EA046513B1 - SUBSTITUTED IMIDAZOLIDIN-2-ONE DERIVATIVES AS PRMT5 INHIBITORS - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to therapeutically active substituted imidazolidin-2-one derivatives, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, which are useful for the treatment of PRMT5-dependent conditions and disorders. The present invention also relates to pharmaceutical compositions containing such compounds.

BACKGROUND OF THE INVENTION

Methyltransferase is an enzyme that catalyzes the transfer of a methyl group from one molecule to another. Protein methyltransferases (PMTs) are regulatory systems that regulate gene expression by transferring methyl groups to substrates, including protein, DNA, RNA, and small molecules. The transfer of a methyl group to an arginine residue in a protein is catalyzed by the PRMT family of enzymes, which facilitates the transfer of a methyl (-CH3) group to specific nucleophilic sites on proteins, nucleic acids, or other biomolecules. Methylation is a significant transformation in small molecule metabolism and is a common modification of DNA and RNA carried out by PMTs. In general, PMTs are divided into two main families: protein lysine methyltransferase (PLMT) and protein arginine methyltransferase (PRMT). PRMTs use S-adenosyl-1-methionine (SAM) as a ubiquitous cofactor to catalyze the transfer of a highly specific methyl group from the methyl donor SAM to arginine residues at various biological targets. In addition, based on the products of enzymatic reactions, PRMTs can be classified as type I-IV enzymes. Type I enzymes catalyze the formation of ω-NG-monomethylarginine (c')MMA) and asymmetric ω-NG, NG-dimethylarginine (ω-aDMA). Type II enzymes catalyze the formation of ωMMA and symmetric ω-NG, NG-dimethylarginine (ω-sDMA). Type III enzymes catalyze the formation of ωMMA only, while type IV enzymes catalyze the formation of δ-NG-MMA.

Types I-III exist in mammalian cells, but type IV has been described only in yeast and possibly plants. To date, ten PRMTs have been identified in mammalian cells. PRMTs 1, 2, 3, 4, 6, and 8 exhibit type I activity. PRMT 5, 7, and 9 exhibit type II activity. In addition to type II activity, PRMT 7 also exhibits type III activity.

Protein arginine methyltransferase 5 (PRMT5) is a typical type II methyltransferase, transferring methyl groups from SAM to the two nitrogen atoms of ω-guanidino arginine, resulting in ω-NG, NG disymmetric methylation of the protein substrate. It is localized in both the nucleus and the cytoplasm and performs various functions, modifying either histones or non-histone proteins. PRMT5 was originally identified as Janus kinase (JAK) binding protein 1 (JBP1). It can symmetrically methylate histones H2AR3, H3R2, H3R8 and H4R3. PRMT5 can also methylate many non-histone proteins, and many of these events have been implicated in tumorigenesis. PRMT5 also plays an important role in cell cycle progression and DNA repair processes. PRMT5 is involved in the regulation of cell growth, apoptosis and inflammation. PRMT5 interacts with a number of binding partners that influence its substrate specificity. MEP50, a member of the WD40 family of proteins, is an essential cofactor of PRMT5 that directly binds PRMT5 and increases PRMT5 histone methyltransferase activity. Nuclear PRMT5 forms complexes with chromatin remodeling complexes (hSWI/SNF, NuRD) and epigenetically controls genes involved in cell development, proliferation and differentiation, including tumor suppressor, through histone methylation (Kharkhanis et al. Trends Biochem Sci. 36, 633-41 , 2011). Fabbrizio, E. et al. showed that PRMT5 is a transcriptional repressor (Fabbrizio et al., EMBO Rep. 3, 641-645, 2002). H3R8me2 and H4R3me2 are keys in repressive histone methylation. Therefore, as a transcriptional repressor, PRMT5 has oncogenic properties due to its ability to suppress the expression of tumor suppressor genes. Overexpression of PRMT5 has been shown to correlate with proliferation of human glioblastoma cells and inversely correlates with patient survival (Yan el al., Cancer Res. 74, 1752-1765, 2014). PRMT5 has been reported to be upregulated in human malignant melanoma tumors compared to normal epidermis (Nicholas et al., PLoS One, 30, 8(9): e74710, 2013). Depletion of PRMT5 by siRNA has been shown to modulate cell proliferation in an ovarian cancer cell line (Bao et al., J. Histochem. Cytochem., 61, 206-217, 2013). Gu et al. showed that PRMT5 expression is important for the growth of lung cancer cells (Gu et al. Biochem. J., 446, 235-41, 2012). Pal et al. and Wang et al. reported that PRMT5 levels are increased in various transformed cells, and knockdown of PRMT5 is associated with decreased cell growth, whereas overexpression of PRMT5 causes cellular hyperproliferation (Pal et al., EMBO J. 8, 26, 3558-69, 2007, and Wang et al. ., Mol Cell. Biol., 28, 6262-6277, 2008). Jansson et al. reported that overexpression of PRMT5 in an orthotopic mouse model of breast cancer accelerates tumor growth (Jansson et al., Nature Cell Biol, 10, 1431-1439, 2008). PRMT5 represses transcription of the Rb family of tumor suppressors in leukemia and lymphoma cells (Wang et al., Mol. Cell. Biol., 28, 6262-6277, 2008).

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Some cell lines and patient samples from B-cell lymphoma and leukemia show overexpression of PRMT5 (Pal et al., EMBO J. 8, 26, 3558-69, 2007). Targeting PRMT5 methyltransferase eliminates leukemia stem cells in chronic myelogenous leukemia (Jin et al., J. Clin. Invest., 126, 3961-3980, 2016; Yan et al., Cancer Res., 74, 1752-1765, 2014, and Chan-Penebre et al., Nature Chemical Biology, 11, 432-437, 2015). Selective inhibition of PRMT5 blocks the initiation and maintenance of B cell transformation (Alinari et al., Blood, 125, 2530-43, 2015). In addition to glioblastoma, melanoma, ovarian and lung cancer, PRMT5 is also involved in other solid tumors such as prostate cancer, breast cancer, colon cancer, gastric cancer, esophageal cancer and hepatocellular carcinoma. In addition, aberrant methylation of PRMT5 substrates is associated with other indications such as metabolic disorders, inflammation, autoimmune disease, and hemoglobinopathies.

Some PRMT5 inhibitors have been described, for example, in WO2017/211958, WO/2017/153518, WO/2017/153513, WO 2016/034675, WO 2016/022605, WO 2015/200677, WO 2015/200680, WO 2014 /145214, WO2014/128465, WO2014/100764, WO 2014/100734, WO 2014/100730, WO 2014/100719 and WO 2014/100716.

However, there is a need for effective and selective PRMT5 inhibitors that are suitable for use as a medicament in the treatment of conditions and disorders in which PRMT5 inhibition is desired, such as cancer, metabolic disorders, inflammation, autoimmune disease and hemoglobinopathies.

Brief Disclosure of the Present Invention

The compounds of formula (1) have been found to be effective and selective inhibitors of PRMT5. The compounds of the present invention are thus useful as medicaments in the treatment of cancer such as glioblastoma, melanoma, ovarian cancer, lung cancer, prostate cancer, breast cancer, colon cancer, gastric cancer, esophageal cancer, hepatocellular carcinoma , and other conditions and disorders mediated by PRMT5, such as metabolic disorders, inflammation, autoimmune disease, and hemoglobinopathies.

In one aspect, the present invention provides a compound of formula (I):

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof;

wherein X1, _X2 and _X3 are each independently CR ₅ or N;

ring A is cycloalkyl, aryl, heterocycloalkyl or heteroaryl;

R represents hydrogen, alkyl or halogen;

R1 represents

R2 is hydrogen or alkyl;

alternatively, R1 and R2, together with the nitrogen atom to which they are attached, form a bicyclic heterocyclyl ring, optionally containing from 1 to 3 additional heteroatoms selected from N, O and S; where the bicyclic heterocyclyl ring is optionally substituted with one or more R ₆ ,

R3 is hydrogen or alkyl;

R4 is in each case independently hydrogen, halogen, haloalkyl, cyano, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -C(O)R ₇ , -alkyl-C(O) ₇ , -S(O) ₂ R ₇ ; wherein said alkyl, alkenyl and alkynyl are optionally substituted with 1-3 groups selected from hydroxyl, halogen, heterocycloalkyl and heteroaryl;

alternatively, two R4 on the same atom together form an oxo (=O) group;

R ₅ is in each case independently hydrogen, alkyl, halogen, haloalkyl or alkoxy;

R6 is alkyl, alkoxy, hydroxy, cyano, halogen or haloalkyl;

R ₇ is alkyl, hydroxy, alkoxy, -NRgR _f , cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is further optionally substituted with one or more R6,

R _a and R _b are each independently hydrogen or alkyl;

Rc and Rd are each independently hydrogen or alkyl; alternatively Rc and Rd together represent an oxo (=O) group;

Re and R _f are each independently hydrogen or alkyl; alternatively, Re and R _f together with the nitrogen atom to which they are attached form an optionally substituted 3-7 membered hetero

- 2 046513 cyclic ring with 1-2 additional heteroatoms selected from N, O and S; wherein the additional substituent is one or more R6, m is an integer from 1 to 3; and n is 0 or 1.

According to yet another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).

According to yet another aspect, the present invention relates to the preparation of a compound of formula (I).

According to yet another aspect of the present invention, there are provided substituted imidazolidin-2-one derivatives of formula (I) that are useful as PRMT5 inhibitors and their therapeutic use.

Detailed Description of the Present Invention

The present invention relates to substituted imidazolidin-2-one derivatives in the form of compounds of formula (I), which are useful as PRMT5 inhibitors. In addition, the present invention relates to pharmaceutical compositions containing these compounds and their derivatives as therapeutic agents.

Each embodiment is presented as an explanation of the present invention and not to limit the present invention. In fact, those skilled in the art will appreciate that various modifications and variations may be made to the compounds, compositions and methods described herein without departing from the scope or spirit of the present invention. For example, features illustrated or described as part of one embodiment may be related to another embodiment to produce yet another embodiment. Thus, the present invention is intended to include such modifications and variations and their equivalents. Other objects, features and aspects of the present invention are set forth in or will be apparent from the following detailed description. One skilled in the art will appreciate that the present invention is a description of illustrative embodiments only and is not intended to limit the broader aspects of the present invention.

In one aspect, the present invention provides a compound of formula (I):

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof;

wherein X1, X2 and _X3 are each independently CR5 or N;

ring A is cycloalkyl, aryl, heterocycloalkyl or heteroaryl;

R represents hydrogen, alkyl or halogen;

„ ..^ΐΟΌο.....<00.

R1 represents '' ^J '

R2 is hydrogen or alkyl;

alternatively, R1 and R2, together with the nitrogen atom to which they are attached, form a bicyclic heterocyclyl ring, optionally containing from 1 to 3 additional heteroatoms selected from N, O and S;

wherein the bicyclic heterocyclyl ring is optionally substituted with one or more R6;

R ₃ represents hydrogen or alkyl;

R4 is in each case independently hydrogen, halogen, haloalkyl, cyano, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -C(O)R ₇ , -alkyl-C(O) ₇ , -S(O) ₂ R ₇ ;

wherein said alkyl, alkenyl and alkynyl are optionally substituted with 1-3 groups selected from hydroxyl, halogen, heterocycloalkyl and heteroaryl;

alternatively, two R4 on the same atom together form an oxo (=O) group;

R5 is in each instance independently hydrogen, alkyl, halogen, haloalkyl or alkoxy;

R6 is alkyl, alkoxy, hydroxy, cyano, halogen or haloalkyl;

R ₇ is alkyl, hydroxy, alkoxy, -NReRf, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is further optionally substituted with one or more R6,

- 3 046513

Ra and R _b are each independently hydrogen or alkyl;

Rc and Rd are each independently hydrogen or alkyl; alternatively Rc and Rd together represent an oxo (=O) group;

Re and Rf are each independently hydrogen or alkyl; alternatively, R _e and Rf together with the nitrogen atom to which they are attached form an optionally substituted 3-7 membered heterocyclic ring with 1-2 additional heteroatoms selected from N, O and S; wherein the additional substituent is one or more R6, m is an integer from 1 to 3; and n is 0 or 1.

According to another aspect, the present invention relates to a compound of formula (I'):

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof;

wherein X1, X2 and _X3 are each independently CR5 or N;

ring A is cycloalkyl, aryl, heterocycloalkyl or heteroaryl;

R represents hydrogen, alkyl or halogen;

......*cq

R1 represents '' ^or '

R2 represents hydrogen or alkyl;

alternatively, R1 and R2, together with the nitrogen atom to which they are attached, form a bicyclic heterocyclyl ring, optionally containing from 1 to 3 additional heteroatoms selected from N, O and S;

wherein the bicyclic heterocyclyl ring is optionally substituted with one or more R6;

R ₃ represents hydrogen or alkyl;

R4 in each occurrence is independently hydrogen, halogen, haloalkyl, cyano, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -C(O)R ₇ , -alkyl-C(O^ ₇ , -S(O) ₂ R ₇ ;

wherein said alkyl, alkenyl and alkynyl are optionally substituted with 1-3 groups selected from hydroxyl, halogen, heterocycloalkyl and heteroaryl;

alternatively, two R4 on the same atom together form an oxo (=O) group;

R ₅ is in each instance independently hydrogen, alkyl, halogen, haloalkyl or alkoxy;

R ₆ is alkyl, alkoxy, hydroxy, cyano, halogen, or haloalkyl;

R7 is alkyl, hydroxy, alkoxy, -NReRf, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is further optionally substituted with one or more R6;

Ra and Rb are each independently hydrogen or alkyl;

Rc and Rd are each independently hydrogen or alkyl; alternatively Rc and _Rd together represent an oxo (=O) group;

Rc and Rf are each independently hydrogen or alkyl; alternatively, Re and Rf together with the nitrogen atom to which they are attached form an optionally substituted 3-7 membered heterocyclic ring with 1-2 additional heteroatoms selected from N, O and S; wherein the additional substituent is one or more R6;

m is an integer from 1 to 3; and n is 0 or 1.

According to another aspect, the present invention relates to compounds of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof;

wherein X1, X2 and _X3 are each independently CR5 or N;

ring A is C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 5-12 membered heterocycloalkyl or 512 membered heteroaryl;

R represents hydrogen, alkyl or halogen;

*with

R1 represents ⁴ -> ₅ -/ _Or

R2 is hydrogen or alkyl;

alternatively, R1 and R2, together with the nitrogen atom to which they are attached, form a bicyclic heterocyclyl ring, optionally containing from 1 to 3 additional heteroatoms selected from N, O and S; wherein the bicyclic heterocyclyl ring is optionally substituted with one or

- 4 046513 several R6;

R3 is hydrogen or alkyl;

R4 in each instance is independently hydrogen, halogen, haloalkyl, cyano, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -C(O) _R7 , -alkyl-C(O^ ₇ , -S(O) _2R7 ; wherein said alkyl, alkenyl and alkynyl are optionally substituted with 1-3 groups selected from hydroxyl, halogen, heterocycloalkyl and heteroaryl;

alternatively, two R4 on the same atom together form an oxo (=O) group;

R5 is in each instance independently hydrogen, alkyl, halogen, haloalkyl or alkoxy;

R6 is alkyl, alkoxy, hydroxy, cyano, halogen, or haloalkyl;

R ₇ is alkyl, hydroxy, alkoxy, -NReRf, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is further optionally substituted with one or more R6;

Ra and Rb are each independently hydrogen or alkyl;

Rc and Rd are each independently hydrogen or alkyl; alternatively Rc and _Rd together represent an oxo (=O) group;

Re and Rf are each independently hydrogen or alkyl; alternatively, R _e and Rf together with the nitrogen atom to which they are attached form an optionally substituted 3-7 membered heterocyclic ring with 1-2 additional heteroatoms selected from N, O and S; wherein the additional substituent is one or more R6;

m is an integer from 1 to 3; and n is 0 or 1.

In some embodiments, the present invention provides a compound of formula (I), wherein X1, X2, and _X3 are each independently CR5 or N;

ring A is C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 5-12 membered heterocycloalkyl or 512 membered heteroaryl;

R represents hydrogen, alkyl or halogen;

the group ^R2 is wherein each bicyclic heterocyclyl ring is optionally substituted with one or more R6,

R3 is hydrogen or alkyl;

R ₄ in each occurrence is independently hydrogen, halogen, haloalkyl, cyano, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -C(O)R ₇ , -alkyl-C(O^ ₇ , -S(O) ₂ R ₇ ; wherein said alkyl, alkenyl and alkynyl are optionally substituted with 1-3 groups selected from hydroxyl, halogen, heterocycloalkyl and heteroaryl;

alternatively, two R4 on the same atom together form an oxo (=O) group;

R5 is in each instance independently hydrogen, alkyl, halogen, haloalkyl or alkoxy;

R ₆ represents alkyl, alkoxy, hydroxy, cyano, halogen or haloalkyl;

R7 is alkyl, hydroxy, alkoxy, -NReRf, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is further optionally substituted with one or more R6,

Ra and Rb are each independently hydrogen or alkyl;

R _c and R _d are each independently hydrogen or alkyl; alternatively R _c and R _d together represent an oxo (=O) group;

Re and Rf are each independently hydrogen or alkyl; alternatively, Re and Rf together with the nitrogen atom to which they are attached form an optionally substituted 3-7 membered heterocyclic ring with 1-2 additional heteroatoms selected from N, O and S; wherein the additional substituent is one or more R6;

m is an integer from 1 to 3; and n is 0 or 1.

According to another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is a 3-10 membered monocyclic ring system or a 6-12 membered bicyclic ring selected from fused, bridged and spirocyclic ring systems.

According to another aspect, the present invention relates to compounds of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof; wherein R4 is in each case independently hydrogen, halogen, haloalkyl, cyano, alkyl, hydroxy, alkoxy, -C(O)R ₇ , -alkyl-C(O)2K ₇ or -S(O) ₂ R ₇ ; wherein said alkyl is further optionally substituted with heterocycloalkyl or hethe

- 5 046513 roaril.

In some embodiments, the present invention provides formula (I), wherein R is hydrogen and n is 1.

In some embodiments, the present invention relates to formula (IA)

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof;

where the ring A, X1, X2, X ₃ , R1, R2, R4, Ra, Rb and m are the same as defined in formula (I).

In some embodiments, the present invention relates to compounds of formula (IB) compounds compounds compounds

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof;

where the ring A, X1, X2, _X3 , _R3 , R4, Ra, Rb, Rc, Rd and m are the same as defined in formula (I).

In some embodiments, the present invention provides compounds of formula (IC)

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof;

where ring A, X1, X2, X ₃ R4 and m are the same as defined in formula (I).

In some embodiments, the present invention provides compounds of formula (ID)

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; where ring A, R1, R2, _R4 , Ra, Rb and m are the same as defined in formula (I). In some embodiments, the present invention provides compounds of formula (IE)

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; where ring A, R1, R2, R4 and m are the same as defined in formula (I). In some embodiments, the present invention provides compounds of formula (IF)

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; where X1, X2, X ₃ , R1, R2, R4, Ra, Rb and m are the same as defined in formula (I). In some embodiments, the present invention provides compounds of formula (IG)

- 6 046513

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof;

where X1, X2, X ₃ , R1, R2, R4, R _a , R _b and m are the same as defined in formula (I).

In some embodiments, the present invention provides compounds of formula (IH)

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; where X1, X2, X ₃ , R1, R2, R4, R _a , R _b and m are the same as defined in formula (I). In some embodiments, the present invention provides compounds of formula (Ii)

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof;

where A, X1, X2, X ₃ , R _a , R _b , Rc, Rd, R ₃ , R ₄ and m are the same as defined in formula (I).

In some embodiments, the present invention provides compounds of formula (Ii), wherein X1, X2, and _X3 are each independently CR5 or N;

ring A is heterocycloalkyl or heteroaryl;

R3 is hydrogen or alkyl;

R4 in each occurrence is independently hydrogen, halogen, haloalkyl, cyano, alkyl, -C(O)R ₇ , -alkyl-C(O^ ₇ , -S(O)2R ₇ ; wherein said alkyl is optionally substituted with 1-3 groups selected from hydroxyl, halogen, heterocycloalkyl and heteroaryl; alternatively, two R4 on the same atom together form an oxo (=O) group;

R ₅ is in each case independently hydrogen, alkyl or halogen;

R ₆ represents alkyl, alkoxy, hydroxy, cyano, halogen or haloalkyl;

R ₇ is alkyl, hydroxy, alkoxy, -NReRf, cycloalkyl, heterocycloalkyl or heteroaryl; wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is further optionally substituted with one or more R ₆ ;

Ra and Rb are each independently hydrogen or alkyl;

Rc and Rd are each independently hydrogen or alkyl; alternatively Rc and _Rd together represent an oxo (=O) group;

Re and Rf are each independently hydrogen or alkyl; alternatively, R _e and Rf together with the nitrogen atom to which they are attached form an optionally substituted 3-7 membered heterocyclic ring with 1-2 additional heteroatoms selected from N, O and S; wherein the additional substituent is one or more R6;

m represents an integer from 1 to 3.

