CYP11A1 inhibitors

Abstract

The present invention relates to a compound of formula (I) or (II), wherein R1, R2, R3, R4, R5, R 23 , R 24 , R 25 , R 26 , R 27 , L, A, and B are as defined in claim 1, or pharmaceutically acceptable salts thereof. Compounds of formula (I) or (II) have utility as cytochrome P450 monooxygenase 11A1 (CYP11A1) inhibitors. The compounds are useful as pharmaceuticals in the treatment of steroid receptor, particularly androgen receptor, addictive conditions and diseases, such as prostate cancer. TIFF2023525137000160.tif5070

Description

[Technical Field]

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

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

[0003] The androgen receptor (AR) signaling axis plays an important role in all stages of prostate cancer. In the CPRC stage, the disease is characterized by high AR expression, AR amplification, and persistent activation of the AR signaling axis by residual tissue / tumor androgens and other steroid hormone and steroid biosynthetic intermediates. Therefore, treatment of advanced prostate cancer involves androgen-deprivation therapy (ADT), such as hormonal manipulation using gonadotropin-releasing hormone (GnRH) agonists / antagonists, surgical castration, and AR antagonists or CYP17A1 inhibitors (e.g., abiraterone acetate in combination with prednisone).

[0004] Although treatment initially leads to disease regression, many patients ultimately develop disease that is ineffective against current therapies. Increased progesterone levels in patients treated with abiraterone acetate have been hypothesized to be one of the resistance mechanisms. Several preclinical and clinical studies have pointed to upregulation of enzymes catalyzing steroid biosynthesis in the later stages of CRPC. 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 bind and activate AR as efficiently as testosterone and dihydrotestosterone. These steroids have been found at elevated 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 remains steroid-dependent and may respond to treatments that can further suppress de novo intratumoral steroid synthesis upstream of CYP17A1, such as CYP11A1 inhibitor therapy (Non-patent Document 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 (the precursor of all steroid hormones). By inhibiting CYP11A1, a key enzyme in steroid biosynthesis upstream of CYP17A1, global blockade of all steroid biosynthesis can be achieved. CYP11A1 inhibitors may therefore have great potential for treating steroid hormone-dependent cancers, such as prostate cancer, even in advanced stages of the disease, and particularly in those patients considered to be hormone-resistant. It has been shown that compounds with CYP11A1 inhibitory activity significantly inhibited tumor growth in vivo in a mouse CRPC xenograft model (Non-Patent Document 2). CYP11A1 inhibitors have been previously described in Patent Document 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 Summary of the Invention

[0008] It has been found that the compounds of formula (I) or (II) are potent CYP11A1 inhibitors, and in vitro studies have shown that they are associated with a lower potential for forming reactive metabolites, meaning that as drug candidates they have a lower risk of idiosyncratic toxicity.The compounds of the present invention are therefore particularly useful as pharmaceuticals for treating steroid hormone-dependent conditions and diseases in which the inhibition of CYP11A1 is desired.Such conditions and diseases include, but are not limited to, endocrine cancer, prostate cancer, and breast cancer.In particular, the compounds of the present invention are useful in treating AR-dependent conditions 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 membered monocyclic or bicyclic or spiro bicyclic ring containing 0-4 heteroatoms independently selected from N, O, or S; Ring A is one of the following groups: [ka] Either; 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, haloC 1-7 Alkyl or haloC 1-7 is 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 forming a cycloalkyl ring; or R1 and R2 together with the carbon atoms to which they are attached form a fused C 3-7 forming a cycloalkyl ring; R3 is hydrogen, halogen, nitro, cyano, oxo, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Cycloalkyl, hydroxy C 3-7 Cycloalkyl, C 1-7 Alkoxy, Hydroxy C 1-7 Alkyl, HaloC 1-7 Alkyl, Cyano C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkylthio, aminocarbonyl C 2-7 Alkenyl, HaloC 1-7 Alkylthio, C 1-7 Alkoxycarbonyl C 1-7 Alkyl, C 1-7 Alkoxycarbonyl C 2-7 Alkenyl, =NSOR 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- to 10-membered carbocyclyl, optionally substituted 3- to 10-membered carbocyclyl C 1-7 Alkyl, optionally substituted 4- to 10-membered heterocyclyl or optionally substituted 4- to 10-membered heterocyclylC 1-7 is alkyl; R4 is hydrogen, halogen, hydroxy, C 1-7 Alkyl, HaloC 1-7 alkyl or oxo; R5 is hydrogen, halogen or C 1-7 is alkyl; R6 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Cycloalkyl, hydroxy C 1-7 Alkyl, Cyano C 1-7 Alkyl, -C 1-7 Alkyl-OC(O)C 1-7 alkyl or optionally substituted 4-10 membered heterocyclyl; R8 is hydrogen, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Cycloalkyl, C 1-7 Alkoxy, HaloC 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkyl carbonyl, C 1-7 Alkoxycarbonyl, -C 1-7 Alkyl-OC(O)-C 1-7 Alkyl, -C 1-7 Alkyl-SO2(C 1-7 alkyl), -N=S(O)(C 1-7 Alkyl)(C 1-7 alkyl) or optionally substituted 4-10 membered heterocyclyl; 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, 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 is alkylcarbonyl; R7, R 10 , R 13 , R 18 , and R 19 are independently hydrogen, C 1-7 Alkyl or C 3-7 is 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 is C 1-7 alkyl or optionally substituted 3- to 10-membered carbocyclyl; R20 and R 21 independently, C 1-7 Alkyl, C 3-7 cycloalkyl or optionally substituted 3- to 10-membered carbocyclyl; R 22 is C 1-7 Alkyl or C 3-7 is cycloalkyl; R 23 is hydrogen, C 1-7 Alkylcarbonyl, Hydroxyimino C 1-7 Alkyl, C 1-7 Alkoxyimino C 1-7 Alkyl, hydroxy optionally substituted with 1 to 3 halogen atoms C 1-7 alkyl or optionally substituted 4-10 membered heterocyclyl; R 24 is hydrogen, C 1-7 Alkyl or haloC 1-7 is alkyl; R 25 is hydrogen or C 1-7 is alkyl; R 26 is C 1-7 Alkylcarbonyl, Hydroxyimino C 1-7 Alkyl, C 1-7 Alkoxyimino C 1-7 Alkyl, hydroxy optionally substituted with 1 to 3 halogen atoms C 1-7 alkyl or optionally substituted 4- to 10-membered heterocyclyl, provided that when ring B is a spiro bicyclic ring, R 26 can also be hydrogen; R 27 is C 1-7 Alkyl or C 3-7 is cycloalkyl; D: None, C: 1-7 Alkyl or C 2-7 is alkenyl; wherein the optional substituent at each occurrence is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 Alkyl carbonyl, 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 wherein the heterocyclyl group at each occurrence has 1 to 4 heteroatoms independently selected from N, O, and S; or a pharmaceutically acceptable salt thereof.

[0010] According to one embodiment, the present invention provides a method for treating or preventing steroid receptor, particularly androgen receptor (AR) dependent conditions and diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or (II). [ka] (In the formula, Ring B is a 4-12 membered monocyclic or bicyclic or spiro bicyclic ring containing 0-4 heteroatoms independently selected from N, O, or S; Ring A is one of the following groups: [ka] Either; 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, haloC 1-7 Alkyl or haloC 1-7 is 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 forming a cycloalkyl ring, or R1 and R2 together with the carbon atoms to which they are attached form a fused C 3-7forming a cycloalkyl ring; R3 is hydrogen, halogen, nitro, cyano, oxo, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Cycloalkyl, hydroxy C 3-7 Cycloalkyl, C 1-7 Alkoxy, Hydroxy C 1-7 Alkyl, HaloC 1-7 Alkyl, Cyano C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkylthio, aminocarbonyl C 2-7 Alkenyl, HaloC 1-7 Alkylthio, C 1-7 Alkoxycarbonyl C 1-7 Alkyl, C 1-7 Alkoxycarbonyl C 2-7 Alkenyl, =NSOR 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- to 10-membered carbocyclyl, optionally substituted 3- to 10-membered carbocyclyl C 1-7 Alkyl, optionally substituted 4- to 10-membered heterocyclyl or optionally substituted 4- to 10-membered heterocyclylC 1-7 is alkyl; R4 is hydrogen, halogen, hydroxy, C 1-7 Alkyl, HaloC 1-7 alkyl or oxo; R5 is hydrogen, halogen or C 1-7 is alkyl; R6 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 2-7 Alkenyl, C3-7 Cycloalkyl, hydroxy C 1-7 Alkyl, Cyano C 1-7 Alkyl, -C 1-7 Alkyl-OC(O)C 1-7 alkyl or optionally substituted 4-10 membered heterocyclyl; R8 is hydrogen, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Cycloalkyl, C 1-7 Alkoxy, HaloC 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkyl carbonyl, C 1-7 Alkoxycarbonyl, -C 1-7 Alkyl-OC(O)-C 1-7 Alkyl, -C 1-7 Alkyl-SO2(C 1-7 alkyl), -N=S(O)(C 1-7 Alkyl)(C 1-7 alkyl) or optionally substituted 4-10 membered heterocyclyl; 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 cycloalkyl); R 11 is C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Cycloalkyl, HaloC 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 is alkylcarbonyl; R7, R 10 , R 13 , R 18 , and R 19 are independently hydrogen, C 1-7 Alkyl or C 3-7 is 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 is 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 cycloalkyl or optionally substituted 3- to 10-membered carbocyclyl; R 22 is C 1-7 Alkyl or C 3-7 is cycloalkyl; R 23 is hydrogen, C 1-7 Alkylcarbonyl, Hydroxyimino C 1-7 Alkyl, C 1-7 Alkoxyimino C 1-7 Alkyl, hydroxy optionally substituted with 1 to 3 halogen atoms C 1-7 alkyl or optionally substituted 4-10 membered heterocyclyl; R 24 is hydrogen, C 1-7 Alkyl or haloC 1-7 is alkyl; R 25is hydrogen or C 1-7 is alkyl; R 26 is C 1-7 Alkylcarbonyl, Hydroxyimino C 1-7 Alkyl, C 1-7 Alkoxyimino C 1-7 Alkyl, hydroxy optionally substituted with 1 to 3 halogen atoms C 1-7 alkyl or optionally substituted 4- to 10-membered heterocyclyl, provided that when ring B is a spiro bicyclic ring, R 26 can also be hydrogen; R 27 is C 1-7 Alkyl or C 3-7 is cycloalkyl; D: None, C: 1-7 Alkyl or C 2-7 is alkenyl; wherein the optional substituent at each occurrence is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 Alkyl carbonyl, 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 wherein the heterocyclyl group at each occurrence has 1 to 4 heteroatoms independently selected from N, O, and S; or a pharmaceutically acceptable salt thereof.

[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-dependent conditions and diseases, particularly androgen receptor (AR)-dependent conditions and diseases.Such conditions and diseases include, but are not limited to, endocrine cancer, and diseases such as prostate cancer and breast cancer.The method comprises administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I) or (II) as defined in any of the above embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present patent application provides novel compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, which are useful as CYP11A1 inhibitors.

[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 membered monocyclic or bicyclic or spiro bicyclic ring containing 0-4 heteroatoms independently selected from N, O, or S; Ring A is one of the following groups: [ka] Either; 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, haloC 1-7 Alkyl or haloC 1-7 is 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 C3-7 forming a cycloalkyl ring; or R1 and R2 together with the carbon atoms to which they are attached form a fused C 3-7 forming a cycloalkyl ring; R3 is hydrogen, halogen, nitro, cyano, oxo, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Cycloalkyl, hydroxy C 3-7 Cycloalkyl, C 1-7 Alkoxy, Hydroxy C 1-7 Alkyl, HaloC 1-7 Alkyl, Cyano C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkylthio, aminocarbonyl C 2-7 Alkenyl, HaloC 1-7 Alkylthio, C 1-7 Alkoxycarbonyl C 1-7 Alkyl, C 1-7 Alkoxycarbonyl C 2-7 Alkenyl, =NSOR 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- to 10-membered carbocyclyl, optionally substituted 3- to 10-membered carbocyclyl C 1-7 Alkyl, optionally substituted 4- to 10-membered heterocyclyl or optionally substituted 4- to 10-membered heterocyclylC 1-7 is alkyl; R4 is hydrogen, halogen, hydroxy, C 1-7 Alkyl, HaloC 1-7 alkyl or oxo; R5 is hydrogen, halogen or C 1-7 is alkyl; R6 is hydrogen, C1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Cycloalkyl, hydroxy C 1-7 Alkyl, Cyano C 1-7 Alkyl, -C 1-7 Alkyl-OC(O)C 1-7 alkyl or optionally substituted 4-10 membered heterocyclyl; R8 is hydrogen, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Cycloalkyl, C 1-7 Alkoxy, HaloC 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkyl carbonyl, C 1-7 Alkoxycarbonyl, -C 1-7 Alkyl-OC(O)-C 1-7 Alkyl, -C 1-7 Alkyl-SO2(C 1-7 alkyl), -N=S(O)(C 1-7 Alkyl)(C 1-7 alkyl) or optionally substituted 4-10 membered heterocyclyl; 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 cycloalkyl); R 11 is C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Cycloalkyl, HaloC 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 is alkylcarbonyl; R7, R 10 , R 13 , R 18 , and R 19 are independently hydrogen, C 1-7 Alkyl or C 3-7 is 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 is 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 cycloalkyl or optionally substituted 3- to 10-membered carbocyclyl; R 22 is C 1-7 Alkyl or C 3-7 is cycloalkyl; R 23 is hydrogen, C 1-7 Alkylcarbonyl, Hydroxyimino C 1-7 Alkyl, C 1-7 Alkoxyimino C 1-7 Alkyl, hydroxy optionally substituted with 1 to 3 halogen atoms C 1-7 alkyl or optionally substituted 4-10 membered heterocyclyl; R24 is hydrogen, C 1-7 Alkyl or haloC 1-7 is alkyl; R 25 is hydrogen or C 1-7 is alkyl; R 26 is C 1-7 Alkylcarbonyl, Hydroxyimino C 1-7 Alkyl, C 1-7 Alkoxyimino C 1-7 Alkyl, hydroxy optionally substituted with 1 to 3 halogen atoms C 1-7 alkyl or optionally substituted 4- to 10-membered heterocyclyl, provided that when ring B is a spiro bicyclic ring, R 26 can also be hydrogen; R 27 is C 1-7 Alkyl or C 3-7 is cycloalkyl; D: None, C: 1-7 Alkyl or C 2-7 is alkenyl; wherein the optional substituent at each occurrence is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 Alkyl carbonyl, 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 wherein the heterocyclyl group at each occurrence has 1 to 4 heteroatoms independently selected from N, O, and S; or a pharmaceutically acceptable salt thereof to provide.

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

[0016] According to one embodiment, there is specifically provided a compound according to any of the above embodiments of formula (I) or (II), wherein L is none, -CH2- or -CH(CH3)-, for example, L is absent, or as another example L is -CH2-, or as another example L is -CH(CH3)-.

[0017] According to one embodiment, specifically, compounds according to any of the above embodiments of formula (I) or (II), wherein ring B is a group [ka] wherein R3, R4 and R5 are bonded to ring B.

[0018] In a subclass of the above embodiment, the compound is one in which Ring B is [ka] wherein R3, R4 and R5 are bonded to ring B, and the wavy line indicates the bonding site to L.

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

[0020] In a subclass of the above embodiment, the compound is according to any of the above embodiments wherein Ring B is (1a'), (2a'), (3a'), (4a'), (5a'), (6a'), (7'), (8'), or (9a').

[0021] In one embodiment, R3 is preferably hydrogen, halogen, cyano, C 1-7 Alkyl, C 2-7 Alkenyl, Hydroxy C 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- to 10-membered carbocyclyl, optionally substituted 3- to 10-membered carbocyclyl C 1-7 Alkyl, optionally substituted 4- to 10-membered heterocyclyl or optionally substituted 4- to 10-membered heterocyclylC 1-7 alkyl; wherein the optional substitution at each occurrence is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 Alkyl carbonyl, C 1-7 Alkoxy, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Compounds according to any of the above embodiments are provided wherein the heterocyclyl group in each occurrence has 1 to 4 heteroatoms independently selected from N, O and S, selected from 1 to 3 substituents independently selected from alkoxycarbonyl or oxo.

