CYP11a1 inhibitor compounds and uses thereof

Abstract

There are provided therapeutically active CYP11A1 inhibitor compounds of Formula (I) and pharmaceutical compositions thereof that are useful in the treatment of steroid receptor-dependent conditions and diseases, in particular androgen receptor-dependent conditions and diseases such as endocrine cancer, prostate cancer, castration-resistant prostate cancer, and breast cancer.

Description

CYP11A1 INHIBITOR COMPOUNDS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of and priority to U.S. provisional patent application No. 63 / 678,855, filed on August 2, 2024; the content of which is herein incorporated in entirety by reference.TECHNICAL FIELD

[0002] The present disclosure relates to therapeutically active compounds useful in the treatment of a steroid receptor, in particular androgen receptor (AR), dependent conditions and diseases, and to pharmaceutical compositions containing such compounds.BACKGROUND

[0003] Prostate cancer is the most common cancer in men worldwide. Even though the 5-year survival rate of patients with localized prostate cancer is high, the prognosis for those patients who develop castration-resistant prostate cancer (CRPC) within that 5-year follow-up period is poor.

[0004] The androgen receptor (AR) signaling axis is critical in all stages of prostate cancer. In the CRPC stage, disease is characterized by high AR expression, AR amplification and persistent activation of the AR signaling axis by residual tissue / tumor androgens, and by other steroid hormones and intermediates of steroid biosynthesis. Thus, treatment of advanced prostate cancer involves androgen deprivation therapy (ADT) such as hormonal manipulation using gonadotropin-releasing hormone (GnRH) agonists / antagonists or surgical castration, AR antagonists or cytochrome P450 monooxygenase 17A1 (CYP17A1) inhibitors (such as abiraterone acetate in combination with prednisone).

[0005] CYP17A1 inhibition has played an important role in the treatment of prostate cancer. Although abiraterone treatment can initially lead to disease regression, resistance to abiraterone is a major medical issue in prostate cancer, as most responders develop resistance to the treatment, and the duration of response varies. Key mechanisms and reasons for abiraterone resistance include AR amplifications, AR mutations and AR splicing variants. AR mutations can lead to promiscuous activation by other steroids such as pregnenolone and progesterone. In themeantime, the inhibition of CYP17A causes increased pregnenolone and progesterone levels in patients. Several nonclinical and clinical studies have indicated upregulation of enzymes that catalyze steroid biosynthesis at the late stage of CRPC. It has been shown that these steroids are found in high levels in plasma and tissue in prostate cancer patients, suggesting their role as AR agonists in CRPC. Furthermore, it has been addressed that prostate cancer resistance to CYP17A1 inhibition may still remain steroid dependent and responsive to therapies that can further suppress de novo intratumoral steroid synthesis upstream of CYP17A1, such as by cytochrome P450 monooxygenase 11A1 (CYP11A1) inhibition therapy (Cai, C. et al, Cancer Res., 71(20), 6503-6513, 2011). CYP11A1, also called cholesterol side chain cleavage enzyme, is a mitochondrial monooxygenase which catalyzes the conversion of cholesterol to pregnenolone, the precursor of all steroid hormones. By inhibiting CYP11A1, the key enzyme of steroid biosynthesis upstream of CYP17A1, the total block of the whole steroid biosynthesis can be achieved. CYP11A1 inhibitors may therefore have a great potential for treating steroid hormone dependent cancers, such as prostate cancer, even in advanced stages of the disease, and especially in those patients who appear to be hormone refractory. It has been recently shown that a compound having CYP11A1 inhibitory effect significantly inhibited tumor growth in vivo in a murine CRPC xenograft model (Oksala, R. et al, Annals of Oncology, (2017) 28 (suppl. 5): Abstract / Poster 28P).

[0006] Patent application WO 2018 / 115591 discloses pyran based CYP11A1 inhibitors and patent application WO2024 / 230825 discloses other heterocyclic CYP11A1 inhibitors, however, there is still a need for more potent, efficacious, and less toxic agents.SUMMARY

[0007] It has been found that compounds of Formula (I) are potent CYP11A1 inhibitors. Compounds of Formula (I) are therefore useful as medicaments in the treatment of steroid hormone dependent conditions and diseases where CYP11A1 inhibition is desired. Such conditions and diseases include, but are not limited to, endocrine cancers and diseases, such as prostate cancer and breast cancer. In particular, the compounds of Formula (I) are useful in the treatment of AR dependent conditions and diseases including prostate cancer and castration- resistant prostate cancer.

[0008] Thus, in one broad aspect, the present disclosure provides a compound according to Formula (I)wherein X1is O, S, S=O, SO2, C(R2)2, C1-3alkylene substituted with 0 to 6 R4, C=O, or NR1;L1is C(R2)2, NR8, CO, or O;X2is a 4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 0-4 heteroatoms, wherein X2is substituted with 0 to 6 R2;L2is C(R2)2, or C1-3alkylene substituted with 0 to 6 R4;R6is H, C1-6alkyl, C2-6alkenyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or cyclobutylmethyl, wherein said C1-6alkyl, C2-6alkenyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or cyclobutylmethyl is substituted with 05 R4;R7is a 4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 0-4 heteroatoms, wherein the 4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 0-4 heteroatoms is substituted with 0 to 6 R4; or, R6and R7together with the nitrogen atom to which they are attached, form a 4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 1-4 heteroatoms wherein the 4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 1-4 heteroatoms is substituted with 0 to 6 R4and wherein at least one of the 1-4 heteroatoms is N;Z is O or S;R1is independently H, C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, or C3-7cycloalky1-C1-6alkyl, wherein the C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, or C3-7cycloalky1-C1-6alkyl is substituted with 0-5 R4;R2is independently H, Cl, Br, F, I, cyano, azido, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C3-7cycloalkyl, or C3-7cycloalky1-C1-6alkyl, wherein the C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C3-7cycloalkyl, or C3-7cycloalky1-C1-6alkyl is substituted with 0-5 R4;Q is C or N;R9is R3when Q is N;R9is R10when Q is C;R10is a 5 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl or 6-membered aryl wherein the said 5 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl or 6-membered aryl is substituted with 0 to 5 R4;R3is SO2R8, SO2NR8R8, SONHR8, CONR8R8, COR8, or COOR8;R4is independently H, Cl, Br, F, I, hydroxyl, cyano, azido, oxo, SO2NR8R8, NR8SO2R8, NR8R8, CONR8R8, OCONR8R8, NR8CONR8R8, C1-7alkyl substituted with 0-5 R5, C1.7 alkoxy substituted with 0-5 R5, 3-7 membered cycloalkyl substituted with 0-5 R3, C3-7cycloalky1-C1-6alkyl substituted with 0-5 R3, 3-7 membered heterocycloalkyl substituted with 0-5 R5, or 4-10 membered heterocycloalkyl C1-6alkyl substituted with 0-5 R5;R3is independently H, Cl, Br, F, I, hydroxyl, C1-3alkoxy, cyano, amino substituted with 0-2 C1-3alkyl, or azido; andR8is independently H, C1.7 alkyl substituted with 0-5 R5, C1-7alkoxy substituted with 0-5 R5, 3-7 membered cycloalkyl substituted with 0-5 R5, C3-7cycloalkyl C1-6alkyl substituted with 0-5 R3, 3-7 membered heterocycloalkyl substituted with 0-5 R5, or 4-10 membered heterocycloalkyl C1-6alkyl substituted with 0-5 R5; or a pharmaceutically acceptable salt thereof.

[0009] According to one embodiment, the disclosure provides a pharmaceutical composition comprising a compound of Formula (I) as defined in any of the above embodiments together with a pharmaceutically acceptable carrier.

[0010] According to one embodiment, the disclosure provides a method for the treatment or prevention of a steroid receptor, in particular androgen receptor (AR), dependent conditions and diseases. Such conditions and diseases include, but are not limited to, endocrine cancers and diseases, such as prostate cancer, castration-resistant prostate cancer, and breast cancer. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) as defined in any of the above embodiments.

[0011] In another broad aspect, the present disclosure provides a compound according to Formula (II)wherein X1is O;R1is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl and 2,2,2- trifluoroethyl;R2is H;L1is CH2or CHCH3;L2is CH2or CHCH3;NR6R7isR4is independently H, F, OCH3, CF3, CHF2, Cl, Br, or cyclopropyl; and Q is N; or a pharmaceutically acceptable salt thereof.

[0012] According to one embodiment, the disclosure provides a pharmaceutical composition comprising a compound of Formula (II) as defined in any of the above embodiments together with a pharmaceutically acceptable carrier.

[0013] According to one embodiment, the disclosure provides a method for the treatment or prevention of a steroid receptor, in particular androgen receptor (AR), dependent conditions and diseases. Such conditions and diseases include, but are not limited to, endocrine cancers and diseases, such as prostate cancer, castration-resistant prostate cancer and breast cancer. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (II) as defined in any of the above embodiments.

[0014] According to one embodiment, the disclosure provides the use of the compound or the pharmaceutically acceptable salt thereof according as defined herein or the pharmaceutical composition as defined herein in the treatment or prevention of a steroid receptor-dependent condition or disease in a subject in need thereof.

[0015] According to one embodiment, the disclosure provides the use of the compound or the pharmaceutically acceptable salt thereof as defined herein or the pharmaceutical composition as defined herein in the preparation of a medicament for the treatment or prevention of a steroid receptor-dependent condition or disease in a subject in need thereof.

[0016] According to one embodiment, the present disclosure provides a compound according to Formula (III)wherein R100isR200isandR300 is; or a pharmaceutically acceptable salt thereof.

[0017] According to one embodiment, the disclosure provides a pharmaceutical composition comprising a compound of Formula (III) as defined in any of the above embodiments together with a pharmaceutically acceptable carrier.

[0018] According to one embodiment, the disclosure provides a method for the treatment or prevention of a steroid receptor, in particular androgen receptor (AR), dependent conditions and diseases. Such conditions and diseases include, but are not limited to, endocrine cancers and diseases, such as prostate cancer, castration-resistant prostate cancer and breast cancer. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (III) as defined in any of the above embodiments.In another embodiment, the present disclosure provides for a compound selected from the group consisting of:2-(isoindolin-2-ylmethyl)-3-methyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,3-ethyl-2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,2-(isoindolin-2-ylmethyl)-3-isopropy1-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-propylpyrimidin-4(3H)-one,2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,2-((1,1-dioxidobenzo[d]isothiazo1-2(3H)-yl)methyl)-3-methyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,3-ethyl-2-(isoindolin-2-ylmethyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6- yl)methoxy)pyrimidin-4(3H)-one,2-((5-bromoisoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,2-((5-chloroisoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,3-ethyl-2-((5-fluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,2-((5-cyclopropylisoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,2-(((2,3-dihydro-1H-inden-2-yl)(methyl)amino)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,2-(isoindolin-2-ylmethyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,2-((5-chloroisoindolin-2-yl)methyl)-5-((l -(methyl sulfonyl )piperidin-4-yl)methoxy)-3-(2, 2, 2- trifluoroethyl)pyrimidin-4(3H)-one,3-ethyl-2-(1-(isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin- 4(3H)-one,3-ethyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)isoindolin-2- yl)methyl)pyrimidin-4(3H)-one,2-((5-(difluoromethyl)isoindolin-2-yl)rnethyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,2-((5-fluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,2-((5-fluoroisoindolin-2-yl)rnethyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,2-((5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,2-((5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,2-((2-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,2-((5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,2-((2-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,(R)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-5-((1-(rnethylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,(S)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,2-(((2,3-dihydro-1H-inden-2-yl)amino)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,2-(((4-chlorobenzyl)(methyl)amino)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,3-ethyl-2-((2-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,3-ethyl-2-((2-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,(S)-2-(1-(5-fluoroisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,(S)-2-(1-(isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,(S)-5-((1-acetylpiperidin-4-yl)methoxy)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one, methyl (S)-4-(((2-(1-(5-chloroisoindolin-2-yl)ethyl)-6-oxo-1-(2,2,2-trifluoroethyl)-l,6- dihydropyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylate,(S)-2-(1-(isoindolin-2-yl)ethyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,(R)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-(2,2,2-trifluoro-1-(isoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,(R)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-2-(2,2,2-trifluoro-1-(isoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,(R)-5 -(( 1 -(methyl sulfony l)piperidin-4-y l)m ethoxy )-2-(2, 2, 2-trifluoro- 1 -(5 -fluoroi soindolin-2- yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,(R)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-2-(2,2,2-trifluoro-1-(5- fluoroisoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,5-((3-chloro-4-(1H-pyrazo1-3-yl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one, and5-((3-chloro-4-(isothiazo1-3-yl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.

[0019] According to one embodiment, the disclosure provides a pharmaceutical composition comprising a compound as defined in any of the above or below embodiments (e.g., a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a specific compound listed above or described in Table 2) together with a pharmaceutically acceptable carrier.

[0020] According to one embodiment, the disclosure provides a method for the treatment or prevention of a steroid receptor, in particular androgen receptor (AR), dependent conditions and diseases. Such conditions and diseases include, but are not limited to, endocrine cancers and diseases, such as prostate cancer and breast cancer. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound as defined in any of the above or below embodiments (e.g., a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a specific compound listed above or described in Table 2). In some embodiments, the method comprises administering to a subject in need thereof a pharmaceutical composition as described herein.

[0021] In some embodiments of methods of the disclosure, the subject is a human.DETAILED DESCRIPTION

[0022] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used herein, the following definitions are supplied in order to facilitate the understanding of the present invention.

[0023] The term "subject", as employed herein, refers to humans and animals.

[0024] The term "steroid receptor" refers to a receptor which binds to and is activated by a steroid hormone. Examples of steroid receptors include, but are not limited to, androgen, glucocorticoid, and progesterone receptors.

[0025] The term "endocrine cancer" refers to partially or completely unregulated growth of one or more cellular components of the endocrine system, including, but not limited to, cancers of one or more of the adrenal glands.

[0026] The term “C1-7alkyl” as used herein refers to a linear or branched alkyl group consisting of 1,2, 3, 4, 5, 6 or 7 carbons. Representative, but not limiting examples include methyl, ethyl, propyl, isopropyl, hexyl, isohexyl and 2,2-dimethylpentyl.

[0027] The term “C1-6alkyl” as used herein refers to a linear or branched alkyl group consisting of 1,2, 3, 4, 5, 6 or 7 carbons. Representative, but not limiting examples include methyl, ethyl, propyl, isopropyl, hexyl, and isohexyl.

[0028] The term “C1-3alkyl” as used herein refers to a linear or branched alkyl group consisting of 1,2, or 3 carbons. Representative, but not limiting examples include methyl, ethyl, propyl, and isopropyl.

[0029] The term "C1-3alkylene", as employed herein as such or as part of another group, refers to a bivalent saturated aliphatic hydrocarbon group having 1, 2, or 3, carbon atoms. Representative examples include, but are not limited to, methylene, ethylene and propylene.

[0030] The term "halo" or "halogen", as employed herein as such or as part of another group, refers to chlorine, bromine, fluorine or iodine.

[0031] The term “4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 0-4 heteroatoms, wherein the 4- 13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 0-4 heteroatoms” as employed herein as such or as part of another group refers to a carbocyclic or heterocyclic ring or ring system comprising 0-4 heteroatoms selected from the group consisting of O, S, and N. Representative, but non-limiting examples include phenyl, pyridyl, naphthyl, bicyclo[3.3.2]decanyl, azabicyclo[3.3.2]decanyl, and 1 ,2-dihydro- 1 -oxa-thiopheno[2,3 -f]naphthalene.

[0032] The term “4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 1-4 heteroatoms, wherein the 4- 13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 1-4 heteroatoms” as employed herein as such or as part of another group refers to a carbocyclic or heterocyclic ring or ring system comprising 1-4 heteroatoms selected from the group consisting of O, S, and N, where at least one of the heteroatoms is N. Representative, but non-limiting examples include, pyridyl, azabicyclo[3.3.2]decanyl, and isoindolinyl.

[0033] The term "C2-6alkenyl", as employed herein as such or as part of another group, refers to an aliphatic hydrocarbon group having 2, 3, 4, 5, or 6 carbon atoms and containing one or several double bonds. Representative examples include, but are not limited to, ethenyl, propenyl and cyclohexenyl.

[0034] The term "C3-7cycloalkyl", as employed herein as such or as part of another group, refers to 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.

[0035] The term "C3-7cycloalky1-C1-6alkyl", as employed herein refers to a C3-7cycloalkyl group, as defined herein, appended to the parent molecular moiety through a C1-6alkyl group, as defined herein.

[0036] The term "hydroxy", as employed herein as such or as part of another group, refers to an -OH group.

[0037] The term "cyano", as employed herein as such or as part of another group, refers to a -CN group.

[0038] The term "carboxy", as employed herein as such or as part of another group, refers to -COOH group.

[0039] The term "carbonyl", as employed herein as such or as part of another group, refers to a carbon atom double-bonded to an oxygen atom (C=0).

[0040] The term "oxo", as employed herein as such or as part of another group, refers to an oxygen atom linked to another atom by a double bond (=0).

[0041] The term " C1-7alkoxy", as employed herein as such or as part of another group, refers to C1.7 alkyl, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of C1-7alkoxy include, but are not limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

[0042] The term "4-10 membered heterocyclyl C1-7alkyl" as employed herein, refers to a 4-10 membered heterocyclyl group, appended to the parent molecular moiety through an C1-7alkyl group, as defined herein.

[0043] The term "substituted" as used herein in connection with various residues refers to, if not otherwise defined, to halogen substituents, such as fluorine, chlorine, bromine, iodine, or Ci- 7 alkyl, C3-7cycloalkyl, hydroxy, amino, nitro, cyano, thiol C1-7alkyl, methylsulfonyl, C1-7alkoxy, halo C1-7alkyl, hydroxy C1-7alkyl or amino C1-7alkyl substituents. Preferred are halogen, C1-7alkyl, hydroxy, amino, halo C1-7alkyl, C1-7alkoxy and methyl sulfonyl substituents. In one group of preferred substituents are 1-2 substituents selected from C1-7alkyl or halogen substituents, particularly C1-3alkyl or halogen substituents, particularly methyl, ethyl, chloro, fluoro or bromo substituents.

[0044] The "substituted" groups may contain 1 to 3, preferably 1 or 2, of the above- mentioned substituents, if not otherwise defined.

[0045] Optically active enantiomers or diastereomers of compounds of Formula (I), Formula (II), or Formula (III) can be prepared e.g. by resolution of the racemic end product by known methods or by using suitable optically active starting materials. Similarly, racemic compounds of Formula (I), Formula (II), or Formula (III) can be prepared by using racemic starting materials. Resolution of racemic compounds of Formula (I), Formula (II) or Formula (III), or a racemic starting material thereof can be carried out, for example, by converting the racemic compound into its diastereromeric salt mixture by reaction with an optically active acid and subsequent separation of the diastereomers by crystallization, Representative examples of said optically active acids include, but are not limited to, D- tartaric acid and dibenzoy1-D-tartaric acid.Alternatively, preparative chiral chromatography may be used for resolution of the racemic mixture.

[0046] Pharmaceutically acceptable salts are well known in the field of pharmaceuticals. Non-limiting examples of suitable salts include metal salts, ammonium salts, salts with an organic base, salts with an inorganic acid, salts with organic acid, and salts with basic or acidic amino acid. Non-limiting examples of metal salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, and magnesium salt. Non-limiting examples of salts with inorganic or organic acids include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methane sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates, acetates, oxalates, fumarates, hemifumarates, and succinates. Pharmaceutically acceptable esters, when applicable, may be prepared by known methods using pharmaceutically acceptable acids that are conventional in the field of pharmaceuticals and that retain the pharmacological properties of the free form. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl esters. Phosphate esters and carbonate esters are also within the scope of the disclosure.

[0047] The definition of Formula (I), Formula (II), or Formula (III) above is inclusive of all the possible isotopes and isomers, such as stereoisomers, of the compounds, including geometric isomers, for example Z and E isomers (cis and trans isomers), and optical isomers, e.g. diastereomers and enantiomers, and prodrug esters, e g. phosphate esters and carbonate esters.

[0048] It will be appreciated by those skilled in the art that the present compounds may contain at least one chiral center. Accordingly, the compounds may exist in optically active or racemic forms. It is to be understood that the Formula (I), Formula (II) and Formula (III) includes any racemic or optically active form, or mixtures thereof. In one embodiment, the compounds are the pure (R)-isomers. In another embodiment, the compounds are the pure (S)-isomers. In another embodiment, the compounds are a mixture of the (R) and the (S) isomers. In another embodiment, the compounds are a racemic mixture comprising an equal amount of the (R) and the (S) isomers. The compounds may contain two or more chiral centers. In such case, according to one embodiment, the compounds are a mixture of diastereomers, or in another embodiment an enriched mixture of diastereomers. In another embodiment, the compounds may be substantially pure diastereomers.

[0049] According to another embodiment, the compounds of the disclosure are a mixture of enantiomers. According to still another embodiment, the compounds are pure enantiomers. The individual isomers may be obtained using the corresponding isomeric forms of the starting material or they may be separated after the preparation of the end compound according to conventional separation methods. For the separation of optical isomers, e.g. enantiomers or diastereomers, from the mixture thereof the conventional resolution methods, e.g. fractional crystallisation, may be used.