In some embodiments, the present invention provides compounds of formula (IJ)

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; where X1, X2, X ₃ , R1, R2, R4, R _a , R _b and m are the same as defined in formula (I). In some embodiments, the present invention provides compounds of formula (IK)

- 7 046513

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; where X1, X2, X ₃ , R1, R2, R _a and Rb are the same as defined in formula (I). In some embodiments, the present invention provides compounds of formula (IL)

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof;

where the ring A, X1, X2, X ₃ , R1, R2, R ₇ , R _a and Rb are the same as defined in formula (I).

In some embodiments, the present invention provides compounds of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof;

wherein X1, X2 and _X3 are each independently CR5 or N;

ring A is 3-10 membered heterocycloalkyl or 3-10 membered heteroaryl;

R represents hydrogen, alkyl or halogen;

R1 represents or

R2 is hydrogen or alkyl; alternatively, R1 and R2 together with the nitrogen atom to which they are attached form a bicyclic heterocyclyl ring optionally containing 12 additional heteroatoms selected from N, O and S; wherein the bicyclic heterocyclyl ring is optionally substituted with one or more R6,

R3 is hydrogen or alkyl;

R4 in each occurrence is independently hydrogen, halogen, haloalkyl, cyano, alkyl, -C(O)R ₇ , -alkyl-C(O^ ₇ , -S(O) ₂ R ₇ ; wherein said alkyl is optionally substituted with 1- 3 groups selected from hydroxyl, halogen, 3-10 membered heterocycloalkyl and 3-10 membered heteroaryl; alternatively, two R4 on the same atom together form an oxo (=O) group;

R5 is in each case independently hydrogen, alkyl, or halogen;

R6 is alkyl, alkoxy, hydroxy, cyano, halogen or haloalkyl;

R ₇ is alkyl, hydroxy, alkoxy, -NReRf, 3-10 membered cycloalkyl, 3-8 membered heterocycloalkyl or 3-10 membered heteroaryl; wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is further optionally substituted with one or more R ₆ ;

Ra and Rb are each independently hydrogen or alkyl;

Rc and Rd are each independently hydrogen or alkyl; alternatively Rc and _Rd together represent an oxo (=O) group;

R _e and R _f are each independently hydrogen or alkyl; alternatively, R _e and R _f together with the nitrogen atom to which they are attached form an optionally substituted 3-7 membered heterocyclic ring with 1-2 additional heteroatoms selected from N, O and S; wherein the additional substituent is one or more R6, m is an integer from 1 to 3; and n is 0 or 1.

According to some other embodiments, the present invention relates to a compound that is

formula (I), where the ring

In some embodiments, Ring A is a 3-10 membered monocyclic ring system.

According to the previous embodiment, the monocyclic ring system is a carbocyclyl ring system or a heterocyclyl ring system.

In some embodiments, ring A is a 6-12 member ring

- 8 046513 lic ring selected from fused, bridged and spirocyclic ring systems.

According to the previous embodiment, the bicyclic ring system is a carbocyclyl ring system or a heterocyclyl ring system.

In some embodiments, ring A is

where X represents the site of attachment to the ring containing X1, X2 and _X3 . In some embodiments, ring A is

where X represents the site of attachment to the ring containing X1, X2 and _X3 .

In some embodiments, ring A is

where X represents the site of attachment to the ring containing X1, X2 and _X3 .

In some embodiments, X1, X2, and _X3 are each CR5; or X1 is N, X2 and _X3 are CR5; or X2 is N, X1 and _X3 are CR5; or X2 is CR5, X1 and _X3 are N; or X1 is CR5, X2 and _X3 are N; or each X1, X2 and _X3 represent N; or X ₃ represents CR5, X1 and X2 represent N.

In some embodiments, X1, X2, and _X3 are each CR5; X1 represents N, X2 and X3 represent CR5; or X2 is N, X1 and _X3 are CR5; or X1 is CR5, X2 and _X3 are N; or X2 is CR5, X1 and _X3 are N; or X ₃ represents CR5, X1 and X2 represent N.

In some embodiments, X1, X2, and _X3 are each CR5; where R5 represents hydrogen.

In some embodiments, X1, X2, and _X3 are each CR5; where R5 independently represents halogen or alkoxy.

According to some options

and R2 is hydrogen.

implementation R ₁ represents

Ar ^R ' implementation group ^R 2 represents

According to some options

- 9 046513

^4'R ' ^OO

In some embodiments, the ^R 2 group is R ⁷ , optionally substituted with one or more halogens or alkoxy.

4- ^R '

In some embodiments, the group ^R2 is WYn/CQ.....KO

In some embodiments, R ₃ , Ra, Rb, Rc, and Rd are each hydrogen.

In some embodiments, R1 and R2, together with the nitrogen atom to which they are attached, form a bicyclic heterocyclyl ring, optionally containing from 1 to 3 additional heteroatoms selected from N, O and S; wherein the bicyclic heterocyclyl ring is optionally substituted with one or more halogens or alkoxy.

In some embodiments, R2 is hydrogen.

In some embodiments, R3 is hydrogen.

In some embodiments, R4 is hydrogen in each case.

In some embodiments, R4 is acyl.

In some embodiments, R4 is each independently hydrogen, halogen, haloalkyl, cyano, alkyl, hydroxy, or alkoxy; wherein said alkyl is optionally substituted with 1-3 groups selected from hydroxyl, halogen, heterocycloalkyl and heteroaryl.

In some embodiments, R4 is, in each instance, independently -C(O)R7, -alkyl-C(O^ ₇ , or -S(O)2R7; wherein R7 is selected from alkyl, alkoxy, -NReRf cycloalkyl, or heterocycloalkyl; each alkyl, cycloalkyl and heterocycloalkyl are further optionally substituted with one or more R6.

In some embodiments, R4 is, in each instance, independently, hydrogen, halogen, -C(O)R7, -alkyl-C(O^ ₇ , or -S(O)2R7, ' ^or

In some embodiments, two R ₄ on the same atom together form an oxo (=O) group.

In some embodiments, R4 is -C(CH ₃ ) ₂ -COOH or -C(CH3)2-COOCH2CH3.

In some embodiments, R5 is each independently hydrogen, alkyl, or halogen.

In some embodiments, R5 is independently hydrogen or fluorine.

In some embodiments, R6 is each independently alkyl, alkoxy, or halogen.

In some embodiments, R ₇ is alkyl, hydroxy, alkoxy, or -NR _e Rf, each optionally substituted with one or more R6.

In some embodiments, R7 is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; wherein the optional substituent is selected from one or more R6.

In some embodiments, Ra, Rb, _Rc , and Rd are each hydrogen.

In some embodiments, Rc and Rd together represent an oxo (=O) group.

In some embodiments, Re and Rf, together with the nitrogen atom to which they are attached, form an optionally substituted 3-7 membered heterocyclic ring with 1-2 additional heteroatoms selected from N, O and S; wherein the optional substituent is independently selected from alkyl, alkoxy, hydroxy, cyano and halogen.

In some embodiments, R _e and R _f are each alkyl; wherein alkyl represents methyl.

In some embodiments, n is 0. In some embodiments of the present invention, if n is 0, then a ring containing X1, X2, and _X3 is directly attached to a central imidazolidinone ring containing Ra to Rd, as described in connection formula (I).

In some embodiments, m is at least 2 for oxo substitution.

In some embodiments, n is 1.

- 10 046513

In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from: ________

Connected not no. Nomenclature name GORAS 1 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((5-(4(pyrrolidin-1-carbonyl)piperidin-1 -yl) pyridine-2- yl)methyl)imidazolidin-2-one; 2 (R)-1 -((5 -(4-acetylpiperazin-1 -yl)pyrazin-2-yl)methyl)-3 -(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) In-2-one azolide imide; 3 (R)-1 -((5 -(4-acetylpiperazin-1 -yl)pyridin-2-yl)methyl)-3 -(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) In-2-one azolide imide; 4 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((5morpholinopyridin-2-yl)methyl)imidazolidin-2-one; 5 (R)-1 -((5 -(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)methyl)-3 -(3 (3,4-dihydroisoquinoline-2( 1 H)-yl)-2-hydroxypropyl)imide azolidin-2one; 6 (R)-1 -((5 -(4-(cyclopropanecarbonyl)piperazin-1 -yl)pyrid in-2yl)methyl)-3 -(3-(3,4-dihydroisoquinolin-2(1H)-yl)- 2hydroxypropyl)imidazolidin-2-one; 7 (R)-1 -((5 -(4-acetylpiperide in-1 -yl)pyrazin-2-yl)methyl)-3 -(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )imide azolide in-2-one; 8 (R)-1 -((5 -(4-(cyclopropanecarbonyl)piperazin-1 -yl)pyrazin-2yl)methyl)-3 -(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2hydroxypropyl )imidazolidin-2-one; 9 (R)-1 -(6-((3 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1 -yl)methyl)pyr idin-3 - yl)piperide in-4carbonitrile; 10 (R)-1 -(5 -((3 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1 -yl)methyl)pyrazin-2-yl )piperidine-4-

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carbonitrile; eleven (R)-1 -((5 -(4-acetylpiperide in-1 -yl)pyridin-2-yl)methyl)-3 -(3 -(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )imide azolide in-2-one; 12 (R)-1 -((5 -(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)methyl)-3 -(3 (3,4-dihydroisoquinoline-2( 1 H)-yl)-2-hydroxypropyl)imide azolidin-2one; 13 3thh(R)-2-(1 -(6-((3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2hydroxypropyl)-2-oxoimid azolidin-1 -yl)methyl)pyride in-3 yl)piperidin-4-yl)-2-methylpropanoate; 14 (R)-2-(l -(6-((3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)2-oxoimid azolidin-1 -yl)methyl)pyr idin-3-yl)piperidin-4-yl)-2methylpropanoic acid; 15 (R)-1 -(6-((3 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1 -yl)methyl)pyr idin-3 - yl)-1H, N-dimethylpiper idine4-sulfonamide; 16 (R)-1 -(5 -((3 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)pyridin-2-yl )-K, N-dimethylpiper idine4-sulfonamide; 17 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1 H)-yl)-2-hydroxypropyl)-3 -((6-(4(pyrrolidin-1 -carbonyl)piperidin-1 -yl )pyr idin-3 yl)methyl)imidazolidin-2-one; 18 1-((5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)methyl)-3-(^)3 -(3,4-d ihydroisoquinoline-2 (1H)-yl)-2-hydroxypropyl)imide azolidin2-one; 19 1-((5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)methyl)-3-(^)3 -(3,4-d ihydroisoquinoline-2 (1H)-yl)-2-hydroxypropyl)imide azolidin2-one; 20 1 -((5 -((3R, 5 8)-4-acetyl-3,5-d imethylpiperazin-1 -yl)pyrid in-2yl)methyl)-3 -((R)-3 -(3,4 -d ihydroisoquinolin-2(1H)-yl)-2hydroxypropyl)imidazolidin-2-one; 21 1 -((5 -(4-acetyl-2-methylpiperazin-1 -yl)pyridin-2-yl)methyl)-3 -((R)-3 (3,4-dihydroisoquinolin-2(1H)-yl )-2-hydroxypropyl)imide azolidin-2one; 22 1 -((5 -(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrid in-2-yl)methyl)-3 -((R)3 -(3,4-d ihydroisoquinoline -2(1H)-yl)-2-hydroxypropyl)imide azolidin2-one; 23 1 -((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)methyl)-3 -((R)3-(3,4-dihydroisoquinoline- 2(1H)-yl)-2-hydroxypropyl)imidazolidin2-one; 24 1-((5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrazin-2-yl)methyl)-3-(^)3 -(3,4-d ihydroisoquinoline-2 (1H)-yl)-2-hydroxypropyl)imide azolidin2-one; 25 1 -((6-(3,3-difluoro-8-azabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)methyl)-3 (^)-3-(3,4-dihydroisoquinoline- 2(1H)-yl)-2- hydroxypropyl)imidazolidin-2-one; 26 1-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzyl)-3-(^)-3-(3,4dihydroisoquinolin-2(1H)-yl)-2- hydroxypropyl)imidazolidin-2-one; 27 1 -((6-(3-oxa-6-azabicyclo[3.1.1] heptan-6-yl)pyridin-3-yl)methyl)-3 (^)-3-(3,4-dihydroisoquinoline-2 (1H)-yl)-2-

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hydroxypropyl)imidazolidin-2-one; 28 1-(4-(3 -oxa-8 -azabicyclo[3.2.1 ]octan-8-yl)-3 -fluorobenzyl)-3 -((R)-3 -(3,4dihydroisoquinolin-2(1H)-yl )-2-hydroxypropyl)imide azolide in-2-one; 29 1-((5-(3-oxa-6-azabicyclo[3.1.1] heptan-6-yl)pyridin-2-yl)methyl)-3 ((K)-3-(3,4-dihydroisoquinoline-2 (1H)-yl)-2- hydroxypropyl)imidazolidin-2-one; thirty 1-((5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-fluoropyridin-2yl)methyl)-3 -((R)-3 -(3,4-d ihydroisoquinolin-2(1H)-yl)-2hydroxypropyl)imidazolidin-2-one; 31 1-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-fluorobenzyl)-3-(^)-3-(3,4dihydroisoquinolin-2(1H)-yl) -2-hydroxypropyl)imide azolide in-2-one; 32 (R)-1-((6-(1-acetylpiperide in-4-yl)pyridin-3-yl)methyl)-3 -(3 -(3,4dihydroisoquinolin-2(1H)-yl)-2- hydroxypropyl)imide azolide in-2-one; 33 (R)-1-((5-(1-acetylpiperide in-4-yl)pyridin-2-yl)methyl)-3 -(3 -(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )imide azolide in-2-one; 34 (R)-1-((5-(1-acetylpiperide in-4-yl)pyrazin-2-yl)methyl)-3 -(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )imide azolide in-2-one; 35 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((5(tetrahydro-2H-pyran-4-yl)pyridin-2-yl )methyl)imidazolidin-2-one; 36 (R)-1-((5-(1 -(cyclopropanecarbonyl)piper idin-4-yl)pyr idin-2 yl)methyl)-3 -(3-(3,4-dihydroisoquinolin-2(1H)-yl )-2hydroxypropyl)imidazolidin-2-one; 37 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((5(pyridin-3-yl)pyrazin-2-yl)methyl)imidazolidine -2-she; 38 (R)-1-((6-(1-acetylpiperide in-4-yl)pyridazin-3-yl)methyl)-3 -(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )imide azolide in-2-one; 39 1 -((5 -(1 -acetylpiperidin-4-yl)pyridin-2-yl)methyl)-3 -(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,4dimethylimidazolidine -2-she; 40 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((5(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl )methyl)imidazolidin-2-one; 41 (R)-1-((5-(1 -(cyclopropanecarbonyl) piper idin-4-yl)pyraz in-2yl)methyl)-3 -(3-(3,4-dihydroisoquinolin-2(1H)-yl) -2hydroxypropyl)imidazolidin-2-one; 42 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((5(pyrimidin-5-yl)pyridin-2-yl)methyl)imidazolidine -2-she; 43 (R)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((5-(1(methylsulfonyl)piperidin-4-yl)pyridin-2 -yl)methyl)imide azolide in-2one; 44 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((5-( 1 propionylpiperidin-4-yl)pyridin-2-yl)methyl )imidazolidin-2-one; 45 (S)-1 -((5 -(1-acetylpiperidin-4-yl)pyridin-2-yl)methyl)-3 -(3 -(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) In-2-one azolide imide; 46 1 -((5 -(1 -acetylpiper idin-3 -yl)pyridin-2-yl)methyl)-3 -((R)-3 -(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )imide azolide in-2-one; 47 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((5-(1 methylpiperidin-4-yl)pyridin-2-yl)methyl )imidazolidin-2-one; 48 ^)-1-((G-acetyl-G,2',3',6'-tetrahydro-[3,4'-bipyridin]-6-yl)methyl)-3-(3(3,4-dihydroisoquinoline -2(1H)-yl)-2-hydroxypropyl)imide azolidin-2-

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she; 49 (R)-1 -((5-(3,6-d ihydro-2H-pyran-4-yl)pyrid in-2-yl)methyl)-3 -(3-(3,4dihydroisoquinoline-2(1H) -yl)-2-hydroxypropyl)imide azolide in-2-one; 50 ^)-5-(6-((3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1 -yl)methyl)pyr idin-3 -yl) pyrimidine-2carbonitrile; 51 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((6(tetrahydro-2H-pyran-4-yl)pyridazin-3- yl)methyl)imidazolidin-2-one; 52 (R)-6'-((3 -(3 -(3,4-dihydroisoquinolin-2( 1 H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1 -yl)methyl)-1 -methyl-[3 ,3'-bipyridine]-6(1H)-one; 53 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((5-( 1 (3 -methyloxetane-3-carbonyl)piper idin-4 -yl)pyr idin-2yl)methyl)imidazolidin-2-one; 54 ^)-5-(2-((3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)pyridin-4-yl)pyrimidine -2carbonitrile; 55 ^)-5-(6-((3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)pyridin-2-yl)pyrimidine -2carbonitrile; 56 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((2'hydroxy-[3,4'-bipyridin]-6-yl) methyl)imidazolidin-2-one; 57 (R)-1-((6-(1 -(cyclopropanecarbonyl)piperidin-4-yl)pyridin-3 yl)methyl)-3 -(3-(3,4-dihydroisoquinolin-2(1H)-yl) -2hydroxypropyl)imidazolidin-2-one; 58 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((2'methoxy-[2,4'-bipyridin]-5 -yl) methyl)imidazolidin-2-one; 59 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((2'methoxy-[2,4'-bipyridin]-5 -yl) methyl)imidazolidin-2-one; 60 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((6'methoxy-[2,3'-bipyridin]-5 -yl) methyl)imidazolidin-2-one; 61 (R)-6'-((3 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)-[3,3'- bipyridine]-6(1H)-one; 62 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((6'methoxy-[3,3'-bipyridin]-6-yl) methyl)imidazolidin-2-one; 63 (R)-5-((3 -(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)-[2,3'-bipyridine ]-6'(1'H)-she; 64 (R)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((2'isopropoxy-[3,4'-bipyridin]-6-yl )methyl)imidazolidin-2-one; 65 (R)-6-((3 -(3-(3,4-dihydroisoquinolin-2( 1 H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1 -yl)methyl)-1 '-methyl-[ 3 ,4'-bipyridine]-2'(1'H)-one; 66 1 -((5 -(8-oxabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methyl)-3 -((R)-3 (3,4-dihydroisoquinoline-2( 1 H )-yl)-2-hydroxypropyl)imide azolidin-2one; 67 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((2'isopropoxy-|'2,4'-bipyridin]-5-yl )methyl)imidazolidin-2-one; 68 1 -((R)-3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((5-(3 methyltetrahydro-2H-pyran-4-yl)pyridin-2 -yl)methyl)imide azolidin-2 she; 69 (R)-5-((3 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-

