CYP11A1 inhibitors

Abstract

This invention provides compounds useful as cytochrome P450 monooxygenase 11A1 (CYP11A1) inhibitors. [Solution] Compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, are provided. Compounds of formula (I) or (II) are useful as pharmaceuticals in the treatment of steroid receptors, particularly androgen receptors, and dependent symptoms and diseases, such as prostate cancer. TIFF2026048803000159.tif5070

Description

Technical Field

[0001] The present invention relates to therapeutically active compounds useful for the treatment of steroid receptor-dependent conditions and diseases such as androgen receptor (AR), and pharmaceutical compositions containing such compounds.

Background Art

[0002] Prostate cancer is one of the most common cancers in men worldwide. Despite the high 5-year survival rate of patients with localized prostate cancer, the prognosis of these patients who develop castration-resistant prostate cancer (CRPC) within a 5-year follow-up period is poor.

[0003] The androgen receptor (AR) signaling axis is of great significance at all stages of prostate cancer. At the CPRC stage, the disease is characterized by high AR expression, AR amplification, and persistent activation of the AR signaling axis by residual tissue / tumor androgen and other steroid hormones and intermediates of steroid biosynthesis. Therefore, the treatment of progressive prostate cancer involves hormonal manipulation using gonadotropin-releasing hormone (GnRH) agonists / antagonists, etc., surgical castration, androgen-deprivation therapy (ADT) such as AR antagonists or CYP17A1 inhibitors (such as abiraterone acetate combined with prednisone).

[0004] While treatment initially leads to disease regression, ultimately, many patients develop a disease that is resistant to current therapies. Elevated progesterone levels in patients treated with abiraterone acetate are hypothesized to be one mechanism of resistance. Several nonclinical and clinical studies have indicated upregulation of enzymes that catalyze steroid biosynthesis in the later stages of CRPC. Most recently, it has been published that 11β-OH androstenedione can be metabolized to 11-ketotestosterone (11-KT) and 11-ketodehydrotestosterone (11-K-DHT), which can efficiently bind to and activate ARs, as well as testosterone and dihydrotestosterone. These steroids have been found at high levels in the plasma and tissues of prostate cancer patients, suggesting their role as AR agonists in CRPC. Furthermore, it has been noted that prostate cancer resistant to CYP17A1 inhibition is still steroid-dependent and may respond to therapies that can further suppress de novo intratumoral steroid synthesis upstream of CYP17A1, such as CYP11A1 inhibitor therapy (Non-Patent Literature 1).

[0005] Cytochrome P450 monooxygenase 11A1 (CYP11A1), also known as cholesterol side-chain cleavage enzyme, is a mitochondrial monooxygenase that catalyzes the conversion of cholesterol to pregnenolone (a precursor of all steroid hormones). By inhibiting CYP11A1, a key enzyme in steroid biosynthesis upstream of CYP17A1, overall inhibition of steroid biosynthesis can be achieved. CYP11A1 inhibitors therefore have great potential for treating steroid hormone-dependent cancers, such as prostate cancer, even in advanced stages of the disease, and especially in patients who are considered hormone-resistant. Compounds with CYP11A1 inhibitory activity have been shown to significantly inhibit tumor growth in vivo in a mouse CRPC xenograft model (Non-Patent Literature 2). CYP11A1 inhibitors are described in the previous Patent Literature 1. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2018 / 115591 [Non-patent literature]

[0007] [Non-Patent Document 1] Cai, C. et al, Cancer Res., 71(20), 6503-6513, 2011 [Non-Patent Document 2] (Oksala, R. et al, Annals of Oncology, (2017) 28 (suppl. 5): Abstract / Poster 28P [Overview of the project]

[0008] Compounds of formula (I) or (II) are potent CYP11A1 inhibitors, and in in vitro studies, they have been found to be associated with a lower potential to form reactive metabolites, meaning they have a lower risk of idiotoxicity as drug candidates. The compounds of the present invention are therefore useful as pharmaceuticals, particularly in the treatment of steroid hormone-dependent symptoms and diseases in which inhibition of CYP11A1 is desired. Such symptoms and diseases include, but are not limited to, endocrine cancers, prostate cancer, and breast cancer. In particular, the compounds of the present invention are useful in the treatment of AR-dependent symptoms and diseases such as prostate cancer.

[0009] The present invention relates to compounds of formula (I) or (II). [ka] (In the formula, Ring B is a 4-12 member monocyclic, bicyclic, or spirodicyclic ring containing 0-4 heteroatoms independently selected from N, O, or S; Ring A is based on the following basis [Chemical] is any of; L is none, -CH2-, -CH(CH3)-, -CH2-CH2- or -CH2-CH2-CH2-; R1 is hydrogen, C 15 alkyl, C 1-7 alkoxy, halogen, cyano, nitro, haloC 1-7 alkyl or haloC 1-7 alkoxy; R2 is hydrogen, C 1-7 alkyl, halogen, hydroxy, C 1-7 alkoxy, haloC 1-7 alkyl or oxo; or R1 and R2 are bonded to the same carbon atom and together with the carbon atom to which they are bonded form a C 3-7 cycloalkyl ring; or R1 and R2 together with the carbon atom to which they are bonded form a fused C 3-7 cycloalkyl ring; R3 is hydrogen, halogen, nitro, cyano, oxo, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, hydroxyC 3-7 cycloalkyl, 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 alkylthio, aminocarbonylC 2-7 alkenyl, haloC 1-7 alkylthio, C 1-7 alkoxycarbonylC 1-7 alkyl, C 1-7 alkoxycarbonylC 2-7 alkenyl, =NSO2R 20 , -S(O)-C 1-7 alkyl, -S(O)(NR 14 ) (R 22 ) ), -S(NR 15 ) (C1-7 Alkyl), -C(S)NR 18 R 19 , -DC(O)-NR6R7, -C(O)R8, -D-NR9R 10 , -SO2R 11 , optionally substituted 3-10 member carbocyclyl, optionally substituted 3-10 member carbocyclyl C 1-7 Alkyl, optionally substituted 4-10 member heterocyclyl, or optionally substituted 4-10 member heterocyclyl C 1-7 It is alkyl; R4 is hydrogen, halogen, hydroxyl, C 1-7 Alkyl, Halo C 1-7 Alkyl or oxo; R5 is hydrogen, halogen or C 1-7 It is alkyl; R6 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 2-7 Alkenil, C 3-7 Cycloalkyl, hydroxy C 1-7 Alkyl, cyano C 1-7 Alkyl, -C 1-7 Alkyl-OC(O)C 1-7 It is an alkyl or optionally substituted 4- to 10-membered heterocycline; R8 is hydrogen, C 1-7 Alkyl, C 2-7 Alkenil, C 3-7 Cycloalkyl, C 1-7 Alkoxy, Halo C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkylcarbonyl, C 1-7 Alkoxycarbonyl, -C 1-7 Alkyl-OC(O)-C 1-7 Alkyl, -C 1-7 Alkyl-SO2(C 1-7 Alkyl), -N=S(O)(C 1-7 Alkyl)(C 1-7 It is an alkyl or optionally substituted 4- to 10-membered heterocycline; R9 is hydrogen, C1-7 alkyl, C 3-7 cycloalkyl, C 1-7 alkylcarbonyl, -SO2(C 1-7 alkyl) or -SO2(C 3-7 cycloalkyl); 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- to 10-membered carbocyclic or optionally substituted 4- to 10-membered heterocyclic; R 12 is hydrogen, C 1-7 alkyl, hydroxyC 1-7 alkyl, cyanoC 1-7 alkyl, C<00000​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​20 and R 21 Independently, C 1-7 Alkyl, C 3-7 It is a cycloalkyl or optionally substituted 3- to 10-membered carbocyclyl; R 22 C 1-7 Alkyl or C 3-7 It is a cycloalkyl; R 23 is hydrogen, C 1-7 Alkylcarbonyl, hydroxyimino C 1-7 Alkyl, C 1-7 Alkoxyimino C 1-7 Alkyl, hydroxyl atoms optionally substituted with 1-3 halogen atoms 1-7 It is an alkyl or optionally substituted 4- to 10-membered heterocycline; R 24 is hydrogen, C 1-7 Alkyl or Halo C 1-7 It is alkyl; R 25 is hydrogen or C 1-7 It is alkyl; R 26 C 1-7 Alkylcarbonyl, hydroxyimino C 1-7 Alkyl, C 1-7 Alkoxyimino C 1-7 Alkyl, hydroxyl atoms optionally substituted with 1-3 halogen atoms 1-7 R is an alkyl or optionally substituted 4- to 10-membered heterocycline, provided that ring B is a spirodicyclic ring. 26 It could also be hydrogen; R 27 C 1-7 Alkyl or C 3-7 It is a cycloalkyl; D is none, C 1-7 Alkyl or C 2-7 It is an alkenil; Here, any substituent in each presence is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 Alkylcarbonyl, C 1-7 Alkoxy, C 1-7Alkoxy C 1-7 Alkyl, C 1-7 Selected from 1 to 3 substituents independently selected from alkoxycarbonyl or oxo; and Here, each heterocyclyl group has 1 to 4 heteroatoms independently selected from N, O, and S. or relating to a pharmaceutically acceptable salt thereof.

[0010] According to one embodiment, the present invention relates to a method for treating or preventing steroid receptor, particularly androgen receptor (AR)-dependent symptoms and diseases, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or (II). [ka] (In the formula, Ring B is a 4-12 member monocyclic, bicyclic, or spirodicyclic ring containing 0-4 heteroatoms independently selected from N, O, or S; Ring A is based on the following basis [ka] It is either one of the following; L is none, -CH2-, -CH(CH3)-, -CH2-CH2-, or -CH2-CH2-CH2-; R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, cyano, nitro, halo C 1-7 Alkyl or Halo C 1-7 It is an alkoxy; R2 is hydrogen, C 1-7 Alkyl, halogen, hydroxy, C 1-7 Alkoxy, Halo C 1-7 Alkyl or oxo; Alternatively, R1 and R2 are bonded to the same carbon atom, and together with the carbon atom to which they are bonded, C 3-7 Forming a cycloalkyl ring, Alternatively, R1 and R2 fuse together with the carbon atoms they bond to. 3-7Forming a cycloalkyl ring; R3 is hydrogen, halogen, nitro, cyano, oxo, C 1-7 Alkyl, C 2-7 Alkenil, C 3-7 Cycloalkyl, hydroxy C 3-7 Cycloalkyl, C 1-7 Alkoxy, Hydroxy C 1-7 Alkyl, Halo C 1-7 Alkyl, cyano C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkylthio, aminocarbonyl C 2-7 Alkenil, Halo 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 , optionally substituted 3-10 member carbocyclyl, optionally substituted 3-10 member carbocyclyl C 1-7 Alkyl, optionally substituted 4-10 member heterocyclyl, or optionally substituted 4-10 member heterocyclyl C 1-7 It is alkyl; R4 is hydrogen, halogen, hydroxyl, C 1-7 Alkyl, Halo C 1-7 Alkyl or oxo; R5 is hydrogen, halogen or C 1-7 It is alkyl; R6 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 2-7 Alkenil, C3-7 Cycloalkyl, hydroxy C 1-7 Alkyl, cyano C 1-7 Alkyl, -C 1-7 Alkyl-OC(O)C 1-7 It is an alkyl or optionally substituted 4- to 10-membered heterocycline; R8 is hydrogen, C 1-7 Alkyl, C 2-7 Alkenil, C 3-7 Cycloalkyl, C 1-7 Alkoxy, Halo C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkylcarbonyl, C 1-7 Alkoxycarbonyl, -C 1-7 Alkyl-OC(O)-C 1-7 Alkyl, -C 1-7 Alkyl-SO2(C 1-7 Alkyl), -N=S(O)(C 1-7 Alkyl)(C 1-7 It is an alkyl or optionally substituted 4- to 10-membered heterocycline; R9 is hydrogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-7 Alkylcarbonyl, -SO2(C 1-7 Alkyl) or -SO2(C 3-7 It is a cycloalkyl group; R 11 is C 1-7 Alkyl, C 2-7 Alkenil, 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 , optionally substituted 3- to 10-membered carbocyclyl or optionally substituted 4- to 10-membered heterocyclyl; R 12 is hydrogen, C 1-7 Alkyl, hydroxy C 1-7 Alkyl, cyano C 1-7 Alkyl, C1-7 Alkoxy, C 1-7 Alkoxy C 1-7 Alkyl or C 1-7 It is an alkylcarbonyl; R7, R 10 , R 13 , R 18 , and R 19 These are, independently, hydrogen and C 1-7 Alkyl or C 3-7 It is a cycloalkyl; R 14 is hydrogen, C 1-7 Alkyl, C 1-7 Alkylcarbonyl or -SO2R 21 and; R 15 is hydrogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-7 Alkylcarbonyl, -SO2R 17 and; R 17 C 1-7 It is an alkyl or optionally substituted 3- to 10-membered carbocyclyl; R 20 and R 21 Independently, C 1-7 Alkyl, C 3-7 It is a cycloalkyl or optionally substituted 3- to 10-membered carbocyclyl; R 22 C 1-7 Alkyl or C 3-7 It is a cycloalkyl; R 23 is hydrogen, C 1-7 Alkylcarbonyl, hydroxyimino C 1-7 Alkyl, C 1-7 Alkoxyimino C 1-7 Alkyl, hydroxyl atoms optionally substituted with 1-3 halogen atoms 1-7 It is an alkyl or optionally substituted 4- to 10-membered heterocycline; R 24 is hydrogen, C 1-7 Alkyl or Halo C 1-7 It is alkyl; R 25is hydrogen or C 1-7 It is alkyl; R 26 C 1-7 Alkylcarbonyl, hydroxyimino C 1-7 Alkyl, C 1-7 Alkoxyimino C 1-7 Alkyl, hydroxyl atoms optionally substituted with 1-3 halogen atoms 1-7 R is an alkyl or optionally substituted 4- to 10-membered heterocycline, provided that ring B is a spirodicyclic ring. 26 It could also be hydrogen; R 27 C 1-7 Alkyl or C 3-7 It is a cycloalkyl; D is none, C 1-7 Alkyl or C 2-7 It is an alkenil; Here, any substituent in each presence is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 Alkylcarbonyl, C 1-7 Alkoxy, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Selected from 1 to 3 substituents independently selected from alkoxycarbonyl or oxo; and Here, each heterocyclyl group has 1 to 4 heteroatoms independently selected from N, O, and S. or a pharmaceutically acceptable salt thereof is provided.

[0011] According to one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or (II) as defined in any of the above embodiments, together with a pharmaceutically acceptable carrier.

[0012] According to one embodiment, the present invention provides a method for treating or preventing steroid receptor, particularly androgen receptor (AR)-dependent symptoms and diseases. Such symptoms and diseases include, but are not limited to, endocrine cancers and diseases such as prostate cancer and breast cancer. The method comprises administering to a subject in need a therapeutically effective amount of a compound of formula (I) or (II) as defined in any of the above embodiments. [Modes for carrying out the invention]

[0013] This patent application provides a novel compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof that is useful as a CYP11A1 inhibitor.

[0014] One embodiment of the present invention is a compound of formula (I) or (II). [ka] (In the formula, Ring B is a 4-12 member monocyclic, bicyclic, or spirodicyclic ring containing 0-4 heteroatoms independently selected from N, O, or S; Ring A is based on the following basis [ka] It is either one of the following; L is none, -CH2-, -CH(CH3)-, -CH2-CH2-, or -CH2-CH2-CH2-; R1 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy, halogen, cyano, nitro, halo C 1-7 Alkyl or Halo C 1-7 It is an alkoxy; R2 is hydrogen, C 1-7 Alkyl, halogen, hydroxy, C 1-7 Alkoxy, Halo C 1-7 Alkyl or oxo; Alternatively, R1 and R2 are bonded to the same carbon atom, and together with the carbon atom to which they are bonded, C3-7 Forming a cycloalkyl ring; Alternatively, R1 and R2 fuse together with the carbon atoms they bond to. 3-7 Forming a cycloalkyl ring; R3 is hydrogen, halogen, nitro, cyano, oxo, C 1-7 Alkyl, C 2-7 Alkenil, C 3-7 Cycloalkyl, hydroxy C 3-7 Cycloalkyl, C 1-7 Alkoxy, Hydroxy C 1-7 Alkyl, Halo C 1-7 Alkyl, cyano C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkylthio, aminocarbonyl C 2-7 Alkenil, Halo 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 , optionally substituted 3-10 member carbocyclyl, optionally substituted 3-10 member carbocyclyl C 1-7 Alkyl, optionally substituted 4-10 member heterocyclyl, or optionally substituted 4-10 member heterocyclyl C 1-7 It is alkyl; R4 is hydrogen, halogen, hydroxyl, C 1-7 Alkyl, Halo C 1-7 Alkyl or oxo; R5 is hydrogen, halogen or C 1-7 It is alkyl; R6 is hydrogen, C1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 2-7 Alkenil, C 3-7 Cycloalkyl, hydroxy C 1-7 Alkyl, cyano C 1-7 Alkyl, -C 1-7 Alkyl-OC(O)C 1-7 It is an alkyl or optionally substituted 4- to 10-membered heterocycline; R8 is hydrogen, C 1-7 Alkyl, C 2-7 Alkenil, C 3-7 Cycloalkyl, C 1-7 Alkoxy, Halo C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkylcarbonyl, C 1-7 Alkoxycarbonyl, -C 1-7 Alkyl-OC(O)-C 1-7 Alkyl, -C 1-7 Alkyl-SO2(C 1-7 Alkyl), -N=S(O)(C 1-7 Alkyl)(C 1-7 It is an alkyl or optionally substituted 4- to 10-membered heterocycline; R9 is hydrogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-7 Alkylcarbonyl, -SO2(C 1-7 Alkyl) or -SO2(C 3-7 It is a cycloalkyl group; R 11 is C 1-7 Alkyl, C 2-7 Alkenil, 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 , optionally substituted 3- to 10-membered carbocyclyl or optionally substituted 4- to 10-membered heterocyclyl; R12 is hydrogen, C 1-7 Alkyl, hydroxy 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 It is an alkylcarbonyl; R7, R 10 , R 13 , R 18 , and R 19 These are, independently, hydrogen and C 1-7 Alkyl or C 3-7 It is a cycloalkyl; R 14 is hydrogen, C 1-7 Alkyl, C 1-7 Alkylcarbonyl or -SO2R 21 and; R 15 is hydrogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-7 Alkylcarbonyl, -SO2R 17 and; R 17 C 1-7 It is an alkyl or optionally substituted 3- to 10-membered carbocyclyl; R 20 and R 21 Independently, C 1-7 Alkyl, C 3-7 It is a cycloalkyl or optionally substituted 3- to 10-membered carbocyclyl; R 22 C 1-7 Alkyl or C 3-7 It is a cycloalkyl; R 23 is hydrogen, C 1-7 Alkylcarbonyl, hydroxyimino C 1-7 Alkyl, C 1-7 Alkoxyimino C 1-7 Alkyl, hydroxyl atoms optionally substituted with 1-3 halogen atoms 1-7 It is an alkyl or optionally substituted 4- to 10-membered heterocycline; R24 is hydrogen, C 1-7 Alkyl or Halo C 1-7 It is alkyl; R 25 is hydrogen or C 1-7 It is alkyl; R 26 C 1-7 Alkylcarbonyl, hydroxyimino C 1-7 Alkyl, C 1-7 Alkoxyimino C 1-7 Alkyl, hydroxyl atoms optionally substituted with 1-3 halogen atoms 1-7 R is an alkyl or optionally substituted 4- to 10-membered heterocycline, provided that ring B is a spirodicyclic ring. 26 It could also be hydrogen; R 27 C 1-7 Alkyl or C 3-7 It is a cycloalkyl; D is none, C 1-7 Alkyl or C 2-7 It is an alkenil; Here, any substituent in each presence is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 Alkylcarbonyl, C 1-7 Alkoxy, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Selected from 1 to 3 substituents independently selected from alkoxycarbonyl or oxo; and Here, each heterocyclyl group has 1 to 4 heteroatoms independently selected from N, O, and S. or a pharmaceutically acceptable salt thereof To provide.

[0015] It can be understood that the left-hand bond in linker L is bonded to ring B of formula (I) or (II).

[0016] Specifically, according to one embodiment, a compound according to either of the above embodiments of formula (I) or (II) is provided, where L is none, -CH2- or -CH(CH3)-, for example, L is absent, or in another example L is -CH2-, or in another example L is -CH(CH3)-.

[0017] According to one embodiment, specifically, a compound according to either of the above embodiments of formula (I) or (II), wherein ring B is the following group [ka] A compound is provided in which R3, R4, and R5 are bonded to the above ring B.

[0018] In the above embodiment subclass, the compound has the following group: [ka] It is one of the above, and R3, R4, and R5 are bonded to ring B, and the wavy line indicates the bond site to L.

[0019] Furthermore, according to one embodiment, a compound according to any of the above embodiments is provided, specifically wherein ring B is (1'), (2'), (3'), (4'), (5'), (6'), (7'), (8'), or (9').

[0020] In the subclass of the above embodiments, the compound is any of the above embodiments in which ring B is (1a'), (2a'), (3a'), (4a'), (5a'), (6a'), (7'), (8'), or (9a').

[0021] According to one embodiment, specifically, R3 is hydrogen, halogen, cyano, C 1-7 Alkyl, C 2-7 Alkenyl, HydroxyC 1-7 Alkyl, C 1-7 Alkylthio, C 1-7 Alkoxycarbonyl C 1-7 Alkyl, -S(O)(NR14 )(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 , optionally substituted 3-10 member carbocyclyl, optionally substituted 3-10 member carbocyclyl C 1-7 Alkyl, optionally substituted 4-10 member heterocyclyl, or optionally substituted 4-10 member heterocyclyl C 1-7 It is alkyl; where any substitution in each presence is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 Alkylcarbonyl, C 1-7 Alkoxy, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 A compound according to any of the above embodiments is provided, wherein the heterocyclyl group in each presence has 1 to 4 heteroatoms, which are selected from 1 to 3 substituents independently selected from alkoxycarbonyl or oxo.

[0022] In the subclass of the above embodiment, the compound is such that R3 is hydrogen, cyano, or hydroxy C 1-7 Alkyl, -S(O)(NR 14 )(R 22 ), -DC(O)-NR6R7, -C(O)R8, -SO2R 11 , optionally substituted 4-10 member heterocyclils or optionally substituted 4-10 member heterocyclils C 1-7 It is alkyl; where any substitution in each presence is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 One to three substituents are selected independently from the alkylcarbonyl, and in each presence the heterocyclyl group has one to four heteroatoms independently selected from N, O, and S. In a further subclass of the above embodiments, the compound is R 14 is hydrogen, R22 C 1-7 It is alkyl, D is absent, and R6 is C 1-7 Alkyl or C 1-7 Alkoxy C 1-7 It is an alkyl group, and R7 is C 1-7 It is alkyl, and R8 is C 1-7 Alkyl, C 1-7 It is an alkoxy or optionally substituted 4- to 10-membered heterocycline, and / or R 11 C 1-7 These are alkyl groups, optionally substituted 3-10 membered carbocyclyl groups, or optionally substituted 4-10 membered heterocyclyl groups. R3, R8 and R 11 In the definition, specific examples of 4- to 10-membered heterocyclyls are pyridinyl, pyrazolyl, azetidinyl, and pyrimidinyl rings, while a specific example of a 3- to 10-membered carbocyclyl is a phenyl ring.

[0023] According to one embodiment, specifically, R1 is hydrogen, C 1-7 Alkyl, halogen, cyano, or halo C 1-7 It is alkyl; R2 is hydrogen or C 1-7 It is alkyl; or R1 and R2, along with the carbon atom to which they are bonded, are spiro C 3-7 Forming a cycloalkyl ring; or R1 and R2, together with the carbon atom to which they are bonded, fused C 3-7 Compounds according to any of the above embodiments that form a cycloalkyl ring are provided.

[0024] According to one embodiment, specifically, a compound according to any of the above embodiments is provided in which R4 is hydrogen or a halogen and R5 is hydrogen.

[0025] In the subclass of the above embodiment, the compound has hydrogen as R4 and R5.

[0026] According to one embodiment, specifically, a compound according to either of the above embodiments is provided, wherein ring A is (1) or (2).

[0027] According to one embodiment, specifically, R 24 C 1-7 Alkyl or Halo C 1-7 Compounds according to any of the above embodiments, which are alkyl, are provided.

[0028] According to one embodiment, the compound of the present invention is of formula (IA): [ka] (In the formula, R1, R2, R3, R4, R5, R 23 , R 24 , R 25 , R 27 L and B are defined in either of the above embodiments for formula (I) or (II), It is represented by or by a pharmaceutically acceptable salt thereof.

[0029] According to one embodiment, the compound of the present invention is of formula (IB): [ka] (In the formula, R1, R2, R3, R4, R5, R 23 , R 24 , R 25 , R 27 (where L and B are defined in either of the above embodiments for formula (I) or (II)) It is represented by or by a pharmaceutically acceptable salt thereof.

[0030] According to one embodiment, the compound of the present invention is of formula (IC): [ka] (In the formula, R1, R2, R3, R4, R5, R 23 , R 24 , R 25 , R 27 (where L is defined in either of the above embodiments for formula (I) or (II)) It is represented by or by a pharmaceutically acceptable salt thereof.

[0031] According to one embodiment, the compound of the present invention is of formula (IIA): [ka] (In the formula, R1, R2, R3, R4, R5, R 24 , R 25 , R 26 (where L and B are defined in either of the above embodiments for formula (I) or (II)) It is represented by or by a pharmaceutically acceptable salt thereof.

[0032] According to one embodiment, the compound of the present invention is of formula (IIB): [ka] (In the formula, R1, R2, R3, R4, R5, R 24 , R 25 , R 26 (where L and B are defined in either of the above embodiments for formula (I) or (II)) It is represented by or by a pharmaceutically acceptable salt thereof.

[0033] According to one embodiment, the compound of the present invention is of formula (IIC): [ka] (In the formula, R1, R2, R3, R4, R5, R 24 , R 25 , R 26 (where L and B are defined in either of the above embodiments for formula (I) or (II)) It is represented by or by a pharmaceutically acceptable salt thereof.

[0034] According to one embodiment, the compound of the present invention is of formula (IID): [ka] (In the formula, R1, R2, R3, R4, R5, R 24 , R 25 and R 26 (This is defined in either of the above embodiments for formula (I) or (II).) It is represented by or by a pharmaceutically acceptable salt thereof.

[0035] According to one embodiment, the compound of the present invention is of formula (IIE): [ka] (In the formula, R1, R2, R3, R4, R5, R 24 , R 25 and R 26 (This is defined in either of the above embodiments for formula (I) or (II).) It is represented by or by a pharmaceutically acceptable salt thereof.

[0036] According to one embodiment, specifically, R 26 Compounds according to any of the above embodiments are provided, wherein R is an optionally substituted 4-10 membered heterocycline having 1-4 heteroatoms independently selected from N, O, and S. 26 In the definition, specific examples of 4- to 10-membered heterocyclyls are oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, and pyrazolyl rings, while a specific example of a 3- to 10-membered carbocyclyl is the phenyl ring.

[0037] According to one embodiment, specifically, R3 is -SO2R 11 R1, R2, R4, and R5 are hydrogen; and R 11 is C 1-7 Compounds according to any of the above embodiments, which are alkyl, are provided.

[0038] According to one embodiment, specifically, R 24 C 1-7 Alkyl or Halo C 1-7Compounds according to any of the above embodiments, which are alkyl, are provided.

[0039] According to one embodiment, specifically, a 4-10 member heterocycline C in which R3 is optionally substituted. 1-7 It is alkyl; any substitution is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 A compound according to any of the above embodiments is provided, comprising one to three substituents independently selected from the alkylcarbonyl, the heterocyclyl group having one to four heteroatoms independently selected from N, O, and S; and R1, R2, R4, and R5 being hydrogen.

[0040] According to one embodiment, specifically, R 23 However, compounds according to any of the above embodiments are provided, which are optionally substituted 4-10 membered heterocyclines having 1-4 heteroatoms independently selected from N, O, and S. 23 In the definition, specific examples of 4- to 10-membered heterocyclyls are oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, thiazolyl, and pyrazolyl rings, while a specific example of a 3- to 10-membered carbocyclyl is the phenyl ring.

[0041] According to one embodiment, specifically, ring B is (2a'), (3a'), (4a'), (5a') or (6a'); R1, R2, R3, R4, R5, R 24 , R 25 , R 26 A compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, is provided, wherein L is defined in claim 1.

[0042] According to one embodiment, specifically, R3 is hydrogen, -C(O)R8, -SO2R 11 , optionally substituted 4-10 member heterocyclines, or optionally substituted 4-10 member heterocyclines C 1-7 It is alkyl; R8 is C 1-7 It is an alkoxy; R 11 C 1-7 Alkyl, optionally substituted 4-10 member heterocyclyl, or optionally substituted 3-10 member carbocyclyl; Any substituent in each presence is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 The substituents are selected from 1 to 3 atoms independently selected from the alkylcarbonyl, and in each presence, the heterocyclyl group has 1 to 4 heteroatoms independently selected from N, O, and S. A compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, is provided.

[0043] According to one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or (II) as defined in any of the above embodiments, together with a pharmaceutically acceptable carrier.

[0044] According to one embodiment, the present invention provides a method for treating steroid receptors, particularly androgen receptors (ARs), dependence symptoms and diseases, comprising administering a therapeutically effective amount of a compound of formula (I) or (II) as defined in any of the above embodiments to a subject in need thereof.

[0045] According to one embodiment, steroid receptor-dependent diseases or conditions are androgen receptor-dependent diseases or conditions, including endocrine cancers and diseases such as prostate cancer or breast cancer, particularly castration-resistant prostate cancer (CRPC). According to one embodiment, the CRPC to be treated does not respond to CYP17A1 inhibitor treatment. According to another embodiment, the androgen receptor-dependent disease or condition is an endocrine cancer that progresses upon CYP11A1 activation.

[0046] The compounds of the present invention can be prepared using appropriate starting materials by a variety of synthetic routes similar to those known in the literature. Compounds of formula (I) or (II) can be prepared, for example, in or in accordance with the following reaction scheme. Some compounds included in formula (I) or (II) can be obtained by transforming the functional groups of other compounds of formula (I) or (II) obtained according to the following scheme by oxidation, reduction, hydrolysis, acylation, alkylation, amidation, amination, sulfonation, and other well-known reaction steps. It should be noted that any suitable leaving group, such as an N-protecting group such as a t-butoxycarbonyl (t-BOC) group or a phenylsulfonyl group, can be used in known ways during synthesis to improve the selectivity of the reaction steps.

[0047] The compound of formula (I) can be prepared by scheme 1. In scheme 1, R1, R2, R3, R4, R5, R 23 , R 24 , R 25 , R 27 L, A, and B are as defined above, and X is a halogen. In the method of Scheme 1, the compound of formula [1] is coupled with the compound of formula [2] in a suitable solvent such as CH3CN at an elevated temperature in the presence of a base such as DIPEA to produce the compound of formula (I). [ka]

[0048] Alternatively, the compound of formula (I) can be prepared by scheme 2. In scheme 2, R1, R2, R3, R4, R5, R 23 , R 24 , R 25 , R 27 L, A, and B are as defined above, and X is a halogen. In the method of Scheme 2, the compound of formula [3] is heated in a suitable solvent such as DMSO in the presence of a base such as K2CO3, and then NaSO2R 27It is combined with the compound of formula (I) to produce the compound of formula (I). [ka]

[0049] The compound of formula (I) can be prepared by scheme 3. In scheme 3, R1, R2, R3, R4, R5, R 23 , R 27 L, A, and B are as defined above. In the method of Scheme 3, the compound of formula [4] is combined with the compound of formula [2] by reductive amination in the presence of acetic acid in a suitable solvent such as DCM to produce the compound of formula (Ia). [ka]

[0050] The compound of formula (II) can be prepared by scheme 4. In scheme 4, R1, R2, R3, R4, R5, R 24 , R 25 , R 26 L, A, and B are as defined above, and X is a halogen. In the method of Scheme 4, the compound of formula [5] is coupled with the TFA or HCl salt of the compound of formula [6] in a suitable solvent such as CH3CN, in the presence of a base such as DIPEA, by heating to produce the compound of formula (II). [ka]

[0051] Alternatively, the compound of formula (II) can be prepared by scheme 5. In scheme 5, R1, R2, R3, R4, R5, R 24 , R 25 , R 26L, A, and B are as defined above, and Z is a mesyl or tosyl group. In the method of Scheme 5, the 5-hydroxy-4H-pyran-4-one derivative[7] is bonded to the ring B derivative[8] (with a mesylate or tosylate acting as a leaving group) by heating and in the presence of a base in a suitable solvent, for example in DMSO with Cs2CO3 or K2CO3, to produce the compound of formula (II). [ka]

[0052] Alternatively, the compound of formula (II) can be prepared by scheme 6. In scheme 6, R1, R2, R3, R4, R5, R 24 , R 25 , R 26 L, A, and B are as defined above, and Z is a mesyl or tosyl group. In the method of Scheme 6, compound [9] is heated and combined with ring A derivative

[10] (with a mesylate or tosylate acting as a leaving group) using Et3N in a suitable solvent, for example in THF, in the presence of a base, to produce the compound of formula (II). [ka]

[0053] The compound of formula (II) can be prepared by scheme 7. In scheme 7, R1, R2, R3, R4, R5, R 24 , R 25 , R 26 L, A, and B are as defined above, and X is a halogen. In the method of Scheme 7, the 5-hydroxy-4H-pyran-4-one derivative [7] is bonded with the ring B derivative

[11] (in which the halogen acts as a leaving group) in a suitable solvent, for example in DMF with K2CO3, by heating and in the presence of a base, to produce the compound of formula (II). [ka]

[0054] Alternatively, the compound of formula (II) can be prepared by scheme 8. In scheme 8, R1, R2, R3, R4, R5, R 24 , R 25 , R 26 L, A, and B are as defined above. In the method of Scheme 8, the 5-hydroxy-4H-pyran-4-one derivative [7] is bonded with the ring A derivative

[12] in a suitable solvent such as THF in the presence of triphenylphosphine and DIAD to produce the compound of formula (II). [ka]

[0055] Alternatively, the compounds of formula (I) or (II) can be manufactured as disclosed in the specific examples of this disclosure.