[0022] In a subclass of the above embodiment, compounds are those in which R3 is hydrogen, cyano, hydroxyC 1-7 Alkyl, -S(O)(NR 14 )(R 22 ), -DC(O)-NR6R7, -C(O)R8, -SO2R 11 , optionally substituted 4- to 10-membered heterocyclyl or optionally substituted 4- to 10-membered heterocyclylC 1-7 alkyl; wherein the optional substitution at each occurrence is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 and alkylcarbonyl, wherein the heterocyclyl group at each occurrence has 1 to 4 heteroatoms independently selected from N, O, and S. In a further subclass of the above embodiment, the compound is selected from R 14 is hydrogen and R22 C 1-7 alkyl, D is absent, and R6 is C 1-7 Alkyl or C 1-7 Alkoxy C 1-7 alkyl, and R7 is C 1-7 alkyl and R8 is C 1-7 Alkyl, C 1-7 alkoxy or optionally substituted 4-10 membered heterocyclyl, and / or R 11 C 1-7 R3, R8 and R are alkyl, optionally substituted 3- to 10-membered carbocyclyl or optionally substituted 4- to 10-membered heterocyclyl. 11 In the definition of, particular examples of 4- to 10-membered heterocyclyl are pyridinyl, pyrazolyl, azetidinyl and pyrimidinyl rings, and particular examples of 3- to 10-membered carbocyclyl are phenyl rings.

[0023] According to one embodiment, in particular, R is hydrogen, C 1-7 Alkyl, halogen, cyano or haloC 1-7 alkyl; R2 is hydrogen or C 1-7 alkyl; or R1 and R2, together with the carbon atom to which they are attached, form a spiro C 3-7 or R1 and R2, together with the carbon atom to which they are attached, form a fused C 3-7 Compounds according to any of the above embodiments are provided which form a cycloalkyl ring.

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

[0025] In a subclass of the above embodiment, compounds are those in which R4 and R5 are hydrogen.

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

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

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

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

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

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

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

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

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

[0035] According to one embodiment, the compound of the present invention has formula (IIE): [ka] (In the formula, R1, R2, R3, R4, R5, R 24 , R 25 and R 26 is defined in any of the above embodiments for formula (I) or (II). or 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 heterocyclyl having 1-4 heteroatoms independently selected from N, O and S. 26 In the definition of, particular examples of 4-10 membered heterocyclyl are oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl and pyrazolyl rings, and particular examples of 3-10 membered carbocyclyl are phenyl rings.

[0037] In particular, according to one embodiment, 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 are provided wherein: is alkyl.

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

[0039] In one embodiment, R3 is specifically an optionally substituted 4-10 membered heterocyclyl C 1-7 alkyl; optional substitutions include C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 Compounds according to any of the above embodiments are provided wherein the heterocyclyl group has 1 to 4 heteroatoms independently selected from N, O, and S; and R, R, R, and R are hydrogen.

[0040] According to one embodiment, specifically R 23 Compounds according to any of the above embodiments are provided wherein R is an optionally substituted 4-10 membered heterocyclyl having 1-4 heteroatoms independently selected from N, O and S. 23 In the definition of, particular examples of 4- to 10-membered heterocyclyl are oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, thiazolyl and pyrazolyl rings, and particular examples of 3- to 10-membered carbocyclyl are phenyl rings.

[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 and L is as defined in claim 1, or a pharmaceutically acceptable salt thereof.

[0042] According to one embodiment, specifically: R3 is hydrogen, -C(O)R8, -SO2R 11 , optionally substituted 4- to 10-membered heterocyclyl, or optionally substituted 4- to 10-membered heterocyclylC 1-7 is alkyl; R8 is C 1-7 is alkoxy; R 11 C 1-7 alkyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 3-10 membered carbocyclyl; The optional substituents at each occurrence are C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 and each occurrence of 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 yet one embodiment, the present invention provides a method for the treatment of steroid receptor, particularly androgen receptor (AR), addictive conditions and diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or (II) as defined in any of the above embodiments.

[0045] According to one embodiment, the steroid receptor-dependent disease or condition is an androgen receptor-dependent disease or condition, including endocrine cancers and diseases, such as prostate cancer or breast cancer, particularly castration-resistant prostate cancer (CRPC). According to one embodiment of the present invention, 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 by various synthetic routes similar to those known in the literature using appropriate starting materials. Compounds of formula (I) or (II) can be prepared, for example, similarly to or according to the following reaction schemes. Some compounds included in formula (I) or (II) can be obtained by converting the functional groups of other compounds of formula (I) or (II) obtained according to the following schemes through oxidation, reduction, hydrolysis, acylation, alkylation, amidation, amination, sulfonation, and other well-known reaction steps. It should be noted that any suitable leaving group, for example, an N-protecting group such as a t-butoxycarbonyl (t-BOC) group or a phenylsulfonyl group, can be used in well-known ways during synthesis to improve the selectivity of the reaction steps.

[0047] Compounds of formula (I) can be prepared according to 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, a compound of formula [1] is coupled with a compound of formula [2] in the presence of a base such as DIPEA at an elevated temperature in a suitable solvent such as CH3CN to produce a compound of formula (I). [ka]

[0048] Alternatively, compounds of formula (I) can be prepared according to 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, a compound of formula [3] can be prepared by reacting NaSO2R in the presence of a base such as K2CO3 in a suitable solvent such as DMSO at an elevated temperature. 27to form a compound of formula (I). [ka]

[0049] The compound of formula (I) can be prepared according to 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, a compound of formula [4] is coupled by reductive amination with a compound of formula [2] in the presence of acetic acid in a suitable solvent such as DCM to produce a compound of formula (Ia). [ka]

[0050] The compound of formula (II) can be prepared according to 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, a compound of formula [5] is coupled with a TFA or HCl salt of a compound of formula [6] in the presence of a base such as DIPEA at elevated temperature in a suitable solvent such as CH3CN to produce a compound of formula (II). [ka]

[0051] Alternatively, compounds of formula (II) can be prepared according to Scheme 5. In Scheme 5, R1, R2, R3, R4, R5, R 24 , R 25 , R 26, L, A, and B are as defined above, and Z is a mesylate or tosylate group. In the method of Scheme 5, a 5-hydroxy-4H-pyran-4-one derivative [7] is coupled with a ring B derivative [8] (mesylate or tosylate acts as a leaving group) using Cs2CO3 or K2CO3 in the presence of a base in a suitable solvent, such as DMSO, at elevated temperatures to form a compound of formula (II). [ka]

[0052] Alternatively, compounds of formula (II) can be prepared according to 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 mesylate or tosylate group. In the method of Scheme 6, compound [9] is coupled with a ring A derivative

[10] (mesylate or tosylate acting as a leaving group) using EtN in a suitable solvent, such as THF, in the presence of a base at elevated temperature to form a compound of formula (II). [ka]

[0053] The compound of formula (II) can be prepared according to 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, a 5-hydroxy-4H-pyran-4-one derivative [7] is coupled with a ring B derivative

[11] (where the halogen acts as a leaving group) using K2CO3 in the presence of a base in a suitable solvent, such as DMF, at elevated temperature to form a compound of formula (II). [ka]

[0054] Alternatively, compounds of formula (II) can be prepared according to 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, a 5-hydroxy-4H-pyran-4-one derivative [7] is coupled with a ring A derivative

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

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

[0056] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter herein belongs. As used herein, the following definitions are provided to facilitate the understanding of the present invention.

[0057] As used herein, the term "subject" refers to humans and animals.

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

[0059] As used herein, the term "endocrine cancer" refers to the partially or completely uncontrolled growth of one or more cellular components of the endocrine system, including, but not limited to, cancer of one or more adrenal glands.

[0060] The terms "halo" or "halogen" as used herein by themselves or as part of another group mean chlorine, bromine, fluorine, or iodine.

[0061] As used herein, the term "C" as used by itself or as part of another group 1-7 "Alkyl" means a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5, 6 or 7 carbon atoms. 1-7 Representative examples of alkyl 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 The term "C" is an alkyl group. 1-3 "Alkyl" refers to a group having 1, 2 or 3 carbon atoms. 1-7 "Alkyl" refers to a preferred embodiment of "alkyl."

[0062] As used herein, the term "C" as used by itself or as part of another group 2-7 "Alkenyl" means an aliphatic hydrocarbon group having 2, 3, 4, 5, 6, or 7 carbon atoms and containing one or several double bonds. Representative examples include, but are not limited to, ethenyl, propenyl, and cyclohexenyl.

[0063] As used herein, the term "C" as used by itself or as part of another group 3-7 "Cycloalkyl" means a saturated cyclic hydrocarbon group containing 3, 4, 5, 6, or 7 carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0064] As used herein, the term "C 3-7 Cycloalkyl C 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein.1-7 C as defined herein attached through an alkyl group 3-7 It means a cycloalkyl group.

[0065] The term "hydroxy" as used herein by itself or as part of another group refers to an --OH group.

[0066] The term "cyano" as used herein by itself or as part of another group refers to the group --CN.

[0067] The term "carboxy" as used herein by itself or as part of another group refers to a -COOH group.

[0068] The term "carbonyl" as used herein by itself or as part of another group means a carbon atom double bonded to an oxygen atom (C=O).

[0069] The term "oxo" as used herein by itself or as part of another group refers to an oxygen atom (=O) that is attached to another atom by a double bond.

[0070] As used herein, the term "C" as used by itself or as part of another group 1-7 "Alkoxy" refers to a C alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. 1-7 It means alkyl. 1-7 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0071] As used herein, the term "hydroxy C 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein. 1-7 means at least one hydroxy group, as defined herein, attached through an alkyl group. 1-7Representative examples of alkyl 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] As used herein, the term "hydroxy C 3-7 "Cycloalkyl" refers to the parent molecular moiety C as defined herein. 3-7 means at least one hydroxy group, as defined herein, attached through a cycloalkyl group. Hydroxy C 1-7 Representative examples of alkyl include, but are not limited to, hydroxycyclopropyl, hydroxycyclobutyl, hydroxycyclopentyl, hydroxycyclohexyl, and 2,2-dihydroxycyclopropyl.

[0073] As used herein, the term "halo C" 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein. 1-7 HaloC means at least one halogen, as defined herein, attached through an alkyl group. 1-7 Representative examples of alkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, and 3-bromopropyl.

[0074] As used herein, the term "cyano C 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein. 1-7 It means a cyano group attached through an alkyl group. Cyano C 1-7 Representative examples of alkyl include, but are not limited to, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, and 2-cyanopropyl.

[0075] As used herein, the term "halo C" 1-7"Alkoxy" refers to the parent molecular moiety C as defined herein. 1-7 It means at least one halogen, as defined herein, attached through an alkoxy group.

[0076] As used herein, the term "phenyl C 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein. 1-7 It means at least one phenyl group attached through an alkyl group.

[0077] As used herein, the term "C" as used by itself or as part of another group 1-7 "Alkylcarbonyl" refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. 1-7 It means an alkyl group.

[0078] As used herein, the term "C" as used by itself or as part of another group 1-7 Alkoxy C 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein. 1-7 at least one C as defined herein attached through an alkyl group 1-7 It means an alkoxy group.

[0079] As used herein, the term "hydroxy C" as used by itself or as part of another group 1-7 "Alkoxy" refers to the parent molecular moiety C as defined herein. 1-7 It means at least one hydroxy group, as defined herein, attached through an alkoxy group.

[0080] As used herein, the term "hydroxy C 1-7 Alkoxy C 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein. 1-7 Hydroxy C as defined herein attached through an alkyl group 1-7 It means an alkoxy group.

[0081] The term "4- to 10-membered heterocyclyl" as used herein means a saturated, partially saturated, or aromatic ring having 4 to 10 ring atoms, 1 to 4 of which are heteroatoms selected from the group consisting of N, O, and S. One embodiment of "4- to 10-membered heterocyclyl" is a "4- to 6-membered heterocyclyl," which means a saturated, partially saturated, or aromatic ring having 4 to 6 ring atoms, 1 to 4 of which are heteroatoms selected from the group consisting of N, O, and S. Representative examples of "4- to 10-membered heterocyclyl" include, but are not limited to, oxetanyl, azetidinyl, pyrazolyl, 1,2,4-triazol-1-yl, 1,2,3-triazol-1-yl, pyrimidinyl, pyridinyl, piperidinyl, tetrazolyl, piperazinyl, furanyl, morpholinyl, piperidinyl, pyrrolidinyl, thiazolyl, isoxazolyl, pyrazinyltetrahydropyranyl, 1,2,4-oxadiazolyl, oxazolyl, imidazolyl, indolyl, and 4,5-dihydroimidazolyl rings.

[0082] The term "3- to 10-membered carbocyclyl" as used herein refers to a saturated, partially saturated, or aromatic ring having 3 to 10 ring atoms consisting solely of carbon atoms. One embodiment of "3- to 10-membered carbocyclyl" is "3- to 6-membered carbocyclyl," which refers to a saturated, partially saturated, or aromatic ring having 3 to 6 ring atoms consisting solely of carbon atoms. Representative examples of 3- to 10-membered carbocyclyl include, but are not limited to, phenyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, and cyclobutyl rings.

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

[0084] The term "spiro bicyclic ring" as used herein means a bicyclic ring in which the two rings are both attached at the same carbon atom.

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

[0086] As used herein, the term "4- to 10-membered heterocyclyl C 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein. 1-7 It means a "4- to 10-membered heterocyclyl" as defined herein attached through an alkyl group.

[0087] As used herein, the term "3- to 10-membered carbocyclyl C 1-7 "Alkyl" refers to the parent molecular moiety C, as defined herein. 1-7 It means a "3 to 10 membered carbocyclyl" as defined herein attached through an alkyl group.

[0088] The term "substituted" as used herein in connection with various residues means, unless otherwise specified, 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, HaloC 1-7 Alkyl, hydroxy C 1-7 Alkyl or amino C 1-7 alkyl substituents. Preferred substituents are halogen, C 1-7 Alkyl, hydroxy, amino, haloC 1-7 Alkyl, C 1-7 Alkoxy and methylsulfonyl substituents. One group of preferred substituents is C 1-7 one or two substituents selected from alkyl or halogen substituents, in particular C 1-3Alkyl or halogen substituents, particularly methyl, ethyl, chloro, fluoro, bromo substituents.

[0089] A "substituted" group can contain from 1 to 3, preferably 1 or 2, of the above substituents, unless otherwise specified.

[0090] Optically active enantiomers or diastereomers of compounds of formula (I) or (II) can be prepared, for example, by resolution of racemic final products by known methods or by using appropriate optically active starting materials. 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 to a mixture of diastereomeric salts by reaction with an optically active acid, followed by separation of the diastereomers by crystallization. Representative examples of optically active acids include, but are not limited to, D-tartaric acid and dibenzoyl-D-tartaric acid. Alternatively, preparative chiral chromatography can be used to resolve racemic mixtures.

[0091] Pharmaceutically acceptable salts are well known in the field of formulation. 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 salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts. Non-limiting examples of salts with inorganic or organic acids include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methanesulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbic acids, acetates, oxalates, fumarates, hemifumarates, and succinates. Pharmaceutically acceptable esters, if applicable, can be prepared by known methods using pharmaceutically acceptable acids commonly used in the pharmaceutical field, and retain the pharmacological properties of the free form. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl esters. Phosphate and carbonate esters are also within the scope of the present invention.

[0092] The above definition of formula (I) includes all possible isotopes and isomers, such as stereoisomers, of the compounds, geometric isomers, e.g., Z and E isomers (cis and trans isomers), and optical isomers, e.g., 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 can have at least one chiral center. Therefore, the compounds can exist in optically active or racemic forms. Formula (I) or (II) should be understood to include any racemic or optically active form, or mixtures thereof. In one embodiment, the compound is the pure (R)-isomer. In yet another embodiment, the compound is the pure (S)-isomer. In another embodiment, the compound is a mixture of the (R)- and (S)-isomers. In another embodiment, the compound is a racemic mixture containing an equal mixture of the (R)- and (S)-isomers. The compound 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 mixtures of enantiomers. According to yet another embodiment, the compounds are pure enantiomers. The individual isomers may be obtained using the corresponding isomers of the starting materials, or may be separated after preparation of the final compound using conventional separation methods. Separation of optical isomers, eg enantiomers or diastereomers, from a mixture thereof may be achieved using conventional resolution methods, eg fractional crystallisation.

[0094] The compounds of the present invention may exist as tautomers or as equal mixtures thereof in which a proton of the compound shifts from one atom to another. Examples of tautomers include, but are not limited to, amide-imide, keto-enol, phenol-keto, oxime-nitroso, nitro-aci, imine-enamine, cyclic tautomers of heterocycles, and the like. Tautomeric forms are intended to be encompassed by the compounds of formula (I) or (II), even if only one tautomeric form is shown.