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oxoimidazolidin-1 -yl)methyl)-1'-methyl-[2,4'-bipyridin]-2'(1'H)-one; 70 1 -((R)-3 -(3,4-dihydroisoquinolin-2(1 H)-yl)-2-hydroxypropyl)-3 -((6-(3 methyltetrahydro-2H-pyran-4-yl)pyr idine -3-yl)methyl)imide azolidin-2 she; 71 1 -((R)-3 -(3,4-dihydroisoquinolin-2(1 H)-yl)-2-hydroxypropyl)-3 -((6-(3 methyltetrahydro-2H-pyran-4-yl)pyr idine -3-yl)methyl)imide azolidin-2 she; 72 1-((5-(8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methyl)-3((E)-3-(3,4-dihydroisoquinoline-2 (1H)-yl)-2hydroxypropyl)imidazolidin-2-one; 73 1-((6-(8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)methyl)-3(^)-3-(3,4-dihydroisoquinoline-2( 1H)-yl)-2hydroxypropyl)imidazolidin-2-one; 74 1 -((6-(8-oxabicyclo[3.2.1 ]octan-3 -yl)pyridin-3 -yl)methyl)-3 -((R)-3 (3,4-dihydroisoquinoline-2(1H) -yl)-2-hydroxypropyl)imide azolidin-2one; 75 1 -((6-cyclopropylpyridin-3 -yl)methyl)-3 -(3 -(3,4-dihydroisoquinolin2(1H)-yl)-2-hydroxypropyl)imidazolidin-2-one; 76 3 -((6-cyclopropylpyridin-3 -yl)methyl)-1 -(3 -(3,4-d ihydroisoquinolin2(1H)-yl)-2-hydroxypropyl)-5,5-dimethylimidazolidine-2,4-dione ; 77 1 -((R)-3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((5(tetrahydro-2H-pyran-3-yl)pyridin-2-yl )methyl)imidazolidin-2-one; 78 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((5(oxetan-3-yl)pyridin-2-yl)methyl)imidazolidine -2-she; 79 (R)-1-((5-(1-acetylazetide in-3-yl)pyrid in-2-yl)methyl)-3 -(3 -(3,4dihydroisoquinolin-2(1H)-yl)-2- hydroxypropyl)imide azolide in-2-one; 80 1 -((5 -(1 -acetylpyrrolid in-3 -yl)pyridin-2-yl)methyl)-3 -((R)-3 -(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )imide azolide in-2-one; 81 1 -((5 -(4-acetylpiperazin-1 -yl)pyridin-2-yl)methyl)-3 -(3 -(8-fluoro-3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) In-2-one azolide imide; 82 1 -((5 -(4-acetylpiperazin-1 -yl)pyridin-2-yl)methyl)-3 -(3-(6,7dihydrothieno[3,2-c]pyridin-5(4H)-yl)- 2- hydroxypropyl)imidazolidin-2-one; 83 1 -((5 -(4-acetylpiperazin-1 -yl)pyridin-2-yl)methyl)-3 -(3-(3,4dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)- 2- hydroxypropyl)imidazolidin-2-one; 84 1 -((5 -(4-acetylpiperazin-1 -yl)pyridin-2-yl)methyl)-3 -(2-hydroxy-3 (isoindolin-2-yl)propyl)imidazolidin-2-one; 85 1 -((5 -(4-acetylpiperazin-1 -yl)pyridin-2-yl)methyl)-3 -(3-(6,7d ihydropyrazolo[1,5-a]pyrazin-5 (4H)-yl) -2- hydroxypropyl)imidazolidin-2-one; 86 1-((5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)methyl)-3-(3((2,3-dihydro-1 H-indene -2-yl)amino)-2-hydroxypropyl)imide azolidin2-one; 87 1-((5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)methyl)-3-(2hydroxy-3-(quinolin-2-ylamino)propyl) imidazolidin-2-one; 88 1-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-3 -((5(tetrahydro-2H-pyran-4-yl)pyridin-2- yl)methyl)imidazolidin-2-one; 89 (R)-1-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-3 -((5-

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(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)methyl)imidazolidin-2-one; 90 (S)-1 -(3 -((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-3 -((5 (tetrahydro-2H-pyran-4-yl) pyridin-2-yl)methyl)imidazolidin-2-one; 91 5-(6-((3-(3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2hydroxypropyl)-2-oxoimid azolidin-1-yl)methyl)pyride in- 3 yl)pyrimidine-2-carbonitrile; 92 5-(6-((3 -(3 -((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2oxoimidazolidin-1 -yl)methyl)pyridin-3 -yl )pyrimidine-2carbonitrile; 93 1-(3-((2,3-dihydro-1H-inden-5-yl)amino)-2-hydroxypropyl)-3 -((5(tetrahydro-2H-pyran-4-yl)pyridin-2- yl)methyl)imidazolidin-2-one; 94 1 -(2-hydroxy-3 -(naphthalene-2-ylamino)propyl)-3 -((5 -(tetrahydro-2Hpyran-4-yl)pyridin-2-yl)methyl)imidazolidin-2-one; 95 (R)-1 -(6-((3 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1 -yl)methyl)pyr idin-3 - yl)in-4-carboxylic acid piperid; 96 (R)-1 -((5 -(4-(azetidine-1-carbonyl)piperidin-1-yl)pyride in-2-yl)methyl)3 -(3 -(3,4-dihydroisoquinoline-2( 1 N)-yl)-2- hydroxypropyl)imidazolidin-2-one; 97 (R)-1 -(6-((3 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1 -yl)methyl)pyr idin-3- yl)-N, N-dimethylpiper idine4-carboxamide; 98 (R)-1 -((5-( 1 -((1H-1,2,3-triazol-4-yl)methyl)piperidin-4-yl)pyridin-2yl)methyl)-3 -(3-( 3,4-dihydroisoquinolin-2(1H)-yl)-2- hydroxypropyl)imidazolidin-2-one; 99 (R)-1 -((5-(1 -((2H-tetra azol-5-yl)methyl)piperidin-4-yl)pyridin-2yl)methyl)-3 -(3-(3,4-dihydroisoquinoline -2(1H)-yl)-2- hydroxypropyl)imidazolidin-2-one; 100 (R)-6'-((3 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)-2-oxo-2H- [1,3'-bipyr idine]-4carbonitrile; 101 (R)-6'-((3 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)-2H-|'1, 3'-bipyridine]-2-one; 102 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((5-(2(pyrrolidin-1-carbonyl)pyrimidin-5 -yl) pyride in-2- yl)methyl)imidazolidin-2-one; 103 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1 H)-yl)-2-hydroxypropyl)-3 -((6-(2(pyrrolidin-1 -carbonyl)pyrimidin-5 -yl )pyrid in-3 - yl)methyl)imidazolidin-2-one and 104 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-methoxypropyl)-3 -((5 (tetrahydro-2H-pyran-4-yl)pyridin-2- yl)methyl)imidazolidin-2-one;

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

Pharmaceutical compositions.

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

In some embodiments, the pharmaceutical composition of the present invention further includes at least one agent selected from an anticancer agent, a chemotherapeutic agent, and an antiproliferative compound.

In some embodiments, the anticancer agent, chemotherapeutic agent, and antiproliferative compound is selected from 1) an aldosterone synthase inhibitor; 2) ALK inhibitor; apoptosis inducer; 3) aromatase inhibitor; 4) CART cells (eg, CD19-targeting CART cells); 5) BCR-ABL inhibitor; 6) BRAF inhibitor; 7) CDK inhibitor; 8) SEACAM inhibitor (for example, SEACAM-1, -3 and/or -5); 9) c-KIT inhibitor; 10) c-MET inhibitor; 10) cRAP inhibitor; 11) CTLA4 inhibitor; 12) a cytochrome P450 inhibitor (for example, a CYP17 inhibitor); 13) EGF inhibitor; 14) ERK1/2 ATP inhibitor; 15) an FGF inhibitor (eg, an FGFR2 or FGFR4 inhibitor); 16) Flt3 inhibitor (eg FLK2/STK1); 17) P-cycloprotein 1 inhibitor; 18) HDAC inhibitor; 19) HDM2 inhibitor; 20) FIER3 inhibitor; 21) histamine release inhibitor; 22) HSP90 inhibitor; 23) IAP inhibitor; 24) IDH inhibitor; 25) IDO inhibitor; 26) IGF-1R inhibitor; 27) iron chelating agent; 28) Janus inhibitor; 29) LAG-3 inhibitor; 30) M-CSF inhibitor; 31) MEK inhibitor; 32) mTOR inhibitor; 33) p53 inhibitor (eg, p53/Mdm2 interaction inhibitor); 34) PDGFRP inhibitor; 35) PKC inhibitor; 36) PI3K inhibitor; 37) PIM inhibitor; 38) PRLR inhibitor; 39) Raf kinase C inhibitor; 40) Smoothened receptor inhibitor (SMO); 41) a somatostatin agonist and/or growth hormone release inhibitor; 42) transduction modulator and/or angiogenesis inhibitor; 43) VEGFR-2 inhibitor (eg, FLK-1/KDR); 44) a tyrosine kinase inhibitor (for example, CSF-1R tyrosine kinase); 45) Wnt signal transduction inhibitor; 46) Bcl-2 inhibitor; 47) Mc1-1 inhibitor; 48) BTK inhibitor; 49) molecules with dual activity, such as CUDC-907 (dual PI3K/HDAC inhibitor) and 50) bromodomain inhibitor BET.

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The compositions and methods of the present invention can be used to treat a subject in need thereof. In some embodiments, the subject is a mammal, such as a human or non-human. When administered to an animal, such as a human, the composition or compound is preferably administered in the form of a pharmaceutical composition containing, for example, a compound of the present invention and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers are well known in the art and include, for example, water or aqueous solutions such as physiologically buffered saline or other solvents or carriers such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, if such pharmaceutical compositions are suitable for administration to humans, in particular for invasive routes of administration (i.e. routes such as injection or implantation that bypass transport or diffusion across an epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients may be selected, for example, to provide sustained release of the agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition may be in the form of a dosage unit such as a tablet, capsule (including break-open capsule and gelatin capsule), granule, lyophilic reconstitution, powder, solution, syrup, suppository, injection or the like. The composition may also be present in a transdermal delivery system, such as a skin patch. The composition may also be present in a solution suitable for topical application, such as eye drops.

The pharmaceutically acceptable carrier may contain physiologically acceptable agents that act, for example, to stabilize, increase solubility, or increase absorption of a compound, such as a compound of the present invention. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose or dextrans, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or adjuvants. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The pharmaceutical composition may be a self-emulsifying drug delivery system or a self-forming microemulsion drug delivery system. The pharmaceutical composition (drug) may also be a liposome or other polymer matrix, which may contain, for example, a compound of the present invention. Liposomes, for example, which contain phospholipids or other lipids, are non-toxic, physiologically acceptable and metabolizable carriers that are relatively easy to prepare and administer.

The compositions may, for convenience, be presented in unit dosage form and may be prepared by any methods well known in the pharmaceutical art. The amount of active ingredient that can be combined with the carrier to form a unit dosage form will vary depending on the host being treated and the particular route of administration. The amount of active ingredient that can be combined with the carrier to form a unit dosage form will generally be that amount of the compound that produces a therapeutic effect. Typically, this amount will range from about 1 percent to about ninety-nine percent active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

Methods for preparing such formulations or compositions include the step of coupling an active compound, such as a compound of the present invention, to a carrier and, optionally, one or more additional ingredients. In general, the formulations are prepared by uniformly and intimately binding the compound of the present invention to liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

The compositions of the present invention suitable for oral administration may be in the form of capsules (including pop capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, typically sucrose and gum or tragacanth ), lyophilic powders, granules, or in the form of a solution or suspension in an aqueous or non-aqueous liquid, or in the form of an oil-in-water or water-in-oil liquid emulsion, or in the form of an elixir or syrup, or in the form of lozenges (using an inert bases such as gelatin and glycerin or sucrose and gum) and/or mouthwash and the like, each of which contains a predetermined amount of a compound of the present invention as an active ingredient. The compositions or compounds may also be administered as a bolus, electuary, or paste.

In some embodiments, the present invention provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more therapeutically active co-administered agents.

Combination Therapeutics Products.

In some embodiments, a compound of formula (I) may be administered together

- 17 046513 with another therapeutic agent, for example, with 1) an aldosterone synthase inhibitor; 2) ALK inhibitor; apoptosis inducer; 3) an aromatase inhibitor; 4) CART cells (eg, CD19-targeting CART cells); 5) BCR-ABL inhibitor; 6) BRAF inhibitor; 7) CDK inhibitor; 8) a SEACAM inhibitor (for example, SEACAM-1, -3 and/or -5); 9) c-KIT inhibitor; 10) c-MET inhibitor; 10) cRAP inhibitor; 11) CTLA4 inhibitor; 12) a cytochrome P450 inhibitor (for example, a CYP17 inhibitor); 13) EGF inhibitor; 14) ERK1/2 ATP inhibitor; 15) an FGF inhibitor (eg, an FGFR2 or FGFR4 inhibitor); 16) Flt3 inhibitor (eg FLK2/STK1); 17) Rcycloprotein 1 inhibitor; 18) FTDAC inhibitor; 19) HDM2 inhibitor; 20) HER3 inhibitor; 21) histamine release inhibitor; 22) HSP90 inhibitor; 23) IAP inhibitor; 24) IDH inhibitor; 25) IDO inhibitor; 26) IGF-1R inhibitor; 27) iron chelating agent; 28) Janus inhibitor; 29) LAG-3 inhibitor; 30) M-CSF inhibitor; 31) MEK inhibitor; 32) mTOR inhibitor; 33) p53 inhibitor (eg, p53/Mdm2 interaction inhibitor); 34) PDGFRP inhibitor; 35) PKC inhibitor; 36) PI3K inhibitor; 37) PIM inhibitor; 38) PRLR inhibitor; 39) Raf kinase C inhibitor; 40) Smoothened receptor inhibitor (SMO); 41) a somatostatin agonist and/or growth hormone release inhibitor; 42) a transduction modulator and/or an angiogenesis inhibitor; 43) VEGFR-2 inhibitor (eg, FLK-1/KDR); 44) a tyrosine kinase inhibitor (for example, CSF-1R tyrosine kinase); 45) Wnt signal transduction inhibitor; 46) Bcl-2 inhibitor; 47) Mcl-1 inhibitor; 48) BTK inhibitor; 49) molecules with dual activity, such as CUDC907 (dual PI3K/FTDAC inhibitor) and 50) bromodomain inhibitor BET.

Additional therapeutic agents suitable for co-administration with the compounds and compositions disclosed herein have been described, for example, in the following publications: WO2016/100882; WO2016/054555; WO2016/040892; WO2015/097536; WO2015/088847; WO2015/069770, WO2015/026634; WO 2015/009856; EP 1377609 B1; Antonia, et al., Clin. Cancer Res. 2014 20:6258-6268; and Melero, et al., Nature Reviews Cancer 2015 15:457-472. Each publication is incorporated herein by reference in its entirety.

In some embodiments, the present invention provides a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

The compounds of the present invention can be prepared by a number of synthetic routes similar to those known in the literature using suitable starting materials. The compounds according to formula (I) can be prepared, for example, analogously or in accordance with the reaction schemes given in the experimental section of this application.

Methods of treatment.

In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof as described herein for use as a medicament.

In some embodiments, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for the manufacture of a medicament for inhibiting protein arginine methyltransferase 5 (PRMT5).

In some embodiments, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof as described herein for the manufacture of a medicament for the treatment of diseases or disorders mediated by PRMT5.

In some embodiments, the present invention provides a method of treating cancer or a proliferative disorder comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the present invention provides methods for inhibiting tumor cell growth and/or metastasis by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the present invention provides a method of treating or preventing PRMT5-mediated diseases or disorders comprising administering to a subject, as needed, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the present invention provides a method for treating or preventing cancer, an inflammatory disorder, an autoimmune disease, a metabolic disorder, an inherited disease, a hormone-related disease, an immunodeficiency disorder, a cell death condition, a bone destructive disorder, thrombin-induced platelet aggregation , liver disease and cardiovascular disorder, comprising administering to the subject, as needed, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof.

In other embodiments, the metabolic disorder is diabetes mellitus or obesity.

- 18 046513

In some embodiments, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for the manufacture of a medicament for the treatment of cancer, an inflammatory disorder, an autoimmune disease, a metabolic disorder, an inherited disease, a hormone-related disease, an immunodeficiency disorder, a condition, associated with cell death, bone destruction disorder, thrombin-induced platelet aggregation, liver disease and cardiovascular disorder.

In some embodiments, the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, for the treatment of cancer.

In some embodiments, the present invention relates to the use of the compounds of the present invention for the manufacture of a medicament for the treatment and prevention of a proliferative disease. In some embodiments, the proliferative disease is cancer. In some embodiments, the proliferative disease is a benign neoplasm, an angiogenic disease, an inflammatory disease, an autoinflammatory disease, or an autoimmune disease. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is Hodgkin's lymphoma. In some embodiments, the cancer is non-Hodgkin's lymphoma. In some embodiments, the cancer is Burkitt's lymphoma. In some embodiments, the cancer is diffuse large B cell lymphoma (DLBCL). In some embodiments, the cancer is a MALT lymphoma. In some embodiments, the cancer is germinal center B cell-derived diffuse large B cell lymphoma (GCB-DLBCL) or primary mediastinal B cell lymphoma (PMBL). In some embodiments, the cancer is activated B cell-derived diffuse large B cell lymphoma (ABC-DLBCL).

In any of the above embodiments, the cancer or proliferative disorder is selected from the group consisting of solid tumor, benign or malignant tumor, brain, kidney, liver, stomach, vaginal, ovarian, stomach, breast, bladder, colon, prostate, pancreas, lung, cervix, testicle, skin, bone or thyroid; sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck and head tumors, hyperproliferation of the epidermis, psoriasis, prostatic hyperplasia, neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphomas, lymphomas Hodgkin and non-Hodgkin lymphoma, breast carcinoma, follicular carcinoma, papillary carcinoma, seminoma, melanoma; hematological malignancies selected from leukemia, diffuse large B-cell lymphoma (DLBCL) derived from activated B-cells DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia (WM), splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma and multiple myeloma.

In some embodiments, the present invention provides a method of inhibiting protein arginine methyltransferase 5 (PRMT5) comprising administering to a subject, as needed, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for use in the treatment or prevention of diseases or disorders mediated by PRMT5.

In some embodiments, the diseases or disorders mediated by PRMT5 are cancer, a blood disorder, an inflammatory disorder, an autoimmune disease, a metabolic disorder, an inherited disorder, a hormone-related disease, an immunodeficiency disorder, a cell death condition, a bone destructive disorder, thrombin-induced platelet aggregation, liver disease or cardiovascular disorder.

In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for use in the treatment of diseases or disorders mediated by PRMT5.

In some embodiments, the diseases or disorders mediated by PRMT5 are cancer, metabolic disorder, inflammation, autoimmune disease, or hemoglobinopathy.

- 19 046513

In some embodiments, the diseases or disorders mediated by PRMT5 are cancer, a blood disorder, a metabolic disorder, inflammation, an autoimmune disease, or a hemoglobinopathy.

In some embodiments, the cancer as defined herein is selected from glioblastoma, melanoma, ovarian cancer, lung cancer, prostate cancer, breast cancer, colon cancer, gastric cancer, esophageal cancer, and hepatocellular carcinoma.

In some embodiments, the cancer is a solid tumor, benign or malignant tumor, carcinoma of the brain, kidney, liver, stomach, vagina, ovary, stomach, breast, bladder, colon, prostate, pancreas, lung, cervix uterus, testicle, skin, bone or thyroid gland; sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck and head tumor, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, lymphoma Hodgkin and non-Hodgkin lymphoma, breast carcinoma, follicular carcinoma, papillary carcinoma, seminoma, melanoma; hematological malignancies selected from leukemia, diffuse large B-cell lymphoma (DLBCL) derived from activated B-cells DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia (WM), splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma and multiple myeloma.

In some embodiments, the cancer is medulloblastoma, glioblastoma, melanoma, ovarian cancer, lung cancer, prostate cancer, breast cancer, colon cancer, gastric cancer, esophageal cancer, and hepatocellular carcinoma.

In some embodiments, the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, for the manufacture of a medicament for the treatment or prevention of cancer.

In some embodiments, the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, for the manufacture of a medicament for the treatment or prevention of diseases or disorders selected from glioblastoma, melanoma, ovarian cancer, lung cancer, prostate cancer, cancer breast, colon cancer, gastric cancer, esophageal cancer and hepatocellular carcinoma.

In some embodiments, the blood disorder is sickle cell disease or beta thalassemia.

In some embodiments, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for the manufacture of a medicament for the treatment or prevention of beta thalassemia.

In some embodiments, the present invention provides for administering to a subject, as appropriate, this therapeutically effective amount of a compound of the present invention along with one or more additional chemotherapeutic agents independently selected from antiproliferative agents, anticancer agents, immunosuppressive agents, and analgesics.

Definitions.

Unless otherwise noted, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which the subject matter of the present invention belongs. As used in the specification and appended claims, unless otherwise noted, the following terms have the meanings given to facilitate understanding of the present invention.

Singular forms cover plural references unless the context clearly indicates otherwise.

As used herein, the terms optional or optional mean that the sequentially described event or condition may or may not occur, and that the description includes cases in which the event or condition occurs as well as cases in which it does not occur. For example, optionally substituted alkyl refers to an alkyl that may be substituted, as well as an event or condition in which the alkyl is not substituted.

The term substituted refers to moieties containing substituents that replace hydrogen at one or more backbone carbon atoms. It will be understood that substitution or substituted includes the presupposition that such substitution occurs according to the permissible valency of the substituted atom and substituent and that the substitution results in a stable compound, for example, that does not spontaneously undergo transformations such as redistribution, cyclization, exclusion, etc. P. As used herein, the term substituted

- 20 046513 is intended to include all permissible substituents for organic compounds. In broad terms, acceptable substituents include acyclic and cyclic, branched and straight-chain, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Acceptable substituents may be one or more and may be the same or different for the respective organic compounds. For purposes of the present invention, heteroatoms, such as nitrogen, may contain hydrogen substituents and/or any permissible substituents of the organic compounds described in the present invention that satisfy the valency of the heteroatoms. Substituents may include any of the substituents described in the present invention, for example, halogen, hydroxyl, alkyl, alkenyl, alkynyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as a thioester, thioacetate or thioformate), alkoxyl, oxo, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heteroaryl, heterocycloalkyl, aralkyl, or an aromatic or heteroaromatic moiety . Those skilled in the art will appreciate that the substituents themselves may be substituted as desired.