[0050] The present compounds may also exist as tautomers or equilibrium mixtures thereof wherein a proton of a compound shifts from one atom to another. Examples of tautomerism include, but are not limited to, amido-imido, keto-enol, pheno1-keto, oxime- nitroso, nitro-aci, imine-enamine, annular tautomerism of heterocyclic rings, and the like. Tautomeric forms are intended to be encompassed by compounds of Formula (I), Formula (II) or Formula (III), even though only one tautomeric form may be depicted.

[0051] Thus, in one embodiment, the present disclosure provides a compound according to Formula (I)wherein X1is O, S, S=O, SO2, C(R2)2, C1-3alkylene substituted with 0 to 6 R4, C=O, or NR1;L1is C(R2)2, NR8, CO, or O;X2is a 4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 0-4 heteroatoms, wherein X2is substituted with 0 to 6 R2;L2is C(R2)2, or Ci-3 alkylene substituted with 0 to 6 R4;R6is H, C1-6alkyl, C2-6alkenyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or cyclobutylmethyl, wherein said C1-6alkyl, C2-6alkenyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or cyclobutylmethyl is substituted with 0-5 R4;R7is a 4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 0-4 heteroatoms, wherein the 4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 0-4 heteroatoms is substituted with 0 to 6 R4; or, R6and R7together with the nitrogen atom they are attached to, form a 4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 1-4 heteroatoms wherein the 4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 1-4 heteroatoms is substituted with 0 to 6 R4and wherein at least one of the 1-4 heteroatoms is N;Z is O or S;R1is independently H, C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, or C3-7cycloalkyl C1-6alkyl, wherein the C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, or C3-7cycloalky1-C1-6alkyl is substituted with 0-5 R4;R2is independently H, Cl, Br, F, I, cyano, azido, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C3-7cycloalkyl, or C3-7cycloalkyl Ci-6 alkyl, wherein the C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C3-7cycloalkyl, or C3-7cycloalky1-C1-6alkyl is substituted with 0-5 R4;Q is C or N;R9is R3when Q is N;R9is R10when Q is C;R10is a 5 to 6 membered, heterocyclyl, 5 to 6 membered heteroaryl or 6-membered aryl wherein the said 5 to 6 membered, heterocyclyl, 5 to 6 membered heteroaryl or 6-membered aryl is substituted with 0 to 5 R4;R3is SO2R8, SO2NR8R8, SONHR8, CONR8R8, COR8, or COOR8;R4is independently H, Cl, Br, F, I, hydroxyl, cyano, azido, oxo, SO2NR8R8, NR8SO2R8, NR8R8, CONR8R8, OCONR8R8, NR8CONR8R8, C1-7alkyl substituted with 0-5 R5, C1.7 alkoxy substituted with 0-5 R5, 3-7 membered cycloalkyl substituted with 0-5 R5, C3-7cycloalkyl C1-6alkyl substituted with 0-5 R\ 3-7 membered heterocycloalkyl substituted with 0-5 R?, or 4-10 membered heterocycloalkyl C1-6alkyl substituted with 0-5 R5;R5is independently H, Cl, Br, F, I, hydroxyl, C1-3alkoxy, cyano, amino substituted with 0-2 C1-3alkyl, or azido; andR8is independently H, C1.7 alkyl substituted with 0-5 R5, C1-7alkoxy substituted with 0-5 R5, 3-7 membered cycloalkyl substituted with 0-5 R5, C3-7cycloalkyl C1-6alkyl substituted with 0-5 R5, 3-7 membered heterocycloalkyl substituted with 0-5 R5, or 4-10 membered heterocycloalkyl C1-6alkyl substituted with 0-5 R5; or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is ethyl.

[0053] In some embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is 2,2,2-trifluroethyl.

[0054] In some embodiments, the present disclosure provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein

[0055] In some embodiments, the present disclosure provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein

[0056] In some embodiments, the present disclosure provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein

[0057] In some embodiments, the present disclosure provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein

[0058] In some embodiments, the present disclosure provides a compound of Formula(1), or a pharmaceutically acceptable salt thereof, wherein

[0059] In some embodiments, the present disclosure provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein

[0060] In some embodiments, the present disclosure provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, whereinis

[0061] In some embodiments, the present disclosure provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein

[0062] In some embodiments, the present disclosure provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein

[0063] In some embodiments, the present disclosure provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, whereinis

[0064] In some embodiments, the present disclosure provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, whereinand R1is 2,2,2-trifluroethyl.

[0065] In some embodiments, the present disclosure provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, whereinis and R1is 2,2,2-trifluroethyl.

[0066] In some embodiments, the present disclosure provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, whereinand R1is 2,2,2-trifluroethyl.

[0067] In some embodiments, the present disclosure provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, whereinand R1is 2,2,2-trifluroethyl.

[0068] In some embodiments, the present disclosure provides a compound of Formula(1), or a pharmaceutically acceptable salt thereof, whereinisand R100is 2,2,2-trifluroethyl.

[0069] In some embodiments, the present disclosure provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, whereinisand R100is 2,2,2-trifluroethyl.

[0070] In some embodiments, the present disclosure provides a compound of Formula(I), or a pharmaceutically acceptable salt thereof, whereinisand R100is 2,2,2-trifluroethyl.

[0071] In another embodiment, the present disclosure provides a compound according to Formula (II)wherein X1is O;R1is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl and 2,2,2- tri fluoroethyl;R2is H;L1is CH2orCHCH3;L2is CH2or CHCH3;NR6R7isR4is independently H, F, OCH3, CF3, CHF2, Cl, Br, or cyclopropyl; andQ is N;or a pharmaceutically acceptable salt thereof.

[0072] In one embodiment, the present disclosure provides a compound according to Formula (III)R300is; or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the present disclosure provides a compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R100is ethyl.

[0074] In some embodiments, the present disclosure provides a compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R100is 2,2,2-trifluroethyl.

[0075] In some embodiments, the present disclosure provides a compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R200is

[0076] In some embodiments, the present disclosure provides a compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R200is

[0077] In some preferred embodiments, the present disclosure provides a compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R200is

[0078] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R200is

[0079] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is

[0080] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is

[0081] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is

[0082] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is

[0083] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is

[0084] In some embodiments, the present disclosure provides a compound of Formula(Ill), or a pharmaceutically acceptable salt thereof, wherein R300is

[0085] In some embodiments, the present disclosure provides a compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R200is and R100is 2,2,2-trifluroethyl.

[0086] In some embodiments, the present disclosure provides a compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R200is and R100is 2,2,2-trifluroethyl.

[0087] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R200isand R100is 2,2,2-trifluroethyl.

[0088] In some embodiments, the present disclosure provides a compound of Formula(111), or a pharmaceutically acceptable salt thereof, wherein R200isR100is 2,2,2-trifluroethyl.

[0089] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300isR100is 2,2,2-trifluroethyl.

[0090] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300isR100is 2,2,2-trifluroethyl.

[0091] In some embodiments, the present disclosure provides a compound of Formula(Ill), or a pharmaceutically acceptable salt thereof, wherein R300isand R100is 2, 2, 2-trifl uroethyl.

[0092] In some embodiments, the present disclosure provides a compound of Formula(Ill), or a pharmaceutically acceptable salt thereof, wherein R300isR100is 2,2,2-trifluroethyl.

[0093] In some embodiments, the present disclosure provides a compound of Formula(Ill), or a pharmaceutically acceptable salt thereof, wherein R300isR100is 2,2,2-trifluroethyl.

[0094] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300isR100is 2,2,2-trifluroethyl.

[0095] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300isand R200

[0096] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is

[0097] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is R200

[0098] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is

[0099] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is and

[0100] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is and

[0101] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is

[0102] In some embodiments, the present disclosure provides a compound of Formula(Ill), or a pharmaceutically acceptable salt thereof, wherein R300isR200is

[0103] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is

[0104] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is andR200is

[0105] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is

[0106] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300isR200is

[0107] In some embodiments, the present disclosure provides a compound of Formula(Ill), or a pharmaceutically acceptable salt thereof, wherein R300is

[0108] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300isR200is

[0109] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300isR200is

[0110] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is andR200is[0011 1] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is andR200is

[0112] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is andR200is

[0113] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is andR200is

[0114] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300isandR200is

[0115] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300isand

[0116] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300isanc|

[0117] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300is and

[0118] In some embodiments, the present disclosure provides a compound of Formula(III), or a pharmaceutically acceptable salt thereof, wherein R300isR200is

[0119] According to one embodiment, the disclosure provides a pharmaceutical composition comprising a compound of Formula (III) as defined in any of the above embodiments together with a pharmaceutically acceptable carrier.

[0120] According to one embodiment, the disclosure provides a method for the treatment or prevention of a steroid receptor, in particular androgen receptor (AR), dependent conditions and diseases. Such conditions and diseases include, but are not limited to, endocrine cancers and diseases, such as prostate cancer, castration-resistant prostate cancer, and breast cancer. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (III) as defined in any of the above embodiments.

[0121] In another embodiment, the present disclosure provides for a compound selected from the group consisting of:2-(isoindolin-2-ylmethyl)-3-methyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,3-ethyl-2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,2-(isoindolin-2-ylmethyl)-3-isopropy1-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-propylpyrimidin-4(3H)-one,2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,2-((1,1-dioxidobenzo[d]isothiazo1-2(3H)-yl)methyl)-3-methyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,3-ethyl-2-(isoindolin-2-ylmethyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6- yl)methoxy)pyrimidin-4(3H)-one,2-((5-bromoisoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,2-((5-chloroisoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,3-ethyl-2-((5-fluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,2-((5-cyclopropylisoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,2-(((2,3-dihydro-lH-inden-2-yl)(methyl)amino)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,2-(isoindolin-2-ylmethyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,2-((5-chloroisoindolin-2-yl)methyl)-5-((l -(methyl sulfonyl )piperidin-4-yl)methoxy)-3-(2, 2, 2- trifluoroethyl)pyrimidin-4(3H)-one,3-ethyl-2-(1-(isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin- 4(3H)-one,3-ethyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)isoindolin-2- yl)methyl)pyrimidin-4(3H)-one,2-((5-(difluoromethyl)isoindolin-2-yl)rnethyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,2-((5-fluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,2-((5-fluoroisoindolin-2-yl)rnethyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,2-((5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,2-((5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,2-((2-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,2-((5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,2-((2-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,(R)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-5-((1-(rnethylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,(S)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,2-(((2, 3-dihy dro-1 H-inden-2-yl)amino)methyl)-3-ethyl-5-((l -(methyl sulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,2-(((4-chlorobenzyl)(methyl)amino)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,3-ethyl-2-((2-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,3-ethyl-2-((2-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,(S)-2-(1-(5-fluoroisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,(S)-2-(1-(isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,(S)-5-((1-acetylpiperidin-4-yl)methoxy)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one, methyl (S)-4-(((2-(1-(5-chloroisoindolin-2-yl)ethyl)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6- dihydropyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylate,(S)-2-(1-(isoindolin-2-yl)ethyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,(R)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-(2,2,2-trifluoro-1-(isoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,(R)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-2-(2,2,2-trifluoro-1-(isoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,(R)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-(2,2,2-trifluoro-1-(5-fluoroisoindolin-2- yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,(R)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-2-(2,2,2-trifluoro-1-(5- fluoroisoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,5-((3-chloro-4-(1H-pyrazo1-3-yl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one, and5-((3-chloro-4-(isothiazo1-3-yl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.

[0122] According to some embodiments, the disclosure provides a pharmaceutical composition comprising a compound as defined in any of the above or below embodiments (e.g., a compound of Formula (I), a compound of Formula (II), or a specific compound named above or described in Table 2), together with a pharmaceutically acceptable carrier.

[0123] According to some embodiments, the disclosure provides a method for the treatment or prevention of a steroid receptor, in particular androgen receptor (AR), dependent conditions and diseases. Such conditions and diseases include, but are not limited to, endocrine cancers and diseases, such as prostate cancer, castration resistant prostate cancer, and breast cancer. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound as defined in any of the above or below embodiments (e.g., a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), or a specific compound named above or described in Table 2).Reaction Schemes

[0124] The compounds of the disclosure may, in general, be synthesized according to the following schemes.

[0125] In some embodiments, a substituted isoindoline A can be alkylated with 2- bromoisonitrile to provide cyanomethylisoindoline B, which can be converted to amidine C. 3- (dimethylamino)acrylate E can be prepared from ester D, condensation of acrylate E and amidine C gives pyrimidin-4(3H)-one F, alkylation of F affords 3-alky1-pyrimidin-4(3H)-one G, deprotection of benzyl group yields 3-alky1-5-hydroxypyrimidin-4(3H)-one H as shown in Scheme 1.Scheme 1Alternatively, as shown in Scheme 2, reaction of ester D with ethyl formate followed by condensation with amidine I gives pyrimidin-4(3H)-one J. Alkylation of J affords 3-alky1- pyrimidin-4(3H)-one K, Bromination of K provides L, which reacts with isoindoline C to give coupling product M. Deprotection of benzyl group yields 3-alky1-5-hydroxypyrimidin-4(3H)-one N. Alternatively, compound M is obtained through reductive amination of aldehyde or ketone LI with isoindoline C, which is produced by oxidation of K.Scheme 2

[0126] Substitutions of hydroxy H with LG of P, R, Q will produce T (Tl , T2 and T3). Alternatively, T3 can be prepared by substituting N with S to T3’ then coupling with heterocycles, as shown in Scheme 3.Scheme 3

[0127] The compounds of the disclosure can be prepared by a variety of synthetic routes analogously to the methods known in the literature using suitable starting materials.

[0128] Compounds of the disclosure may be administered to a patient in therapeutically effective amounts which range usually from about 1 to about 2000 mg, more typically from about 10 to about 1500 mg, daily depending on the age, sex, weight, ethnic group, condition of thepatient, condition to be treated, administration route and the active ingredient used. The compounds of the disclosure can be formulated into dosage forms using the principles known in the art. The compound can be given to a patient as such or in combination with suitable pharmaceutical excipients in the form of tablets, granules, capsules, suppositories, emulsions, suspensions or solutions. Choosing suitable ingredients for the composition is a routine for those of ordinary skill in the art. Suitable carriers, solvents, gel forming ingredients, dispersion forming ingredients, antioxidants, colours, sweeteners, wetting compounds and other ingredients normally used in this field of technology may also be used. The compositions containing the active compound can be given enterally or parenterally, the oral route being the preferred way. The contents of the active compound in the composition is from about 0.5 to 100 %, preferably from about 0.5 to about 20 %, per weight of the total composition. The compounds of the invention can be given to the subject as the sole active ingredient or in combination with one of more other active ingredients for treatment of a particular disease.

[0129] The pharmaceutical compositions described herein may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal means. In some embodiments, a pharmaceutical composition provided herein can be administered orally, for example in the form of pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example in the form of suppositories.

[0130] In other embodiments, a pharmaceutical composition provided herein can be administered parenterally, for example subcutaneously, intramuscularly or intravenously in the form of solutions for injection or infusion. Other suitable administration forms are, for example, percutaneous or topical administration, for example in the form of ointments, creams, tinctures, sprays or transdermal therapeutic systems, or the inhalative administration in the form of nasal sprays or aerosol mixtures, or, for example, microcapsules, implants or wafers.

[0131] Pharmaceutical compositions typically must be sterile and stable under the conditions of manufacture and storage. A composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (forexample, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin. Moreover, a compound can be administered in a time release formulation, for example in a composition which includes a slow-release polymer. The compound can be prepared with carriers that will protect against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG).

[0132] For any compound, the therapeutically effective dose may be estimated initially either in cell culture assays or in animal models such as mice, rats, rabbits, dogs, or pigs. An animal model may also be used to determine the concentration range and route of administration. Such information may then be used to determine useful doses and routes for administration in humans. These techniques are well known to one skilled in the art and a therapeutically effective dose refers to that amount of active ingredient that ameliorates the symptoms or condition. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or with experimental animals, such as by calculating and contrasting the ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). Any of the pharmaceutical compositions described herein may be applied to any subject in need of therapy, including, but not limited to, mammals such as dogs, cats, cows, horses, rabbits, monkeys, and especially humans.

[0133] The term "therapeutically effective” dose or amount is defined as an amount sufficient to treat or to ameliorate or at least partially arrest the disease or condition and its complications in a patient already suffering from the disease. A therapeutically effective amount of a compound or composition described herein generally results in a decrease in severity of disease symptoms, an increase in frequency or duration of disease symptom-free periods or aprevention of impairment or disability due to the disease affliction. In some embodiments, a therapeutically effective amount is an amount or dose of a compound or composition described herein that treats a steroid receptor dependent disease or condition as described herein.

[0134] Amounts or doses effective for this use will depend on the disorder to be treated (the indication), the delivered compound, the therapeutic context and objectives, the severity of the disease, prior therapy, the patient's clinical history and response to the therapeutic agent, the route of administration, the size (body weight, body surface or organ size) and / or condition (the age and general health) of the patient, and the general state of the patient's own immune system. The proper dose can be adjusted according to the judgment of the attending physician such that it can be administered to the patient once or over a series of administrations, and in order to obtain the optimal therapeutic effect.

[0135] In the treatment of a steroid receptor dependent disease or condition, such as endocrine cancers and disorders including prostate cancer and breast cancer, a combination of therapeutic agents and / or other treatments (e.g., radiation therapy) is often advantageous. The second (or third) agent to be administered may have the same or different mechanism of action than the primary therapeutic agent.

[0136] Accordingly, a compound of the disclosure may be administered in combination with other anti -cancer treatments useful in the treatment of cancers such as prostate cancer or breast cancer. For example, a compound of the disclosure can be packaged together with instructions that the compound is to be used in combination with other anti-cancer agents and treatments for the treatment of cancer. The present technology further comprises combinations of a compound of the disclosure and one or more additional agents in kit form, for example, where they are packaged together or placed in separate packages to be sold together as a kit, or where they are packaged to be formulated together.

[0137] According to one embodiment of the disclosure, a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III) or as described in Table 2 is coadministered with a glucocorticoid and / or a mineralocorticoid and, optionally, with one or more anti-cancer agents.

[0138] Examples of suitable glucocorticoids include, but are not limited to, hydrocortisone, prednisone, prednisolone, methylprednisolone and dexamethasone.

[0139] Examples of suitable mineralocorticoids include, but are not limited to, fludrocortisone, deoxycorticosterone, 11 -desoxy corti sone and deoxycorticosterone acetate.

[0140] The optional other anti-cancer agents which can be administered in addition to a compound of Formula (I), Formula (II), Formula (III), or as described in Table 2 include, but are not limited to non-steroidal androgen receptor antagonists (e.g. enzalutamide, 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), radiopharmaceuticals (e g. alpharadin), GnRH / LHRH analogues (such as leuprorelin), PI3K inhibitors (e.g. idelalisib), and CDK4 / 6 inhibitors (e.g. ribocyclib).

[0141] According to one embodiment, a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), or as described in Table 2 is administered to a subject in need thereof in addition to a therapeutically effective amount of one or more anti-cancer agents selected from the group consisting of non-steroidal androgen receptor antagonists (e g. enzalutamide, 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), radiopharmaceuticals (e.g. alpharadin), GnRH / LHRH analogues (such as leuprorelin), PI3K inhibitors (e.g. idelalisib), and CDK4 / 6 inhibitors (e.g. ribocyclib).

[0142] According to one embodiment, a therapeutically effective amount of a compound of Formula (I), Formula (II), or Formula (III), or as described in Table 2 is administered to a subject in need thereof in addition to a therapeutically effective amount of a steroidogenesis inhibitor (e.g. a CYP17A1 inhibitor). Examples of suitable CYP17A1 inhibitors include, but are not limited to, abiraterone acetate and seviteronel.

[0143] According to another embodiment, a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), or as described in Table 2 is administered to a subject in need thereof in addition to a therapeutically effective amount of a non-steroidal androgen receptor antagonist. Examples of suitable non-steroidal androgen receptor (AR) antagonists include, but are not limited to, enzalutamide, apalutamide and darolutamide.

[0144] According to still another embodiment, the present disclosure provides a pharmaceutical combination comprising a compound of Formula (I), Formula (II), Formula (III) or as described in Table 2 and at least one additional active ingredient selected from the group consisting of a glucocorticoid, a mineralocorticoid, a steroidogenesis inhibitor (e.g. a CYP17A1 inhibitor), a non-steroidal androgen receptor antagonist, 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), radiopharmaceuticals (e.g. alpharadin), GnRH / LHRH analogues (such as leuprorelin), PI3K inhibitors (e.g. idelalisib), and CDK4 / 6 inhibitors (e.g. ribocyclib), for simultaneous, separate or sequential administration. The above other therapeutic agents, when employed in combination with a compound of the disclosure can be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

[0145] In another embodiment, the present technology provides for the use of a compound of Formula (I), Formula (II), Formula (III), or as described in Table 2 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a steroid receptor dependent disease or condition, such as without limitation endocrine cancers and disorders including prostate cancer and breast cancer.