[0056] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly understood by those with ordinary skill in the art to which the subject matter herein pertains. The following definitions, used herein, are provided to facilitate understanding of the invention.

[0057] As used herein, the term "subject" means human and animal.

[0058] As used herein, the term "steroid receptor" refers to a receptor that binds to and is activated by steroid hormones. Examples of steroid receptors, but are not limited to, include androgen, glucocorticoid, and progesterone receptors.

[0059] As used herein, the term “endocrine cancer” means the partially or completely uncontrolled proliferation of one or more cellular components of the endocrine system, and includes, but is not limited to, cancers of one or more adrenal glands.

[0060] In this specification, the terms "halo" or "halogen" as used by themselves or as part of another group mean chlorine, bromine, fluorine, or iodine.

[0061] The term "C" as used in this specification, either by itself 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. 1-7 Typical examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, and n-hexyl. 1-7 One preferred embodiment of "alkyl" is C 1-3 It is alkyl. Term "C 1-3 "Alkyl" refers to a group of atoms that have one, two, or three carbon atoms. 1-7 This means a preferred embodiment of "alkyl".

[0062] The term "C" as used in this specification, either by itself 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. Typical examples include, but are not limited to, ethenyl, propenyl, and cyclohexenyl.

[0063] The term "C" as used in this specification, either by itself 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. Typical examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0064] The term "C" as used herein 3-7 Cycloalkyl C 1-7 "Alkyl" refers to the parent molecule as defined herein by C1-7 C as defined herein, which is added through an alkyl group. 3-7 This refers to a cycloalkyl group.

[0065] In this specification, the term "hydroxy" as used by itself or as part of another group means the -OH group.

[0066] In this specification, the term "cyano" as used by itself or as part of another group means the -CN group.

[0067] In this specification, the term "carboxyl" as used by itself or as part of another group means the -COOH group.

[0068] In this specification, the term "carbonyl," as used by itself or as part of another group, means a carbon atom (C=O) double-bonded to an oxygen atom.

[0069] In this specification, the term "oxo," as used by itself or as part of another group, refers to an oxygen atom (=O) bonded to another atom by a double bond.

[0070] The term "C" as used in this specification, either by itself or as part of another group. 1-7 "Alkoxy" is a C molecule as defined herein, which is added to the parent molecule via an oxygen atom. 1-7 It means alkyl. 1-7 Typical examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0071] The term "hydroxy C" as used herein 1-7 "Alkyl" refers to the parent molecule as defined herein by C 1-7 This means at least one hydroxyl group as defined herein, which is added through an alkyl group. 1-7Typical examples of alkyl 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.

[0072] The term "hydroxy C" as used herein 3-7 "Cycloalkyl" refers to a C molecule as defined herein in its parent molecule. 3-7 This means at least one hydroxyl group as defined herein, which is added via a cycloalkyl group. 1-7 Typical examples of alkyl groups include, but are not limited to, hydroxycyclopropyl, hydroxycyclobutyl, hydroxycyclopentyl, hydroxycyclohexyl, and 2,2-dihydroxycyclopropyl.

[0073] The term "halo C" as used herein 1-7 "Alkyl" refers to the parent molecule as defined herein by C 1-7 Halo C means at least one halogen as defined herein, which is added through an alkyl group. 1-7 Typical examples of alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, and 3-bromopropyl.

[0074] The term "cyanoC" as used herein 1-7 "Alkyl" refers to the parent molecule as defined herein by C 1-7 This refers to a cyano group added through an alkyl group. (Cyano C) 1-7 Typical examples of alkyl groups include, but are not limited to, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, and 2-cyanopropyl.

[0075] The term "halo C" as used herein 1-7"Alkoxy" is defined as C in the parent molecule portion. 1-7 This means at least one halogen as defined herein, which is added through an alkoxy group.

[0076] The term "phenyl C" as used herein 1-7 "Alkyl" refers to the parent molecule as defined herein by C 1-7 This means at least one phenyl group added through an alkyl group.

[0077] The term "C" as used in this specification, either by itself or as part of another group. 1-7 "Alkylcarbonyl" is a compound formed by adding a carbonyl group as defined herein to the parent molecule, as defined herein. 1-7 It means alkyl group.

[0078] The term "C" as used in this specification, either by itself or as part of another group. 1-7 Alkoxy C 1-7 "Alkyl" refers to the parent molecule as defined herein by C 1-7 At least one C as defined herein is added through an alkyl group. 1-7 It means an alkoxy group.

[0079] The term "hydroxy C" as used herein, either by itself or as part of another group. 1-7 "Alkoxy" is defined as C in the parent molecule portion. 1-7 This means at least one hydroxyl group as defined herein, which is added through an alkoxy group.

[0080] The term "hydroxy C" as used herein 1-7 Alkoxy C 1-7 "Alkyl" refers to the parent molecule as defined herein by C 1-7 Hydroxy C as defined herein, added via alkyl groups. 1-7 It means an alkoxy group.

[0081] As used herein, the term "4-10 membered heterocyclil" means a saturated ring, partially saturated ring, or aromatic ring having 4 to 10 ring atoms, wherein 1 to 4 of the atoms are heteroatoms selected from the group consisting of N, O, and S. One embodiment of "4-10 membered heterocyclil" is a "4-6 membered heterocyclil" which means a saturated ring, partially saturated ring, or aromatic ring having 4 to 6 ring atoms, wherein 1 to 4 of the atoms are heteroatoms selected from the group consisting of N, O, and S. Typical examples of "4-10 member heterocyclyls" include, but are not limited to, oxetanil, azetidinil, pyrazolyl, 1,2,4-triazol-1-yl, 1,2,3-triazol-1-yl, pyrimidinil, pyridinil, piperidinil, tetrazolyl, piperazinil, furanil, morpholinil, piperidinil, pyrrolidinil, thiazolyl, isoxazolyl, pyrazinyltetrahydropyranil, 1,2,4-oxadiazolyl, oxazolyl, imidazolyl, indolyl, and 4,5-dihydroimidazolyl rings.

[0082] As used herein, the term "3-10 membered carbocyclyl" refers to a saturated, partially saturated, or aromatic ring having 3 to 10 ring atoms consisting 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 to 6 ring atoms consisting solely of carbon atoms. Typical examples of 3-10 membered carbocyclyls include, but are not limited to, phenyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, and cyclobutyl rings.

[0083] As used herein, the term "4- to 12-membered monocyclic, bicyclic, or spiro-dicyclic ring" means a saturated, partially saturated, or aromatic monocyclic or bicyclic (fused, bridging, or spiro-structured) ring having 4 to 12 ring atoms.

[0084] As used herein, the term "spiro-bicyclic ring" refers to a bicyclic ring in which both rings are bonded together by the same carbon atoms.

[0085] As used herein, the term "4- to 12-membered bicyclic ring" means a saturated, partially saturated, or aromatic ring system in which two rings have two common ring atoms.

[0086] The term "4-10 member heterocyclyl C" as used herein 1-7 "Alkyl" refers to the parent molecule as defined herein by C 1-7 This refers to a "4- to 10-membered heterocycline" as defined herein, which is added via an alkyl group.

[0087] The term "3-10 membered carbocyclyl C" as used herein 1-7 "Alkyl" refers to the parent molecule as defined herein by C 1-7 This refers to a "3- to 10-membered carbocyclyl" as defined herein, which is added via an alkyl group.

[0088] As used herein in relation to various residues, the term "substituted" refers, unless otherwise specified, to halogen substituents such as fluorine, chlorine, bromine, iodine, or C 1-7 Alkyl, C 3-7 Cycloalkyl, hydroxy, amino, nitro, cyano, thiol C 1-7 Alkyl, methylsulfonyl, C 1-7 Alkoxy, Halo C 1-7 Alkyl, hydroxy C 1-7 Alkyl, or amino C 1-7 This refers to alkyl substituents. Preferred substituents are halogens and C 1-7 Alkyl, hydroxy, amino, halo C 1-7 Alkyl, C 1-7 These are alkoxy and methylsulfonyl substituents. One group of preferred substituents is C 1-7 One or two substituents selected from alkyl or halogen substituents, particularly C 1-3These are alkyl or halogen substituents, particularly methyl, ethyl, chloro, fluoro, and bromo substituents.

[0089] Unless otherwise specified, the "substituted" group may include 1 to 3, preferably 1 or 2, of the above substituents.

[0090] Optically active enantiomers or diastereomers of compounds of formula (I) or (II) can be prepared, for example, by the resolution of the final product of a racemic compound by known methods, or by using a suitable optically active starting material. Similarly, racemic compounds of formula (I) or (II) can be prepared using racemic starting materials. Resolution of racemic compounds of formula (I) or (II) or their racemic starting materials can be carried out, for example, by converting the racemic compound into a mixture of salts of its diastereomers by reaction with an optically active acid, and then separating the diastereomers by crystallization. Typical examples of such optically active acids include, but are not limited to, D-tartaric acid and dibenzoyl-D-tartaric acid. Alternatively, preparative chiral chromatography may be used to resolve the racemic mixture.

[0091] Pharmaceutically acceptable salts are well known in the field of pharmaceutical formulations. 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; and 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, sulfons, methanesulfons, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbicates, acetates, oxalates, fumarates, hemifumarates, and succinates. Pharmaceutically acceptable esters, where applicable, can be prepared by known methods using pharmaceutically acceptable acids commonly used in the field of medicine, and retain the pharmacological properties of their free forms. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl esters. Phosphate esters and carbonate esters are also within the scope of the present invention.

[0092] The definition of formula (I) above includes all possible isotopes and stereoisomers of the compound, including geometric isomers such as Z and E isomers (cis and trans isomers), optical isomers such as diastereomers and enantiomers, and all prodrug esters such as phosphate esters and carbonate esters.

[0093] It will be understood by those skilled in the art that the compounds of the present invention may have at least one chiral center. Therefore, the compounds may exist in an optically active form or a racemic mixture. It should be understood that formula (I) or (II) may include any racemic mixture or optically active form or mixture thereof. In one embodiment, the compound is a pure (R)-isomer. In another embodiment, the compound is a pure (S)-isomer. In yet another embodiment, the compound is a mixture of the (R)-isomer and the (S)-isomer. In yet another embodiment, the compound is a racemic mixture containing an equimolar mixture of the (R)-isomer and the (S)-isomer. The compounds may also have two chiral centers. In such cases, according to one embodiment, the compound is a mixture of diastereomers. According to another embodiment, the compounds of the present invention are a mixture of enantiomers. According to yet another embodiment, the compound is a pure enantiomer. Individual isomers may be obtained using the corresponding isomers of the starting materials, or they may be separated after the preparation of the final compound according to conventional separation methods. Conventional separation methods, such as fractional crystallization, may be used to separate optical isomers, such as enantiomers or diastereomers, from their mixture.

[0094] The compounds of the present invention may exist as tautomers or as equimolar mixtures thereof in which the proton of the compound shifts from one atom to another. Examples of tautomerism include, but are not limited to, amide-imide, keto-enol, phenol-keto, oxime-nitroso, nitro-ac, imine-enamine, and heterocyclic tautomerism. It is intended that tautomers should be encompassed within the compound of formula (I) or (II), even if only one tautomer is shown.

[0095] Examples of preferred compounds from one group of formula (I) or (II) include: 2-((5-(1,3,4-oxadiazol-2-yl)isoindorin-2-yl)methyl)-5-(((methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 1); 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((5-(oxazol-5-yl)isoindorin-2-yl)methyl)-4H-pyran-4-one (compound 2); 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((5-(oxazol-2-yl)isoindorin-2-yl)methyl)-4H-pyran-4-one (compound 3); 2-((5-(isoxazol-5-yl)isoindorin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 4); 2-((5-(isoxazol-3-yl)isoindorin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 5); 2-((5-(1,3,4-thiadiazol-2-yl)isoindorin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 6); 2-((5-(1H-pyrazol-1-yl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 7); 2-((5-(1,2,4-oxadiazol-3-yl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 8); 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((5-(2,2,2-trifluorohydroxyethyl)isoindorin-2-yl)methyl)-4H-pyran-4-one (compound 9); 2-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)-1,3,4-oxadiazole (compound 10); 3-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)isoxazole (compound 11); 5-Bromo-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 12a); 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)-5-(1H-pyrazol-1-yl)isoindoline (compound 12b); 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)oxazole (compound 13a); 2-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)oxazole (compound 13b); 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)thiazole (compound 14); 1-(2-(3-(methylsulfonyl)-4-((1(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)ethane-1-one (compound 15a); 3-(dimethylamino)-1-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)prop-2-en-1-one (compound 15b); 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)isoxazole (compound 15c); 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline-5-carbonitrile (compound 16a); N-hydroxy-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline-5-carboxyimidamide (compound 16b); 3-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)-1,2,4-oxadiazole (compound 16c); 2-(1-(5-bromoisoindoline-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 17a); 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-(1-(5-(oxazol-2-yl)isoindorin-2-yl)-ethyl)-4H-pyran-4-one (compound 17b); 2-(1-(5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)ethyl)isoindoline-5-carbonitrile (compound 18a); N-hydroxy-2-(1-(5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)ethyl)isoindoline-5-carboximidamide (compound 18b); 2-(1-(5-(1,2,4-oxadiazol-3-yl)isoindorin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 18c); 2-(1-(3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 19); 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-(2,2,2-trifluoro-1-(isoindorin-2-yl)ethyl)-4H-pyran-4-one (compound 20); 2-(2,2,2-trifluoro-1-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)ethyl)isoindoline (compound 21); 2-(2,2-difluoro-1-(3-(methylsulfonyl)-4-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)phenyl)ethyl)isoindoline (compound 22); 2-((5-(1,3,4-oxadiazol-2-yl)isoindorin-2-yl)methyl)-5-(piperidine-4-ylmethoxy)-4H-pyran-4-one (compound 23a); 2-((5-(1,3,4-oxadiazol-2-yl)isoindoline-2-yl)methyl)-5-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 23b); 2-((5-(1,3,4-oxadiazol-2-yl)-2H-isoindol-2-yl)methyl)-5-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 23c); 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((S*)-1-((1aR*,7bR*)-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinoline-2-yl)ethyl)-4H-pyran-4-one (compound 24a); 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((R*)-1-((1aR*,7bR*)-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinoline-2-yl)ethyl)-4H-pyran-4-one (compound 24b); 2-(3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 25); 2-(3-(cyclopropylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 26); 2-(3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)-5-(trifluoromethyl)isoindoline (compound 27); 2-(3-(butylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 28); 2-((1'H-Spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 29); tert-butyl 6-(((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-2-azaspiro[3.3]heptane-2-carboxylate (compound 30); tert-butyl 6-((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (compound 31); tert-butyl 2-((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)-7-azaspiro[3.5]nonane-7-carboxylate (compound 32); tert-butyl 2-((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)-6-azaspiro[3,4]octane-6-carboxylate (compound 33); tert-butyl 7-((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)-5-oxa-2-azaspiro[3,4]octane-2-carboxylate (compound 34); tert-butyl 2-(((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-7-azaspiro[3.5]nonane-7-carboxylate (compound 35); tert-butyl 6-(1-((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)ethyl)-2-azaspiro[3.3]heptane-2-carboxylate (compound 36); tert-butyl 2-(1-((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)ethyl)-7-azaspiro[3.5]nonane-7-carboxylate (compound 37); 5-((2-azaspiro[3,3]heptan-6-yl)oxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one bis-trifluoroacetate (compound 38); 5-((7-azaspiro[3,5]nonan-2-yl)oxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one (compound 39); 5-((7-azaspiro[3.5]nonan-2-yl)methoxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one (compound 40); 5-((6-azaspiro[3,4]octan-2-yl)oxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one (compound 41); 5-((2-azaspiro[3,3]heptan-6-yl)methoxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one (compound 42); 5-(1-(2-azaspiro[3,3]heptan-6-yl)ethoxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one (compound 43); 5-(1-(7-azaspiro[3.5]nonan-2-yl)ethoxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one (compound 44); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((2-(pyrimidine-2-yl)-2-azaspiro[3,3]heptan-6-yl)oxy)-4H-pyran-4-one (compound 45); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-(pyrimidine-2-yl)-7-azaspiro[3.5]nonane-2-yl)oxy)-4H-pyran-4-one (compound 46); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-(pyrimidine-2-ylmethyl)-7-azaspiro[3.5]nonane-2-yl)oxy)-4H-pyran-4-one (compound 47); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-(pyrimidine-2-yl)-7-azaspiro[3.5]nonane-2-yl)methoxy)-4H-pyran-4-one (compound 48); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((6-(pyrimidine-2-yl)-6-azaspiro[3,4]octan-2-yl)oxy)-4H-pyran-4-one (compound 49); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((2-(pyrimidine-2-yl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-4H-pyran-4-one (compound 50); 6-(6-(((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-2-azaspiro[3.3]heptan-2-yl)nicotinonitrile (compound 51); 6-(3-(((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)azetidine-1-yl)nicotinonitrile (compound 52); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)oxy)-4H-pyran-4-one (compound 53); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-(pyridine-3-ylsulfonyl)-7-azaspiro[3.5]nonane-2-yl)oxy)-4H-pyran-4-one (compound 54); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)oxy)-4H-pyran-4-one (compound 55); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((2-(pyridine-3-ylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)-4H-pyran-4-one (compound 56); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-4H-pyran-4-one (compound 57); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((2-((4-fluorophenyl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-4H-pyran-4-one (compound 58); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-(1-(2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)ethoxy)-4H-pyran-4-one (compound 59); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-(1-(2-(pyridine-3-ylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)ethoxy)-4H-pyran-4-one (compound 60); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-(1-(7-(methylsulfonyl)-7-azaspiro[3.5]nonan-2-yl)ethoxy)-4H-pyran-4-one (compound 61); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-4H-pyran-4-one (compound 62); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-(methylsulfonyl)-7-azaspiro[3.5]nonane-2-yl)oxy)-4H-pyran-4-o (compound 63); 2-(1-(5-acetylisoindoline-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 64); 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 65); 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 66); 1-((1r,4r)-4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)cyclohexyl)ethane-1-one (compound 67); 4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)-N,N-dimethylbenzamide (compound 68); 4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)-N-(2-methoxyethyl)-N-methylbenzamide (compound 69); 1-(4-((4-isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)piperidine-1-yl)propan-1-one (compound 70); Ethyl(imino)(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)-λ 6 -Sulfanone (compound 71); Imino(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)(methyl)-λ 6 -Sulfanone (compound 72); 1-(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)piperidine-1-yl)-2-methylpropan-1-one (compound 73); 4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)-N,N-dimethylcyclohexane-1-carboxamide (compound 74); 2-(3-(methylsulfonyl)-4-((1-(oxetane-3-ylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 75); 2-(4-((4-(ethylsulfonyl)benzyl)oxy)-3-(methylsulfonyl)benzyl)isoindoline (compound 76); 1-((4-((4-((isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)sulfonyl)azetidine-3-ol (compound 77); N-(dimethyl(oxo)-λ) 6 -Sulfanylidene)-4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)benzamide (compound 78); (1r,4r)-4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)-N,N-dimethylcyclohexane-1-carboxamide (compound 79); Azetidine-1-yl(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)cyclohexyl)methanone (compound 80); 2-(4-((3-fluoro-4-(methylsulfonyl)benzyl)oxy)-3-(methylsulfonyl)benzyl)isoindoline (compound 81); 2-(3-(methylsulfonyl)-4-((4-(methylsulfonyl)benzyl)oxy)benzyl)isoindoline (compound 82); 2-(3-(methylsulfonyl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzyl)isoindoline (compound 83); (4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)(methyl)-λ 4 -Sulfanimine (compound 84); Imino(methyl)(4-((2-(methylsulfonyl)-4-((5-(trifluoromethyl)isoindolin-2-yl)methyl)phenoxy)methyl)phenyl)-λ 6 -Sulfanone (compound 85); 2-(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)propan-2-ol (compound 86); 1-(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)piperidine-1-yl)ethane-1-one (compound 87); 2-((1'H-Spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-((1-Tosylpiperidine-4-yl)methoxy)-4H-pyran-4-one (compound 88); 2-((5-acetylisoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 89); (E)-2-((5-(1-(hydroxyimino)ethyl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 90); (E)-2-((5-(1-(methoxyimino)ethyl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 91); 1-(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)ethanone (compound 92a); 1-(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)ethanol (compound 92b); 2-((5-(1-hydroxyethyl)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 93); 1-(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)cyclohexyl)ethane-1-ol (compound 94); (R)-Imino(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)(methyl)-λ 6 -Sulfanone (compound 95); (S)-Imino(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)(methyl)-λ 6 -Sulfanone (compound 96); (S)-Ethyl(imino)(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)-λ 6 -Sulfanone (compound 97); (R)-Ethyl(imino)(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)-λ 6 -Sulfanone (compound 98); (R)-2-(1-(3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl)-5-((1(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 99); (S)-2-(1-(3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 100); 2-((6-(isoxazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 101); 2-((6-(1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 102); 2-((1'H-Spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 103); 2-((1'H-Spiro[cyclopentan-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-((4-(2-hydroxypropan-2-yl)benzyl)oxy)-4H-pyran-4-one (compound 104); 4-Fluoro-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 105); This also includes its tautomers and pharmaceutically acceptable salts.

[0096] The compounds of the present invention can be administered to a patient in a therapeutically effective amount typically ranging from about 0.5 to about 2000 mg per day, and usually from about 1 to about 1500 mg, depending on age, sex, weight, ethnicity, patient condition, symptoms to be treated, route of administration, and active ingredient used. The compounds of the present invention can be formulated into dosage forms using principles known in the art. The compounds can be administered to a patient as is or in combination with appropriate pharmaceutically acceptable excipients, in the form of tablets, granules, capsules, suppositories, emulsions, suspensions, or solutions. The selection of appropriate components for a composition is a routine task for those skilled in the art. Appropriate carriers, solvents, gel-forming components, dispersion-forming components, antioxidants, colorants, sweeteners, humectants, and other components commonly used in the art can also be used. Compositions containing the active compound can be administered enterally or parenterally, with the oral route being the most preferred route. The content of the active compound in the composition is about 0.5 to 100%, preferably about 0.5 to about 20%, based on the total weight of the composition.

[0097] The compounds of the present invention can be administered to a patient as a single active ingredient or in combination with one of other active ingredients for the treatment of a specific disease.

[0098] In the treatment of steroid receptor-dependent diseases or conditions such as endocrine cancers, prostate cancer, and breast cancer, combinations of therapeutic agents and / or other treatments (e.g., radiation therapy) are often beneficial. The second (or third) agent administered may have the same mechanism of action as the first therapeutic agent, or it may have a different mechanism of action.

[0099] Therefore, the compounds of the present invention can be administered in combination with other anticancer therapies useful in the treatment of cancers such as prostate cancer or breast cancer. For example, the compounds of the present invention can be packaged with instructions indicating that the compounds are to be used in combination with other anticancer agents and therapies for the treatment of cancer. The present invention further includes combinations of the compounds of the present invention with one or more further agents in the form of a kit, for example, in which they are packaged together or sold together as a kit even if they are in separate packaging or in which they are formulated and packaged together.

[0100] According to one embodiment of the present invention, a therapeutically effective amount of a compound of formula (I) or (II) is used in combination with a glucocorticoid and / or mineralocorticoid, and optionally one or more anticancer agents.

[0101] Suitable glucocorticoids include, but are not limited to, hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone. Suitable mineralocorticoids include, but are not limited to, fludrocortisone, deoxycorticosterone, 11-desoxycortisone, and deoxycorticosterone acetate.

[0102] Any other anticancer agents that can be administered in addition to the compound of formula (I) or (II) are, but are not limited to, - Nonsteroidal androgen receptor antagonists (e.g., esaltamide, apalutamide, and darolutamide); - Steroid synthesis inhibitors (e.g., CYP17A1 inhibitors such as abiraterone acetate and ceviteronel); - Chemotherapy agents (e.g., docetaxel and paciritaxel); - Anti-estrogens (e.g., tamoxifen and fulvestrant); - Epigenetic modulators (e.g., BET inhibitors and HDAC inhibitors); -mTOR inhibitors (e.g., everolimus); - AKT inhibitors (e.g., AZ5363); - Radiopharmaceuticals (e.g., alfalazine); -GnRH / LHRH analog (e.g., leuprorelin); -PI3K inhibitors (e.g., idelalisib); and - CDK4 / 6 inhibitors (e.g., ribociclib) These are some examples.

[0103] According to one embodiment of the present invention, a therapeutically effective amount of a compound of formula (I) or (II) is administered to a target that requires it. - Nonsteroidal androgen receptor antagonists (e.g., esaltamide, apalutamide, and darolutamide); - Steroid synthesis inhibitors (e.g., CYP17A1 inhibitors such as abiraterone acetate and ceviteronel); - Chemotherapy agents (e.g., docetaxel and paciritaxel); - Anti-estrogens (e.g., tamoxifen and fulvestrant); - Epigenetic modulators (e.g., BET inhibitors and HDAC inhibitors); -mTOR inhibitors (e.g., everolimus); - AKT inhibitors (e.g., AZ5363); - Radiopharmaceuticals (e.g., alfalazine); -GnRH / LHRH analog (e.g., leuprorelin); -PI3K inhibitors (e.g., idelalisib); and - CDK4 / 6 inhibitors (e.g., ribociclib) It is administered in addition to a therapeutically effective amount of one or more anticancer drugs selected from a list consisting of [the specified substances].

[0104] According to one embodiment of the present invention, a therapeutically effective amount of a compound of formula (I) or (II) is administered to a subject in need, in addition to a therapeutically effective amount of a steroid synthesis inhibitor (e.g., a CYP17A1 inhibitor). Suitable CYP17A1 inhibitors include, but are not limited to, abiraterone acetate and ceviteronel.

[0105] According to another embodiment of the present invention, a therapeutically effective amount of the compound of formula (I) or (II) is administered to a subject in need, in addition to a therapeutically effective amount of a nonsteroidal androgen receptor (AR) antagonist. Suitable nonsteroidal androgen receptor (AR) antagonists include, but are not limited to, ezaltamide, apalutamide, and darolutamide.

[0106] In another embodiment, the present invention relates to a compound of formula (I) or (II) and - Glucocorticoids, - Mineralocorticoids, - Steroid synthesis inhibitors (e.g., CYP17A1 inhibitors), - Nonsteroidal androgen receptor antagonist, - Chemotherapy agents (e.g., docetaxel and paciritaxel), - Anti-estrogens (e.g., tamoxifen and fulvestrant), - Epigenetic modulators (e.g., BET inhibitors and HDAC inhibitors), -mTOR inhibitors (e.g., everolimus); - AKT inhibitors (e.g., AZ5363); - Radiopharmaceuticals (e.g., alfalazine); -GnRH / LHRH analog (e.g., leuprorelin); -PI3K inhibitors (e.g., idelalisib); and - CDK4 / 6 inhibitors (e.g., ribociclib) The present invention provides a pharmaceutically acceptable combination for simultaneous, separate, or sequential administration, comprising at least one additional active ingredient selected from a list consisting of the following:

[0107] When used in combination with the compounds of the present invention, the other therapeutic agents mentioned above may be used, for example, in the amounts specified in Physicians' Desk Reference (PDR), or in amounts separately determined by those skilled in the art.

[0108] The compounds of the present invention can be produced by various synthetic routes similar to those known in the literature, using appropriate starting materials. The present invention is illustrated in more detail by the following experiments and examples. The experiments and examples are for illustrative purposes only and do not limit the scope of the present invention as defined in the claims. [Examples]

[0109] Intermediate 2a: 2-(isoindorin-5-yl)-1,3,4-oxadiazole trifluoroacetate [ka] a) tert-butyl 5-(hydrazinecarbonyl)isoindoline-2-carboxylate (3) To a 25 mL solution of 2-(tert-butyl)5-methyl isoindoline-2,5-dicarboxylate (3.50 g, 12.6 mmol, 1.0 equivalent) in EtOH, hydrazine hydrate (0.40 g, 0.40 mL, 12.6 mmol, 1.0 equivalent) was added at 25°C. The resulting mixture was heated at 80°C for 24 hours. After the reaction was complete, the solvent was evaporated under reduced pressure, and the crude product obtained was not further purified before proceeding to the next step. f (EtOAc / heptane:8 / 2)=0.2. Yield 4.5g (crude). MS (ESI) m / z [M+1] + : 278.09.

[0110] b) tert-butyl 5-(1,3,4-oxadiazol-2-yl)isoindoline-2-carboxylate (5) 4.5 g, 16.2 mmol, 1.0 equivalent of tert-butyl 5-(hydrazinecarbonyl)isoindoline-2-carboxylate and 50 mL of triethyl orthoformate were placed in a 100 mL sealed tube. The mixture was then heated at 120 °C for 16 hours. After the reaction was complete, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography using 0-50% ethyl acetate in heptane as the eluent. f (EtOAc / heptane:5 / 5)=0.3. Yield 0.6g, 13%. MS (ESI) m / z [M+1] + : 288.03. 1 H-NMR (400 MHz, DMSO-d6): δ 9.34 (s, 1H), 7.84-8.01 (m, 2H), 7.53-7.60 (m, 1H), 4.31-4.70 (m, 4H), 1.46 (s, 9H).

[0111] c) 2-(isoindolin-5-yl)-1,3,4-oxadiazole trifluoroacetate (2a) To a 10 mL LDCM solution of tert-butyl 5-(1,3,4-oxadiazolu-2-yl)isoindoline-2-carboxylate (0.24 g, 2.09 mmol, 1.0 equivalent), 2,2,2-trifluoroacetic acid (1.5 mL) was added at 0°C. The resulting mixture was then stirred at 0°C for 1 hour. After the reaction was complete, the solvent was evaporated under reduced pressure, and the crude product was proceeded to the next step without further purification. f (EtOAc / heptane:3 / 7)=0.2. Yield 0.6g (crude). MS (ESI) m / z [M+1] + :188,08. 1 H-NMR (400 MHz, DMSO-d6): δ 9.55 (bs, 2H), 9.43 (s, 1H), 8.13 (s, 1H), 8.03 (d, 1H), 7.64 (d, 1H), 4.62 (s, 4H).

[0112] Intermediates 2b and 2c: 5-(isoindolin-5-yl)oxazole hydrochloride (2b) and 2-(isoindolin-5-yl)oxazole hydrochloride (2c) [ka] a) tert-butyl 5-(oxazol-5-yl)isoindoline-2-carboxylate (4a) and tert-butyl 5-(oxazol-2-yl)isoindoline-2-carboxylate (4b) To a 20 mL solution of tert-butyl 5-bromoisoindoline-2-carboxylate (2.0 g, 6.73 mmol, 1.0 equivalent) in DMA, oxazole (1.85 g, 26.9 mmol, 4 equivalents), cesium carbonate (5.47 g, 16.8 mmol, 2.5 equivalents), and pivalic acid (0.28 g, 2.69 mmol, 0.4 equivalents) were added at 25°C. This mixture was degassed with argon for 15 minutes. Then, palladium(II) acetate (0.83 g, 0.34 mmol, 0.05 equivalents) and di(1-adamantyl)-N-butylphosphine (0.12 g, 0.34 mmol, 0.05 equivalents) were added to the reaction mixture, and the resulting reaction mixture was heated at 110°C for 16 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with SiO2 (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography using 0-20% siRNA in heptane as the eluent. Two corresponding positional isomers were obtained. f (SiO / Heptane:3 / 7) = 0.2. Yields: 0.42g, 22% and 0.72g, 37%. MS(ESI) m / z [M+1] + : 287.01. Intermediate (4a): 1 H-NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 7.63-7.90 (m, 3H), 7.35-7.47 (m, 1H), 4.57-4.65 (m, 4H), 1.53 (s, 9H). Intermediate (4b):1 H-NMR (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 7.89-7.94 (m, 2H), 7.46-7.49 (m, 1H), 7.38 (s, 1H), 4.60-4.68 (m, 4H), 1.46 (s, 9H).

[0113] b) 5-(isoindoline-5-yl)oxazole hydrochloride (2b) The product described in the title was obtained as a white solid by treating tert-butyl 5-(oxazol-5-yl)isoindoline-2-carboxylate (0.25 g, 0.87 mmol, 1.0 equivalent) with HCl (12.0 mL, 1.0 M solution) in  (30 mL) and MeOH (2 mL) for 12 hours. Yield 0.20 g (crude). MS(ESI) m / z [M+1] + :187.08. 1 H-NMR (400 MHz, DMSO-d6): δ 9.80 (bs, 2H), 8.48 (s, 1H), 7.75-7.77 (m, 1H), 7.73 (s, 1H), 7.51 (d, 1H), 4.53-4.62 (m, 4H).