As used herein, the term alkyl refers to saturated aliphatic groups, including, but not limited to, C|-C| ₀ straight chain alkyl groups or C ₃ C ₁₀ branched chain alkyl groups. Preferably, the alkyl group is a straight chain QC ₆ alkyl group or a branched chain C ₃ -C ₆ alkyl group. Most preferably, the alkyl group is a straight chain C1- _C4 alkyl group or a branched chain _C3 -C8 alkyl group. Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1- hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl and 4-octyl. The alkyl group may optionally be substituted.

As used herein, the term alkenyl refers to a carbon chain that contains at least one carbon-carbon double bond and which may be straight or branched or combinations thereof. Examples of alkenyl include, but are not limited to, vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, and 2-methyl-2-butenyl. The alkenyl group may optionally be substituted.

As used herein, the term alkynyl refers to straight or branched carbon chains with one or more triple bonds, where the number of atoms ranges from C ₂ to C ₆ . The alkynyl group may be optionally substituted.

As used herein, the term halo or halogen, alone or in combination with other term(s), means fluorine, chlorine, bromine or iodine.

As used herein, the term haloalkyl means an alkyl substituted with one or more halogen atoms, with halogen and alkyl groups as defined above. The term halo in the present invention is used interchangeably with the term halogen, which means F, Cl, Br or I. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.

As used herein, the term hydroxy or hydroxyl, alone or in combination with other term(s), means -OH.

As used herein, the term oxo refers to the =O group.

As used herein, the term alkoxy refers to the group -O-alkyl, where alkyl groups are defined above. An exemplified C1- _C10 alkoxy group includes, but is not limited to, methoxy, ethoxy, n-propoxy, n-butoxy or t-butoxy. The alkoxy group may be optionally substituted with one or more suitable groups.

As used herein, the term cyano refers to the -CN group.

Amino as used herein refers to the -NH2 group.

As used herein, the term cycloalkyl, alone or in combination with other term(s), means a C ₃ -C ₁₀ saturated cyclic hydrocarbon ring. The cycloalkyl may be a simple ring, which typically contains from 3 to 7 carbon ring atoms. Examples of single-ring cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused and spirocyclic carbocyclyls.

As used herein, the term heterocycloalkyl refers to a non-aromatic, saturated or partially saturated, bridged bicyclic, spirocyclic, monocyclic or polycyclic ring system of 3-15 members containing at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O) ₂ , NH or C(O), with the remaining ring atoms independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. The term heterocycloalkyl also refers to a bridged bicyclic ring system containing at least one heteroatom or heterogroup selected from O, N, S, S(O),

- 21 046513

S(O)2, NH or C(O). Examples of heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl , oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl , tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, azabicyclooctanyl, azocinyl, chromanyl, isochromanyl, xanthenyl, 2-oxa-6-azaspiro[3.3]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl and their N- oxides The addition of a heterocycloalkyl substituent can occur either through a carbon atom or a heteroatom. The heterocycloalkyl group may be optionally substituted by one or more suitable groups from one or more of the above groups. Preferably, heterocycloalkyl refers to a 5-6 membered ring selected from the group consisting of azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-di oksanila and their N-oxides. More preferably, heterocycloalkyl includes azetidinyl, pyrrolidinyl, morpholinyl, oxetane, pyridin-2(III)-one, 3,6-dihydro-2H-pyran, 1,2,3,6tetrahydropyridine, 3-oxa-6-azabicyclo[ 3.1.1]heptane and piperidinyl. All heterocycloalkyls are optionally substituted with one or more of the above groups.

As used herein, the term heteroaryl refers to an aromatic heterocyclic ring system containing from 5 to 20 ring atoms, in particular from 5 to 10 ring atoms, which may be a single ring (monocyclic) or multiple rings (bicyclic, tricyclic or polycyclic) fused together or bonded covalently. Preferably, the heteroaryl is a 5-6 membered ring. The rings may contain from 1 to 4 heteroatoms selected from N, O and S, where the N or S atom is optionally oxidized or the N atom is optionally quaternized. Any suitable ring position in a heteroaryl moiety can be covalently linked to a specific chemical structure.

Examples of heteroaryl include, but are not limited to: furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, N-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, tianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, α-carboline, indolizinyl, benzo isothiazolyl, benzoxazolyl, pyrrolopyridyl, pyrazolopyrimidyl, furopyridinyl, purinyl, benzothiadiazolyl, benzooxadiazolyl, benzotriazolyl, benzotriadiazolyl, carbazolyl, dibenzothienyl, 3-oxa-8azabicyclo[3.2.1]octane, 2-oxa-6-azaspiro[3.3]heptane, 2-oxa-7- azaspiro[3.5]nonane, acridinyl, etc. Preferably, heteroaryl refers to a 5-6 membered ring selected from the group consisting of furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, N-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinil. More preferably pyrazolyl, pyridyl, oxazolyl and furanyl. All heteroaryls are optionally substituted with one or more groups selected from halogen, hydroxyl, carboxylic acid, alkoxycarbonyl, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, oxo, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine , imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido and sulfonyl group.

As used herein, the term heterocyclyl, alone or in combination with other term(s), includes both heterocycloalkyl and heteroaryl groups as defined above.

As used herein, the term aryl is an optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms. Examples of _C6 - _C14 aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, fluorenyl, indanyl, biphenylenyl and acenaphthyl. The aryl group may be optionally substituted with one or more substituents selected from halogen, hydroxyl, carboxylic acid, alkoxycarbonyl, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxyl, oxo, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido , amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido and sulfonyl group.

The term acyl refers to the group R-CO-, where R represents an optionally substituted alkyl group as defined above. Examples of acyl groups include, but are not limited to, CH3CO-, CH3CH2CO-, CH3CH2CH2CO- or (CH3)2CHCO-.

The term monocyclic ring refers to a saturated, partially saturated or aromatic single ring system.

The term bicyclic ring refers to a saturated, partially saturated or aromatic two-ring system. The bicyclic ring contains fused, spiro and also bridged rings.

- 22 046513

The term fused ring refers to a ring that is part of a ring system with two rings containing at least one bond and two common atoms.

The term spiro refers to a ring system consisting of two rings containing only one common carbon atom.

As used herein, the term heteroatom refers to a sulfur, nitrogen or oxygen atom.

The term bridged bicyclic refers to two rings that have three or more atoms in common, separating the two atoms at the head of the bridge by a bridge containing at least one atom.

As used herein, the term compound(s) includes the compounds disclosed in the present invention.

As used herein, the term contains or containing is generally used in the sense of inclusion, in other words allowing the presence of one or more features or components.

As used herein, the term either means and/or, unless otherwise noted.

As used herein, the term including, as well as other forms such as include, includes and included, are not limiting.

As used herein, the term composition covers a product containing specific ingredients in specific amounts, as well as any product that results, directly or indirectly, from the combination of specific ingredients in specific amounts. By pharmaceutically acceptable is meant a carrier, diluent or excipient that is compatible with the other ingredients of the formulation and not harmful to its recipient.

As used herein, the term pharmaceutical composition refers to composition(s) containing a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The pharmaceutical composition(s) typically contains from about 1% to 99%, for example from about 5% to 75% or from about 10% to about 30% by weight of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. The amount of a compound of formula (I) or pharmaceutically acceptable salts thereof in the pharmaceutical composition(s) may range from about 1 mg to about 1000 mg, or from about 2.5 mg to about 500 mg, or from about 5 mg to about 500 mg. 250 mg or any range falling within the wider range of 1 mg to 1000 mg or higher or lower than the above range.

As used herein, the term treat, treatment, and treatment technique refers to a method of alleviating or stopping a disease and/or its accompanying symptoms.

As used herein, the term prevent, warning and prevention refers to a method of preventing the onset of a disease and/or its accompanying symptoms or preventing the onset of a disease in a subject. As used herein, prevent, warn and prevent also include delaying the onset of a disease and/or its accompanying symptoms and reducing the risk of a subject becoming ill.

As used herein, the term subject, which may be interchangeable with patient, refers to an animal, preferably a mammal, and most preferably a human.

As used herein, the term therapeutically effective amount refers to the amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof; or a composition containing a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, effective in producing a desired therapeutic response in a particular patient suffering from a disease or disorder, in particular for use in diseases or disorders associated with cancer. In particular, the term therapeutically effective amount includes an amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, when administered, that produces beneficial changes in the disease or disorder being treated, or is sufficient to prevent the development of or alleviate to some extent one or more than one symptom of a disease or disorder being treated in the subject. Relative to the therapeutic amount of the compound, the amount of the compound used to treat the subject is low enough to avoid unnecessary or severe side effects, and may also be considered within the scope from a medical point of view. The therapeutically effective amount of a compound or composition will vary depending on the particular condition being treated, the severity of the condition being treated or prevented, the duration of treatment, the nature of the concomitant therapy, the age and physical condition of the end user, the particular compound or composition, and the particular pharmaceutically acceptable carrier used.

The term pharmaceutically acceptable salt refers to the product obtained by reacting a compound of the present invention with a suitable acid or base.

- 23 046513 vaniyam. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic bases, such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts. Examples of pharmaceutically acceptable, non-toxic acid addition salts are amine salts formed with inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate , ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, forat, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4methylbenzenesulfonate or para-toluenesulfonate salts, etc. Certain compounds of the present invention (compound of formula (I)) can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium or zinc salts.

Pharmaceutically acceptable means one that is useful for the preparation of a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes such a composition that is acceptable for veterinary as well as pharmaceutical use in humans.

The present invention also relates to methods for preparing compositions of compounds for pharmaceutical administration.

In a preferred embodiment, if such pharmaceutical compositions are suitable for administration to humans, in particular for invasive routes of administration (i.e. routes such as injection or implantation that bypass transport or diffusion across the epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free . Excipients may be selected, for example, to provide sustained release of the drug or to selectively target one or more cells, tissues or organs. The pharmaceutical composition may be in the form of a dosage form such as a tablet, capsule (including break-open capsule and gelatin capsule), granule, lyophilic, dissolvable, powder, solution, syrup, suppository, injection or the like. The composition may also be present in a transdermal delivery system, such as a skin patch. The composition may also be present in a solution suitable for topical administration, such as eye drops.

The term stereoisomers refers to any enantiomers, diastereoisomers or geometric isomers of the compounds of formula (I), whether they are chiral or whether they bear one or more double bonds. If the compounds of formula (I) and related formulas are chiral, they may exist in racemic or optically active form. It should be understood that the present invention covers all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as d-isomers and l-isomers and mixtures thereof. Individual stereoisomers of compounds can be obtained by synthesis from commercially available starting materials that contain chiral centers, or by preparing mixtures of enantiomeric products followed by resolution, for example, conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatography columns or any other appropriate method known in the art. The starting compounds of a particular stereochemistry are either commercially available or can be prepared and separated by methods known in the art. In addition, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis-, trans-, syn-, anti-, (E) and (Z) isomers, as well as suitable mixtures thereof.

The compounds of the present invention can be used as a single drug or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable substances.

Experimental section.

The following abbreviations refer as appropriate to the definitions herein: DMSO—dimethyl sulfoxide; DIPEA - NN-diisopropylethylamine; NaHCO ₃ - sodium bicarbonate; KF - potassium fluoride; EtOH - ethanol; MeOH - methanol; THF - tetrahydrofuran; SOC12 - thionyl chloride; NaH - sodium hydride; IPA - isopropyl alcohol; SiO2 - silicon dioxide; TFA - trifluoroacetic acid; DMAP - 4-dimethylaminopyridine; BINAP - 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; Pd(dppf)Cl ₂ [1,G-bis(diphenylphosphino)ferrocene]palladium(P) dichloride; Pd ₂ (dba) ₃ - tris(dibenzylideneacetone)dipalladium(O); dppf-1,1'-bis(diphenylphosphino)ferrocene; NiI ₂ - nickel(II) iodide; MgCl ₂ - magnesium chloride; DMA - dimethylacetamide; CuI - copper iodide; HATU - 1-[bis(dimethylamino)methylene]-1H-1,2,3triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; DME - dimethoxyethane; K ₃ PO ₄ - tripotassium phosphate; CDI - 1,1'-carbonyldiimidazole; MeI - methyl iodide; Na2CO3 - sodium carbonate; TMS-N3 - trimethylsilyl azide; H2O - water; br - wide; A - angstrom; °C - degrees Celsius; conc. - concentrated; CHC13 chloroform; CDCl ₃ /chloroform-d - deuterated chloroform; DMSO-dg - deuterated dimethyl sulfoxide; CH ₂ Cl ₂ - DCM -dichloromethane; DMF-^^dimethylformamide; Et ₂ O - diethyl ether; g gram; h - hours; 1H - proton; Hz - hertz; J is the interaction constant; LC-MS - liquid chromatograph

- 24 046513 Physics-mass spectroscopy; HPLC - high performance liquid chromatography; chiral HPLC chiral high performance liquid chromatography; M - molar; MHz - megahertz (frequency); MS mass spectroscopy; mmol - millimole; ml - milliliter; min - minutes; mole - mole; M+ - molecular ion; m/z is the ratio of mass to charge; n - normality; NMR - nuclear magnetic resonance; Et ₃ N/TEA triethylamine; ppm - parts per million; k.t./K. T. - room temperature; s - singlet; d - doublet, t triplet; q - quartet; m - multiplet; dd - doublet of doublets; td - triplet of doublets; qd - quartet of doublets; ddd - doublet of doublet of doublets; dt - doublet of triplets; ddt - doublet of doublet of triplets; p - pentane; TLC thin layer chromatography; THF - tetrahydrofuran; % - percentage ratio; mk - micron; µl microliter and δ - delta; without - anhydrous; and ± is a racemic mixture.

General methods of obtaining.

The following general rules apply to all experimental procedures described in the present invention. Unless otherwise noted, experiments were performed under positive nitrogen pressure and the temperature reported represents ambient temperature (ie, oil bath temperature). Reagents and solvents obtained from suppliers were used as received without additional drying or purification. The molarities mentioned in the present invention for reagents in solution are approximate because they have not been confirmed by previous titration with a standard. All reactions were carried out with stirring with a magnetic stirrer. Cooling to sub-zero temperatures was carried out using acetone/dry ice or natural ice/salts. Magnesium sulfate and sodium sulfate were used as the drying solvent after the reaction treatment and are interchangeable. Solvent removal under reduced pressure or vacuum refers to the distillation of solvents in a rotary evaporator.

The compounds of the present invention can be prepared by chemical synthesis methods, examples of which are shown in the present invention. It is understood that the order of steps in the processes can be changed such that reagents, solvents and reaction conditions can be substituted for those specifically indicated and that unprotected moieties can be protected or unprotected as needed.

Features of the process for obtaining the compounds of the present invention are described in detail in the experimental section.

The present invention will be illustrated by some examples, which should not be construed as limiting the scope of the present invention.

Unless otherwise specified, processing includes partitioning the reaction mixture between the organic and aqueous phases, separating the layers and drying the organic layer over anhydrous sodium sulfate, filtration and evaporation of the solvent. Purification, unless otherwise noted, involves purification by silica gel chromatographic methods, typically using ethyl acetate/petroleum ether of suitable polarity as the mobile phase.

The analysis of the compounds of the present invention, unless otherwise indicated, was carried out by general methods well known to one skilled in the art. Having described the present invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from the description. The present invention is further defined by reference to the following examples detailing the analysis of the compounds of the present invention.

It will be apparent to those skilled in the art that many modifications to the materials and methods may be practiced without departing from the scope of the present invention. Some intermediates were carried forward to the next step based on thin layer chromatography (TLC) results without further characterization unless otherwise noted.

Synthesis of intermediate compounds.

Intermediate-1. Synthesis of ^)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4dihydroisoquinolin-2(1H)-yl)propyl)imidazolidin-2-one.

Stage-a. Synthesis of ^)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline.

To a stirred solution of 1,2,3,4-tetrahydroisoquinoline (100.0 g, 750.0 mmol) in 1500 ml THF, KF (218.07 g, 3750.0 mmol) was added under nitrogen atmosphere and the reaction mixture was left stirring for 30 min at 0°C, N)-oxiran-2-ylmethyl-3nitrobenzenesulfonate in THF (500 ml) (213.86 g, 825.0 mmol) was added dropwise to this reaction mixture and stirred at room temperature for 12 hours After completion of the reaction (observed by TLC, eluent: 5% methanol in chloroform), the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 200 g of ^)-2-(oxiran-2-ylmethyl)-1,2 ,3,4-tetrahydroisoquinoline as a brown liquid, which was carried on to the next step without further purification.

^1H NMR (600 MHz, Chloroform-d) δ 7.17 - 7.08 (m, 3H), 7.07 -7.02 (m, 1H), 3.80 (d, J=14.8 Hz , 1H), 3.70 (d, J=14.9 Hz, 1H), 3.21 (dq, J=6.7, 3.3, 3.3, 3.2 Hz, 1H), 3, 01 - 2.86 (m, 4H), 2.86 - 2.76 (m, 2H), 2.56 (dd, J=5.1, 2.7 Hz, 1H), 2.45 (dd, J=13.3, 6.8 Hz, 1H).

Stage-b. Synthesis of ^)-1-((2-aminoethyl)amino)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol.

- 25 046513

Ethane-1,2-diamine (190.53 g, 3170 mmol) under a nitrogen atmosphere and the reaction mixture was stirred for 12 hours at 60°C. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with DCM, and the combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. pressure to obtain 250.0 g of ^)-1-((2-aminoethyl)amino)-3-(3,4dihydroisoquinolin-2(1H)-yl)propan-2-ol, which was transferred further to the next stage without further purification . LCMS: 250.1 [M+H]+.

Stage-s. Synthesis of (R)-1 -(3 -(3,4-dihydroisoquinolin-2(III)-yl)-2-hydroxypropyl)imidazolidin-2one.

To a stirred solution of ^)-1-((2-aminoethyl)amino)-3-(3,4-dihydroisoquinolin-2(III)yl)propan-2-ol (250.0 g, 1002.0 mmol) in 2500 ml DCM, DMAP (24.5 g, 200.5 mmol) and CDI (243.8 g, 1503.0 mmol) were added. The reaction mixture was stirred for 16 hours at RT. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was concentrated under reduced pressure to give (83.0 g, 30.08%) -1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)2-hydroxypropyl)imidazolidin-2-one in the form of a pale yellow viscous liquid. LCMS: 276.3 [M+H]+.

Stage-d. Synthesis of U)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(III)yl)propyl)imidazolidin-2-one.

To a stirred solution of A)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2hydroxypropyl)imidazolidin-2-one (83.0 g, 301.0 mmol) in 2500.0 ml DCM DIPEA (116.8 g, 904.0 mmol) and tert-butyldimethylsilyltrifluoromethanesulfonate (87.5 g, 331.0 mmol) were added at -78°C. The reaction mixture was stirred for 1 hour at -78°C and another 1 hour at 0°C. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was diluted with DCM and washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ , 30-100% ethyl acetate in hexane) to give (80.0 g, 68.21%) A)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3 ,4-dihydroisoquinolin-2(1H)-yl)propyl)imidazolidin-2-one as an off-white solid.

1H NMR (300 MHz, DMSO-d6) δ 7.15 - 6.98 (m, 4H), 6.27 (s, 1H), 4.06 - 3.94 (m, 1H), 3.67 - 3.51 (m, 2H), 3.51 - 3.38 (m, 2H), 3.26 - 3.02 (m, 4H), 2.85 - 2.63 (m, 4H), 2, 44 (dd, J=5.7, 3.3 Hz, 2H), 0.86 (s, 9H), 0.09 - -0.03 (m, 6H); TCMS: 390.3 [M+H]+.

Intermediate-2. Synthesis of A)-1-((5-bromopyridin-2-yl)methyl)-3-(2-((tertbutyldimethylsilyl)oxy)-3 -(3,4-dihydroisoquinolin-2(1H)-yl)propyl)imidazolidine -2-she.