[0146] In accordance with the present disclosure, the compounds and compositions described herein may be assembled into kits or pharmaceutical systems for use in treatment or prevention of a steroid receptor, in particular androgen receptor (AR), dependent conditions and diseases. Kits or pharmaceutical systems may comprise a container (e.g., packaging, a box, a carton, a vial, etc.), having in close confinement therein one or more container, such as vials, tubes, ampoules, bottles, and the like, that contain the compounds and / or compositions described herein. Additional kit components may include acids, bases, buffering agents, inorganic salts, solvents,antioxidants, preservatives, or metal chelators. The additional kit components may be present as pure compositions, or as aqueous or organic solutions that incorporate one or more additional kit components. Any or all of the kit components optionally further comprise buffers. Kits may also include tools for administration, such as needles, syringes, and the like. The kit may be used according to the methods described herein and may include instructions for use in such methods. Kits may also include instructions for administration and use of the compounds and pharmaceutical compositions.

[0147] In some embodiments, a kit comprises one or more recipients (such as vials, ampoules, containers, syringes, bottles, bags) of any appropriate shape, size and material (preferably waterproof, e.g., plastic or glass) containing the compound or composition of the present disclosure in an appropriate dosage for administration. The kit may additionally contain directions for use (e.g., in the form of a leaflet or instruction manual), means for administering the compound or compositions of the present disclosure such as a syringe, pump, infuser or the like, means for reconstituting the compounds or compositions of the disclosure and / or means for diluting the compounds or compositions of the disclosure. The disclosure also provides kits for a single-dose administration unit. The kit of the disclosure may also contain a first recipient comprising a dried / lyophilized compound or composition described herein and a second recipient comprising an aqueous formulation.EXAMPLES

[0148] The present technology will be explained in more detail by the following experiments and examples. The experiments and examples are meant only for illustrative purposes and do not limit the scope of the invention defined in the claims.Example 1 - 2-(Isoiadolin-2-ylmethyl)-3-methyl-5-((l-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-onePreparation of 2-(isoindolin-2-yl )acetonitrileA solution of isoindoline (10.0 g, 83.9 mmol, 1.0 eq) in DMF (500 mL) was added 2- bromoacetonitrile (12.1 g, 101 mmol, 1.2 eq) and DIEA (108 g, 836 mmol, 10.0 eq). The reaction mixture was stirred at 80 °C for 1 h. Water (1 L) was added, the reaction mixture was extracted with EtOAc (1 L x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by silica gel column chromatography (Petroleum ether : EtOAc = 7 : 3) to give 2-(isoindolin-2-yl)acetonitrile (10.5 g, 79.1% yield) as a colorless oil.1HNMR (300MHz, CDCI3) δ(ppm) 7.24-7.22 (m, 4H), 4.11 (s, 4H), 3.83 (s, 2H). LCMS (ESI) m / z calcd for C10H10N2 158.08 found 159.2 [M+H]+.Preparation of 2-(isoindolin-2-yl)acetimidamideTo a solution of 2-(isoindolin-2-yl)acetonitrile (17.0 g, 107 mmol, 1.0 eq) in MeOH (200 mL) was added MeONa (580 g, 10.7 mmol, 0.1 eq). The reaction mixture was stirred at roomtemperature for 2 h. Then the reaction mixture was added NH4CI (6.61 g, 123 mmol, 1.15 eq). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (DCM : MeOH = 10 : 1) to give 2-(isoindolin-2-yl)acetimidamide (5.00 g, 26.6% yield) as a white solid.1HNMR (300MHz, DMSO-d6) δ(ppm) 9.00 (s, 3H), 7.31 - 7.16 (m, 4H), 4.01 (s, 4H), 3.76 (s, 2H). LCMS (ESI) m / z calcd for C10H13N3 175.11 found 176.2 [M+H]+.Preparation of (1 -(methyl sulfonyl )piperidin-4-yl)methyl methanesulfonateTo a solution of piperidin-4-ylmethanol (1.00 g, 8.68 mmol, 1 eq) in ACN (3 mL) and pyridine (3.80 mL) was added methanesulfonic anhydride (3.78 g, 21.7 mmol, 2.5 eq) over 30 min under Nz while keep the temperature of reaction mixture below 35 °C. The resulting reaction mixture was stirred at 40 °C for 3 h. Water (5 mL) was added followed by acetic acid (0.5 mL). The resulting mixture was cooled to 0 °C and stirred for an additional 1 h before filtration. The filtrate was washed with water (5 mL). The organic layers were collected, dried over Na2SO4, filtered and evaporated to dryness to afford (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (0.90 g, 38.2% yield) as a white solid which was used for next step without further purification.1HNMR. (400MHz, CDCI3) δ(ppm) 4.10 (d, J=6.0 Hz, 2H), 3.95 - 3.79 (m, 2H), 3.02 (s, 3H), 2.78 (s, 3H), 2.68 (td, J=12.0, 2.4 Hz, 2H), 1.95 - 1.83 (m, 3H), 1.44 - 1.28 (m, 2H). LCMS (ESI) m / z calcd for C8H17NO5S2 271.05 found 272.0 [M+H]+.Preparation of methyl (E)-2-(benzyloxy)-3-(dimethylamino)acrylateA solution of methyl 2-(benzyloxy)acetate (9.30 g, 51.6 mmol, 1.0 eq) in 1-tert-butoxy- N,N,N',N' -tetramethylmethanediamine (40.5 g, 232 mmol, 4.5 eq) was stirred at 80 °C forovernight. Water (200 mL) was added, and the reaction mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by silica gel column chromatography (Petroleum ether : EtOAc = 5 : 1) to give methyl (E)-2-(benzyloxy)-3- (dimethylamino)acrylate (11.0 g, 90.6% yield) as a colorless liquid.1HNMR (300MHz, CDCI3) δ(ppm) 7.46 - 7.27 (m, 5H), 6.87 (s, 1H), 4.72 (s, 2H), 3.73 (s, 3H), 2.98 (s, 6H).Preparation of 5-(benzyloxy)-2-(isoindolin-2-ylmethyl)pyrimidin-4(3H)-oneTo a solution of 2-(isoindolin-2-yl)acetimidamide (1.09 g, 6.20 mmol, 1.0 eq) in MeOH (15 mL) was added MeONa (368 mg, 6.81 mmol, 1.1 eq) and methyl (E)-2-(benzyloxy)-3- (dimethylamino)acrylate (2.19 g, 9.31 mmol, 1.5 eq). The reaction mixture was stirred at 70 °C for overnight. Water (200 mL) was added, and the reaction mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, fdtered and evaporated to dryness. The crude product was purified by silica gel column chromatography (DCM MeOH = 30 : 1) to give 5-(benzyloxy)-2-(isoindolin-2- ylmethyl)pyrimidin-4(3H)-one (400 mg, 21.0% yield) as a yellow solid.1HNMR (300MHz, CDCI3) δ(ppm) 7.47 - 7.41 (m, 3H), 7.40 -7.32 (m, 2H), 7.27 - 7.16 (m, 5H), 5.14 (s, 2H), 4.05 (s, 4H), 3.85 (s, 2H). LCMS (ESI) m / z calcd for C20H19N3O2 333.15 found 334.1 [M+H]+.Preparation of 5-(benzyloxy)-2-(isoindolin-2-ylmethyl)-3-methylpyrimidin-4(3H)-oneTo a solution of 5-(benzyloxy)-2-(isoindolin-2-ylmethyl)pyrimidin-4(3H)-one (330 mg, 0.990 mmol, 1.0 eq) in dioxane (4 mL) was added CS2CO3(322 mg, 0.990 mmol, 1.0 eq) and dimethylsulfate (63 mg, 0.500 mmol, 0.5 eq). The reaction mixture was stirred at 100 °C for 6 h. Water (20 mL) was added, and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by silica gel column chromatography (Petroleum ether : EtOAc = 1 : 1) to give 5-(benzyloxy)-2-(isoindolin-2-ylmethyl)-3-methylpyrimidin-4(3H)-one (130 mg, 37.8% yield) as a yellow solid.1HNMR (300MHz, CDCI3) δ(ppm) 7.40 - 7.36 (m, 6H), 7.23 - 7.14 (m, 4H), 5.14 (s, 2H), 3.99 (s, 4H), 3.90 (s, 2H), 3.73 (s, 3H). LCMS (ESI) m / z calcd for C21H21N3O2 347.16 found 348.1 [M+H]+.Preparation of 5-hydroxy-2-(isoindolin-2-ylmethyl)-3-methylpyrimidin-4(3H)-oneA solution of 5 -(benzyloxy)-2-(isoindolin-2-ylmethyl)-3-methylpyrimidin-4(3H)-one (180 mg, 0.518 mmol, 1.0 eq) in HC1 (6M) (3 mL) was stirred at 70 °C overnight. The mixture was concentrated to give 5-hydroxy-2-(isoindolin-2-ylmethyl)-3-methylpyrimidin-4(3H)-one (130 mg, crude) as a white solid, which was used for next step without further purification. LCMS (ESI) m / z calcd for C14H15N3O2 257.12 found 258.1 [M+H]+.Preparation of 2-(isoindolin-2-ylmethyl)-3-methyl-5-((l -(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-oneTo a solution of 5-hydroxy-2-(isoindolin-2-ylmethyl)-3-methylpyrimidin-4(3H)-one (130 mg, 0.505 mmol, 1.0 eq), (1 -(methyl sulfonyl )piperidin-4-yl)methyl methanesulfonate (137 mg, 0.505 mmol, 1.0 eq) in DMSO (2 mL) was added CS2CO3(494 mg, 1.52 mmol, 3.0 eq). The mixture was stirred at 60 °C for 3 h. The reaction was quenched with water (5 mL) and extracted with EtOAc(10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, fdtered and evaporated to dryness. The crude product was purified by prep-HPLC (ACN with 5 mmol NH4HCO3in H2O, 40%-55% ACN) to give 2-(isoindolin-2-ylmethyl)-3-methyl-5-((1- (methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one (30.0 mg, 13.7% yield for two steps) as a white solid.1HNMR (400MHz, CDCI3) δ(ppm) 7.40 (s, 1H), 7.25 - 7.18 (m, 4H), 4.17 (bs, 4H), 4.02 (bs, 2H), 3.88 - 3.83 (m, 4H), 3.71 (s, 3H), 2.79 (s, 3H), 2.76 - 2.65 (m, 2H), 2.04- 1.93 (m, 3H), 1.53 - 1.38 (m, 2H). LCMS (ESI) m / z calcd for C22H30N4O4S 432.18 found 433.2 [M+H]+.Example 2 - 3-Ethyl-2-(isoindolin-2-ylmethyl)-5-((l-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-onePreparation of 5-(benzyloxy)-3-ethyl-2-(isoindolin-2-ylmethyl)pyrimidin-4(3H)-oneTo a solution of 5-(benzyloxy)-2-(isoindolin-2-ylmethyl)pyrimidin-4(3H)-one (400 mg, 1.20 mmol, 1.0 eq) in DMF (5 mL) was added CS2CO3 (782 mg, 2.40 mmol, 2.0 eq) and lodoethane (187 mg, 1.20 mmol, 1.0 eq). The reaction mixture was stirred at 0 °C for 1 h. Water (20 mL) was added, and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by silica gel column chromatography (Petroleum ether : EtOAc = 1 : 1) to give 5-(benzyloxy)-3-ethyl-2-(isoindolin-2-ylmethyl)pyrimidin-4(3H)-one (120 mg, 27.7% yield) as a yellow solid .1HNMR (300MHz, CDCI3) δ(ppm) 7.47 - 7.28 (m, 7H), 7.20 (s,3H), 5.30 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 4.00 (s, 4H), 3.90 (s, 2H), 1.35 (t, J=7.1 Hz, 3H). LCMS (ESI) m z calcd for C22H23N3O2 361.18 found 362.2 [M+H]+.Preparation of 3-ethyl-2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one3-Ethy1-2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy) pyrimidin- 4(3H)-one was prepared using the same procedures as in the preparation of 2-(isoindolin-2- ylmethyl)-3-methyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one except that 5-(benzyloxy)-3-ethyl-2-(isoindolin-2-ylmethyl)pyrimidin-4(3H)-one was used instead of 5- (benzyloxy)-2-(isoindolin-2-ylmethyl)-3-methylpyrimidin-4(3H)-one (white solid, 32.5% yield for two steps).1HNMR (400MHz, CDCI3) δ(ppm) 7.39 (s, 1H), 7.19-7.26 (m, 4H), 4.29 (q, J=7.2 Hz, 2H), 4.10 (bs, 4H), 3.98 (bs, 2H), 3.88 - 3.82 (m, 4H), 3.71 (s, 3H), 2.79 (s, 3H), 2.76 - 2.65 (m, 2H), 2.09 - 1.97 (m, 3H), 1.53 - 1.38 (m, 2H). LCMS (ESI) m / z calcd for C22H30N4O4S 446.20 found 447.2 [M+H]+.2-(Isoindolin-2-ylmethyl)-3-isopropy1-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one was prepared by using the same procedures for preparation of 3-ethyl-2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy) pyrimidin- 4(3H)-one except that 2-iodopropane was used instead of iodoethane.1HNMR (300MHz, DMSO-d6) δ(ppm) 8.21 (s, 1H), 7.31 - 7.17 (m, 4H), 5.33 - 5.29 (m, 1H), 4.20 (bs, 4H), 4.11 (s, 2H), 3.96 (d, J= 6.0 Hz, 2H), 3.60 - 3.56 (m, 2H), 2.85 (s, 3H), 2.74 (t, J=\ 1.1 Hz, 2H), 1.86 - 1.82 (m, 3H), 1.34 - 1.28 (m, 2H), 1.30 (d, J=6.0 Hz, 6H). LCMS (ESI) m / z calcd for C23H32N4O4S 460.21 found 461.2 [M+H]+.Example 4 - 2-(Isoindolin-2-ylmethyl)-5-((l-(methylsulfonyl)piperidin-4-yl)methoxy)-3- propylpyrimidin-4( 3H)-onePreparation of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)rnethoxy)-3- propylpyrimidin-4(3H)-one2-(Isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-propylpyrimidin- 4(3H)-one was prepared by using the same procedures as preparation of 3-ethyl-2-(isoindolin-2- ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy) pyrimidin-4(3H)-one except that 1- iodopropane was used instead of iodoethane (white solid).1HNMR (300MHz, CDCI3) δ(ppm) 7.39 (s, 1H), 7.24 - 7.16 (m, 4H), 4.24 - 4.12 (m, 2H), 4.04 (s, 4H), 3.93 (s, 2H), 3.91 - 3.82 (m, 4H), 2.79 (s, 3H), 2.70 (td, J=12.0, 2.1 Hz, 2H), 2.06 - 1.97 (m, 3H), 1.79 - 1.72 (m, 2H), 1.48 - 1.43 (m, 2H), 0.98 (t, J=7.5 Hz, 3H). LCMS (ESI) m / z calcd for C23H32N4O4S 460.21 found 461.2 [M+H]+.Example 5 - 2-((l , l-Dioxidobenzo[d]isothiazol-2(3H)-yl)methyl)-3-methyl-5-((l-(methylsulfonyl)piperidm-4-yl)methoxy)pyrimidin-4(3EI)-onePreparation of 5-(benzyloxy)-2-methylpyrimidin-4(3H)-one

[0149] To a solution of methyl 2-(benzyloxy)acetate (19.5 g, 108 mmol, 1.0 eq) and ethyl formate (9.61 g, 130 mmol, 1.2 eq) in THF (80 mL) was added NaH (3.37 g, 140 mmol, 1.3 eq) at 0 °C, the mixture was stirred at 50 °C for 1 h. Then the mixture was concentrated to give oily residue. A solution of acetimidamide hydrochloride (10.0 g, 108 mmol, 1.0 eq) and EtONa (7.36 g, 108 mmol, 1.0 eq) in EtOH (50 mL) was stirred at room temperature for 45 min, the mixture was filtered to remove solid and was added the oily residue. The reaction mixture was stirred at 100 °C under N2overnight. The mixture was cooled and adjusted pH = 6~7 by HCI (IN), the aqueous phase was extracted EtOAc (50 mL x 3) and DCM (50 mL x 3), the organic phase was concentrated and triturated by petroleum ether : ethyl acetate = 3: 1 (100 mL) to give product 5- (benzyloxy)-2-methylpyrimidin-4(3H)-one (10 g, 42.8% yield) as a white solid. 'HNMR (300MHz, DMSO-d6) δ(ppm) 12.43 (s, 1H), 7.49 (s, 1H), 7.47 - 7.29 (m, 5H), 5.02 (s, 2H), 2.20 (s, 3H). LCMS (ESI) m / z calcd for C12H12N2O2216.09 found 217.1 [M+H]+.Preparation of 5-(benzyloxy)-2,3-dimethylpyrimidin-4(3H)-one