[0095] Examples of preferred compounds of one group of formula (I) or (II) include: 2-((5-(1,3,4-oxadiazol-2-yl)isoindolin-2-yl)methyl)-5-(((methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 1); 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(oxazol-5-yl)isoindolin-2-yl)methyl)-4H-pyran-4-one (compound 2); 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(oxazol-2-yl)isoindolin-2-yl)methyl)-4H-pyran-4-one (compound 3); 2-((5-(isoxazol-5-yl)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 4); 2-((5-(isoxazol-3-yl)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 5); 2-((5-(1,3,4-thiadiazol-2-yl)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 6); 2-((5-(1H-pyrazol-1-yl)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 7); 2-((5-(1,2,4-oxadiazol-3-yl)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 8); 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(2,2,2-trifluorohydroxyethyl)isoindolin-2-yl)methyl)-4H-pyran-4-one (compound 9); 2-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)-1,3,4-oxadiazole (compound 10); 3-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)isoxazole (compound 11); 5-Bromo-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 12a); 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)-5-(1H-pyrazol-1-yl)isoindoline (compound 12b); 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)oxazole (compound 13a); 2-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)oxazole (compound 13b); 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)thiazole (compound 14); 1-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)ethan-1-one (compound 15a); 3-(dimethylamino)-1-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)prop-2-en-1-one (compound 15b); 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)isoxazole (compound 15c); 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline-5-carbonitrile (compound 16a); N-hydroxy-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline-5-carboximidamide (compound 16b); 3-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)-1,2,4-oxadiazole (compound 16c); 2-(1-(5-bromoisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 17a); 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-(1-(5-(oxazol-2-yl)isoindolin-2-yl)-ethyl)-4H-pyran-4-one (compound 17b); 2-(1-(5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)ethyl)isoindoline-5-carbonitrile (compound 18a); N-hydroxy-2-(1-(5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)ethyl)isoindoline-5-carboximidamide (compound 18b); 2-(1-(5-(1,2,4-oxadiazol-3-yl)isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 18c); 2-(1-(3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 19); 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-(2,2,2-trifluoro-1-(isoindolin-2-yl)ethyl)-4H-pyran-4-one (compound 20); 2-(2,2,2-trifluoro-1-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)ethyl)isoindoline (compound 21); 2-(2,2-difluoro-1-(3-(methylsulfonyl)-4-((1-(pyrimidin-2-ylmethyl)piperidin-4-yl)methoxy)phenyl)ethyl)isoindoline (compound 22); 2-((5-(1,3,4-oxadiazol-2-yl)isoindolin-2-yl)methyl)-5-(piperidin-4-ylmethoxy)-4H-pyran-4-one (compound 23a); 2-((5-(1,3,4-oxadiazol-2-yl)isoindolin-2-yl)methyl)-5-((1-(pyrimidin-2-ylmethyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 23b); 2-((5-(1,3,4-oxadiazol-2-yl)-2H-isoindol-2-yl)methyl)-5-((1-(pyrimidin-2-ylmethyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 23c); 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((S*)-1-((1aR*,7bR*)-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinolin-2-yl)ethyl)-4H-pyran-4-one (compound 24a); 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((R*)-1-((1aR*,7bR*)-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinolin-2-yl)ethyl)-4H-pyran-4-one (compound 24b); 2-(3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 25); 2-(3-(cyclopropylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 26); 2-(3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)-5-(trifluoromethyl)isoindoline (compound 27); 2-(3-(butylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 28); 2-((1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 29); tert-Butyl 6-(((6-((3,4-dihydroisoquinolin-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-dihydroisoquinolin-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-dihydroisoquinolin-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-dihydroisoquinolin-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-dihydroisoquinolin-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-dihydroisoquinolin-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-dihydroisoquinolin-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-dihydroisoquinolin-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-dihydroisoquinolin-2(1H)-yl)methyl)-4H-pyran-4-one bis-trifluoroacetate (compound 38); 5-((7-azaspiro[3.5]nonan-2-yl)oxy)-2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4H-pyran-4-one (compound 39); 5-((7-azaspiro[3.5]nonan-2-yl)methoxy)-2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4H-pyran-4-one (compound 40); 5-((6-azaspiro[3.4]octan-2-yl)oxy)-2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4H-pyran-4-one (compound 41); 5-((2-azaspiro[3.3]heptan-6-yl)methoxy)-2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4H-pyran-4-one (compound 42); 5-(1-(2-azaspiro[3.3]heptan-6-yl)ethoxy)-2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4H-pyran-4-one (compound 43); 5-(1-(7-azaspiro[3.5]nonan-2-yl)ethoxy)-2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4H-pyran-4-one (compound 44); 2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-((2-(pyrimidin-2-yl)-2-azaspiro[3.3]heptan-6-yl)oxy)-4H-pyran-4-one (compound 45); 2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-((7-(pyrimidin-2-yl)-7-azaspiro[3.5]nonan-2-yl)oxy)-4H-pyran-4-one (compound 46); 2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-((7-(pyrimidin-2-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)oxy)-4H-pyran-4-one (compound 47); 2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-((7-(pyrimidin-2-yl)-7-azaspiro[3.5]nonan-2-yl)methoxy)-4H-pyran-4-one (compound 48); 2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-((6-(pyrimidin-2-yl)-6-azaspiro[3.4]octan-2-yl)oxy)-4H-pyran-4-one (compound 49); 2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-((2-(pyrimidin-2-yl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-4H-pyran-4-one (compound 50); 6-(6-(((6-((3,4-dihydroisoquinolin-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-dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)azetidin-1-yl)nicotinonitrile (compound 52); 2-((3,4-dihydroisoquinolin-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-dihydroisoquinolin-2(1H)-yl)methyl)-5-((7-(pyridin-3-ylsulfonyl)-7-azaspiro[3.5]nonan-2-yl)oxy)-4H-pyran-4-one (compound 54); 2-((3,4-dihydroisoquinolin-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-dihydroisoquinolin-2(1H)-yl)methyl)-5-((2-(pyridin-3-ylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)-4H-pyran-4-one (compound 56); 2-((3,4-dihydroisoquinolin-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-dihydroisoquinolin-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-dihydroisoquinolin-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-dihydroisoquinolin-2(1H)-yl)methyl)-5-(1-(2-(pyridin-3-ylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)ethoxy)-4H-pyran-4-one (compound 60); 2-((3,4-dihydroisoquinolin-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-dihydroisoquinolin-2(1H)-yl)methyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-4H-pyran-4-one (compound 62); 2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-((7-(methylsulfonyl)-7-azaspiro[3.5]nonan-2-yl)oxy)-4H-pyran-4-o (compound 63); 2-(1-(5-acetylisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 64); 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 65); 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 66); 1-((1r,4r)-4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)cyclohexyl)ethan-1-one (compound 67); 4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)-N,N-dimethylbenzamide (compound 68); 4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)-N-(2-methoxyethyl)-N-methylbenzamide (compound 69); 1-(4-((4-isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)propan-1-one (compound 70); Ethyl(imino)(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)-λ 6 -sulfanone (compound 71); Imino(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)(methyl)-λ 6 -sulfanone (compound 72); 1-(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)-2-methylpropan-1-one (compound 73); 4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)-N,N-dimethylcyclohexane-1-carboxamide (compound 74); 2-(3-(methylsulfonyl)-4-((1-(oxetan-3-ylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 75); 2-(4-((4-(ethylsulfonyl)benzyl)oxy)-3-(methylsulfonyl)benzyl)isoindoline (compound 76); 1-((4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)sulfonyl)azetidin-3-ol (compound 77); N-(dimethyl(oxo)-λ 6 -sulfanylidene)-4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)benzamide (compound 78); (1r,4r)-4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)-N,N-dimethylcyclohexane-1-carboxamide (compound 79); Azetidin-1-yl(4-((4-(isoindolin-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-(isoindolin-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-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)propan-2-ol (compound 86); 1-(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethan-1-one (compound 87); 2-((1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-((1-tosylpiperidin-4-yl)methoxy)-4H-pyran-4-one (compound 88); 2-((5-acetylisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 89); (E)-2-((5-(1-(hydroxyimino)ethyl)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 90); (E)-2-((5-(1-(methoxyimino)ethyl)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 91); 1-(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)ethanone (compound 92a); 1-(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)ethanol (compound 92b); 2-((5-(1-hydroxyethyl)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 93); 1-(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)cyclohexyl)ethan-1-ol (compound 94); (R)-Imino(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)(methyl)-λ 6 -sulfanone (compound 95); (S)-Imino(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)(methyl)-λ 6 -sulfanone (compound 96); (S)-Ethyl(imino)(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)-λ 6 -sulfanone (compound 97); (R)-Ethyl(imino)(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)-λ 6 -sulfanone (compound 98); (R)-2-(1-(3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 99); (S)-2-(1-(3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 100); 2-((6-(isoxazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 101); 2-((6-(1H-pyrazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-((1-(methylsulfonyl)piperidin-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)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 103); 2-((1'H-spiro[cyclopentane-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)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 105); and tautomers and pharmaceutically acceptable salts thereof.

[0096] The compounds of the present invention can be administered to patients in therapeutically effective amounts, typically in the range of about 0.5 to about 2000 mg per day, typically about 1 to about 1500 mg per day, depending on the patient's age, sex, weight, ethnicity, 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 patients directly or in combination with appropriate pharmaceutical excipients in the form of tablets, granules, capsules, suppositories, emulsions, suspensions, or solutions. Selecting appropriate ingredients for a composition is a routine task for those skilled in the art. Suitable carriers, solvents, gel-forming ingredients, dispersion-forming ingredients, antioxidants, colorants, sweeteners, humectants, and other ingredients 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%, by weight of the total composition.

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

[0098] In the treatment of steroid receptor-dependent diseases or conditions, such as endocrine cancers and diseases such as prostate and breast cancer, the combination of therapeutic agents and / or other treatments (e.g., radiation therapy) is 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 compound of the present invention can be administered in combination with other anti-cancer treatments that are useful in treating cancer, such as prostate cancer or breast cancer.For example, the compound of the present invention can be packaged with instructions that the compound is to be used in combination with other anti-cancer drugs and treatments for treating cancer.The present invention also includes the combination of the compound of the present invention and one or more additional drugs in the form of a kit, for example, they are packaged together or sold together as a kit even if they are in separate packages, or 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 combined with a glucocorticoid and / or a mineralocorticoid, and optionally one or more anti-cancer agents.

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

[0102] Any other anti-cancer agent that can be administered in addition to the compound of formula (I) or (II) includes, but is not limited to: -Nonsteroidal androgen receptor antagonists (e.g., ezalutamide, apalutamide, and darolutamide); -steroidogenesis inhibitors (e.g., CYP17A1 inhibitors such as abiraterone acetate and seviteronel); - Chemotherapeutic agents (e.g., docetaxel and paclitaxel); -Antiestrogens (e.g., tamoxifen and fulvestrant); - epigenetic modulators (e.g., BET inhibitors and HDAC inhibitors); -mTOR inhibitors (e.g., everolimus); -AKT inhibitors (e.g., AZ5363); -Radioactive pharmaceuticals (e.g., alpharazine); -GnRH / LHRH analogues (e.g., leuprorelin); PI3K inhibitors (e.g., idelalisib); and CDK4 / 6 inhibitors (e.g., ribociclib) Examples include:

[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 subject in need thereof: -Nonsteroidal androgen receptor antagonists (e.g., ezalutamide, apalutamide, and darolutamide); -steroidogenesis inhibitors (e.g., CYP17A1 inhibitors such as abiraterone acetate and seviteronel); - Chemotherapeutic agents (e.g., docetaxel and paclitaxel); -Antiestrogens (e.g., tamoxifen and fulvestrant); - epigenetic modulators (e.g., BET inhibitors and HDAC inhibitors); -mTOR inhibitors (e.g., everolimus); -AKT inhibitors (e.g., AZ5363); -Radioactive pharmaceuticals (e.g., alpharazine); -GnRH / LHRH analogues (e.g., leuprorelin); PI3K inhibitors (e.g., idelalisib); and CDK4 / 6 inhibitors (e.g., ribociclib) is administered in addition to a therapeutically effective amount of one or more anti-cancer agents selected from the list consisting of:

[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 thereof in addition to a therapeutically effective amount of a steroidogenesis 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 a compound of formula (I) or (II) is administered to a subject in need thereof in addition to a therapeutically effective amount of a non-steroidal androgen receptor antagonist. Suitable non-steroidal androgen receptor (AR) antagonists include, but are not limited to, ezalutamide, apalutamide, and darolutamide.

[0106] According to yet another embodiment, the present invention provides a compound of formula (I) or (II) - glucocorticoids, - mineralocorticoids, steroidogenesis inhibitors (e.g., CYP17A1 inhibitors), -nonsteroidal androgen receptor antagonists, -chemotherapeutic agents (e.g., docetaxel and paclitaxel), antiestrogens (e.g., tamoxifen and fulvestrant), epigenetic modulators (e.g., BET inhibitors and HDAC inhibitors), -mTOR inhibitors (e.g., everolimus); -AKT inhibitors (e.g., AZ5363); -Radioactive pharmaceuticals (e.g., alpharazine); -GnRH / LHRH analogues (e.g., leuprorelin); PI3K inhibitors (e.g., idelalisib); and CDK4 / 6 inhibitors (e.g., ribociclib) and at least one additional active ingredient selected from the list consisting of:

[0107] Such other therapeutic agents, when used in combination with the compounds of the present invention, can be used, for example, in those amounts as described in the Physicians' Desk Reference (PDR), or as otherwise determined by one of skill in the art.

[0108] The compounds of the present invention can be prepared by various synthetic routes analogous to methods known in the literature using appropriate starting materials. The present invention is explained in more detail by the following experiments and examples. The experiments and examples are intended for illustrative purposes only and do not limit the scope of the invention as defined in the claims. [Example]