To a stirred solution of A)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin2(III)-yl)propyl)imidazolidin-2-one (intermediate-1) (5, 0 g, 12.833 mmol) in 110.0 ml THF, NaH (60%) (0.616 g, 15.4 mmol) was added at 0°C and the reaction mixture was left stirring for 30 min at room temperature. Again the reaction mixture was cooled to 0°C and 5-bromo2-(bromomethyl)pyridine (3.83 g, 115.40 mmol) in THF (40.0 ml) was added dropwise and stirred for 12 h at RT. After completion of the reaction (observed using TLC, eluent: 5% methanol in DCM), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organics were washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ , 1-2% MeOH in DCM) to give (4.6 g, 64.05%) A)-1-((5-bromopyridin-2-yl)methyl)-3 -(2-((tertbutyldimethylsilyl)oxy)-3 -(3,4-dihydroisoquinolin-2(1H)-yl)propyl)imidazolidin-2-one.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.63 (dd, J=2.4, 0.7 Hz, 1H), 8.02 (dd, J=8.4, 2.5 Hz, 1H ), 7.29 - 7.22 (m, 1H), 7.13 - 6.98 (m, 4H), 4.32 (d, J=2.1 Hz, 2H), 4.08 - 4, 00 (m, 1H), 3.65 - 3.54 (m, 2H), 3.45 (dd, J=8.8, 6.8 Hz, 1H), 3.27 (q, J=8, 7, 7.9, 7.9 Hz, ZN), 2.79 (d, J=5.7 Hz, 2H), 3.23 - 3.13 (m, 2H), 2.71 (t, J =5.3, 5.3 Hz, 2H), 2.46 (t, J=6.0, 6.0 Hz, 1H) 2.35 -2.30 (m, 1H), 0.84 (s , 9H), 0.08 - -0.02 (m, 6H).

Intermediate-3. Synthesis of A)-1-((6-bromopyridin-3-yl)methyl)-3-(2-((tertbutyldimethylsilyl)oxy)-3 -(3,4-dihydroisoquinolin-2(1H)-yl)propyl)imidazolidine -2-she.

To a stirred solution of A)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin2(III)-yl)propyl)imidazolidin-2-one (intermediate-1) (30, 0 g, 76.998 mmol) in 400.0 ml THF, NaH (60%) (4.61 g, 115.497 mmol) was added at 0°C and the reaction mixture was left stirring for 30 min at room temperature, again the reaction mixture was cooled to 0°C, 2bromo-5-(bromomethyl)pyridine (22.98 g, 92.397 mmol) in THF (250.0 ml) was added dropwise and stirred for 12 hours at room temperature. After completion of the reaction (observed at using TLC, eluent: 5% methanol in DCM), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organics were washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 2-3% MeOH in DCM) to give (40.0 g, 93.0%) A)-1-((6-bromopyridin-3-yl)methyl)-3- (2-((tert

- 26 046513 butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propyl)imidazolidin-2-one.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.29 (dd, J=2.1, 1.3 Hz, 1H), 7.62 (q, J=1.4, 1.3, 1, 3 Hz, 2H), 7.13 - 7.06 (m, 3H), 7.05 - 6.97 (m, 1H), 4.26 (s, 2H), 4.03 (t, J=5 ,5, 5.5 Hz, 1H), 3.59 (d, J=4.2 Hz, 2H), 3.47 - 3.37 (m, 1H), 3.32 - 3.12 (m, 5H), 2.86 - 2.65 (m, 4H), 2.48 - 2.40 (m, 2H), 0.83 (d, J=1.7 Hz, 9H), 0.06 - - 0.03 (m, 6H).

Intermediate-4. Synthesis of ^)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4dihydroisoquinolin-2(1H)-yl)propyl)-3-((5-(piperidin-4-yl)pyridin- 2-yl)methyl)imidazolidin-2-one.

Stage-a. Synthesis of tert-butyl^)-6-((3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4dihydroisoquinolin-2(1H)-yl)propyl)-2-oxoimidazolidin-1-yl) methyl)-3',6'-dihydro-[3,4'-bipyridine]1'(2'H)-carboxylate.

^)-1-((5-bromopyridin-2-yl)methyl)-3-(2-((tertbutyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl) was added to the sealed test tube. propyl)imidazolidin-2-one (intermediate-2) (3.0 g, 5.36 mmol), DME/H2O (4:1) (100 ml), tert-butyl-4-(4,4,5 ,5-tetramethyl-1,3,2dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.3 g, 10.7 mmol), sodium carbonate (1.98 g, 18. 7 mmol) and Pd(dppf)Cl ₂ (1.02 g, 1.34 mmol), the reaction mixture was degassed with argon gas for 10 minutes and the reaction mixture was stirred for 12 hours at 70°C. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was diluted with water and extracted with ethyl acetate, the combined organics were washed with brine and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ , 1% MeOH in DCM) to give (2.8 g, 79.09%) tert-butyl^)-6-((3-(2-((tert-butyldimethylsilyl) oxy)-3-(3,4-dihydroisoquinolin-2(III)-yl)propyl)-2oxoimidazolidin-1-yl)methyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate. LCMS: 662.1 [M+H]+.

Stage-b. Synthesis of tert-butyl^)-4-(6-((3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4dihydroisoquinolin-2(1H)-yl)propyl)-2-oxoimidazolidin-1 -yl)methyl)pyridin-3-yl)piperidin-1carboxylate.

A mixture of tert-butyl^)-6-((3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)yl)propyl)-2-oxoimidazolidin-1-yl )methyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (1.5 g, 2.26 mmol) and 10% Pd-C (0. 3 g) in 70 ml ethanol were transferred to a Parr mixing vessel and hydrogenated at 60 psi. inch for 12 hours at RT. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ , 2% MeOH in DCM) to give (1.06 g, 70.66%) tert-butyl^)-4-(6-((3-(2((tert- butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propyl)-2-oxoimidazolidin-1yl)methyl)pyridin-3-yl)piperidin-1-carboxylate. LCMS: 664.6 [M+H] ⁺ .

Stage-s. Synthesis of ^)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(III)yl)propyl)-3-((5-(piperidin-4-yl)pyridine -2-yl)methyl)imidazolidin-2-one.

To a stirred solution of tert-butyl^)-4-(6-((3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4dihydroisoquinolin-2(1H)-yl)propyl)-2-oxoimidazolidine -1-yl)methyl)pyridin-3-yl)piperidin-1carboxylate (1.06 g, 1.596 mmol) in 20.0 ml DCM was added with TFA (3.0 ml) at 0°C and stirred for 12 h at RT. After completion of the reaction (observed by TLC, eluent: 10% methanol in DCM), the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water, made basic with sodium carbonate and extracted with DCM. The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.875 g ^)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4dihydroisoquinoline-2(III)- yl)propyl)-3-((5-(piperidin-4-yl)pyridin-2-yl)methyl)imidazolidin-2-one. LCMS: 564.5 [M+H] ⁺ .

Examples

The present invention is further illustrated, but not limited, by the following examples, which show the preparation of the compounds of the present invention.

Example-I. Synthesis of ^)-1-(3-(3,4-dihydroisoquinolin-2(III)-yl)-2-hydroxypropyl)-3-((5-(4(pyrrolidin-1-carbonyl)piperidin-1-yl) pyridin-2-yl)methyl)imidazolidin-2-one.

Compound-1

Stage-a. Synthesis of ^)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)yl)propyl)-3 -((5-(4-(pyrrolidine-1 - carbonyl)piperidin-1-yl)pyridin-2-yl)methyl)imidazolidin-2-one.

^)-1-((5-bromopyridin-2-yl)methyl)-3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl) was added to the stoppered test tube. propyl)imidazolidin-2-one (intermediate

- 27 046513 exact compound-2) (15.0 g, 26.8 mmol), 1,4-dioxane (300 ml), the reaction mixture was degassed with argon gas for 10 minutes. To this reaction mixture was added piperidin-4-yl(pyrrolidin1-yl)methanone (5.58 g, 32.2 mmol), sodium tert-butoxide (3.8 g, 40.0 mmol), Pd ₂ (dba) ₃ (2.45 g, 2.6 mmol) and BINAP (3.29 g, 5.3 mmol) and stirred for 12 h at 100°C. After completion of the reaction (observed by TLC, eluent: 5% methanol in CHCl ₃ ), the reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 1-2% MeOH in DCM) to give (9.0 g, 50.84%) ^)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3, 4-dihydroisoquinolin-2(1H)-yl)propyl)-3-((5-(4-(pyrrolidin-1carbonyl)piperidin-1-yl)pyridin-2-yl)methyl)imidazolidin-2-one. LCMS: 660.5 [M+H]+.

Stage-b. Synthesis of ^)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((5-(4(pyrrolidin-1-carbonyl)piperidin-1-yl) pyridin-2-yl)methyl)imidazolidin-2-one.

To a stirred solution ^)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin2(1H)-yl)propyl)-3-((5-(4-(pyrrolidin-1 -carbonyl)piperidin-1-yl)pyridin-2-yl)methyl)imidazolidin2-one (15.0 g, 22.6 mmol) in 200.0 ml THF was added TBAF (1 M solution in THF) (68.0 ml, 68.0 mmol) at 0°C and the reaction mixture was stirred for 12 hours at room temperature. After completion of the reaction (observed by TLC, eluent: 5% methanol in CHCl ₃ ), the reaction mixture was concentrated under reduced pressure and the residue diluted with water and extracted with ethyl acetate. The combined extracts were washed with saline and dried over anhydrous sodium sulfate. The resulting residue was purified by column chromatography (SiO ₂ , 6% MeOH in CHCl ₃ ) to give (R)-1-(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -( (5-(4-(pyrrolidin-1-carbonyl)piperidin-1 yl)pyridin-2-yl)methyl)imidazolidin-2-one as an off-white solid.

1H NMR (400 MHz, methanol^) δ 9.24 (dd, J=2.3, 0.9 Hz, 1H), 9.13 (d, J=1.6 Hz, 1H), 8.71 ( d, J=1.5 Hz, 1H), 8.64 (dd, J=5.0, 1.6 Hz, 1H), 8.52 (ddd, J=8.0, 2.3, 1, 6 Hz, 1H), 7.59 (ddd, J=8.1, 5.0, 0.9 Hz, 1H), 7.11 7.05 (m, 3H), 7.04 - 6.99 ( m, 1H), 4.58 (s, 2H), 4.08 (tt, J=7.2, 4.6 Hz, 1H), 3.73 (s, 2H), 3.63- 3.54 (m, 2H), 3.48 (td, J=7.8, 1.4 Hz, 2H), 3.37 (dd, J=14.2, 4.4 Hz, 1H), 3.21 ( dd, J=14.2, 7.1 Hz, 1H), 2.90 (d, J=5.5 Hz, 2H), 2.88 - 2.81 (m, 2H), 2.65 - 2 .55 (m, 2H), 2.009 -1.992 (m, 2H). TCMS: 547.2 [M+H]+.

The connections shown in the table below. 1 was prepared by a procedure similar to that described in Example-1 with appropriate variations in reagents, amounts of reagents, introduction and deprotection, solvents and reaction conditions. The characteristics of the compounds are shown in the table below.

Table 1 Connection no.

Characteristics

Ή NMR (400 MHz, Methanol-d4) δ 8.18 (d, J= 1.5 Hz, 1H), 8.11 - 8.07 (m, 1H), 7.13 - 7.07 (m, 3H), 7.03 (dd, J= 7.6, 2.3 Hz, 1H), 5.36 - 5.30 (m, 1H), 4.35 (d, J = 1.6 Hz, 2H ), 4.07 (tt, J = 7.1, 4.6 Hz, 1H), 3.77 (d, J = 2.7 Hz, 1H), 3.73 - 3.64 (m, 5H) , 3.61 (dd, J= 6.7, 3.7 Hz, 2H), 3.57 - 3.45 (m, 2H), 3.39 - 3.32 (m, 1H), 3.18 (dd, J = 14.2, 6.9 Hz, 1H), 2.91 (dq, J = 8.9, 4.7 Hz, 3H), 2.63 (dd, J = 6.1, 3 .6 Hz, 1H), 2.21-2.12 (m, 4H), 2.02 (q, J = 6.5 Hz, 2H), 1.59 (t, J = 7.3 Hz, 2H ). LCMS: 494.4[M+H] ⁺ , 'H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J= 2.9 Hz, 1H), 7.34 (dd, J= 8, 6, 3.0 Hz, 1H), 7.14 - 7.06 (m, 4H), 7.05 - 7.00 (m, 1H), 4.74 (d, J= 4.8 Hz, 1H ), 4.25 (s, 2H), 3.86 (s, 1H), 3.64 - 3.54 (m, 5H), 3.46 - 3.39 (m, 1H), 2.91 - 2.86 (m, 1H), 3.27 (dd, J= 13.9, 4.1 Hz, 1H), 3.20 (t, J = 6.5 Hz, 4H), 3.12 (t , J = 5.3 Hz, 2H), 3.01 (dd, J = 13.9, 7.2 Hz, 1H), 2.80 (t, J = 5.8 Hz, 2H), 2.75 - 2.65 (m, 3H), 2.43 (d, J = 6.0 Hz, 2H), 2.03 (s, 3H). LCMS: 493.4 [M+H] ⁺ .

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Ή NMR (400 MHz, Chloroform-d) δ 8.20 (dd, J= 2.9, 0.7 Hz, 1H), 7.23 (dd, J = 8.6, 0.7 Hz, 1H) , 7.20 - 7.09 (m, 4H), 7.04 - 6.97 (m, 1H), 4.48 - 4.38 (m, 2H), 3.99 (dddd, J= 9, 4, 6.5, 4.5, 3.2 Hz, 1H), 3.89 - 3.77 (m, 5H), 3.65 - 3.42 (m, 4H), 3.31 (t, J = 8.1 Hz, 2H), 3.20 - 3.12 (m, 5H), 2.96 - 2.86 (m, 3H), 2.79 - 2.69 (m, 1H), 2 .62 - 2.49 (m, 2H). LCMS: LCMS: 452 [M+H] ⁺ ._________________________ 'H NMR (400 MHz, DMSO-d6) δ 7.74 (dd, J = 2.9, 0.7 Hz, 1H), 7.13 - 7 .00 (m, 5H), 6.84 - 6.79 (m, 1H), 4.70 (s, 4H), 4.21 (s, 2H), 4.01 (d, J = 0.6 Hz, 4H), 3.86 (s, 1H), 3.60 (s, 2H), 3.40 (dd, J = 9.1, 7.5 Hz, 2H), 3.31 - 3.21 (m, 2H), 3.16 (t, J = 7.9 Hz, 2H), 3.00 (dd, J = 13.9, 7.2 Hz, 1H), 2.80 (t, J = 5.8 Hz, 2H), 2.71 (s, 2H), 2.43 (d, J = 6.3 Hz, 2H), LCMS: 464.4 [M+H] ⁺ ,___________ *H NMR ( 400 MHz, DMSO-d6) δ 8.24 (d, J= 2.9 Hz, 1H), 7.35 (dd, J= 8.6, 2.9 Hz, 1H), 7.15 - 7, 06 (m, 4H), 7.02 (dd, J = 6.6, 2.6 Hz, 1H), 4.73 (d, J = 4.8 Hz, 1H), 4.25 (s, 2H ), 3.84 (d, J = 15.8 Hz, 3H), 3.60 (s, 4H), 3.45 - 3.37 (m, 1H), 3.28 - 3.09 (m, 8H), 3.01 (dd, J = 13.9, 7.2 Hz, 1H), 2.80 (t, J = 5.8 Hz, 2H), 2.75 - 2.64 (m, 2H ), 2.44 (dd, J= 6.1, 3.5 Hz, 2H), 2.03 (tt, J= 7.7, 4.9 Hz, 1H), 0.77 0.68 (m , 4H). LCMS: 519.5 [M+H] ⁺ .

'H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.98 (s, 1H), 7.09 (d, J = 4.2 Hz, 3H), 7.02 ( d, J = 6.0 Hz, 1H), 4.73 (s, 1H), 4.33 - 4.20 (m, 3H), 3.86 (s, 1H), 3.60 (s, 2H ), 2.05 - 1.94 (m, 3H), 3.28 3.16 (m, 3H), 3.07 - 2.87 (m, 3H), 2.78 (d, J= 6, 1 Hz, 2H), 2.68 (s, 4H), 2.42 (s, 1H), 2.13 (s, 3H), 1.88 (d, J = 13.2 Hz, 2H), 1 .40 (d, J = 11.5 Hz, 2H). LCMS: 493.5 [M+H] ⁺ .

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8 J+, k .z _ V^z c>° s Ή NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 1.5 Hz, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.39 - 7.02 (m, 4H), 4.57 (t, J = 12.9, 12.9 Hz, 1H), 4.37 (dt, J = 22.7, 10.1, 10.1 Hz, 2H), 4.30 - 4.19 (m, 3H), 3.80 (s, 5H), 3.56 (s, 3H), 3.41 (t, J= 7.6, 7.6 Hz, 2H) , 3.30 - 3.21 (m, 3H), 3.18 (d, J = 5.6 Hz, 2H), 3.02 (t, J = 16.6, 16.6 Hz, 1H), 2.72 - 2.63 (m, 2H), 2.42 - 2.26 (m, 1H), 2.11 - 1.87 (m, 2H), 0.74 (tt, J = 7.9 , 7.9, 2.8, 2.8 Hz, 4H).LCMS: 520.5 [M+H] ⁺ . 9 O X XX but /J N hr 'H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J= 2.9 Hz, 1H), 7.32 (dd, J= 8.6, 3.0 Hz, 1H), 7, 08 (qd, J = 3.8, 1.5 Hz, 4H), 7.03 - 6.97 (m, J = 3.4 Hz, 1H), 4.72 (d, J = 4.7 Hz , 1H), 4.22 (s, 2H), 3.85 (h, J = 6.0 Hz, 1H), 3.62 - 3.56 (m, 2H), 3.44 3.35 (m , 3H), 3.28 - 3.15 (m, 4H), 3.09 2.95 (m, 4H), 2.78 (t, J = 5.8 Hz, 2H), 2.73 - 2 .64 (m, 2H), 2.42 (dd, J= 6.1, 3.5 Hz, 2H), 1.96 (ddt, J= 13.7, 7.1, 3.7 Hz, 2H ), 1.79 (dtd, J= 12.4, 8.5, 3.5 Hz, 2H); LCMS: LCMS: 475.4 [M+H] ⁺ . 10 0 Λνάν-Ύ. ^{H O} CO Ή NMR (400 MHz, DMSO-d6) δ 8.29 (d, J= 1.6 Hz, 1H), 8.01 (d, J= 1.5 Hz, 1H), 7.12 - 7.06 (m, 3H), 7.05 - 7.00 (m, 1H), 4.72 (d, J = 4.8 Hz, 1H), 4.23 (s, 2H), 3.85 (ddd, J = 13.6, 6.3, 3.7 Hz, ZN), 3.60 (s, 2H), 3.40 (td, J = 9.0, 4.5 Hz, ZN), 3.29 - 3.19 (m, 4H), 3.13 (tt, J = 8.4, 3.9 Hz, 1H), 3.00 (dd, J = 13.7, 7.2 Hz, 1H), 2.79 (d, J = 5.8 Hz, 2H), 2.70 (dd, J = 5.9, 3.7 Hz, 2H), 2.43 (dd, J = 6.1, 2, 5 Hz, 2H), 1.93 (ddt, J= 13.6, 7.3, 3.6 Hz, 2H), 1.79 - 1.63 (m, 2H); LCMS: LCMS: 476.4 [M+H] ⁺ . AND 0 X χχ ^but j o 'NMR (400 MHz, Methanol-d4) δ 8.17 (d, J = 2.9 Hz, 1H), 7.41 (dd, J = 8.7, 3.0 Hz, 1H), 7.25 (d, J= 8.7 Hz, 1H), 7.16 7.10 (m, 3H), 7.06 (dd, J = 7.8, 2.2 Hz, 1H), 4.38 (s , 2H), 4.11 (tt, J = 7.1, 4.5 Hz, 1H), 3.85 - 3.72 (m, 4H), 3.60 - 3.49 (m, 2H), 3.41 - 3.34 (m, 1H), 3.22 (dd, J = 14.2, 6.9 Hz, 1H), 2.96 (s, 4H), 2.84 (td, J= 12.2, 2.7 Hz, 2H), 2.73 - 2.55 (m, 3H), 2.21 (s, 3H), 2.09 - 1.96 (m, 2H), 1.77 - 1.60 (m, 4H); LCMS: 492.4 [M+H] ⁺ .

