicals). The final DMSO concentration was 1%. Cell culture medium was extracted with a dextran-coated charcoal suspension and the radioactively labelled isocaproic acid was determined by mixing 100 μl of the supernatant fraction in 200 μl scintillation fluid (OptiPhase SuperMix, Perkin Elmer). Radioactivity was determined using a Microbeta scintillation counter (1450 MicroBeta Trilux, Wallac). All test compounds were investigated in duplicate at 10 concentrations.

[1499] The compounds of the present application were screened in the above described assay and the IC 50 values of the compounds are shown in Table 1 below, where "A" means IC 50 values less than 150 nM, "B" means IC 50 values in the range of 150-300 nM, "C" means IC 50 values in the range of 301 nM-2000 nM.

[1500] Table 1.

[1501]

[1502] Abbreviations

[1503] ACN - acetonitrile

[1504] DAST - diethylaminosulfur trifluoride

[1505] DCE - 1,2-dichloroethane

[1506] DCM - dichloromethane

[1507] DEA - diethanolamine

[1508] DIBAL-H - diisobutylaluminum hydride solution

[1509] DIPEA - N,N-diisopropylethylamine

[1510] DMF - N,N-dimethylformamide

[1511] DMSO - dimethyl sulfoxide

[1512] DPPA - diphenyl azidophosphate

[1513] DBU - 1,8-diazabicyclo[5.4.0]undec-7-ene

[1514] EtOAc - ethyl acetate

[1515] EtOH - ethanol

[1516] IPA - isopropyl alcohol

[1517] LAH - lithium aluminum hydride

[1518] LiHMDS - lithium hexamethyldisilazane TAI lithium bis(trimethylsilyl)amide

[1519] m-CPBA - 3-chloroperbenzoic acid

[1520] MeOH - methanol

[1521] Ms - methanesulfonyl

[1522] MTBE - methyl tert-butyl ether

[1523] PPh3 - triphenylphosphine

[1524] Pd2(dba)3 - tris(dibenzylideneacetone)dipalladium(0)

[1525] Pd(PPh3)4 - tetrakis(triphenylphosphine)palladium(0)

[1526] PPTS - pyridinium p-toluenesulfonate

[1527] rac-BINAP - racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[1528] RT - room temperature