[0109] Intermediate 2a: 2-(isoindolin-5-yl)-1,3,4-oxadiazole trifluoroacetate [ka] a) tert-Butyl 5-(hydrazinecarbonyl)isoindoline-2-carboxylate (3) To a solution of 2-(tert-butyl)5-methyl isoindoline-2,5-dicarboxylate (3.50 g, 12.6 mmol, 1.0 equiv.) in 25 mL of EtOH was added hydrazine hydrate (0.40 g, 0.40 mL, 12.6 mmol, 1.0 equiv.) at 25° C. The resulting mixture was heated at 80° C. for 24 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting crude product was carried on to the next step without further purification. 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) tert-Butyl 5-(hydrazinecarbonyl)isoindoline-2-carboxylate (4.5 g, 16.2 mmol, 1.0 equiv.) and triethyl orthoformate (50 mL) were placed in a 100 mL sealed tube. The mixture was then heated at 120 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with EtOAc (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 0-50% 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 solution of tert-butyl 5-(1,3,4-oxadiazol-2-yl)isoindoline-2-carboxylate (0.24 g, 2.09 mmol, 1.0 equiv.) in 10 mL of LDC was added 2,2,2-trifluoroacetic acid (1.5 mL) at 0° C. The resulting mixture was then stirred at 0° C. for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting crude product was carried on 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 solution of tert-butyl 5-bromoisoindoline-2-carboxylate (2.0 g, 6.73 mmol, 1.0 equiv.) in DMA (20 mL) was added oxazole (1.85 g, 26.9 mmol, 4 equiv.), cesium carbonate (5.47 g, 16.8 mmol, 2.5 equiv.), and pivalic acid (0.28 g, 2.69 mmol, 0.4 equiv.) at 25 °C. The mixture was degassed with argon for 15 min. Palladium(II) acetate (0.83 g, 0.34 mmol, 0.05 equiv.) and di(1-adamantyl)-N-butylphosphine (0.12 g, 0.34 mmol, 0.05 equiv.) were then added to the reaction mixture, and the resulting reaction mixture was heated at 110 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc (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% EtOAc in heptane as the eluent. The two corresponding regioisomers were obtained, respectively. f (EtOAc / heptane: 3 / 7) = 0.2. Yield 0.42 g, 22% and 0.72 g, 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-(isoindolin-5-yl)oxazole hydrochloride (2b) Treatment of tert-butyl 5-(oxazol-5-yl)isoindoline-2-carboxylate (0.25 g, 0.87 mmol, 1.0 equiv) with HCl in EtOAc (12.0 mL, 1.0 M solution) in EtOAc (30 mL) and MeOH (2 mL) for 12 hours afforded the title product as a white solid. 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) Treatment of tert-butyl 5-(oxazol-2-yl)isoindoline-2-carboxylate (0.25 g, 0.87 mmol, 1.0 equiv) with HCl in EtOAc (12.0 mL, 1.0 M solution) in EtOAc (30 mL) and MeOH (2 mL) for 12 hours afforded the title product as a white solid. 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-(isoindolin-5-yl)isoxazole hydrochloride [ka] a) tert-Butyl (E)-5-(3-(dimethylamino)acryloyl)isoindoline-2-carboxylate (3) To a solution of tert-butyl 5-acetylisoindoline-2-carboxylate (0.9 g, 3.40 mmol, 1.0 equiv.) in 12 mL of DMF was added DMF-DMA (40 mL) at 25° C. The resulting mixture was stirred at 90° C. for 16 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting crude product was carried on 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 equiv.) and hydroxylamine hydrochloride (0.22 g, 3.22 mmol, 1.2 equiv.) in 40 mL of EtOH was refluxed for 16 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting crude product was carried on to the next step without further purification. 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) Treatment of tert-butyl 5-(oxazol-5-yl)isoindoline-2-carboxylate (0.35 g, 1.22 mmol, 1.0 equiv) with HCl in EtOAc (20.0 mL, 1.0 M solution) in MeOH (2 mL) for 12 hours afforded the title product as a white solid. 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-(isoindolin-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 equiv) in a DCM:DMSO (5:1, 24 mL) mixture was added EtN (2.86 g, 3.9 mL, 28.1 mmol, 7.0 equiv) and sulfur trioxide pyridine (3.18 g, 20.0 mmol, 5.0 equiv) at 0 °C. The resulting mixture was stirred at 25 °C for 12 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by Combiflash chromatography using 0-30% ethyl acetate in heptane 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 equiv.) in EtOH (90 mL) was added EtN (0.60 g, 0.82 mL, 5.80 mmol, 1.5 equiv.) and hydroxylamine hydrochloride (0.41 g, 5.80 mmol, 1.5 equiv.) at 25 °C. The resulting mixture was stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was carried on to the next step without further purification. R f (EtOAc / heptane: 3 / 7) = 0.4. Yield 0.96 g (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 equiv.) in 60 mL of DMF was added N-chlorosuccinimide (0.49 g, 3.66 mmol, 1.0 equiv.) at 0° C. The resulting mixture was stirred at 25° C. for 16 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was carried on to the next step without purification. R f (EtOAc / 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 equiv.) in 20 mL of DCM, triethylamine (1.48 g, 2.01 mL, 13.0 mmol, 3.5 equiv.) and trimethylsilylacetylene (1.20 g, 1.6 mL, 11.1 mmol, 3.0 equiv.) were added at 0 °C. The resulting mixture was stirred at 25 °C for 16 h. After completion of the reaction, the solvent was evaporated under reduced pressure to give the crude product. This crude product was purified by Combiflash chromatography using 0-30% ethyl acetate in heptane 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 equiv.) in 25 mL of MeOH was added potassium carbonate (0.60 g, 5.0 mmol, 1.5 equiv.) at 25° C. The resulting mixture was stirred at 60° C. for 2 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was carried on to the next step without further purification. R 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) Treatment of 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) afforded the title product as a black gummy mass. 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-(isoindolin-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 equiv) 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 equiv) and cesium carbonate (1.97 g, 6.10 mmol, 2.0 equiv) were added at 25 °C. The mixture was then degassed with argon for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.35 g, 0.30 mmol, 0.1 equiv) was then added, and the resulting reaction mixture was heated at 80 °C for 16 hours. After completion of the reaction, the mixture was quenched with water and extracted with EtOAc (3 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) Treatment of tert-butyl 5-(1,3,4-thiadiazol-2-yl)isoindoline-2-carboxylate (0.40 g, 1.32 mmol) in EtOAc (10 mL) with HCl in EtOAc (10.0 mL, 1.0 M solution) afforded the title product as a white solid. 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 equiv.) in 20 mL of DMA was added 1H-pyrazole (0.91 g, 13.4 mmol, 2.0 equiv.) and potassium carbonate (2.7 g, 20.2 mmol, 3.0 equiv.) at 25 °C. The mixture was then degassed with argon for 15 minutes. DMEDA (0.29 g, 3.36 mmol, 0.5 equiv.) and CuI (0.63 g, 3.3 mmol, 0.5 equiv.) were then added, and the resulting reaction mixture was heated at 150 °C for 16 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc (3 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)=0.6. 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) Treatment of tert-butyl 5-(1H-pyrazol-1-yl)isoindoline-2-carboxylate (0.4 g, 1.40 mmol, 1.0 equiv) with trifluoroacetic acid (2 mL) in DCM (20 mL) at 25° C. for 16 hours afforded the title product. 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-(isoindolin-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 equiv.) was dissolved in 30 mL of EtOH under a nitrogen atmosphere. EtN (4.5 g, 6.1 mL, 42.6 mmol, 8.0 equiv.) and NHOH.HCl (1.1 g, 15.9 mmol, 3.0 equiv.) were then added, and the mixture was stirred at 90 °C for 12 hours. After completion of the reaction, the reaction mixture was filtered, and the resulting solid was triturated with EtOH and dried under vacuum to give the title product. 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 equiv.) was dissolved in 15 mL of triethyl orthoformate under a nitrogen atmosphere. TFA (0.2 mL) was then added, and the mixture was stirred at 70 °C for 12 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This crude product was carried on 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) Treatment of tert-butyl 5-(1,2,4-oxadiazol-3-yl)isoindoline-2-carboxylate (0.4 g, 1.39 mmol, 1.0 equiv) with trifluoroacetic acid (2 mL) in DCM (12 mL) at 25° C. for 2 h afforded the title product as a black viscous liquid. 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-(isoindolin-5-yl)ethan-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 equiv.) in 10 mL of DMF was added trimethyl(trifluoromethyl)silane (3.5 g, 25.3 mmol, 2.5 equiv.) and potassium carbonate (1.39 g, 10.1 mmol, 1.0 equiv.) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. After 0.5 h, the starting material was consumed and a nonpolar spot was observed by TLC. The mixture was quenched with ice-cold water and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude residue was dissolved in 10 mL of MeOH, and K2CO3 (0.7 g, 5.06, 0.5 equiv.) was added, followed by stirring at 50 °C for 0.25 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with EtOAc (3 times). The combined organic layers were washed as above, dried, and concentrated under reduced pressure to give the crude product. The 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-(isoindolin-5-yl)ethan-1-ol hydrochloride (2i) Treatment of tert-butyl 5-(2,2,2-trifluoro-1-hydroxyethyl)isoindoline-2-carboxylate (0.40 g, 1.26 mmol, 1.0 equiv) in EtOAc (10 mL) with HCl in EtOAc (10.0 mL, 1.0 M solution) for 12 hours afforded the title product as a white solid. 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) was added 1-propanephosphonic acid cyclic anhydride (50% in EtOAc, 0.80 mL, 1.358 mmol). The mixture was stirred overnight at RT, then diluted with water and extracted with EtOAc. The organic phase was washed with saturated NaHCO3 solution, water, and brine, then dried and evaporated to give 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]heptane-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) was added methylmagnesium bromide (3 M in ethanol, 0.40 ml, 1.20 mmol). The mixture was stirred at 0-5°C for 1 h and then at RT overnight. The reaction was quenched by adding saturated NH4Cl solution and water, followed by extraction with DCM. The organic phase was dried and evaporated to give 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) was added sodium borohydride (0.045 g, 1.191 mmol) in small portions. The mixture was stirred at RT until the reaction was complete. Methanol was evaporated, water and EtOAc were added, and the phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried, and evaporated to give 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 indicated in the table following the procedures described in Example 10(a).

[0137] TIFF0007789697000036.tif245162 TIFF0007789697000037.tif37162

[0138] In the following synthetic examples, reference is made to preparative HPLC methods A, B or C.

[0139] Preparative HPLC: Method A: Instrument: Agilent Technologies 1260 Infinity Column: SUNFIRE C-18, 10 micron, 19 x 250 mm; Gradient [time (min) / solvent B (%) in A]: 0.01 / 10, 3.00 / 10, 13.00 / 35; Solvents: 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 x 250 mm; Gradient [time (min) / solvent B (%) in A]: 0.01 / 15, 3.00 / 15, 12.00 / 35, 16.00 / 35; Solvents: Solvent A = 0.1% TFA in water; Solvent B = acetonitrile, detection wavelength 214 nm; Flow rate 15 mL / min.

[0141] Method C: Equipment: Agilent Technologies 1260 Infinity Column: X Crosslinked Shield, 10 micron, 19 x 250 mm; Gradient [time (min) / solvent B (%) in A]: 0.01 / 45, 3.00 / 45, 13.00 / 65, 14.00 / 65; Solvents: 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)isoindolin-2-yl)methyl)-5-(((methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (Compound 1) [ka] To a solution of 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (0.29 g, 0.86, 1.0 equiv.) in CH3CN (30 mL) was added DIPEA (0.55 g, 4.3 mmol, 5.0 equiv.) and 2-(isoindolin-5-yl)-1,3,4-oxadiazole trifluoroacetate (0.25 g, 0.86 mmol, 1.0 equiv.). The resulting mixture was stirred at 90 °C for 16 h. After completion of the reaction as indicated by TLC, the mixture was quenched with ice-cold water and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give the pure product as a white solid. R f (MeOH / DCM:0.5 / 9.5)=0.3. Yield: 0.070 g. 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)piperidin-4-yl)methoxy)-2-((5-oxazol-5-yl)isoindolin-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 equiv.) was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (0.30 g, 0.90 mmol, 1.0 equiv.) and DIPEA (0.46 g, 3.60 mmol, 4.0 equiv.) in CHCN (10 mL) at 70° C. for 15 h, followed by purification by preparative HPLC using Method A (rt: 12.03 min) to give the title product as the TFA salt. f (MeOH / DCM:0.5 / 9.5)=0.6. Yield 0.021 g. 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)piperidin-4-yl)methoxy)-2-((5-oxazol-2-yl)isoindolin-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 equiv.) was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (0.30 g, 0.90 mmol, 1.0 equiv.) and DIPEA (0.46 g, 3.60 mmol, 4.0 equiv.) in CHCN (10 mL) at 70° C. for 16 h, followed by purification by preparative HPLC using Method A (rt: 12.46 min) to give the title product as the TFA salt. f (MeOH / DCM:0.5 / 9.5)=0.6. Yield 0.011 g. 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)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-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 equiv.) was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (0.41 g, 1.22 mmol, 1.0 equiv.) and DIPEA (0.79 g, 1.1 mL, 6.10 mmol, 5.0 equiv.) in CHCN (15 mL) at 80° C. for 16 hours, followed by purification by preparative HPLC using Method A to afford 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)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-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 equiv) was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (0.35 g, 1.06 mmol, 1.0 equiv) and DIPEA (0.68 g, 0.98 mL, 5.30 mmol, 5.0 equiv) in CHCN (20 mL) at 80° C. for 16 h, followed by purification by preparative HPLC using Method A (rt: 11.78 min) to give 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)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-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)piperidin-4-yl)methoxy)-4H-pyran-4-one (0.28 g, 0.83 mmol, 1.0 equiv.) and DIPEA (0.54 g, 0.76 mL, 4.15 mmol, 5.0 equiv.) in CHCN (10 mL) at 80° C. for 16 h, followed by purification by preparative HPLC using Method A (rt: 11.43 min) to give 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)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-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 equiv.) was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (0.41 g, 1.24 mmol, 1.0 equiv.) and DIPEA (0.80 g, 1.14 mL, 6.2 mmol, 5.0 equiv.) in CHCN (10 mL) at 90° C. for 16 h, followed by purification by preparative HPLC using Method A (rt: 11.33 min) to give the title product as the TFA salt. f (MeOH / DCM:0.5 / 9.5)=0.3. Yield: 0.060 g. 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)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (Compound 8) [ka] Following the procedure of Example 1, 3-(isoindolin-5-yl)-1,2,4-oxadiazole trifluoroacetate (0.4 g, 1.40 mmol, 1.0 equiv.) was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (0.47 g, 1.40 mmol, 1.0 equiv.) and DIPEA (0.90 g, 1.3 mL, 7.0 mmol, 5.0 equiv.) in CH3CN (50 mL) at 90°C for 12 hours and purified by column chromatography to give 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 lyophilizing. f (MeOH / DCM:0.5 / 9.5)=0.5. Yield: 0.34 g. 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)piperidin-4-yl)methoxy)-2-((5-(2,2,2-trifluorohydroxyethyl)isoindolin-2-yl)methyl)-4H-pyran-4-one (Compound 9) [ka] Following the procedure of Example 1, 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (0.25 g, 0.75 mmol, 1.0 equiv.) was treated with 2,2,2-trifluoro-1-(isoindolin-5-yl)ethan-1-ol hydrochloride (0.28 g, 1.12 mmol, 1.5 equiv.) and DIPEA (0.48 g, 0.69 mL, 3.75 mmol, 5.0 equiv.) in CHCN (10 mL) at 65° C. for 12 hours, followed by column chromatography to give the desired product as a brown solid. f (MeOH / DCM:0.5 / 9.5)=0.5. Yield: 0.25 g. 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)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)-1,3,4-oxadiazole (Compound 10) [ka] a) Methyl 3-iodo-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzoate (4) To a solution of methyl 4-hydroxy-3-iodobenzoate (20.0 g, 71.9 mmol, 1.0 equiv.) in 400 mL of DMF, (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (19.5 g, 71.9 mmol, 1.0 equiv.) and potassium carbonate (14.5 g, 107.91 mmol, 1.5 equiv.) were added at 25° C. The resulting mixture was stirred at 110° C. for 16 hours. After completion of the reaction, the mixture was cooled to 0° C. and quenched with ice-cold water to obtain a precipitate. The mixture was filtered, and the resulting solid was washed with water and dried under vacuum. This product was carried on to the next step without further purification. R 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) methyl 3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzoate (5) To a solution of methyl 3-iodo-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzoate (20.0 g, 44.2 mmol, 1.00 equiv.) in 200 mL of DMSO, sodium methanesulfinate (9.0 g, 88.3 mmol, 2.0 equiv.) and sodium hydride (1.76 g, 44.2 mmol, 1.0 equiv.) were added at 25 °C. The mixture was then degassed with argon gas for 15 minutes. After that, copper(II) iodide (0.8.38 g, 44.2 mmol, 1.0 equiv.) and picolinic acid (5.43 g, 44.15 mmol, 1.0 equiv.) were added, followed by heating at 100 °C for 16 hours. After completion of the reaction, the mixture was quenched with water and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography using 100-200 mesh silica gel and 0-60% ethyl acetate in heptane as the eluent. f (EtOAc / heptane: 6 / 4) = 0.2. Yield 12.0 g, 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)piperidin-4-yl)methoxy)phenyl)methanol (6) To a solution of methyl 3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzoate (6.0 g, 14.8 mmol, 1.0 equiv.) in 20 mL of THF was added lithium tetrahydroborate (24.6 mL, 73.98 mmol, 5.0 equiv.) at 0° C. The resulting mixture was heated at 50° C. for 24 h. After completion of the reaction, the mixture was cooled to 0° C., quenched with NH4Cl solution, and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This crude residue was carried on to the next step without further purification. R 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 solution of (3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)methanol (1.70 g, 4.50 mmol, 1.0 equiv.) in 50 mL of CH3CN and DMF (2-3 drops) was added thionyl chloride (8.04 g, 4.9 mL, 67.6 mmol, 15.0 equiv.) at 0 °C. The mixture was stirred at 25 °C for 1 h. After completion of the reaction, the solvent was evaporated under reduced pressure to give the crude product. R 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)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)-1,3,4-oxadiazole 2-(isoindolin-5-yl)-1,3,4-oxadiazole trifluoroacetate (0.4 g, 1.32 mmol, 1.0 equiv.) was treated with 4-((4-(chloromethyl)-2-(methylsulfonyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine (0.52 g, 1.3 mmol, 1.0 equiv.) in the presence of DIPEA (0.85 g, 1.2 mL, 6.6 mmol, 5.0 equiv.) in CH3CN (20 mL) at 90 °C for 16 h, followed by column chromatography to afford the title compound as a pale pink solid. The oxalate salt of the product was synthesized using oxalic acid (0.5 equiv.) in MeOH at 0 °C for 3 h, followed by filtration of the product. f (MeOH / DCM:0.5 / 9.5)=0.6. Yield: 0.34 g. 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)piperidin-4-yl)methoxy)benzyl)isoindolin-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 equiv.) was treated with 4-((4-(chloromethyl)-2-(methylsulfonyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine (0.25 g, 0.63 mmol, 1.0 equiv.) in the presence of DIPEA (0.40 g, 0.6 mL, 3.16 mmol, 5.0 equiv.) in CHCN (10 mL) at 90° C. for 16 hours, followed by column chromatography to give the title product as a white solid. The TFA salt of the product was synthesized by treating the title compound with 0.1% TFA in CHCN at 25° C. for 5 minutes and 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)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 12a) and 2-(3-(methylsulfonyl)-4-((1-methylsulfonyl)piperidin-4-yl)methoxy)benzyl)-5-(1H-pyrazol-1-yl)isoindoline (compound 12b) [ka] a) 5-bromo-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 12a) 5-Bromoisoindoline hydrochloride (0.5 g, 2.11 mmol, 1.0 equiv.) was treated with 4-((4-(chloromethyl)-2-(methylsulfonyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine (1.02 g, 2.59 mmol, 1.2 equiv.) in the presence of DIPEA (1.0 g, 1.5 mL, 8.44 mmol, 4.0 equiv.) in 10 mL of CH3CN at 100°C for 3 h, followed by column chromatography to give the title product. 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)piperidin-4-yl)methoxy)benzyl)-5-(1H-pyrazol-1-yl)isoindoline (compound 12b) 5-Bromo-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (0.36 g, 0.64 mmol, 1.00 equiv.) was treated with 1H-pyrazole (0.88 g, 1.29 mmol, 2.0 equiv.) in the presence of potassium carbonate (0.27 g, 1.92 mmol, 3.0 equiv.), DMEDA (0.028 g, 0.32 mmol, 0.5 equiv.), and CuI (0.061 g, 0.32 mmol, 0.5 equiv.) in 20 mL of DMA at 150° C. for 20 h, followed by preparative HPLC purification using Method A (rt: 12.32 min) afforded the title product as a white solid. 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)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)oxazole (compound 13a) and 2-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)oxazole (compound 13b) [ka] 5-Bromo-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (0.25 g, 0.45 mmol, 1.0 equiv.) was dissolved in 20 mL of DMF with cesium carbonate (0.36 g, 1.12 mmol, 2.5 equiv.), pivalic acid (0.018 g, 0.18 mmol, 0.4 equiv.), and paradiacetic acid. Treatment with oxazole (0.046 g, 0.67 mmol, 1.5 equiv.) in the presence of ammonium(II) (0.006 g, 0.022 mmol, 0.05 equiv.) and di(1-adamantyl)-n-butylphosphine (0.008 g, 0.022 mmol, 0.05 equiv.) at 110° C. for 16 h, followed by preparative HPLC purification using Method C (rt: 10.43 min and 11.41 min, Column: X Sunfire C18) afforded the two regioisomers as white solids. f (MeOH / DCM: 0.5 / 9.5) = 0.4. Yield: 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)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)thiazole (Compound 14) [ka] 5-Bromo-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (0.5 g, 0.90 mmol, 1.0 equiv.) was dissolved in 20 mL of DMF with cesium carbonate (0.73 g, 2.24 mmol, 2.5 equiv.), pivalic acid (0.04 g, 0.35 mmol, 0.4 equiv.), palladium(II) acetate (0 Treatment with thiazole (0.098 g, 1.16 mmol, 1.3 equiv) in the presence of thiazole (0.01 g, 0.04 mmol, 0.05 equiv) and di(1-adamantyl)-n-butylphosphine (0.02 g, 0.04 mmol, 0.05 equiv) at 110° C. for 16 h, followed by preparative HPLC purification using Method B (rt: 10.36 min) afforded the title product 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)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)ethan-1-one (compound 15a), 3-(dimethylamino)-1-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)prop-2-en-1-one (compound 15b) and 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)isoxazole (Compound 15c) [ka] a) 1-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)ethan-1-one (compound 15a) To a solution of 5-bromo-2-(3-methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (2.0 g, 3.59 mmol, 1.0 equiv.) in 20 mL of DMA was added tributyl(1-ethoxyvinyl)tin (2.0 g, 5.53 mmol, 1.4 equiv.) 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 equiv.) was added, and the resulting mixture was heated at 100° C. for 16 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 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 EtOAc (3 times), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 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)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)prop-2-en-1-one (compound 15b) 1-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)ethan-1-one (1.0 g, 1.92 mmol, 1.0 equiv) was treated with DMF-DMA (40 mL) in DMF at 90° C. for 16 hours to give the title product as a yellow gummy 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)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)isoxazole (compound 15c) 3-(Dimethylamino)-1-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)prop-2-en-1-one (0.9 g, 1.56 mmol, 1.0 equiv) was treated with hydroxylamine hydrochloride (0.32 g, 4.6 mmol, 3.0 equiv) in 40 mL of EtOH at 80° C. for 3 h, followed by preparative HPLC purification using Method B (rt: 14.01 min) afforded the title product as a brown solid. f (MeOH / DCM:0.5 / 9.5)=0.6. Yield 0.10 g. 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)piperidin-4-yl)methoxy)benzyl)isoindoline-5-carbonitrile (compound 16a), N-hydroxy-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline-5-carboximidamide (compound 16b) and 3-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)-1,2,4-oxadiazole (compound 16c) [ka] a) 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline-5-carbonitrile (Compound 16a) Isoindoline-5-carbonitrile hydrochloride (0.9 g, 5.0 mmol, 1.0 equiv.) was treated with 4-((4-(chloromethyl)-2-(methylsulfonyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine (1.97 g, 5.0 mmol, 1.0 equiv.) in the presence of DIPEA (3.88 g, 5.2 mL, 30.0 mmol, 6.0 equiv.) in CHCN (15 mL) at 80° C. for 4 hours, followed by column chromatography to afford the title product as a white solid. 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)piperidin-4-yl)methoxy)benzyl)isoindoline-5-carboximidamide (compound 16b) 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline-5-carbonitrile (0.3 g, 0.6 mmol, 1.0 equiv.) was treated with NHOH.HCl (0.04 g, 0.6 mmol, 1.0 equiv.) in the presence of EtN (0.32 g, 0.4 mL, 3.0 mmol, 5.0 equiv.) in EtOH (10 mL) at 90° C. for 12 hours to afford the title product 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)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)-1,2,4-oxadiazole (compound 16c) 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline-5-carboximidamide (0.28 g, 0.52 mmol, 1.0 equiv) was treated with trimethyl orthoformate (10 mL) in the presence of TFA (0.1 mL) at 70° C. for 2 h, followed by preparative HPLC using Method A to afford the title product as a white solid. 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)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 17a), and 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-(1-(5-(oxazol-2-yl)isoindolin-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 equiv.) in 300 mL of THF was added dropwise methylmagnesium bromide (3.0 M solution) (23 mL, 69.5 mmol, 1.6 equiv.) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. After completion of the reaction, the reaction mixture was quenched with NH4Cl solution and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude residue was purified by Combiflash chromatography using 0-50% ethyl acetate in heptane as the eluent. f (EtOAc / heptane: 8 / 2) = 0.2. Yield 6.0 g, 56%. MS (ESI) m / z [M+1] +: 247.07.