[0114] c) 2-(isoindolin-5-yl)oxazole hydrochloride (2c) The product described in the title was obtained as a white solid by treating tert-butyl 5-(oxazol-2-yl)isoindoline-2-carboxylate (0.25 g, 0.87 mmol, 1.0 equivalent) with HCl (12.0 mL, 1.0 M solution) in SiO (30 mL) and MeOH (2 mL) for 12 hours. Yield 0.20 g (crude). MS (ESI) m / z [M+1] + :187.08. 1 H-NMR (400 MHz, / DMSO-d6): δ 10.01 (s, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.97 (d, 1H), 7.56 (d, 1H), 7.40 (s, 1H), 4.50-4.59 (m, 4H).

[0115] Intermediate 2d: 5-(isoindoline-5-yl)isoxazole hydrochloride [ka] a) tert-butyl (E)-5-(3-(dimethylamino)acryloyl)isoindoline-2-carboxylate(3) To a 12 mL solution of tert-butyl 5-acetylisoindoline-2-carboxylate (0.9 g, 3.40 mmol, 1.0 equivalent) in DMF, 40 mL of DMF-DMA was added at 25°C. The resulting mixture was stirred at 90°C for 16 hours. After the reaction was complete, the solvent was evaporated under reduced pressure, and the crude product was proceeded to the next step without purification. f (MeOH / DCM:0.5 / 9.5)=0.3. Yield 0.89g (crude). MS (ESI) m / z [M+1] + :317.20.

[0116] b) tert-butyl 5-(isoxazol-5-yl)isoindoline-2-carboxylate (4) A mixture of tert-butyl (E)-5-(3-(dimethylamino)acryloyl)isoindoline-2-carboxylate (0.85 g, 2.68 mmol, 1.0 equivalent) and hydroxylamine hydrochloride (0.22 g, 3.22 mmol, 1.2 equivalents) in 40 mL of EtOH was refluxed for 16 hours. After the reaction was complete, the solvent was evaporated under reduced pressure, and the resulting crude product was not further purified before proceeding to the next step. f (MeOH / DCM:0.5 / 9.5)=0.5. Yield 0.55g (crude). MS (ESI) m / z [M-1] + : 285.01. 1 H-NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.85 (d, 1H), 7.81 (d, 1H), 7.48-7.53 (m, 1H), 7.01 (d, 1H), 4.60-4.68 (m, 4H), 1.36 (s, 9H).

[0117] c) 5-(isoindolin-5-yl)isoxazole hydrochloride (2d) The product described in the title was obtained as a white solid by treating tert-butyl 5-(oxazol-5-yl)isoindoline-2-carboxylate (0.35 g, 1.22 mmol, 1.0 equivalent) in HCl in siRNA (20.0 mL, 1.0 M solution) in MeOH (2 mL) for 12 hours. f (EtOAc / heptane:8 / 2)=0.2. Yield 0.27g (crude). MS (ESI) m / z [M+1] + :187.03. 1 H-NMR (400 MHz, DMSO-d6): δ 9.87 (bs, 1H), 8.68 (s, 1H), 7.93-7.98 (m, 1H), 7.82-7.90 (m, 1H), 7.57 (d, 1H), 7.06 (s, 1H), 4.57 (s, 4H).

[0118] Intermediate 2e:3-(isoindorin-5-yl)isoxazole trifluoroacetate [ka] a) tert-butyl 5-formylisoindoline-2-carboxylate (3) To a solution of tert-butyl 5-(hydroxymethyl)isoindoline-2-carboxylate (1.00 g, 4.01 mmol, 1.0 equivalent) in a DCM:DMSO (5:1, 24 mL) mixture, Et3N (2.86 g, 3.9 mL, 28.1 mmol, 7.0 equivalents) and sulfur trioxide pyridine (3.18 g, 20.0 mmol, 5.0 equivalents) were added at 0°C. The resulting mixture was stirred at 25°C for 12 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by combiflash chromatography using ethyl acetate in heptane at a concentration of 0-30% as the eluent. f (EtOAc / heptane:5 / 5)=0.4. Yield 0.96g, 96%. MS (ESI) m / z [M+1]+ : 248.10. 1 H-NMR (400 MHz, DMSO-d6): δ 10.0 (s, 1H), 7.84-7.87 (m, 2H), 7.54-7.58 (m, 1H), 4.63-4.68 (m, 4H), 1.46 (s, 9H).

[0119] b) tert-butyl (E)-5-((hydroxyimino)methyl)isoindoline-2-carboxylate(4) To a solution of tert-butyl 5-formylisoindoline-2-carboxylate (0.96 g, 3.87 mmol, 1.00 equivalent) in EtOH (90 mL), Et3N (0.60 g, 0.82 mL, 5.80 mmol, 1.5 equivalent) and hydroxylamine hydrochloride (0.41 g, 5.80 mmol, 1.5 equivalent) were added at 25°C. The resulting mixture was stirred at 90°C for 16 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was proceeded to the next step without further purification. f (SiO / Heptane: 3 / 7) = 0.4. Yield 0.96g (crude). MS (ESI) [M+1] + : 263.04. 1 H-NMR (400 MHz, DMSO-d6): δ 11.21 (s, 1H), 8.13 (s, 1H), 7.48-7.55 (m, 2H), 7.33-7.36 (m, 1H), 4.54-4.61 (m, 4H), 1.45 (s, 9H).

[0120] c) tert-butyl (Z)-5-(chloro(hydroxyimino)methyl)isoindoline-2-carboxylate(5) To a solution of tert-butyl (E)-5-((hydroxyimino)methyl)isoindoline-2-carboxylate (0.96 g, 3.66 mmol, 1.00 equivalent) in 60 mL of DMF, N-chlorosuccinimide (0.49 g, 3.66 mmol, 1.0 equivalent) was added at 0°C. The resulting mixture was stirred at 25°C for 16 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was proceeded to the next step without purification. f (ԅ / heptane:5 / 5) = 0.4. Yield 1.10 g (crude). MS (ESI) did not ionize. 1 H-NMR (400 MHz, DMSO-d6): δ 12.37 (s, 1H), 7.70-7.75 (m, 2H), 7.40-7.43 (m, 1H), 4.62 (s, 4H), 1.46 (s, 9H).

[0121] d) tert-butyl 5-(5-(trimethylsilyl)isoxazol-3-yl)isoindoline-2-carboxylate(6) To a solution of tert-butyl (Z)-5-(chloro(hydroxyimino)methyl)isoindoline-2-carboxylate (1.10 g, 3.7 mmol, 1.00 equivalent) in 20 mL of DCM, triethylamine (1.48 g, 2.01 mL, 13.0 mmol, 3.5 equivalents) and trimethylsilylacetylene (1.20 g, 1.6 mL, 11.1 mmol, 3.0 equivalents) were added at 0°C. The resulting mixture was stirred at 25°C for 16 hours. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. This crude product was purified by combiflash chromatography using ethyl acetate in heptane at a concentration of 0-30% as the eluent. f (EtOAc / heptane:3 / 7)=0.4. Yield 1.2g, 90%. MS (ESI) m / z [M+1] + : 359.11. 1H-NMR (400 MHz, CDCl3): δ 7.69-7.80 (m, 2H), 7.31-7.41 (m, 1H), 6.71-6.79 (m, 1H), 4.60-4.81 (m, 4H), 1.53 (s, 9H), 0.38 (s, 9H).

[0122] e) tert-butyl 5-(isoxazol-3-yl)isoindoline-2-carboxylate (7) To a solution of tert-butyl 5-(5-(trimethylsilyl)isoxazol-3-yl)isoindoline-2-carboxylate (1.20 g, 3.3 mmol, 1.00 equivalent) in 25 mL of MeOH, potassium carbonate (0.60 g, 5.0 mmol, 1.5 equivalent) was added at 25°C. The resulting mixture was stirred at 60°C for 2 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was proceeded to the next step without further purification. f (EtOAc / heptane:5 / 5)=0.4. Yield 1.1g (crude). MS (ESI) m / z [M+1-56] + : 231.04. 1 H-NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 7.70-7.75 (m, 2H), 7.34 (dd, 1H), 6.61-6.69 (m, 1H), 4.61-4.82 (m, 4H), 1.45 (s, 9H).

[0123] f) 3-(isoindolin-5-yl)isoxazole trifluoroacetate (2e) The product described in the title was obtained as a black, rubbery mass by treating tert-butyl 5-(isoxazol-3-yl)isoindoline-2-carboxylate (0.3 g, 1.05 mmol) with trifluoroacetic acid (2.0 mL) in DCM (20 mL). f (MeOH / DCM:0.5 / 9.5)=0.3. Yield 0.3g (crude). MS (ESI) m / z [M+1]+:187.05. 1H-NMR (400 MHz, CDCl3): δ 9.10 (bs, 2H), 8.52 (d, 1H), 7.83 (d, 1H), 7.81 (s, 1H), 7.48 (d, 1H), 6.71 (d, 1H), 4.78 (s, 4H).

[0124] Intermediate 2f: 2-(isoindorin-5-yl)-1,3,4-thiadiazole hydrochloride [ka] a) tert-butyl 5-(1,3,4-thiadiazol-2-yl)isoindoline-2-carboxylate (4) To a solution of 2-bromo-1,3,4-thiadiazole (0.50 g, 3.05 mmol, 1.00 equivalent) in a mixture of dioxane and water (2:1, 15 mL), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate (1.88 g, 5.49 mmol, 1.8 equivalent) and cesium carbonate (1.97 g, 6.10 mmol, 2.0 equivalent) were added at 25°C. The mixture was then degassed with argon for 15 minutes. Subsequently, tetrakis(triphenylphosphine)palladium(0) (0.35 g, 0.30 mmol, 0.1 equivalent) was added, and the resulting reaction mixture was heated at 80°C for 16 hours. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography using 0-20% ethyl acetate in heptane as the eluent. f (EtOAc / heptane:3 / 7)=0.4. Yield 0.43g, 91%. MS(ESI) m / z [M+1] + : 304.05.

[0125] b) 2-(isoindolin-5-yl)-1,3,4-thiadiazole hydrochloride (2f) The product described in the title was obtained as a white solid by treatment of tert-butyl 5-(1,3,4-thiadiazol-2-yl)isoindoline-2-carboxylate (0.40 g, 1.32 mmol) in HCl (10.0 mL, 1.0 M solution) in HCl (10 mL). Yield: 0.24 g (crude). MS(ESI) m / z [M+1] + : 203.97. 1 H NMR (DMSO-d6) δ: 9.66 (s, 1H), 9.63 (bs, 1H), 8.10 (s, 1H), 8.02 (d, 1H), 7.59 (d, 1H), 4.56-4.60 (m, 4H).

[0126] Intermediate 2g: 5-(1H-pyrazol-1-yl)isoindoline trifluoroacetate [ka] a) tert-butyl 5-(1H-pyrazol-1-yl)isoindoline-2-carboxylate (4) To a solution of tert-butyl 5-bromoisoindoline-2-carboxylate (2.0 g, 6.73 mmol, 1.00 equivalent) in 20 mL of DMA, 1H-pyrazole (0.91 g, 13.4 mmol, 2.0 equivalent) and potassium carbonate (2.7 g, 20.2 mmol, 3.0 equivalent) were added at 25°C. The mixture was then degassed with argon for 15 minutes. Subsequently, DMEDA (0.29 g, 3.36 mmol, 0.5 equivalent) and CuI (0.63 g, 3.3 mmol, 0.5 equivalent) were added, and the resulting reaction mixture was heated at 150°C for 16 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with siRNA (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This crude product was purified by combiflash chromatography using 0-20% ethyl acetate in heptane as the eluent. f (EtOAc / heptane:3 / 7)=0.6. Yield 0.5g, 26%. MS (ESI) m / z [M+1] + : 286.14. 1H-NMR (400 MHz, DMSO-d6): δ 8.46 (d, 1H), 7.72-7.82 (m, 3H), 7.41-7.46 (m, 1H), 6.54 (s, 1H), 4.56-4.66 (m, 4H), 1.46 (s, 9H).

[0127] b) 5-(1H-pyrazol-1-yl)isoindoline trifluoroacetate (2g) The product described in the title was obtained by treating tert-butyl 5-(1H-pyrazol-1-yl)isoindoline-2-carboxylate (0.4 g, 1.40 mmol, 1.0 equivalent) in DCM (20 mL) with trifluoroacetic acid (2 mL) at 25°C for 16 hours. f (MeOH / DCM:0.5 / 9.5)=0.5. Yield 0.35g (crude). MS (ESI) m / z [M+1] + :186.02. 1 H-NMR (400 MHz, DMSO-d6): δ 9.50-9.80 (bs, 2H), 8.50 (s, 1H), 7.90 (s, 1H), 7.84 (d, 1H), 7.76 (s, 1H), 7.51 (d, 1H), 6.56 (s, 1H), 4.50-4.60 (m, 4H).

[0128] Intermediate 2h: 3-(isoindorin-5-yl)-1,2,4-oxadiazole trifluoroacetate [ka] a) tert-butyl 5-(N-hydroxycarbamimidoyl)isoindoline-2-carboxylate (3) In a 100 mL sealed tube, tert-butyl 5-cyanoisoindoline-2-carboxylate (1.3 g, 5.32 mmol, 1.00 equivalent) was dissolved in 30 mL of EtOH under a nitrogen atmosphere. Then, Et3N (4.5 g, 6.1 mL, 42.6 mmol, 8.0 equivalent) and NH2OH.HCl (1.1 g, 15.9 mmol, 3.0 equivalent) were added, and the mixture was stirred at 90°C for 12 hours. After the reaction was complete, the reaction mixture was filtered, the resulting solid was pulverized with EtOH, and dried under vacuum to obtain the product described in the title. f (EtOAc / heptane:3 / 7)=0.6. Yield 1.4g (crude). MS (ESI) m / z [M+1] + : 278.13. 1 H-NMR (400 MHz, DMSO-d6): δ 9.61 (s, 1H), 7.55-7.65 (m, 2H), 7.25-7.38 (m, 1H), 5.72-5.89 (m, 2H), 4.51-4.61 (m, 4H), 1.45 (s, 9H).

[0129] b) tert-butyl 5-(1,2,4-oxadiazol-3-yl)isoindoline-2-carboxylate (4) In a 100 mL sealed tube, tert-butyl 5-(N-hydroxycarbamimidoyl)isoindoline-2-carboxylate (0.85 g, 3.06 mmol, 1.00 equivalent) was dissolved in 15 mL of triethyl orthoformate under a nitrogen atmosphere. Then, TFA (0.2 mL) was added, and the mixture was stirred at 70°C for 12 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This crude product was proceeded to the next step without further purification. f (EtOAc / heptane:3 / 7)=0.5. Yield 0.88g (crude). MS (ESI) m / z [M+1-100] + : 188.04. 1H-NMR (400 MHz, DMSO-d6): δ 9.71 (s, 1H), 8.00 (d, 1H), 7.96 (d, 1H), 7.49-7.55 (m, 1H), 4.62-4.70 (m, 4H), 1.47 (s, 9H).

[0130] c) 3-(isoindolin-5-yl)-1,2,4-oxadiazole trifluoroacetate (2h) The product described in the title was obtained as a black, viscous liquid by treating tert-butyl 5-(1,2,4-oxadiazol-3-yl)isoindoline-2-carboxylate (0.4 g, 1.39 mmol, 1.0 equivalent) with trifluoroacetic acid (2 mL) in DCM (12 mL) at 25 °C for 2 hours. f (MeOH / DCM:0.5 / 9.5)=0.3. Yield 0.41g (crude). MS (ESI) m / z [M+1] + :188.04. 1 H-NMR (400 MHz, DMSO-d6): δ 9.75 (s, 1H), 9.58 (bs, 2H), 8.10 (s, 1H), 8.05 (d, 1H), 7.62 (d, 1H), 4.58-4.63 (m, 4H).

[0131] Intermediate 2i: 2,2,2-trifluoro-1-(isoindorin-5-yl)ethane-1-ol hydrochloride a) tert-butyl 5-(2,2,2-trifluoro-1-hydroxyethyl)isoindoline-2-carboxylate (3) To a solution of tert-butyl 5-formylisoindoline-2-carboxylate (2.5 g, 10.1 mmol, 1.0 equivalent) in 10 mL of DMF, trimethyl(trifluoromethyl)silane (3.5 g, 25.3 mmol, 2.5 equivalents) and potassium carbonate (1.39 g, 10.1 mmol, 1.0 equivalent) were added at 0°C. The mixture was stirred at 0°C for 0.5 hours. After 0.5 hours, the starting material was consumed and nonpolar spots were observed by TLC. The mixture was quenched with ice-cold water and extracted with  (3 times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude residue was dissolved in 10 mL of MeOH, K2CO3 (0.7 g, 5.06 mmol, 0.5 equivalents) was added, and the mixture was stirred at 50°C for 0.25 hours. After the reaction was complete, the reaction mixture was quenched with ice-cold water and extracted with RINKAN (three times). The combined organic layers were washed and dried as described above, and concentrated under reduced pressure to obtain the crude product. This crude residue was purified by combiflash chromatography using 0-50% ethyl acetate in heptane as the eluent. f (EtOAc / heptane:8 / 2)=0.6. Yield 1.5g, 47%. MS (ESI) m / z [M+1]+: 318.13. 1 H-NMR (400 MHz, DMSO-d6) δ: 7.31-7.47 (m, 3H), 6.90 (d, 1H), 5.12-5.24 (m, 1H), 4.39-4.80 (m, 4H), 1.52 (s, 9H).

[0132] b) 2,2,2-trifluoro-1-(isoindoline-5-yl)ethane-1-ol hydrochloride (2i) The product described in the title was obtained as a white solid by treating tert-butyl 5-(2,2,2-trifluoro-1-hydroxyethyl)isoindoline-2-carboxylate (0.40 g, 1.26 mmol, 1.0 equivalent) in HCl (10.0 mL, 1.0 M solution) in siRNA (10.0 mL) for 12 hours. f (MeOH / DCM:0.5 / 9.5)=0.3. Yield 0.25g (crude). MS (ESI) m / z [M+1] + : 218.04.1 H-NMR (400 MHz, DMSO-d6): δ 9.88 (bs, 2H), 7.53 (s, 1H), 7.41-7.47 (m, 2H), 6.96 (d, 1H), 5.16-5.27 (m, 1H), 4.50 (s, 4H).

[0133] Intermediate 3: tert-butyl 6-(1-hydroxyethyl)-2-azaspiro[3.3]heptane-2-carboxylate [ka] a) tert-butyl 6-(methoxy(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a cooled (0-5°C) mixture of 2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (0.241 g, 1.0 mmol), N,O-dimethylhydroxylamine hydrochloride (0.122 g, 1.25 mmol), and triethylamine (0.80 ml, 5.74 mmol) in dry DMF (2.0 ml), 1-propanephosphonic acid cyclic anhydride (50% in HCl, 0.80 ml, 1.358 mmol) was added. The mixture was stirred overnight at RT, then diluted with water and extracted with HCl. The organic phase was washed with saturated NaHCO3 solution, water, and brine, then dried and evaporated to obtain the title compound. Yield 0.23 g. 1 H NMR (400 MHz, CDCl3): δ 3.96 (s, 2H), 3.85 (s, 2H), 3.65 (s, 2H), 3.26-3.43 (m, 1H), 3.17 (s, 3H), 2.41-2.52 (m, 2H), 2.28-2.38 (m, 2H), 1.43 (s, 9H).

[0134] b) tert-butyl 6-acetyl-2-azaspiro[3.3]heptan-2-carboxylate [ka] To a cooled (0-5°C) solution of tert-butyl 6-(methoxy(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (0.23 g, 0.809 mmol) in dry THF (3.0 ml), methylmagnesium bromide (3 M in ethanol, 0.40 ml, 1.20 mmol) was added. The mixture was stirred at 0-5°C for 1 hour, then stirred overnight at RT. The reaction was quenched by adding saturated NH4Cl solution and water, and then extracted with DCM. The organic phase was dried and evaporated to obtain the title compound. Yield 0.19 g. 1 H NMR (400 MHz, CDCl3): δ 3.94 (s, 2H), 3.81 (s, 2H), 3.12 (quint, 1H), 2.27-2.42 (m, 4H), 2.09 (s, 3H), 1.43 (s, 9H).

[0135] c) tert-butyl 6-(1-hydroxyethyl)-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 6-acetyl-2-azaspiro[3.3]heptane-2-carboxylate (0.19 g, 0.794 mmol) in dry methanol (3.0 ml), sodium borohydride (0.045 g, 1.191 mmol) was added in small increments. The mixture was stirred at RT until the reaction was complete. Methanol was evaporated, water and ethyl acetate were added, and the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried, and evaporated to obtain the title compound. Yield 0.19 g. 1 H NMR (400 MHz, CDCl3): δ 3.92 (s, 2H), 3.76-3.84 (m, 2H), 3.60-3.69 (m, 1H), 2.06-2.25 (m, 3H), 1.98-2.05 (m, 1H), 1.86-1.94 (m, 1H), 1.43 (s, 9H), 1.32 (d, 1H), 1.09 (d, 3H).

[0136] The following intermediates were prepared from the starting materials shown in the table, according to the method described in Example 10(a).

[0137] TIFF2026048803000036.tif245162 TIFF2026048803000037.tif37162

[0138] In the following synthesis examples, the reference material is prepared according to preparative HPLC method A, B, or C.

[0139] Preparative HPLC: Method A: Instrument: Agilent Technologies 1260 Infinity Column: SUNFIRE C-18, 10 microns, 19 × 250 mm; Gradient [Time (min) / Solvent B in A (%)]: 0.01 / 10, 3.00 / 10, 13.00 / 35; Solvent: Solvent A = 0.1% TFA in water; Solvent B = Acetonitrile, detection wavelength 214 nm; Flow rate 20 mL / min.

[0140] Method B: Instrument: Agilent Technologies 1260 Infinity Column: X Select Hexyl Phenyl, 5 micron, 19 × 250 mm; Gradient [Time (min) / Solvent B in A (%)]: 0.01 / 15, 3.00 / 15, 12.00 / 35, 16.00 / 35; Solvent: Solvent A = 0.1% TFA in water; Solvent B = Acetonitrile, detection wavelength 214 nm; Flow rate 15 mL / min.

[0141] Method C: Instrument: Agilent Technologies 1260 Infinity column: X cross-linked shield, 10 micron, 19 × 250 mm; gradient [time (min) / solvent B in A (%)]: 0.01 / 45, 3.00 / 45, 13.00 / 65, 14.00 / 65; solvent: solvent A = 5 mM ammonium acetate in water; solvent B = acetonitrile, detection wavelength 214 nm; flow rate 18 mL / min.

[0142] Example 1 2-((5-(1,3,4-oxadiazol-2-yl)isoindoline-2-yl)methyl)-5-(((methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 1) [ka] To a solution of 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (0.29 g, 0.86 mmol, 1.0 equivalent) in CH3CN (30 mL), DIPEA (0.55 g, 4.3 mmol, 5.0 equivalent) and 2-(isoindorin-5-yl)-1,3,4-oxadiazole trifluoroacetate (0.25 g, 0.86 mmol, 1.0 equivalent) were added. The resulting mixture was stirred at 90°C for 16 hours. After the reaction was complete as shown by TLC, the mixture was quenched with ice-cold water and extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by preparative HPLC to obtain the pure product as a white solid. f (MeOH / DCM: 0.5 / 9.5) = 0.3. Yield: 0.070g. 1 H NMR (400 MHz, DMSO-d6) δ: 9.33 (s, 1H), 8.16 (s, 1H), 7.92 (s, 1H), 7.89 (d, 1H), 7.48 (d, 1H), 6.41 (s, 1H), 4.04 (s, 4H), 3.82 MS (ESI) m / z [M+1] + : 487.4.

[0143] Example 2 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((5-oxazol-5-yl)isoindorin-2-yl)methyl)-4H-pyran-4-one (compound 2) [ka] Following the procedure of Example 1, 2-(isoindolin-5-yl)oxazole hydrochloride (0.2 g, 0.90 mmol, 1.0 equivalent) was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (0.30 g, 0.90 mmol, 1.0 equivalent) and DIPEA (0.46 g, 3.60 mmol, 4.0 equivalents) in CH3CN (10 mL) at 70°C for 15 hours. The product was then purified by preparative HPLC using Method A (rt: 12.03 min) to obtain the title product as the TFA salt. f (MeOH / DCM: 0.5 / 9.5) = 0.6. Yield: 0.021g. 1 H NMR (400 MHz, DMSO-d6) δ: 8.46 (s, 1H), 8.21 (s, 1H), 7.70-7.71 (m, 3H), 7.45 (d, 1H), 6.57 (s, 1H), 4.42-4.53 (m, 6H), 3.73 (d, MS (ESI) m / z (M+1) + 486.3.

[0144] Example 3 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((5-oxazol-2-yl)isoindorin-2-yl)methyl)-4H-pyran-4-one (compound 3) [ka] Following the procedure of Example 1, 2-(isoindolin-5-yl)oxazole hydrochloride (0.2 g, 0.90 mmol, 1.0 equivalent) was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (0.30 g, 0.90 mmol, 1.0 equivalent) and DIPEA (0.46 g, 3.60 mmol, 4.0 equivalents) in CH3CN (10 mL) at 70°C for 16 hours. The product was then purified by preparative HPLC using Method A (rt: 12.46 min) to obtain the title product as the TFA salt. f (MeOH / DCM: 0.5 / 9.5) = 0.6. Yield: 0.011g. 1 H NMR (400 MHz, DMSO-d6) δ: 8.22 (d, 2H), 7.93-7.97 (m, 2H), 7.50 (d, 1H), 7.40 (s, 1H), 6.49-6.58 (m, 1H), 4.42-4.85 (m, 6H), 3.73 (d, 2H), 3.59 (d, 2H), 2.86 (s, 3H), 2.72 (t, 2H), 1.83-1.86 (m, 3H), 1.25-1.34 (m, 2H). MS (ESI) m / z [M+1] + : 486.3.

[0145] Example 4 2-((5-(isoxazol-5-yl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 4) [ka] Following the procedure of Example 1, 5-(isoindolin-5-yl)isoxazole hydrochloride (0.27 g, 1.22 mmol, 1.0 equivalent) was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (0.41 g, 1.22 mmol, 1.0 equivalent) and DIPEA (0.79 g, 1.1 mL, 6.10 mmol, 5.0 equivalent) in CH3CN (15 mL) at 80°C for 16 hours. The product was then purified by preparative HPLC using Method A to obtain the title product as a brown solid. f (MeOH / DCM: 0.5 / 9.5) = 0.2. Yield: 0.048g. 1 H NMR (400 MHz, DMSO-d6) δ: 8.67 (d, 1H), 8.21 (s, 1H), 7.84-7.87 (m, 2H), 7.51 (d, 1H), 7.03 (s, 1H), 6.56 (s, 1H), 4.30-4.48 (m, MS (ESI) m / z [M+1] + : 486.3.

[0146] Example 5 2-((5-(isoxazol-3-yl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 5) [ka] Following the procedure of Example 1, 3-(isoindolin-5-yl)isoxazole trifluoroacetate (0.3 g, 1.06 mmol, 1.0 equivalent) was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (0.35 g, 1.06 mmol, 1.0 equivalent) and DIPEA (0.68 g, 0.98 mL, 5.30 mmol, 5.0 equivalent) in CH3CN (20 mL) at 80°C for 16 hours. The product was then purified by preparative HPLC using Method A (rt: 11.78 min) to obtain the title product as the TFA salt. f (MeOH / DCM: 0.5 / 9.5) = 0.3. Yield: 0.019g. 1 H NMR (400 MHz, DMSO-d6) δ: 9.02 (s,1H), 8.21 (s,1H), 7.80-7.90 (m, 2H), 7.45-7.55 (m, 1H), 7.14 (d, 1H), 6.49-6.60 (m, 1H), MS (ESI) m / z [M+1] + : 486.2.

[0147] Example 6 2-((5-(1,3,4-thiadiazol-2-yl)isoindorin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 6) [ka] Following the procedure of Example 1, 2-(isoindolin-5-yl)-1,3,4-thiadiazole hydrochloride (0.20 g, 0.83 mmol) was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (0.28 g, 0.83 mmol, 1.0 equivalent) and DIPEA (0.54 g, 0.76 mL, 4.15 mmol, 5.0 equivalents) in CH3CN (10 mL) at 80°C for 16 hours. The product was then purified by preparative HPLC using Method A (rt: 11.43 min) to obtain the title product as the TFA salt. f (MeOH / DCM:1 / 9) = 0.3. Yield 0.044g. 1 H NMR (400 MHz, DMSO-d6) δ: 9.64 (d, 1H), 8.22 (s, 1H), 8.03 (s, 1H), 7.96 (d, 1H), 7.53 (d, 1H), 6.57 (s, 1H), 4.48 (s, 6H), 3.73 (d, 2H), 3.59 (d, 2H), 2.86 (s, 3H), 2.72 (t, 2H), 1.83-1.85 (m, 3H), 1.25-1.34 (m, 2H). MS (ESI) m / z [M+1] + : 503.2.

[0148] Example 7 2-((5-(1H-pyrazol-1-yl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 7) [ka] Following the procedure of Example 1, 5-(1H-pyrazol-1-yl)isoindoline trifluoroacetate (0.35 g, 1.24 mmol, 1.0 equivalent) was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (0.41 g, 1.24 mmol, 1.0 equivalent) and DIPEA (0.80 g, 1.14 mL, 6.2 mmol, 5.0 equivalent) in CH3CN (10 mL) at 90°C for 16 hours. The product was then purified by preparative HPLC using Method A (rt: 11.33 min) to obtain the title product as the TFA salt. f (MeOH / DCM: 0.5 / 9.5) = 0.3. Yield: 0.060g. 1 H NMR (400 MHz, DMSO-d6) δ: 8.47 (d, 1H), 8.22 (s, 1H), 7.86 (s, 1H), 7.80 (d, 1H), 7.75 (s, 1H), 7.46 (d, 1H), 6.59 (s, 1H), 6.56 MS (ESI) m / z [M+1] + : 485.3.

[0149] Example 8 2-((5-(1,2,4-oxadiazol-3-yl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 8) [ka] Following the procedure of Example 1, 3-(isoindolin-5-yl)-1,2,4-oxadiasol trifluoroacetate (0.4 g, 1.40 mmol, 1.0 equivalent) was treated in CH3CN (50 mL) with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (0.47 g, 1.40 mmol, 1.0 equivalent) and DIPEA (0.90 g, 1.3 mL, 7.0 mmol, 5.0 equivalent) at 90°C for 12 hours. The product was purified by column chromatography to obtain the title product as a white solid. The TFA salt of this compound was synthesized by treating the title compound with 0.1% aqueous TFA in CH3CN (5 ml) for 15 minutes and then lyophilizing. f (MeOH / DCM: 0.5 / 9.5) = 0.5. Yield: 0.34g. 1 H NMR (400 MHz, DMSO-d6) δ: 9.69 (s, 1H), 8.16 (s, 1H), 7.90-7.92 (m, 2H), 7.45 (d, 1H), 6.41 (s, 1H), 4.04 (s, 2H), 4.03 (s, 2H), 4.82 (d, 2H), 3.72 (d, 2H), 3.58 (d, 2H), 2.85 (s, 3H), 2.72 (t, 2H), 1.83-1.85 (m, 3H), 1.24-1.33 (m, 2H). MS (ESI) m / z [M+1] + : m / z 487.2.

[0150] Example 9 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((5-(2,2,2-trifluorohydroxyethyl)isoindorin-2-yl)methyl)-4H-pyran-4-one (compound 9) [ka] Following the procedure of Example 1, 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (0.25 g, 0.75 mmol, 1.0 equivalent) was treated with 2,2,2-trifluoro-1-(isoindorin-5-yl)ethane-1-ol hydrochloride (0.28 g, 1.12 mmol, 1.5 equivalents) and DIPEA (0.48 g, 0.69 mL, 3.75 mmol, 5.0 equivalents) in CH3CN (10 mL) at 65°C for 12 hours, and the desired product was then obtained as a brown solid by column chromatography. f (MeOH / DCM: 0.5 / 9.5) = 0.5. Yield: 0.25g. 1 H NMR (400 MHz, DMSO-d6) δ: 8.15 (s, 1H), 7.22-7.38 (m, 3H), 6.79 (d, 1H), 6.39 (s, 1H), 5.08-5.15 (m, 1H), 3.96 (s, 4H), 3.79 (s, MS (ESI) m / z [M+1] + : 517.3.

[0151] Example 10 2-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)-1,3,4-oxadiazole (compound 10) [ka] a) 3-iodo-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)methyl(4) benzoate To a solution of methyl 4-hydroxy-3-iodobenzoate (20.0 g, 71.9 mmol, 1.0 equivalent) in 400 mL of DMF, (1-(methylsulfonyl)piperidine-4-yl)methylmethanesulfonate (19.5 g, 71.9 mmol, 1.0 equivalent) and potassium carbonate (14.5 g, 107.91 mmol, 1.5 equivalents) were added at 25°C. The resulting mixture was stirred at 110°C for 16 hours. After the reaction was complete, the mixture was cooled to 0°C and quenched with ice water to obtain a precipitate. The mixture was filtered, the resulting solid was washed with water, and vacuum-dried. The product was proceeded to the next step without further purification. f (EtOAc / heptane:6 / 4)=0.5. Yield 28.1g. MS (ESI) m / z [M+1]+: 454.10. 1 H-NMR (400 MHz, DMSO-d6) δ: 8.28 (s, 1H), 7.95 (d, 1H), 7.09 (d, 1H), 4.04 (d, 2H), 3.82 (s, 3H), 3.61 (d, 2H), 2.86 (s, 3H), 2.76 (t, 2H), 1.87-1.94 (m, 3H), 1.40-1.53 ​​(m, 2H).