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12 8 b b A Ή NMR (400 MHz, DMSO-d6) δ 8.21 (d, J= 2.9 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.08 (tt, J = 8, 6, 4.2 Hz, 4H), 7.04 - 7.00 (m, 1H), 4.72 (d, J= 4.8 Hz, 1H), 4.33 (s, 4H), 4, 22 (s, 2H), 3.86 (s, 1H), 3.60 (s, 2H), 3.46 - 3.39 (m, 1H), 3.18 (t, J = 7.9 Hz , 2H), 3.13 - 3.08 (m, 3H), 3.05 - 2.96 (m, 4H), 2.79 (t, J= 5.9 Hz, 2H), 2.71 ( t, J = 5.2 Hz, 2H), 2.45 - 2.39 (m, 2H), 1.91 - 1.81 (m, 4H); LCMS: 492.5 [M+H] ⁺ . 13 o L o 88A8 ^but / ^Ν Ά__ ° l ^<ν -\3 'H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J= 2.9 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.31 - 7.23 (m , 3H), 7.18 (dd, J = 19.1, 7.7 Hz, 2H), 5.84 (s, 1H), 4.55 (d, J = 11.7 Hz, 1H), 4 .40 (s, 2H), 4.28 (d, J = 1.8 Hz, 2H), 4.23 (d, J = 12.9 Hz, 1H), 4.07 (q, J = 7, 1, 7.1, 7.1 Hz, 3H), 3.81 (d, J= 12.6 Hz, 3H), 3.43 (t, J= 7.8, 7.8 Hz, 1H), 3.33 - 3.16 (m, 6H), 3.13 - 2.98 (m, 2H), 2.70 - 2.59 (m, 2H), 1.72 - 1.56 (m, 3H ), 1.35 (td, J = 12.5, 12.5, 3.9 Hz, 2H), 1.17 (t, J = 7.1, 7.1 Hz, 3H), 1.08 ( s, 6H). LCMS: 564.5 [M+H] ⁺ . 14 O JI _ JSC/Gr, An\J/ ABOUT ( \ Hc/fy Ή NMR (400 MHz, DMSO-d6) δ 8.19 (d, J= 2.9 Hz, 1H), 7.29 (dd, J = 8.7, 3.0 Hz, 1H), 7.12 - 7.05 (m, 4H), 7.04 - 7.00 (m, 1H), 4.73 (s, 1H), 4.22 (s, 2H), 3.86 (p, J= 5 .9 Hz, 1H), 3.78 (d, J= 12.2 Hz, 2H), 3.60 (s, 2H), 3.47 - 3.38 (m, 1H), 3.27 (dd , J = 13.8, 4.0 Hz, 1H), 2.35 2.31 (m, 1H), 3.19 (t, J = 8.0 Hz, 2H), 3.00 (dd, J = 13.9, 7.2 Hz, 1H), 2.79 (t, J = 6.1 Hz, 2H), 2.75 - 2.66 (m, 2H), 2.64 - 2.54 ( m, 2H), 2.46 - 2.39 (m, 3H), 1.63 (td, J = 13.8, 12.0, 7.5 Hz, 3H), 1.44 1.28 (m , 2H), 1.04 (s, 6H); LCMS: 536.5 [M+H] ⁺ . 15 0 if V^n^ _n _ \ AAL / < GG Z^A °\ 1 j HO Ν-Λ ъ _ъ Cq 'H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J= 2.9 Hz, 1H), 7.33 (dd, J= 8.7, 3.0 Hz, 1H), 7, 12 - 7.06 (m, 4H), 7.05 - 7.00 (m, 1H), 4.73 (d, J= 4.7 Hz, 1H), 4.24 (s, 2H), 3 .83 (d, J = 13.2 Hz, 2H), 3.60 (s, 2H), 3.52 - 3.37 (m, 3H), 3.31 - 3.17 (m, 3H), 3.01 (dd, J= 13.9, 7.2 Hz, 1H), 2.85 (s, 6H), 2.82 - 2.76 (m, 5H), 2.76 - 2.64 ( m, 3H), 2.44 (s, 2H), 1.97 (d, J = 11.9 Hz, 2H), 1.70 (qd, J = 12.4, 4.1 Hz, 2H); LCMS: 557.4 [M+H] ⁺ .

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Ή NMR (400 MHz, DMSO-d6) δ 7.99 (d, J= 2.4 Hz, 1H), 7.40 (dd, .J ~ 8.7, 2.5 Hz, 1H), 7, 13 - 7.05 (m, 3H), 7.04 - 6.99 (m, 1H), 6.84 (d, J= 8.7 Hz, 1H), 4.73 (d, J = 4, 8 Hz, 1H), 4.37 (d, J = 13.4 Hz, 2H), 4.12 (s, 2H), 3.85 (d, J = 6.6 Hz, 1H), 3.59 (s, 2H), 3.55 - 3.46 (m, 1H), 3.32 - 3.22 (m, 3H), 3.09 (t, J = 7.9 Hz, ZN), 2, 99 (dd, J = 13.9, 7.1 Hz, 2H), 2.83 (s, 8H), 2.73 - 2.64 (m, 2H), 2.42 (dd, J = 6, 1, 2.9 Hz, 2H), 1.93 (d, J = 11.9 Hz, 2H), 1.54 (qd, J = 12.4, 4.1 Hz, 2H); LCMS: 557.4 [M+H] ⁺ o

Ή NMR (400 MHz, Methanol-d4) δ 7.99 (d, J= 2.4 Hz, 1H), 7.48 (dd, J= 8.8, 2.5 Hz, 1H), 7.15 - 7.06 (m, 3H), 7.03 (dd, J = 5.4, 2.2 Hz, 1H), 6.82 (d, J = 8.9 Hz, 1H), 4.31 ( dt, J= 13.2, 3.3 Hz, 2H), 4.21 (dd, J = 8.4, 1.9 Hz, 2H), 4.05 (tt, J= 7.2, 4, 6 Hz, 1H), 3.74 (d, J = 2.2 Hz, 2H), 3.61 (t, .7 = 6.8 Hz, 2H), 3.54 - 3.45 (m, 2H ), 3.43 - 3.34 (m, 3H), 3.28 - 3.11 (m, 4H), 2.95 - 2.84 (m, 5H), 2.78 (ddt, J = 11 ,4, 7.2, 4.0 Hz, 1H), 2.66 - 2.56 (m, 2H), 2.00 (p, J= 6.8 Hz, 2H), 1.93 - 1, 85 (m, 2H), 1.82 - 1.64 (m, 4H). LCMS: 547.5 [M+H] ⁺ .

Ή NMR (400 MHz, DMSO-d6) δ 7.99 (dd, J = 2.3, 0.7 Hz, 1H), 7.40 (dd, J = 8.6, 2.4 Hz, 1H) , 7.16 - 7.06 (m, 3H), 7.03 (d, J = 5.0 Hz, 1H), 6.77 (dd, J = 8.7, 0.8 Hz, 1H), 4.73 (s, 1H), 4.42 (s, 2H), 4.12 (s, 2H), 3.85 (s, 1H), 3.61 (d, J = 10.8 Hz, ZN ), 3.51 - 3.46 (m, 2H), 3.44 - 3.36 (m, 1H), 3.31 - 3.22 (m, 3H), 3.19 - 3.08 (m , 3H), 3.00 (dd, J = 13.8, 7.1 Hz, 1H), 2.79 (s, 2H), 2.70 (s, 2H), 2.44 (d, J= 9.5 Hz, 1H), 1.98 - 1.89 (m, 2H), 1.81 (dd, J = 8.1, 4.2 Hz, 2H). LCMS: 478.8 [M+H] ⁺ .

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^X H NMR (400 MHz, Methanol-d4) δ 8.07 (dd, J - 2.9, 0.7 Hz, 1H), 7.29 (dd, J 8.7, 2.9 Hz, 1H) , 7.25 - 7.20 (m, 1H), 7.13 - 7.06 (m, 3H), 7.05 - 7.00 (m, 1H), 4.35 (s, 2H), 4 .22 - 4.14 (m, 2H), 4.07 (tt, J= 7.3, 7.3, 4.6, 4.6 Hz, 1H), 3.82 (d, J = 10, 9 Hz, 2H), 3.73 (s, 2H), 3.58 3.47 (m, 4H), 3.41 - 3.32 (m, 3H), 3.19 (dd, J = 14, 2, 7.1 Hz, 1H), 2.95 - 2.81 (m, 4H), 2.67 - 2.53 (m, 2H), 2.13 - 1.95 (m, 4H); LCMS: 478.3 [M+H] ⁺ .

Ή NMR (400 MHz, DMSO-d6) δ 7.99 (d, J= 2.4 Hz, 1H), 7.42 (dd, J= 8.8, 2.4 Hz, 1H), 7.09 (dd, J = 5.4, 3.6 Hz, 3H), 7.05 - 7.00 (m, 1H), 6.90 (d, J = 8.7 Hz, 1H), 4.73 ( d, J = 4.8 Hz, 1H), 4.20 (d, J = 12.9 Hz, 2H), 4.13 (s, 2H), 3.85 (s, 1H), 3.60 ( s, 2H), 3.39 (d, J = 7.9 Hz, 1H), 2.36 - 2.31 (m, 2H), 3.26 (dd, J = 13.9, 4.1 Hz , 1H), 3.10 (t, J = 7.9, 7.9 Hz, 2H), 3.00 (dd, J = 13.9, 7.2 Hz, 1H), 2.91 (s, 3H), 2.79 (t, J = 5.9, 5.9 Hz, 2H), 2.70 (dd, J = 5.7, 3.5 Hz, 1H), 2.43 (dd, J = 6.1, 2.6 Hz, 2H), 2.05 (s, 3H), 2.00 (q, J= 6.8, 6.8, 6.1 Hz, 1H), 1.24 ( s, 6H); LCMS: 521.3 [M+H] ⁺ .

Ή NMR (400 MHz, Methanol-d4) δ 8.04 (t, J= 2.1, 2.1 Hz, 1H), 7.51 (dd, J= 8.8, 2.5 Hz, 1H) , 7.14 - 7.01 (m, 4H), 6.80 6.74 (m, 1H), 5.37 - 5.30 (m, 1H), 4.60 4.41 (m, 2H) , 4.39 - 4.28 (m, 1H), 4.24 (d, J= 1.7 Hz, 2H), 4.13 - 3.92 (m, 2H), 3.82 (d, J = 11.7 Hz, 2H), 3.57 - 3.45 (m, 2H), 3.38 - 3.33 (m, 2H), 3.27 - 3.14 (m, 4H), 3, 11 - 3.02 (m, 2H), 2.94 (s, 4H), 2.66 (dd, J= 8.8, 2.7 Hz, 2H), 2.24 - 2.16 (m, 2H), 2.12 (s, 1H), 2.02 (d, J = 6.5 Hz, 2H); LCMS: 507.3 [M+H] ⁺ .

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'H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J= 2.9 Hz, 1H), 7.20 (dd, J = 8.7, 3.0 Hz, 1H), 7, 14 - 7.00 (m, 5H), 4.73 (d, J = 4.8 Hz, 1H), 4.42 (d, J = 3.3 Hz, 2H), 4.23 (s, 2H ), 4.12 (q, J= 5.3, 5.3, 5.3 Hz, 1H), 3.85 (p, J = 5.7, 5.7, 5.7, 5.7 Hz , 1H), 3.60 (s, 2H), 3.47 - 3.37 (m, 4H), 3.27 (dd, J= 13.9, 4.1 Hz, 1H), 3.22 3 .14 (m, 3H), 3.00 (dd, 7= 13.9, 7.2 Hz, 1H), 2.81 (dt, 7= 11.7, 3.7, 3.7 Hz, 2H ), 2.71 (p, 7 = 5.9, 5.9, 5.8, 5.8 Hz, 2H), 2.46 - 2.38 (m, 2H), 1.83 (t, J = 2.7, 2.7 Hz, 4H); LCMS: 478.1 [M+H] ⁺ .

'NMR (300 MHz, DMSO-d6) 67.98 (d, 7= 2.4 Hz, 1H), 7.40 (dd, 7= 8.7, 2.5 Hz, 1H), 7.13 - 6.98 (m, 4H), 6.69 (d, 7= 8.7 Hz, 1H), 4.72 (s, 1H), 4.41 (s, 2H), 4.12 (s, 2H ), 3.85 (s, 1H), 3.81 - 3.71 (m, 2H), 3.64 - 3.56 (m, 2H), 3.37 (dq, J = 1.7 , 0.6, 0.6, 0.6 Hz, 1H), 3.32 - 3.20 (m, 2H), 3.04 (dt, 7= 21.6, 7.2, 7.2 Hz , 3H), 2.89 (dd, 7= 12.4, 2.6 Hz, 2H), 2.79 (d, J - 5.6 Hz, 2H), 2.75 - 2.67 (m, 2H), 2.46 - 2.37 (m, 2H), 1.89 - 1.66 (m, 4H). LCMS: 478.1 [M+H] ⁺ .

'H NMR (400 MHz, Methanol-d4) δ 8.11 (d, 7= 1.4 Hz, 1H), 8.08 (d, 7= 1.4 Hz, 1H), 7.36 - 7, 17 (m, 1H), 7.14 - 7.00 (m, 3H), 4.52 (d, 7 = 4.5 Hz, 2H), 4.35 (s, 2H), 4.07 (tt , J = 6.9, 6.9, 4.6, 4.6 Hz, 1H), 3.81 - 3.70 (m, 4H), 3.64 - 3.47 (m, 4H), 3 .44 - 3.35 (m, 3H), 3.19 (dd, J = 14.2, 7.0 Hz, 1H), 2.92 (t, 7 = 6.0, 6.0 Hz, 2H ), 2.85 (dd, 7 = 6.6, 4.2 Hz, 2H), 2.65 - 2.54 (m, 2H), 2.15 - 1.96 (m, 4H); LCMS: 479.0 [M+H] ⁺ ,_______________ 'll NMR (300 MHz, DMSO-d6) δ 8.04 (d, 7= 2.3 Hz, 1H), 7.45 (dd, 7= 8 ,6, 2.4 Hz, 1H), 7.07 (d, 7= 17.3 Hz, 4H), 6.84 (d, 7= 8.6 Hz, 1H), 4.73 (s, 1H ), 4.61 (s, 2H), 4.14 (s, 2H), 3.93 - 3.81 (m, 1H), 3.69 - 3.55 (m, 2H), 3.45 - 3.39 (m, 2H), 3.30 - 3.20 (m, 2H), 3.15 - 3.09 (m, 2H), 3.07 - 2.95 (m, 2H), 2, 80 (s, 2H), 2.75 2.70 (m, 1H), 2.44 (dq, 7 = 3.7, 1.8, 1.8, 1.8 Hz, 2H), 2.09 (d, 7 = 3.6 Hz, 2H), 1.95 (dt, 7 = 19.8, 10.4, 10.4 Hz, 5H); LCMS: 512.1 [M+H] ⁺ .

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Ή NMR (400 MHz, DMSO-d6) δ 7.14 6.99 (m, 6H), 6.81 (s, 1H), 6.79 (s, 1H), 4.73 (s, 1H), 4.12 (s, 3H), 3.85 (s, 2H), 3.68 (d, J= 10.7 Hz, 2H), 3.60 (s, 2H), 2.37-2.31 (m, 2H), 3.41 (d, J= 10.2 Hz, 2H), 3.31 - 3.23 (m, 2H), 3.09 (t, J= 7.9, 7.9 Hz, 3H), 3.00 (dd, J = 13.8, 7.0 Hz, 1H), 2.79 (d, J = 5.8 Hz, 2H), 2.70 (s, 1H), 2.43 (s, 1H), 1.96 - 1.82 (m, 4H); LCMS: 477.3 [M+H] ⁺ ,_______________ 'H NMR (400 MHz, DMSO-d6) δ 8.00 (dd, J = 2.4, 0.8 Hz, 1H), 7.41 (dd , J = 8.5, 2.4 Hz, 1H), 7.15 - 6.98 (m, 4H), 6.53 (dd, J = 8.4, 0.8 Hz, 1H), 4, 73 (d, J = 4.8 Hz, 1H), 4.29 (d, J = 6.1 Hz, 2H), 4.14 (d, J = 9.6 Hz, 3H), 3.85 ( d, J= 5.4 Hz, 1H), 3.67 - 3.58 (m, 4H), 3.46 - 3.38 (m, 2H), 3.30 - 3.22 (m, 2H) , 3.12 (t, J = 7.9, 7.9 Hz, 2H), 3.00 (dd, ./= 13.9, 7.2 Hz, 1H), 2.79 (t, J = 5.8, 5.8 Hz, 2H), 2.73 - 2.60 (m, 3H), 2.47 - 2.38 (m, 2H), 1.78 (d, J = 8.1 Hz , 1H); LCMS: 464.3 [M+H] ⁺ .

'H NMR (400 MHz, DMSO-d6) δ 7.13 7.06 (m, 3H), 7.02 (d, J = 5.1 Hz, 1H), 7.00 - 6.88 (m, 3H), 4.73 (s, 1H), 4.15 (s, 2H), 3.95 (s, 1H), 3.86 (s, 1H), 3.71 (d, J = 10.6 Hz, 2H), 3.60 (s, 2H), 2.37 - 2.27 (m, 2H), 3.50 (dd, J= 10.9, 1.9 Hz, 2H), 3.40 (dd, J= 8.8, 7.5 Hz, 1H), 3.31 - 3.21 (m, 2H), 3.11 (t, J = 7.9, 7.9 Hz, 2H), 3.01 (dd, J= 13.8, 7.1 Hz, 1H), 2.80 (s, 2H), 2.70 (s, 2H), 2.44 (d, J = 6.4 Hz , 1H), 1.86 (dt, J= 11.6, 8.2, 8.2 Hz, 4H); LCMS: 495.2 [M+H] ⁺ ,_______________ 'H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J= 2.7 Hz, 1H), 7.19-6.91 (m , 6H), 4.73 (d, J = 4.7 Hz, 1H), 4.30 (d, J = 6.1 Hz, 2H), 4.23 (s, 2H), 4.11 (d , J = 10.7 Hz, 2H), 3.87 (d, J= 6.5 Hz, 1H), 3.66 3.58 (m, 3H), 3.47 - 3.35 (m, 2H ), 3.30 3.20 (m, 3H), 3.01 (dd, J= 13.9, 7.2 Hz, 1H), 2.79 (d, J = 5.7 Hz, 2H), 2.69 (d, J = Ί$ Hz, 3H), 2.43 (d, J = 6.2 Hz, 3H), 1.82 (d, J = 8.1 Hz, 1H); LCMS: 464.2 [M+H] ⁺ ,___________________________ 'H NMR (400 MHz, DMSO-d6) δ 8.00 (t, J = 1.9, 1.9 Hz, 1H), 7.16 (dd , J = 13.1, 2.3 Hz, 1H), 7.12 - 7.03 (m, 3H), 6.99 (dd, J = 6.7, 2.4 Hz, 1H), 4, 71 (s, 1H), 4.24 (dd, J = 23.3, 3.0 Hz, 3H), 3.82 (s, 1H), 3.61 (t, J = 11.1, 11, 1 Hz, 3H), 3.43 - 3.36 (m, 3H), 3.26 - 3.09 (m, 4H), 2.95 (dd, J = 13.9, 7.1 Hz, 1H ), 2.76 (d, J = 5.6 Hz, 2H), 2.69 (s, 2H), 2.41 (d, J = 6.0 Hz, 2H), 1.96 - 1.82 (m, 4H), 1.52 (q, J = 8.1, 7.6, 7.6 Hz, 1H), 1.28 (dt, .7 = 14.8, 7.2, 7.2 Hz, 1H); LCMS: 496.3 [M+H] ⁺ .

Ή NMR (400 MHz, Methanol-d4) δ 7.18 - 7.07 (m, 4H), 7.04 - 7.00 (m, 1H), 6.65 -6.56 (m, 2H), 4.29 (d, J = 1.6 Hz, 2H), 4.12 - 4.01 (m, 3H), 3.82 (d, J = 10.9 Hz, 2H), 3.74 (s , 2H), 3.53 - 3.45 (m, 3H), 3.34 (d, J= 4.6 Hz, 1H), 3.26 (d, J= 8.4 Hz, 2H), 3 .16 (dd, J= 14.2, 6.9 Hz, 2H), 2.89 (dd, J = 15.1, 5.0 Hz, 4H), 2.66 2.55 (m, 2H) , 2.06 - 1.94 (m, 4H); LCMS: 495.2 [M+H] ⁺ .

- 35 046513

Example-II. Synthesis of ^)-1-((6-(1-acetylpiperidin-4-yl)pyridin-3-yl)methyl)-3-(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) imidazolidin-2-one.

Compound-32

Stage-a. Synthesis of tert-butyl^)-5-((3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4dihydroisoquinolin-2(1H)-yl)propyl)-2-oxoimidazolidin-1-yl) methyl)-3',6'-dihydro-[2,4'-bipyridine]1'(2'H)-carboxylate.