[0150] To a solution of 5-(benzyloxy)-2-methylpyrimidin-4(3H)-one (600 mg, 2.78 mmol, 1.0 eq) in dioxane (6 mL) was added Dimethyl sulfate (210 mg, 1.67 mmol, 0.6 eq) and CS2CO3 (904 mg, 2.78 mmol, 1.0 eq), the mixture was heated to 100 °C and stirred for 4 h under N2. The mixture was quenched with water (5 mL), extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude product. The residue was purified by column chromatography to give 5-(benzyloxy)-2,3-dimethylpyrimidin-4(3H)-one (120 mg, 18.7% yield) as a white solid.1HNMR (300MHz, CDCI3) δ(ppm) 7.47 - 7.31 (m, 5H), 6.78 (s, 1H), 5.13 (s, 2H), 3.49 (s, 3H), 2.40 (s, 3H). LCMS (ESI) m / z calcd for C13H14N2O2 230.11 found 231.1 [M+H]+.Preparation of 5-(benzyloxy)-2-(bromomethyl)-3-methylpyrimidin-4(3H)-oneTo a solution of 5-(benzyloxy)-2,3-dimethylpyrimidin-4(3H)-one (180 mg, 0.782 mmol, 1.0 eq} in DCE (5 mb) was added AIBN (26.0 mg, 0.158 mmol, 0.2 eq) and NBS (167 mg, 0.938 mmol, 1.2 eq}, the mixture was stirred at reflux under N2 with a 200 W tungsten lamp overnight. The mixture was quenched with water (5 mL), extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude product. The residue was purified by column chromatography to give 5-(benzyloxy)-2-(bromomethyl)-3-methylpyrimidin- 4(3H)-one (80.0 mg, 33.1% yield) as abrown solid.1HNMR (400MHz, CDCI3) δ(ppm) 7.38 - 7.25 (m, 6H), 5.15 (s, 2H), 4.34 (s, 2H), 3.68 (s, 3H).Preparation of 2,3-dihydrobenzo[d]isothiazole 1,1- dioxideTo a solution of benzo[d]isothiazo1-3(2H)-one 1,1-dioxide (2.00 g, 10.9 mmol, 1.0 eq} in THF (10 mL) was added LiAlITi (1.24 g, 32.7 mmol, 3.0 eq} at 0 °C under N2, the mixture was stirred at room temperature for 4 h. The mixture was quenched with H2SO4(30 mL, 30%) at 0 °C and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4and concentrated to give the crude product. The residue was purified by column chromatography to give 2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (1.5 g, 81.2% yield) as a white solid. LCMS (ESI) m z calcd for C7H7NO2S 169.02 found 170.1 [M+H]+.Preparation of 5-(benzyloxy)-2-((11-dioxidobenzord]isothiazo1-2(3H)-yl)methyl)-3- methylpyrimidin-4(3H)-oneTo a solution of 2,3-dihydrobenzo[d]isothiazole 1, 1-dioxide (53.0 mg, 0.313 mmol, 1.2 eq} and 5-(benzyloxy)-2-(bromomethyl)-3-methylpyrimidin-4(3H)-one (80.0 mg, 0.259 mmol, 1.0 eq} in DMF (3 mL) was added CS2CO3(127 mg, 0.390 mmol, 1.5 eq} at 0 °C, the mixture was stirred at room temperature overnight. Water (15 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4and concentrated to give the crude product. The residue was purified by column chromatography to give 5-(benzyloxy)-2-((l,1-dioxidobenzo[d]isothiazo1-2(3H)-yl)methyl)-3-methylpyrimidin- 4(3H)-one (90.0 mg, 87.3% yield) as a white solid. LCMS (ESI) m,z cal cd for C20H19N3O4S 397.11 found 398.1 [M+H]+.Preparation of 2-((l.1-dioxidobenzo[d]isothiazo1-2(3H)-yl)methyl)-5-hydroxy-3- methylpyrimidin-4(3H)-oneTo a solution of 5-(benzyloxy)-2-((l,1-dioxidobenzo[d]isothiazo1-2(3H)-yl)methyl)-3- methylpyrimidin-4(3H)-one (80.0 mg, 0.201 mmol, 1.0 eq} in MeOH (2 mL) was added Pd / C (50.0 mg, 0.470 mmol, 2.3 eq}, the mixture was stirred room temperature for 2 h under H2. The mixture was filtered and concentrated to give a residue. The mixture was purified by prep-TLC to give 2-((1,1-dioxidobenzo[d]isothiazo1-2(3H)-yl)methyl)-5-hydroxy-3-methylpyrimidin-4(3H)- one (60.0 mg, 97.0% yield) as a white solid.1HNMR (400MHz, CDCI3) δ(ppm) 7.84 (d, J = 7.6 Hz, 1H), 7.67 - 7.54 (m, 3H), 7.39 (d, J= 7.6 Hz, 1H), 6.37 (s, 1H), 4.41 (s, 2H), 4.38 (s, 2H), 3.78 (s, 3H). LCMS (ESI) m / z calcd for C13H13N3O4S 307.06 found 308.1 [M+H]+.Preparation of 2-((L1-dioxidobenzord1isothiazo1-2(3H)-yl)methyl)-3-methy1-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-oneTo a solution of 2-((l,1-dioxidobenzo[d]isothiazo1-2(3H)-yl)methyl)-5-hydroxy-3- methylpyrimidin-4(3H)-one (30.0 mg, 0.0976 mmol, 1.0 eq) and (1-(methylsulfonyl)piperidin-4- yl)methyl methanesulfonate (29.0 mg, 0.107 mmol, 1.1 eq) in DMSO (2 mL) was added K2CO3(20.0 mg, 0.145 mmol, 1.5 eq), the mixture was stirred at 50 °C under N2 for 4 h. Water (10 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4and concentrated to give the crude product. The residue was purified by prep-TLC (DCM MeOH = 10: 1) to give 2-((l,1- dioxidobenzo[d]isothiazo1-2(3H)-yl)methyl)-3-methyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one (5.00 mg, 10.6% yield) as a white solid.1HNMR (300MHz, CDCI3) δ(ppm) 7.84 (d, J = 6.5 Hz, 1H), 7.72 - 7.51 (m, 2H), 7.39 (s, 1H), 7.38 (d, J = 6.5 Hz, 1H), 4.45 - 4.36 (m, 4H), 3.91 - 3.81 (m, 4H), 3.72 (s, 3H), 2.79 (s, 3H), 2.75 - 2.65 (m, 2H), 2.09 - 1.96 (m, 3H), 1.52 - 1.39 (m, 2H). LCMS (ESI) m / z calcd for C20H26N4O6S2 482.13 found 483.1 [M+H]+.Example 6 - 3-Ethyl-2-(isomdolin-2-ylmethyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6- yl)methoxy)pyrimidin-4(3EI)-onePreparation of tert-butyl 6-(hydroxymethyl)-2-azaspiror3.3]heptane-2-carboxylate2-(tert-Butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (1.0 g, 4.10 mmol 1.0 eq}, obtained commercially, was dissolved in THF (20 mL), and the reaction mixture was cooled to 0 °C under an inert atmosphere. Borane-methyl sulfide complex (1.6 g, 20.4 mmol, 5.0 eq} was then added dropwise. The resulting solution was warmed to room temperature and stirred for 1 h, after which time the solution was heated to 65 °C and refluxed 4 h. The reaction mixture was then slowly added to a stirring solution of EtOH (20 mL) at 0 °C and was allowed to stir for 30 min. Solvents were removed under reduced pressure, and the resulting residue was re-dissolved in DCM (30 mL) and washed with H2O (30 mL x 2). The organic layer was concentrated to give crude tertbutyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (1.1 g, crude) as a colorless oil. which was used for the next step without further purification.1H NMR (300 MHz, CDCI3) δ(ppm) 3.92 (s, 2H), 3.82 (s, 2H), 3.56 (d, J= 6.0 Hz, 2H), 2.29 - 2.18 (m, 2H), 1.99 - 1.88 (m, 2H), 1.42 (s, 11H).Preparation of (2-azaspiro[3.3]heptan-6-yl)methanol hydrochlorideTo a solution of tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (1.1 g, 4.84 mmol, 1.0 eq) in DCM (1 mL) was added HCI-dioxane (1 mL). Then the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to give (2-azaspiro[3.3]heptan- 6-yl)methanol hydrochloride (0.9 g, crude) as a white solid, which was used for the next step without further purification. LCMS (ESI) m / z calcd for C7H14CINO 163.08 found: 128.2 [M- HC1+H]+.Preparation of (2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methyl methanesulfonateTo a solution of (2-azaspiro[3.3]heptan-6-yl)methanol hydrochloride (400 mg, 2.44 mmol, 1.0 eq) in ACN (3.0 mL) and Pyridine (3.8 mL) was added methanesulfonic anhydride (1.1 g, 6.10mmol, 2.5 eq) over 30 min under N2below 35 °C. The reaction mixture was stirred at 35 °C for 4 h. Water (10 mL) was quickly added followed by acetic acid (10 mL). The resulting mass was cooled over to 0 °C and mixed for 1 h to filtration. The product was washed with water (10 mL x 2) and dried under vacuum to give (2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methyl methanesulfonate (0.5 g, 1.77 mmol, 72.5% yield) as a yellow solid, which was used for the next step without further purification. LCMS (ESI) m / z calcd for C9H17NO5S2 283.05 found: 283.9 [M+H]+.Preparation of 3-ethyl-2-(isoindolin-2-ylmethyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)pyrimidin-4(3H)-one3-Ethy1-2-(isoindolin-2-ylmethyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6- yl)methoxy)pyrimidin-4(3H)-one was prepared by using the same procedures as preparation of 3- ethyl-2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy) pyrimidin-4(3H)- one except that (2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methyl methanesulfonate was used instead of (1 -(methyl sulfonyl)piperidin-4-yl)m ethyl methanesulfonate.1HNMR (300MHz, CDCI3) δ(ppm) 7.41 (s, 1H), 7.24 - 7.19 (m, 4H), 4.28 (q, J=1.2 Hz, 2H), 4.10 (bs, 4H), 4.02 - 3.84 (m, 8H), 2.84 (s, 3H), 2.79 - 2.61 (m, 1H), 2.46 - 2.33 (m, 2H), 2.21 - 2.11 (m, 2H), 1.35 (t, J=7.2 Hz, 3H). LCMS (ESI) m / z calcd for C23H30N4O4S 458.20 found 459.2 [M+H]+.Example 7 - 2-( (5-Bromoisoindolm-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-onePreparation of 5-(benzyloxy)-3-ethyl-2-methylpyrimidin-4(3H)-oneTo a solution of 5-(benzyloxy)-2-methylpyrimidin-4(3H)-one (3.90 g, 18.0 mmol, 1.0 eq) and Cs2CO3(11.8 g, 36.1 mmol, 2.0 eq) in DMF (20 mL) was added lodoethane (4.22 g, 27.1 mmol, 1.5 eq) at 0 °C, the mixture was stirred at room temperature for 4 h under N2. Water (30 mL) was added and the mixture was extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4and concentrated to give the crude product. The residue was purified by column chromatography to give 5-(benzyloxy)-3-ethyl-2- methylpyrimidin-4(3H)-one (1.90 g, 43.1% yield) as a yellow oil.1HNMR (400MHz, CDCI3) δ(ppm) 7.41 (d, J= 7.2 Hz, 2H), 7.37 - 7.24 (m, 4H), 5.09 (s, 2H), 4.07 (q, J= 7.2 Hz, 2H), 2.47 (s, 3H), 1.31 (t, J= 7.2 Hz, 3H). LCMS (ESI) m / z calcd for C14H16N2O2244.12 found 245.2 [M+H]Preparation of 5-(benzyloxy)-2-(bromomethyl)-3-ethylpyrimidin-4(3H)-one5-(benzyloxy)-2-(bromomethyl)-3-ethylpyrimidin-4(3H )-one (800 mg, 33.6% yield) as a white solid was prepared by using the same procedure as the preparation of 5-(benzyloxy)-2- (bromomethyl)-3-methylpyrimidin-4(3H)-one except that 5-(benzyloxy)-2,3-dimethylpyrimidin- 4(3H)-one was replaced with 5-(benzyloxy)-3-ethyl-2-methylpyrimidin-4(3H)-one. LCMS (ESI) m / z calcd for C14H15BrN2O2 322.03 found 323.1, 325.1 [M+H]+.Preparation of 5-(benzyloxy)-2-((5-bromoisoindolin-2-yl)methyl)-3-ethylpyrimidin-4(3H)-oneTo a solution of 5-(benzyloxy)-2-(bromomethyl)-3-ethylpyrimidin-4(3H)-one (650 mg, 2.01 mmol, 1.0 eq) and 5-bromoisoindoline hydrochloride (742 mg, 3.19 mmol, 1.5 eq) in DMF (6 mL) was added Cs2CO3(2.17 g, 6.03 mmol, 3.0 eq), the mixture was stirred at room temperature for 4 h. Water (20 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4and concentrated to give the crude product. The residue was purified by column chromatography to give 5-(benzyloxy)-2-((5- bromoisoindolin-2-yl)methyl)-3-ethylpyrimidin-4(3H)-one (500 mg, 56.5% yield) as a brown solid. LCMS (ESI) m / z calcd for C22H22BrN3O2439.09 found 440.1, 442.1 [M+H]+.Preparation of 2-((5-bromoisoindolin-2-yl)methyl)-3-ethyl-5-hydroxypyrimidin-4(3H)-oneA solution of 5-(benzyloxy)-2-((5-bromoisoindolin-2-yl)methyl)-3-ethylpyrimidin-4(3H)-one (500 mg, 1.14 mmol, 1 .0 eq) in HCI (6 mL, 6N) was stirred at 70 °C overnight. The mixture was concentrated and added water (10 mL). NaHCO3(aq) was added and the reaction mixture was adjusted pH to about 7~8. The aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4and concentrated togive 2-((5-bromoisoindolin-2-yl)methyl)-3-ethyl-5-hydroxypyrimidin-4(3H)-one (230 mg, 57.8% yield) as a brown solid.1HNMR (400MHz, CDCI3) δ(ppm) 7.58 (s, 1H), 7.36 - 7.32 (m, 2H), 7.07 (d, J= 8.4 Hz, 1H), 4.31 (q, J= 7.2 Hz, 2H), 4.12 - 3.83 (m, 6H), 1.37 (t, J = 7.2 Hz, 3H). LCMS (ESI) m / z calcd for C15H16BrN3O2 349.04 found 350.1, 352.1 [M+H]+.Preparation of 2-((5-bromoisoindolin-2-yl)methyl)-3-ethy1-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-oneTo a solution of 2-((5-bromoisoindolin-2-yl)methyl)-3-ethyl-5-hydroxypyrimidin-4(3H)-one (200 mg, 0.571 mmol, 1.0 eq) and (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (186 mg, 0.685 mmol, 1.2 eq) in DMSO (4 mL) was added CS2CO3(372 mg, 1.14 mmol, 2.0 eq), the mixture was stirred at 60 °C under N2 for 4 h. Water (10 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4and concentrated to give the crude product. The residue was purified by prep- TLC (DCM : MeOH = 10:1) to give 2-((5-bromoisoindolin-2-yl)methyl)-3-ethyl-5-((1- (methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one (170 mg, 56.7% yield) as a white solid.1HNMR (300MHz, CDCI3) δ(ppm) 7.40 - 7.32 (m, 3H), 7.07 (d, J = 8.7 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.05 - 3.98 (m, 4H), 3.94 (bs, 2H), 3.89 - 3.81 (m, 4H), 2.79 (s, 3H), 2.70 (dt, J = 1.8, 9 Hz, 2H), 2.08 - 2.00 (m, 3H), 1.56 - 1.41 (m, 2H), 1.34 (t, J= 7.2 Hz, 3H). LCMS (ESI) m / z calcd for C22H29BrN4O4S 524.11 found 525.1, 527.1 [M+H]+.Example 8 - 2-(Isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-onePreparation of 5-(benzyloxy)-2-methyl-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-oneTo a solution of 5-(benzyloxy)-2-methylpyrimidin-4(3H)-one (12.9 g, 59.7 mmol, 1.0 eq) in DMF (150 mL) was added 2,2,2-Trifluoroethyl trifluoromethanesulfonate (20.8 g, 89.5 mmol, 1.5 eq) and Cs2CO3(38.9 g, 119 mmol, 2.0 eq), the mixture was stirred at room temperature for 3 h. The mixture was quenched with water (300 mL), extracted with EtOAc (500 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude. The residue was purified by silica gel column chromatography (EtOAc : Petroleum ether = 1 : 1) to give 5- (benzyloxy)-2-methyl-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (5.10 g, 28.7% yield) as a yellow solid.1HNMR (300MHz, CDCI3) δ(ppm) 7.43 - 7.31 (m, 6H), 5.12 (s, 2H), 4.79 - 4.71 (m, 2H), 2.52 (s, 3H). LCMS (ESI) m / z calcd for C14H13F3N2O2298.09 found 299.1 [M+H]+Preparation of 5-(benzyloxy)-2-(bromomethyl)-3-(2.2.2-trifluoroethyl)pyrimidin-4(3H)-oneTo a solution of 5-(benzyloxy)-2-methyl-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (5.10 g, 17.1 mmol, 1.0 eq) in DCE (50 mL) was added AIBN (562 mg, 3.42 mmol, 0.2 eq) and NBS (3.65 g, 20.5 mmol, 1.2 eq), the mixture was stirred at 80 °C for overnight. The mixture was quenched with water (50 mL), extracted with EtOAc (70 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude. The residue was purified by silica gel column chromatography (EtOAc . Petroleum ether = 1 : 1) to give 5-(benzyloxy)-2-(bromomethyl)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (2.75 g, 42.6% yield) as a yellow solid. 'HNMR (300MHz, CDCI3) δ(ppm) 7.44 - 7.33 (m, 6H), 5.14 (s, 2H), 4.98 - 4.90 (m, 2H), 4.38 (s, 2H). LCMS (ESI) m / z calcd for C14H12BrF3N2O2 376.00 found 377.0, 379.0 [M+H]+.Preparation of 5-(benzyloxy)-2-(isoindolin-2-ylmethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)- oneTo a solution of 5-(benzyloxy)-2-(bromomethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (2.75 g, 7.29 mmol, 1.0 eq) in DMF (30 mL) was added isoindoline (1.30 g, 10.9 mmol, 1.5 eq) and Cs2CO3(3.56 g, 10.9 mmol, 1.5 eq), the mixture was stirred at room temperature for overnight. The mixture was quenched with water (30 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude. The residue was purified by silica gel column chromatography (EtOAc : Petroleum ether = 1 : 1 ) to give 5-(benzyloxy)-2- (isoindolin-2-ylmethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (2.1 g, 69.3% yield) as a yellow solid.1HNMR (300MHz, CDCI3) δ(ppm) 7.37 - 7.25 (m, 6H), 7.20 - 7.09 (m, 4H), 5.31 - 5.22 (m, 2H), 5.07 (s, 2H), 3.90 (s, 2H), 3.88 (s, 4H). LCMS (ESI) m / z ealed for C22H20F3N3O2 415.15 found 416.2 [M+H]+.Preparation of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one2-(Isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3 -(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one was prepared by using the same procedure as preparation of 3-ethyl-2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy) pyrimidin- 4(3H)-one except that 5-(benzyloxy)-2-(isoindolin-2-ylmethyl)-3-(2,2,2-trifluoroethyl)pyrimidin- 4(3H)-one was used instead of 5-(benzyloxy)-2-((5-bromoisoindolin-2-yl)methyl)-3- ethylpyrimidin-4(3H)-one.1HNMR (300MHz, CDCI3) δ(ppm) 7.37 (s, 1H), 7.25 - 7.19 (m, 4H), 5.35 - 5.28 (m, 2H), 4.06 - 3.92 (m, 6H), 3.91 - 3.83 (m, 4H), 2.80 (s, 3H), 2.71 (t, J=12.0 Hz, 2H), 2.09 - 2.01 (m, 3H), 1.52 - 1.41 (m, 2H). LCMS (ESI) m / z ealed for C22H27F3N4O4S 500.17 found 501.2 [M+H]+.Example 9 - 3-Ethyl-2-((5-fluoroisoiiidolin-2-yl)methyl)-5-((l-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3EI)-onePreparation of 5-fluoroisoindoline-1,3-dioneA solution of 5-fluoroisobenzofuran-1,3-dione (2.00 g, 12.0 mmol, 1.0 eq) in Formamide (24 mL) was stirred at 120 °C for 3 h under N2. The mixture was cooled to r.t. and water (90 mL) was added. The mixture was stirred at room temperature for 1 h, then the mixture was filtered to give the 5-fluoroisoindoline-l, 3-dione (1.40 g, 70.4% yield) as a white solid.1HNMR (400MHz, DMSO-d6) δ(ppm) 11.46 (s, 1H), 7.98 - 7.82 (m, 1H), 7.77 - 7.50 (m, 2H). LCMS (ESI) m / z calcd for C8H4FNO2 165.02 found 165.9 [M+H]+.Preparation of 5-fluoroisoindolineTo a solution of A1CL (1.21 g, 9.09 mmol, 5.0 eq) in THF (20 mL) was added LiA1H4(0.550 g,14.5 mmol, 8.0 eq), the reaction mixture was stirred at room temperature for 10 min. Then 5-fluoroisoindoline-1, 3-dione (0.300 g, 1 .82 mmol, 1 .0 eq) in THF (2 mL) was added to the mixture at 0 °C. Then the reaction mixture was stirred at reflux for 5 h, water (10 mL) was added, then NaHCO3(10 mL) was added, the mixture was filtered and the filtrate was extracted with EtOAc (20 mL x 3), the combined organic layers were washed with brine (10 mL), dried over Na2SO4and concentrated to give crude product, which was purified by column chromatography to give 5- fluoroisoindoline (0.120 g, 48.2% yield) as a brown oil. LCMS (ESI) m / z calcd for C8H8FN 137.06 found 138.2 [M+H]+.Preparation of 5-(benzyloxy)-3-ethyl-2-((5-fluoroisoindolin-2-yl)methyl)pyrimidin-4(3H)-oneTo a solution of 5-(benzyloxy)-2-(bromomethyl)-3-ethylpyrimidin-4(3H)-one (300 mg, 0.928 mmol, 1.0 eq) and 5-fluoroisoindoline (190 mg, 1.39 mmol, 1.5 eq) in DMF (3 mL) was added Cs2CO3(756 mg, 2.32 mmol, 2.5 eq), the mixture was stirred at room temperature overnight. Water (10 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4and concentrated to give the crude product. The residue was purified by column chromatography to give 5-(benzyloxy)-3-ethyl-2- ((5-fluoroisoindolin-2-yl)methyl)pyrimidin-4(3H)-one (200 mg, 56.8% yield) as a brown solid. LCMS (ESI) m / z calcd for C22H22FN3O2 379.17 found 380.2 [M+H]+.Preparation of 3-ethyl-2-((5-fluoroisoindolin-2-yl)methyl)-5-hydroxypyrimidin-4(3H)-oneA solution of 5-(benzyloxy)-3-ethyl-2-((5-fluoroisoindolin-2-yl)methyl)pyrimidin-4(3H)-one (200 mg, 0.527 mmol, 1.0 eq) in HC1 (3 mL, 6N) was stirred at 70 °C overnight. The mixture was concentrated and added water (10 mL). NaHCO3(aq.) was added and the mixture was adjustedpH to about 7~8. The aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4and concentrated to give 3-ethyl-2-((5- fluoroisoindolin-2-yl)methyl)-5-hydroxypyrimidin-4(3H)-one (100 mg, 65.7% yield) as a brown solid, which was used directly for next step without purification. LCMS (ESI) m z calcd for C15H16FN3O2 289.12 found 290.2 [M+H]+.Preparation of 3-ethyl-2-((5-fluoroisoindolin-2-yl)methyl)-5-((l -(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one3-Ethy1-2-((5-fluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperi din-4- yl)methoxy)pyrimidin-4(3H)-one was prepared by using the same procedures for preparation of 2-((5-bromoisoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one except that 5 -fluoroisoindoline was used instead of 5- bromoisoindoline (26.0 mg, 32.4% yield) as a white solid.1HNMR (300MHz, CDCI3) δ(ppm) 7.38 (s, 1H), 7.20 - 7.04 (m, 1H), 7.01 - 6.79 (m, 2H), 4.28 (q, J=1.2 Hz, 2H), 4.01 (d, J=7.5 Hz, 4H), 3.93 (s, 2H), 3.90 - 3.77 (m, 4H), 2.79 (s, 3H), 2.75 - 2.65 (m, 2H), 2.1 1 - 1.95 (m, 3H), 1.53 - 1.41 (m, 2H), 1.35 (t, J=7.2 Hz, 3H). LCMS (ESI) m / z calcd for C22H29FN4O4S 464.19 found 465.2 [M+H]+.Example 10 - 2-((5-Chloroisoindolin-2-yl)methyl)-3-ethyl-5-((l-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one2-((5-Chloroisoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one was prepared by using the same procedures for preparation of 3-ethyl-2-((5-fluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one except that 5-fluoroisoindoline-1,3-dione was replaced with 5- chloroisoindoline-1, 3-dione.1HNMR (300MHz, CDCI3) δ(ppm) 7.38 (s, 1H), 7.22 - 7.15 (m, 2H), 7.13 (d, J=6.0 Hz, 1H), 4.27 (q, J=7.2 Hz, 2H), 4.13 (bs, 4H), 4.00 (bs, 2H), 3.89 - 3.79 (m, 4H),2.79 (s, 3H), 2.70 (t, J=8.4 Hz, 2H), 2.03 (m, 3H), 1.55 - 1.42 (m, 2H), 1.34 (t, J=7.2 Hz, 3H).LCMS (ESI) m / z calcd for C22H29CIN4O4S 480.16 found 481.2 [M+H]+.Example 11 - 2-((5-Cyclopropylisoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-onePreparation of 2-((5-cyclopropylisoindolin-2-yl)methyl)-3-ethyl-5-((1- (methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-oneTo a solution of 2-((5-bromoisoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin- 4-yl)methoxy)pyrimidin-4(3H)-one (60.0 mg, 0.114 mmol, 1.0 eq) and cyclopropylboronic acid (29.0 mg, 0.338 mmol, 3.0 eq) in Toluene (1.5 mL) and H2O (0.3 mL) was added K3PO4(121 mg, 0.570 mmol, 5.0 eq), PCy3(6.00 mg, 0.023 mmol, 0.2 eq) and palladium (II) acetate (5.00 mg, 0.023 mmol, 0.2 eq) under N2. The mixture was stirred at 100 °C for 3 h. Water (10 mL) was added, and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by column chromatography (DCM : MeOH = 10 : 1) and triturated with petroleum ether : DCM = 5 : 1 (1 mL) to give desired 2-((5-cyclopropylisoindolin-2- yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one (15.0 mg, 27.2% yield) as a white solid.1HNMR (300MHz, CDCI3) δ(ppm) 7.39 (s, 1H), 7.20 (d, J= 7.8 Hz, 1H), 7.11 (d, J= 7.8 Hz, 1H), 7.01 (s, 1H), 4.86 (bs, 4H), 4.56 (bs, 2H), 3.97 (bs, 2H), 3.88 - 3.81 (m, 4H), 2.79 (s, 3H), 2.70 (t, J = 11.4 Hz, 2H), 2.07 - 1.90 (m, 4H), 1.50 - 1.40 (m, 2H), 1.32 (m, 3H), 1.13 - 0.92 (m, 2H), 0.72 - 0.67 (m, 2H). LCMS (ESI) m / z calcd for C25H34N4O4S 486.23 found 487.2 [M+H]+.Example 12 - 2-(lsoindolin-2-ylmethyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one2-(Isoindolin-2-ylmethyl)-5 -((2-(m ethyl sulfonyl)-2-azaspiro [3.3 ]heptan-6-y l)methoxy)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one was prepared by using the same procedure as the preparation of 3-ethyl-2-(isoindolin-2-ylmethyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6- yl)methoxy)pyrimidin-4(3H)-one except that 3-ethyl-5-hydroxy-2-(isoindolin-2- ylmethyl)pyrimidin-4(3H)-one was replaced with 5-hydroxy-2-(isoindolin-2-ylmethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one .1HNMR (400MHz, CDCI3) δ(ppm) 7.37 (s, 1H), 7.24 - 7.20 (m, 4H), 5.29 (q, J=8.4 Hz, 2H), 4.07 (bs, 6H), 3.98 - 3.87 (m, 6H), 2.84 (s, 3H), 2.78 - 2.64 (m, 1H), 2.46 - 2.37 (m, 2H), 2.22 - 2.14 (m, 2H). LCMS (ESI) m / z calcd for C23H27F3N4O4S 512.17 found 513.2 [M+H]+.Example 13 - 2-((5-Chloroisoiadolin-2-yl)methyl)-5-( 1-(methylsulfonyl)piperidin-4-yl)methoxy)- 3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one2-((5-Chloroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one was prepared by using the same procedure as in the preparation of 2-(isoindolin-2-ylraethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-One except that isoindoline was replaced with 5-cholor isoindoline.1HNMR (400MHz, CDCI3) δ(ppm) 7.45 - 7.38 (m, 2H), 7.34 (s, 1H), 7.28 - 7.26 (m, 1H), 4.98 - 4.71 (bs, 6H), 4.61 (bs, 2H), 3.93 - 3.79 (m, 4H), 2.80 (s, 3H), 2.70 (t, J=11.2 Hz, 2H), 2.08 - 1.98 (m, 3H), 1.52 - 1.42 (m, 2H). LCMS (ESI) m / z calcd for C22H26CIF3N4O4S 534.13 found 535.1 [M+H]+.Example 14 - 3-Ethyl-2-(1-(isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-onePreparation of 5-(benzyloxy)-2-ethylpyrimidin-4(3H?)-oneTo a solution of methyl 2-(benzyloxy)acetate (8.45 g, 46.9 mmol, 1.0 eq) and ethyl formate (4.17 g, 56.3 mmol, 1.2 eq) in THF (50 mL) was added NaH (60%) (2.43 g, 61.0 mmol, 1.3 eq) at 0 °C, the mixture was stirred at 50 °C for 1 h. Then the mixture was concentrated to give the oily residue. A solution of propionimidamide hydrochloride (5.00 g, 46.1 mmol, 1.0 eq) and EtONa (3.19 g, 46.9 mmol, 1.0 eq) in EtOH (50 mL) was stirred at room temperature for 45 min, the mixture was filtered to remove solid and was added the oily residue. The reaction mixture was stirred at 100 °C under N2overnight. TLC and LCMS showed the complete consumption of methyl 2-(benzyloxy)acetate. The mixture was quenched with water (50 mL), the aqueous layer was acidified with 1 N HCI until pH=4, the mixture was filtered to give the crude. The residue was purified by trituration using petroleum ether : EtOAc = 1 : 1 (10 mL) to give 5-(benzyloxy)-2- ethylpyrimidin-4(3H)-one (4.70 g, 43.5% yield) as a white solid1HNMR (400MHz, DMSO-d6) δ(ppm) 12.45 (s, 1H), 7.53 (s, 1H), 7.45 - 7.29 (m, 5H), 5.02 (s, 2H), 2.49 - 2.44 (m, 2H), 1.13 (t, J=7.6 Hz, 3H). LCMS (ESI) m / z calcd for C13H14N2O2 230.11 found 231. 