[1529] rt - retention time

[1530] TBABr - tetrabutylammonium bromide

[1531] TBAF - tetrabutylammonium fluoride

[1532] TBME - methyl tert-butyl ether

[1533] TBSCl -tert-butyldimethylsilyl chloride

[1534] TEA -triethylamine

[1535] TFA -trifluoroacetic acid

[1536] TFAA -trifluoroacetic anhydride

[1537] THF -tetrahydrofuran

[1538] TMEDA -tetramethylethylenediamine

[1539] Tf -triflyl

[1540] Ts -p-toluenesulfonyl

Claims

1. Use of a compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating castration-resistant prostate cancer, wherein said compound is 5-((1-(oxecyclobutane-3-ylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)isoindoline-2-yl)methyl)-4H-pyran-4-one; 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)isoindoline-2-yl)methyl)-4H-pyran-4-one; 2-(isoindoline-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one; 2-((5-fluoroisoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one; 5-((1-(cyclopropylsulfonyl)piperidin-4-yl)methoxy)-2-(isoindoline-2-ylmethyl)-4H-pyran-4-one; 5-((1-(ethylsulfonyl)piperidin-4-yl)methoxy)-2-(isoindoline-2-ylmethyl)-4H-pyran-4-one; 5-((1-(ethylsulfonyl)piperidin-4-yl)methoxy)-2-((5-fluoroisoindoline-2-yl)methyl)-4H-pyran-4-one; 5-((1-(cyclopropylsulfonyl)piperidin-4-yl)methoxy)-2-((5-fluoroisoindoline-2-yl)methyl)-4H-pyran-4-one; 5-((1-(ethylsulfonyl)-4-methylpiperidin-4-yl)methoxy)-2-(isoindoline-2-ylmethyl)-4H-pyran-4-one; 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethoxy)-isoindoline-2-yl)methyl)-4H-pyran-4-one; 2-(isoindoline-2-ylmethyl)-5-((1-(pyrrolidine-1-carbonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one; 5-((1-Butyrylpiperidin-4-yl)methoxy)-2-(isoindoline-2-ylmethyl)-4H-pyran-4-one; 5-((1-(2,2-difluoropropionyl)piperidin-4-yl)methoxy)-2-(isoindoline-2-ylmethyl)-4H-pyran-4-one; 5-((1-(2,2-difluoropropionyl)piperidin-4-yl)methoxy)-2-((5-fluoroisoindoline-2-yl)methyl)-4H-pyran-4-one; 2-((5-fluoroisoindoline-2-yl)methyl)-5-((1-propionylpiperidin-4-yl)methoxy)-4H-pyran-4-one; 4-(((6-(isoindoline-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N-dimethylpiperidine-1-sulfonamide; 4-(((6-(isoindoline-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N-methylpiperidine-1-carboxamide; 4-(((6-(Isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N-isopropyl- piperidine-1-carboxamide; 4-(((6-((5-Fluoroisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-N,N- dimethylpiperidine-1 -sulfonamide; 2-(Isoindolin-2-ylmethyl)-5-((4-(oxetan-3-ylsulfonyl)benzyl)oxy)-4H-pyran-4-one; 2-((5-Chloroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)- 4H-pyran-4-one; 5-((1-Propionylpiperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)isoindolin-2-yl)methyl)- 4H-pyran-4-one; N-(tert-Butyl)-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl) piperidine-1-carboxamide; 2-(Isoindolin-2-ylmethyl)-5-((1-neopentanoylpiperidin-4-yl)methoxy)-4H-pyran-4- one; 5-((1-Acetylpiperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one; 2-(Isoindolin-2-ylmethyl)-5-((1-propionylpiperidin-4-yl)methoxy)-4H-pyran-4-one; 2-(Isoindolin-2-ylmethyl)-5-((1-((2-methoxyethyl)sulfonyl)piperidin-4-yl)methoxy)- 4H-pyran-4-one; 2-(Isoindolin-2-ylmethyl)-5-((1-(isopropylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran- 4-one; 5-((1-(Isobutylsulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4- one; 5-((1-Isobutyrylpiperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one; or 2-(Isoindolin-2-ylmethyl)-5-((1-(2,2,2-trifluoroacetyl)piperidin-4-yl)methoxy)-4H- pyran-4-one.

2. The use according to claim 1, wherein the drug is used in combination with a glucocorticoid and / or a mineralocorticoid.

3. The use according to claim 2, wherein the drug is used in combination with one or more anticancer agents.

4. The use according to claim 3, wherein the one or more anticancer agents are selected from the group consisting of: - non-steroidal androgen receptor antagonists; - inhibitors of steroidogenesis; - chemotherapeutic agents; - antiestrogens; - epigenetic modulators; - mTOR inhibitors; - AKT inhibitors; - radiopharmaceuticals; - GnRH / LHRH analogues; - PI3K inhibitors; and - CDK4 / 6 inhibitors.

5. The use of a compound in the manufacture of a medicament for the treatment of castration-resistant prostate cancer, wherein the structure of the compound is:

6. Use of a pharmaceutically acceptable salt of a compound having the structure: in the manufacture of a medicament for the treatment of castration-resistant prostate cancer.

7. Use of a compound or a pharmaceutically acceptable salt thereof having the structure: in the manufacture of a medicament for the treatment of castration-resistant prostate cancer.

8. Use of a compound having the structure: in the manufacture of a medicament for the treatment of castration-resistant prostate cancer.

9. Use of a pharmaceutically acceptable salt of a compound having the structure: in the manufacture of a medicament for the treatment of castration-resistant prostate cancer.

10. Use of a compound or a pharmaceutically acceptable salt thereof having the structure: in the manufacture of a medicament for the treatment of castration-resistant prostate cancer.

11. The use according to any one of claims 5 to 10, wherein the medicament is used in combination with a glucocorticoid and / or a mineralocorticoid.

12. The use according to any one of claims 5 to 10, wherein the medicament is used in combination with one or more anticancer agents.

13. The use according to claim 12, wherein the one or more anticancer agents are selected from the group consisting of: - non-steroidal androgen receptor antagonists; - inhibitors of steroidogenesis; - chemotherapeutic agents; - antiestrogens; - epigenetic modulators; - mTOR inhibitors; - AKT inhibitors; - radiopharmaceuticals; - GnRH / LHRH analogues; - PI3K inhibitors; and - CDK4 / 6 inhibitors. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​

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