^)-1-((6-bromopyridin-3-yl)methyl)-3-(2-((tertbutyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl) was added to the stoppered test tube. propyl)imidazolidin-2-one (intermediate-3) (10.0 g, 17.869 mmol), DME/H2O (4:1) (250 ml), the reaction mixture was degassed with argon gas for 10 min. To this reaction mixture was added tert-butyl 4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (6.63 g , 21.443 mmol), sodium carbonate (4.73 g, 44.673 mmol) and Pd(dppf)Cl ₂ (1.459 g, 1.787 mmol) and stirred for 12 hours at 70°C. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was diluted with water, extracted with ethyl acetate and the combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ , 3-5% MeOH in DCM) to give (11.0 g, 93.37%) tert-butyl^)-5-((3-(2-((tert- butyldimethylsilyl)oxy)-3-(3,4dihydroisoquinolin-2(1H)-yl)propyl)-2-oxoimidazolidin-1-yl)methyl)-3',6'-dihydro-[2,4'-bipyridine]G (2'H)-carboxylate. LCMS: 662.6 [M+H]+.

Stage-b. Synthesis of tert-butyl^)-4-(5-((3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4dihydroisoquinolin-2(III)-yl)propyl)-2-oxoimidazolidin-1 -yl)methyl)pyridin-2-yl)piperidin-1 carboxylate.

A mixture of tert-butyl^)-5-((3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(III)yl)propyl)-2-oxoimidazolidin-1 -yl )methyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (11.0 g, 16.617 mmol) and 10% Pd-C (3.3 g ) in 300 ml ethanol was transferred to a Parr mixing vessel and hydrogenated at 60 psi. inch for 12 hours at RT. After completion of the reaction (monitored by TLC, eluent: 5% methanol in DCM), the reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ , 3-5% MeOH in DCM) to give (9.5 g, 86.36%) tert-butyl^)-4-(5-((3(2-(( tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propyl)-2-oxoimidazolidin-1yl)methyl)pyridin-2-yl)piperidin-1-carboxylate. LCMS: 664.2 [M+H] ⁺ .

Stage-s. Synthesis of (R)-1 -(2-((tert-butyldimethylsilyl)oxy)-3 -(3,4-dihydroisoquinolin-2(1H)yl)propyl)-3-((6-(piperidin-4-yl) pyridin-3-yl)methyl)imidazolidin-2-one.

To a stirred solution of tert-butyl^)-4-(5-((3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4dihydroisoquinolin-2(1H)-yl)propyl)-2-oxoimidazolidine -1-yl)methyl)pyridin-2-yl)piperidin-1carboxylate (9.5 g, 14.308 mmol) in 200.0 ml DCM was added with TFA (8.15 g, 71.54 mmol) at 0°C and stirred for 12 hours at room temperature. After completion of the reaction (observed by TLC, eluent: 10% methanol in DCM), the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water, made basic with sodium carbonate and extracted with DCM. The combined organics were washed with brine, anhydrous sodium sulfate and concentrated under reduced pressure to give 6.0 g ^)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinoline-2(1H)- yl)propyl)-3-((6-(piperidin-4-yl)pyridin3-yl)methyl)imidazolidin-2-one. LCMS: 564.5 [M+H] ⁺ .

Stage-d. Synthesis of (R)-1 -((6-( 1 -acetylpiperidin-4-yl)pyridin-3-yl)methyl)-3 -(2-((tertbutyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinoline- 2(1H)-yl)propyl)imidazolidin-2-one.

To a stirred solution ^)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin2(1H)-yl)propyl)-3-((6-(piperidin-4-yl) pyridin-3-yl)methyl)imidazolidin-2-one (6.0 g, 10.614 mmol) in 180 ml DCM was added TEA (3.23 g, 31.923 mmol) and acetic anhydride (1.086 g, 10.641 mmol) at 0° C and left to stir for 12 hours at the same temperature. After completion of the reaction (observed by TLC, eluent: 10% methanol in DCM), the reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate solution, water, brine and anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ , 3-5% MeOH in DCM) to give (4.5 g, 74.3%) ^)-1-((6-(1-acetylpiperidin-4yl)pyridin-3 -yl)methyl)-3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinoline-2(1H)

- 36 046513 yl)propyl)imidazolidin-2-one. LCMS: 606.8 [M+H]+.

Stage-e. Synthesis of (R)-1 -((6-( 1 -acetylpiperidin-4-yl)pyridin-3 -yl)methyl)-3-(3 -(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )imidazolidin-2-one.

To a stirred solution ^)-1-((6-(1-acetylpiperidin-4-yl)pyridin-3-yl)methyl)-3-(2-((tertbutyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinoline -2(1H)-yl)propyl)imidazolidin-2-one (4.5 g, 7.427 mmol) in 90.0 ml THF was added TBAF (1 M solution in THF) (22.3 ml, 22.281 mmol) at 0 °C and the reaction mixture was stirred for 12 hours at room temperature. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine and dried over anhydrous sodium sulfate. The resulting residue was purified by column chromatography (SiO ₂ , 3-5% MeOH in DCM) to give (3.0 g, 82.6%) (R)-1-((6-(1-acetylpiperidin-4-yl) pyridin-3-yl)methyl)-3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2hydroxypropyl)imidazolidin-2-one.

1H NMR (600 MHz, DMSO-d6) δ 8.42 (t, J=1.8 Hz, 1H), 7.66 (dt, J=8.1, 1.9 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.09 (p, J=4.8, 4.4 Hz, 3H), 7.03 (d, J=6.6 Hz, 1H), 4 .74 (s, 1H), 4.53 (d, J=13.0 Hz, 1H), 4.38 (d, J=13.3 Hz, 1H), 4.32 (d, J=1, 5 Hz, 2H), 3.88 (s, 1H), 3.61 (s, 2H), 3.49 - 3.37 (m, 2H), 3.31 - 3.24 (m, 3H), 1.12 - 1.06 (m, 1H), 3.17 (t, J=13.1 Hz, 1H), 3.02 (dd, J=13.9, 7.1 Hz, 1H), 2 .83 (ddt, J=23.3, 10.8, 4.5 Hz, 3H), 2.71 (s, 2H), 2.61 (q, J=15.5, 14.2 Hz, 1H ), 2.46 - 2.37 (m, 2H), 2.00 (dt, J=9.4, 6.2 Hz, 1H), 1.84 (d, J=13.0 Hz, 1H) , 1.76 (d, J=12.9 Hz, 1H), 1.59 (d, J=13.3 Hz, 1H), 1.46 (d, J=13.4 Hz, 1H), 1 .23 (s, 1H). LCMS: 492.4 [M+H]+.

The connections shown in the table below. 2 was prepared by a procedure similar to that described in Example-II with appropriate variations in reagents, amounts of reagents, introduction and deprotection, solvents and reaction conditions. The characteristics of the compounds are shown in the table below.

Table 2 Connection no. Structure

Characteristics

Ή NMR (400 MHz, DMSO-d6) δ 8.42 8.39 (m, 1H), 7.65 (dd, J= 8.1, 2.4 Hz, 1H), 7.21 - 7.17 (m, 1H), 7.09 (dd, J = 5.2, 3.5 Hz, 3H), 7.05 - 6.99 (m, 1H), 4.74 (d, J = 4.8 Hz, 1H), 4.56 - 4.48 (m, 1H), 4.31 (s, 2H), 3.89 (dd, J= 17.2, 10.3 Hz, 2H), 3.60 (s, 2H), 3.50 - 3.36 (m, 2H), 3.31 - 3.21 (m, 3H), 3.11 (td, 7 = 13.5, 13.1, 2, 6 Hz, 1H), 3.01 (dd, J = 13.8, 7.2 Hz, 1H), 2.80 (t, 7 = 5.7 Hz, 3H), 2.70 (q, 7= 6.0, 5.5 Hz, 2H), 2.62 2.52 (m, 1H), 2.46 - 2.39 (m, 2H), 2.02 (s, 3H), 1.76 ( t, 7= 13.7 Hz, 2H), 1.61 (td, J = 12.5, 4.2 Hz, 1H), 1.50 - 1.38 (m, 1H); LCMS: 492.4 [M+H] ⁺

Ή NMR (600 MHz, DMSO-d6) δ 8.55 (d, 7= 1.7 Hz, 1H), 8.48 (d, 7= 1.6 Hz, 1H), 7.13 - 7.05 (m, 3H), 7.02 (d, 7= 6.2 Hz, 1H), 4.75 (d, 7= 4.7 Hz, 1H), 4.49 (dq, 7 = 12.8, 2.3 Hz, 1H), 4.39 (s, 2H), 3.94 3.82 (m, 2H), 3.60 (s, 2H), 3.44 (td, J = 16.1, 15.6, 7.9 Hz, 1H), 3.31 - 3.23 (m, 4H), 3.15 (td, 7= 13.0, 2.4 Hz, 1H), 3.06 - 2 .97 (m, 2H), 2.78 (d, 7 = 5.9 Hz, 2H), 2.70 (h, 7 - 5.4, 5.0 Hz, 2H), 2.62 (td, ./13.0, 2.4 Hz, 1H), 2.43 (t, 7 = 5.6 Hz, 2H), 2.02 (d, 7 = 1.5 Hz, 3H), 1.89 - 1.80 (m, 2H), 1.68 (qd, 7= 12.4, 4.1 Hz, 1H), 1.53 (qd, 7= 12.5, 4.2 Hz, 1H); LCMS: 493.4 [M+H] ⁺ .

- 37 046513

35 ABOUT And ν_Ζ^ν _ BUT (GE 0-Ά *H NMR (600 MHz, DMSO-d6) δ 8.42 (d, J= 1.9 Hz, 1H), 7.66 (dt, J = 8.0, 1.9 Hz, 1H), 7, 23 - 7.18 (m, 1H), 7.13 - 7.07 (m, 3H), 7.05 - 7.01 (m, 1H), 4.75 (s, 1H), 4.32 ( d, J = 1.7 Hz, 2H), 3.94 (dt, J = 13.3, 2.8 Hz, 2H), 3.88 (q, J = 5.8, 5.1 Hz, 1H ), 3.61 (s, 2H), 3.47 - 3.37 (m, 4H), 3.30 - 3.22 (m, 3H), 3.02 (ddd, J= 13.7, 7 ,2, 1.5 Hz, 1H), 2.84 - 2.77 (m, 3H), 2.72 (dq, J= 16.0, 8.6, 7.9 Hz, 2H), 2, 44 (q, J= 11.6, 8.7 Hz, 2H), 1.67 (tt, J= 5.9, 2.1 Hz, 4H); LCMS: 451.6 [M+H] ⁺ 36 0 Ϊ N-^^N_^х ur> but (G A y\^,N^Z ABOUT NMR (600 MHz, DMSO-d6) δ 8.42 (t, J= 1.8 Hz, 1H), 7.66 (dt, J= 8.1, 1.9 Hz, 1H), 7.19 ( d, J = 8.0 Hz, 1H), 7.09 (p, J = 4.8, 4.4 Hz, 3H), 7.03 (d, J = 6.6 Hz, 1H), 4, 74 (s, 1H), 4.53 (d, J = 13.0 Hz, 1H), 4.38 (d, J = 13.3 Hz, 1H), 4.32 (d, J = 1.5 Hz, 2H), 3.88 (s, 1H), 3.61 (s, 2H), 3.49 3.37 (m, 2H), 3.31 - 3.24 (m, 3H), 1, 12 1.06 (m, 1H), 3.17 (t, J= 13.1 Hz, 1H), 3.02 (dd, J= 13.9, 7.1 Hz, 1H), 2.83 ( ddt, J = 23.3, 10.8, 4.5 Hz, 3H), 2.71 (s, 2H), 2.61 (q, J = 15.5, 14.2 Hz, 1H), 2 .00 (dt, J = 9.4, 6.2 Hz, 1H), 1.84 (d, J = 13.0 Hz, 1H), 1.76 (d, J = 12.9 Hz, 1H) , 1.59 (d, J = 13.3 Hz, 1H), 1.46 (d, J = 13.4 Hz, 1H), 1.23 (s, 1H), 0.79 - 0.66 ( m, 4H); LCMS: 518.4 [M+H] ⁺ . 37 0 ^-ΛίΆ^'Ύ* ⁵ ] N=Z \_-J OH A *H NMR (400 MHz, Methanol-d4) δ 9.24 (dd, J = 2.3, 0.9 Hz, 1H), 9.13 (d, J = 1.6 Hz, 1H), 8, 71 (d, J = 1.5 Hz, 1H), 8.64 (dd, J = 5.0, 1.6 Hz, 1H), 8.52 (ddd, J = 8.0, 2.3, 1.6 Hz, 1H), 7.59 (ddd, J= 8.1, 5.0, 0.9 Hz, 1H), 7.11 - 7.05 (m, 3H), 7.04 - 6 .99 (m, 1H), 4.58 (s, 2H), 4.08 (tt, J = 7.2, 4.6 Hz, 1H), 3.73 (s, 2H), 3.63 3 .54 (m, 2H), 3.48 (td, J = 7.8, 1.4 Hz, 2H), 3.37 (dd, J = 14.2, 4.4 Hz, 1H), 3, 21 (dd, J= 14.2, 7.1 Hz, 1H), 2.90 (d, J= 5.5 Hz, 2H), 2.88 - 2.81 (m, 2H), 2.65 - 2.55 (m, 2H); LCMS: 493.4 [M+H] ⁺

- 38 046513

*H NMR (400 MHz, Methanol-d4) δ 7.67 - 7.60 (m, 2H), 7.19 - 7.11 (m, 3H), 7.09 - 7.04 (m, 1H) , 4.71 - 4.64 (m, 1H), 4.63 (s, 2H), 4.14 (ddd, J= 11.6, 7.2, 4.5 Hz, 1H), 4.06 (ddd, J= 11.3, 4.5, 2.3 Hz, 1H), 3.95 (s, 2H), 3.60 - 3.55 (m, 2H), 3.45 3.39 ( m, 2H), 3.38 - 3.32 (m, 1H), 3.28 3.16 (m, 3H), 3.08 (t, J = 6.1 Hz, 2H), 3.00 ( d, J = 6.0 Hz, 2H), 2.86 - 2.72 (m, 3H), 2.13 (s, 3H), 2.07 - 1.93 (m, 2H), 1.78 (dqd, J = 49.3, 12.6, 4.3 Hz, 2H); LCMS: 493.4 [M+H] ⁺ .

*H NMR (400 MHz, DMSO-d6) δ 8.43 8.39 (m, 1H), 7.65 (dd, J = 8.1, 2.3 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.12 - 7.00 (m, 4H), 5.32 (s, 1H), 4.87 (s, 1H), 4.52 (d, J = 13 ,3 Hz, 1H), 4.39 - 4.27 (m, 2H), 4.05 (dq, J = 1.7, 0.9, 0.9, 0.9 Hz, ZN), 3, 91 (d, J= 11.2 Hz, 2H), 3.60 (d, J= 8.4 Hz, 1H), 2.72 - 2.62 (m, 2H), 3.19 (ddd, J = 17.7, 12.9, 5.6 Hz, 1H), 3.09 (dd, J = 13.5, 5.0 Hz, 2H), 2.90 (dd, J = 14.2, 7 .0 Hz, 1H), 2.79 (s, 2H), 2.40 (s, 1H), 2.02 (s, 3H), 1.76 (t, J = 13.7, 13.7 Hz , 2H), 1.64 - 1.54 (m, 1H), 1.47 - 1.38 (m, 2H), 1.20 (s, 3H), 1.16 (s, 3H).LCMS: 520.5 [M+H] ⁺ .

*H NMR (600 MHz, DMSO-d6) δ 8.54 (t, J= 1.5 Hz, 1H), 8.49 (d, J= 1.5 Hz, 1H), 7.13 - 7, 05 (m, 3H), 7.05 - 6.98 (m, 1H), 4.75 (d, J= 4.8 Hz, 1H), 4.42 - 4.36 (m, 2H), 3 .95 (dt, J= 10.8, 3.0 Hz, 2H), 3.87 (h, J = 5.8 Hz, 1H), 3.60 (s, 2H), 3.49 3.39 (m, 4H), 3.33 - 3.22 (m, 3H), 3.07 2.99 (m, 2H), 2.79 (t, J = 6.0 Hz, 2H), 2.70 (hept., J = 5.4 Hz, 2H), 2.46 - 2.38 (m, 2H), 1.81 - 1.73 (m, 4H); LCMS: 452.5 [M+H] ⁺ .

- 39 046513

41 0 ^ν^ ^/ Ύ>'''Υ ⁴ ] Ν=Ζ VJ OH Ν-Υ 0 *H NMR (600 MHz, DMSO-d6) δ 8.55 (d, J= 1.4 Hz, 1H), 8.48 (s, 1H), 7.09 (dq, J = 9.5, 5 ,3, 4.6 Hz, 3H), 7.05 - 7.00 (m, 1H), 4.75 (s, 1H), 4.49 (d, J = 12.7 Hz, 1H), 4 .39 (s, 2H), 3.91 - 3.82 (m, 1H), 3.60 (s, 2H), 3.52 - 3.41 (m, 2H), 3.33 3.25 ( m, 3H), 3.18 (ddd, J = 27.8, 10.9, 6.2 Hz, 3H), 3.04 (ddt, J = 24.8, 13.8, 7.6 Hz, 2H), 2.79 (d, J = 5.8 Hz, 2H), 2.75 2.64 (m, 3H), 2.44 (s, 2H), 2.00 (td, J = 8, 2, 7.6, 3.8 Hz, 1H), 1.95 - 1.89 (m, 1H), 1.83 (d, J = 13.1 Hz, 1H), 1.68 (d, J = 13.4 Hz, 1H), 1.56 (dp, J= 17.1, 6.2, 4.9 Hz, 2H), 1.35 - 1.21 (m, 2H), 0.78 - 0.66 (m, 4H); LCMS: 519.4 [M+H] ⁺ 42 Ο /A+'^V+VT N=Z VJ OH W w Ή NMR (400 MHz, Methanol-d4) δ 9.19 (d, J = 1.0 Hz, 1H), 9.12 (d, J = 1.0 Hz, 2H), 8.86 (dd, J = 2.4, 0.9 Hz, 1H), 8.17 (ddd, J= 8.1, 2.4, 0.9 Hz, 1H), 7.55 (dd, J = 8.1, 0 ,9 Hz, 1H), 7.09 (dq, J= 4.4, 2.8, 2.2 Hz, 3H), 7.05 - 6.99 (m, 1H), 4.55 (s, 2H), 4.09 (tt, J = 7.4, 4.6 Hz, 1H), 3.74 (d, J = 1.7 Hz, 2H), 3.63 - 3.54 (m, 2H ), 3.47 - 3.34 (m, 3H), 3.25 - 3.18 (m, 1H), 2.91 (d, J= 5.6 Hz, 2H), 2.86 (dd, J= 6.7, 3.6 Hz, 2H), 2.64 - 2.59 (m, 2H); LCMS: 445.4 [M+H] ⁺ . 43 _z o ^χ ω( d kD c>° d : Ή NMR (400 MHz, DMSO-d6) δ 8.45 8.42 (m, 1H), 7.69 (dd, J = 8.1, 2.3 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.12 - 7.06 (m, 3H), 7.05 - 6.98 (m, 1H), 4.74 (d, J = 4.8 Hz, 1H) , 4.32 (s, 2H), 3.87 (s, 1H), 3.67 (d, J= 11.9 Hz, 2H), 3.60 (s, 2H), 3.48 - 3, 37 (m, 2H), 3.31 - 3.20 (m, 3H), 3.02 (dd, J = 13.9, 7.2 Hz, 1H), 2.90 (d, J = 0, 5 Hz, 3H), 2.86 - 2.77 (m, 4H), 2.74 2.64 (m, 3H), 2.44 (dd, J = 6.1, 3.5 Hz, 2H) , 1.86 (d, J = 12.7 Hz, 2H), 1.70 (tt, J = 12.5, 6.3 Hz, 2H); LCMS: 528.4 [M+H] ⁺ .