1 [M+H]+.Preparation of 5-(benzyloxy)-2.3-diethylpyrimidin-4(3H)-oneTo a solution of 5~(benzyloxy )-2-ethylpyrimidin-4(.3H)-one (2.30 g, 9.99 mmol, 1.0 eq) in DMF (25 mL) was added CS2CO3 (6.51 g, 20.0 mmol, 2.0 eq) and Etl (1.56 g, 9.99 mmol, 1.0 eq) at 0 °C and the mixture was stirred at room temperature for 3 h under N2. TLC and LCMS showed the complete consumption of 5-(benzyloxy)-2-ethylpyrimidin-4(3H)-one The mixture was quenched with water (15 mL), extracted with EtOAc (15 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude product. The residue was purified by flash (EtOAc : petroleum ether = 0-50%) to give 5-(benzyloxy)-2,3-diethylpyrimidin-4(3H)-one (850 mg, 32.9% yield) as a white solid.1HNMR (400MHz, CDCI3) δ(ppm) 7.59 (s, 1H), 7.46 - 7.29 (m, 5H), 5.04 (s, 2H), 4.00 (q, J=7.2 Hz, 2H), 2.75 (q, J=7.2 Hz, 2H), 1.22 - 1.12 (m, 6H). LCMS (ESI) m / z calcd for C15H18N2O2 258.14 found 259.2 [M+H]+.Preparation of 5-(benzyloxy)-2-(1-bromoethyl)-3-ethylpyrimidin-4(3H)-oneA solution of 5-(benzyloxy)-2,3-diethylpyrimidin-4(3H)-one (700 mg, 2.71 mmol, 1.0 eq) and NaOAc (270 mg, 3.25 mmol, 1.2 eq) in AcOH (5 mL) was heated to 40 °C, Br2 (563 mg, 3.52 mmol, 1.3 eq) in AcOH (2 mL) was added dropwise at same temperature and the mixture was stirred at 40 °C for overnight. LCMS showed 50% product The mixture was quenched with water (5 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude product. The residue was purified by flash (EtOAc . petroleum ether = 0-35%) to give 5-(benzyloxy)-2-(1-bromoethyl)-3-ethylpyrimidin-4(3H)-one (370 mg, 40.5% yield) as a white solid.1HNMR (400MHz, DMSO-d6) δ(ppm) 7.72 (s, 1H), 7.54 - 7.30 (m, 5H), 5.46 (q, J=6.4 Hz, 1H), 5.10 (d, .J=1.2 Hz, 2H), 4.35 - 4.22 (m, 1H), 3.99 - 3.85 (m, 1H), 1.98 (t, J=7.2 Hz, 3H), 1 .27 (t, J=7.2 Hz, 3H). LCMS (ESI) m / z calcd for C15H17BrN2O2 336.05 found 337.1, 339.0 [M+H]+.Preparation of 5-(benzyloxy)-3-ethyl-2-(l -(isoindolin-2-yl)ethyl)pyrimidin-4(3H)-oneTo a solution of 5-(benzyloxy)-2-(1-bromoethyl)-3-ethylpyrimidin-4(3H)-one (250 mg, 0.741 mmol, 1.0 eq) and isoindoline (132 mg, 1.11 mmol, 1.5 eq) in DMF (3 mL) was added CS2CO3 (604 mg, 1.85 mmol, 2.5 eq) and the mixture was stirred at room temperature for 3 h. The mixture was quenched with water (5 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over ISfeSCL and concentrated to give the crude product. The residue was purified by flash (EtOAc : petroleum ether = 0- -50%) to give 5-(benzyloxy)-3- ethyl-2-(1-(isoindolin-2-yl)ethyl)pyrimidin-4(3H)-one (130 mg, 46.7% yield) as a white solid. LCMS (ESI) m / z calcd for C23H25N3O2 375.19 found 376.2 [M+H]1.Preparation of 3-ethy1-5-hvdroxy-2-(1-(isoindolin-2-yl)ethyl)pyrimidin-4(3H)-oneA solution of 5-(benzyloxy)-3-ethyl-2-(1-(isoindolin-2-yl)ethyl)pyrimidin-4(3H)-one (130 mg, 0.346 mmol, 1.0 eq) in 6 N HC1 (3 mL) was heated to 70 °C and stirred for 3 h. TLC and LCMS showed die complete consumption of 5-(benzyloxy)-3-ethyl-2-(1-(isoindolin-2- yl)ethyl)pyrimidin-4(3H)-one. The mixture was concentrated to give 3-ethyl-5-hydroxy-2-(1- (isoindolin-2-yl)ethyl)pyrimidin-4(3H)-one (90.0 mg, 91.1% yield) as a brown solid. LCMS (ESI) m / z calcd for C16H19N3O2 285.15 found 286.1 [M+H]+.Preparation of 3-ethyl-2-(1-(isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-oneTo a solution of 3-ethyl-5-hydroxy-2-(1-(isoindolin-2-yl)ethyl)pyrimidin-4(3H)-one (80.0 mg, 0.280 mmol, 1.0 eq) and (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (114 mg, 0.420 mmol, 1 .5 eq) in DMSO (2 mL) was added CS2CO3(228 mg, 0.700 mmol, 2.5 eq) and the mixture was heated to 80 °C under N2and stirred for 2 h. TLC and LCMS showed the complete consumption of 3-ethyl-5-hydroxy-2-(1-(isoindolin-2-yl)ethyl)pyrimidin-4(3H)-one. Water (5 mL) was added, and the mixture was extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4and concentrated to give the crude product. The residue was purified by C-18 flash (H2O ACN = 0-22% ) to give 3-ethyl-2-(1- (isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one (23.2 mg, 17.9% yield) as a white solid. 'HNMR (400MHz, DMSO-d6) δ(ppm) 7.58 (s, 1H), 7.26 - 7.15 (m, 4H), 4.32 (q, J=6.4 Hz, 1H), 4.26 - 4.12 (m, 2H), 4.01 (m, 2H), 3.86 (dd,J= 13.2, 8.8 Hz, 4H), 3.59 (d, J= 11.6 Hz, 2H), 2.86 (s, 3H), 2.74 (t, J=11.6 Hz, 2H), 1.86 (m, 3H), 1.39 (m, J=6.4 Hz, 3H), 1.36 - 1.26 (m, 2H), 1.22 (t, J=6.8 Hz, 3H). LCMS (ESI) m / z calcd for C23H32N4O4S 460.21 found 461.2 [M+H]+.Example 15 - 2-((5-Fluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)- 3-( 2, 2, 2-trifluoroethyl)pyrimidin-4(3H)-one2-((5-Fluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2.2,2- trifluoroetbyl)pyrimidin-4(3H)-one was prepared following the same procedures as die preparation of 3-ethyl-2-((5-fluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one except replacing 5-(benzyloxy)-2-(bromomethyl)-3- ethylpyrimidin-4(3H)-one with 5-(benzyloxy)-2-(bromomethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one.1HNMR (300MHz, CDCI3) δ(ppm) 7.38 (s, 1H), 7.33 - 7.26 (m, 1H), 7.16 - 7.01 (m, 2H), 4.81 (m, 6H), 4.59 (bs, 2H), 3.93 - 3.79 (m, 4H), 2.79 (s, 3H), 2.70 (t, J=11.1 Hz, 2H), 2.00 (m, 3H), 1.48 - 1.43 (m, 2H). LCMS (ESI) m / z calcd for C22H26F4N4O4S 518.16 found 519.1 [M+H]+.Example 16 - 2-(((2,3-Dihydro-lH-inden-2-yl)amir)o)methyl)-3-ethyl-5-((l-(methylsulfonyl)piperidm-4-yl)methoxy)pyrimidin-4(3H)-onePreparation of L3-dihydro-2H-inden-2-one oximeA mixture of l ,3-dihydro-2H-inden-2-one (1.00 g, 7.57 mmol, 1.0 eq) and hydroxylamine hydrochloride (657 mg, 9.46 mmol, 1.25 eq) in EtOH (10 mL) and H2O (10 mL) was stirred for 1.5 h at room temperature and for additional 2 h at 50 °C. The reaction mixture was cooled to room temperature. The precipitate formed was fdtered and washed with water (5 mL). The precipitate was recrystallized the with EtOH (10 mL) to give the product 1,3-dihydro-2H-inden-2-one oxime (250 mg, 22.5% yield) as a white solid. LCMS (ESI) m / z calcd for C9H9NO 147.07 found 148.2 [M+H]+.Preparation of 2,3 -dihydro- 1H-inden-2-amine hydrochlorideTo a solution of 1,3-dihydro-2H-inden-2-one oxime (140 mg, 0.951 mmol, 1.0 eq) in HCI- MeOH (3 mL) was added Pd / C (101 mg, 0.949 mmol, 1.0 eq), the reaction mixture was stirred at room temperature for 2 h under H2. The mixture was filtered, the filtrate was concentrated to give 2,3-dihydro-1H-inden-2-amine hydrochloride (130 mg, crude) as a white solid. LCMS (ESI) m / z calcd for C9H12CIN 169.07 found 134.2 [M-HC1+H]+.Preparation of 2-(((2,3-dihydro-1H-inden-2-yl)amino)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one2-(((2,3-Dihydro-1H-inden-2-yl)amino)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one was prepared following the same procedures as the preparation of 2-((5-bromoisoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one except replacing 5 -bromoisoindoline hydrochloride with 2,3- dihydro-lH-inden-2-amine hydrochloride.1HNMR (400MHz, DMSO-d6) δ (ppm) 7.52 (s, 1H), 7.22 - 7.15 (m, 2H), 7.14 - 7.06 (m, 2H), 4.08 (q, , / =7.2 Hz, 2H), 3.89 - 3.73 (m, 4H), 3.65 - 3.48 (m, 3H), 3.09 - 3.03 (m, 2H), 2.85 (s, 3H), 2.79 - 2.64 (m, 5H), 1.86 - 1.83 (m, 3H), 1.36 - 1.26 (m, 2H), 1.21 (t, . / =7 2 Hz, 3H). LCMS (ESI) m / z calcd for C23H32N4O4S 460.21 found 461.3 [M+H]+.Example 17 - 2-(((2,3-Dihydro-lH-mden-2-yl)(methyl)amino)methyl)-3-ethyl-5-((l-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-onePreparation of 2-(((2,3-dihvdro-lH-inden-2-yl)(methyl)amino)methyl)-3-ethy1-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-oneTo a solution of 2-(((2,3-dihydro-1H-inden-2-yl)amino)methyl)-3-ethyl-5-((1- (methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one (35.0 mg, 0.0760 mmol, 1.0 eq) in MeOH (1 mL) was added sodium cyanoborohydride (21.0 mg, 0.334 mmol, 4.5 eq), Formaldehyde (0.1 mL) and AcOH (0.1 mL), the mixture was stirred at room temperature for 2 h. Then the mixture was concentrated to give oily residue. The residue was purified by prep-HPLC (45-63- 100-9min-20mL / min lcc278 NH4HCO3) to give 2-(((2,3-dihydro-lH-inden-2- yl)(methyl)amino)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin- 4(3H)-one (2.50 mg, 6.93% yield) as a white solid.1HNMR (300MHz, CDCI3) δ (ppm) 7.35 (s, 1H), 7.22 - 7.13 (m, 4H), 4.38 (q, J=7.2 Hz, 2H), 3.91 - 3.78 (m, 4H), 3.61 (s, 2H), 3.49 - 3.40 (m, 1H), 3.16 - 3.04 (m, 2H), 3.00 - 2.88 (m, 2H), 2.79 (s, 3H), 2.75 - 2.64 (m, 2H), 2.21 (s, 3H), 2.12 - 1.93 (m, 3H), 1.59 - 1.43 (m, 2H), 1.35 (t, J=7.2 Hz, 3H). LCMS (ESI) m / z calcd for C24H34N4O4S 474.23 found 475.2 [M+H]+.Example 18 - 2-(5-Fluoroisoindolin-2-ylmethyl)-5-( (2-(methylsulfonyl)-2-azaspiro[3.3 ]heptan-6- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-onePreparation of 2-((5-fluoroisoindolin-2-yl)methyl)-5-((2-(methylsulfonyl)-2-azaspiror3.31heptan-6-yl)methoxy)-3-(2.2.2-trifluoroethyl)pyrimidin-4(3H)-one2-((5-Fluoroisoindolin-2-yl)methyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one was prepared by using the same procedure as the preparation of 3-ethyl-2-(isoindolin-2-ylmethyl)-5-((2-(methylsulfonyl)-2- azaspiro[3.3]heptan-6-yl)methoxy)pyrimidin-4(3H)-one except that 3-ethyl-5-hydroxy-2- (isoindolin-2-ylmethyl)pyrimidin-4(3H)-one was replaced with 2-((5-fluoroisoindolin-2- yl)methyl)-5-hydroxy-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one. .1HNMR (400 MHz, DMSO) δ 7.57 (s, 1H), 7.24 (dd, J=8.4, 5.2 Hz, 1H), 7.09 (dd,J= 8.8, 2.0 Hz, 1H), 7.05 - 6.97 (m, 1H), 5.21 (q,J=9.2 Hz, 2H), 3.92 - 3.91 (m, 6H), 3.88 (brs, 4H), 3.83 (s, 2H), 2.94 (s, 3H), 2.62 - 2.53 (m, 1H), 2.34 - 2.31 (m, 2H), 2.08 - 2.00 (m, 2H). LCMS (ESI) m / z calcd for C23H26F4N4O4S 530.16 found 531.0 [M+H]+.Example 19 - 3-Ethyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)isoindolm-2-yl)methyl)pyrimidin-4(3H)-onePreparation of 5-(trifluoromethyl)isobenzofuran-1,3-dioneA solution of 4-(trifluoromethyl)phthalic acid (2.00 g, 8.54 mmol, 1.0 eq) in SOCh (10 mL) was stirred at 50 °C for 3 h under N2. The mixture was cooled and concentrated to give the 5- (trifluoromethyl)isobenzofuran-1,3-dione (1.80 g, 97.5% yield) as a white solid, which was used for next step directly without further purification.1HNMR (400MHz, DMSO-de) 8(ppm) 8.50 (s, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.29 (d, J=8.0 Hz, 1H).Preparation of 3-ethyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5- (trifluoromethyl)isoindolin-2-yl)methyl)pyrimidin-4(3H)-one3-Ethy1-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)isoindolin-2- yl)methyl)pyrimidin-4(3H)-one was prepared following the same procedure as parathion of 3- ethyl-2-((5-fluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one except that 5-(trifluoromethyl)isobenzofuran-1,3-dione was used instead of 5-fluoroisobenzofuran-1,3-dione.1HNMR (300MHz, CDCI3) δ (ppm) 7.50 (d, J-7.8 Hz, 1H), 7.46 (s, H), 7.38 (s, 1H), 7.31 (d, J=7.8 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 4.14 (brs,4H), 3.99 (brs, 2H), 3.93 - 3.78 (m, 4H), 2.79 (s, 3H), 2.76 - 2.64 (m, 2H), 2.05 - 2.01 (tn, 3H), 1.56 - 1.42 (m, 2H), 1.35 (t, J=6.9 Hz, 3H). LCMS (ESI) m / z calcd for C23H29F3N4O4S 514.19 found 515.2 [M+H]+.Example 20 - 2-((5-(Difluoromethyl)isoindolin-2-yl)methyl)-3-ethyl-5-((l-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-onePreparation of tert-butyl 5-bromoisoindoline-2-carboxylateTo a solution of 5-bromoisoindoline (3.00 g, 15.1 mmol, 1.0 eq) in THF (30 mL) and water (5 mL) was added saturated Na2SO4(5 mL) and (Boc)2O (14.1 g, 64.5 mmol, 4.0 eq) and the mixture was stirred at room temperature for 2 h. TLC and LCMS showed the complete consumption of 5- bromoisoindoline. The mixture was quenched with water (20 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude product. The residue was purified by flash (EtOAc : petroleum ether = 0- 10%) to give tert-butyl 5-bromoisoindoline-2-carboxylate (3.40 g, 75.3% yield) as a colorless oil.1HNMR (400MHz, DMSO-d6) δ(ppm) 7.55 (d,J=4.4 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.28 (dd,J= 8.0, 4.0 Hz, 1H),4.63 - 4.47 (m, 4H), 1.45 (s, 9H). LCMS (ESI) m / z calcd for Ci3Hi6BrNO2297.04 found 242.1 , 244.0 [M-56+H]+.Preparation of tert-butyl 5-vinylisoindoline-2-carboxylateTo a solution of tert-butyl 5-bromoisoindoline-2-carboxylate (1.86 g, 6.23 mmol, 1.0 eq) in dioxane (15 mL) and H2O (3 mL) was added potassium trifluoro(vinyl)borate (1.00 g, 7.47 mmol, 1.2 eq), K2CO3(1.73 g, 12.5 mmol, 2.0 eq) and Pd(dppf)CI2(457 mg, 0.624 mmol, 0.1 eq) and the mixture was heated to 80 °C and stirred for 3 h under N2. TLC and LCMS showed the complete consumption of tert-butyl 5-bromoisoindoline-2-carboxylate The mixture was quenched with water (15 mL), extracted with EtOAc (15 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude product. The residue was purified by flash (EtOAc : petroleum ether = 0-9%) to give tert-butyl 5-vinylisoindoline-2-carboxylate (980 mg, 64.0% yield) as a yellow oil. LCMS (ESI) m z calcd for C15H19NO2245.14 found 190.1 [M-56+H]+.Preparation of tert-butyl 5-formylisoindoline-2-carboxylateTo a solution of tert-butyl 5-vinylisoindoline-2-carboxylate (1.00 g, 4.07 mmol, 1.0 eq) in dioxane (5 mL) and H2O (4 mL) was added NaIO4(1.76 g, 8.15 mmol, 2.0 eq) and K2OSO4(127 mg, 0.41 mmol, 0.1 eq) and the mixture was stirred at room temperature for 3 h. TLC and LCMS showed the complete consumption of tert-butyl 5-vinylisoindoline-2-carboxylate. The mixture was quenched with water (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude product. The residue was purified by flash (EtOAc . petroleum ether = 0-10%) to give tert-butyl 5-formylisoindoline-2-carboxylate (410 mg, 40.7% yield) as a white solid. 'HNMR (400MHz, CDCI3) δ(ppm) 10.01 (s, 1H), 7.78 (t,J=\ 1 .6 Hz, 2H), 7.41 (dd,J=22.0, 8.0 Hz, 1H), 4.73 (d, J=14.4 Hz, 4H), 1 .52 (s, 9H). LCMS (ESI) m / z calcd for C14H17NO3 247.12 found 192.1 [M-56+H]+.Preparation of tert-butyl 5-(difluoromethyl)isoindoline-2-carboxylateTo a solution of tert-butyl 5-formylisoindoline-2-carboxylate (410 mg, 1.66 mmol, 1.0 eq) in DCM (5 mL) was added EtOH (7.65 mg, 0.166 mmol, 0.1 eq) and DAST (1.34 g, 8.29 mmol, 5.0 eq) and the mixture was stirred at room temperature for overnight. TLC and LCMS showed the complete consumption of tert-butyl 5-formylisoindoline-2-carboxylate. The mixture was quenched with water (5 mL), extracted with DCM (5 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude product. The residue was purified by flash (EtOAc . petroleum ether = 0 ' 10%) to give tert-butyl 5-(difluoromethyl)isoindoline-2-carboxylate (276 mg, 61.8% yield) as a yellow oil.1HNMR (400 MHz, CDCI3) δ(ppm) 7.49 - 7.27 (m, 3H), 6.64 (t,J= 56.4 Hz, 1H), 4.70 (d,J= 14.4 Hz, 4H), 1.52 (s, 9H). LCMS (ESI) m / z calcd for C14H17F2NO2 269.12 found 214.1 [M-56+H]+.Preparation of 5-(difluoromethyl)isoindoline 2,2,2-trifluoroacetateTo a solution of tert-butyl 5-(difluoromethyl)isoindoline-2-carboxylate (285 mg, 1.06 mmol, 1.0 eq) in DCM (4 mL) was added TFA (2 mL) and the mixture was stirred at room temperature for 3 h. TLC and LCMS showed the complete consumption of 5-(difluoromethyl)isoindoline-2- carboxylate. The mixture was concentrated to give 5-(difluoromethyl)isoindoline 2,2,2- trifluoroacetate (230 mg, 76.7% yield) as a brown oil, which was used without further purification.1HNMR (400 MHz, DMSO-d6) δ(ppm) 9.55 (s, 1H), 7.70 - 7.50 (m, 3H), 7.08 (t, J=55.6 Hz, 1H), 4.57 (s, 4H). LCMS (ESI) m / z calcd for C11H10F5NO2 283.06 found 170.1 [M-TFA+H]+.Preparation of 2-((5-(difluoromethyl)isoindolin-2-yl)methyl)-3-ethyl-5-((1- (methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one2-((5-(Difluoromethyl)isoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one was prepared by following the same procedures as the preparation of 3-ethyl-2-((5-fluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one except that 5-(difluoromethyl)isoindoline 2,2,2-trifluoroacetate was used instead of 5-fluoroisoindoline.1HNMR (400MHz, DMSO-d6) δ(ppm) 7.66 (s, 1H), 7.63 (s, 1H), 7.63 - 7.49 (m, 2H), 7.09 (t, J=55.6 Hz, 1H), 4.95 - 4.75 (m, 5H), 3.95 - 3.85 (m, 4H), 3.60 - 3.45 (m, 6H), 2.86 (s, 3H), 2.74 (t, J=11.2 Hz, 2H), 1.95 - 1.80 (m, 3H), 1.38 - 1.30 (m, 2H), 1.23 (t, J=7,2 Hz, 3H). LCMS (ESI) ndz calcd for C23H30F2N4O4S 496.20 found 497.2 [M+H]+.Example 21 - 2-(((4-Chlorobenzyl)(methyl)amino)methyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one2-(((4-chlorobenzyl)(methyl)amino)methyl)-5-((1-(rnethylsulfonyl)piperidin-4-yl)methoxy)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one was prepared by following the same procedures as the preparation of 2-(((2,3-dihydro-1H-inden-2-yl)(methyl)amino)methyl)-3-ethyl-5-((1- (methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one except replacing 2, 3 -dihydro- 1H- inden-2-amine hydrochloride with 4-chlorobenzyl amine and 5-(benzyloxy)-2-(bromomethyl)-3- ethylpyrimidin-4(3H)-one with 5-(benzyloxy)-2-methyl-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)- one.1HNMR (400MHz, CDCI3) δ(ppm) 7.33 - 7.27 (m, 3H), 7.20 (brs, 2H), 5.17 (brs, 2H), 3.86 (d, J=11.2 Hz, 2H), 3.80 (d, J=4,0 Hz, 2H), 3.63 (brs, 4H), 2.79 (s, 3H), 2.69 (t, J=11.6 Hz, 2H), 2.31 (brs, 2H), 2.02 - 1.99 (m, 4H), 1.44 - 1.42 (m, 2H). LCMS (ESI) m / z calcd for C22H28CIF3N4O4S 536.15 found 537.2 [M+H]+.Example 22 and Example 23 - (R)-2-(1 -(5-Chloroisoindolin-2-yl)ethyl)-5-((1- (methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2-triflnoroethyl)pyrimidin-4(3H)-one and (S)-2- (1-(5-chloroisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-onePreparation of 5-(benzyloxy)-2-ethyl-3-(2.2.2-trifluoroethyl)pyrimidin-4(3H)-one5-(Benzyloxy)-2-ethyl-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one was prepared by following the same procedure as the preparation of 5-(benzyloxy)-2-methyl-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one except replacing 5-(benzyloxy)-2-methylpyrimidin-4(3H)- one with 5-(benzyloxy)-2-ethylpyrimidin-4(3H)-one.1HNMR (400MHz, DMSO) δ(ppm) 7.65 (s, 1H), 7.48 - 7.31 (m, 5H), 5.07 (s, 2H), 4.98 (q, J = 9.2 Hz, 2H), 2.75 (q, J = 7.2 Hz, 2H), 1.17 (t, J= 7.2 Hz, 3H). LCMS (ESI) ndz calcd for C15H15F3N2O2312.11 found 313.1 [M+H]+.Preparation of 5-(benzyloxy)-2-(1-bromoethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one5-(Benzyloxy)-2-(1-bromoethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one was prepared by following the same procedure as the preparation of 5-(benzyloxy)-2-(1-bromoethyl)-3- ethylpyrimidin-4(3H)-one except replacing 5-(benzyloxy)-2,3-diethylpyrimidin-4(3H)-one with 5-(benzyloxy)-2-ethyl-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one.1HNMR (400MHz, CDCI3) δ(ppm) 7.47 (s, 1H), 7.45 - 7.31 (m, 5H), 5.57 - 5.42 (m, 1H), 5.15 (s, 2H), 4.93 (q, J=6.4 Hz, 1H), 4.51 - 4.38 (m, 1H), 2.05 (d, J=6.4 Hz, 3H). LCMS (ESI) m / z calcd for C15H14BrF3N2O2 309.02 found 309.9 [M+H] +.Preparation of 2-(1-(5-chloroisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one2-(1-(5-Chloroisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one was prepared by following the same procedures in the preparation of 3-ethyl-2-(1-(isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one except replacing 5-(benzyloxy)-2-(1-bromoethyl)-3- ethylpyrimidin-4(3H)-one with 5-(benzyloxy)-2-(1-bromoethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one and isoindoline with 5 -chloroisoindoline hydrochloride.The racemic mixture was separated by SFC to give (R)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-5- ((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (fast eluted isomer) and (S)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-5-((l -(methyl sulfonyl )piperidin-4- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one. Chiral separation condition: Apparatus: Waters SFC; Column: CHIRALCEL OD-H 30mm x 250mm, 5um; Mobile phase: CCh / MeOH (0.1DEA in MeOH)=70 / 30; Flow rate: 30mL / min; Wavelength: UV 254 nm; Temperature: 35 °C.(R)-2-(1-(5-Chloroisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one.1HNMR (400MHz, CDCI3) δ(ppm) 7.41 (s, 1H), 7.24 - 7.17 (m, 2H), 7.14 - 7.08 (m, 1H), 5.23 - 5.09 (m, 2H), 4.29 (brs, 1H), 4.07 (brs, 2H), 3.94 -3.75 (tn, 6H), 2.79 (s, 3H), 2.73 - 2.67 (m, 2H), 2.06 - 1 .99 (m, 3H), 1 .49 - 1 .25 (tn, 5H). LCMS (ESI) m z calcd for C23H28CIF3N4O4S 548.15 found 549.2 [M+H]+.(S)-2-(1-(5-Chloroisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one. 'HNMR (400MHz, CDCI3) δ(ppm) 7.41 (s, 1H), 7.24- 7.08 (m, 3H), 5.20 -5.13 (m, 2H), 4.29 (brs, 1H), 4.07 (brs, 2H), 3.94 - 3.75 (m, 6H), 2.79 (s, 3H), 2.70 (t, J = 11.6 Hz, 2H), 2.06 - 1.99 (m, 3H), 1.49 - 1.25 (m, 5H). LCMS (ESI) m z calcd for C23H28CIF3N4O4S 548.15 found 549.2 [M+H]+.Example 24 - 3-Ethyl-2-((2-methoxy-5, 7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-5-((l- (methylsulfonyl)piperidm-4-yl)methoxy)pyrimidin-4(3EI)-onePreparation of 5-methoxy-2,3-dimethylpyrazineTo a solution of 5-chloro-2,3-dimethylpyrazine (3.70 g, 26.0 mmol, 1.0 eq) in MeOH (55 mL) was added NaOMe (39.0 mL, 2 N in MeOH, 78.0 mmol, 3.0 eq) and the mixture was heated to 65 °C for overnight. HPLC and LCMS showed the complete consumption of 5-chloro-2,3- dimethylpyrazine The mixture was quenched with water (40 mL), extracted with DCM (40 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give 5-methoxy-2,3- dimethylpyrazine (3.40 g, 97.6% yield) as a yellow oil, which was used for next step directly without further purification.1HNMR (400MHz, DMSO-d6) δ(ppm) 7.97 (s, 1H), 3.85 (s, 3H), 2.39 (s, 3H), 2.38 (s, 3H).Preparation of 2,3-bis(bromomethyl )-5-methoxypyrazineTo a solution of 5-methoxy-2,3-dimethylpyrazine (3.50 g, 25.3 mmol, 1.0 eq) in CCI4 (45 mL) was added AIBN (416 mg, 2.53 mmol, 0.1 eq) and NBS (13.5 g, 75.9 mmol, 3.0 eq) and the mixture was heated to 80 °C for overnight. TLC and LCMS showed the complete consumption of 5-methoxy-2,3-dimethylpyrazine. The mixture was filtered, and filtrate was concentrated to give the crude. The residue was purified by flash (EA: PE =0 - 10%) to give 2,3-bis(bromomethyl)-5- methoxypyrazine as a brown oil (2.1 g, 28.0% yield) LCMS (ESI) m / z calcd for CrHgB^^O 295.90 found 294.9, 296.9 [M+H]+.Preparation of 2-methoxy-6-trity1-6,7-dihydro-5H-pyrrolo[3.4-b1pyrazineTo a solution of 2,3-bis(bromomethyl)-5-methoxypyrazine (2.10 g, 7. 10 mmol, 1.0 eq) in DMF (20 mL) was added DIEA (2.75 g, 21.3 mmol, 3.0 eq) and Tritylamine (2.02 g, 7.81 mmol, 1.1 eq) and the mixture was heated to 60 °C for 2 h. TL C and LCMS showed the complete consumption of 2,3-bis(bromomethyl)-5-methoxypyrazine. The mixture was quenched with water (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude product. The residue was purified by flash (EtOAc : petroleum ether=0 -10%) to give 2-methoxy-6-trity1-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine as a white solid (1.0 g, 35.7% yield).1HNMR (400MHz, DMSO-d6) δ(ppm) 7.96 (s, 1H), 7.51 (d, J=1.6 Hz, 6H), 7.34 (t, J=7,6 Hz, 6H), 7.20 (t, J=7.2 Hz, 3H), 3.94 (s, 4H), 3.80 (s, 3H).Preparation of 2.2.2-trifluoroacetaldehyde compound with 2-methoxy-6,7-dihydro-5H- pyrrolo[3,4-b]pyrazine (1 : 1)To a solution of 2-methoxy-6-trity1-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (500 mg, 1.27 mmol, 1.0 eq) in MeOH (2 mL) and CH3CI (2 mL) was added TFA (2 mL) at 0 °C and the mixture was stirred at room temperature for 1 h. TLC and LCMS showed the complete consumption of 2- methoxy-6-trity1-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine. The mixture was quenched with water (5 mL), extracted with DCM (5 mL x 3). The aqueous layer was concentrated to give 2,2,2- trifluoroacetaldehyde compound with 2-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (1 : 1) (310 mg, 98.1% yield) as a brown solid.1HNMR (300 MHz, DMSO-d6) δ(ppm) 10.04 (s, 2H), 8.28 (s, 1H), 4.54 (d, J=6.3 Hz, 4H), 3.93 (s, 3H). LCMS (ESI) m / z calcd for C9H10F3N3O2249.07 found 152.1 [M-TFA+H]+.Preparation of 3-ethy1-2-((2-methoxy-5,7-dihvdro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-5-((1- (methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one3-Ethy1-2-((2-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-5-((1- (methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one (10.0 mg, 13.9% yield) as a white solid.1HNMR (400MHz, DMSO-d6) δ(ppm) 8.21 (s, 1H), 7.58 (s, 1H), 4.58 - 4.39 (m, 3H), 4.10 (d, J=6.0 Hz, 1H), 4.05 - 3.96 (m, 3H), 3.91 (s, 3H), 3.86 (d, J=6.0 Hz, 2H), 3.62 - 3.54 (m, 3H), 2.85 (s, 3H), 2.78 - 2.65 (m, 2H), 1.94 - 1.74 (m, 3H), 1.40 - 1.28 (m, 2H), 1.23 (t, J=7.2 Hz, 3H). LCMS (ESI) m / z calcd for C21H30N6O5S 478.20 found 479.2 [M+H]+.Example 25 - (S)-2-( 1 -(5-Fluoroisomdolm-2-yl)ethyl)-5-(( 1 -(methylsulfonyl)piperidin-4- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidm-4(3H)-oneTo a solution of 5 -fluoroisobenzofuran- 1,3 -di one (1.00 g, 6.02 mmol, 1.0 eq) in THF (10 mL) was added LAH (457 mg, 12.0 mmol, 2.0 eq) at 0 °C and the mixture was stirred at room temperature for 2 h. The mixture was quenched with water (0.45 mL), 15% NaOH (0.45 mL), water (1.35 mL) and dried over NazSCL for 15 min, filtered and filtrate was concentrated to give (4-fluoro-1,2-phenylene)dimethanol (920 mg, 97.8% yield) as a colorless oil which was used directly for next step without further purification.1HNMR (400MHz, CDCI3) δ (ppm) 7.23 - 7.20 (m, 1H), 6.99 (dd, J=9.2, 2.8 Hz, 1H), 6.94-6.88 (m, 1H), 4.57 (s, 2H), 4.55 (s, 2H), 3.53 (s, 2H). Preparation of 1,2-bis(bromomethyl)-4-fluorobenzeneThe solution of (4-fluoro-1,2-phenylene)dimethanol (920 mg, 5.33 mmol, 1.0 eq) in 48% aq. HBr (15 mL) was heated to 135 °C for 3 h. The mixture was quenched with water (10 mL),extracted with EtOAc (15 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude product. The residue was purified by flash chromatography (EtOAc : petroleum ether =0 -5%) to give 1,2-bis(bromomethyl)-4-fluorobenzene (1.12 g, 67.4% yield) as a white solid.1HNMR (300MHz, CDCI3) 6 δ (ppm) 7.34 (m, 1H), 7.09 (dd, J=9.0, 3.6 Hz, 1H), 7.04-6.95 (m, 1H), 4.62 (s, 2H), 4.60 (s, 2H).Preparation of 5-(benzyloxy)-2-(l -hydroxyethyl)-3-(2.2.2-trifluoroethyl)pyrimidin-4(3H)-oneThe solution of 5-(benzyloxy)-2-(1-bromoethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (5.72 g, 14.6 mmol, 1.0 eq) in DMSO (60 mL) and H2O (10 mL) was heated to 90 °C for 2 h. The mixture was quenched with water (30 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (50 mL x 2), brine (50 mL x 2), dried over Na2SO4and concentrated to give 5 -(benzyloxy)-2-(1-hydroxyethyl)-3 -(2,2, 2-trifluoroethyl)pyrimidin-4(3H)- one (4.40 g, 91.7% yield) as a colorless oil which was used directly for next step without further purification. LCMS (ESI) m / z calcd for C15H15F3N2O3 328.10 found 329.1 [M+H]+.Preparation of 2-acety1-5-(benzyloxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-oneTo a solution of 5-(benzyloxy)-2-(1-hydroxyethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (3.74 g, 11.4 mmol, 1.0 eq) in DCM (50 mL) was added Dess-martin (7.25 g, 17.1 mmol, 1.5 eq) and the mixture was stirred at room temperature for 3 h. The resulting mixture was quenched with 10% Na2S2Ch (50 mL) and saturated NaHCO3(50 mL), extracted with DCM (50 mL x 2). The combined organic layers were dried over Na2SO4and concentrated to give the crude product. The residue was purified by flash (EtOAc : petroleum ether = 0-20%) to give 2-acety1-5-(benzyloxy)- 3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (2.52 g, 68.7% yield) as a white solid.1HNMR (400 MHz, DMSO-d6) δ(ppm) 7.85 (s, 1H), 7.50-7.36 (m, 5H), 5.30-5.16 (m, 4H), 2.58 (s, 3H). LCMS (ESI) m / z calcd for C15H13F3N2O3 326.09 found 327.0 [M+H]+.Preparation of (S,E)-N-(1 -(5-(benzyloxy)-6-oxo-1 -(2,2,2-trifluoroethyl)- 1,6-dihydropyrimidin-2- yl)ethylidene)-2-methylpropane-2-sulfinamideTo a solution of 2-acety1-5-(benzyloxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (2.27 