[0152] b) 3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)methyl benzoate (5) To a solution of 3-iodo-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)methyl benzoate (20.0 g, 44.2 mmol, 1.00 equivalent) in DMSO, sodium methanesulfinate (9.0 g, 88.3 mmol, 2.0 equivalent) and sodium hydride (1.76 g, 44.2 mmol, 1.0 equivalent) were added at 25°C. The mixture was then degassed with argon gas for 15 minutes. Subsequently, copper(II) iodide (0.838 g, 44.2 mmol, 1.0 equivalent) and picolinic acid (5.43 g, 44.15 mmol, 1.0 equivalent) were added, and the mixture was heated at 100°C for 16 hours. After the reaction was complete, the mixture was quenched with water and extracted with SiO2 (three times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This crude residue was purified by column chromatography using 100-200 mesh silica gel and 0-60% ethyl acetate in heptane as the eluent. f (SiO / Heptane: 6 / 4) = 0.2. Yield 12.0g, 67%. MS (ESI) m / z [M+1] + : 406.20. 1 H-NMR (400 MHz, DMSO-d6) δ: 8.35 (d, 1H), 8.24 (dd, 1H), 7.43 (d, 1H), 4.19 (d, 2H), 3.87 (s, 3H), 3.60 (d, 2H), 3.29 (s, 3H), 2.82 (s, 3H), 2.76 (t, 2H), 1.94-2.02 (m, 1H), 1.91 (d, 2H), 1.35-1.49 (m, 2H).

[0153] c) (3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)methanol (6) To a 20 mL solution of 3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)methyl benzoate (6.0 g, 14.8 mmol, 1.0 equivalent) in THF, lithium tetrahydroborate (24.6 mL, 73.98 mmol, 5.0 equivalent) was added at 0°C. The resulting mixture was heated at 50°C for 24 hours. After the reaction was complete, the mixture was cooled to 0°C, quenched with NH4Cl solution, and extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This crude residue was proceeded to the next step without further purification. f (MeOH / DCM:0.5 / 9.5)=0.2. Yield 3.2g (crude). MS (ESI) m / z [M+1] + : 378.18. 1 H-NMR (400 MHz, DMSO-d6) δ: 7.78 (s, 1H), 7.57 (d, 1H), 7.24 (d, 1H), 5.30 (t, 1H), 4.48 (d, 2H), 4.07 (d, 2H), 3.60 (d, 2H), 3.23 (s, 3H), 2.86 (s, 3H), 2.75 (t, 2H), 1.87-2.01 (m, 3H), 1.33-1.47 (m, 2H).

[0154] d) 4-((4-(chloromethyl)-2-(methylsulfonyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine(7) To a 50 mL solution of (3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)methanol (1.70 g, 4.50 mmol, 1.0 equivalent) in CH3CN and DMF (2-3 drops), thionyl chloride (8.04 g, 4.9 mL, 67.6 mmol, 15.0 equivalent) was added at 0°C. The mixture was stirred at 25°C for 1 hour. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. f (MeOH / EtOAc:0.5 / 9.5)=0.6. Yield 1.6g (crude). MS (ESI) m / z [M+1] + : 396.17. 1H-NMR (400 MHz, DMSO-d6) δ: 7.89 (d, 1H), 7.74 (d, 1H), 7.34 (d, 1H), 4.84 (s, 2H), 4.10 (d, 2H), 3.60 (d, 2H), 3.27 (s, 3H), 2.86 (s, 3H), 2.75 (t, 2H), 1.85-2.02 (m, 3H), 1.41-1.49 (m, 2H).

[0155] e) 2-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)-1,3,4-oxadiazole In 20 mL of CH3CN, 2-(isoindolin-5-yl)-1,3,4-oxadiazole trifluoroacetate (0.4 g, 1.32 mmol, 1.0 equivalent) was treated with 4-((4-(chloromethyl)-2-(methylsulfonyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine (0.52 g, 1.3 mmol, 1.0 equivalent) at 90°C for 16 hours in the presence of DIPEA (0.85 g, 1.2 mL, 6.6 mmol, 5.0 equivalent), and the title compound was obtained as a pale pink solid by column chromatography. The oxalate of the product was synthesized by oxalic acid (0.5 equivalent) in MeOH at 0°C for 3 hours, and then filtering the product. f (MeOH / DCM: 0.5 / 9.5) = 0.6. Yield: 0.34g. 1 H NM R(400 MHz, DMSO-d6) : δ 9.32 (s, 1H), 7.88-7.94 (m, 3H), 7.72 (d, 1H), 7.50 (d, 1H), 7.31 (d, 1H), 3.90-4.30 (m, 8H), 3.61 (d, 2H), 3.26 (s, 3H), 2.86 (s, 3H), 2.76 (t, 2H), 1.95-2.05 (m, 1H), 1.92 (d, 2H), 1.38-1.46 (m, 2H).

[0156] Example 11 3-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)isoxazole (compound 11) [ka] Following the procedure of Example 10, 3-(isoindolin-5-yl)isoxazole hydrochloride (0.19 g, 0.63 mmol, 1.0 equivalent) was treated in CH3CN (10 mL) with 4-((4-(chloromethyl)-2-(methylsulfonyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine (0.25 g, 0.63 mmol, 1.0 equivalent) in the presence of DIPEA (0.40 g, 0.6 mL, 3.16 mmol, 5.0 equivalents) at 90°C for 16 hours, and the title product was obtained as a white solid by column chromatography. The TFA salt of the product was synthesized by treating the title compound with 0.1% TFA in CH3CN at 25°C for 5 minutes and then lyophilizing. f (MeOH / DCM:0.5 / 9.5)=0.6. Yield 0.055g. MS (ESI) m / z [M+1] + : 546.3 (M+H) + . 1 H NMR (400 MHz, DMSO-d6): δ 10.90 (bs, 1H), 9.04 (s, 1H), 8.10-8.15 (m, 1H), 7.94-7.99 (s, 1H), 7.80-7.90 (m, 2H), 7.55 (d, 1H), 7.43 (d, 1H), 7.14 (s, 1H), 4.60-4.78 (s, 6H), 4.14 (d, 2H), 3.62 (d, 2H), 3.28 (s, 3H), 2.87 (s, 3H), 2.76 (t, 2H), 1.95-2.05 (m, 1H), 1.92 (d, 2H), 1.38-1.47 (m, 2H).

[0157] Example 12 5-Bromo-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 12a) and 2-(3-(methylsulfonyl)-4-((1-methylsulfonyl)piperidine-4-yl)methoxy)benzyl)-5-(1H-pyrazol-1-yl)isoindoline (compound 12b) [ka] a) 5-Bromo-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 12a) 5-Bromoisoindoline hydrochloride (0.5 g, 2.11 mmol, 1.0 equivalent) was treated with 4-((4-(chloromethyl)-2-(methylsulfonyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine (1.02 g, 2.59 mmol, 1.2 equivalents) in 10 mL of CH3CN in the presence of DIPEA (1.0 g, 1.5 mL, 8.44 mmol, 4.0 equivalents) at 100°C for 3 hours, and the product described in the title was obtained by column chromatography. f (MeOH / EtOAc:0.5 / 9.5)=0.2. Yield 0.66g. MS (ESI) m / z [M+1] + : 557.11. 1 H-NMR (400 MHz, DMSO-d6): δ 7.80 (d, 1H), 7.65 (dd, 1H), 7.43-7.47 (m, 1H), 7.37 (d, 1H), 7.27 (d, 1H), 7.19 (d, 1H), 4.08 (d, 2H), 3.86 (s, 2H), 3.82 (s, 2H), 3.79 (s, 2H), 3.60 (d, 2H), 3.25 (s, 3H), 2.87 (s, 3H), 2.75 (t, 2H), 1.88-2.01 (m, 3H), 1.36-1.51 (m, 2H).

[0158] b) 2-(3-(methylsulfonyl)-4-((1-methylsulfonyl)piperidine-4-yl)methoxy)benzyl)-5-(1H-pyrazol-1-yl)isoindoline (compound 12b) 5-Bromo-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (0.36 g, 0.64 mmol, 1.00 equivalent) was treated in 20 mL of DMA with 1H-pyrazole (0.88 g, 1.29 mmol, 2.0 equivalent) in the presence of potassium carbonate (0.27 g, 1.92 mmol, 3.0 equivalent), DMEDA (0.028 g, 0.32 mmol, 0.5 equivalent), and CuI (0.061 g, 0.32 mmol, 0.5 equivalent) at 150°C for 20 hours. The product described in the title was then purified as a white solid by preparative HPLC using Method A (rt: 12.32 min). f (MeOH / DCM:0.5 / 9.5)=0.3. Yield 0.072g. MS (ESI) m / z [M+1] + : 545.4. 1 H NMR (400 MHz, DMSO-d6): δ 8.48 (d, 1H), 8.11 (s, 1H), 7.83-7.91 (m, 3H), 7.76 (s, 1H), 7.51 (d, 1H), 7.43 (d, 1H), 6.57 (s, 1H), 4.62-4.68 (m, 6H), 4.14 (d, 2H), 3.62 (d, 2H), 3.28 (s, 3H), 2.87 (s, 3H), 2.76 (t, 2H), 1.95-2.05 (m, 1H), 1.93 (d, 2H), 1.39-1.47 (m, 2H).

[0159] Example 13 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)oxazole (compound 13a) and 2-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)oxazole (compound 13b) [ka] 5-Bromo-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (0.25g, 0.45 mmol, 1.0 equivalent) in 20 mL of DMF, cesium carbonate (0.36g, 1.12 mmol, 2.5 equivalents), pivalic acid (0.018g, 0.18 mmol, 0.4 equivalents), paradiacetic acid The oxazole (0.046 g, 0.67 mmol, 1.5 equivalents) was treated with um(II) (0.006 g, 0.022 mmol, 0.05 equivalents) and di(1-adamantyl)-n-butylphosphine (0.008 g, 0.022 mmol, 0.05 equivalents) at 110°C for 16 hours, and then the two positional isomers were obtained as white solids by preparative HPLC purification using method C (rt: 10.43 min and 11.41 min, column: X Sunfire C18). f (MeOH / DCM: 0.5 / 9.5) = 0.4. Yields: 0.008 g (compound 13a) and 0.005 g (compound 13b). Compound 13a:MS (ESI) m / z [M+1] + : 546.4. 1 H NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 7.80-7.87 (m, 1H), 7.40-7.70 (m, 4H), 7.31 (dd, 2H), 4.09 (d, 2H), 3.80-3.95 (m, 5H), 3.61 (d, 2H), 3.27 (s, 3H), 2.86 (s, 3H), 2.76 (t, 2H), 2.40-2.60 (m, 1H), 1.95-2.05 (m, 1H), 1.92 (d, 2H), 1.38-1.46 (m, 2H). Compound 13b:MS (ESI) m / z [M+1] + : 546.4. 1H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.81-7.85 (m, 3H), 7.66-7.68 (m, 1H), 7.38 (d, 1H), 7.35 (s, 1H), 7.28 (d, 1H), 4.09 (d, 2H), 3.85-3.95 (m, 6H), 3.61 (d, 2H), 3.26 (s, 3H), 2.86 (s, 3H), 2.76 (t, 2H), 1.95-2.05 (m, 1H), 1.92 (d, 2H), 1.38-1.46 (m, 2H).

[0160] Example 14 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)thiazole (compound 14) [ka] 5-Bromo-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (0.5g, 0.90 mmol, 1.0 equivalent) in 20 mL of DMF, cesium carbonate (0.73g, 2.24 mmol, 2.5 equivalents), pivalic acid (0.04g, 0.35 mmol, 0.4 equivalents), palladium(II) acetate (0 The product was treated with thiazole (0.098 g, 1.16 mmol, 1.3 equivalents) at 110°C for 16 hours in the presence of 0.01 g, 0.04 mmol, 0.05 equivalents of thiazole (0.098 g, 1.16 mmol, 1.3 equivalents), followed by preparative HPLC purification using method B (rt: 10.36 mins) to obtain the product described in the title as a white solid. f (MeOH / DCM:0.5 / 9.5)=0.5. Yield 0.050g. MS (ESI) m / z [M+1] + : 562.4. 1H NMR (400 MHz, DMSO-d6): δ 10.84 (bs, 1H), 9.11 (s, 1H), 8.33 (s, 1H), 8.11 (s, 1H), 7.87 (d, 1H), 7.70-7.80 (m, 2H), 7.48 (d, 1H), 7.43 (d, 1H), 4.58-4.75 (m, 6H), 4.14 (d, 2H), 3.62 (d, 2H), 3.28 (s, 3H), 2.87 (s, 3H), 2.76 (t, 2H), 1.95-2.05 (m, 1H), 1.92 (d, 2H), 1.38-1.48 (m, 2H).

[0161] Example 15 1-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)ethane-1-one (compound 15a), 3-(dimethylamino)-1-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)prop-2-en-1-one (compound 15b) and 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)isoxazole (compound 15c) [ka] a) 1-(2-(3-(methylsulfonyl)-4-((1(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)ethane-1-one (compound 15a) To a 20 mL solution of 5-bromo-2-(3-methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (2.0 g, 3.59 mmol, 1.0 equivalent) in DMA, tributyl(1-ethoxyvinyl)tin (2.0 g, 5.53 mmol, 1.4 equivalents) was added at 25°C. The mixture was degassed with argon for 15 minutes. Then, bis(triphenylphosphine)palladium(II) dichloride (0.13 g, 0.17 mmol, 0.05 equivalents) was added, and the resulting mixture was heated at 100°C for 16 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was dissolved in 2N HCl (10 mL) and stirred at 25°C for 2 hours. The mixture was then extracted with toluene (three times), the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude residue was purified by combiflash chromatography using 0-25% ethyl acetate in heptane as the eluent. f (MeOH / EtOAc:0.5 / 9.5)=0.6. Yield 0.8g, 43%. MS (ESI) m / z [M+1] + : 521.38.

[0162] b) 3-(dimethylamino)-1-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)prop-2-en-1-one (compound 15b) 1-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)ethane-1-one (1.0 g, 1.92 mmol, 1.0 equivalent) was treated in DMF with DMF-DMA (40 mL) at 90°C for 16 hours to obtain the product described in the title as a yellow, rubbery mass. f (MeOH / DCM:0.5 / 9.5)=0.6. Yield 0.9g (crude). MS (ESI) m / z [M+1] + : 576.14. 1H-NMR (400 MHz, DMSO-d6): δ 7.82 (s, 1H), 7.75 (s, 1H), 7.64-7.71 (m, 2H), 7.52-7.59 (m, 1H), 7.28 (d, 1H), 7.22 (d, 1H), 6.66 (s, 1H), 4.08 (d, 2H), 3.81-3.90 (m, 6H), 3.61 (d, 2H), 3.31 (s, 6H), 3.26 (s, 3H), 2.87 (s, 3H), 2.75 (t, 2H), 1.90-1.95 (m, 3H), 1.40-1.45 (m, 2H).

[0163] c) 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)isoxazole (compound 15c) 3-(dimethylamino)-1-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)prop-2-en-1-one (0.9 g, 1.56 mmol, 1.0 equivalent) was treated with hydroxylamine hydrochloride (0.32 g, 4.6 mmol, 3.0 equivalent) in 40 mL of EtOH at 80°C for 3 hours, and the product described in the title was obtained as a brown solid by preparative HPLC purification using method B (rt: 14.01 min). f (MeOH / DCM: 0.5 / 9.5) = 0.6. Yield: 0.10g. 1 H NMR (400 MHz, DMSO-d6): δ 8.68 (d, 1H), 8.11 (s, 1H), 7.86-7.93 (m, 3H), 7.57 (d, 1H), 7.43 (d, 1H), 7.04 (d, 1H), 4.67 (bs, 6H), MS (ESI) m / z [M+1] + : 546.4.

[0164] Example 16 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline-5-carbonitrile (compound 16a), N-hydroxy-2-(3-(methylsulfonyl)-4-((1(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline-5-carboxyimidamide (compound 16b) and 3-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)-1,2,4-oxadiazole (compound 16c) [ka] a) 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline-5-carbonitrile (compound 16a) Isoindoline-5-carbonitride hydrochloride (0.9 g, 5.0 mmol, 1.0 equivalent) was treated with 4-((4-(chloromethyl)-2-(methylsulfonyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine (1.97 g, 5.0 mmol, 1.0 equivalent) in CH3CN (15 mL) in the presence of DIPEA (3.88 g, 5.2 mL, 30.0 mmol, 6.0 equivalents) at 80°C for 4 hours, and the product described in the title was obtained as a white solid by column chromatography. f (MeOH / DCM:0.5 / 9.5)=0.6. Yield 0.7g, 61%. MS (ESI) m / z [M+1] + : 504.23.

[0165] b) N-hydroxy-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline-5-carboxyimidamide (compound 16b) 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline-5-carbonitrile (0.3 g, 0.6 mmol, 1.0 equivalent) was treated with NH2OH.HCl (0.04 g, 0.6 mmol, 1.0 equivalent) in EtOH (10 mL) in the presence of Et3N (0.32 g, 0.4 mL, 3.0 mmol, 5.0 equivalents) at 90°C for 12 hours to obtain the product described in the title as a white solid. f (MeOH / DCM:0.5 / 9.5)=0.4. Yield 0.28 (crude). MS (ESI) m / z [M+1] + : 537.15. 1 H-NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1H), 7.81 (s, 1H), 7.69 (d, 1H), 7.47-7.67 (m, 2H), 7.28 (d, 1H), 7.20 (d, 1H), 5.73 (s, 2H), 4.08 (d, 2H), 3.81-3.90 (m, 6H), 3.60 (d, 2H), 3.26 (s, 3H), 2.86 (s, 3H), 2.76 (t, 2H), 1.88-1.95 (m, 3H), 1.35-1.48 (m, 2H).

[0166] c) 3-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)-1,2,4-oxadiazole (compound 16c) 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline-5-carboxyimidamide (0.28 g, 0.52 mmol, 1.0 equivalent) was treated with trimethyl orthoformate (10 mL) in the presence of TFA (0.1 mL) at 70°C for 2 hours, and the title product was obtained as a white solid by preparative HPLC using method A. f (MeOH / DCM:0.5 / 9.5)=0.4. Yield 0.14g. MS (ESI) m / z [M+1] + : 547.3. 1H NMR (400 MHz, DMSO-d6): δ 11.00 (bs, 1H), 9.74 (s, 1H), 8.10 (bs, 2H), 8.05 (d, 1H), 7.88 (d, 1H), 7.61 (d, 1H), 7.43 (d, 1H), 4.60-4.80 (m, 6H), 4.14 (d, 2H), 3.62 (d, 2H), 3.28 (s, 3H), 2.87 (s, 3H), 2.76 (t, 2H), 1.95-2.05 (m, 1H), 1.92 (d, 2H), 1.40-1.50 (m, 2H).

[0167] Example 17 2-(1-(5-bromoisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 17a), and 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-(1-(5-(oxazol-2-yl)isoindorin-2-yl)ethyl)-4H-pyran-4-one (compound 17b) [ka] a) 5-(benzyloxy)-2-(1-hydroxyethyl)-4H-pyran-4-one To a solution of 5-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde (10.0 g, 43.4 mmol, 1.0 equivalent) in 300 mL of THF, methylmagnesium bromide (3.0 M solution) (23 mL, 69.5 mmol, 1.6 equivalents) was added dropwise at 0°C. The mixture was stirred at 0°C for 0.5 hours. After the reaction was complete, the reaction mixture was quenched with NH4Cl solution and extracted with Â(3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude residue was purified by combiflash chromatography using ethyl acetate in heptane at a concentration of 0-50% as the eluent. f (SiO / Heptane:8 / 2) = 0.2. Yield 6.0g, 56%. MS (ESI) m / z [M+1] +: 247.07.

[0168] b) 1-(5-(benzyloxy)-4-oxo-4H-pyran-2-yl)ethyl methanesulfonate To a 50 mL solution of 5-(benzyloxy)-2-(1-hydroxyethyl)-4H-pyran-4-one (4.0 g, 16.3 mmol, 1.0 equivalent) in THF, Et3N (4.9 g, 6.6 mL, 48.8 mmol, 3.0 equivalents) and methanesulfonyl chloride (2.8 g, 1.8 mL, 24.4 mmol, 1.5 equivalents) were added dropwise at 0°C. The mixture was stirred at 25°C for 1.5 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with ELISA (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This crude product was proceeded to the next step without further purification. f (EtOAc / heptane:4 / 6)=0.3. Yield 4.0g (crude). MS (ESI) m / z [M+1] + : 325.14. 1 H-NMR (400 MHz, DMSO-d6): δ 8.30 (s, 1H), 7.34-7.44 (m, 5H), 6.56 (s, 1H), 5.61 (q, 1H), 4.95 (s, 2H), 3.29 (s, 3H), 1.58 (d, 3H).

[0169] c) 5-(benzyloxy)-2-(1-(5-bromoisoindoline-2-yl)ethyl)-4H-pyran-4-one 1-(5-(benzyloxy)-4-oxo-4H-pyran-2-yl)ethyl methanesulfonate (2.2 g, 6.8 mmol, 1.0 equivalent) was treated with 5-bromoisoindoline (2.0 g, 6.8 mmol, 1.0 equivalent) in 20 mL of CH3CN in the presence of DIPEA (2.6 g, 3.6 mL, 20.3 mmol, 3.0 equivalent) at 70°C for 16 hours, and the product described in the title was obtained by column chromatography. f (MeOH / DCM:0.5 / 9.5)=0.8. Yield 1.5g, 52%. MS (ESI) m / z [M+1] + : 426.14.

[0170] d) 2-(1-(5-bromoisoindoline-2-yl)ethyl)-5-hydroxy-4H-pyran-4-one 5-(benzyloxy)-2-(1-(5-bromoisoindolin-2-yl)ethyl)-4H-pyran-4-one (1.4 g, 3.3 mmol, 1.0 equivalent) and 10 mL of concentrated HCl were placed in a 30 mL reaction vial. The mixture was heated at 60°C for 16 hours. After the reaction was complete, the reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was proceeded to the next step without purification. f (MeOH / DCM:0.5 / 9.5)=0.1. Yield 1.05g (crude). MS (ESI) m / z [M+1] + : 336.11.

[0171] e) 2-(1-(5-bromoisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 17a) To a solution of 2-(1-(5-bromoisoindolin-2-yl)ethyl)-5-hydroxy-4H-pyran-4-one (1.05 g, 3.12 mmol, 1.0 equivalent) in 10 mL of DMSO, (1-(methylsulfonyl)piperidine-4-yl)methylmethanesulfonate (0.84 g, 3.13 mmol, 1.0 equivalent), cesium carbonate (2.04 g, 6.25 mmol, 2.0 equivalent), and tris(2-(2-methoxyethoxy)ethyl)amine (0.10 g, 0.31 mmol, 0.1 equivalent) were added at 25°C. The resulting mixture was stirred at 60°C for 16 hours. After the reaction was complete, the reaction mixture was quenched with ice-cold water and extracted with siRNA (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white, rubbery mass as the crude product. This crude product was purified by combiflash chromatography using 0-50% ethyl acetate in heptane as the eluent. f(MeOH / DCM:0.5 / 9.5)=0.5. Yield 0.25g, 16%. MS (ESI) m / z [M+1] + : 511.11. 1 H-NMR (400 MHz, DMSO-d6): δ 8.16 (s, 1H), 7.45 (s, 1H), 7.37 (d, 1H), 7.20 (d, 1H), 6.37 (s, 1H), 3.80-3.94 (m, 5H), 3.65-3.80 (m, 2H), 3.57 (d, 2H), 2.85 (s, 3H), 2.66-2.80 (m, 2H), 1.79-1.90 (m, 3H), 1.38 (d, 3H), 1.21-1.35 (m, 2H).

[0172] f) 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-(1-(5-(oxazol-2-yl)isoindorin-2-yl)ethyl)-4H-pyran-4-one (compound 17b) A solution of 2-(1-(5-bromoisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (0.10 g, 0.19 mmol, 1.0 equivalent) in 5 mL of dioxane was degassed with argon for 10 minutes. Then, 2-(tributylstannyl)oxazole (0.084 g, 0.23 mmol, 1.2 equivalents) and tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.02 mmol, 0.1 equivalents) were added to the reaction mixture, and the mixture was purged again with argon for 10 minutes. The reaction vial was sealed and heated at 110°C for 16 hours. After the reaction was complete, the reaction mixture was quenched with ice-cold water and extracted with siRNA (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC using method C (rt: 13.17 mins). The TFA salt of this compound was prepared by passing the compound through a reverse-phase column using 0.1% TFA as buffer, and the product indicated in the title was obtained as the TFA salt. f(MeOH / DCM:0.5 / 9.5)=0.4. Yield 0.02g. MS (ESI) m / z [M+1] + : 500.2. 1 H NMR (400 MHz, DMSO-d6): δ 8.22 (d, 2H), 7.90-7.99 (m, 2H), 7.49 (d, 1H), 7.39 (s, 1H), 6.52-6.61 (m, 1H), 4.35-4.71 (m, 2H), 3.50-3.76 (m, 7H), 2.86 (s, 3H), 2.66-2.75 (m, 2H), 1.83-1.85 (m, 3H), 1.51-1.65 (m, 3H), 1.24-1.33 (m, 2H).

[0173] Example 18 2-(1-(5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)ethyl)isoindoline-5-carbonitrile (compound 18a), N-hydroxy-2-(1-(5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)ethyl)isoindoline-5-carboximidamide (compound 18b) and 2-(1-(5-(1,2,4-oxadiazol-3-yl)isoindoline-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 18c) [ka] a) 2-(1-(5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)ethyl)isoindoline-5-carbonitrile (compound 18a) To a solution of 2-(1-(5-bromoisoindolin-2-yl)ethyl)-5-((1-methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (0.65 g, 1.27 mmol, 1.0 equivalent) in 1,4-dioxane (15 mL), zinc(II) cyanide (0.44 g, 3.8 mmol, 3.0 equivalent) was added. The mixture was degassed with argon for 15 minutes. Then, tetrakis(triphenylphosphine)palladium(O) (0.29 g, 0.25 mmol, 0.2 equivalent) was added, and the mixture was again degassed with argon for 10 minutes. The reaction vial was sealed and heated at 110 °C for 16 hours. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This crude residue was purified by combiflash chromatography using ethyl acetate in heptane at a concentration of 0-80% as the eluent. f (EtOAc / heptane:8 / 2)=0.3. Yield 0.25g, 43%. MS (ESI) m / z [M+1] + : 458.36.

[0174] b) N-hydroxy-2-(1-(5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)ethyl)isoindoline-5-carboximidamide (compound 18b) 2-(1-(5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)ethyl)isoindoline-5-carbonitrile (0.25 g, 0.546 mmol, 1.0 equivalent) was treated with hydroxylamine hydrochloride (0.075 g, 1.09 mmol, 2.0 equivalent) in 10 mL of EtOH in the presence of Et3N (0.22 g, 0.30 mL, 2.18 mmol, 4.0 equivalents) at 70°C for 18 hours, and the product described in the title was obtained by column chromatography. f (MeOH / DCM:0.5 / 9.5)=0.5. Yield 0.26g, 97%. MS (ESI) m / z [M+1] + : 491.37. 1H-NMR (400 MHz, DMSO-d6): δ 9.91-10.19 (m, 4H), 8.17 (s, 1H), 7.51-7.54 (m, 2H), 7.26 (s, 1H), 3.84-3.99 (m, 4H), 3.70-3.74 (m, 3H), 3.56 (d, 2H), 2.85 (s, 3H), 2.65-2.75 (m, 2H), 1.82-1.84 (m, 3H), 1.74 (d, 3H), 1.39-49 (m, 2H).

[0175] c) 2-(1-(5-(1,2,4-oxadiazol-3-yl)isoindoline-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 18c) N-hydroxy-2-(1-(5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)ethyl)isoindoline-5-carboximidamide (0.4 g, 0.85 mmol, 1.0 equivalent) was treated with trimethyl orthoformate (1.7 g, 1.8 mL, 16.3 mmol, 20.0 equivalents) at 60°C for 18 hours, and the compound described in the title was obtained by preparative HPLC purification using method C (rt: 13.24 min, column: X cross-linked C18). f (MeOH / DCM:0.5 / 9.5)=0.5. Yield 0.011g. MS (ESI) m / z [M+1] + : 501.2. 1 H NMR (400 MHz, DMSO-d6): δ 9.67 (s,1H), 8.16 (s,1H), 7.89 (d, 2H), 7.44 (d, 1H), 6.40 (s, 1H), 3.92-4.05 (m, 4H), 3.71-3.77 (m, 3H), 3.57 (d, 2H), 2.85 (s, 3H), 2.69-2.75 (m, 2H), 1.82-1.89 (m, 3H), 1.42 (d, 3H), 1.23-1.33 (m, 2H).

[0176] Example 19 2-(1-(3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 19) [ka] a) 2-((5-(benzyloxy)-4-oxo-4H-pyran-2-yl)methylene)-1,2,3,4-tetrahydroisoquinoline-2-ium To a 10 mL solution of 5-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde (1.0 g, 4.3 mmol, 1.0 equivalent) in DCE, tetrahydroisoquinoline (0.57 g, 4.3 mmol, 1.0 equivalent) and acetic acid (0.3 mL) were added at 25°C. The mixture was heated at 50°C for 16 hours. After the reaction was complete, the solvent was evaporated under reduced pressure, and the resulting crude product (stored under nitrogen conditions at -40°C) was proceeded to the next step without further purification. f (EtOAc / heptane:5 / 5)=0.3. Yield 1.5g (crude). MS(ESI) m / z [M+1] + : 347.25.

[0177] b) 5-(benzyloxy)-2-(1-(3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl-4H-pyran-4-one In a 100 mL sealed tube, 2-((5-(benzyloxy)-4-oxo-4H-pyran-2-yl)methylene)-1,2,3,4-tetrahydroisoquinoline-2-ium (1.5 g, 4.3 mmol, 1.0 equivalent) was dissolved in 60 mL of CH3CN. The resulting mixture was heated at 120°C for 16 hours. After the reaction was complete, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography using 100-200 mesh silica gel and 0-50% ethyl acetate in heptane as the eluent. f(SiO / Heptane: 5 / 5) = 0.3. Yield 0.4g, 22%. MS (ESI) m / z [M+1] + : 416.26. 1 H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.14-7.43 (m, 9H), 6.43 (s, 1H), 4.93 (s, 2H), 4.69-4.78 (m, 1H), 3.81-3.93 (m, 2H), 3.17-3.22 (m, 1H), 2.79-2.86 (m, 1H), 2.65-2.75 (m, 2H).

[0178] c) 2-(1-(3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl)-5-hydroxy-4H-pyran-4-one 5-(benzyloxy)-2-(1-(3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl-4H-pyran-4-one (0.30 g, 0.72 mmol, 1.0 equivalent) was treated with concentrated HCl (3 mL) and AcOH (0.6 mL) at 65°C for 16 hours to obtain the product described in the title as a brown solid. f (EtOAc / heptane:4 / 6)=0.6. Yield 0.13g (crude). MS (ESI) m / z [M+1] + : 326.05. 1 H NMR (400 MHz, DMSO-d6): δ 9.10 (s, 1H), 8.03 (s, 1H), 7.21-7.35 (m, 4H), 6.43 (s, 1H), 4.73 (q, 1H), 3.79-3.93 (m, 2H), 3.13-3.28 (m, 1H), 2.79-2.89 (m, 1H), 2.65-2.78 (m, 2H).

[0179] d) 2-(1-(3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 19) 2-(1-(3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl)-5-hydroxy-4H-pyran-4-one (0.13 g, 0.39 mmol, 1.0 equivalent) was treated with (1-(methylsulfonyl)piperidine-4-yl)methylmethanesulfonate (0.11 g, 0.44 mmol, 1.1 equivalent) in DMSO (10 mL) in the presence of tris(2-(2-methoxyethoxy)ethyl)amine (0.077 g, 0.24 mmol, 0.6 equivalents) and cesium carbonate (0.26 g, 0.80 mmol, 2.0 equivalents) at 60°C for 2 hours. The compound in question was then purified by preparative HPLC using Method A (rt: 13.53 min) to obtain the title compound as a white solid. f (MeOH / DCM:1 / 9)=0.3. Yield 0.095g. MS (ESI) m / z [M+1] + : 501.4. 1 H NMR (400 MHz, DMSO-d6): δ 8.13 (s, 1H), 7.20-7.32 (m, 4H), 6.40 (s, 1H), 4.73 (q, 1H), 3.82-3.91 (m, 2H), 3.70 (d, 2H), 3.57 (d, 2H), 3.12-3.20 (m, 1H), 2.70-2.80 (m, 4H), 2.68-2.74 (m, 4H), 1.81-1.84 (m, 3H), 1.23-1.32 (m, 2H).

[0180] Example 20 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-(2,2,2-trifluoro-1-(isoindorin-2-yl)ethyl)-4H-pyran-4-one (compound 20) [ka] a) tert-butyl 4-(((6-(hydroxymethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate 5-Hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (10.0 g, 70.4 mmol, 1.0 equivalent) was treated with tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (29.0 g, 105.6 mmol, 1.5 equivalent) in 120 mL of DMF in the presence of potassium carbonate (29.1 g, 211.1 mmol, 3.0 equivalents) at 70°C for 16 hours to obtain the compound described in the title as a white solid. f (EtOAc / heptane:10 / 0)=0.4. Yield 8.1g, 34%. MS (ESI) m / z [M+1] + : 340.31. 1 H-NMR (400 MHz, DMSO-d6): δ 8.10 (s, 1H), 6.29 (s, 1H), 5.67 (t, 1H), 4.28 (d, 2H), 3.95 (d, 2H), 3.67 (d, 2H), 2.65-2.75 (m, 2H), 1.79-1.91 (m, 1H), 1.70 (d, 2H), 1.39 (s, 9H), 1.04-1.16 (m, 2H).