[0168] b) 1-(5-(benzyloxy)-4-oxo-4H-pyran-2-yl)ethyl methanesulfonate To a solution of 5-(benzyloxy)-2-(1-hydroxyethyl)-4H-pyran-4-one (4.0 g, 16.3 mmol, 1.0 equiv.) in 50 mL of THF, EtN (4.9 g, 6.6 mL, 48.8 mmol, 3.0 equiv.) and methanesulfonyl chloride (2.8 g, 1.8 mL, 24.4 mmol, 1.5 equiv.) were added dropwise at 0° C. The mixture was stirred at 25° C. for 1.5 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This crude product was carried on to the next step without further purification. R 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-bromoisoindolin-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 equiv.) was treated with 5-bromoisoindoline (2.0 g, 6.8 mmol, 1.0 equiv.) in the presence of DIPEA (2.6 g, 3.6 mL, 20.3 mmol, 3.0 equiv.) in 20 mL of CH3CN at 70 °C for 16 hours, followed by column chromatography to give the title product. 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-bromoisoindolin-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 equiv.) 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 completion of the reaction, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was carried on to the next step without purification. R 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)piperidin-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 equiv.) in 10 mL of DMSO, (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (0.84 g, 3.13 mmol, 1.0 equiv.), cesium carbonate (2.04 g, 6.25 mmol, 2.0 equiv.), and tris(2-(2-methoxyethoxy)ethyl)amine (0.10 g, 0.31 mmol, 0.1 equiv.) were added at 25° C. The resulting mixture was stirred at 60° C. for 16 hours. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white gummy mass as the crude product. The 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)piperidin-4-yl)methoxy)-2-(1-(5-(oxazol-2-yl)isoindolin-2-yl)ethyl)-4H-pyran-4-one (compound 17b) A solution of 2-(1-(5-bromoisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (0.10 g, 0.19 mmol, 1.0 equiv) in 5 mL of dioxane was degassed with argon for 10 minutes. 2-(tributylstannyl)oxazole (0.084 g, 0.23 mmol, 1.2 equiv) and tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.02 mmol, 0.1 equiv) were then added to the reaction mixture, which was then purged with argon again for 10 minutes. The reaction vial was sealed and heated at 110° C. for 16 hours. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC using Method C (rt: 13.17 min). The TFA salt of this compound was prepared by passing the compound through a reverse phase column using 0.1% TFA as the buffer to give the title product 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)piperidin-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)ethyl)isoindoline-5-carbonitrile (compound 18a), N-hydroxy-2-(1-(5-((1-(methylsulfonyl)piperidin-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)isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 18c) [ka] a) 2-(1-(5-((1-(methylsulfonyl)piperidin-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)piperidin-4-yl)methoxy)-4H-pyran-4-one (0.65 g, 1.27 mmol, 1.0 equiv) in 1,4-dioxane (15 mL) was added zinc(II) cyanide (0.44 g, 3.8 mmol, 3.0 equiv). The mixture was degassed with argon for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.25 mmol, 0.2 equiv) was then 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 completion of the reaction, the mixture was quenched with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by Combiflash chromatography using 0-80% ethyl acetate in heptane 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)piperidin-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)ethyl)isoindoline-5-carboximidamide (compound 18b) 2-(1-(5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)ethyl)isoindoline-5-carbonitrile (0.25 g, 0.546 mmol, 1.0 equiv.) was treated with hydroxylamine hydrochloride (0.075 g, 1.09 mmol, 2.0 equiv.) in the presence of EtN (0.22 g, 0.30 mL, 2.18 mmol, 4.0 equiv.) in 10 mL of EtOH at 70° C. for 18 hours, followed by column chromatography to give the title product. 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)isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 18c) N-hydroxy-2-(1-(5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-oxo-4H-pyran-2-yl)ethyl)isoindoline-5-carboximidamide (0.4 g, 0.85 mmol, 1.0 equiv.) was treated with trimethyl orthoformate (1.7 g, 1.8 mL, 16.3 mmol, 20.0 equiv.) at 60° C. for 18 hours, followed by preparative HPLC purification using Method C (rt: 13.24 min, column: X bridge C18) to give the title compound. 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-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethyl)-5-((1-(methylsulfonyl)piperidin-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-tetrahydroisoquinolin-2-ium To a solution of 5-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde (1.0 g, 4.3 mmol, 1.0 equiv.) in 10 mL of DCE was added tetrahydroisoquinoline (0.57 g, 4.3 mmol, 1.0 equiv.) and acetic acid (0.3 mL) at 25° C. The mixture was heated at 50° C. for 16 h. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting crude product (stored under nitrogen at −40° C.) was carried on 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-dihydroisoquinolin-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-tetrahydroisoquinolin-2-ium (1.5 g, 4.3 mmol, 1.0 equiv.) was dissolved in 60 mL of CH3CN. The resulting mixture was heated at 120 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with EtOAc (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 column chromatography using 100-200 mesh silica gel and 0-50% ethyl acetate in heptane as the eluent. f(EtOAc / heptane: 5 / 5) = 0.3. Yield 0.4 g, 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-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethyl)-5-hydroxy-4H-pyran-4-one 5-(Benzyloxy)-2-(1-(3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethyl-4H-pyran-4-one (0.30 g, 0.72 mmol, 1.0 equiv) was treated with concentrated HCl (3 mL) and AcOH (0.6 mL) at 65° C. for 16 h to give the title product 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-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (Compound 19) 2-(1-(3,4-Dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethyl)-5-hydroxy-4H-pyran-4-one (0.13 g, 0.39 mmol, 1.0 equiv.) was treated with (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (0.11 g, 0.44 mmol, 1.1 equiv.) in the presence of tris(2-(2-methoxyethoxy)ethyl)amine (0.077 g, 0.24 mmol, 0.6 equiv.) and cesium carbonate (0.26 g, 0.80 mmol, 2.0 equiv.) in DMSO (10 mL) at 60° C. for 2 h, followed by preparative HPLC purification using Method A (rt: 13.53 min) to afford 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)piperidin-4-yl)methoxy)-2-(2,2,2-trifluoro-1-(isoindolin-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 equiv.) was treated with tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (29.0 g, 105.6 mmol, 1.5 equiv.) in the presence of potassium carbonate (29.1 g, 211.1 mmol, 3.0 equiv.) in 120 mL of DMF at 70° C. for 16 hours to give the title compound 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 equiv.) was dissolved in 100 mL of MeOH. Activated manganese dioxide (10.63 g, 10.63 mmol, 5.0 equiv.) was then added to the solution at 25° C. The mixture was heated at 90° C. for 16 hours. After completion of the reaction, the mixture was filtered, washed with MeOH, and the resulting solution was concentrated under reduced pressure to give 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 a 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 equiv.) in 100 mL of DMF, trimethyl(trifluoromethyl)silane (3.42 mL, 23.1 mmol, 1.5 equiv.) and potassium carbonate (0.21 g, 1.54 mmol, 0.1 equiv.) were added at 0° C., followed by stirring at 25° C. for 4 h. After completion of the reaction, the mixture was quenched with ice-cold water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by Combiflash chromatography using 0–50% ethyl acetate in heptane as the eluent. f (EtOAc / heptane: 8 / 2) = 0.4. Yield 3.0 g, 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 a 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 equiv) in 20 mL of DCM, pyridine (0.58 g, 0.58 mL, 7.35 mmol, 3.0 equiv) and trifluoromethanesulfonic anhydride (1.72 g, 1.03 mL, 6.14 mmol, 2.5 equiv) were added at 0° C. The mixture was stirred at 0° C. for 0.5 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was carried on to the next step without further purification. R 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 a 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 equiv) in 20 mL of DMF was added sodium azide (0.25 g, 5.56 mmol, 2.5 equiv) at 25° C., followed by stirring at 25° C. for 16 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This crude residue was carried on to the next step without further purification. R 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 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 equiv) in 10 mL of MeOH was added 10% Pd / C (50% wet, 0.6 g, 0.28 mmol) at 25 °C under a nitrogen atmosphere. H2 gas was then purged into the reaction mixture with a hydrogen balloon, and the resulting mixture was stirred at 25 °C for 2 h. After completion of the reaction, the mixture was filtered through Celite and washed with MeOH. The organic fraction was concentrated under reduced pressure. The crude product was purified by column chromatography using 100-200 mesh silica gel and 0-10% MeOH in EtOAc 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-(isoindolin-2-yl)ethyl)-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate To a 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 equiv.) in 10 mL of CH3CN, 1,2-bis(bromomethyl)benzene (0.38 g, 1.47 mmol, 3.0 equiv.) and N-ethyl-N-isopropylpropan-2-amine (0.19 g, 0.27 mL, 1.42 mmol, 3.0 equiv.) were added at 25 °C, followed by stirring at 65 °C for 12 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by column chromatography using 100-200 mesh silica gel and 0-10% MeOH in EtOAc as the eluent. f(EtOAc / heptane: 8 / 2) = 0.2. Yield 0.05 g, 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)piperidin-4-yl)methoxy)-2-(2,2,2-trifluoro-1-(isoindolin-2-yl)ethyl)-4H-pyran-4-one (Compound 20) To a 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 equiv) in EtOAc was added HCl in EtOAc (5.0 mL, 1.0 M solution) and then stirred for 12 hours. The reaction mass was concentrated to give the crude product as a brown gummy mass. The crude product was dissolved in 50 mL of THF and EtN (0.21 g, 0.29 mL, 2.06 mmol, 3.0 equiv) was added followed by the dropwise addition of methanesulfonyl chloride (0.12 g, 0.08 mL, 1.03 mmol, 1.5 equiv) at 0° C. The mixture was stirred at 25° C. for 1.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC using Method C (rt: 11.98 min, column: Sunfire C-18) to give 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)piperidin-4-yl)methoxy)phenyl)ethyl)isoindoline (Compound 21) [ka] a) 3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzaldehyde (3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)methanol (3.0 g, 7.94 mmol, 1.0 equiv.) was treated with activated manganese dioxide (3.4 g, 39.7 mmol, 5.0 equiv.) in 40 mL of MeOH at 60° C. for 12 hours to afford the title compound as a white solid. f (EtOAc / heptane: 8 / 2) = 0.4. Yield 2.0 g, 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)piperidin-4-yl)methoxy)phenyl)ethan-1-ol (Methylsulfonyl)piperidin-4-yl)methoxy)benzaldehyde (2.0 g, 5.327 mmol, 1.0 equiv.) was treated with trimethyl(trifluoromethyl)silane (3.0 g, 21.31 mmol, 4.0 equiv.) in the presence of potassium carbonate (0.36 g, 2.6 mmol, 0.5 equiv.) in 20 mL of DMF at 0° C. for 4 hours, followed by column chromatography to give the title compound as a white solid. 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)piperidin-4-yl)methoxy)phenyl)ethyl methanesulfonate 2,2,2-Trifluoro-1-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)ethan-1-ol (1.1 g, 3.7 mmol, 1.0 equiv.) was treated with methanesulfonyl chloride (0.42 g, 3.69 mmol, 1.5 equiv.) in the presence of EtN (0.37 g, 3.7 mmol, 1.5 equiv.) in 20 mL of DCM at 0° C. for 2 hours to afford the title compound 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)piperidin-4-yl)methoxy)phenyl)ethyl methanesulfonate (1.3 g, 2.48 mmol, 1.0 equiv.) was treated with sodium azide (1.6 g, 24.8 mmol, 10.0 equiv.) in 20 mL of DMF at 90° C. for 12 hours to afford the title compound 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)piperidin-4-yl)methoxy)phenyl)ethan-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 equiv.) was treated with platinum oxide (2.90 g, 12.8 mmol, 5.0 equiv.) in 20 mL of MeOH at 25° C. for 2 hours, followed by column chromatography to give the title compound as a yellow gummy mass. f (EtOAc / heptane: 8 / 2) = 0.2 (ninhydrin). Yield 0.35 g, 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)piperidin-4-yl)methoxy)phenyl)ethyl)isoindoline (Compound 21) 2,2,2-Trifluoro-1-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)ethan-1-amine (0.2 g, 0.45 mmol, 1.0 equiv.) was treated with 1,2-bis(bromomethyl)benzene (0.35 g, 1.35 mmol, 3.0 equiv.) in the presence of N-ethyl-N-isopropylpropan-2-amine (0.17 g, 1.35 mmol, 3.0 equiv.) in 10 mL of CH3CN at 65°C for 12 hours, followed by preparative HPLC purification using Method C (rt: 13.28 min) afforded the title compound as a white solid. 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-(pyrimidin-2-ylmethyl)piperidin-4-yl)methoxy)phenyl)ethyl)isoindoline (Compound 22) [ka] a) 1-(3-bromo-4-methoxyphenyl)-2,2-difluoro-2-(phenylsulfonyl)ethan-1-ol To a solution of 3-bromo-4-methoxybenzaldehyde (20.0 g, 93.5 mmol, 1.0 equiv.) in THF (200 mL) and HMPA (3.0 mL) was added ((difluoromethyl)sulfonyl)benzene (18.0 g, 93.5 mmol, 1.0 equiv.) at 0 °C. Then, lithium bis(trimethylsilyl)amide solution (93.5 mL, 1.0 M in THF, 93.5 mmol, 1.0 equiv.) was slowly added at 0 °C and 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 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 0–10% ethyl acetate in hexane as the eluent. The desired fractions were concentrated under reduced pressure to give the title compound as an off-white sticky 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 To a solution of 1-(3-bromo-4-methoxyphenyl)-2,2-difluoro-2-(phenylsulfonyl)ethan-1-ol (10 g, 25 mmol, 1.0 equiv) in ACN (10 mL) was added HSO (5 mL) at 0 °C and heated at 70 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a brown sticky 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)ethan-1-amine hydrochloride A solution of N-(1-(3-bromo-4-methoxyphenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl)acetamide (11.0 g, 24.5 mmol, 1.0 equiv) in MeOH (100.0 mL) and concentrated HCl (100.0 mL) was added, and the mixture was heated at 100° C. for 2 days. After completion of the reaction, the mixture was concentrated under reduced pressure to give 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)ethan-1-amine (10.0 g, 24.6 mmol, 1.0 equiv.) and 1,2-bis(bromomethyl)benzene (13.0 g, 49.2 mmol, 2.0 equiv.) were treated in CHCN (100 mL) in the presence of N-ethyl-N-isopropylpropan-2-amine (15.9 g, 21 mL, 123 mmol, 5.0 equiv.) at 70° C. for 36 h, followed by CombiFlash column chromatography to afford the title compound as a white solid. 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 equiv) was placed in aqueous HBr (200 mL) at 25° C. The mixture was heated at 110° C. for 5 days. After completion of the reaction, the mixture was concentrated under reduced pressure to give 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-(isoindolin-2-yl)-2-(phenylsulfonyl)ethyl)phenol (3.0 g, 6.1 mmol, 1.0 equiv.) was treated with tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (3.2 g, 11.0 mmol, 1.8 equiv.) in the presence of potassium carbonate (4.2 g, 30.5 mmol, 5.0 equiv.) in DMF (50 mL) at 60° C. for 16 hours, followed by column chromatography to give the title compound as a white solid. 