g, 6.96 mmol, 1.0 eq) in THF (25 mL), S)-(-)-2-Methyl-2-propanesulfinamide (1.01 g, 8.35 mmol, 1.2 eq) and Titanium ethoxide(3.18 g, 13.9 mmol, 2.0 eq) were added and the mixture was heated to 68 °C for overnight. The mixture was quenched with water (8 mL), filtered and filtrate was concentrated to give the crude product. The residue was purified by flash (EtOAc : petroleum ether0 -25%) to give (S,E)-N-(1-(5-(benzyloxy)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6- dihydropyrimidin-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (2.08 g, 69.6% yield) as a yellow oil.1HNMR (400 MHz, DMSO-d6) δ(ppm) 7.82 (s, 1H), 7.50-7.36 (m, 5H), 5.43-5.22 (m, 1H), 5.17 (s, 2H), 2.64 (s, 3H), 1.19 (s, 9H). LCMS (ESI) m z calcd for C19H22F3N3O3S 429.13 found 430.1 [M+H]+.Preparation of (S)-N-((S)-1-(5-(benzyloxy)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyrimidin- 2-yl)ethyl)-2-methylpropane-2-sulfinamideTo a solution of (S,E)-N-(1-(5-(benzyloxy)-6-oxo-1-(2,2,2-trifhioroethyl)-l,6- dihydropyrimidin-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (960 mg, 2.24 mmol, 1.0 eq) in THF (10 mL) and H2O (0.5 mL), NaBIL* (257 mg, 6.78 mmol, 3.0 eq) was added at -50 °C and the mixture was stirred at room temperature for 3 h, then was concentrated to give the crude product. The residue was purified by flash (EtOAc : petroleum ether = 0-43%) to give (S)-N-((S)- 1 -(5-(benzyloxy)-6-oxo- 1 -(2,2,2-trifluoroethyl)- 1 ,6-dihy dropyrimidin-2-yl)ethyl)-2- methylpropane-2-sulfmamide (460 mg, 47.6% yield) as a yellow oil.1HNMR (400 MHz, DMSO- d6) δ(ppm) 7.72 (s, 1H), 7.47-7.35 (m, 5H), 5.25-5.13 (m, 1H), 5.11 (s, 2H), 5.06-4.94 (m, 1H),4.57-4.46 (m, 1H), 1 .47 (d, J=6.4 Hz, 3H), 1 .06 (s, 9H). LCMS (ESI) m / z calcd for C19H24F3N3O3S431.15 found 432.2 [M+H]+.Preparation of (S)-2-(1-aminoethyl)-5-(benzyloxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-oneTo a solution of (S)-N-((S)-1-(5-(benzyloxy)-6-oxo-1-(2,2,2-trifhioroethyl)-l,6- dihydropyrimidin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (450 mg, 1.04 mmol, 1.0 eq) in DCM (4 mL) was added 4 N HCl / dioxane (2 mb) at 0 °C and the mixture was stirred at room temperature for 2 h. The mixture was concentrated to give (S)-2-(1-aminoethyl)-5-(benzyloxy)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one hydrochloride (370 mg, 97.9% yield) as a brown solid which was used directly for next step without further purification. LCMS (ESI) m / z calcd for C15H17CIF3N3O2 363.10 found 328.1 [M-HC1+H]+.Preparation of (S)-5-(benzyloxy)-2-(1-(5-fluoroisoindolin-2-yl)ethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-oneTo a solution of (S)-2-(1-aminoethyl)-5-(benzyloxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)- one hydrochloride (200 mg, 0.55 mmol, 1.0 eq) in DMF (5 mL) was added DIEA (355 mg, 2.75 mmol, 5.0 eq) and l,2-bis(bromomethyl)-4-fluorobenzene (172 mg, 0.61 mmol, 1.1 eq) and the mixture was heated to 60 °C for 2 h. The resulting mixture was quenched with water (5 mL), extracted with EtOAc (5 mL x 3). The combined organic layers were washed with water (10 mL x 2), brine (10 mL x 2), dried over Na2SO4and concentrated to give the crude product. The residue was purified by flash (EtOAc : petroleum ether = 0-20%) to give (S)-5-(benzyloxy)-2-(1-(5- fluoroisoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (98.0 mg, 22.0% yield) as a brown oil. LCMS (ESI) m / z calcd for C23H21F4N3O2 447.16 found 448.2 [M+H]+.Preparation of (S)-2-(1 -(5-fluoroisoindolin-2-yl)ethyl)-5-((1 -(methylsulfonyl)piperidin-4- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one(S)-2-(1 -(5-Fluoroisoindolin-2-yl)ethyl)-5-((1 -(methyl sulfonyl )piperidin-4-yl)methoxy)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one was prepared by using the same procedures as in the preparation of 2-((5-bromoisoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one except that 5-(benzyloxy)-2-((5-bromoisoindolin-2-yl)methyl)- 3-ethylpyrimidin-4(3H)-one was replaced with (S)-5-(benzyloxy)-2-(1-(5-fluoroisoindolin-2- yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one.1HNMR (400MHz, DMSO-d6) δ (ppm) 7.63 (s, 1H), 7.25 - 7.21 (m, 1H), 7.08 - 7.05 (m, 1H), 7.00 (t, J=8.0 Hz, 1H), 5.28-5.06 (m, 2H), 4.35-4.27 (m, 1H), 4.06-3.94 (m, 2H), 3.92-3.78 (m, 4H), 3.63-3.55 (m, 2H), 2.85 (s, 3H), 2.80- 2.68 (m, 2H), 1.93 - 1.80 (m, 3H), 1.40 - 1.27 (m, 5H). LCMS (ESI) Wz calcd for C23H28F4N4O4S 532.18 found 533.2 [M+H]+.Example 26 - (S)-2-( I -(Isoindolin-2-yl)ethyl)-5-( < I -(methylsulfonyl)piperidin-4-yl)methoxy)-3- (2, 2, 2-trifluoroethyl)pyrimidin-4(3H)-onePreparation of (S)-5-(benzyloxy)-2-(1-(isoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one(S)-5-(Benzyloxy)-2-(1-(isoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one was prepared by using the same procedures as in the preparation of (S)-5-(benzyloxy)-2-(1-(5- fluoroisoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one except that 1,2- bis(bromomethyl)benzene was used instead of 1,2-bis(bromomethyl)-4-fluorobenzene. LCMS (ESI) m / z calcd for C23H22F3N3O2 429.17 found 430.1 [M+H]1.Preparation of (S)-2-(1 -(isoindolin-2-yl)ethyl)-5-((1 -(methylsulfonyl)piperidin-4-yl)methoxy)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one(S)-2-(1-(Isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one was prepared by using the same procedures as in the preparation of 2-((5-bromoisoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one except that 5-(benzyloxy)-2-((5-bromoisoindolin-2-yl)methyl)- 3-ethylpyrimidin-4(3H)-one was replaced with (S)-5-(benzyloxy)-2-(1-(isoindolin-2-yl)ethyl)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one.1HNMR (400MHz, DMSO-d6) δ (ppm) 7.63 (s, 1H), 7.25-7.15 (m, 4H), 5.28-5.09 (m, 2H), 4.35-4.27 (m, 1H), 4.06-3.94 (m, 2H), 3.92-3.82 (m, 4H), 3.64-3.54 (m, 2H), 2.85 (s, 3H), 2.80-2.69 (m, 2H), 1.93-1.81 (m, 3H), 1.37 (d, J=6.4 Hz, 3H), 1.35-1.26 (m, 2H). LCMS (ESI) m / z calcd for C23H28F4N4O4S 514.19 found 515.2 [M+H]+.Example 27 - (S)-5-( ( I -Acetylpiperidin-4-yl)methoxy)-2-( 1 -(5-chloroisoindolin-2-yl)ethyl)-3- (2,2, 2-trifluoroethyl)pyrimidin-4 ( 3H) -onePreparation of l,2-bis(bromomethyl)-4-chlorobenzene1,2-Bis(bromomethyl)-4-chlorobenzene was synthesized by following the same procedure as in the preparation of l,2-bis(bromomethyl)-4-fluorobenzene except that 5-chloroisobenzofuran-1,3-dione was used instead of 5-fuloroisobenzofuran-l, 3-dione.1HNMR (300MHz, CDCI3) δ (ppm) 7.37 (d,J= 1.5 Hz, 1H), 7.34-7.26 (m, 2H), 4.61 (s, 2H), 4.59 (s, 2H).Preparation of tert-butyl 4-(hvdroxymethyl)piperidine-1-carboxylateTo a solution of piperidin-4-ylmethanol (1.00 g, 8.68 mmol, 1.0 eq) in DCM (15 mb) was added (Boc)2O (1.71 g, 7.81 mmol, 0.9 eq) and the mixture was stirred at room temperature for 3 h. TLC and LCMS showed the complete consumption of piperidin-4-ylmethanol. The mixture was quenched with water (10 mL), extracted with EtOAc (10 mb x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude product. The residue was purified by flash (EtOAc : petroleum ether = 0-35%) to give tert-butyl 4-(hydroxymethyl)piperidine-1- carboxylate (1.55 g, 82.9% yield) as a white solid.1HNMR (400MHz, CDCI3) δ (ppm) 4.20-4.00 (m, 2H), 3.47 (d,J= 6.0 Hz, 2H), 2.68 (t,J= 12.4 Hz, 2H), 1.73-1.56 (m, 3H), 1.43 (s, 9H), 1.19- 1.06 (m, 2H). LCMS (ESI) m / z calcd for C11H21NO3 215.15 found 160.2 [M-56+H]+.Preparation of tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylateTo a solution of tert-butyl 4-(hydroxymethyl)piperidine-1 -carboxylate (1.50 g, 6.97 mmol, 1.0 eq) in DCM (15 mL), TEA (1.40 g, 13.9 mmol, 1.2 eq) and Ms2O (1.82 g, 14.5 mmol, 1.5 eq) were added and the mixture was stirred at room temperature for 3 h. TLC and LC MS showed the complete consumption of tert-butyl 4-(hydroxymethyl)piperidine-l -carboxylate. The mixture was quenched with water (10 mL), extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude product. The residue was purified by flash (EtOAc : petroleum ether 0-30%) to give tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (2.00 g, 97.9% yield) as a yellow solid.1HNMR (400MHz, CDCI3) δ (ppm) 4.14 (s, 2H), 4.06 (d,J= 6.4 Hz, 2H), 3.00 (s, 3H), 2.70 (t, J=12.4 Hz, 2H), 1.99-1.84 (m, 1H), 1.73 (d,J= 13.2 Hz, 2H), 1.44 (s, 9H), 1.27-1.14 (m, 2H). LCMS (ESI) m / z calcd for C12H23NO5S 293.13 found 238.2 [M-56+H]+.Preparation of tert-butyl (S)-4-(((2-(1-(5-chloroisoindolin-2-yl)ethyl)-6-oxo-1-(2,2,2- trifluoroethyl)- 1,6-dihydropyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylatetert-Butyl (S)-4-(((2-(1-(5-chloroisoindolin-2-yl)ethyl)-6-oxo-1-(2,2,2-trifluoroethyl)-l,6- dihydropyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylate was prepared by using the same procedures as in the preparation (S)-2-(1-(5-fluoroisoindolin-2-yl)ethyl)-5-((1- (methylsulfonyl)piperidin-4-yl)methoxy)-3 -(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one of except that tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate was used instead of (1- (methylsulfonyl)piperidin-4-yl)methyl methanesulfonate and 1,2-bis(bromomethyl)-4- chlorobenzene used instead of l,2-bis(fluoromomethyl)-4-chlorobenzene. LCMS (ESI) m / z calcd for C27H34CIF3N4O4 570.22 found 571.3 [M+H]+.Preparation of (S)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-5-(piperidin-4-ylmethoxy)-3-(2,2,2- trifluoroethyl )pyrimidin-4(3H)-one hydrochlorideTo a solution of tert-butyl (S)-4-(((2-(1-(5-chloroisoindolin-2-yl)ethyl)-6-oxo-1-(2,2,2- trifluoroethyl)-l,6-dihydropyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylate (240 mg, 0.42 mmol, 1.0 eq) in DCM (3 mL) was added 4 N HCl / dioxane (1 mL) and the mixture was stirred at room temperature for 2 h. TLC and LCMS showed the complete consumption of tert-butyl (S)-4- (((2-(1-(5-chloroisoindolin-2-yl)ethyl)-6-oxo-1-(2,2,2-trifluoroethyl)-l,6-dihydropyrimidin-5- yl)oxy)methyl)piperidine-1-carboxylate. The mixture was concentrated to give (S)-2-(1-(5- chloroisoindolin-2-yl)ethyl)-5-(piperidin-4-ylmethoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)- one hydrochloride (200 mg, 93.9% yield) as a brown solid LCMS (ESI) m / z calcd for C22H27CI2F3N4O2 506.15 found 471.2 [M-HC1+H]+.Preparation of (S)-5-((1-acetylpiperidin-4-yl)methoxy)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-oneTo a solution of (S)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-5-(piperidin-4-ylmethoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one hydrochloride (50.0 mg, 0.10 mmol, 1.0 eq) in DCM (2 mL) was added DIEA (39.0 mg, 0.30 mmol, 3.0 eq) and Ac?O (6.00 mg, 0.05 mmol, 0.5 eq) and the mixture was stirred at room temperature for overnight under N2. TLC and LCMS showed the complete consumption of (S)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-5-(piperidin-4-ylmethoxy)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one hydrochloride. The mixture was quenched with water (5 mL), extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4and concentrated to give the crude product. The residue was purified by HPLC (ACN in 0.1% TFA, 25%~ 38%) to give (S)-5-((1-acetylpiperidin-4-yl)methoxy)-2-(1-(5- chloroisoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (2.60 mg, 5.1% yield) as a white solid.1HNMR (400MHz, DMSO-d6) 8(ppm) 7.69 (s, 1H), 7.54 - 7.26 (m, 3H), 5.26 - 5.00 (m, 2H), 4.42 - 4.38 (m, 1H), 3.96 - 3.75 (m, 6H), 3.06 (t, J=12.0 Hz, 1H), 2.60 - 2.51 (m, 2H), 2.10 - 1.92 (m, 4H), 1.83 - 1.70 (m, 2H), 1.55 (s, 3H), 1.32 - 1.04 (m, 3H). LCMS (ESI) / ?? z calcd for C24H28CIF3N4O3 512.18 found 513.2 [M+H]l.Example 28 - Methyl (S)-4-(((2-(l-(5-chloroisoindolin-2-yl)ethyl)-6-oxo-1-(2,2,2-trifluoroethyl)~ 1,6-dihydropyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylatePreparation of methyl (S)-4-(((2-(1-(5-chloroisoindolin-2-yl)ethyl)-6-oxo-1-(2.2.2- trifluoroethyl)- 1,6-dihydropyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylateTo a solution of (S)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-5-(piperidin-4-ylmethoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one hydrochloride (50.0 mg, 0.10 mmol, 1.0 eq) in DCM (2 mL) was added DIEA (39.0 mg, 0.30 mmol, 3.0 eq) and dimethyl dicarbonate (16.0 mg, 0.12 mmol, 1.2 eq) and the mixture was stirred at room temperature for overnight under N2. The mixture was quenched with water (5 mL), extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4and concentrated to give the crude product. The residue was purified by HPLC (ACN in 0.1% TEA, 40%- -60%) to give methyl (S)-4-(((2-(1-(5- chloroisoindolin-2-yl)ethyl)-6-oxo-1 -(2,2,2-trifluoroethyl)-1 ,6-dihydropyrimidin-5- yl)oxy)methyl)piperidine-1-carboxylate (4.00 mg, 7.6%> yield) as a white solid.1HNMR (400MHz,DMSO-d6) δ(ppm) 7.67 (s, 1H), 7.51 - 7.25 (m, 3H), 5.25 - 5.03 (m, 2H), 4.05 - 3.96 (m, 2H), 3.92 - 3.84 (m, 2H), 3.59 (s, 3H), 2.93 -2.74 (m, 2H), 2.07 - 1.89 (m, 2H), 1.82 - 1.67 (m, 2H), 1.52 (s, 3H), 1.32 - 1.12 (m, 6H). LCMS (ESI) m z calcd for C24H28CIF3N4O4528.18 found 529.2 [M+H]+.Example 29 - (S)-2-( 1 -(Isoindolin-2-yl)ethyl)-5-((2-(methylsulfonyl)-2-azaspiro[ 3.3 ]heptan-6- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidm-4(3H)-one(S)-2-CI -(isoindolin-2-yl )ethyl )-5-((2-(methyl sulfonyl )-2-azaspiro [3.3 ]heptan-6-yl )methoxy)- 3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one was prepared by using the same procedures as in the preparation of (S)-2-(1-(isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one except that (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate was replaced with (2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methyl methanesulfonate.1HNMR (300MHz, CDCI3) δ(ppm) 7.41 (s, 1H), 7.22 (m, 4H), 5.23 - 5.19 (m, 2H), 4.39 - 4.00 (m, 3H), 4.01 - 3.89 (m, 8H), 2.84 (s, 3H), 2.78 - 2.62 (m, 1H), 2.48 - 2.34 (m, 2H), 2.21 - 2.10 (m, 2H), 1.68 - 1.42 (m, 3H). LCMS (ESI) m 'z calcd for C24H29F3N4O4S 526.19 found 527.1 [M+H]+.Example 30 - (R)-5-((1 -(Methylsulfonyl)piperidin-4-yl)methoxy)-2-(2,2,2-trifluoro-1-(isoindolin- 2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-onePreparation of 5-(benzyloxy)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyrimidine-2- carbaldehydeTo a solution of 5-(benzyloxy)-2-methyl-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (11.0 g, 36.9 mmol, 1.0 eq) in 1,4-dioxane (100 mL) was added SeCh (8.20 g, 73.8 mmol, 2.0 eq) and the mixture was heated to 100 °C and stirred for 2 h. The mixture was filtered, the filtrate was added 5% NaHCO3until pH=7 and extracted with DCM (50 mL x 3), the combined organic layers were dried over Na2SO4and concentrated to give 5-(benzyloxy)-6-oxo-1-(2,2,2-trifluoroethyl)-l,6- dihydropyrimidine-2-carbaldehyde (9.90 g, crude) as a brown solid. LCMS (ESI) m / z calcd for C14H11F3N2O3 312.07 found 313.0 [M+H]+.Preparation of (S,E)-N-((5-(benzyloxy)-6-oxo-1-(2.2.2-trifluoroethyl)-1,6-dihydropyrimidin-2- yl)methylene)-2-methylpropane-2-sulfinamideTo a solution of 5-(benzyloxy)-6-oxo-l ~(2,2,2-trifluoroethyl)-1,6-dihydropyrimidine-2- carbaldehyde (10.9 g, 34.9 mmol, 1.0 eq) in DCM (100 mb) was added CuSO4(11.1 g, 69.8 mmol, 2.0 eq) and (S)-2-methylpropane-2-sulfmamide (4.23 g, 34.9 mmol, 1.0 eq) and the mixture was stirred at room temperature for overnight. TLC and LCMS showed the complete consumption of 5-(benzyloxy)-6-oxo- 1 -(2,2,2-trifluoroethyl)- 1 ,6-dihydropyrimidine-2-carbaldehyde. The mixture was fdtered and concentrated to give (S,E)-N-((5-(benzyloxy)-6-oxo-1-(2,2,2- trifluoroethyl)-1,6-dihydropyrimidin-2-yl)methylene)-2-methylpropane-2-sulfmamide (11.0 g, crude) as a white solid. LCMS (ESI) m / z calcd for C18H20F3N3O3S 415.12 found 416.1 [M+H]+.Preparation of (S)-N-((R)- 1 -(5-(benzyloxy)-6-oxo- 1 -(2,2,2-trifluoroethyl)- 1 ,6-dihydropyrimidin- 2-yl)-2.2.2-trifluoroethyl)-2-methylpropane-2-sulfinamideTo a solution of (S,E)-N-((5-(benzyloxy)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyrimidin- 2-yl)methylene)-2-methylpropane-2-sulfinamide (3.80 g, 9.15 mmol, 1.0 eq) and Tetrabutylammonium acetate (2.76 g, 9.15 mmol, 1.0 eq) in DMF (35 mL) was added TMSCF3 (3.26 g, 22.9 mmol, 2.5 eq) dropwise at -10 °C and the mixture was stirred at same temperature for 3 h. The mixture was quenched with NH4CI (30 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude product. The residue was purified by flash (EtOAc : petroleum ether = 0-26%) to give (S)-N-((R)-1-(5- (benzyloxy)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyrimidin-2-yl)-2,2,2-trifluoroethyl)-2- methylpropane-2-sulfmamide (2.10 g, 47.3% yield) as a yellow solid.1HNMR (300MHz, DMSO-d6) δ(ppm) 7.79 (s, 1H), 7.49 - 7.34 (m, 5H), 6.02 (d, J=7.5 Hz, 1H), 5.53 - 5.41 (m, 1H), 5.33 -5.15 ( m, 2H), 5.14 (s, 2H), 1.16 (s, 9H). LCMS (ESI) m / z cal cd for C19H21F6N3O3S 485.12 found 486.1 [M+H]+.Preparation of (R)-5-(piperidin-4-ylmethoxy)-2-(2,2,2-trifluoro-1-(isoindolin-2-yl)ethyl)-3- (2,2,2-trifluoroethyDpyrimidin-4(3H)-one(R)-5-(Piperi din-4-ylmethoxy)-2-(2,2,2-trifluoro-1-(isoindolin-2-yl)ethyl)-3-(2, 2,2- trifluoroethyl)pyrimidin-4(3H)-one was prepared by using the same procedures as in the preparation of (S)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-5-(piperidin-4-ylmethoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one hydrochi oride_except that (S)-5-(benzyloxy)-2-(1- (isoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one was replaced with (S)-N- ((R)-1-(5-(benzyloxy)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyrimidin-2-yl)-2,2,2- trifluoroethyl)-2-methylpropane-2-sulfinamide and 1,2-bis(bromomethyl)-4-chlorobenzene was replaced with 1,2-bis(bromomethyl)-benzene. LCMS (ESI) m / z cal cd for C22H24F6N4O2 490.18 found 491.0 [M+H]+.Preparation of (R)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-(2,2,2-trifluoro-1- (isoindolin-2-yl)ethyl)-3-(2,2.2-trifluoroethyl)pyrimidin-4(3H)-oneTo a solution of (R)-5-(piperidin-4-ylmethoxy)-2-(2,2,2-trifluoro-1-(isoindolin-2-yl)ethyl)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (60.0 mg, 0.122 mmol, 1.0 eq) in DCM (2 mL) was added TEA (24.7 mg, 0.244 mmol, 2.0 eq) and MsCl (30.0 mg, 0.244 mmol, 2.0 eq) at 0 °C and the mixture was stirred at room temperature for 2 h. The mixture was quenched with water (5 mL), extracted with DCM (5 mL x 3). The combined organic layers were dried over Na2SO4andconcentrated to give the crude product. The residue was purified by prep-TLC (petroleum ether : EtOAc = 1 : 1) to give (R)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-(2,2,2-trifluoro-1- (isoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (20.0 mg, 28.7% yield) as a white solid.1HNMR (300MHz, DMSO-d6) δ(ppm) 7.71 (s, 1H), 7.27 - 7.17 (m, 4H), 5.40 - 5.20 (m, 2H), 5.03 - 4.86 (m, 1H), 4.33 - 4.18 (m, 4H), 3.96 - 3.87 (m, 2H), 3.58 (d, J=11.4 Hz, 2H), 2.85 (s, 3H), 2.79 - 2.67 (m, 2H), 1.96 - 1.78 (m, 3H), 1.36 - 1.27 (m, 2H). LCMS (ESI) m / z calcd for C23H26F6N4O4S 568.16 found 568.9 [M+H]+.Example 31 - (R)-5-((2-(Methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-2-(2,2,2-trifluoro- 1-(isoindolin-2-yl)ethyl)-3-(2, 2, 2-trifluoroethyl)pyrimidin-4(3H)-one 2, 2, 2 -trifluoroacetate(R)-5-((2-(Methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-2-(2,2,2-trifluoro-1- (isoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one was prepared by using the same procedures as in the preparation of (R)-5-(piperidin-4-ylmethoxy)-2-(2,2,2-trifluoro-1- (isoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one except that 4- (((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate was replaced with tert-butyl 6- (hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate.1HNMR (300MHz, DMSO-d6) δ (ppm) 7.69 (s, 1H), 7.27 - 7.17 (m, 4H), 5.39 - 5.19 (m, 2H), 4.98 - 4.91 (m, 1H), 4.31 - 4.18 (m, 4H), 3.95 (d, J=4,8 Hz, 2H), 3.87 (s, 2H), 3.83 (s, 2H), 2.93 (s, 3H), 2.64 - 2.51 (m, 1H), 2.39 - 2.28 (m, 2H), 2.08 - 1.97 (m, 2H). LCMS (ESI) m / z calcd for C26H27F9N4O6S 694.15 found 580.9 [M- TFA+H]+.Example 32 - (R)-5-((1-(Methylsulfonyl)piperidin-4-yl)methoxy)-2-(2,2,2-trifluoro-1-(5- fluoroisomdolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one(R)-5-((1-(Methylsulfonyl)piperidin-4-yl)methoxy)-2-(2,2,2-trifluoro-1-(5-fluoroisoindolin-2- yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one was prepared by using the same procedures as in the preparation of (R)-5-(piperidin-4-ylmethoxy)-2-(2,2,2-trifluoro-1-(isoindolin-2-yl)ethyl)- 3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one except that l,2-bis(bromomethyl)-benzene was replaced withl,2-bis(bromomethyl)-4-fluorobenzene.1HNMR (400MHz, DMSO-d6) δ(ppm) 7.70 (s, 1H), 7.29 - 7.22 (m, 1H), 7.14 - 7.08 (m, 1H), 7.06 - 6.98 (m, 1H), 5.39 - 5.18 (m, 2H), 5.00 - 4.87 (m, 1H), 4.30 - 4.17 (m, 4H), 3.95 - 3.87 (m, 2H), 3.58 (d, J=12.0 Hz, 2H), 2.85 (s, 3H), 2.79 - 2.69 (m, 2H), 1.95 - 1.80 (m, 3H), 1.36 - 1.29 (m, 2H). LCMS (ESI) m / z calcd for C23H25F7N4O4S 586.15 found 586.9 [M+H]+.Example 33 - (R)-5-((2-(Methylsulfonyl)-2-azaspiro[ 3.3 ]heptan-6-yl)methoxy)-2-(2, 2, 2-trifluoro- 1-(5-fluoroisoindolin-2-yl)ethyl)-3-(2, 2,2-trifluoroethyl)pyrimidin-4(3H)-one(R)-5-((2-(Methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-2-(2,2,2-trifluoro-1-(5- fluoroisoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one was prepared by using the same procedures as in the preparation of (R)-5-(piperidin-4-ylmethoxy)-2-(2,2,2-trifluoro-1- (isoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one except that 4- (((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate was replaced with tert-butyl 6- (hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate and 1,2-bis(bromomethyl)-benzene was replaced with 1,2-bis(bromomethyl)-4-fluorobenzene.1HNMR (300MHz, DMSO-d6) δ(ppm) 7.68 (s, 1H), 7.30 - 7.21 (m, 1H), 7.14 - 6.97 (m, 2H), 5.40 - 5.16 (m, 2H), 5.03 - 4.86 (m, 1H), 4.30 - 4.14 (m, 4H), 4.00 - 3.91 (m, 2H), 3.87 (s, 2H), 3.82 (s, 2H), 2.93 (s, 3H), 2.64 - 2.54 (m, 1H), 2.39 - 2.26 (m, 2H), 2.08 - 1.97 (m, 2H). LCMS (ESI) m / z calcd for C24H25F7N4O4S 598.15 found 598.9 [M+H]+.Example 34 - 5-((3-Chloro-4-(1H-pyrazol-3-yl)benzyl)oxy)-2-(isomdolm-2-ylmethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-onePreparation of 5-((4-bromo-3-chlorobenzyl)oxy)-2-(isoindolin-2-ylmethyl)-3-(2,2,2- trifluoroethyl)Dyrimidin-4(3H)-oneTo a solution of 5-hydroxy-2-(isoindolin-2-ylmethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)- one (1.10 g, 3.38 mmol, 1.0 eq) in THF (10 mL) was added (4-bromo-3-chlorophenyl)methanol (890 mg, 4.06 mmol, 1.2 eq) and PPI13 (1.33 g, 5.07 mmol, 1.5 eq). DIAD (1.03 g, 5.07 mmol, 1.5 eq) was added at 0 °C and the mixture was stirred at room temperature for 4 h. The mixture was quenched with water (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to dryness. The residue was purified by flash (EtOAc : petroleum ether = 0-20%) to give 5-((4-bromo-3-chlorobenzyl)oxy)-2-(isoindolin-2-ylmethyl)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (1.71 g, 95.7% yield) as an off-white solid. LCMS (ESI) m / z calcd for C22H18BrClF3N3O2 527.02 found 527.8, 529.8 [M+H]TPreparation of 5-((3-chloro-4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-oneTo a solution of 5-((4-bromo-3-chlorobenzyl)oxy)-2-(isoindolin-2-ylmethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one (1.35 g, 2.55 mmol, 1.0 eq) in dioxane (15 mL) was added B2Pin2 (780 mg, 3.07 mmol, 1.2 eq), AcOK (754 mg, 7.68 mmol, 3.0 eq) and Pd(dppf)C12-DCM (209 mg, 0.256 mmol, 0.1 eq), were added and the mixture was heated to 100 °C and stirred for 2 h. The mixture was filtered and the filtrate was concentrated to give the crude product. The residue was purified by flash (EtOAc : petroleum ether = 0-20%) to give 5-((3-chloro-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one (1.34 g, 91.1% yield) as a brown solid. LCMS (ESI) m / z calcd for C28H30BCIF3N3O4 575.20 found 576.2 [M+H]+.Preparation of 5-((3-chloro-4-(lH-pyrazo1-3-yl)benzynoxy)-2-(isoindolin-2-ylmethyn-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-oneTo a solution of 5-((3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-2- (isoindolin-2-ylmethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (100 mg, 0.174 mmol, 1.0 eq) in dioxane (3 mL) and H2O (1 mL) was added 3-bromo-1H-pyrazole (25.6 mg, 0.174 mmol, 1.0 eq), K3PO4(H 1 mg, 0.524 mmol, 3.0 eq) and Pd(dppf)Cl2DCM (28.6 mg, 0.0350 mmol, 0.2 eq), the mixture was heated to 100 °C and stirred for 2 h. The mixture was quenched with water (5 mL), extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude product. The residue was purified by prep-HPLC (5 mmol NH4CO3in H2O, 60% -81%) to give 5-((3-chloro-4-(1H-pyrazo1-3-yl)benzyl)oxy)-2-(isoindolin-2- ylmethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (4.00 mg, 4.46% yield) as a white solid. 1HNMR (400MHz, DMSO-d6) δ(ppm) 13.11 (s, 1H), 7.84 (s, 2H), 7.70 (s, 1H), 7.62 (s, 1H), 7.54 - 7.41 (m, 1H), 7.22 (d, J=1.2 Hz, 4H), 6.76 (s, 1H), 5.34 - 5.19 (m, 2H), 5.16 (s, 2H), 3.93 (s, 6H). LCMS (ESI) m / z calcd for C25H21CIF3N5O2 515.13 found 516.1 [M+H]+.Example 35 - 5-((3-Chloro-4-(isothiazol-3-yl)benzyl)oxy)-2-(isoiadolin-2-ylmethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-oneTo a solution of 5-((3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-2- (isoindolin-2-ylmethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (100 mg, 0.174 mmol, 1.0 eq) in dioxane (3 mL) and H2O (1 mL) was added 3-bromoisothiazole (28.5 mg, 0.174 mmol, 1.0 eq), KjPCUQ 11 mg, 0.524 mmol, 3.0 eq) and Pd(dppf)Cl2-DCM (28.6 mg, 0.0350 mmol, 0.2 eq), the mixture was heated to 100 °C and stirred for 2 h. The mixture was quenched with water (5 mL), extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude product. The residue was purified by prep-HPLC (5 mmol NH4CO3in H2O, 60%~80%) to give 5-((3-chloro-4-(isothiazo1-3-yl)benzyl)oxy)-2-(isoindolin-2- ylmethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one (4.00 mg, 4.32% yield) as a white solid.1HNMR (400MHz, DMSO-d6) δ(ppm) 9.20 (d, ,7=4.8 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.74 - 7.67 (m, 2H), 7.57 - 7.51 (m, 1H), 7.27- 7.16 (m, 4H), 5.33 - 5.21 (m, 2H), 5.19 (s, 2H), 3.99 - 3.88 (m, 6H). LCMS (ESI) m 'z calcd for C25H20CIF3N4O2S 532.09 found 533.1 [M+H]+.Example 36 - CYP11A1 inhibition Assay