[0181] b) tert-butyl 4-(((6-formyl-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate In a 250 mL sealed tube, 4-(((6-(hydroxymethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (8.1 g, 23.9 mmol, 1.0 equivalent) was dissolved in 100 mL of MeOH. Activated manganese dioxide (10.63 g, 10.63 mmol, 5.0 equivalents) was then added to the solution at 25°C. The mixture was heated at 90°C for 16 hours. After the reaction was complete, the mixture was filtered, washed with MeOH, and the resulting solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by combiflash chromatography using ethyl acetate as the eluent. f (EtOAc / heptane:8 / 2)=0.4. Yield 5.2g, 65%. MS (ESI) m / z [M+1] + : 337.9.

[0182] c) tert-butyl 4-(((4-oxo-6-(2,2,2-trifluoro-1-hydroxyethyl)-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate To 100 mL of DMF solution of tert-butyl 4-(((6-formyl-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (5.2 g, 15.40 mmol, 1.0 equivalent), trimethyl(trifluoromethyl)silane (3.42 mL, 23.1 mmol, 1.5 equivalent) and potassium carbonate (0.21 g, 1.54 mmol, 0.1 equivalent) were added at 0°C, and the mixture was stirred at 25°C for 4 hours. After the reaction was complete, the mixture was quenched with ice-cold water and extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by combiflash chromatography using 0-50% ethyl acetate in heptane as the eluent. f (SiO / Heptane: 8 / 2) = 0.4. Yield 3.0g, 47%. MS (ESI) m / z [M+1] + : 408.05.

[0183] d) tert-butyl 4-(((4-oxo-6-(2,2,2-trifluoro-1-(((trifluoromethyl)sulfonyl)oxy)ethyl)-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate To 20 mL of a DCM solution of tert-butyl 4-(((4-oxo-6-(2,2,2-trifluoro-1-hydroxyethyl)-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (1.0 g, 2.45 mmol, 1.0 equivalent), pyridine (0.58 g, 0.58 mL, 7.35 mmol, 3.0 equivalent) and trifluoromethanesulfonic anhydride (1.72 g, 1.03 mL, 6.14 mmol, 2.5 equivalent) were added at 0°C. The mixture was stirred at 0°C for 0.5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was not further purified before proceeding to the next step. f(EtOAc / heptane:8 / 2)=0.7. Yield 1.2g (crude). MS (ESI) m / z [M+1] + : 540.05.

[0184] e)tert-butyl 4-(((6-(1-azido-2,2,2-trifluoroethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate To 20 mL of DMF solution of tert-butyl 4-(((4-oxo-6-(2,2,2-trifluoro-1-(((trifluoromethyl)sulfonyl)oxy)ethyl)-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (1.2 g, 2.23 mmol, 1.0 equivalent), sodium azide (0.25 g, 5.56 mmol, 2.5 equivalents) was added at 25°C, and the mixture was stirred at 25°C for 16 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This crude residue was not further purified before proceeding to the next step. f (EtOAc / heptane:8 / 2)=0.4. Yield 1.2g (crude). MS (ESI) m / z [M+1] + : 433.09.

[0185] f)tert-butyl 4-(((6-(1-amino-2,2,2-trifluoroethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate To a 10 mL MeOH solution of tert-butyl 4-(((6-(1-azido-2,2,2-trifluoroethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (1.2 g, 2.78 mmol, 1.0 equivalent), 10% Pd / C (50% wet, 0.6 g, 0.28 mmol) was added at 25°C under a nitrogen atmosphere. The reaction mixture was then purged with H2 gas using a hydrogen balloon, and the resulting mixture was stirred at 25°C for 2 hours. After the reaction was complete, the mixture was filtered through Celite and washed with MeOH. The organic fraction was concentrated under reduced pressure. This crude product was purified by column chromatography using 100-200 mesh silica gel and 0-10% MeOH in siRNA as the eluent. f (EtOAc / heptane:8 / 2)=0.2. Yield 0.2g, 22%. MS (ESI) m / z [M+1] + : 407.09.

[0186] g)tert-butyl 4-(((4-oxo-6-(2,2,2-trifluoro-1-(isoindoline-2-yl)ethyl)-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate To 10 mL of CH3CN solution of tert-butyl 4-(((6-(1-amino-2,2,2-trifluoroethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (0.2 g, 0.49 mmol, 1.0 equivalent), 1,2-bis(bromomethyl)benzene (0.38 g, 1.47 mmol, 3.0 equivalent) and N-ethyl-N-isopropylpropan-2-amine (0.19 g, 0.27 mL, 1.42 mmol, 3.0 equivalent) were added at 25°C, and the mixture was stirred at 65°C for 12 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with siRNA (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This crude residue was purified by column chromatography using 100-200 mesh silica gel and 0-10% MeOH in ¼ as the eluent. f(SiO / Heptane:8 / 2) = 0.2. Yield 0.05g, 20%. MS (ESI) m / z[M+1] + : 509.09. 1 H-NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.19-7.30 (m, 4H), 6.52 (s, 1H), 5.01-5.10 (m, 1H), 4.12-4.20 (m, 4H), 3.92 (d, 2H), 3.67 (d, 2H), 2.65-2.80 (m, 2H), 1.81-1.92 (m, 1H), 1.69 (d, 2H), 1.38 (s, 9H), 1.01-1.15 (m, 2H).

[0187] h)5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-(2,2,2-trifluoro-1-(isoindorin-2-yl)ethyl)-4H-pyran-4-one (compound 20) To an ethyl acetate solution of tert-butyl 4-(((4-oxo-6-(2,2,2-trifluoro-1-(isoindolin-2-yl)ethyl)-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (0.35 g, 0.68 mmol, 1.0 equivalent), HCl in ethyl acetate (5.0 mL, 1.0 M solution) was added, and the mixture was stirred for 12 hours. The reaction mixture was concentrated to obtain the crude product as a brown, rubbery mass. The crude product was dissolved in 50 mL of THF, Et3N (0.21 g, 0.29 mL, 2.06 mmol, 3.0 equivalents) was added, and then methanesulfonyl chloride (0.12 g, 0.08 mL, 1.03 mmol, 1.5 equivalents) was added dropwise at 0°C. The mixture was stirred at 25°C for 1.5 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC using method C (rt: 11.98 min, column: Sunfire C-18) to obtain the title compound as a white solid. f (MeOH / DCM:0.5 / 9.5)=0.3. Yield 0.006g. MS (ESI) m / z [M+1] + : 487.2. 1H NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1H), 7.20-7.27 (m, 4H), 6.60 (s, 1H), 5.05 (q, 1H), 4.11-4.16 (m, 4H), 3.70-3.76 (m, 2H), 3.56 (d, 2H), 2.85 (s, 3H), 2.67-2.74 (m, 2H), 1.84-1.90 (m, 3H), 1.26-1.29 (m, 2H).

[0188] Example 21 2-(2,2,2-trifluoro-1-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)ethyl)isoindoline (compound 21) [ka] a) 3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzaldehyde (3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)methanol (3.0 g, 7.94 mmol, 1.0 equivalent) was treated with activated manganese dioxide (3.4 g, 39.7 mmol, 5.0 equivalent) in 40 mL of MeOH at 60°C for 12 hours to obtain the compound described in the title as a white solid. f (SiO / Heptane:8 / 2) = 0.4. Yield 2.0g, 67%. MS (ESI) m / z [M+1] + : 376.13. 1 H-NMR (400 MHz, DMSO-d6): δ 9.98 (s, 1H), 8.34 (s, 1H), 8.22 (d, 1H), 7.52 (d, 1H), 4.23 (d, 2H), 3.61 (d, 2H), 3.34 (s, 3H), 2.87 (s, 3H), 2.76 (t, 2H), 1.97-2.04 (m, 1H), 1.92 (d, 2H), 1.37-1.49 (m, 2H).

[0189] b) 2,2,2-trifluoro-1-(3-(methylsulfonyl)-4-((1(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)ethane-1-ol (Methylsulfonyl)piperidine-4-yl)methoxy)benzaldehyde (2.0 g, 5.327 mmol, 1.0 equivalent) was treated with trimethyl(trifluoromethyl)silane (3.0 g, 21.31 mmol, 4.0 equivalents) in 20 mL of DMF in the presence of potassium carbonate (0.36 g, 2.6 mmol, 0.5 equivalents) at 0°C for 4 hours, and the compound described in the title was obtained as a white solid by column chromatography. f (EtOAc / heptane:8 / 2)=0.4. Yield 1.1g, 46%. MS (ESI) m / z [M+1] + : 445.99. 1 H-NMR (400 MHz, DMSO-d6): δ 7.96 (s, 1H), 7.80 (d, 1H), 7.34 (d, 1H), 6.96 (d, 1H), 5.26-5.31 (m, 1H), 4.11 (d, 2H), 3.61 (d, 2H), 3.27 (s, 3H), 2.86 (s, 3H), 2.76 (t, 2H), 1.95-2.01 (m, 1H), 1.91 (d, 2H), 1.35-1.47 (m, 2H).

[0190] c) 2,2,2-trifluoro-1-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)ethyl methanesulfonate 2,2,2-trifluoro-1-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)ethane-1-ol (1.1 g, 3.7 mmol, 1.0 equivalent) was treated with methanesulfonyl chloride (0.42 g, 3.69 mmol, 1.5 equivalent) in 20 mL of DCM in the presence of Et3N (0.37 g, 3.7 mmol, 1.5 equivalent) at 0°C for 2 hours to obtain the compound described in the title as a yellow liquid. f (EtOAc / heptane:8 / 2)=0.6. Yield 1.7g (crude). MS (ESI) m / z [M+1]+ : 523.89.

[0191] d) 4-((4-(1-azido-2,2,2-trifluoroethyl)-2-(methylsulfonyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine 2,2,2-trifluoro-1-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)ethyl methanesulfonate (1.3 g, 2.48 mmol, 1.0 equivalent) was treated with sodium azide (1.6 g, 24.8 mmol, 10.0 equivalent) in 20 mL of DMF at 90°C for 12 hours to obtain the compound described in the title as a yellow liquid. f (EtOAc / heptane:8 / 2)=0.5. Yield 1.2g (crude). MS (ESI) m / z [M+1] + : 471.07.

[0192] e) 2,2,2-trifluoro-1-(3(methylsulfonyl)-4-((1(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)ethane-1-amine 4-((4-(1-azido-2,2,2-trifluoroethyl)-2-(methylsulfonyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine (1.2 g, 2.55 mmol, 1.0 equivalent) was treated with platinum oxide (2.90 g, 12.8 mmol, 5.0 equivalent) in 20 mL of MeOH at 25°C for 2 hours, and the compound described in the title was obtained as a yellow, rubbery mass by column chromatography. f (SiO / Heptane:8 / 2) = 0.2 (Ninhydrin). Yield 0.35g, 31%. MS (ESI) m / z [M+1] + : 445.11. 1H-NMR (400 MHz, DMSO-d6): δ 7.93 (s, 1H), 7.80 (d, 1H), 7.32 (d, 1H), 4.60-4.63 (m, 1H), 4.10 (d, 2H), 3.59 (d, 2H), 3.26 (s, 3H), 2.86 (s, 3H), 2.76 (t, 2H), 2.60 (bs, 2H), 1.90-1.99 (m, 3H), 1.32-1.49 (m, 2H).

[0193] f) 2-(2,2,2-trifluoro-1-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)ethyl)isoindoline (compound 21) 2,2,2-trifluoro-1-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)ethane-1-amine (0.2 g, 0.45 mmol, 1.0 equivalent) was treated with 1,2-bis(bromomethyl)benzene (0.35 g, 1.35 mmol, 3.0 equivalent) in 10 mL of CH3CN at 65°C for 12 hours in the presence of N-ethyl-N-isopropylpropan-2-amine (0.17 g, 1.35 mmol, 3.0 equivalent), and then the compound described in the title was obtained as a white solid by preparative HPLC purification using method C (rt: 13.28 min). f (EtOAc / heptane:8 / 2)=0.5. Yield 0.035g. MS (ESI) m / z (M+H) + : 547.3. 1 H NMR (400 MHz, DMSO-d6): δ 7.96 (d, 1H), 7.83 (dd, 1H), 7.39 (d, 1H), 7.18-7.24 (m, 4H), 4.77-4.83 (m, 1H), 4.13 (d, 2H), 3.94 (s, 2H), 3.90 (s, 2H), 3.59-3.62 (m, 2H), 3.30 (s, 3H), 2.86 (s, 3H), 2.74-2.79 (m, 2H), 1.92-2.07 (m, 1H), 1.93 (d, 2H), 1.37-1.47 (m, 2H).

[0194] Example 22 2-(2,2-difluoro-1-(3-(methylsulfonyl)-4-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)phenyl)ethyl)isoindoline (compound 22) [ka] a) 1-(3-bromo-4-methoxyphenyl)-2,2-difluoro-2-(phenylsulfonyl)ethane-1-ol To a solution of 3-bromo-4-methoxybenzaldehyde (20.0 g, 93.5 mmol, 1.0 equivalent) in THF (200 mL) and HMPA (3.0 mL), ((difluoromethyl)sulfonyl)benzene (18.0 g, 93.5 mmol, 1.0 equivalent) was added at 0°C, followed by the slow addition of bis(trimethylsilyl)amide lithium solution (93.5 mL, 1.0 M in THF, 93.5 mmol, 1.0 equivalent) at 0°C. The mixture was stirred at 25°C for 3 days. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (3 times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography using 0-10% ethyl acetate in hexane as the eluent. The desired fraction was concentrated under reduced pressure to obtain the title compound as an off-white, viscous solid. Yield 10g, 26%. MS (ESI) m / z [M+1] + : 407.01. 1 H NMR (400 MHz, DMSO-d6): δ 7.99 (d, 2H), 7.72-7.80 (m, 1H), 7.58-7.68 (m, 3H), 7.39 (d, 1H), 6.89 (d, 1H), 5.49 (d, 1H), 3.89 (s, 3H).

[0195] b) N-(1-(3-bromo-4-methoxyphenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl)acetamide A solution of 1-(3-bromo-4-methoxyphenyl)-2,2-difluoro-2-(phenylsulfonyl)ethane-1-ol (10 g, 25 mmol, 1.0 equivalent) in ACN (10 mL) was mixed with H2SO4 (5 mL) at 0 °C and heated at 70 °C for 16 hours. After the reaction was complete, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound as a brown, viscous solid. Yield 11.0 g (crude). MS (ESI) m / z [M+1] + : 448.04. 1 H NMR (400 MHz, DMSO-d6): δ 9.02 (d, 1H), 7.88-7.92 (m, 3H), 7.71-7.75 (m, 2H), 7.67 (s, 1H), 7.41-7.43 (m, 1H), 7.10 (d, 1H), 5.85-5.95 (m, 1H), 3.84 (s, 3H), 1.84 (s, 3H).

[0196] c) 1-(3-bromo-4-methoxyphenyl)-2,2-difluoro-2-(phenylsulfonyl)ethane-1-amine hydrochloride N-(1-(3-bromo-4-methoxyphenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl)acetamide (11.0 g, 24.5 mmol, 1.0 equivalent) was added to a solution of MeOH (100.0 mL) and concentrated HCl (100.0 mL), and the mixture was heated at 100°C for 2 days. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the title compound as a white solid. Yield 10.0 g (crude). MS (ESI) m / z [M+1] + : 405.99. 1 H NMR (400 MHz, DMSO-d6): δ 9.27 (bs, 3H), 7.88-7.92 (m, 1H), 7.80-7.82 (m, 2H), 7.76 (s, 1H), 7.68-7.71 (m, 2H), 7.57 (d, 1H), 7.18 (d, 1H), 5.58-5.71 (m, 1H), 3.89 (s, 3H).

[0197] d) 2-(1-(3-bromo-4-methoxyphenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl)isoindoline 1-(3-bromo-4-methoxyphenyl)-2,2-difluoro-2-(phenylsulfonyl)ethane-1-amine (10.0 g, 24.6 mmol, 1.0 equivalent) and 1,2-bis(bromomethyl)benzene (13.0 g, 49.2 mmol, 2.0 equivalents) were treated in CH3CN (100 mL) in the presence of N-ethyl-N-isopropylpropan-2-amine (15.9 g, 21 mL, 123 mmol, 5.0 equivalents) at 70°C for 36 hours. The title compound was then obtained as a white solid by combiflash column chromatography. Yield: 8.0 g, 64%. MS (ESI) m / z [M+1] + : 507.97. 1 H NMR (400 MHz, DMSO-d6): δ 7.86 (d, 2H), 7.70-7.75 (m, 2H), 7.48-7.53 (m, 3H), 7.10-7.20 (m, 5H), 5.12-5.21 (m, 1H), 3.97 (d, 2H), 3.84 (s, 3H), 3.77 (d, 2H).

[0198] e) 2-bromo-4-(2,2-difluoro-1-(isoindolin-2-yl)-2-(phenylsulfonyl)ethyl)phenol 2-(1-(3-bromo-4-methoxyphenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl)isoindoline (8.0 g, 15.7 mmol, 1.0 equivalent) was added to aqueous HBr (200 mL) at 25°C. The mixture was heated at 110°C for 5 days. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the title compound as a brown solid. Yield 7.5 g (crude). MS (ESI) m / z [M+1] + 494.01. 1H NMR (400 MHz, DMSO-d6): δ 7.85 (d, 2H), 7.70-7.75 (m, 1H), 7.61-7.66 (m, 1H), 7.49-7.53 (m, 2H), 7.31 (d, 1H), 7.10-7.20 (m, 4H), 6.96 (d, 1H), 5.10-5.25 (m, 1H), 3.95-4.05 (m, 2H), 3.79-3.84 (m, 2H).

[0199] f)tert-butyl 4-((2-bromo-4-(2,2-difluoro-1-(isoindolin-2-yl)-2-(phenylsulfonyl)ethyl)phenoxy)methyl)piperidine-1-carboxylate 2-Bromo-4-(2,2-difluoro-1-(isoindorin-2-yl)-2-(phenylsulfonyl)ethyl)phenol (3.0 g, 6.1 mmol, 1.0 equivalent) was treated with tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (3.2 g, 11.0 mmol, 1.8 equivalents) in DMF (50 mL) in the presence of potassium carbonate (4.2 g, 30.5 mmol, 5.0 equivalents) at 60°C for 16 hours. The title compound was then obtained as a white solid by column chromatography. Yield: 3.0 g, 72%. MS (ESI) m / z [M+1] + : 691.25. 1 H NMR (400 MHz, DMSO-d6): δ 8.03 (d, 2H), 7.68-7.75 (m, 2H), 7.44-7.52 (m, 3H), 7.05-7.15 (m, 5H), 5.11-5.20 (m, 1H), 3.90-4.00 (m, 4H), 3.70-3.82 (m, 2H), 2.60-2.72 (m, 2H), 1.92-2.00 (m, 2H), 1.70-1.80 (m, 3H), 1.38 (s, 9H), 1.15-1.30 (m, 2H).

[0200] g)2-(1-(3-bromo-4-(piperidine-4-ylmethoxy)phenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl)isoindoline tert-butyl 4-((2-bromo-4-(2,2-difluoro-1-(isoindolin-2-yl)-2-(phenylsulfonyl)ethyl)phenoxy)methyl)piperidine-1-carboxylate (3.0 g, 4.3 mmol, 1.0 equivalent) was treated with trifluoroacetic acid (4.9 g, 43.4 mmol, 10.0 equivalents) in DCM (20 mL) to obtain the title compound as a brown solid. Yield: 3.0 g (crude). MS (ESI) m / z [M+1] + : 591.05.

[0201] h)2-(1-(3-bromo-4-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)phenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl)isoindoline To a solution of 2-(1-(3-bromo-4-(piperidine-4-ylmethoxy)phenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl)isoindoline (3.0 g, 5.07 mmol, 1.0 equivalent) in THF (30.0 mL) and H2O (10.0 mL), pyrimidine-2-ylmethylmethanesulfonate (1.9 g, 10.2 mmol, 2.0 equivalents) and Et3N (5.1 g, 7 mL, 51.0 mmol, 10.0 equivalents) were added at 25°C. The reaction mixture was stirred at 25°C for 24 hours. After the reaction was complete, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography using 0-50% ethyl acetate in heptane as the eluent, yielding the title compound as a white solid. Yield: 1.3 g, 38%. MS (ESI) m / z [M+1] + : 683.16. 1H NMR (400 MHz, DMSO-d6): δ 8.76 (d, 2H), 7.85 (d, 2H), 7.70-7.92 (m, 2H), 7.46-7.55 (m, 2H), 7.43-7.45 (m, 1H), 7.38 (t, 1H), 7.09-7.18 (m, 5H), 5.10-5.19 (m, 1H), 3.90-4.00 (m, 2H), 3.85-3.89 (m, 2H), 3.70-3.80 (m, 2H), 3.68 (bs, 2H), 2.88-2.92 (m, 2H), 2.08-2.15 (m, 2H), 1.68-1.75 (m, 3H), 1.30-1.40 (m, 2H).

[0202] i)2-(1-(3-bromo-4-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)phenyl)-2,2-difluoroethyl)isoindoline To a 10 mL solution of 2-(1-(3-bromo-4-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)phenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl)isoindoline (0.5 g, 0.73 mmol, 1.0 equivalent) in DMF (10 mL), acetic acid (0.88 g, 0.837 mL, 14.6 mmol, 20.0 equivalents) and sodium acetate (1.20 g, 14.6 mmol, 20.0 equivalents) were added stepwise at 0°C. Then, magnesium shavings (0.366 g, 14.6 mmol, 20.0 equivalents) were added, and the reaction mixture was stirred at 25°C for 16 hours. After the reaction was complete, the mixture was quenched with ice-cold water and extracted with 10% methanol in ethyl acetate (3 times). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography using 0-10% methanol in ethyl acetate as the eluent. The desired fraction was concentrated under reduced pressure to obtain the title compound as a brown, viscous solid. Yield: 0.13 g, 33%. MS (ESI) m / z [M+1] + : 543.14. 1H NMR (400 MHz, DMSO-d6): δ 8.77 (d, 2H), 7.63-7.69 (m, 1H), 7.44-7.52 (m, 2H), 7.15-7.25 (m, 4H), 7.11-7.13 (m, 1H), 6.47 (t, 1H), 4.03-4.05 (m, 1H), 3.88-3.91 (m, 4H), 3.79-3.82 (m, 2H), 3.65-3.69 (m, 2H), 2.91-2.94 (m, 2H), 2.11-2.16 (m, 2H), 1.70-1.80 (m, 3H), 1.35-1.38 (m, 2H). MS (ESI) m / z [M+1] + : 543.14.

[0203] j)2-(2,2-difluoro-1-(3-(methylsulfonyl)-4-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)phenyl)ethyl)isoindoline (compound 22) 2-(1-(3-bromo-4-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)phenyl)-2,2-difluoroethyl)isoindoline (0.14 g, 0.25 mmol, 1.0 equivalent) was treated with sodium methanesulfinate (0.13 g, 1.29 mmol, 5.0 equivalent) in DMSO (4.0 mL) in the presence of potassium carbonate (0.03 g, 10.25 mmol, 1.0 equivalent), copper(I) iodide (0.048 g, 0.25 mmol, 1.0 equivalent), and 2-picolinic acid (0.061 g, 0.5 mmol, 2.0 equivalents) at 110 °C for 16 hours. The compound described in the title was then purified as a white solid by preparative HPLC using Method A (rt: 13.38 min). Yield: 0.012 g. MS (ESI) m / z [M+1] + : 543.2. 1H NMR (400 MHz, DMSO-d6): δ 10.05 (bs,1H), 8.95 (d, 2H), 7.90 (s, 1H), 7.75 (d, 1H), 7.61 (t, 1H), 7.37 (d, 1H), 7.18-7.24 (m, 4H), 6.48 (t, 1H), 4.64 (bs, 2H), 4.24 (bs, 1H), 4.12 (d, 2H), 3.63-3.94 (m, 4H), 3.39 (bs, 1H), 3.30 (s, 3H), 3.16-3.21 (m, 2H), 1.98-2.15 (m, 4H), 1.69- 1.78 (m, 2H).

[0204] Example 23 2-((5-(1,3,4-oxadiazol-2-yl)isoindorin-2-yl)methyl)-5-(piperidine-4-ylmethoxy)-4H-pyran-4-one (compound 23a), 2-((5-(1,3,4-oxadiazol-2-yl)isoindoline-2-yl)methyl)-5-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 23b) and 2-((5-(1,3,4-oxadiazol-2-yl)-2H-isoindol-2-yl)methyl)-5-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 23c) [ka] a) tert-butyl 4-(((6-((5-(1,3,4-oxadiazol-2-yl)isoindorin-2-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate 2-(isoindolin-5-yl)-1,3,4-oxadiazole 2,2,2-trifluoroethane-1-one salt (1.0 g, 3.52 mmol, 1.0 equivalent) was treated with tert-butyl 4-(((6-(((methylsulfonyl)oxy)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (1.47 g, 3.52 mmol, 1.0 equivalent) in THF (10 mL) and water (10 mL) in the presence of Et3N (1.78 g, 2.4 mL, 17.6 mmol, 5.0 equivalents) at 65°C for 4 hours to obtain the title compound as a brown liquid. Yield: 1.0 g, 33%. MS (ESI) m / z [M+1] + : 509.25.

[0205] b) 2-((5-(1,3,4-oxadiazol-2-yl)isoindoline-2-yl)methyl)-5-(piperidine-4-ylmethoxy)-4H-pyran-4-one (compound 23a) tert-butyl 4-(((6-((5-(1,3,4-oxadiazol-2-yl)isoindorin-2-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (1.0 g, 1.96 mmol, 1.0 equivalent) was treated with TFA (5 mL) in DCM (10 mL) at 0°C for 1 hour to obtain the compound described in the title as a brown, sticky solid. Yield 1.0 g (crude). MS (ESI) m / z [M+1]+: 409.28.

[0206] c) 2-((5-(1,3,4-oxadiazol-2-yl)isoindoline-2-yl)methyl)-5-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 23b) 2-((5-(1,3,4-oxadiazol-2-yl)isoindolin-2-yl)methyl)-5-(piperidine-4-ylmethoxy)-4H-pyran-4-one (1.0 g, 2.4 mmol, 1.0 equivalent) was treated with pyrimidine-2-ylmethylmethanesulfonate (0.46 g, 2.4 mmol, 1.0 equivalent) in CH3CN (10 mL) in the presence of DIPEA (1.6 g, 2.1 mL, 12 mmol, 5.0 equivalents) at 65°C for 2 hours to obtain the compound described in the title as a colorless liquid. Yield: 0.40 g. MS (ESI) m / z [M+1] + : 501.41. 1 H NMR (400 MHz, DMSO-d6): δ 9.32 (s, 1H), 8.71-8.77 (m, 2H), 8.13 (s, 1H), 7.88-7.91 (m, 2H), 7.48 (d, 1H), 7.35-7.45 (m, 1H), 6.39 (s, 1H), 4.07 (s, 4H), 3.81 (s, 2H), 3.60-3.75 (m, 4H), 2.85-3.00 (m, 2H), 2.00-2.20 (m, 2H), 1.60-180 (m, 3H), 1.20-135 (m, 2H).

[0207] d) 2-((5-(1,3,4-oxadiazol-2-yl)-2H-isoindol-2-yl)methyl)-5-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 23c) To a solution of 2-((5-(1,3,4-oxadiazol-2-yl)isoindorin-2-yl)methyl)-5-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (0.4 g, 0.8 mmol, 1.0 equivalent) in trifluoroethanol (6 mL) under an N2 atmosphere, chloro[5-methoxy-2-[1-[(4-methoxyphenyl)imino-N]ethyl]phenyl-C][(1,2,3,4,5-eth)-1,2,3,4,5-pentamethyl-2,4-cyclopentadiene-1-yl]iridium (0.049 g, 0.08 mmol, 0.1 equivalent) was added at 25°C, and the mixture was then heated at 110°C for 48 hours under dark conditions. The mixture was filtered under dark conditions, and the filtrate was concentrated under vacuum. This crude product was purified by preparative HPLC using method C (rt: 13.79 min, column: X-Select Hexyl Phenylen) to obtain the title compound as a brown solid. Yield: 0.04 g. MS (ESI) m / z [M+1] + : 499.26. 1 H NMR (400 MHz, DMSO-d6): δ 9.25 (s, 1H), 8.75 (d, 2H), 8.27 (s, 1H), 8.11 (s, 1H), 7.67 (d, 2H), 7.49 (s, 1H), 7.45 (d, 1H), 7.37 (t, 1H), 6.29 (s, 1H), 5.48 (s, 2H), 3.61-3.66 (m, 4H), 2.87 (d, 2H), 2.08 (t, 2H), 1.64 (d, 3H), 1.20-123 (m, 2H).

[0208] Example 24 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((S * )-1-((1aR * ,7bR * )-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinoline-2-yl)ethyl)-4H-pyran-4-one (compound 24a) and 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((R * )-1-((1aR* ,7bR * )-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinoline-2-yl)ethyl)-4H-pyran-4-one (compound 24b) [ka] a) tert-butyl 1,1a,3,7b-tetrahydro-2H-cyclopropane[c]isoquinoline-2-carboxylate To a solution of 1,1a,2,7b-tetrahydro-3H-cyclopropa[c]isoquinoline-3-one (0.85 g, 5.34 mmol, 1.0 equivalent) in THF (20 mL), borane-DMS (6.08 g, 7.60 mL, 80.1 mmol, 15.0 equivalents) was added at 0°C, and the mixture was stirred at 60°C for 16 hours. The mixture was cooled to 0°C, quenched with methanol, refluxed at 60°C for 1 hour, and concentrated under high vacuum to obtain a colorless liquid. This crude product was placed in DCM (10 mL). Et3N (1.62 g, 2.23 mL, 16.02 mmol, 3.0 equivalents) and boc-anhydrous (2.33 g, 2.45 mL, 10.6 mmol, 2.0 equivalents) were added at 0°C, and the mixture was stirred at 25°C for 16 hours. After the reaction was complete, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography using 0-10% ethyl acetate in hexane as the eluent. The desired fraction was concentrated under reduced pressure to obtain tert-butyl 1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinoline-2-carboxylate as a colorless, viscous solid. Yield 0.40 g, 39%. MS (ESI) m / z [M+1-56] + : 190.11. 1H NMR (400 MHz, DMSO-d6): δ 7.36 (d, 1H), 7.19 (t, 1H), 7.12 (t, 1H), 7.05-7.10 (m, 1H), 4.27-4.56 (m, 2H), 3.30-3.40 (m, 1H), 2.09-2.15 (m, 1H), 1.47 (s, 9H), 1.20-1.30 (m, 1H), 0.69-0.83 (m, 1H).

[0209] b) 1a,2,3,7b-Tetrahydro-1H-cyclopropa[c]isoquinoline tert-butyl 1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinoline-2-carboxylate (0.40 g, 1.63 mmol, 1.0 equivalent) was treated in HCl (2 mL) with HCl in HCl (5.0 mL, 1.0 M solution) for 12 hours to obtain the compound described in the title as a white solid. Yield: 0.20 g (crude). MS (ESI) m / z [M+1] + : 146.02. 1 H NMR (400 MHz, DMSO-d6): δ 10.31 (bs, 1H), 9.40-9.70 (bs, 1H), 7.45 (d, 1H), 7.26-7.31 (m, 1H), 7.19-7.23 (m, 2H), 4.01-4.23 (m, 2H), 3.40-3.50 (m, 1H), 2.26-2.32 (m, 1H), 1.52-1.57 (m, 1H), 1.10-1.25 (m, 1H).

[0210] c) 5-(benzyloxy)-2-(1-(1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinoline-2-yl)ethyl)-4H-pyran-4-one 1a,2,3,7b-tetrahydro-1H-cyclopropa[c]isoquinoline hydrochloride (0.50 g, 3.44 mmol, 1.0 equivalent) was treated with 1-(5-(benzyloxy)-4-oxo-4H-pyran-2-yl)ethyl methanesulfonate (0.54 g, 1.65 mmol, 0.6 equivalent) in THF and H2O (1:1, 10.0 mL) in the presence of Et3N (1.74 g, 2.3 mL, 17.2 mmol, 5.0 equivalent) at 25°C for 24 hours. The title compound was then obtained as a colorless liquid mixture of diastereomers by column chromatography. Yield: 0.40 g, 31%. MS (ESI) m / z [M+1] + : 374.27. 1 H NMR (400 MHz, DMSO-d6): δ 8.15, 8.18 (2 s, 1H), 7.30-7.40 (m, 5H), 7.23 (t, 1H), 7.08-7.12 (m, 1H), 6.96-7.04 (m, 2H), 6.34, 6.38 (2 s, 1H), 4.90 (d, 2H), 3.80-3.85 (m, 1H), 3.50-3.66 (m, 2H), 2.81-2.89 (m, 1H), 1.86-1.91 (m, 1H), 1.39-1.42 (m, 3H), 0.91-0.98 (m, 1H), 0.71-0.77 (m, 1H).