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-(piperidin-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 equiv.) in DCM (20 mL) was treated with trifluoroacetic acid (4.9 g, 43.4 mmol, 10.0 equiv.) to afford 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-(pyrimidin-2-ylmethyl)piperidin-4-yl)methoxy)phenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl)isoindoline To a solution of 2-(1-(3-bromo-4-(piperidin-4-ylmethoxy)phenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl)isoindoline (3.0 g, 5.07 mmol, 1.0 equiv) in THF (30.0 mL) and HO (10.0 mL) was added pyrimidin-2-ylmethyl methanesulfonate (1.9 g, 10.2 mmol, 2.0 equiv) and EtN (5.1 g, 7 mL, 51.0 mmol, 10.0 equiv) at 25 °C. The reaction mixture was stirred at 25 °C for 24 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (3 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 0-50% ethyl acetate in heptane as the eluent to give 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-(pyrimidin-2-ylmethyl)piperidin-4-yl)methoxy)phenyl)-2,2-difluoroethyl)isoindoline To a solution of 2-(1-(3-bromo-4-((1-(pyrimidin-2-ylmethyl)piperidin-4-yl)methoxy)phenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl)isoindoline (0.5 g, 0.73 mmol, 1.0 equiv.) in DMF (10 mL) was added acetic acid (0.88 g, 0.837 mL, 14.6 mmol, 20.0 equiv.) and sodium acetate (1.20 g, 14.6 mmol, 20.0 equiv.) stepwise at 0° C. Then, magnesium turnings (0.366 g, 14.6 mmol, 20.0 equiv.) were added and the reaction mass was stirred at 25° C. for 16 hours. After completion of the reaction, the mixture was quenched with ice-cold water and extracted with 10% methanol in ethyl acetate (3 times). The combined organic layers were 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 fractions were concentrated under reduced pressure to give the title compound as a brown sticky 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-(pyrimidin-2-ylmethyl)piperidin-4-yl)methoxy)phenyl)ethyl)isoindoline (Compound 22) 2-(1-(3-Bromo-4-((1-(pyrimidin-2-ylmethyl)piperidin-4-yl)methoxy)phenyl)-2,2-difluoroethyl)isoindoline (0.14 g, 0.25 mmol, 1.0 equiv.) was treated with sodium methanesulfinate (0.13 g, 1.29 mmol, 5.0 equiv.) in the presence of potassium carbonate (0.03 g, 10.25 mmol, 1.0 equiv.), copper(I) iodide (0.048 g, 0.25 mmol, 1.0 equiv.) and 2-picolinic acid (0.061 g, 0.5 mmol, 2.0 equiv.) in DMSO (4.0 mL) at 110° C. for 16 h, followed by preparative HPLC purification using Method A (rt: 13.38 min) afforded the title compound as a white solid. 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)isoindolin-2-yl)methyl)-5-(piperidin-4-ylmethoxy)-4H-pyran-4-one (compound 23a), 2-((5-(1,3,4-oxadiazol-2-yl)isoindolin-2-yl)methyl)-5-((1-(pyrimidin-2-ylmethyl)piperidin-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-(pyrimidin-2-ylmethyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 23c) [ka] a) tert-Butyl 4-(((6-((5-(1,3,4-oxadiazol-2-yl)isoindolin-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-trifluoroethan-1-one salt (1.0 g, 3.52 mmol, 1.0 equiv.) 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 equiv.) in the presence of EtN (1.78 g, 2.4 mL, 17.6 mmol, 5.0 equiv.) in THF (10 mL) and water (10 mL) at 65° C. for 4 hours to give 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)isoindolin-2-yl)methyl)-5-(piperidin-4-ylmethoxy)-4H-pyran-4-one (compound 23a) tert-Butyl 4-(((6-((5-(1,3,4-oxadiazol-2-yl)isoindolin-2-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (1.0 g, 1.96 mmol, 1.0 equiv) in DCM (10 mL) was treated with TFA (5 mL) at 0° C. for 1 h to give the title compound 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)isoindolin-2-yl)methyl)-5-((1-(pyrimidin-2-ylmethyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 23b) 2-((5-(1,3,4-Oxadiazol-2-yl)isoindolin-2-yl)methyl)-5-(piperidin-4-ylmethoxy)-4H-pyran-4-one (1.0 g, 2.4 mmol, 1.0 equiv.) was treated with pyrimidin-2-ylmethyl methanesulfonate (0.46 g, 2.4 mmol, 1.0 equiv.) in the presence of DIPEA (1.6 g, 2.1 mL, 12 mmol, 5.0 equiv.) in CH3CN (10 mL) at 65 °C for 2 h to give the title compound 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-(pyrimidin-2-ylmethyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (compound 23c) To a solution of 2-((5-(1,3,4-oxadiazol-2-yl)isoindolin-2-yl)methyl)-5-((1-(pyrimidin-2-ylmethyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (0.4 g, 0.8 mmol, 1.0 equiv.) in trifluoroethanol (6 mL) under N2 atmosphere was added chloro[5-methoxy-2-[1-[(4-methoxyphenyl)imino-N]ethyl]phenyl-C][(1,2,3,4,5-etha)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium (0.049 g, 0.08 mmol, 0.1 equiv.) at 25 °C, followed by heating at 110 °C for 48 h in the dark. The mixture was filtered in the dark, and the filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC using Method C (rt: 13.79 min, column: X-Select Hexyl Phenyl) to give 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)piperidin-4-yl)methoxy)-2-((S * )-1-((1aR * ,7bR * )-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinolin-2-yl)ethyl)-4H-pyran-4-one (compound 24a) and 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((R * )-1-((1aR* ,7bR * )-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinolin-2-yl)ethyl)-4H-pyran-4-one (compound 24b) [ka] a) tert-Butyl 1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinoline-2-carboxylate To a solution of 1,1a,2,7b-tetrahydro-3H-cyclopropa[c]isoquinolin-3-one (0.85 g, 5.34 mmol, 1.0 equiv) in THF (20 mL) was added borane-DMS (6.08 g, 7.60 mL, 80.1 mmol, 15.0 equiv) at 0 °C, followed by stirring at 60 °C for 16 h. The mixture was cooled to 0 °C, quenched with methanol, refluxed at 60 °C for 1 h, and concentrated under high vacuum to give a colorless liquid. The crude product was taken up in DCM (10 mL). EtN (1.62 g, 2.23 mL, 16.02 mmol, 3.0 equiv) and boc-anhydride (2.33 g, 2.45 mL, 10.6 mmol, 2.0 equiv) were added at 0 °C, followed by stirring at 25 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with EtOAc (3 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 0-10% ethyl acetate in hexane as the eluent. The desired fractions were concentrated under reduced pressure to give tert-butyl 1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinoline-2-carboxylate as a colorless sticky 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 equiv) in EtOAc (2 mL) was treated with HCl in EtOAc (5.0 mL, 1.0 M solution) for 12 hours to afford the title compound 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]isoquinolin-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 equiv.) was treated with 1-(5-(benzyloxy)-4-oxo-4H-pyran-2-yl)ethyl methanesulfonate (0.54 g, 1.65 mmol, 0.6 equiv.) in the presence of EtN (1.74 g, 2.3 mL, 17.2 mmol, 5.0 equiv.) in THF and HO (1:1, 10.0 mL) at 25 °C for 24 h, followed by column chromatography to afford the title compound as a mixture of diastereomers as a colorless liquid. 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]isoquinolin-2-yl)ethyl)-4H-pyran-4-one 5-(Benzyloxy)-2-(1-(1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinolin-2-yl)ethyl)-4H-pyran-4-one (0.40 g, 1.07 mmol, 1.0 mmol) was treated with concentrated HCl (5 mL) for 16 h to give 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)piperidin-4-yl)methoxy)-2-((S * )-1-((1aR * ,7bR * )-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinolin-2-yl)ethyl)-4H-pyran-4-one (compound 24a, diastereomer 1) and 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((R * )-1-((1aR * ,7bR * )-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinolin-2-yl)ethyl)-4H-pyran-4-one (compound 24b, diastereomer 2) 5-Hydroxy-2-(1-(1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinolin-2-yl)ethyl)-4H-pyran-4-one (0.3 g, 1.06 mmol, 1.0 equiv.) was treated with (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (0.23 g, 1.06 mmol, 1.0 equiv.) in the presence of cesium carbonate (0.86 g, 2.65 mmol, 2.5 equiv.) and tris(2-(2-methoxyethoxy)ethyl)amine (0.03 g, 0.11 mmol, 0.1 equiv.) in DMSO (5 mL) at 60° C. for 5 hours to give 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 give the two corresponding diastereomers as white solids. Yield 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)piperidin-4-yl)methoxy)benzyl)isoindoline (Compound 25) [ka] a) methyl 3-iodo-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzoate [ka] 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) was added potassium carbonate (0.304 g, 2.20 mmol). The mixture was stirred at 100° C. until the reaction was complete. Water was added to the cooled reaction mixture, which was then stirred at RT overnight. The precipitated product was filtered, washed with water, and dried in vacuo to give 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) methyl 3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzoate [ka] A mixture of methyl 3-iodo-4-((1-(methylsulfonyl)piperidin-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 h. Then, more sodium ethanesulfinate (0.273 g, 2.352 mmol) was added, and stirring was continued at 100° C. for 4 h. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried over anhydrous NaSO, filtered, and evaporated to give the crude product. Purification by flash chromatography gave the title compound (0.19 g). 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)piperidin-4-yl)methoxy)phenyl)methanol [ka] To a cooled (0-5°C) mixture of methyl 3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzoate (0.19 g, 0.453 mmol) in dry THF (2 ml) was added lithium borohydride (2 M in THF, 0.6 ml, 1.20 mmol). The mixture was stirred at RT for 3.5 h and 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 EtOAc (2x). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and evaporated to give 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] To a mixture of (3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)methanol (0.17 g, 0.434 mmol) in dry DCM (3 ml) containing a catalytic amount of DMF was added 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 evaporation was repeated. Drying under vacuum gave 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)piperidin-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, which was then stirred at RT for 30 min. The precipitated product was filtered, washed with water, and dried under vacuum to give the crude product. Purification by reverse-phase flash chromatography gave the title compound (0.061 g). 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)piperidin-4-yl)methoxy)benzyl)isoindoline (Compound 26) [ka] a) methyl 3-(cyclopropylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzoate [ka] The compound was prepared according to the procedure of Example 25(b) starting from 3-iodo-4-((1-(methylsulfonyl)piperidin-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). Purification by column chromatography gave the title compound (0.25 g). 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)piperidin-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)piperidin-4-yl)methoxy)benzoate (0.25 g, 0.579 mmol) and lithium borohydride (2 M in THF, 0.9 ml, 1.80 mmol) in dry THF (3.0 ml) at 60° C. Purification by reverse-phase flash chromatography gave the title compound (0.0814 g). 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)piperidin-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)piperidin-4-yl)methoxy)benzyl)isoindoline (Compound 26) [ka] The compound was prepared according to the procedure of Example 25(e) starting from 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 raw product was triturated with diethyl ether-methanol and dried under vacuum to give 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)piperidin-4-yl)methoxy)benzyl)-5-(trifluoromethyl)isoindoline (Compound 27) [ka] The compound was prepared according to the procedure of Example 25(e) starting from 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 dry DMSO (1.5 ml). Purification by reverse-phase flash chromatography gave the title compound (0.0313 g). 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)piperidin-4-yl)methoxy)benzyl)isoindoline (Compound 28) [ka] a) Butyl 3-(butylsulfonyl)-4-fluorobenzoate [ka] 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) in dry DMF (1.0 ml) was stirred at 80 °C until the reaction was complete. The cooled reaction mixture was diluted with water and extracted with EtOAc (2x). The combined organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product. Purification by phase flash chromatography gave the title compound (0.14 g). 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) butyl 3-(butylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzoate [ka] To a cooled mixture of sodium hydride (50% wt. in oil, 0.013 g, 0.553 mmol) in dry DMF (1.5 ml) was added a solution of (1-(methylsulfonyl)piperidin-4-yl)methanol (0.094 g, 0.487 mmol). The mixture was stirred at RT for 15 minutes, after which a solution of butyl 3-(butylsulfonyl)-4-fluorobenzoate (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 EtOAc (2×). The combined organic phase was washed with water and brine, dried over anhydrous NaSO, filtered, and evaporated to give the crude product. Purification by phase flash chromatography gave the title compound (0.10 g). 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)piperidin-4-yl)methoxy)phenyl)methanol [ka] The compound was prepared according to the procedure of Example 25(c) starting with butyl 3-(butylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)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). Yield 0.108 g of crude product. 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)piperidin-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)piperidin-4-yl)methoxy)benzyl)isoindoline (Compound 28) [ka] The compound was prepared according to the procedure of Example 25(e) starting from 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). Purification by reverse-phase flash chromatography gave the title compound (0.015 g). 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)piperidin-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)piperidin-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) was stirred at 60 °C until the reaction was complete. The reaction mixture was diluted with water and extracted with EtOAc (2x). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated to give the crude product. Purification by reverse-phase flash chromatography gave the title compound (0.087 g). 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-dihydroisoquinolin-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) was added methanesulfonyl chloride (0.072 mL, 0.924 mmol) dissolved in dry DCM (2.0 mL). The reaction mixture was stirred overnight at RT, then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic phase was dried and evaporated to give 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-dihydroisoquinolin-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 of the crude product (60 mg) 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) [ka] To a cooled (0-5 °C) mixture of 2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-hydroxy-4H-pyran-4-one (0.077 g, 0.300 mmol), tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (0.064 g, 0.300 mmol), and triphenylphosphine (0.118 g, 0.450 mmol) in dry THF (2.5 ml) was added diisopropyl azodicarboxylate (0.089 ml, 0.450 mmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with DCM and washed with water and brine. The organic phase was dried and evaporated. The crude product was purified by reverse-phase flash chromatography to give the title compound (0.039 g). 1 H NMR (600 MHz, DMSO-d6): δ 7.98 (s, 1H), 7.07-7.16 (m, 3H), 7.03 (d, 1H), 6.37 (s, 1H), 4.37-4.47 (m, 1H), 3.71-3.95 (m, 4H), MS: m / z 453.8 (M+H) + .