[0151] Testing of inhibition of conversion of cholesterol to pregnenolone and isocaproic acid was carried out following the isocaproic acid release assay (IARA) described by Ruangwises et al (Biology of reproduction 1991, 45, 143-50) with the following modifications and procedures. NIH H295R cell line (ATCC) was used and treated with increased concentration of compounds for 30 mins before adding3H-Cholesterol, the resulting cell culture medium was incubated at 37°C, 5% CO2incubator for 3 days. The cell culture medium was added to adsorption buffer (12.5 g / L activated charcoal +1.25 g / L dextran+DPBS+10%glycerol), mixed and shaken at 300 rpm for 30 min. The supernatant was extracted. The radiolabeled isocaproic acid was determined by mixing 150uL supernatant to 2 mL ULTIMA GOLD (PerkinElmer). Radioactivity was measured using Tricarb and data analysis was performed with prism5.0. All the test compounds were studied at 6 concentrations in duplicate. The percentage of inhibition was calculated with the equation: %Inhibition = (1 -(Assay well signal -Average_LC) / (Average_HC-Average_LC))*100%. GraphPad Prism graphing software was used to calculate IC50 value.Table 1. IC50range of IARA Assay.IC50range A: = < 100 nM; B: >100 and < 500 nM; C > 500 nMTable 2. Exemplary compounds of the disclosure in accordance with certain embodiments.INCORPORATION BY REFERENCE