[0211] d) 5-Hydroxy-2-(1-(1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinoline-2-yl)ethyl)-4H-pyran-4-one 5-(benzyloxy)-2-(1-(1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinoline-2-yl)ethyl)-4H-pyran-4-one (0.40 g, 1.07 mmol, 1.0 mmol) was treated in concentrated HCl (5 mL) for 16 hours to obtain the title compound as a mixture of diastereomers, as a colorless liquid. Yield 0.30 g (crude). MS (ESI) m / z [M+1] + : 284.19. 1H NMR (400 MHz, DMSO-d6): δ 9.04 (bs, 1H), 7.97, 8.01 (2 s, 1H), 7.21-7.44 (m, 2H), 6.92-7.11 (m, 2H), 6.35, 6.39 (2 s, 1H), 3.80-3.88 (m, 1H), 3.49-3.62 (m, 1H), 3.32-3.39 (m, 1H), 2.80-2.88 (m, 1H), 1.88-198 (m, 1H), 1.40-1.42 (m, 3H), 0.90-0.95 (m, 1H), 0.71-0.85 (m, 1H). MS (ESI) m / z [M+1] + : 284.19.

[0212] e) 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((S * )-1-((1aR * ,7bR * )-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinoline-2-yl)ethyl)-4H-pyran-4-one (compound 24a, diastereomer 1) and 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((R * )-1-((1aR * ,7bR * )-1,1a,3,7b-Tetrahydro-2H-cyclopropa[c]isoquinoline-2-yl)ethyl)-4H-pyran-4-one (Compound 24b, diastereomer 2) 5-Hydroxy-2-(1-(1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinoline-2-yl)ethyl)-4H-pyran-4-one (0.3 g, 1.06 mmol, 1.0 equivalent) was treated with (1-(methylsulfonyl)piperidine-4-yl)methylmethanesulfonate (0.23 g, 1.06 mmol, 1.0 equivalent) in DMSO (5 mL) in the presence of cesium carbonate (0.86 g, 2.65 mmol, 2.5 equivalents) and tris(2-(2-methoxyethoxy)ethyl)amine (0.03 g, 0.11 mmol, 0.1 equivalent) at 60°C for 5 hours to obtain a mixture of diastereomers. This mixture was purified by preparative HPLC using method C (rt: 11.99 min for diastereomer 1, rt: 12.80 min for diastereomer 2) to obtain two corresponding diastereomers as white solids. Yields were 0.03 g for diastereomer 1 and 0.04 g for diastereomer 2. Diastereomer 1: MS (ESI) m / z [M+1] + : 459.15. 1 H NMR (400 MHz, DMSO-d6): δ 8.02 (s,1H),7.22 (d,1H), 7.08 (t, 1H), 6.96-7.05 (m, 2H), 6.31 (s, 1H), 3.83 (d, 1H), 3.66 (d, 2H), 3.50-3.62 (m, 4H), 2.87-2.89 (m, 1H), 2.85 (s, 3H), 2.66-2.74 (m, 2H), 1.81-1.91- (m, 4H), 1.41 (d, 3H), 1.25-1.31 (m, 2H), 0.92-0.96 (m, 1H), 0.69-0.75 (m, 1H). Diastereomer 2: MS (ESI) m / z [M+1] + : 459.15. 1H NMR (400 MHz, DMSO-d6): δ 8.02 (s,1H), 7.24 (d,1H), 7.10 (t, 1H), 6.99-7.06 (m, 2H), 6.36 (s, 1H), 3.78 (d, 1H), 3.69 (d, 2H), 3.50-3.62 (m, 4H), 2.85 (s, 3H), 2.66-2.82 (m, 3H), 1.81-1.91 (m, 4H), 1.39 (d, 3H), 1.25-1.31 (m, 2H), 0.94-0.98 (m, 1H), 0.74-0.80 (m, 1H).

[0213] Example 25 2-(3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 25) [ka] a) 3-iodo-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)methyl benzoate [ka] Potassium carbonate (0.304 g, 2.20 mmol) was added to a mixture of methyl 4-hydroxy-3-iodobenzoate (0.278 g, 1.00 mmol) and 4-(methanesulfonyloxymethyl)-1-methanesulfonylpiperidine (0.298 g, 1.10 mmol) in dry DMSO (3.0 ml). The mixture was stirred at 100°C until the reaction was complete. Water was added to the cooled reaction mixture and stirred overnight at RT. The precipitated product was filtered, washed with water, and dried under vacuum to obtain the title compound (0.41 g). 1H NMR (400 MHz, DMSO-d6): δ 8.29 (d, 1H), 7.96 (dd, 1H), 7.11 (d, 1H), 4.05 (d, 2H), 3.83 (s, 3H), 3.57-3.66 (m, 2H), 2.87 (s, 3H), 2.77 (td, 2H), 1.87-1.99 (m, 3H), 1.40-1.54 (m, 2H).

[0214] b) 3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)methyl benzoate [ka] A mixture of methyl 3-iodo-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzoate (0.41 g, 0.904 mol), sodium ethanesulfinate (0.273 g, 2.352 mmol), copper(I) iodide (0.172 g, 0.904 mmol), and L-proline (0.104 g, 0.904 mmol) in dry DMSO (4.5 ml) was stirred at 100°C for 6 hours. Then, sodium ethanesulfinate (0.273 g, 2.352 mmol) was added, and stirring was continued at 100°C for 4 hours. The mixture was diluted with water and extracted with ELISA (2×). The combined organic phase was washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain the crude product. The title compound (0.19 g) was obtained by purification by flash chromatography. 1 H NMR (400 MHz, CDCl3): δ 8.62 (d, 1H), 8.28 (dd, 1H), 7.07 (d, 1H), 4.08 (d, 2H), 3.87-3.95 (m, 2H), 3.93 (s, 3H), 3.32 (q, 2H), 2.81 (s, 3H), 2.74 (td, 2H), 1.98-2.12 (m, 3H), 1.48-1.62 (m, 2H), 1.25 (t, 3H).

[0215] c) 3-(ethylsulfonyl)-4-((1(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)methanol [ka] To a cooled (0-5°C) mixture of methyl 3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxybenzoate (0.19 g, 0.453 mmol) in dry THF (2 ml), lithium borohydride (2 M in THF, 0.6 ml, 1.20 mmol) was added. The mixture was stirred at RT for 3.5 hours, then at 60°C until the reaction was complete. The mixture was cooled to 0-5°C, treated with dry acetone (2 ml), stirred at RT, and evaporated to dryness. Water and saturated NH4Cl solution were added to the residue, and the mixture was then extracted with ELISA (2 ×). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and evaporated to obtain the title compound (0.17 g). 1 H NMR (400 MHz, CDCl3): δ 7.93 (d, 1H), 7.62 (dd, 1H), 7.02 (d, 1H), 4.70 (d, 2H), 4.01 (d, 2H), 3.85-3.93 (m, 2H), 3.33 (q, 2H), 2.80 (s, 3H), 2.73 (td, 2H), 1.97-2.06 (m, 3H), 1.89-1.95 (m, 1H), 1.46-1.59 (m, 2H), 1.26 (t, 3H).

[0216] d) 4-((4-(chloromethyl)-2-(ethylsulfonyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine [ka] A mixture of (3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)methanol (0.17 g, 0.434 mmol) in dry DCM (3 ml) containing a catalytic amount of DMF was mixed with thionyl chloride (0.063 ml, 0.868 mmol). The mixture was stirred at RT until the reaction was complete. The solvent was evaporated, dry DCM was added, and the evaporation was repeated. The mixture was dried under vacuum to obtain the title compound (0.148 g). 1 H NMR (400 MHz, CDCl3): δ 7.97 (d, 1H), 7.62 (dd, 1H), 7.01 (d, 1H), 4.58 (s, 2H), 4.01 (d, 2H), 3.86-3.94 (m, 2H), 3.33 (q, 2H), 2.81 (s, 3H), 2.74 (td, 2H), 1.97-2.09 (m, 3H), 1.47-1.60 (m, 2H), 1.26 (t, 3H).

[0217] e) 2-(3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 25) [ka] A mixture of 4-((4-(chloromethyl)-2-(ethylsulfonyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine (0.148 g, 0.361 mmol), isoindoline hydrochloride (0.062 g, 0.397 mmol), and N,N-diisopropylamine (0.138 ml, 0.794 mmol) in dry DMSO (1.5 ml) was stirred at 60°C until the reaction was complete. Water was added to the cooled mixture, and the mixture was then stirred at RT for 30 minutes. The precipitated product was filtered, washed with water, and dried under vacuum to obtain the crude product. The title compound (0.061 g) was obtained by purification by reverse-phase flash chromatography. 1H NMR (400 MHz, DMSO-d6): δ 7.79 (d, 1H), 7.67 (dd, 1H), 7.27 (d, 1H), 7.15-7.25 (m, 4H), 4.07 (d, 2H), 3.88 (s, 2H), 3.83 (s, 4H), MS: m / z 493.8 (M+H) + .

[0218] Example 26 2-(3-(cyclopropylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 26) [ka] a) 3-(cyclopropylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)methyl benzoate [ka] The compound was prepared according to the procedure of Example 25(b), starting with 3-iodo-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzoate (0.50 g, 1.103 mmol), sodium cyclopropanesulfinate (0.567 g, 4.425 mmol), copper(I) iodide (0.127 g, 1.103 mmol), and L-proline (0.210 g, 1.103 mmol) in dry DMSO (5.0 ml). The title compound (0.25 g) was obtained by purification by column chromatography. 1H NMR (400 MHz, CDCl3): δ 8.53 (d, 1H), 8.26 (dd, 1H), 7.08 (d, 1H), 4.10 (d, 2H), 3.86-3.95 (m, 2H), 3.92 (s, 3H), 2.81-2.88 (m, 1H), 2.81 (s, 3H), 2.75 (td, 2H), 2.01-2.15 (m, 3H), 1.48-1.62 (m, 2H), 1.28-1.35 (m, 2H), 0.98-1.05 (m, 2H).

[0219] b) (3-(cyclopropylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)methanol [ka] The compound was prepared according to the procedure of Example 25(c), starting with methyl 3-(cyclopropylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxybenzoate (0.25 g, 0.579 mmol) and lithium borohydride (2 M in THF, 0.9 ml, 1.80 mmol) at 60°C in dry THF (3.0 ml). The title compound (0.0814 g) was obtained by purification by reverse-phase flash chromatography. 1 H NMR (400 MHz, CDCl3): δ 7.84 (d, 1H), 7.59 (dd, 1H), 7.03 (d, 1H), 4.68 (d, 2H), 4.03 (d, 2H), 3.85- 3.93 (m, 2H), 2.84-2.92 (m, 1H), 2.80 (s, 3H), 2.74 (td, 2H), 2.00-2.12 (m, 3H), 1.86 (t, 1H), 1.46-1.60 (m, 2H), 1.26-1.32 (m, 2H), 0.96-1.03 (m, 2H).

[0220] c) 4-((4-(chloromethyl)-2-(cyclopropylsulfonyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine [ka] The compound was prepared according to the procedure of Example 25(d), starting with (3-(cyclopropylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)methanol (0.81 g, 0.201 mmol) and thionyl chloride (0.03 ml, 0.411 mmol) in dry DCM (1.5 ml). Yield: 0.081 g. 1 H NMR (600 MHz, DMSO-d6): δ 7.80 (d, 1H), 7.74 (d, 1H), 7.32 (d, 1H), 4.83 (s, 2H), 4.11 (d, 2H), 3.57-3.64 (m, 2H), 2.96-3.02 (m, 1H), 2.87 (s, 3H9, 2.72-2.80 (m, 2H), 1.89-2.04 (m, 3H), 1.36-1.45 (m, 2H), 1.00-1.10 (m, 4H).

[0221] d) 2-(3-(cyclopropylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 26) [ka] The compound was prepared according to the procedure of Example 25(e), starting with 4-((4-(chloromethyl)-2-(cyclopropylsulfonyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine (0.081 g, 0.192 mmol), isoindoline (0.024 ml, 0.211 mmol), and DIPEA (0.074 ml, 0.422 mmol) in dry DMSO (1.0 ml). The untreated (raw) product was pulverized with diethyl ether-methanol and dried under vacuum to obtain the title compound (0.023 g). 1H NMR (400 MHz, DMSO-d6): δ 7.72 (d, 1H), 7.65 (dd, 1H), 7.28 (d, 1H), 7.15-7.25 (m, 4H), 4.09 (d, 2H), 3.87 (s, 2H), 3.83 (d, 4H), 3.57-3.66 (m, 2H), 2.94-3.03 (m, 1H), 2.87 (s, 3H), 2.77 (td, 2H), 1.89-2.05 (m, 3H9, 1.34-1.48 (m, 2H), 1.00-1.07 (m, 4H). MS: m / z 505.8 (M+H) + .

[0222] Example 27 2-(3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)-5-(trifluoromethyl)isoindoline (compound 27) [ka] The compound was prepared according to the procedure of Example 25(e), starting with 4-((4-(chloromethyl)-2-(ethylsulfonyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine (0.143 g, 0.35 mmol), 5-(trifluoromethyl)isoindoline hydrochloride (0.086 ml, 0.385 mmol), and DIPEA (0.134 ml, 0.77 mmol) in 1.5 ml of dry DMSO. The title compound (0.0313 g) was obtained by purification by reverse-phase flash chromatography. 1H NMR (400 MHz, CDCl3): δ 7.95 (d, 1H), 7.65 (dd, 1H), 7.47 (d, 1H), 7.43 (s, 1H), 7.29 (s, 1H), 7.01 (d, 1H), 4.01 (d, 2H), 3.95 (s, 4H9, 3.51-3.93 (m, 4H), 3.35 (q, 2H), 2.81 (s, 3H), 2.68-2.79 (m, 2H), 1.96-2.11 (m, 3H), 1.47-1.61 (m, 2H), 1.26 (t, 3H). MS: m / z 561.5 (M+H) + .

[0223] Example 28 2-(3-(butylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 28) [ka] a) 3-(butylsulfonyl)-4-butyl fluorobenzoate [ka] In 1.0 ml of dry DMF, a mixture of 4-fluoro-3-sulfinobenzoic acid (0.15 g, 0.735 mmol), 1-iodobutane (0.25 ml, 2.204 mmol), and potassium carbonate (0.305 g, 2.204 mmol) was stirred at 80°C until the reaction was complete. The cooled reaction mixture was diluted with water and extracted with phenylethylamine (2×). The combined organic phase was washed with water and brine, dried over anhydrous sodium 2SO4, filtered, and evaporated to obtain the crude product. The title compound (0.14 g) was obtained by purification by phase flash chromatography. 1H NMR (400 MHz, CDCl3): δ 8.61 (dd, 1H), 8.34 (ddd, 1H), 7.32 (dd, 1H), 4.36 (t, 2H), 3.28-3.35 (m, 2H), 1.68-1.82 (m, 4H), 1.39-1.52 (m, 4H), 0.99 (t, 3H), 0.92 (t, 3H).

[0224] b) 3-(butylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)butyl benzoate [ka] To a chilled mixture of sodium hydride (50% by weight in oil, 0.013 g, 0.553 mmol) in dry DMF (1.5 ml), a solution of (1-(methylsulfonyl)piperidine-4-yl)methanol (0.094 g, 0.487 mmol) was added. The mixture was stirred at RT for 15 minutes, then a solution of 3-(butylsulfonyl)-4-fluorobenzoate butyl (0.14 g, 0.442 mmol) in dry DMF (1.0 ml) was added, and stirring at RT was continued until the reaction was complete. The reaction mixture was diluted with water and extracted with RINKAN (2×). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and evaporated to obtain the crude product. The title compound (0.10 g) was obtained by purification by phase flash chromatography. 1 H NMR (400 MHz, DMSO-d6): δ 8.33 (d, 1H), 8.24 (dd, 1H), 7.43 (d, 1H), 4.29 (t, 2H), 4.19 (d, 2H), 3.56-3.65 (m, 2H), 3.37-3.44 (m, 2H), 2.87 (s, 3H), 2.71-2.81 (m, 2H), 1.85-2.04 (m, 3H), 1.65-1.75 (m, 2H), 0.94 (t, 3H), 0.83 (t, 3H).

[0225] c) 3-(butylsulfonyl)-4-((1(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)methanol [ka] The compound was prepared according to the procedure of Example 25(c), starting with 3-(butylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)butyl benzoate (0.10 g, 0.204 mmol) and lithium borohydride (2 M in THF, 0.5 ml, 1.00 mmol) in dry THF (2 ml). The yield of the crude product was 0.108 g. LC-MS: m / z 420.4 (M+H) + .

[0226] d) 4-((2-(butylsulfonyl)-4-(chloromethyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine [ka] The compound was prepared according to the procedure of Example 25(d), starting with (3-(butylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)methanol (0.108 g, 0.206 mmol) and thionyl chloride (0.05 ml, 0.685 mmol) in dry DCM (2.0 ml). Yield: 0.081 g. 1 H NMR (400 MHz, CDCl3): δ 7.97 (d, 1H), 7.62 (dd, 1H), 7.01 (d, 1H), 4.58 (s, 2H), 4.02 (d, 2H), 3.86-3.94 (m, 2H), 3.27-3.34 (m, 2H), 2.81 (s, 3H), 2.74 (td, 2H), 1.97-2.10 (m, 3H), 1.64-1.71 (m, 2H), 1.48-1.60 (m, 2H), 1.36-1.46 (m, 2H), 0.91 (t, 3H).

[0227] e) 2-(3-(butylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 28) [ka] The compound was prepared according to the procedure of Example 25(e), starting with 4-((2-(butylsulfonyl)-4-(chloromethyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine (0.081 g, 0.185 mmol), isoindoline (0.023 ml, 0.203 mmol), and DIPEA (0.081 ml, 0.462 mmol) in dry DMSO (1.0 ml). The title compound (0.015 g) was obtained by purification by reverse-phase flash chromatography. 1 H NMR (600 MHz, DMSO-d6): δ 7.79 (d, 1H), 7.67 (dd, 1H), 7.27 (d, 1H), 7.17-7.24 (m, 4H), 4.08 (d, 2H), 3.88 (s, 2H), 3.92 (s, 4H), 3.57-3.63 (m, 2H), 3.35-3.43 (m, 2H), 2.87 (s, 3H), 2.76 (td, 2H), 1.87-1.98 (m, 3H), 1.47-1.54 (m, 2H), 1.38-1.47 (m, 2H), 1.30-1.38 (m, 2H9, 0.83 (t, 3H). MS: m / z 521.9 (M+H) + .

[0228] Example 29 2-((1'H-Spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 29) [ka] A mixture of 6'-methoxy-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline] hydrochloride (0.050 g, 0.220 mmol), 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (0.074 g, 0.220 mmol), and DIPEA (0.096 ml, 0.550 mmol) in dry DMSO (1.5 ml) was stirred at 60°C until the reaction was complete. The reaction mixture was diluted with water and extracted with ethyl acetate (2 ×). The combined organic phases were washed with water and brine, dried over anhydrous sodium 2SO4, filtered, and evaporated to obtain the crude product. The title compound (0.087 g) was obtained by purification by reverse-phase flash chromatography. 1 H NMR (400 MHz, CDCl3): δ 7.60 (s, 1H), 6.92 (d, 1H), 6.66 (dd, 1H), 6.47 (s, 1H), 6.21 (d, 1H), 3.81-3.90 (m, 2H), 3.82 (s, 2H), 3.75 (s, 3H), 3.74 (d, 2H), 3.56 (s, 2H), 2.79 (s, 3H), 2.69 (td, 2H), 2.66 (s, 2H), 1.95-2.08 (m, 3H), 1.36-1.50 (m, 2H), 1.00-1.06 (m, 2H), 0.82-0.89 (m, 2H). MS: m / z 489.9 (M+H) + .

[0229] Example 30 tert-butyl 6-(((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-2-azaspiro[3,3]heptane-2-carboxylate (compound 30) [ka] a) tert-butyl 6-(((methylsulfonyl)oxy)methyl)-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a cooled (0-5°C) mixture of tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (0.20 g, 0.880 mmol) and triethylamine (0.25 ml, 1.794 mmol) in dry DCM (4.0 ml), methanesulfonyl chloride (0.072 ml, 0.924 mmol) dissolved in dry DCM (2.0 ml) was added. The reaction mixture was stirred overnight in RT, then diluted in DCM and washed with saturated NaHCO3 solution, water, and brine. The organic phase was dried and evaporated to obtain the title compound (0.24 g). 1 H NMR (400 MHz, CDCl3): δ 4.15 (d, 2H), 3.93 (s, 2H), 3.84 (s, 2H), 3.01 (s, 3H), 2.51-2.64 (m, 1H), 2.28-2.37 (m, 2H), 1.99-2.07 (m, 2H), 1.43 (s, 9H).

[0230] b) tert-butyl 6-(((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-2-azaspiro[3.3]heptane-2-carboxylate (compound 30) [ka] A mixture of tert-butyl 6-(((methylsulfonyl)oxy)methyl)-2-azaspiro[3.3]heptane-2-carboxylate (0.229 g, 0.750 mmol), 2-{[3,4-dihydroisoquinolin-2(1H)-yl]methyl}-5-hydroxy-4H-pyran-4-one (0.193 g, 0.750 mmol) and potassium carbonate (0.228 g, 1.650 mmol) in dry DMSO (4.0 mL) was stirred at 100 °C until the reaction was complete. The cooled reaction mixture was diluted with water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried and evaporated to give the title compound (0.28 g). A portion (60 mg) of the crude product was purified by reverse-phase flash chromatography to give the title compound (0.0255 g). 1 H NMR (400 MHz, CDCl3): δ 7.60 (s, 1H), 7.08-7.17 (m, 3H), 6.97-7.02 (m, 1H), 6.49 (s, 1H), 3.93 (s, 2H), 3.85 (s, 3H), 3.83 (d, 2H), 3.71 (s, 2H), 3.55 (s, 2H), 2.90-2.97 (m, 2H), 2.80-2.86 (m, 2H), 2.58-2.70 (m, 1H), 2.30-2.39 (m, 2H), 2.00-2.09 (m, 2H), 1.43 (s, 9H). MS: m / z 468.0 (M+H) + .

[0231] Example 31 tert-butyl 6-(((6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (Compound 31)

Chemical Structure

[0232] The following compounds were prepared following the procedure described for Compound 31 in Example 31, starting with 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-hydroxy-4H-pyran-4-one and another suitable starting material. The compound numbers, characteristic data, and other starting materials are shown in the table.

[0233] TIFF2026048803000085.tif241164

[0234] Example 32 Tert-butyl 6-(1-((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)ethyl)-2-azaspiro[3.3]heptane-2-carboxylate (compound 36, alternative synthesis) [ka] a) tert-butyl 6-(1-((methylsulfonyl)oxy)ethyl)-2-azaspiro[3.3]heptane-2-carboxylate [ka] The compound was prepared according to the procedure of Example 30(a), starting with tert-butyl 6-(1-hydroxyethyl)-2-azaspiro[3.3]heptane-2-carboxylate (0.80 g, 3.31 mmol), triethylamine (0.87 ml, 1.883 mmol), and methanesulfonyl chloride (0.38 ml, 1.481 mmol) in dry DCM (12.5 ml). Yield: 1.06 g. 1 H NMR (400 MHz, CDCl3): δ 4.68 (quint, 1H), 3.93 (s, 2H), 3.78-3.85 (m, 2H), 3.01 (s, 3H), 2.20-2.42 (m, 3H), 2.07-2.16 (m, 1H), 1.94-2.02 (m, 1H), 1.43 (s, 9H(, 1.32 (d, 3H).

[0235] b) Tert-butyl 6-(1-((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)ethyl)-2-azaspiro[3.3]heptan-2-carboxylate A mixture of 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-hydroxy-4H-pyran-4-one (0.854 g, 3.32 mmol), tert-butyl 6-(1-((methylsulfonyl)oxy)ethyl)-2-azaspiro[3.3]heptan-2-carboxylate (1.06 g, 3.32 mmol), cesium carbonate (2.162 g, 6.64 mmol), and tris(2-(2-methoxyethoxy)ethyl)amine (0.054 g, 0.166 mmol) in dry DMSO (10 ml) was stirred at 60°C until the reaction was complete. The cooled mixture was diluted with water and extracted with ELISA (2×). The combined organic phase was washed with water and brine, dried, and evaporated. The crude product was purified by flash chromatography to obtain the title compound (0.72 g). LC-MS: m / z 482.0 (M+H). 1 H NMR (400 MHz, Chloroform-d) δ: 7.65 (s, 1H), 7.08-7.17 (m, 3H), 6.97-7.03 (m, 1H), 6.47 (s, 1H), 4.32 (quint, 1H), 3.93 (s, 2H), 3.77-3.86 (m, 2H), 3.71 (s, 2H), 3.55 (s, 2H), 2.94 (t, 2H), 2.83 (t, 2H), 2.28-2.41 (m, 1H), 2.15-2.28 (m, 3H), 1.99-2.07 (m, 1H), 1.42 (s, 9H), 1.10 (d, 3H).

[0236] Example 33 tert-butyl 2-(1-((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)ethyl)-7-azaspiro[3.5]nonane-7-carboxylate (compound 37) [ka] a) tert-butyl 2-(1-hydroxyethyl)-7-azaspiro[3.5]nonane-7-carboxylate [ka] The compound was prepared by starting with tert-butyl 2-acetyl-7-azaspiro[3.5]nonane-7-carboxylate (0.47 g, 1.758 mmol) and sodium borohydride (0.10 g, 2.64 mmol) in dry methanol (5.0 ml) and following the procedure for intermediate 3(c). Yield: 0.48 g. 1 H NMR (400 MHz, CDCl3): δ 3.63-3.73 (m, 1H), 3.31-3.40 (m, 2H), 3.22-3.30 (m, 2H), 2.15-2.28 (m, 1H), 1.79-1.94 (m, 2H), 1.53-1.65 (m, 4H), 1.32-1.52 (m, 3H), 1.45 (s, 9H), 1.09 (d, 3H).

[0237] b) tert-butyl 2-(1-((methylsulfonyl)oxy)ethyl)-7-azaspiro[3.5]nonane-7-carboxylate [ka] The compound was prepared according to the procedure of Example 32(a), starting with tert-butyl 2-(1-hydroxyethyl)-7-azaspiro[3.5]nonane-7-carboxylate (0.48 g, 1.693 mmol), triethylamine (0.45 ml, 3.23 mmol), and methanesulfonyl chloride (0.20 ml, 2.58 mmol) in dry DCM (7.5 ml). Yield: 0.60 g. 1 H NMR (400 MHz, CDCl3): δ 4.68-4.77 (m, 1H), 3.19-3.43 (m, 4H), 3.01 (s, 3H), 2.39-2.52 (m, 1H), 1.85-1.99 (m, 2H), 1.71 (dd, 1H), 1.51-1.61 (m, 3H), 1.38-1.48 (m, 2H), 1.45 (s, 9H), 1.33 (d, 3H).

[0238] c) tert-Butyl 2-(1-((6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)ethyl)-7-azaspiro[3.5]nonane-7-carboxylate (Compound 37) [Chemical formula] The compound was prepared according to the procedure of Example 32(b) (Step 2a), starting from tert-butyl 2-(1-((methylsulfonyl)oxy)ethyl)-7-azaspiro[3.5]nonane-7-carboxylate (0.60 g, 1.692 mmol), 2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-hydroxy-4H-pyran-4-one (0.435 g, 1.692 mmol), cesium carbonate (1.103 g, 3.38 mmol) and tris(2-(2-methoxyethoxy)ethyl)amine (0.027 g, 0.085 mmol) in dry DMSO (5.0 ml). Yield 0.30 g.[[ID=?]] 1 H NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1H), 7.07 - 7.13 (m, 3H), 7.01 - 7.06 (m, 1H), 6.38 (s, 1H), 4.19 - 4.27 (m, 1H), 3.63 (s, 2H), 3.58 (s, 2H), 3.21 - 3.29 (m, 2H), 3.11 - 3.20 (m, 2H), 2.80 - 2.86 (m, 2H), 2.73 - 2.79 (m, 2H), 2.35 - 2.44 (m, 1H), 1.75 - 1.86 (m, 2H), 1.67 (dd, 1H), 1.45 - 1.58 (m, 3H), 1.32 - 1.41 (m, 2H), 1.38 (s, 9H), 1.05 (d, 3H).

[0239] Example 34 5-((2-Azaspiro[3.3]heptan-6-yl)oxy)-2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4H-pyran-4-one bis-trifluoroacetate (Compound 38) [Chemical formula] To a solution of tert-butyl 6-((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (0.30 g, 0.663 mmol) in dry DCM (5.0 ml), trifluoroacetic acid (0.30 ml, 3.89 mmol) was added. The mixture was stirred overnight at RT. Further trifluoroacetic acid (0.30 ml, 6.89 ml) was added, and stirring was continued at 40°C until the reaction was complete. The solvent was evaporated, and the residue was further treated with DCM, and evaporation was repeated to obtain the title compound (0.44 g). 1 H NMR (400 MHz, DMSO-d6): δ 8.68 (br s, 2H), 8.04 (s, 1H), 7.16-7.33 (m, 4H), 4.45 (quint, 1H), 4.36 (br s, 4H), 3.90-4.05 (m, MS: m / z 353.3 (M-2TFA+H) + .

[0240] The following compounds were prepared according to the procedure described for compound 38 in Example 34. The compound number, characteristic data, starting materials, and possible deviations in reaction conditions (C = concentration of starting material) are shown in the table.

[0241] TIFF2026048803000093.tif222164 TIFF2026048803000094.tif107164

[0242] Example 35 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((2-pyrimidine-2-yl)-2-azaspiro[3,3]heptan-6-yl)oxy)-4H-pyran-4-one (compound 45) [ka] A mixture of 5-((2-azaspiro[3,3]heptan-6-yl)oxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one bis-trifluoroacetate (0.13 g, 0.224 mmol) and triethylamine (0.125 ml, 0.896 mmol) in dry DMF (1.5 ml) was mixed with 2-bromopyrimidine (0.043 g, 0.269 mmol) dissolved in dry DCM (0.5 ml). The mixture was stirred overnight in RT, then diluted with DCM, washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain the title compound (0.046 g). 1 H NMR (600 MHz, DMSO-d6): δ 8.25 (d, 2H), 7.95 (s, 1H), 7.01-7.07 (m, 3H), 6.95-6.98 (m, 1H), 6.58 (t, 1H), 6.32 (s, 1H), 4.43 (quint, MS: m / z 431.7 (M+H)+.

[0243] Example 36 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-(pyrimidine-2-yl)-7-azaspiro[3.5]nonane-2-yl)oxy)-4H-pyran-4-one (compound 46) [ka] A mixture of 5-((7-azaspiro[3,5]nonan-2-yl)oxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one bis-trifluoroacetate (0.152 g, 0.225 mmol) and triethylamine (0.125 ml, 0.900 mmol) in dry DMF (1.5 ml) was mixed with 2-bromopyrimidine (0.043 g, 0.270 mmol) dissolved in dry DMF (0.5 ml). The mixture was stirred overnight at RT, then 2-bromopyrimidine (0.020 mg, 0.126 mmol) was added, and the mixture was stirred at 60°C until the reaction was complete. The cooled mixture was diluted with DCM, washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain the compound indicated in the title (0.023 g). 1 H NMR (400 MHz, CDCl3): δ 8.28 (d, 2H), 7.44 (s, 1H), 7.08-7.18 (m, 3H), 6.97-7.02 (m, 1H), 6.50 )s, 1H), 6.44 (t, 1H), 4.59 (quint, 1H), 3.75-3.80 (m, 2H), 3.68-3.75 (m, 4H), 3.55 (s, 2H), 2.93 (t, 2H), 2.83 (t, 2H), 2.36-2.44 (m, 2H), 2.05-2.13 (m, 2H), 1.60-1.71 (m, 4H). MS: m / z 459.7 (M+H) + .

[0244] Example 37 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-(pyrimidine-2-ylmethyl)-7-azaspiro[3.5]nonane-2-yl)oxy)-4H-pyran-4-one (compound 47) [ka] A mixture of 5-((7-azaspiro[3,5]nonan-2-yl)oxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one bis-trifluoroacetate (0.152 g, 0.225 mmol) and triethylamine (0.125 ml, 0.900 mmol) in dry DMF (1.5 ml) was mixed with pyrimidine-2-ylmethyl methanesulfonate (0.053 g, 0.281 mmol) dissolved in dry DMF (0.5 ml). The mixture was stirred overnight at RT, then further pyrimidine-2-ylmethyl methanesulfonate (0.020 g, 0.106 mmol) was added, and the mixture was stirred at 60°C until the reaction was complete. The cooled mixture was diluted with DCM, washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain the compound indicated in the title (0.018 g). 1 H NMR (400 MHz, CDCl3): δ 8.73 (d, 2H), 7.41 (s, 1H), 7.18 (t, 1H), 7.08-7.16 (m, 3H), 6.97-7.02 (m, 1H), 6.49 (s, 1H), 4.50 (quint, 1H), 3.78 (s, 2H), 3.71 (s, 2H), 3.54 (s, 2H), 2.93 (t, 2H), 2.83 (t, 2H), 2.36-2.59 (m, 4H), 2.26-2.36 (m, 2H), 1.96-2.05 (m, 2H), 1.61-1.79 (m, 4H). MS: m / z 473.5 (M+H) + .