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

[0233] TIFF0007789697000085.tif241164

[0234] Example 32 Tert-butyl 6-(1-((6-((3,4-dihydroisoquinolin-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-dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)ethyl)-2-azaspiro[3.3]heptane-2-carboxylate A mixture of 2-((3,4-dihydroisoquinolin-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]heptane-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 EtOAc (2×). The combined organic phases were washed with water and brine, dried, and evaporated. The crude product was purified by flash chromatography to give 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-dihydroisoquinolin-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 following the procedure for Intermediate 3(c) 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). 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) [ka] 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. 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) [ka] To a solution of 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 (0.30 g, 0.663 mmol) in dry DCM (5.0 ml) was added trifluoroacetic acid (0.30 ml, 3.89 mmol). The mixture was stirred at RT overnight. Further trifluoroacetic acid was added (0.30 ml, 6.89 ml) and stirring was continued at 40° C. until the reaction was complete. The solvent was evaporated and the residue was treated with more DCM and evaporation was repeated to give 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 following the procedure described for compound 38 in Example 34. The compound numbers, characterizing data, starting materials and possible deviations in reaction conditions (C=concentration of starting material) are given in the table.

[0241] TIFF0007789697000093.tif222164 TIFF0007789697000094.tif107164

[0242] Example 35 2-((3,4-Dihydroisoquinolin-2(1H)-yl)methyl)-5-((2-pyrimidin-2-yl)-2-azaspiro[3.3]heptan-6-yl)oxy)-4H-pyran-4-one (Compound 45) [ka] To a mixture of 5-((2-azaspiro[3.3]heptan-6-yl)oxy)-2-((3,4-dihydroisoquinolin-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 added 2-bromopyrimidine (0.043 g, 0.269 mmol) dissolved in dry DCM (0.5 ml). The mixture was stirred at RT overnight, then diluted with DCM, washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to give 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-Dihydroisoquinolin-2(1H)-yl)methyl)-5-((7-(pyrimidin-2-yl)-7-azaspiro[3.5]nonan-2-yl)oxy)-4H-pyran-4-one (Compound 46) [ka] To a mixture of 5-((7-azaspiro[3.5]nonan-2-yl)oxy)-2-((3,4-dihydroisoquinolin-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 added 2-bromopyrimidine (0.043 g, 0.270 mmol) dissolved in dry DMF (0.5 mL). The mixture was stirred at RT overnight, after which additional 2-bromopyrimidine (0.020 mg, 0.126 mmol) was added and 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 give the title compound (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-Dihydroisoquinolin-2(1H)-yl)methyl)-5-((7-(pyrimidin-2-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)oxy)-4H-pyran-4-one (Compound 47) [ka] To a mixture of 5-((7-azaspiro[3.5]nonan-2-yl)oxy)-2-((3,4-dihydroisoquinolin-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 added pyrimidin-2-ylmethyl methanesulfonate (0.053 g, 0.281 mmol) dissolved in dry DMF (0.5 mL). The mixture was stirred at RT overnight, after which additional pyrimidin-2-ylmethyl methanesulfonate (0.020 g, 0.106 mmol) was added and 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 give the title compound (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-Dihydroisoquinolin-2(1H)-yl)methyl)-5-((7-(pyrimidin-2-yl)-7-azaspiro[3.5]nonan-2-yl)methoxy)-4H-pyran-4-one (Compound 48) [ka] The compound was prepared according to the procedure of Example 36 starting from 5-((7-azaspiro[3.5]nonan-2-yl)methoxy)-2-((3,4-dihydroisoquinolin-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-Dihydroisoquinolin-2(1H)-yl)methyl)-5-((6-(pyrimidin-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 from 5-((6-azaspiro[3.4]octan-2-yl)oxy)-2-((3,4-dihydroisoquinolin-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-Dihydroisoquinolin-2(1H)-yl)methyl)-5-((2-(pyrimidin-2-yl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-4H-pyran-4-one (Compound 50) [ka] a) 2-(pyrimidin-2-yl)-2-azaspiro[3.3]heptane-6-carboxylate methyl ester [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 EtOAc. The organic phase was washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to give 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-(pyrimidin-2-yl)-2-azaspiro[3.3]heptan-6-yl)methanol [ka] To a solution of methyl 2-(pyrimidin-2-yl)-2-azaspiro[3.3]heptane-6-carboxylate (0.20 g, 0.857 mmol) in dry THF (4.5 mL) was added lithium aluminum hydride (2.0 M in THF, 1.3 mL, 1.30 mmol), and the mixture was stirred at RT overnight. 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. The mixture was stirred at RT for 1 h. Anhydrous sodium sulfate was added, and stirring was continued for 15 min. The mixture was filtered through a plug of Celite. The filter cake was washed with THF, and the filtrate was evaporated and dried to give 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-(pyrimidin-2-yl)-2-azaspiro[3.3]heptan-6-yl)methyl methanesulfonate [ka] To a cooled (0-5 °C) mixture of (2-(pyrimidin-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 dry DCM (1.5 mL) was added methanesulfonyl chloride (0.033 mL, 0.429 mmol) in dry DCM (0.5 mL). 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 give 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-dihydroisoquinolin-2(1H)-yl)methyl)-5-((2-(pyrimidin-2-yl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-4H-pyran-4-one (compound 50) [ka] A mixture of (2-(pyrimidin-2-yl)-2-azaspiro[3.3]heptan-6-yl)methyl methanesulfonate (0.062 g, 0.219 mmol), 2-((3,4-dihydroisoquinolin-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 EtOAc (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 give 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-dihydroisoquinolin-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-dihydroisoquinolin-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 give 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-dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)azetidin-1-yl)nicotinonitrile (Compound 52) [ka] a) 6-(3-(hydroxymethyl)azetidin-1-yl)nicotinonitrile [ka] A mixture of azetidin-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 give 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-cyanopyridin-2-yl)azetidin-3-yl)methyl methanesulfonate [ka] The compound was prepared following the procedure of Example 30 (Step 1) starting with 6-(3-hydroxymethyl)azetidin-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-dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)azetidin-1-yl)nicotinonitrile (compound 52) [ka] A mixture of (1-(5-cyanopyridin-2-yl)azetidin-3-yl)methyl methanesulfonate (0.049 g, 0.183 mmol), 2-((3,4-dihydroisoquinolin-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 give 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-Dihydroisoquinolin-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] To a mixture of 5-((7-azaspiro[3.5]nonan-2-yl)oxy)-2-((3,4-dihydroisoquinolin-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 added 1-methyl-1H-pyrazole-5-sulfonyl chloride (0.030 g, 0.169 mmol) dissolved in dry DMF (0.5 ml). The mixture was stirred at RT overnight, then diluted with DCM, washed with water and brine, dried, and evaporated. The crude product was purified by reverse-phase flash chromatography to give 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 following the procedure described for compound 53 in Example 43. Compound numbers, characterizing data, and starting materials are listed in the table.

[0257] TIFF0007789697000111.tif239164 TIFF0007789697000112.tif227164 TIFF0007789697000113.tif106164

[0258] Example 44 2-(1-(5-acetylisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-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 according to the procedure of Example 30(a) 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) in dry DCM (5.0 ml). 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-acetylisoindolin-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) was added 1-(5-(benzyloxy)-4-oxo-4H-pyran-2-yl)ethyl methanesulfonate (0.26 g, 0.802 mmol). The mixture was stirred at 90° C. until the reaction was complete. The cooled mixture was diluted with water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried, and evaporated. The crude product was purified by flash chromatography to give 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. The mixture was extracted with EtOAc (2×), and the combined organic phases were washed with brine, dried, and evaporated to give 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-acetylisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-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 give 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)piperidin-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) was added 3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzaldehyde (0.17 g, 0.45 mmol). After 30 min, the reaction mixture was cooled to 0° C., then sodium triacetoxyborohydride (0.14 g, 0.68 mmol) was added. The mixture was stirred at RT overnight and quenched with water (10 ml). The product was extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography to give the title compound. 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 following the procedure described for compound 65 in Example 45. The compound numbers, characterizing data, starting materials, and possible deviations in reaction conditions (solvent, reaction temperature, reaction time, method of preparation, if any) are provided in the table.

[0264] Purification method used: A=crystallization B = Column chromatography C = Precipitation in aqueous media D = semi-preparative HPLC E = Crushing F = salt formation

[0265] TIFF0007789697000120.tif165164 TIFF0007789697000121.tif108164

[0266] The following compounds were prepared according to the procedure described in Example 17(e) starting from 4-(isoindolin-2-yl-methyl)-2-(methylsulfonyl)phenol or a derivative thereof and other appropriate starting materials. The compound number, characterizing data, starting materials, and possible deviations in reaction conditions (solvent, reaction temperature, reaction time, method of preparation, if any) are given in the table.

[0267] Purification method used: A=crystallization B = Column chromatography C = Precipitation in aqueous media D = semi-preparative HPLC E = Crushing F = salt formation

[0268] TIFF0007789697000122.tif213160 TIFF0007789697000123.tif212160 TIFF0007789697000124.tif245160 TIFF0007789697000125.tif175160

[0269] Example 46 2-((1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)methyl)-5-((1-tosylpiperidin-4-yl)methoxy)-4H-pyran-4-one (Compound 88) [ka] To a solution of (4-oxo-5-((1-tosylpiperidin-4-yl)methoxy)-4H-pyran-2-yl)methyl methanesulfonate (0.10 ml, 0.21 mmol) in 2 ml of DMF was added 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 completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase chromatography to give 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 procedures described in Example 1. The compound numbers, characterizing data, starting materials, and possible deviations in reaction conditions (solvent, reaction temperature, reaction time, method of preparation), if any, are given in the table.

[0271] TIFF0007789697000127.tif63164

[0272] Example 47 (E)-2-((5-(1-(hydroxyimino)ethyl)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (Compound 90) [ka] To a solution of (E)-2-((5-(1-(hydroxyimino)ethyl)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (0.2 g, 0.43 mmol) in EtOH (10 ml) was added sodium acetate (0.160 g, 1.9 mmol) and hydroxylamine hydrochloride (0.075 g, 1.08 mmol) at 25° C. The mixture was stirred at 70° C. for 2 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to give 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)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (Compound 91) [ka] To a solution of (E)-2-((5-(1-(hydroxyimino)ethyl)isoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (0.2 g, 0.43 mmol) in EtOH (10 ml) was added sodium acetate (0.160 g, 1.9 mmol) and methoxyamine HCl (0.091 g, 1.08 mmol) at 25° C. The mixture was stirred at 70° C. for 2 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to give 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-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)ethanol (Compound 92b) [ka] a) 4-(chloromethyl)-2-(methylsulfonyl)phenol [ka] To a solution of paraformaldehyde (1.25 g, 41.8 mmol) and concentrated HCl (14.1 ml, 465 mmol) was added 2-(methylsulfonyl)benzeneol (4.0 g, 23.2 mmol). The reaction mixture was stirred at RT for 48 h. The product was filtered, washed with 0.5% Na2CO3 (5 ml) and water (20 ml), and dried to give 3.5 g of the title compound. LC-MS: m / z 221.6 (M+H) + .

[0275] b) 4-(isoindolin-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) was added isoindoline hydrochloride (2.11 g, 13.59 mmol) and DIPEA (7.9 ml, 45.30 mmol). The mixture was stirred at RT for 4 h. The mixture was evaporated, quenched with water (20 ml), and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Column chromatography (heptane / ethyl acetate) afforded 2.0 g of the title compound. LC-MS: m / z 304.3 (M+H) + .

[0276] c) 1-(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)ethanone (compound 92a) [ka] To a solution of 4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenol (0.30 g, 0.99 mmol) in DMF (5 ml) was added 1-[4-(bromomethyl)phenyl]ethanone (0.21 g, 0.99 mmol) and K2CO3 (0.30 g, 2.16 mmol). The reaction mixture was heated at 100 °C for 1 h. The mixture was cooled to RT, water (10 ml) was added, and the product was extracted with EtOAc. The combined extracts were washed with water, and the product was filtered, dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography to give 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-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)ethanol (Compound 92b) [ka] To a solution of 1-(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)ethanone (0.05 g, 0.11 mmol) in MeOH (5 ml) was added NaBH4 (5.32 g, 0.14 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min and at RT for 2 h, quenched with ice-cold water and extracted with DCM. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to give 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. Compound numbers, characterizing data, and starting materials are listed in the table.

[0279] TIFF0007789697000135.tif114164

[0280] The following compounds were made using the preparative HPLC method shown below. Compound numbers, characterization data, and starting materials are listed in the table.

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

[0282] TIFF0007789697000136.tif211164 TIFF0007789697000137.tif134164

[0283] Example 50 2-((6-(isoxazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (Compound 101) [ka] a) tert-Butyl 6-(isoxazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A sealed reaction vessel was charged with 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), 2 M aqueous KCO solution (0.72 mL, 1.441 mmol), and acetonitrile (2 mL) and then carefully purged with nitrogen. The vessel was sealed and heated at 80 °C for 5 h. The reaction was allowed to cool to RT and stirred overnight. The reaction mixture was diluted with EtOAc (5 mL) and water (5 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (5 mL). The combined organic extracts were washed with brine (5 mL) and evaporated onto Celite. The product was purified by reverse phase chromatography to give 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-tetrahydroisoquinolin-6-yl)isoxazole trifluoroacetate A round-bottom flask was charged 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 h and evaporated to dryness to give the crude title compound, which was used directly in the next synthetic step. MS (ESI) m / z [M+1] + : 201.2.

[0285] c) 2-((6-(isoxazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (Compound 101) 4-(1,2,3,4-Tetrahydroisoquinolin-6-yl)isoxazole trifluoroacetate (8 mg, 0.026 mmol) was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (11 mg, 0.032 mmol) in the presence of DIPEA (0.012 mL, 0.066 mmol) in DMSO (1 mL) at RT for 19 h, followed by purification by reverse-phase column chromatography to afford 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-dihydroisoquinolin-2(1H)-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (Compound 102) [ka] a) tert-Butyl 6-(1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A sealed reaction vessel was charged with tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (150 mg, 0.48 mmol), pyrazole (49 mg, 0.72 mmol), CsCO (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). The reaction vessel was carefully purged with nitrogen and then heated at 120 °C for a total of 12 h. The mixture was allowed to cool to RT and stirred overnight. The reaction mixture was diluted with EtOAc (10 mL) and water (10 mL) and then filtered through Celite. The phases were separated, and the aqueous phase was extracted with EtOAc (10 mL). The combined organic extracts were evaporated over Celite. The product was purified by reverse phase chromatography to give 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 charged 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 h and then evaporated to dryness to give the crude title compound, 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-dihydroisoquinolin-2(1H)-yl)methyl)-5-((1-(methylsulfonyl)piperidin-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)piperidin-4-yl)methoxy)-4H-pyran-4-one (27 mg, 0.080 mmol) in the presence of DIPEA (0.035 mL, 0.20 mmol) in DMSO (1 mL) at 60° C. for 5 h, followed by purification by reverse-phase column chromatography to afford 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)piperidin-4-yl)methoxy)-4H-pyran-4-one (Compound 103) [ka] 2',3'-Dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline] hydrochloride (47 mg, 0.24 mmol) was treated with 2-(chloromethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (80 mg, 0.24 mmol) in the presence of DIPEA (0.10 mL, 0.60 mmol) in DMSO (1 mL) at RT for 19 h, followed by purification by reverse-phase column chromatography to afford 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 To 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) in DMSO (5 ml) in a two-necked flask under nitrogen was added DIPEA (0.434 ml, 2.491 mmol) dropwise at 0°C. The mixture was stirred at 60°C for 1 hour and poured onto ice. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with water and brine, dried over Na2SO4, filtered, and evaporated to give 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-hydroxypropan-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) was added 2-(4-(bromomethyl)phenyl)propan-2-ol (0.170 g, 0.742 mmol) in THF (5 ml). The mixture was heated at reflux for 15 min, then cooled to RT, filtered, and evaporated in vacuo. The crude product was purified by reverse-phase column chromatography to give 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)piperidin-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 DMSO (3 ml) in a two-necked flask under nitrogen was stirred at 60 °C for 2 h and then poured onto ice. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with water and brine, dried over Na2SO4, filtered, and evaporated to give the title compound. LC-MS: m / z 322.3. (M+H) +.