[0152] All publications, patents, and patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.EQUIVALENTS

[0153] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the present technology described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

Claims1. A compound according to Formula (I)wherein X1is O, S, S=O, SO2, C(R2)2, C1-3alkylene substituted with 0 to 6 R4, C=O, or NR1;L1is C(R2)2, NR8, CO, or O;X2is a 4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 0-4 heteroatoms, wherein X2is substituted with 0 to 6 R2;L2is C(R2)2, or C1-3alkylene substituted with 0 to 6 R4;R6is H, C1-6alkyl, C2-6alkenyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or cyclobutylmethyl, wherein said C1-6alkyl, C2-6alkenyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or cyclobutylmethyl is substituted with 0-5 R4;R7is a 4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 0-4 heteroatoms, wherein the 4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 0-4 heteroatoms is substituted with 0 to 6 R4; or, R6and R7together with the nitrogen atom to which they are attached, form a 4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ring containing 1-4 heteroatoms wherein the 4-13 membered saturated, partially saturated, partially aromatic or fully aromatic monocyclic, bicyclic, tricyclic, or spiro ringcontaining 1-4 heteroatoms is substituted with 0 to 6 R4and wherein at least one of the 1-4 heteroatoms is N;Z is O or S;R1is independently H, C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, or C3-7cycloalkyl C1-6alkyl, wherein the C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, or C3-7cycloalky1-C1-6alkyl is substituted with 0-5 R4;R2is independently H, Cl, Br, F, I, cyano, azido, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C3-7cycloalkyl, or C3-7cycloalkyl C1-6alkyl, wherein the C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C3-7cycloalkyl, or C3-7cycloalky1-C1-6alkyl is substituted with 0-5 R4;Q is C or N;R9is R3when Q is N;R9is R10when Q is C;R10is a 5 to 6 membered, heterocyclyl, 5 to 6 membered heteroaryl or 6-membered aryl wherein the said 5 to 6 membered, heterocyclyl, 5 to 6 membered heteroaryl or 6-membered aryl is substituted with 0 to 5 R4;R3is SO2R8, SO2NR8R8, SONHR8, CONR8R8, COR8, or COOR8;R4is independently H, Cl, Br, F, I, hydroxyl, cyano, azido, oxo, SO2NR8R8, NR8SO2R8, NR8R8, CONR8R8, OCONR8R8, NR8CONR8R8, C1-7alkyl substituted with 0-5 R5, C1.7 alkoxy substituted with 0-5 R5, 3-7 membered cycloalkyl substituted with 0-5 R5, C3-7cycloalky1-C1-6alkyl substituted with 0-5 R3, 3-7 membered heterocycloalkyl substituted with 0-5 R3, or 4-10 membered heterocycloalkyl C1-6alkyl substituted with 0-5 R5;R3is independently H, Cl, Br, F, I, hydroxyl, C1-3alkoxy, cyano, amino substituted with 0-2 C1-3alkyl, or azido; andR8is independently H, C1-7alkyl substituted with 0-5 R5, C1-7alkoxy substituted with 0-5 R5, 3-7 membered cycloalkyl substituted with 0-5 R5, C3-7cycloalky1-C1-6alkyl substituted with 0-5 R3, 3-7 membered heterocycloalkyl substituted with 0-5 R5, or 4-10 membered heterocycloalkyl C1-6alkyl substituted with 0-5 R5;or a pharmaceutically acceptable salt thereof.

2. A compound according to Formula (II)wherein X1is O;R1is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl and 2,2,2- trifluoroethyl;R2is H;L1is CH2or CHCH3;L2is CH2or CHCH3;NR6R7isR4is independently H, F, OCH3, CF3, CHF2, Cl, Br, or cyclopropyl; andQ is N; or a pharmaceutically acceptable salt thereof.

3. A compound selected from the group consisting of:2-(isoindolin-2-ylmethyl)-3-methyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,3-ethyl-2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,2-(isoindolin-2-ylmethyl)-3-isopropy1-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-propylpyrimidin-4(3H)-one,2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- tri fluoroethyl )pyrimidin-4(3H)-one,2-((l,1-dioxidobenzo[d]isothiazo1-2(3H)-yl)methyl)-3-methyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,3-ethyl-2-(isoindolin-2-ylmethyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6- yl)methoxy)pyrimidin-4(3H)-one,2-((5-bromoisoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,2-((5-chloroisoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,3-ethyl-2-((5-fluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,2-((5-cyclopropylisoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,2-(((2,3-dihydro-1H-inden-2-yl)(methyl)amino)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin- 4-yl)methoxy)pyrimidin-4(3H)-one,2-(isoindolin-2-ylmethyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,2-((5-chloroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,3-ethyl-2-(1-(isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,3-ethyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-((5-(trifluoromethyl)isoindolin-2- yl)methyl)pyrimidin-4(3H)-one,2-((5-(difluoromethyl)isoindolin-2-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,2-((5-fluoroisoindolin-2-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,2-((5-fluoroisoindolin-2-yl)methyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,2-((5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,2-((5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-3-ethyl-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,2-((2-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,2-((5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4- yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,2-((2-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,(R)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,(S)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,2-(((2,3-dihydro-lH-inden-2-yl)amino)methyl)-3-ethyl-5-((1-(rnethylsulfonyl)piperidin-4- yl)methoxy)pyrimidin-4(3H)-one,2-(((4-chlorobenzyl)(rnethyl)amino)methyl)-5-((1-(rnethylsulfonyl)piperidin-4-yl)rnethoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,3-ethyl-2-((2-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)-5-((1-(methylsulfbnyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,3-ethyl-2-((2-methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyrimidin-4(3H)-one,(S)-2-(1-(5-fluoroisoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,(S)-2-(1-(isoindolin-2-yl)ethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one,(S)-5-((1-acetylpiperidin-4-yl)methoxy)-2-(1-(5-chloroisoindolin-2-yl)ethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one, methyl (S)-4-(((2-(1-(5-chloroisoindolin-2-yl)ethyl)-6-oxo-1-(2,2,2-trifluoroethyl)-l,6- dihydropyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylate,(S)-2-(1-(isoindolin-2-yl)ethyl)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,(R)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2-(2,2,2-trifluoro-1-(isoindolin-2-yl)ethyl)-3- (2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,(R)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-2-(2,2,2-trifluoro-1-(isoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,(R)-5-((l -(methylsulfonyl)piperidin-4-yl)methoxy)-2-(2,2,2-trifluoro-1-(5-fluoroisoindolin-2- yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,(R)-5-((2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)methoxy)-2-(2,2,2-trifluoro-1-(5- fluoroisoindolin-2-yl)ethyl)-3-(2,2,2-trifluoroethyl)pyrimidin-4(3H)-one,5-((3-chloro-4-(1H-pyrazo1-3-yl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one, and5-((3-chloro-4-(isothiazo1-3-yl)benzyl)oxy)-2-(isoindolin-2-ylmethyl)-3-(2,2,2- trifluoroethyl)pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to claim 4, wherein the composition is suitable for oral administration.

6. The pharmaceutical composition according to claim 4, wherein the composition is suitable for parenteral administration.

7. The pharmaceutical composition according to claim 4, wherein the composition is suitable for topical administration.

8. The pharmaceutical composition according to claim 4, wherein the composition is suitable for nasal administration or by inhalation.

9. A method for the treatment or prevention of a steroid receptor-dependent condition or disease in a subject in need thereof, comprising administering the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 or the pharmaceutical composition according to any one of claims 4 to 8 to the subject, such that the steroid receptor-dependent condition or disease is treated or prevented in the subject.

10. The method according to claim 9, wherein the steroid receptor-dependent condition or disease is androgen receptor-dependent.

11. The method according to claim 9 or 10, wherein the steroid receptor-dependent condition or disease is an endocrine cancer or disease.

12. The method according to any one of claims 9 to 11, wherein the steroid receptordependent condition or disease is prostate cancer, castration-resistant prostate cancer, or breast cancer.

13. The method according to any one of claims 9 to 12, wherein the subject is a human.

14. Use of the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 or the pharmaceutical composition according to any one of claims 4 to 8 in the treatment or prevention of a steroid receptor-dependent condition or disease in a subject in need thereof.

15. Use of the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 or the pharmaceutical composition according to any one of claims 4 to 8 in the preparation of a medicament for the treatment or prevention of a steroid receptor-dependent condition or disease in a subject in need thereof.

16. The use according to claim 14 or 15, wherein the steroid receptor-dependent condition or disease is androgen receptor-dependent.

17. The use according to claim 14 or 15 wherein the steroid receptor-dependent condition or disease is an endocrine cancer or disease.

18. The use according to any one of claims 14 to 17, wherein the steroid receptor-dependent condition or disease is prostate cancer, castration-resistant prostate cancer, or breast cancer.

19. The use according to any one of claims 14 to 18, wherein the subject is a human.

20. A kit comprising the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 or the pharmaceutical composition according to any one of claims 4 to 8, and optionally, instructions for use thereof.

Images