[0245] Example 38 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-(pyrimidine-2-yl)-7-azaspiro[3.5]nonane-2-yl)methoxy)-4H-pyran-4-one (compound 48) [ka] The compound was prepared according to the procedure of Example 36, starting with 5-((7-azaspiro[3,5]nonan-2-yl)methoxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one bis-trifluoroacetate (0.173 g, 0.225 mmol), triethylamine (0.125 ml, 0.897 mmol), and 2-bromopyrimidine (0.075 mg, 0.472 mmol) in dry DMF (2.0 ml). Yield: 0.047 g. 1 H NMR (400 MHz, CDCl3): δ 8.28 (d, 2H), 7.61 (s, 1H), 7.08-7.18 (m, 3H), 6.97-7.02 (m, 1H), 6.49 (s, 1H), 6.42 (t, 1H), 3.90 (d, 2H), 3.73-3.80 (m, 2H), 3.64-3.73 (m, 4H), 3.55 (s, 2H), 2.93 (t, 2h), 2.73-2.87 (m, 3H), 2.02-2.12 (m, 2H), 1.63-1.72 (m, 4H), 1.54-1.62 (m, 2H).MS: m / z 473.5 (M+H) + .

[0246] Example 39 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((6-(pyrimidine-2-yl)-6-azaspiro[3,4]octan-2-yl)oxy)-4H-pyran-4-one (compound 49) [ka] The compound was prepared according to the procedure of Example 36, starting with 5-((6-azaspiro[3,4]octan-2-yl)oxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one bis-trifluoroacetate (0.149 g, 0.250 mmol), triethylamine (0.14 ml, 1.004 mmol), and 2-bromopyrimidine (0.050 g, 0.313 mmol) in dry DMF (2.0 ml). Yield: 0.041 g. 1H NMR (400 MHz, CDCl3), mixture of diastereomers: δ 8.28-8.34 (m, 2H), 7.40-7.71 (m, 2H), 7.08-7.18 (m, 3H), 6.97-7.03 (m, 1H), 6.44-6.52 (m, 2H), 4.54-4.68 (m, 1H), 3.71 (s, 2H), 3.56-3.65 (m, 4H), 3.55 (s, 2H), 2.93 (t, 2H), 2.83 (t, 2H), 2.43-2.56 (m, 2H), 2.29-2.39 (m, 2H), 2.07 (t, 1H), 2.02 (t, 1H). MS: m / z 445.5 (M+H) + .

[0247] Example 40 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((2-(pyrimidine-2-yl)-2-azaspiro[3,3]heptan-6-yl)methoxy)-4H-pyran-4-one (compound 50) [ka] a) 2-(pyrimidine-2-yl)-2-azaspiro[3.3]heptan-6-carboxylate methyl [ka] A mixture of methyl 2-azaspiro[3,3]heptane-6-carboxylate trifluoroacetate (0.269 g, 1.00 mmol), 2-chloropyrimidine (0.115 g, 1.00 mmol), and DIPEA (0.383 ml, 2.200 mmol) in dry acetonitrile (2.5 ml) was stirred at 90°C until the reaction was complete. The cooled mixture was diluted with water and extracted with butyl. The organic phase was washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain the title compound (0.10 g). 1H NMR (400 MHz, CDCl3): δ 8.30 (d, 2H), 6.52 (t, 1H), 4.16 (s, 2H), 4.09 (s, 2H), 3.70 (s, 3H), 3.07 (quint, 1H), 2.45-2.58 (m, 4H).

[0248] b) 2-(pyrimidine-2-yl)-2-azaspiro[3.3]heptan-6-yl)methanol [ka] To a solution of methyl 2-(pyrimidine-2-yl)-2-azaspiro[3.3]heptane-6-carboxylate (0.20 g, 0.857 mmol) in dry THF (4.5 ml), lithium aluminum hydride (2.0 M in THF, 1.3 ml, 1.30 mmol) was added, and the mixture was stirred overnight at RT. The mixture was cooled to 0-5°C, and water (50 μl), 2 M NaOH (100 μl), and water (150 μl) were added in that order, and the mixture was stirred at RT for 1 hour. Anhydrous sodium sulfate was added, and stirring was continued for 15 minutes. The mixture was filtered through a Celite stopper. The filter cake was washed with THF, the filtrate was evaporated, and the filtrate was dried to obtain the title compound (0.18 g). 1 H NMR (400 MHz, CDCl3 / MeOD-d4): δ 8.28 (d, 2H), 6.52 (t, 1H), 4.15 (s, 2H), 4.05 (s, 2H), 3.57 (d, 2H), 2.29-2.38 (m, 2H), 2.00-2.08 (m, 2H).

[0249] c) 2-(pyrimidine-2-yl)-2-azaspiro[3.3]heptan-6-yl)methylmethanesulfonate [ka] To a cooled (0-5°C) mixture of (2-(pyrimidine-2-yl)-2-azaspiro[3.3]heptan-6-yl)methanol (0.080 g, 0.390 mmol) and trimethylamine (0.067 ml, 0.477 mmol) in 1.5 ml of dry DCM, methanesulfonyl chloride (0.033 ml, 0.429 mmol) in 0.5 ml of dry DCM was added. The mixture was stirred at 0-5°C until the reaction was complete. The mixture was diluted with water and saturated NH4Cl solution and extracted with DCM. The organic phase was dried and evaporated to obtain the title compound (0.063 g). 1 H NMR (400 MHz, CDCl3): δ 8.30 (d, 2H), 6.53 (t, 1H), 4.20 (d, 2H), 4.16 (s, 2H), 4.07 (s, 2H), 3.04 (s, 3H), 2.62-2.71 (m, 1H), 2.39-2.45 (m, 2H), 2.10-2.16 (m, 2H).

[0250] d) 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((2-(pyrimidine-2-yl)-2-azaspiro[3,3]heptan-6-yl)methoxy)-4H-pyran-4-one (compound 50) [ka] A mixture of (2-(pyrimidine-2-yl)-2-azaspiro[3,3]heptan-6-yl)methylmethanesulfonate (0.062 g, 0.219 mmol), 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-hydroxy-4H-pyran-4-one (0.056 g, 0.219 mmol), and potassium carbonate (0.067 g, 0.481 mmol) in dry DMSO (1.5 ml) was stirred at 60°C until the reaction was complete. The cooled mixture was diluted with water and extracted with ELISA (2×). The combined organic phases were washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain the title compound (0.012 g). 1H NMR (600 MHz, DMSO-d6): δ 8.32 (d, 2H), 8.15 (s, 1H), 7.08-7.14 (m, 3H), 7.02-7.05 (m, 1H), 6.64 (t, 1H), 6.39 (s, 1H), 4.05 (s, 2H), 3.97 (s, 2H), 3.80 (d, 2H), 3.62 (s, 2H), 3.58 (s, 2H), 2.83 (t, 2H), 2.76 (t, 2H), 2.53-2.60 (m, 1H), 2.31-2.38 (m, 2H), 2.02-2.08 (m, 2H).MS: m / z 445.7 (M+H) + .

[0251] Example 41 6-(6-(((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-2-azaspiro[3,3]heptan-2-yl)nicotinonitrile (compound 51) [ka] A mixture of 5-((2-azaspiro[3,3]heptan-6-yl)methoxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one bis-trifluoroacetate (0.223 g, 0.225 mmol), 5-cyano-2-fluoropyridine (0.048 g, 0.393 mmol), and DIPEA (0.125 ml, 0.720 mmol) in dry DMSO (1.5 ml) was stirred at 100°C until the reaction was complete. The cooled mixture was diluted with DCM, washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain the title compound (0.033 g). 1H NMR (600 MHz, DMSO-d6): δ 8.43 (d, 1H), 8.15 (s, 1H), 7.80 (dd, 1H), 7.08-7.17 (m, 3H), 7.01-7-06 (m, 1H), 6.39 (s, 1H), 6.38 (d, 1H), 4.09 (s, 2H), 4.02 (s, 2H), 3.80 (d, 2H), 3.62 (s, 2H9, 3.58 (s, 2H), 2.83 (t, 2H), 2.76 (t, 2H), 2.52-2.62 (m, 1H), 2.33-2.42 (m, 2H), 2.03-2.12 (m, 2H). MS: m / z 469.8 (M+H) + .

[0252] Example 42 6-(3-(((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)azetidine-1-yl)nicotinonitrile (compound 52) [ka] a) 6-(3-(hydroxymethyl)azetidine-1-yl)nicotinonitrile [ka] A mixture of azetidine-3-ylmethanol hydrochloride (0.124 g, 1.00 mmol), 5-cyano-2-fluoropyridine (0.122 g, 1.00 mmol), and DIPEA (0.35 ml, 2.009 mmol) in dry DMSO (2.0 ml) was stirred at 110°C until the reaction was complete. The cooled mixture was diluted with DCM, washed with water and brine, dried, and evaporated. The crude product was purified by flash chromatography to obtain the title compound (0.090 g). 1H NMR (400 MHz, DMSO-d6): δ 8.42 (dd, 1H), 7.78 (dd, 1H), 6.40 (dd, 1H), 4.83 (t, 1H), 4.05 (t, 2H), 3.79 (dd, 2H), 3.57 (t, 2H), 2.77-2.89 (m, 1H).

[0253] b) (1-(5-cyanopyridine-2-yl)azetidine-3-yl)methylmethanesulfonate [ka] The compound was prepared according to the procedure of Example 30 (Step 1), starting with 6-(3-hydroxymethyl)azetidine-1-yl)nicotinonitrile (0.090 g, 0.476 mmol), triethylamine (0.106 ml, 0.761 mmol), and methanesulfonyl chloride (0.055 ml, 0.713 mmol). Yield: 0.120 g. 1 H NMR (400 MHz, DMSO-d6): δ 8.39 (dd, 1H), 7.76 (dd, 1H), 6.39 (dd, 1H), 4.38 (d, 2H), 4.09 (t, 2H), 3.80 (dd, 2H), 3.16 8s, 3H), 3.03-3.14 (m, 1H).

[0254] c) 6-(3-(((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)azetidine-1-yl)nicotinonitrile (compound 52) [ka] A mixture of (1-(5-cyanopyridine-2-yl)azetidine-3-yl)methylmethanesulfonate (0.049 g, 0.183 mmol), 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-hydroxy-4H-pyran-4-one (0.047 g, 0.183 mmol), cesium carbonate (0.119 g, 0.367 mmol), and tris(2-(2-methoxyethoxy)ethyl)amine (2.96 mg, 9.17 μmol) in dry DMSO (1.5 ml) was stirred at 60°C until the reaction was complete. The cooled mixture was diluted with DCM, washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain the title compound (0.079 g). 1 H NMR (400 MHz, CDCl3): δ 8.38 (dd, 1H), 7.71 (s, 1H), 7.57 (dd, 1H), 7.08-7.19 (m, 3H), 6.97-7.02 (m, 1H), 6.51 (s, 1H), 6.23 (dd, MS: m / z 429.8 (M+H) + .

[0255] Example 43 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-(1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonan-2-yl)oxy)-4H-pyran-4-one (compound 53) [ka] A mixture of 5-((7-azaspiro[3,5]nonan-2-yl)oxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one bis-trifluoroacetate (0.114 g, 0.169 mmol) and triethylamine (0.125 ml, 0.897 mmol) in dry DMF (1.5 ml) was to which 1-methyl-1H-pyrazole-5-sulfonyl chloride (0.030 g, 0.169 mmol) dissolved in dry DMF (0.5 ml) was added. The mixture was stirred overnight in RT, then diluted with DCM, washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain the title compound (0.055 g). 1 H NMR (600 MHz, DMSO-d6): δ 7.93 (s, 1H), 7.63 (d, 1H), 7.06-7.14 (m, 3H), 7.00-7.05 (m, 1H), 6.82 (d, 1H), 6.36 (s, 1H), 4.50 (quint, 1H), 4.01 (s, 3H), 3.61 (s, 2H), 3.56 (s, 2H), 3.03-3.10 (m, 2H), 2.96-3.03 (m, 2H), 2.81 (t, 2H), 2.74 (t, 2H), 2.26-2.33 (m, 2H), 1.70-1.78 (m, 2H), 1.56-1.67 (m, 4H). MS: m / z 526.1 (M+H) + .

[0256] The following compounds were prepared according to the procedure described for compound 53 in Example 43. The compound numbers, characteristic data, and starting materials are shown in the table.

[0257] TIFF2026048803000111.tif239164 TIFF2026048803000112.tif227164 TIFF2026048803000113.tif106164

[0258] Example 44 2-(1-(5-acetylisoindoline-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 64) [ka] a) 1-(5-(benzyloxy)-4-oxo-4H-pyran-2-yl)ethyl methanesulfonate [ka] The compound was prepared in 5.0 ml of dry DCM from 5-(benzyloxy)-2-(1-hydroxyethyl)-4H-pyran-4-one (0.246 g, 1.00 mmol), triethylamine (0.25 ml, 1.794 mmol), and methanesulfonyl chloride (0.12 ml, 1.551 mmol) according to the procedure of Example 30(a). Yield: 0.261 g. 1 H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 7.33-7.45 (m, 5H), 6.56 (s, 1H), 5.62 (q, 1H), 4.95 (s, 2H), 2.28 (s, 3H), 1.59 (d, 3H).

[0259] b) 2-(1-(5-acetylisoindoline-2-yl)ethyl)-5-(benzyloxy)-4H-pyran-4-one [ka] To a solution of 1-(isoindolin-5-yl)ethanone hydrochloride (0.158 g, 0.802 mmol) and DIPEA (0.50 ml, 2.87 mmol) in dry acetonitrile (4.0 ml), 1-(5-(benzyloxy)-4-oxo-4H-pyran-2-yl)ethyl methanesulfonate (0.26 g, 0.802 mmol) was added. The mixture was stirred at 90°C until the reaction was complete. The cooled mixture was diluted with water and extracted with siRNA (2×). The combined organic phases were washed with water and brine, dried, and evaporated. The crude product was purified by flash chromatography to obtain the title compound (0.085 g). 1 H NMR (400 MHz, CDCl3): δ 7.83 (dd, 1H), 7.79 (br s, 1H), 7.58 (s, 1H), 7.30-7.44 (m, 5H), 7.27 (d, 1H), 6.46 (s, 1H), 5.08 (s, 2H), 3.93-4.08 (m, 4H), 3.63 (q, 1H), 2.59 (s, 3H), 1.50 (d, 3H).

[0260] c) 2-(1-(5-acetylisoindolin-2-yl)ethyl)-5-hydroxy-4H-pyran-4-one [ka] A mixture of 2-(1-(5-acetylisoindolin-2-yl)ethyl)-5-(benzyloxy)-4H-pyran-4-one (0.085 g, 0.218 mmol) and hydrochloric acid (3 M, 1.0 ml, 3.00 mmol) was stirred at 100°C until the reaction was complete. The cooled mixture was diluted with water and neutralized with 2 M aqueous NaOH solution. The mixture was extracted with ELISA (2×), the combined organic phase was washed with brine, dried, and evaporated to obtain the title compound (0.065 g). 1H NMR (400 MHz, CDCl3): δ 7.88 (s, 1H), 7.84 (dd, 1H), 7.80 (br s, 1H), 7.28 (d, 1H), 6.53 (s, 1H), 3.97-4.10 (m, 4H), 3.69 (q, 1H), 2.59 (s, 3H), 1.54 (d, 3H).

[0261] d) 2-(1-(5-acetylisoindoline-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 64) [ka] A mixture of 4-(bromomethyl)-1-(methylsulfonyl)piperidine (0.039, 0.154 mmol), 2-(1-(5-acetylisoindolin-2-yl)ethyl)-5-hydroxy-4H-pyran-4-one (0.040 g, 0.134 mmol), and potassium carbonate (0.041 g, 0.294 mmol) in dry DMSO (1.0 ml) was stirred at 80°C until the reaction was complete. The cooled mixture was diluted with water and extracted with DCM (2×). The combined organic phases were washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to obtain the title compound (0.015 g). 1 H NMR (400 MHz, DMSO-d6): δ 8.16 (s, 1H), 7.80-7.85 (m, 2H), 7.38 (d, 1H), 6.40 (s, 1H), 4.00 (d, 2H), 3.89-3.96 (m, 2H), 3.69-3.77 (3H, m), 3.54-3.61 (m, 2H), 2.85 (s, 3H), 2.69-2.76 (m, 2H), 2.55 (s, 3H), 1.89-1.89 (m, 3H), 1.41 (d, 3H), 1.24-1.34 (m, 2H). MS: m / z 476.2 (M+H) + .

[0262] Example 45 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 65) [ka] To a stirred solution of isoindoline (0.05 ml, 0.45 mmol) and glacial acetic acid (0.05 ml, 0.91 mmol) in DCM (20 ml), 3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzaldehyde (0.17 g, 0.45 mmol) was added. After 30 minutes, the reaction mixture was cooled to 0°C, and then sodium triacetoxyborohydride (0.14 g, 0.68 mmol) was added. The mixture was stirred overnight at RT and quenched with water (10 ml). The product was extracted with ELISA. The combined extract was washed with water, dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography to obtain the title compound. LC-MS: m / z 479.4 (M+H) + . 1 H NMR (Chloroform-d) δ: 7.95 (d, 1H), 7.90 (br d, 1H), 7.19-7.26 (m, 4H), 7.07 (d, 1H), 4.13 (s, 4H), 4.03-4.07 (m, 4H), 3.88-3.94 (m, 2H), 3.21 (s, 3H), 2.81 (s, 3H), 2.70-2.80 (m, 2H), 2.03 (br m, 2H), 1.50-1.62 (m, 3H).

[0263] The following compounds were prepared according to the procedure described for compound 65 in Example 45. The compound number, characteristic data, starting materials, and any possible deviations from the reaction conditions (solvent, reaction temperature, reaction time, method of production) are shown in the table.

[0264] Purification method used: A=crystallization B = Column chromatography C = Precipitation in an aqueous medium D = Half taken HPLC E = Crushing F = salt formation

[0265] TIFF2026048803000120.tif165164 TIFF2026048803000121.tif108164

[0266] The following compounds were prepared according to the procedure described in Example 17(e), starting with 4-(isoindolin-2-yl-methyl)-2-(methylsulfonyl)phenol or its derivatives and other suitable starting materials. The compound number, characteristic data, starting materials, and any possible deviations from the reaction conditions (solvent, reaction temperature, reaction time, method of production) are shown in the table.

[0267] Purification method used: A=crystallization B = Column chromatography C = Precipitation in an aqueous medium D = Half taken HPLC E = Crushing F = salt formation

[0268] TIFF2026048803000122.tif213160 TIFF2026048803000123.tif212160 TIFF2026048803000124.tif245160 TIFF2026048803000125.tif175160

[0269] Example 46 2-((1'H-Spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-((1-Tosylpiperidine-4-yl)methoxy)-4H-pyran-4-one (Compound 88) [ka] (4-oxo-5-((1-tosylpiperidine-4-yl)methoxy)-4H-pyran-2-yl)methylmethanesulfonate (0.10 ml, 0.21 mmol) in 2 ml of DMF was mixed with K2CO3 (0.088 g, 0.634 mmol) and 2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]hydrochloride (0.042 g, 0.21 mmol). The resulting mixture was stirred at 80°C for 2 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by reverse-phase chromatography to obtain the title compound. LC-MS: m / z 535.4 (M+H) + . 1 H NMR (400 MHz, Chloroform-d) δ: 0.78-0.94 (m, 2H), 0.97-1.09 (m, 2 H), 1.21 (t, 1H) 1.40 (qd, 2H) 1.72-1.86 (m, 1 H), 1.91 (br d, 2H) 2.26 (td, 2H), 2.44 (s, 3 H), 2.70 (s, 2H), 3.42-3.55 (m, 1H), 3.59 (s, 2H), 3.67 (d, 2H), 3.78-3.92 (m, 4 H), 6.47 (s, 1H), 6.67 (d, 1H), 6.98 (d, 1H), 7.08 (td, 1H), 7.12-7.17 (m, 1H), 7.27-7.32 (m, 1H), 7.34 (s, 1H), 7.55-7.68 (m, 3H).

[0270] The following compounds were prepared according to the procedure described in Example 1. The compound number, characteristic data, starting materials, and any possible deviations from the reaction conditions (solvent, reaction temperature, reaction time, method of production) are shown in the table.

[0271] TIFF2026048803000127.tif63164

[0272] Example 47 (E)-2-((5-(1-(hydroxyimino)ethyl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 90) [ka] (E)-2-((5-(1-(hydroxyimino)ethyl)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (0.2 g, 0.43 mmol) was dissolved in EtOH (10 ml), to which sodium acetate (0.160 g, 1.9 mmol) and hydroxylamine hydrochloride (0.075 g, 1.08 mmol) were added at 25°C. The mixture was stirred at 70°C for 2 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to obtain 53.2 mg of the title compound. LC-MS: m / z 476.3 (M+H) + . 1 H NMR (600 MHz, DMSO-d6) δ: 11.12 (s, 1H), 8.14 (s, 1H), 7.52 (s, 1H), 7.49 (d, 1H), 7.24 (d, 1H), 6.40 (s, 1H), 3.96 (br d, 4H), 3.79 (s, 2H), 3.72 (d, 2H), 3.58 (br d, 3H), 2.80-2.87 (m, 3H), 2.72 (br t, 2H), 2.14 (s, 3H), 2.09 (d, 1H), 1.84 (br d, 3H), 1.29 (br dd, 2H).

[0273] Example 48 (E)-2-((5-(1-(methoxyimino)ethyl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 91) [ka] (E)-2-((5-(1-(hydroxyimino)ethyl)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (0.2 g, 0.43 mmol) was dissolved in EtOH (10 ml), to which sodium acetate (0.160 g, 1.9 mmol) and methoxyamine HCl (0.091 g, 1.08 mmol) were added at 25°C. The mixture was stirred at 70°C for 2 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to obtain 22.5 mg of the title compound. LC-MS: m / z 490.6 (M+H) + . 1 H NMR (600 MHz, DMSO-d6) δ: 8.14 (s, 2H), 7.48-7.55 (m, 4H), 7.26 (d, 3H), 6.39 (s, 2H), 3.96 (br d, 9H), 3.90 (s, 6H), 3.79 (s, 5H), 3.69-3.75 (m, 6H), 3.58 (br d, 5H), 2.85 (s, 7H), 2.72 (br t, 5H), 2.16 (s, 6H), 2.11 (s, 1H), 1.84 (br d, 7H), 1.24-1.34 (m, 5H).

[0274] Example 49 1-(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)ethanol (compound 92b) [ka] a) 4-(chloromethyl)-2-(methylsulfonyl)phenol [ka] 2-(methylsulfonyl)benzeneol (4.0 g, 23.2 mmol) was added to a solution of paraformaldehyde (1.25 g, 41.8 mmol) and concentrated HCl (14.1 ml, 465 mmol). The reaction mixture was stirred at RT for 48 hours. The product was filtered, washed with 0.5% Na2CO3 (5 ml) and water (20 ml), and dried to obtain 3.5 g of the title compound. LC-MS: m / z 221.6 (M+H) + .

[0275] b) 4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenol [ka] To a solution of 4-(chloromethyl)-2-(methylsulfonyl)phenol (2.5 g, 11.33 mmol) in THF (15 ml), isoindoline hydrochloride (2.11 g, 13.59 mmol) and DIPEA (7.9 ml, 45.30 mmol) were added. The mixture was stirred at RT for 4 hours. The mixture was evaporated, quenched with water (20 ml), and extracted with RINKAN. The organic layer was washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. 2.0 g of the title compound was obtained by column chromatography (heptane / ethyl acetate). LC-MS: m / z 304.3 (M+H) + .

[0276] c) 1-(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)ethanone (compound 92a) [ka] To a solution of 4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenol (0.30 g, 0.99 mmol) in DMF (5 ml), 1-[4-(bromomethyl)phenyl]ethanone (0.21 g, 0.99 mmol) and K2CO3 (0.30 g, 2.16 mmol) were added. The reaction mixture was heated at 100°C for 1 hour. The mixture was cooled to RT, water (10 ml) was added, and the product was extracted with ELISA. The combined extract was washed with water, the product was filtered, dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography to obtain 0.05 g of the title compound. LC-MS: m / z 436.53 (M+H) + . 1 H NMR (Chloroform-d, 400 MHz) δ 8.0-8.0 (m, 3H), 7.6-7.7 (m, 3H), 7.2-7.2 (m, 4H), 7.06 (d, 1H, J=8.6 Hz), 5.32 (s, 2H), 3.9-3.9 (m, 6H), 3.2-3.2 (m, 3H), 2.6-2.6 (m, 3H)

[0277] d) 1-(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)ethanol (compound 92b) [ka] To a solution of 1-(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)ethanone (0.05 g, 0.11 mmol) in MeOH (5 ml), NaBH4 (5.32 g, 0.14 mmol) was added at 0°C. The mixture was stirred at 0°C for 10 minutes and then at RT for 2 hours, quenched with ice-cold water, and extracted by DCM. The combined organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to obtain 5.5 mg of the title compound. LC-MS: m / z 439.7 (M+H) + . 1H NMR (Chloroform-d) δ: 8.00 (d, 1H), 7.66 (m, 1H), 7.48-7.53 (m, 2H), 7.40-7.46 (m, 2H), 7.18 (s, 4H), 7.09 (d, 1H), 5.25 (s, 2H), 4.94 (m, 1H), 3.93 (s, 4H), 3.90 (s, 2H), 3.22 (s, 3H), 1.52 (d, 3H).

[0278] The following compounds were prepared according to the procedure described in Example 49. The compound numbers, characteristic data, and starting materials are shown in the table.

[0279] TIFF2026048803000135.tif114164

[0280] The following compounds were prepared using the preparative HPLC method described below. The compound number, characteristic data, and starting materials are shown in the table.

[0281] Preparative HPLC method: Instrument: Agilent Technologies 1200. Column: Chiralpak IF No: p-41, 5 microns, 20 × 250 mm; Solvent: Solvent A: n-hexane + 0.2% DEA; Solvent B: =EtOH + 0.2% DEA, detection wavelength 228 nm; Flow rate 15 mL / min.

[0282] TIFF2026048803000136.tif211164 TIFF2026048803000137.tif134164

[0283] Example 50 2-((6-(isoxazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 101) [ka] a) tert-butyl 6-(isoxazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 4-Isoxazoleboronic acid pinacol ester (141 mg, 0.721 mmol), tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (150 mg, 0.480 mmol), bis(triphenylphosphine)palladium(II) dichloride (17 mg, 0.024 mmol), 2M K2CO3 aqueous solution (0.72 mL, 1.441 mmol), and acetonitrile (2 mL) were placed in a sealed reaction vessel, and then carefully purged with nitrogen. The vessel was sealed and heated at 80°C for 5 hours. The reaction was allowed to cool to RT and stirred overnight. The reaction mixture was diluted with ethyl acetate (5 mL) and water (5 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (5 mL). The combined organic extracts were washed with brine (5 mL) and evaporated on Celite. The product was purified by reverse-phase chromatography to obtain 10 mg (7%) of the title compound as a beige solid. MS (ESI) m / z [M-tBu+1] + : 245.2.

[0284] b) 4-(1,2,3,4-tetrahydroisoquinoline-6-yl)isoxazole trifluoroacetate A round-bottom flask was filled with tert-butyl 6-(isoxazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (8 mg, 0.027 mmol), dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL). The mixture was stirred at RT for 3 hours and evaporated to dryness to obtain the crude compound described in the title, which was then used directly in the next synthetic step. MS (ESI) m / z [M+1] + : 201.2.

[0285] c) 2-((6-(isoxazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 101) 4-(1,2,3,4-tetrahydroisoquinoline-6-yl)isoxazole trifluoroacetate (8 mg, 0.026 mmol) was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (11 mg, 0.032 mmol) in DMSO (1 mL) in the presence of DIPEA (0.012 mL, 0.066 mmol) by RT for 19 hours, and then purified by reverse-phase column chromatography to obtain 5.7 mg (43%) of the title compound as a white solid. 1 H NMR (400 MHz, CDCl3) δ: 8.65 (s, 1H), 8.53 (s, 1H), 7.61 (s, 1H), 7.26-7.21 (m, 2H), 7.05 (d, 1H), 6.51(m, 1H), 3.90-3.81 (m, 2H), 3.78-3.69 (m, 4H), 3.57 (s, 2H), 2.97 (t, 2H), 2.86 (t, 2H), 2.79 (s, 3H), 2.69 (dt, 2H), 2.10-1.96 (m, 3H), 1.49-1.36 (m, 2H). MS (ESI) m / z [M+1] + : 500.4.

[0286] Example 51 2-((6-(1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 102) [ka] a) tert-butyl 6-(1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate In a sealed reaction vessel, tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (150 mg, 0.48 mmol), pyrazole (49 mg, 0.72 mmol), Cs2CO3 (313 mg, 0.96 mmol), picolinic acid (12 mg, 0.096 mmol), dimethyl sulfoxide (2 mL), and finally copper(I) iodide (18 mg, 0.096 mmol) were added. The reaction vessel was carefully purged with nitrogen and then heated at 120°C for a total of 12 hours. The mixture was allowed to cool to RT and stirred overnight. The reaction mixture was diluted with ELISA (10 mL) and water (10 mL) and then filtered through Celite. The phases were separated and the aqueous phase was extracted with ELISA (10 mL). The combined organic extracts were evaporated over Celite. The product was purified by reverse-phase chromatography to obtain 20 mg (14%) of the title compound as a semi-solid. MS (ESI) m / z [M+1] + : 300.3.

[0287] b) 6-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline trifluoroacetate A round-bottom flask was filled with tert-butyl 6-(1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (20 mg, 0.067 mmol), dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL). The mixture was stirred at RT for 1 hour, then evaporated to dryness to obtain the crude compound described in the title, which was used directly in the next synthetic step. MS (ESI) m / z [M+1] + : 200.2.

[0288] c) 2-((6-(1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((1(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 102) 6-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline trifluoroacetate (21 mg, 0.067 mmol) was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (27 mg, 0.080 mmol) in DMSO (1 mL) in the presence of DIPEA (0.035 mL, 0.20 mmol) at 60°C for 5 hours. The compound was then purified by reverse-phase column chromatography to obtain 11 mg (33%) of the title compound as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ: 7.89 (dd, 1H), 7.71 (d, 1H), 7.61 (s, 1H), 7.49 (d, 1H), 7.43 (dd, 1H), 7.08 (d, 1H), 6.51 (s, 1H), 6.46 (dd, 1H), 3.90-3.81 (m, 2H), 3.77-3.69 (m, 4H), 3.58 (s, 2H), 3.00 (t, 2H), 2.86 (t, 2H), 2.79 (s, 3H), 2.69 (dt, 2H), 2.08-1.95 (m, 3H), 1.50-1.35 (m, 2H).MS (ESI) m / z [M+1] + : 499.3.

[0289] Example 52 2-((1'H-Spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-((1-methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 103) [ka] 47 mg, 0.24 mmol of 2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline] hydrochloride was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (80 mg, 0.24 mmol) in 1 mL of DMSO in the presence of 0.10 mL, 0.60 mmol of DIPEA by RT for 19 hours. The mixture was then purified by reverse-phase column chromatography to obtain 71 mg (65%) of the title compound as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ: 7.60 (s, 1H), 7.14 (dt, 1H), 7.08 (dt, 1H), 7.02-6.96 (m, 1H), 6.68 (dd, 1H), 6.48 (s, 1H), 3.90-3.81 (m, 4H), 3.74 (d, 2H), 3.57 (s, 2H), 2.79 (s, 3H), 2.74-2.64 (m, 4H), 2.07-1.95 (m, 3H), 1.76 (s, 2H), 1.50-1.35 (m, 2H), 1.07-1.00 (m, 2H), 0.90-0.82 (m, 2H). MS (ESI) m / z [M+1] + : 459.5.

[0290] Example 53 2-((1'H-Spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-((4-(2-hydroxypropan-2-yl)benzyl)oxy)-4H-pyran-4-one (compound 104) [ka] a) 2-((1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-hydroxy-4H-pyran-4-one In DMSO (5 ml), a solution of 2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline] (0.233 g, 1.246 mmol) and 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one (0.2 g, 1.246 mmol) was added dropwise at 0°C to a two-necked flask. The mixture was stirred at 60°C for 1 hour and then poured onto ice. The aqueous layer was extracted with ELISA. The organic layers were combined, washed with water and brine, dried over Na2SO4, filtered, and evaporated to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 1.58-1.86 (m, 8H), 2.43-2.48 (m, 2H), 3.53-3.59 (m, 2H), 3.61-3.65 (m, 2H), 6.43 (s, 1H), 6.96-7.01 (m, 1H), 7.04-7.10 (m, 1H), 7.14-7.20 (m, 1H), 7.26-7.31 (m, 1H), 7.96-8.16 (m, 1H), 8.73-9.34 (m, 1H).

[0291] b) 2-((1'H-Spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-((4-(2-hydroxypropane-2-yl)benzyl)oxy)-4H-pyran-4-one (compound 104) To a solution of [2-((1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-hydroxy-4H-pyran-4-one (0.22 g, 0.707 mmol) and potassium carbonate (0.293 g, 2.120 mmol) in THF (5 ml), 2-(4-(bromomethyl)phenyl)propan-2-ol (0.170 g, 0.742 mmol) in THF (5 ml) was added. The mixture was heated under reflux for 15 minutes, then cooled to RT, filtered, and evaporated under vacuum. The crude product was purified by reverse-phase column chromatography to obtain the title compound. 1H NMR (400 MHz, chloroform-d) δ: 8.06 (s, 1H), 7.58 (s, 1H), 7.49 (m, 2H), 7.37 (m, 2H), 7.27 (m, 1H), 7.19 (m, 1H), 7.09 (m, 1H), 6.95 LC-MS: m / z 460.2 (M+H) +.