[0293] b) 4-fluoro-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 105) A mixture of (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (0.150 g, 0.552 mmol), 4-((4-fluoroisoindolin-2-yl)methyl)-2-(methylsulfonyl)phenol (0.178 g, 0.553 mmol), and potassium carbonate (0.115 g, 0.286 mmol) in DMF (2 ml) in a two-necked flask under nitrogen 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 give 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 EtOAc - 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 isocaproic acid was measured by a modification of the isocaproic acid 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, and extraction was performed with dextran-coated charcoal suspension (Isomaa, V. et al., Endocrinology 1982; 111(3):833-843). The H295R cell line has been shown to express all important steroidogenic enzymes. The half maximal inhibitory concentration (IC) of test compounds for CYP11A1 inhibition was determined. 50 To determine the activity of β-amyloid β-amyloid in vivo, cells were treated with increasing concentrations of test compound for 3 days in the presence of 3 nM [24,25-3H]-labeled cholesterol (American Radiolabeled Chemicals). The final DMSO concentration was 1%. Cell culture medium was extracted with a dextran-coated charcoal suspension, and radiolabeled isocaproic acid was measured by mixing 100 μl of the supernatant fraction with 200 μl of scintillation fluid (OptiPhase SuperMix, PerkinElmer). Radioactivity was measured using a Microbeta scintillation counter (1450 MicroBeta Trilux, Wallac). All test compounds were tested in duplicate at 10 concentrations.

[0296] The compounds of the present invention were screened using the above assays, and the IC 50 The values ​​are listed in Table 1 below, where "A" indicates an IC<100 nM. 50 "B" indicates IC values ​​in the range of 101-200 nM. 50 values ​​are shown, and "C" is the IC in the range of 201-2000 nM. 50 Indicates the value.

[0297] [Table 1]

[0298] Experiment 2. Formation of reactive metabolites The formation of reactive metabolites was investigated by incubating test compounds with recombinant human cytochrome P450 (CYP) CYP3A4 enzyme in the presence of the cofactor NADPH and the scavenger agents 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 chosen as the enzyme source because it showed higher metabolic activity toward test compounds than human liver microsomes.

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

[0300] If the peak area after incubation was greater than 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." 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 number 139 and compound number 186, respectively, in WO 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 4-6 membered monocyclic ring containing 0-4 heteroatoms independently selected from N, O, and S; Ring A is the following group: 【Chemistry 2】 either L is none, -CH 2 -, -CH(CH 3 ) -, -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 - and; R 1 is hydrogen; R 2 is hydrogen; R 3 is hydrogen, halogen, nitro, cyano, oxo, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Cycloalkyl, hydroxy C 3-7 Cycloalkyl, C 1-7 Alkoxy, hydroxy C 1-7 Alkyl, haloC 1-7 Alkyl, cyano C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 1-7 Alkylthio, aminocarbonyl C 2-7 Alkenyl, HaloC 1-7 Alkylthio, C 1-7 Alkoxycarbonyl C 1-7 Alkyl, C 1-7 Alkoxycarbonyl C 2-7 Alkenyl, =NSO 2 R 20 , -S(O)-C 1-7 Alkyl, —S(O)(NR 14 ) (R 22 ), -S(NR 15 ) (C 1-7 alkyl), -C(S)NR 18 R 19 , -D-C(O)-NR 6 R 7 , -C(O)R 8 , -D-NR 9 R 10 , -SO 2 R 11 , optionally substituted 3- to 6-membered carbocyclyl, optionally substituted 3- to 6-membered carbocyclyl C 1-7 Alkyl, optionally substituted 4- to 6-membered heterocyclyl or optionally substituted 4- to 6-membered heterocyclyl C 1-7 is alkyl; R 4 is hydrogen; R 5 is hydrogen, halogen or C 1-7 is alkyl; R 6 is hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Cycloalkyl, hydroxy C 1-7 Alkyl, cyano C 1-7 Alkyl, -C 1-7 Alkyl-O-C(O)C 1-7 alkyl or optionally substituted 4-6 membered heterocyclyl; R 8 is hydrogen, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Cycloalkyl, C 1-7 Alkoxy, HaloC 1-7 Alkyl, C 1-7 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 4-6 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 Alkenyl, C 3-7 Cycloalkyl, haloC 1-7 Alkyl, cyano C 1-7 Alkyl, C 1-7 Alkoxy C 1-7 Alkyl, —NR 12 R 13 , optionally substituted 3- to 6-membered carbocyclyl or optionally substituted 4- to 6-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 alkylcarbonyl; R 7 , R 10 , R 13 , R 18 , and R 19 are independently hydrogen, C 1-7 Alkyl or C 3-7 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, or —SO 2 R 17 and R 17 is C 1-7 alkyl or optionally substituted 3- to 6-membered carbocyclyl; R 20 and R 21 are independently 1-7 Alkyl, C 3-7 cycloalkyl or optionally substituted 3- to 6-membered carbocyclyl; R 22 is C 1-7 Alkyl or C 3-7 is cycloalkyl; R 23 is hydrogen, C 1-7 Alkylcarbonyl, hydroxyimino C 1-7 Alkyl, C 1-7 Alkoxyimino C 1-7 alkyl, hydroxy optionally substituted with 1 to 3 halogen atoms; 1-7 alkyl or optionally substituted 4-6 membered heterocyclyl; R 24 is hydrogen, C 1-7 Alkyl or halo C 1-7 is alkyl; R 25 is hydrogen or C 1-7 is alkyl; R 27 is C 1-7 Alkyl or C 3-7 is cycloalkyl; D is none, C is 1-7 Alkyl or C 2-7 alkenyl; wherein the optional substituent at each occurrence 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 wherein the heterocyclyl group at each occurrence has 1 to 4 heteroatoms independently selected from N, O, and S; or a pharmaceutically acceptable salt thereof.

2. The compound has the 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 2. The compound of claim 1, represented by: wherein L, A and B are as defined in claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound has the 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 3. The compound of claim 2, wherein L and B are as defined in claim 1, or a pharmaceutically acceptable salt thereof.

4. The compound has 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 3. The compound of claim 2, wherein L and B are as defined in claim 1, or a pharmaceutically acceptable salt thereof.

5. L is none, -CH 2 - or -CH(CH 3 5. The compound according to claim 1, wherein

6. The compound according to claim 5, wherein L is absent.

7. L is -CH 2 The compound according to claim 5, wherein -.

8. L is -CH(CH 3 6. The compound according to claim 5, wherein:

9. Ring B is the following group 【Transformation 6】 and R 3 , R 4 and R 5 The compound according to any one of claims 1 to 8, wherein

10. Ring B is the following group 【Transformation 7】 and R 3 , R 4 and R 5 The compound of claim 9, wherein is attached to ring B, and the wavy line indicates the site of attachment to L.

11. The compound according to claim 9, wherein ring B is (1'), (6'), (7'), (8'), or (9').

12. The compound according to claim 10, wherein ring B is (1a'), (6a'), (7'), (8'), or (9a').

13. R 3 But hydrogen, cyano, C 1-7 Alkyl, C 2-7 Alkenyl, Hydroxy C 1-7 Alkyl, C 1-7 Alkylthio, C 1-7 Alkoxycarbonyl C 1-7 Alkyl, —S(O)(NR 14 ) (R 22 ), -S(NR 15 ) (C 1-7 alkyl), -C(S)NR 18 R 19 , -D-C(O)-NR 6 R 7 , -C(O)R 8 , -D-NR 9 R 10 , -SO 2 R 11 , optionally substituted 3- to 6-membered carbocyclyl, optionally substituted 3- to 6-membered carbocyclyl C 1-7 Alkyl, optionally substituted 4- to 6-membered heterocyclyl or optionally substituted 4- to 6-membered heterocyclyl C 1-7 alkyl; wherein the optional substitution at each occurrence 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 13. The compound of any one of claims 1 to 12, wherein the heterocyclyl group in each occurrence has 1 to 4 heteroatoms independently selected from N, O and S, and wherein the heterocyclyl group is selected from 1 to 3 substituents independently selected from alkoxycarbonyl and oxo.

14. R 3 is hydrogen, cyano, hydroxy C 1-7 Alkyl, —S(O)(NR 14 ) (R 22 ), -DC(O)-NR 6 R 7 , -C(O)R 8 , -SO 2 R 11 , optionally substituted 4- to 6-membered heterocyclyl or optionally substituted 4- to 6-membered heterocyclyl C 1-7 alkyl; wherein the optional substitution at each occurrence is C 1-7 Alkyl, halogen, hydroxy, cyano, C 1-7 14. The compound of claim 13, wherein the heterocyclyl group in each occurrence has 1 to 4 heteroatoms independently selected from N, O, and S.

15. R 4 and R 5 The compound according to any one of claims 1 to 14, wherein is hydrogen.

16. R 5 The compound of any one of claims 1 to 15, wherein is hydrogen.

17. The compound according to any one of claims 1 to 16, wherein ring A is (1) or (2).

18. R 24 is C 1-7 Alkyl or haloC 1-7 The compound of any one of claims 1 to 17, which is alkyl.

19. 3. The compound of formula (IC): 【Transformation 8】 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 23 , R 24 , R 25 , R 27 2. The compound of claim 1, represented by: wherein L is as defined in claim 1, or a pharmaceutically acceptable salt thereof.

20. R 23 is an optionally substituted 4- to 6-membered heterocyclyl having 1 to 4 heteroatoms independently selected from N, O, and S.

21. R 3 But, -SO 2 R 11 and R 1 , R 2 , R 4 , and R 5 is hydrogen; and R 11 is C 1-7 21. The compound of claim 19 or 20, which is alkyl.

22. R 3 is an optionally substituted 4- to 6-membered heterocyclyl C 1-7 alkyl, where the optional substitutions are 1-7 Alkyl, halogen, hydroxy, cyano, and C 1-7 alkylcarbonyl, 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 21. The compound of claim 19 or 20, wherein is hydrogen.

23. R 24 But C 1-7 Alkyl or halo C 1-7 The compound according to any one of claims 19 to 22, which is alkyl.

24. 2-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)-1,3,4-oxadiazole (compound 10); 3-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)isoxazole (compound 11); 5-bromo-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 12a); 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)-5-(1H-pyrazol-1-yl)isoindoline (compound 12b); 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)oxazole (compound 13a); 2-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)oxazole (compound 13b); 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)thiazole (compound 14); 1-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)ethan-1-one (compound 15a); 5-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)isoxazole (compound 15c); 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline-5-carbonitrile (compound 16a); 3-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)-1,2,4-oxadiazole (compound 16c); 2-(2,2,2-trifluoro-1-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)ethyl)isoindoline (compound 21); 2-(2,2-difluoro-1-(3-(methylsulfonyl)-4-((1-(pyrimidin-2-ylmethyl)piperidin-4-yl)methoxy)phenyl)ethyl)isoindoline (compound 22); 2-(3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 25); 2-(3-(cyclopropylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 26); 2-(3-(ethylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)-5-(trifluoromethyl)isoindoline (compound 27); 2-(3-(butylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 28); 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 65); 2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 66); 1-((1r,4r)-4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)cyclohexyl)ethan-1-one (compound 67); 4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)-N,N-dimethylbenzamide (compound 68); 4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)-N-(2-methoxyethyl)-N-methylbenzamide (compound 69); 1-(4-((4-isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)propan-1-one (compound 70); Ethyl(imino)(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)-λ 6 - sulfanone (compound 71); Imino(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)(methyl)-λ 6 - sulfanone (compound 72); 1-(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)-2-methylpropan-1-one (compound 73); 4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)-N,N-dimethylcyclohexane-1-carboxamide (compound 74); 2-(3-(methylsulfonyl)-4-((1-(oxetan-3-ylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 75); 2-(4-((4-(ethylsulfonyl)benzyl)oxy)-3-(methylsulfonyl)benzyl)isoindoline (compound 76); 1-((4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)sulfonyl)azetidin-3-ol (compound 77); N-(dimethyl(oxo)-λ 6 -sulfanylidene)-4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)benzamide (compound 78); (1r,4r)-4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)-N,N-dimethylcyclohexane-1-carboxamide (compound 79); Azetidin-1-yl(4-((4-(isoindolin-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-(isoindolin-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-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)propan-2-ol (compound 86); 1-(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)piperidin-1-yl)ethan-1-one (compound 87); 1-(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)ethanone (compound 92a); 1-(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)ethanol (compound 92b); 1-(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)cyclohexyl)ethan-1-ol (compound 94); (R)-Imino(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)(methyl)-λ 6 - sulfanone (compound 95); (S)-Imino(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)(methyl)-λ 6 - sulfanone (compound 96); (S)-Ethyl(imino)(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)-λ 6 - sulfanone (compound 97); (R)-Ethyl(imino)(4-((4-(isoindolin-2-ylmethyl)-2-(methylsulfonyl)phenoxy)methyl)phenyl)-λ 6 - sulfanone (compound 98); 4-fluoro-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline (compound 105); their tautomers, or pharmaceutically acceptable salts thereof The compound according to claim 1, wherein 25. 3-(dimethylamino)-1-(2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindolin-5-yl)prop-2-en-1-one (compound 15b); and A compound selected from N-hydroxy-2-(3-(methylsulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl)isoindoline-5-carboximidamide (compound 16b), or a pharmaceutically acceptable salt thereof.

26. A medicament for the treatment of a steroid receptor dependent disease, comprising a compound according to any one of claims 1 to 25.

27. ​​The pharmaceutical described in claim 26, which is for treating an androgen receptor-dependent disease.

28. The pharmaceutical composition according to claim 26, wherein the steroid receptor-dependent disease is cancer.

29. The pharmaceutical composition of claim 28, wherein the cancer is prostate cancer.

30. The pharmaceutical agent according to claim 29, wherein the prostate cancer is castration-resistant prostate cancer (CRPC).

31. A pharmaceutical described in any one of claims 26 to 30, administered in addition to a glucocorticoid and / or a mineralocorticoid, and optionally one or more anticancer agents.

32. - A nonsteroidal androgen receptor antagonist; - steroidogenesis inhibitors; - chemotherapeutic agents; - antiestrogens; - epigenetic modulators; - mTOR inhibitors; - AKT inhibitors; - radiopharmaceuticals; - GnRH / LHRH analogues; - PI3K inhibitors; and -CDK4 / 6 inhibitors The pharmaceutical composition according to any one of claims 26 to 31, which is administered in addition to one or more anticancer drugs selected from the group consisting of:

33. The pharmaceutical described in claim 32, wherein the mTOR inhibitor is everolimus.

34. The pharmaceutical described in claim 32, wherein the AKT inhibitor is AZ5363.

35. The pharmaceutical described in claim 32, wherein the radioactive pharmaceutical is alpharadin.

36. The pharmaceutical according to claim 32, wherein the GnRH / LHRH analog is leuprorelin.

37. A pharmaceutical described in any one of claims 26 to 36, administered in addition to a non-steroidal androgen receptor antagonist.

38. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 together with a pharmaceutically acceptable carrier.

39. A compound according to any one of claims 1 to 25; - glucocorticoids; - mineralocorticoids; - nonsteroidal androgen receptor antagonists; - steroidogenesis inhibitors; - chemotherapeutic agents; - antiestrogens; - epigenetic modulators; - mTOR inhibitors; - AKT inhibitors; - radiopharmaceuticals; - GnRH / LHRH analogues; - PI3K inhibitors; and -CDK4 / 6 inhibitors and at least one additional active ingredient selected from the list consisting of:

40. A combination pharmaceutical according to claim 39, wherein the mTOR inhibitor is everolimus.

41. A combination medicine as described in claim 39, wherein the AKT inhibitor is AZ5363.

42. The combination medicine of claim 39, wherein the radiopharmaceutical is alpharadin.

43. A combination medicine according to claim 39, wherein the GnRH / LHRH analogue is leuprorelin.

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