[0292] Example 54 4-Fluoro-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 105) [ka] a) 4-((4-fluoroisoindolin-2-yl)methyl)-2-(methylsulfonyl)phenol A mixture of 4-fluoroisoindoline hydrochloride (0.393 g, 1.813 mmol), 4-(chloromethyl)-2-(methylsulfonyl)phenol (0.400 g, 1.813 mmol), and calcium carbonate (0.526 g, 3.81 mmol) in a two-necked flask under nitrogen in DMSO (3 ml) was stirred at 60°C for 2 hours, then poured onto ice. The aqueous layer was extracted with phenylethylamine. The organic layers were combined, washed with water and brine, dried over Na2SO4, filtered, and evaporated to obtain the title compound. LC-MS: m / z 322.3. (M+H)+.

[0293] b) 4-Fluoro-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 105) A mixture of (1-(methylsulfonyl)piperidine-4-yl)methylmethanesulfonate (0.150 g, 0.552 mmol), 4-((4-fluoroisoindorin-2-yl)methyl)-2-(methylsulfonyl)phenol (0.178 g, 0.553 mmol), and potassium carbonate (0.115 g, 0.286 mmol) in a two-necked flask under nitrogen in DMF (2 ml) was stirred at 80°C for 2.5 hours, and then poured onto ice. The precipitate was filtered, washed with water, dried, and crystallized from 2-propanol to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 7.80-7.84 (m, 1H), 7.63-7.71 (m, 1H), 7.2 -7.31 (m, 2H), 7.05-7.11 (m, 1H), 7.00-7.05 (m, 1H), 4.05-4.14 (m, 2H), 3.85-3.96 (m, 6H), 3.57-3.66 (m, 2H), 3.26-3.29 (m, 3H), 2.87 (s, 3H), 2.73-2.81 (m, 2H), 1.89-2.08 (m, 3H), 1.37-1.48 (m, 2H). LC-MS: m / z 497.4. (M+H) +.

[0294] Abbreviation ACN - Acetonitrile DCM - Dichloromethane DEA - Diethanolamine DIAD - Diisopropyl azodicarboxylate DIPEA - N,N-diisopropylethylamine DMA - Dimethylacetamide DMEDA - N,N'-dimethylethylenediamine DMF - N,N-dimethylformamide DMS - Dimethyl sulfide DMSO - Dimethyl sulfoxide HCl - ethyl acetate EtOH - Ethanol HIMPA - Hexamethylphosphonamide HPLC - High-Performance Liquid Chromatography LC-MS - Liquid Chromatography-Mass Spectrometry LiHMDS - Lithium hexamethyldisilazane salt TAI Lithium bis(trimethylsilyl)amide MeOH - methanol Ms-Methanesulfonyl RT - room temperature rt - retention time TEA - Triethylamine TFA - Trifluoroacetic acid THF - Tetrahydrofuran TLC - Thin-Layer Chromatography Ts-p-toluenesulfonyl

[0295] experiment Experiment 1. CYP11A1 Inhibition The ability of test compounds to inhibit the conversion of cholesterol to pregnenolone and isocaproate was measured using a modified isocaproate release assay (IARA) described by Ruangwises et al. (Biology of Reproduction 1991; 45(1):143-50), except that the human H295R adrenocortical carcinoma cell line was used as the enzyme source. Extraction was performed using a dextran-coated carbon suspension (Isomaa, V. et al., Endocrinology 1982; 111(3):833-843). The H295R cell line has been shown to express all important steroid-producing enzymes. The median inhibitory concentration (IC) of the test compound against CYP11A1 inhibition was measured. 50 To determine the radioactivity, cells were treated for 3 days in the presence of 3 nM [24,25-3H]-labeled cholesterol (American Radiolabeled Chemicals) with increasing concentrations of the test compound. The final DMSO concentration was 1%. Radiolabeled isocaproic acid was measured by extracting the cell culture medium with a dextran-coated carbon suspension and mixing 100 μl of the supernatant fraction with 200 μl of scintillation solution (OptiPhase SuperMix, PerkinElmer). Radioactivity was measured using a Microbeta scintillation counter (1450 MicroBeta Trilux, Wallac). All test compounds were tested twice at 10 different concentrations.

[0296] The compounds of the present invention are screened by the above assay, and the compound IC 50 The values ​​are listed in Table 1 below. In the table, "A" represents ICs with a impedance of less than 100 nM. 50 The values ​​are shown, and "B" indicates IC in the range of 101-200 nM. 50 The value is shown, and "C" is the IC in the range of 201-2000nM. 50 Show the value.

[0297] [Table 1]

[0298] Experiment 2. Formation of reactive metabolites The formation of reactive metabolites was investigated by incubating the test compound with recombinant human cytochrome P450 (CYP) CYP3A4 enzyme in the presence of cofactor NADPH and scavengers glutathione (GSH), potassium cyanide (KCN), and semicarbazide (SCA), as described in Grillo, M., Expert Opin. Drug Metab. Toxicol. (2015), 11(8):1281-1302. Recombinant human CYP3A4 was selected as the enzyme source because it showed higher metabolic activity toward the test compound than human liver microsomes.

[0299] The compound was dissolved in DMSO and diluted with phosphate buffer (pH 7.4) to obtain a final incubation concentration of 1 or 10 μM. The compound was then sampled with cofactor NADPH (actual sample) and without NADPH (control sample) with one precipitator (unlabeled and unlabeled). 13 C 15 The samples were incubated with a 1:1 mixture of N-labeled capture agents. The incubation time was 1 hour. Samples at 0 minutes (before incubation) and 60 minutes (after incubation) were analyzed using ultra-high pressure liquid chromatography (UHPLC) combined with high-resolution mass spectrometry (HRMS). Preliminary identification of captured metabolites was based on the precise mass of the protonated molecules, the product ion spectra of the found metabolites, and the precise mass difference between the unlabeled and labeled capture agents that reacted with the reactive metabolites.

[0300] If the peak area after incubation exceeded 10% of the parent peak area before incubation, the metabolite was classified as "major." If the peak area was between 1% and 10%, the metabolite was classified as "minor," and if the peak area was less than 1%, the metabolite was classified as "trace." The results are shown in Table 2. Reference compounds A and B represent prior art compounds (compound numbers 139 and 186, respectively, in International Publication No. 2018 / 115591). The results indicate that the compounds of the present invention are less likely to form reactive metabolites than the reference compounds.

[0301] Table 2

Claims

1. Compounds of formula (I) or (II) 【Chemistry 1】 (In the formula, Ring B is a 4-12 member monocyclic, bicyclic, or spirodicyclic ring containing 0-4 heteroatoms independently selected from N, O, or S; Ring A is based on the following basis 【Chemistry 2】 It is either one of the following; L is none, -CH 2 -, -CH(CH 3 ) -, -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 - and; R 1 is hydrogen, C 1-7 alkyl, C 1-7 alkoxy, halogen, cyano, nitro, haloC 1-7 alkyl or haloC 1-7 alkoxy; R 2 is hydrogen, C 1-7 Alkyl, halogen, hydroxy, C 1-7 Alkoxy, Halo C 1-7 Alkyl or oxo; or R 1 and R 2 They bond to the same carbon atom, and together with the carbon atoms to which they bond, C 3-7 Forming a cycloalkyl ring, or R 1 and R 2 They fuse together with the carbon atoms they bond to. 3-7 Forming a cycloalkyl ring; R 3 These are hydrogen, halogen, nitro, cyano, oxo, and C. 1-7 Alkyl, C 2-7 Alkenil, C 3-7 Cycloalkyl, hydroxy C 3-7 Cycloalkyl, C 1-7 Alkoxy, hydroxy C 1-7 Alkyl, Halo C 1-7 Alkyl, cyano C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkylthio, aminocarbonyl C 2-7 Alkenil, Halo C 1-7 Alkylthio, C 1-7 Alkoxycarbonyl C 1-7 Alkyl, C 1-7 Alkoxycarbonyl C 2-7 Alkenil, = NSO 2 R 20 , -S(O)-C 1-7 Alkyl, -S(O)(NR 14 ) (Caution 22 ), -S (NR 15 ) (C 1-7 Alkyl), -C(S)NR 18 R 19 , -D-C(O)-NR 6 R 7 , -C(O)R 8 , -D-NR 9 R 10 , -SO 2 R 11 , optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 3- to 10-membered carbocyclyl C 1-7 Alkyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 4-10 membered heterocyclyl C 1-7 It is alkyl; R 4 is hydrogen, halogen, hydroxyl, C 1-7 Alkyl, Halo C 1-7 Alkyl or oxo; R 5 is hydrogen, halogen or C 1-7 It is alkyl; R 6 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 2-7 Alkenil, C 3-7 Cycloalkyl, hydroxy C 1-7 Alkyl, cyano C 1-7 Alkyl, -C 1-7 Alkyl-O-C(O)C 1-7 Alkyl or optionally substituted 4- to 10-membered heterocyclyl; R 8 is hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 1-7 alkoxy, halo C 1-7 alkyl, 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-SO 2 (C 1-7 alkyl), -N=S(O)(C 1-7 alkyl)(C 1-7 alkyl) or optionally substituted 4- to 10-membered heterocyclyl; R 9 is hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl, C 1-7 alkylcarbonyl, -SO 2 (C 1-7 alkyl) or -SO 2 (C 3-7 cycloalkyl); R 11 is C 1-7 Alkyl, C 2-7 Alkenil, 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 , optionally substituted 3- to 10-membered carbocyclyl or optionally substituted 4- to 10-membered heterocyclyl; R 12 is hydrogen, C 1-7 Alkyl, hydroxy 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 It is an alkylcarbonyl; R 7 , R 10 , R 13 , R 18 , and R 19 These are, independently, hydrogen, C 1-7 Alkyl or C 3-7 It is cycloalkyl; R 14 is hydrogen, C 1-7 Alkyl, C 1-7 Alkylcarbonyl or -SO 2 R 21 And; R 15 is hydrogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-7 Alkylcarbonyl, -SO 2 R 17 And; R 17 C 1-7 Alkyl or optionally substituted 3- to 10-membered carbocyclyl; R 20 and R 21 Independently, C 1-7 Alkyl, C 3-7 A cycloalkyl or optionally substituted 3- to 10-membered carbocyclyl; R 22 C 1-7 Alkyl or C 3-7 It is cycloalkyl; R 23 is hydrogen, C 1-7 Alkylcarbonyl, hydroxyimino C 1-7 Alkyl, C 1-7 Alkoxyimino C 1-7 Alkyl, hydroxyl atoms optionally substituted with 1 to 3 halogen atoms 1-7 Alkyl or optionally substituted 4- to 10-membered heterocyclyl; R 24 is hydrogen, C 1-7 Alkyl or Halo C 1-7 It is alkyl; R 25 is hydrogen or C 1-7 It is alkyl; R 26 C 1-7 Alkylcarbonyl, hydroxyimino C 1-7 Alkyl, C 1-7 Alkoxyimino C 1-7 Alkyl, hydroxyl atoms optionally substituted with 1 to 3 halogen atoms 1-7 A 4- to 10-membered heterocycline that is alkyl or optionally substituted, provided that ring B is a spirodicyclic ring. 26 It could also be hydrogen; R 27 C 1-7 Alkyl or C 3-7 It is cycloalkyl; D is none, C 1-7 Alkyl or C 2-7 It is an alkenil; Here, any substituent in each presence is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 Alkylcarbonyl, C 1-7 Alkoxy, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Selected from 1 to 3 substituents independently selected from alkoxycarbonyl or oxo; and Here, the heterocyclyl group in each configuration has 1 to 4 heteroatoms independently selected from N, O, and S; or a pharmaceutically acceptable salt thereof.

2. The compound is given by formula (I): 【Transformation 3】 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 23 , R 24 , R 25 , R 27 The compound according to claim 1, represented by (where L, A, and B are as defined in claim 1) or by a pharmaceutically acceptable salt thereof.

3. The compound is given by formula (IA): 【Chemistry 4】 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 23 , R 24 , R 25 , R 27 The compound according to claim 2, wherein L and B are as defined in claim 1, or represented by a pharmaceutically acceptable salt thereof.

4. The compound is given by formula (IB): 【Transformation 5】 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 23 , R 24 , R 25 , R 27 The compound according to claim 2, wherein L and B are as defined in claim 1, or represented by a pharmaceutically acceptable salt thereof.

5. The compound is given by formula (II): 【Transformation 6】 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 24 , R 25 , R 26 The compound according to claim 1, represented by (where L, A, and B are as defined in claim 1) or by a pharmaceutically acceptable salt thereof.

6. The compound is given by formula (IIA): 【Transformation 7】 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 24 , R 25 , R 26 The compound according to claim 5, wherein L and B are represented by those defined in claim 1, or by a pharmaceutically acceptable salt thereof.

7. The compound is given by formula (IIB): 【Transformation 8】 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 24 , R 25 , R 26 The compound according to claim 5, wherein L and B are represented by those defined in claim 1, or by a pharmaceutically acceptable salt thereof.

8. The compound is given by formula (IIC): 【Chemistry 9】 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 24 , R 25 , R 26 The compound according to claim 5, wherein L and B are represented by those defined in claim 1, or by a pharmaceutically acceptable salt thereof.

9. L is absent, -CH 2 - or -CH(CH 3 The compound according to any one of claims 1 to 8, wherein the compound is:

10. The compound according to claim 9, wherein L is absent.

11. L is -CH 2 - The compound according to claim 9.

12. L is -CH(CH 3 The compound according to claim 9, which is:

13. Ring B is based on the following 【Chemistry 10】 It is one of the following, R 3 , R 4 and R 5 The compound according to any one of claims 1 to 12, wherein the compound is bonded to the ring B.

14. Ring B is the following base 【Chemistry 11】 It is one of the following, R 3 , R 4 and R 5 The compound according to claim 13, wherein the compound is bonded to ring B, and the wavy line indicates the bond site to L.

15. The compound according to claim 13, wherein ring B is (1'), (2'), (3'), (4'), (5'), (6'), (7'), (8'), or (9').

16. The compound according to claim 14, wherein ring B is (1a'), (2a'), (3a'), (4a'), (5a'), (6a'), (7'), (8'), or (9a').

17. R 3 However, hydrogen, cyano, C 1-7 Alkyl, C 2-7 Alkenyl, HydroxyC 1-7 Alkyl, C 1-7 Alkylthio, C 1-7 Alkoxycarbonyl C 1-7 Alkyl, -S(O)(NR 14 ) (Caution 22 ), -S (NR 15 ) (C 1-7 Alkyl), -C(S)NR 18 R 19 , -D-C(O)-NR 6 R 7 , -C(O)R 8 , -D-NR 9 R 10 , -SO 2 R 11 , optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 3- to 10-membered carbocyclyl C 1-7 Alkyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 4-10 membered heterocyclyl C 1-7 It is alkyl; where any substitution in each presence is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 Alkylcarbonyl, C 1-7 Alkoxy, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 The compound according to any one of claims 1 to 16, wherein one to three substituents are selected independently from alkoxycarbonyl or oxo, and in each presence the heterocyclyl group has one to four heteroatoms independently selected from N, O, and S.

18. R 3 is hydrogen, cyano, hydroxy C 1-7 Alkyl, -S(O)(NR 14 ) (Caution 22 ), -DC(O)-NR 6 R 7 , -C(O)R 8 , -SO 2 R 11 , optionally substituted 4- to 10-membered heterocyclines or optionally substituted 4- to 10-membered heterocyclines C 1-7 It is alkyl; where any substitution in each presence is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 The compound according to claim 17, wherein one to three substituents are selected independently from the alkylcarbonyl, and in each presence the heterocyclyl group has one to four heteroatoms independently selected from N, O, and S.

19. R 4 and R 5 The compound according to any one of claims 1 to 18, wherein is hydrogen.

20. R 1 However, hydrogen, C 1-7 Alkyl, halogen, cyano, or halo C 1-7 It is alkyl; R 2 However, hydrogen or C 1-7 Alkyl; or R 1 and R 2 Along with the carbon atoms to which they are bonded, spiro C 3-7 Forming a cycloalkyl ring; or R 1 and R 2 These, along with the carbon atoms to which they bond, form a fused C 3-7 A compound according to any one of claims 1 to 19, which forms a cycloalkyl ring.

21. R 4 is hydrogen or halogen, and R 5 The compound according to any one of claims 1 to 20, wherein is hydrogen.

22. The compound according to any one of claims 1 to 21, wherein ring A is (1) or (2).

23. R 24 C 1-7 Alkyl, or halo C 1-7 A compound according to any one of claims 1 to 22, wherein it is alkyl.

24. The compound is given by formula (IID): 【Chemistry 12】 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 24 , R 25 and R 26 The compound according to claim 1, represented by (as defined in claim 1) or by a pharmaceutically acceptable salt thereof.

25. The compound is given by formula (IIE): 【Chemistry 13】 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 24 , R 25 and R 26 The compound according to claim 1, represented by (as defined in claim 1) or by a pharmaceutically acceptable salt thereof.

26. R 26 The compound according to claim 24 or 25, which is an optionally substituted 4-10 membered heterocycline having 1-4 heteroatoms independently selected from N, O, and S.

27. R 3 However, -SO 2 R 11 And; R 1 , R 2 , R 4 , and R 5 is hydrogen; and R 11 C 1-7 The compound according to any one of claims 24 to 26, wherein it is alkyl.

28. R 3 However, arbitrarily substituted 4-10 member heterocyclyl C 1-7 It is alkyl, where any substitution is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 The substituents are selected from 1 to 3 substituents independently selected from the alkylcarbonyl group, and the heterocyclyl group has 1 to 4 heteroatoms independently selected from N, O, and S, and R 1 , R 2 , R 4 , and R 5 The compound according to any one of claims 24 to 26, wherein is hydrogen.

29. R 24 However, C 1-7 Alkyl or Halo C 1-7 The compound according to any one of claims 24 to 28, wherein it is alkyl.

30. The compound is given by formula (IC): 【Chemistry 14】 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 23 , R 24 , R 25 , R 27 The compound according to claim 1, wherein L is represented by (as defined in claim 1) or by a pharmaceutically acceptable salt thereof.

31. R 23 The compound according to claim 30, wherein the compound is an optionally substituted 4-10 membered heterocycline having 1-4 heteroatoms independently selected from N, O, and S.

32. R 3 However, -SO 2 R 11 And; R 1 , R 2 , R 4 , and R 5 is hydrogen; and R 11 C 1-7 The compound according to claim 30 or 31, which is alkyl.

33. R 3 However, arbitrarily substituted 4-10 member heterocyclyl C 1-7 It is alkyl, where any substitution is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 The substituents are selected from 1 to 3 substituents independently selected from the alkylcarbonyl group, and the heterocyclyl group has 1 to 4 heteroatoms independently selected from N, O, and S, and R 1 , R 2 , R 4 , and R 5 The compound according to claim 30 or 31, wherein is hydrogen.

34. R 24 However, C 1-7 Alkyl or Halo C 1-7 The compound according to any one of claims 30 to 33, wherein it is alkyl.

35. Ring B is (2a'), (3a'), (4a'), (5a'), or (6a'), R 1 , R 2 , R 3 , R 4 , R 5 , R 24 , R 25 , R 26 , and L are the compounds according to claim 7, or pharmaceutically acceptable salts thereof, as defined in claim 1.

36. R 3 is hydrogen, -C(O)R 8 , -SO 2 R 11 , optionally substituted 4- to 10-membered heterocyclines or optionally substituted 4- to 10-membered heterocyclines C 1-7 It is alkyl; R 8 C 1-7 It is an alkoxy; R 11 is C 1-7 Alkyl, optionally substituted 4- to 10-membered heterocyclyl, or optionally substituted 3- to 10-membered carbocyclyl; Here, any substituent in each presence is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 The compound according to claim 35, wherein one to three substituents are selected independently from the alkylcarbonyl, and in each presence the heterocyclyl group has one to four heteroatoms independently selected from N, O, and S.

37. 2-((5-(1,3,4-oxadiazol-2-yl)isoindoline-2-yl)methyl)-5-(((methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 1); 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((5-(oxazol-5-yl)isoindorin-2-yl)methyl)-4H-pyran-4-one (compound 2); 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((5-(oxazol-2-yl)isoindorin-2-yl)methyl)-4H-pyran-4-one (compound 3); 2-((5-(isoxazol-5-yl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 4); 2-((5-(isoxazol-3-yl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 5); 2-((5-(1,3,4-thiadiazol-2-yl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 6); 2-((5-(1H-pyrazol-1-yl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 7); 2-((5-(1,2,4-oxadiazol-3-yl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 8); 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((5-(2,2,2-trifluorohydroxyethyl)isoindorin-2-yl)methyl)-4H-pyran-4-one (compound 9); 2-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)-1,3,4-oxadiazole (compound 10); 3-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)isoxazole (compound 11); 5-Bromo-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 12a); 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)-5-(1H-pyrazol-1-yl)isoindoline (compound 12b); 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline-5-yl)oxazole (compound 13a); 2-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline-5-yl)oxazole (compound 13b); 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline-5-yl)thiazole (compound 14); 1-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)ethane-1-one (compound 15a); 3-(dimethylamino)-1-(2-(3(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)prop-2-en-1-one (compound 15b); 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline-5-yl)isoxazole (compound 15c); 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline-5-carbonitrile (compound 16a); N-hydroxy-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline-5-carboximidamide (compound 16b); 3-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindorin-5-yl)-1,2,4-oxadiazole (compound 16c); 2-(1-(5-bromoisoindoline-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 17a); 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-(1-(5-(oxazol-2-yl)isoindorin-2-yl)-ethyl)-4H-pyran-4-one (compound 17b); 2-(1-(5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)ethyl)isoindoline-5-carbonitrile (compound 18a); N-hydroxy-2-(1-(5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)ethyl)isoindoline-5-carboximidamide (compound 18b); 2-(1-(5-(1,2,4-oxadiazol-3-yl)isoindoline-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 18c); 2-(1-(3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 19); 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-(2,2,2-trifluoro-1-(isoindoline-2-yl)ethyl)-4H-pyran-4-one (compound 20); 2-(2,2,2-trifluoro-1-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)phenyl)ethyl)isoindoline (compound 21); 2-(2,2-difluoro-1-(3-(methylsulfonyl)-4-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)phenyl)ethyl)isoindoline (compound 22); 2-((5-(1,3,4-oxadiazol-2-yl)isoindoline-2-yl)methyl)-5-(piperidine-4-ylmethoxy)-4H-pyran-4-one (compound 23a); 2-((5-(1,3,4-oxadiazol-2-yl)isoindoline-2-yl)methyl)-5-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 23b); 2-((5-(1,3,4-oxadiazol-2-yl)-2H-isoindol-2-yl)methyl)-5-((1-(pyrimidine-2-ylmethyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 23c); 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((S*)-1-((1aR*,7bR*)-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinoline-2-yl)ethyl)-4H-pyran-4-one (compound 24a); 5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-2-((R*)-1-((1aR*,7bR*)-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinoline-2-yl)ethyl)-4H-pyran-4-one (compound 24b); 2-(3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 25); 2-(3-(cyclopropylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 26); 2-(3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)-5-(trifluoromethyl)isoindoline (compound 27); 2-(3-(butylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 28); 2-((1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 29); tert-butyl 6-(((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-2-azaspiro[3.3]heptan-2-carboxylate (compound 30); tert-butyl 6-((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (compound 31); tert-butyl 2-((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)-7-azaspiro[3.5]nonane-7-carboxylate (compound 32); tert-butyl 2-((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)-6-azaspiro[3.4]octane-6-carboxylate (compound 33); tert-butyl 7-((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (compound 34); tert-butyl 2-(((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-7-azaspiro[3.5]nonane-7-carboxylate (compound 35); tert-butyl 6-(1-((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)ethyl)-2-azaspiro[3.3]heptane-2-carboxylate (compound 36); tert-butyl 2-(1-((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)ethyl)-7-azaspiro[3.5]nonane-7-carboxylate (compound 37); 5-((2-azaspiro[3,3]heptan-6-yl)oxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one bis-trifluoroacetate (compound 38); 5-((7-azaspiro[3.5]nonan-2-yl)oxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one (compound 39); 5-((7-azaspiro[3.5]nonane-2-yl)methoxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one (compound 40); 5-((6-azaspiro[3,4]octan-2-yl)oxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one (compound 41); 5-((2-azaspiro[3,3]heptan-6-yl)methoxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one (compound 42); 5-(1-(2-azaspiro[3,3]heptan-6-yl)ethoxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one (compound 43); 5-(1-(7-azaspiro[3.5]nonan-2-yl)ethoxy)-2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4H-pyran-4-one (compound 44); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((2-(pyrimidine-2-yl)-2-azaspiro[3.3]heptan-6-yl)oxy)-4H-pyran-4-one (compound 45); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-(pyrimidine-2-yl)-7-azaspiro[3.5]nonane-2-yl)oxy)-4H-pyran-4-one (compound 46); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-(pyrimidine-2-ylmethyl)-7-azaspiro[3.5]nonane-2-yl)oxy)-4H-pyran-4-one (compound 47); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-(pyrimidine-2-yl)-7-azaspiro[3.5]nonane-2-yl)methoxy)-4H-pyran-4-one (compound 48); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((6-(pyrimidine-2-yl)-6-azaspiro[3.4]octan-2-yl)oxy)-4H-pyran-4-one (compound 49); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((2-(pyrimidine-2-yl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-4H-pyran-4-one (compound 50); 6-(6-(((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)-2-azaspiro[3.3]heptan-2-yl)nicotinonitrile (compound 51); 6-(3-(((6-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)azetidine-1-yl)nicotinonitrile (compound 52); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-7-azaspiro[3.5]nonane-2-yl)oxy)-4H-pyran-4-one (compound 53); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-(pyridine-3-ylsulfonyl)-7-azaspiro[3.5]nonane-2-yl)oxy)-4H-pyran-4-one (compound 54); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-7-azaspiro[3.5]nonane-2-yl)oxy)-4H-pyran-4-one (compound 55); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((2-(pyridine-3-ylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)-4H-pyran-4-one (compound 56); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-4H-pyran-4-one (compound 57); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((2-((4-fluorophenyl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-4H-pyran-4-one (compound 58); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-(1-(2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)ethoxy)-4H-pyran-4-one (compound 59); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-(1-(2-(pyridine-3-ylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)ethoxy)-4H-pyran-4-one (compound 60); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-(1-(7-(methylsulfonyl)-7-azaspiro[3.5]nonane-2-yl)ethoxy)-4H-pyran-4-one (compound 61); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-4H-pyran-4-one (compound 62); 2-((3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((7-(methylsulfonyl)-7-azaspiro[3.5]nonane-2-yl)oxy)-4H-pyran-4-o (compound 63); 2-(1-(5-acetylisoindoline-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 64); 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 65); 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 66); 1-((1r,4r)-4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)cyclohexyl)ethane-1-one (compound 67); 4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)-N,N-dimethylbenzamide (compound 68); 4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)-N-(2-methoxyethyl)-N-methylbenzamide (compound 69); 1-(4-((4-isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)piperidine-1-yl)propan-1-one (compound 70); Ethyl (imino) (4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)-λ 6 - Sulfanone (compound 71); Imino(4-((4-(Isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)(methyl)-λ 6 - Sulfanone (compound 72); 1-(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)piperidine-1-yl)-2-methylpropan-1-one (compound 73); 4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)-N,N-dimethylcyclohexane-1-carboxamide (compound 74); 2-(3-(methylsulfonyl)-4-((1-(oxetane-3-ylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 75); 2-(4-((4-(ethylsulfonyl)benzyl)oxy)-3-(methylsulfonyl)benzyl)isoindoline (compound 76); 1-((4-((4-((isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)sulfonyl)azetidine-3-ol (compound 77); N-(dimethyl(oxo)-λ) 6 -Sulfanylidene)-4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)benzamide (compound 78); (1r,4r)-4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)-N,N-dimethylcyclohexane-1-carboxamide (compound 79); Azethidine-1-yl(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)cyclohexyl)methanone (compound 80); 2-(4-((3-fluoro-4-(methylsulfonyl)benzyl)oxy)-3-(methylsulfonyl)benzyl)isoindoline (compound 81); 2-(3-(methylsulfonyl)-4-((4-(methylsulfonyl)benzyl)oxy)benzyl)isoindoline (compound 82); 2-(3-(methylsulfonyl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzyl)isoindoline (compound 83); (4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)(methyl)-λ 4 - Sulfanimine (compound 84); Imino(methyl)(4-((2-(methylsulfonyl)-4-((5-(trifluoromethyl)isoindoline-2-yl)methyl)phenoxy)methyl)phenyl)-λ 6 - Sulfanone (compound 85); 2-(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)propan-2-ol (compound 86); 1-(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)piperidine-1-yl)ethane-1-one (compound 87); 2-((1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-((1-tosylpiperidine-4-yl)methoxy)-4H-pyran-4-one (compound 88); 2-((5-acetylisoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 89); (E)-2-((5-(1-(hydroxyimino)ethyl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 90); (E)-2-((5-(1-(methoxyimino)ethyl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 91); 1-(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)ethanone (compound 92a); 1-(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)ethanol (compound 92b); 2-((5-(1-hydroxyethyl)isoindoline-2-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 93); 1-(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)cyclohexyl)ethane-1-ol (compound 94); (R)-Imino(4-((4-(Isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)(methyl)-λ 6 - Sulfanone (compound 95); (S)-imino(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)(methyl)-λ 6 - Sulfanone (compound 96); (S)-ethyl(imino)(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)-λ 6 - Sulfanone (compound 97); (R)-ethyl(imino)(4-((4-(isoindoline-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)-λ 6 - Sulfanone (compound 98); (R)-2-(1-(3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 99); (S)-2-(1-(3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 100); 2-((6-(isoxazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 101); 2-((6-(1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 102); 2-((1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one (compound 103); 2-((1'H-spiro[cyclopentan-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-((4-(2-hydroxypropan-2-yl)benzyl)oxy)-4H-pyran-4-one (compound 104); 4-Fluoro-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidine-4-yl)methoxy)benzyl)isoindoline (compound 105); and tautomers and their pharmaceutically acceptable salts The compound according to claim 1.

38. A method for treating steroid receptor, particularly androgen receptor, dependence, symptoms and diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 37.

39. The method according to claim 38, wherein the steroid receptor-dependent disease is cancer.

40. The method according to claim 39, wherein the cancer is prostate cancer.

41. The method according to claim 40, wherein the prostate cancer is castration-resistant prostate cancer (CRPC).

42. The method according to any one of claims 38 to 41, wherein a therapeutically effective amount of the compound of formula (I) is administered in addition to a glucocorticoid and / or mineralocorticoid, and optionally one or more anticancer agents.

43. A therapeutically effective amount of the compound of formula (I) - Nonsteroidal androgen receptor antagonist; - Steroid synthesis inhibitors; - Chemotherapy agents; - Anti-estrogen; - Epigenetic modulator; - mTOR inhibitors (e.g., everolimus); - AKT inhibitors (e.g., AZ5363); - Radiopharmaceuticals (e.g., alfalazine); - GnRH / LHRH analog (e.g., leuprorelin); - PI3K inhibitors; and - CDK4 / 6 inhibitors The method according to any one of claims 38 to 42, administered in addition to one or more anticancer agents selected from the group consisting of the above.

44. The method according to any one of claims 38 to 43, wherein a therapeutically effective amount of the compound of formula (I) and a therapeutically effective amount of a nonsteroidal androgen receptor antagonist are administered.

45. A compound according to any one of claims 1 to 37 for use in the treatment of steroid receptors, particularly androgen receptors, and addiction disorders.

46. The compound according to claim 45, wherein the steroid receptor-dependent disease is cancer.

47. The compound according to claim 46, wherein the cancer is prostate cancer.

48. The compound according to claim 47, wherein the prostate cancer is castration-resistant prostate cancer (CRPC).

49. Claims 45-48, wherein the compound of formula (I) is administered in addition to glucocorticoids and / or mineralocorticoids, and optionally one or more anticancer agents. A compound as described in any one of the items.

50. A therapeutically effective amount of the compound of formula (I) - Nonsteroidal androgen receptor antagonist; - Steroid synthesis inhibitors; - Chemotherapy agents; - Anti-estrogen; - Epigenetic modulator; - mTOR inhibitors (e.g., everolimus); - AKT inhibitors (e.g., AZ5363); - Radiopharmaceuticals (e.g., alfalazine); - GnRH / LHRH analog (e.g., leuprorelin); - PI3K inhibitors; and - CDK4 / 6 inhibitors A compound according to any one of claims 45 to 49, administered in addition to one or more anticancer agents selected from the group consisting of the above.

51. The compound according to any one of claims 45 to 50, wherein the compound of formula (I) is administered in addition to a nonsteroidal androgen receptor antagonist.

52. A pharmaceutical composition comprising the compound described in claim 1 together with a pharmaceutically acceptable carrier.

53. The compound according to claim 1, - Glucocorticoids, - Mineralocorticoids, - Nonsteroidal androgen receptor antagonist, - Steroid synthesis inhibitors, - Chemotherapy agents, - Anti-estrogen, - Epigenetic modulator, - mTOR inhibitors (e.g., everolimus); - AKT inhibitors (e.g., AZ5363); - Radiopharmaceuticals (e.g., alfalazine); - GnRH / LHRH analog (e.g., leuprorelin); - PI3K inhibitors; and - CDK4 / 6 inhibitors A pharmaceutically acceptable combination for simultaneous, separate, or sequential administration, comprising at least one additional active ingredient selected from a list consisting of the following.

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