- 40 046513

44 0 Ν=Ζ \_D OH W Ν—' ' 0 Ή NMR (400 MHz, DMSO-d6) δ 8.41 (d, J= 2.3 Hz, 1H), 7.64 (dd, J = 8.1, 2.3 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.09 (dd, J = 5.1, 3.4 Hz, ZN), 7.05 - 6.99 (m, 1H), 4.73 ( d, J= 4.8 Hz, 1H), 4.55 (d, J= 13.4 Hz, 1H), 4.31 (s, 2H), 3.96 (d, J = 13.5 Hz, 1H), 3.87 (s, 1H), 3.60 (s, 2H), 3.49 3.37 (m, 3H), 3.25 (dd, J = 9.8, 6.0 Hz, 2H), 3.13 - 2.96 (m, 2H), 2.80 (t, J= 5.9 Hz, ZN), 2.75 - 2.65 (m, 2H), 2.44 (d , J= 6.9 Hz, ZN), 2.34 (q, J= 7.4 Hz, 2H), 1.75 (d, J= 12.9 Hz, 2H), 1.57 (d, 7 = 11.3 Hz, 1H), 1.44 (d, J = 9.1 Hz, 1H), 1.00 (t, J = 7.4 Hz, ZN); LCMS: 506.5 [M+H] ⁺ . 45 ABOUT Ν=Ζ V-J OH w Ν-/ h Ή NMR (400 MHz, DMSO-d6) δ 8.42 8.39 (m, 1H), 7.67 - 7.62 (m, 1H), 7.19 (d, 7 = 8.0 Hz, 1H ), 7.09 (dd, J = 5.2, 3.5 Hz, ZN), 7.02 (d, J = 4.5 Hz, 1H), 4.73 (d, 7 = 4.8 Hz , 1H), 4.52 (d, 7 = 13.1 Hz, 1H), 4.31 (s, 2H), 3.91 (d, 7 = 16.2 Hz, 2H), 3.60 (s , 2H), 3.47 - 3.38 (m, 2H), 3.26 3.21 (m, 4H), 3.11 (s, 1H), 3.05 - 2.95 (m, 2H) , 2.79 (d, 7= 6.0 Hz, 2H), 2.75 2.65 (m, 2H), 2.02 (s, 3H), 1.76 (t, 7 = 13.9 Hz , 2H),1.65 - 1.54 (m, 2H), 1.51 1.39 (m, 2H); LCMS: 492.4 [M+H] 46 Q. ζ 1 T k''? s%° n J 'H NMR (400 MHz, DMSO-d6) δ 8.45 (dd, 7= 22.9, 2.2 Hz, 1H), 7.69 (ddd, 7 = 17.4, 8.1, 2, 3 Hz, 1H), 7.21 (dd, 7= 8.1, 4.1 Hz, 1H), 7.15 - 6.97 (m, 4H), 4.73 (d, J= 4.8 Hz, 1H), 4.46 - 4.29 (m, 3H), 3.95 - 3.75 (m, 2H), 3.61 (s, 2H), 3.44 (dt, 7 = 24, 2, 8.1, 8.1 Hz, ZN), 3.25 (dd, 7= 9.6, 6.2 Hz, ZN), 3.18 - 2.97 (m, ZN), 2.80 (t, 7= 5.9, 5.9 Hz, 2H), 2.75 - 2.62 (m, ZN), 2.44 (dd, 7= 6.1, 3.6 Hz, 2H), 2.02 (d, 7 = 6.8 Hz, ZN), 1.89 (d, 7 = 12.2 Hz, 1H), 1.79 - 1.66 (m, 2H); LCMS: 492.4 [M+H] ⁺ .

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47 0 _/ -Ν^Υ''''Γ'Γ'Υ' ⁴ ι Ν=Ζ ОН W Ν~/ / Ή NMR (400 MHz, DMSO-d6) δ 8.42 8.38 (m, 1H), 7.64 (dd, J - 8.1, 2.3 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.12 - 7.06 (m, 3H), 7.04 - 7.00 (m, 1H), 4.73 (d, J = 4.8 Hz, 1H) , 4.31 (s, 2H), 3.87 (s, 1H), 3.60 (s, 2H), 3.43 (dt, J = 24.6, 8.2 Hz, 2H), 3, 31 - 3.21 (m, 3H), 3.01 (dd, J = 13.8, 7.2 Hz, 1H), 2.85 (d, J = 11.3 Hz, 3H), 2.79 (d,./- 5.7 Hz, 2H), 2.74 - 2.65 (m, 2H), 2.45 - 2.39 (m, 2H), 2.18 (s, 3H), 2 .00 - 1.89 (m, 2H), 1.75 - 1.59 (m, 4H); LCMS: 464.4 [M+H] ⁺ 48 Z-X c>° 4 S 'H NMR (400 MHz, Methanol-d4) δ 8.56 (t, J = 2.8 Hz, 1H), 7.86 (dd, J = 8.2, 2.4 Hz, 1H), 7, 36 (d, J = 8.2 Hz, 1H), 7.09 (dd, J = 5.3, 3.3 Hz, 3H), 7.02 (dd, J = 7.5, 2.5 Hz , 1H), 6.23 (ddd, J= 7.1, 3.6, 1.9 Hz, 1H), 4.46 (s, 2H), 4.22 (dq, J = 6.2, 2 .9 Hz, 2H), 4.11 - 4.03 (m, 1H), 3.81 (t, / = 5.8 Hz, 1H), 3.77 - 3.69 (m, 4H), 3 .61 - 3.51 (m, 2H), 3.41 - 3.32 (m, 3H), 3.20 (dd, J= 14.2, 7.1 Hz, 1H), 2.94 - 2 .88 (m, 2H), 2.84 (dd, J= 6.6, 3.9 Hz, 2H), 2.66 - 2.52 (m, 4H), 2.19 - 2.13 (m , 3H); LCMS: 490.4 [M+H] ⁺ 49 0 ^Ν ==γ ^/ ~' ^Ν \ £? ^ΗΟ O~~U Ή NMR (400 MHz, Methanol-d4) δ 8.55 (dd, J = 2.3, 0.8 Hz, 1H), 7.86 (dd, J = 8.2, 2.4 Hz, 1H) , 7.36 (dd, J = 8.2, 0.8 Hz, 1H), 7.12 - 7.06 (m, 3H), 7.05 - 7.00 (m, 1H), 6.30 (tt, J = 2.9, 1.6 Hz, 1H), 4.46 (s, 2H), 4.30 (q, J = 2.9 Hz, 2H), 4.08 (ddd, J - 7.2, 4.5, 2.6 Hz, 1H), 3.92 (t, J - 5.5 Hz, 2H), 3.73 (s, 2H), 3.61 - 3.51 (m , 2H), 3.41 - 3.33 (m, 3H), 3.20 (dd, J = 14.2, 7.1 Hz, 1H), 2.91 (d, J = 5.6 Hz, 2H), 2.89 - 2.84 (m, 2H), 2.61 (dd, J = 6.0, 4.3 Hz, 2H), 2.51 (ttd, J = 5.5, 2, 8, 1.6 Hz, 2H); LCMS: 449.4 [M+H] ⁺ . 50 0 ν^/\ ₇ ⁿ ^n-vx < \ HO Ν ⁷ ) Λ -Ζ / ^ы ΓΓ 'H NMR (400 MHz, Methanol-d4) δ 9.26 (d, J = 1.9 Hz, 2H), 8.95 - 8.91 (m, 1H), 8.24 (dd, J = 8 ,2, 2.4 Hz, 1H), 7.57 (d, J= 8.2 Hz, 1H), 7.12 - 7.07 (m, 3H), 7.06 7.01 (m, 1H ), 4.56 (s, 2H), 4.09 (tt, J = 7.2, 4.5 Hz, 1H), 3.77 - 3.72 (m, 2H), 3.63 - 3, 55 (m, 2H), 3.48 - 3.34 (m, 3H), 3.22 (dd, J= 14.2, 7.2 Hz, 1H), 2.92 (d, J = 5, 2 Hz, 2H), 2.87 (dd, J = 6.7, 3.4 Hz, 2H), 2.62 (dd, J = 6.1, 4.1 Hz, 2H); LCMS: 470.4 [M+H] ⁺

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51 0 m=sZ^ ^N /\ ^{N n} n' ,) HO f JI ] 0—7 'H NMR (400 MHz, Methanol-d4) δ 7.67 - 7.61 (m, 2H), 7.15 - 7.07 (m, 3H), 7.06 - 7.01 (m, 1H) , 4.63 (s, 2H), 4.12 - 4.01 (m, 2H), 3.78 (s, 2H), 3.65 - 3.54 (m, 4H), 3.48 - 3 .34 (m, 2H), 3.20 (ddd, J = 15.8, 7.2, 3.8 Hz, 2H), 2.99 - 2.87 (m, 4H), 2.68 - 2 .59 (m, 2H), 1.99 - 1.79 (m, 4H), 1.44 - 1.26 (m, 3H); LCMS: 452.4 [M+H] ⁺ . 52 0 ^H0 kJO Ώ~^ '11 NMR (300 MHz, Chloroform-d) δ 8.60 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 8.1, 2.5 Hz, 1H), 7, 58 (dd, J = 9.4, 2.7 Hz, 1H), 7.51 (d, J = 2.7 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.20 - 7.08 (m, 3H), 7.04 - 6.98 (m, 1H), 6.70 (d, 7= 9.4 Hz, 1H), 4.54 (d, J = 2.9 Hz, 2H), 4.03 (dp, J = 11.6, 3.7 Hz, 1H), 3.85 (d, J = 15.0 Hz, 1H), 3.68 (s, 1H), 3.61 - 3.43 (m, 4H), 3.38 (t, J = 8.1 Hz, 3H), 3.18 (dd, J = 14.3, 6.5 Hz, 1H ), 3.01 - 2.87 (m, 4H), 2.78 (t, J = 1.6 Hz, 1H), 2.64 - 2.55 (m, 2H); LCMS: 474.8 [M+H] ⁺ . 53 8 f? °=0 4 r Ή NMR (300 MHz, DMSO-d6) δ 8.40 (d, J= 2.3 Hz, 1H), 7.66 (dd, J= 8.2, 2.3 Hz, 1H), 7.17 (d, J= 8.1 Hz, 1H), 7.12 - 6.97 (m, 4H), 4.85 - 4.67 (m, 3H), 4.49 (d, J= 13.3 Hz, 1H), 4.37 - 4.20 (m, 4H), 3.86 (s, 1H), 3.58 (td, J = 6.4, 3.2 Hz, 2H), 3.53 - 3.38 (m, 2H), 3.29 - 3.20 (m, 3H), 3.20 - 3.09 (m, 2H), 3.09 - 2.96 (m, 2H), 2 .82 - 2.65 (m, 3H), 1.74 (p, J= 3.2 Hz, 1H), 1.54 (s, 4H), 1.41 - 1.20 (m, 3H), 0.91 (t, J = 7.3 Hz, 3H); LCMS: 548.8 GM+H1 ⁺ 54 ___ z Г ^=° 4 S Ή NMR (400 MHz, Methanol-d4) δ 9.32 (s, 2H), 8.69 (dd, J - 5.2, 0.8 Hz, 1H), 7.83 - 7.74 (m, 2H), 7.18 - 7.09 (m, 3H), 7.08 - 7.03 (m, 1H), 4.63 - 4.52 (m, 2H), 4.13 (tt, J = 7.1, 7.1, 4.5, 4.5 Hz, 1H), 3.87 (s, 2H), 3.63 - 3.55 (m, 2H), 3.51 3.42 (m , 2H), 3.41 - 3.33 (m, 1H), 3.26 (dd, J = 14.2, 6.9 Hz, 1H), 2.98 (h, J = 5.3, 5 ,3, 5.1, 5.1, 5.1 Hz, 4H), 2.81 - 2.70 (m, 2H); LCMS: 470.8 [M+H] ⁺

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Ή NMR (600 MHz, DMSO-d6) δ 9.64 9.56 (m, 2H), 8.14 (dd, J = 7.8, 1.5 Hz, 1H), 7.99 (td, J = 7.9, 7.8, 1.9 Hz, 1H), 7.40 (dd, J = 7.8, 1.5 Hz, 1H), 7.06 (dtt, J = 7.7, 5 ,4, 5.4, 2.0, 2.0 Hz, 3H), 7.02 6.93 (m, 1H), 4.75 - 4.69 (m, 1H), 4.50 4.43 (m, 2H), 3.91 - 3.84 (m, 1H), 3.58 (s, 2H), 3.48 (tdd, J = 8.5, 8.5, 6.6, 1, 5 Hz, 1H), 3.45 - 3.38 (m, 2H), 3.30 - 3.25 (m, 2H), 3.02 (ddd, J = 13.8, 7.2, 1, 6 Hz, 1H), 2.80 - 2.73 (m, 2H), 2.68 (q, J= 6.2, 5.3, 5.3 Hz, 2H), 2.45 - 2.38 (m, 2H); LCMS: 470.1 [M+H] ⁺

Ή NMR (300 MHz, Chloroform-d) δ 8.77 (dd, J = 2.4, 0.8 Hz, 1H), 7.86 (dd, J = 8.2, 2.4 Hz, 1H) , 7.48 - 7.39 (m, 2H), 7.18 - 7.07 (m, 4H), 7.04 - 6.98 (m, 1H), 6.79 (d, J= 1, 7 Hz, 1H), 6.51 (dd, J= 6.9, 1.8 Hz, 1H), 4.58 (d, J= 2.7 Hz, 2H), 4.01 (s, 1H) , 3.83 (d, J= 14.9 Hz, 1H), 3.71 3.36 (m, 7H), 3.19 (dd, J = 14.3, 6.6 Hz, 1H), 2 .92 (d, 3.4 Hz, 2H), 2.76 (d, J=

9.0 Hz, 1H), 2.65 - 2.50 (m, 2H); LCMS: 460.4 [M+H] ⁺ .

'H NMR (400 MHz, DMSO-d6) δ 8.41 8.38 (m, 1H), 7.58 (dd, J = 8.0, 2.3 Hz, 1H), 7.28 (dd, J = 8.0, 0.8 Hz, 1H), 7.10 (d, J= 3.5 Hz, 3H), 7.04 (s, 1H), 4.49 (d, J = 13.1 Hz, 1H), 4.36 (d, J = 13.5 Hz, 1H), 4.25 (s, 2H), 4.12 (q, J = 5.3, 5.3, 5.3 Hz , 1H), 3.87 (s, 1H), 3.66 - 3.56 (m, 1H), 3.46 - 3.37 (m, 2H), 3.26 (dd, J = 13.9 , 4.2 Hz, 2H), 3.16 (tt, J = 8.4, 8.4, 4.5, 4.5 Hz, 7H), 3.08 - 2.91 (m, 3H), 2.80 (s, 2H), 2.03 - 1.94 (m, 2H), 1.93 1.76 (m, 3H), 1.63 - 1.45 (m, 4H); LCMS: 518.3 [M+H] ⁺ .

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58 β g? O \ Ή NMR (400 MHz, DMSO-d6) δ 8.61 (dd, J = 2.2, 0.8 Hz, 1H), 8.28 (dd, J = 5.4, 0.7 Hz, 1H) , 8.08 (dd, J= 8.2, 0.8 Hz, 1H), 7.80 (dd, J = 8.2, 2.3 Hz, 1H), 7.66 (dd, J = 5 ,4, 1.5 Hz, 1H), 7.46 (dd, J = 1.5, 0.7 Hz, 1H), 7.12 - 7.05 (m, 3H), 7.05 - 6, 99 (m, 1H), 4.75 (d, J= 4.8 Hz, 1H), 4.36 (s, 2H), 3.90 (m, 4H), 3.60 (s, 2H), 3.49 - 3.37 (m, 2H), 3.28 (dd, J 13.8, 4.1 Hz, 1H), 3.25 - 3.16 (m, 2H), 3.04 (dd , J = 13.9, 7.2 Hz, 1H), 2.79 (t, J = 5.8, 5.8 Hz, 2H), 2.75 - 2.64 (m, 2H), 2, 44 (dd, J = 6.2, 2.7 Hz, 2H); LCMS: 474.1 [M+H] ⁺ . 59 β °=Φ ο\ Ή NMR (400 MHz, DMSO-d6) δ 8.94 (d, J = 2.3 Hz, 1H), 8.27 (d, J = 5.4 Hz, 1H), 8.18 (dd, J = 8.2, 2.4 Hz, 1H), 7.43 - 7.34 (m, 2H), 7.21 (d, J= 1.5 Hz, 1H), 7.14 7.06 (m , 3H), 7.06 - 7.00 (m, 1H), 4.76 (d, J= 4.8 Hz, 1H), 4.42 (s, 2H), 3.90 (s, 4H) , 3.61 (s, 2H), 3.53 - 3.39 (m, 2H), 3.32 - 3.26 (m, 3H), 3.04 (dd, J = 13.9, 7, 3 Hz, 1H), 2.80 (t, J= 5.8, 5.8 Hz, 2H), 2.71 (q, J = 5.7, 5.4, 5.4 Hz, 2H), 2.45 (dd, J= 6.1, 3.5 Hz, 2H); LCMS: 474.3 [M+H] ⁺ . 60 β 8 Ή NMR (300 MHz, DMSO-d6) δ 8.91 8.84 (m, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.36 (ddd, J = 8.7 , 2.5, 1.4 Hz, 1H), 7.98 - 7.89 (m, 1H), 7.73 (dt, J = 8.2, 1.8, 1.8 Hz, 1H), 7.15 - 6.98 (m, 4H), 6.93 (dq, J = 8.7, 0.8, 0.8, 0.8 Hz, 1H), 4.76 (s, 1H), 4.33 (s, 2H), 3.91 (d, J = 1.4 Hz, 3H), 3.60 (tdd, J = 5.3, 4.3, 3.9, 2.3 Hz, 2H), 3.49- 3.39 (m, 3H), 3.27 (td, J= 4.9, 4.1, 1.3 Hz, 1H), 3.18 (t, J= 7, 8, 7.8 Hz, 2H), 3.08 - 2.98 (m, 1H), 2.85 - 2.67 (m, 4H), 2.45 (d, J = 6.2 Hz, 2H ); LCMS: 474.2 [M+H] ⁺ . 61 0 χ ( Λ ' BUT __Τ J ^ην/== Λ s/ Ή NMR (300 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.78 - 8.69 (m, 1H), 7.98 - 7.77 (m, 3H), 7.28 ( d, J= 8.2 Hz, 1H), 7.16 6.96 (m, 4H), 6.45 (d, J = 9.5 Hz, 1H), 4.75 (d, J = 4, 8 Hz, 1H), 4.36 (s, 2H), 3.88 (s, 1H), 3.61 (s, 2H), 3.51 - 3.38 (m, 2H), 3.32 - 3.24 (m, 3H), 3.03 (dd, J = 13.8, 7.2 Hz, 1H), 2.79 (d, J = 5.7 Hz, 2H), 2.76 - 2 .66 (m, 2H), 2.43 (t, J= 1.9, 1.9 Hz, 2H); LCMS: 460 [M+H] ⁺

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62 0 χ f Ύ \—/ Zn-x^ ^HO f //7 N ₃ XY Ό Ή NMR (300 MHz, DMSO-d6) δ 8.85 8.80 (m, 1H), 8.54 (dt, J = 2.6, 0.8, 0.8 Hz, 1H), 8.12 - 8.03 (m, 2H), 7.35 (d, J= 8.1 Hz, 1H), 7.13 - 6.99 (m, 4H), 6.95 (dt, J = 8.7 , 0.8, 0.8 Hz, 1H), 4.76 (d, J = 4.7 Hz, 1H), 4.40 (s, 2H), 3.90 (d, J = 0.7 Hz , ZN), 3.61 (s, 2H), 3.54 - 3.39 (m, 3H), 3.31 - 3.24 (m, 3H), 3.03 (dd, J = 13.9 , 7.2 Hz, 1H), 2.79 (d, J= 5.8 Hz, 2H), 2.70 (d, J = 7.8 Hz, 2H), 2.47 - 2.42 (m , 2H); LCMS: 474.4 [M+H] ⁺ . 63 0 ^N % ' HO (Ϊ J <У~^ 'H NMR (300 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.45 (d, J= 2.2 Hz, 1H), 8.21 8.08 (m, 2H), 7 .84 - 7.76 (m, 1H), 7.65 (dd, J= 8.3, 2.3 Hz, 1H), 7.17 - 6.97 (m, 4H), 6.44 (dt , J = 9.7, 0.8, 0.8 Hz, 1H), 4.74 (d, J = 4.8 Hz, 1H), 4.29 (s, 2H), 3.86 (d, J = 6.7 Hz, 1H), 3.60 (s, 2H), 3.47 - 3.38 (m, 2H), 3.32- 3.23 (m, 2H), 3.16 (t, J = 7.8, 7.8 Hz, 1H), 3.02 (dd, J= 13.8, 7.1 Hz, 1H), 2.79 (t, J = 5.8, 5.8 Hz, 2H), 2.71 (d, J= 5.1 Hz, 2H), 2.46 - 2.40 (m, 2H); LCMS: 460.0 [M+H] ⁺ . 64 ”^o: U 8 *H NMR (400 MHz, DMSO-d6) δ 8.93 (dd, J= 2.4, 0.8 Hz, 1H), 8.27 - 8.21 (m, 1H), 8.17 (dd , 7=8.1, 2.4 Hz, 1H), 7.407.30 (m, 2H), 7.13 - 7.07 (m, 4H), 7.05 7.00 (m, 1H), 5 .30 (p, J = 6.2, 6.2, 6.2, 6.2 Hz, 1H), 4.76 (d, J = 4.7 Hz, 1H), 4.41 (s, 2H ), 3.89 (s, 1H), 3.61 (s, 2H), 3.53 3.38 (m, 2H), 3.28 (s, 2H), 3.04 (dd, J = 13 ,9, 7.3 Hz, 2H), 2.79 (d, J = 5.8 Hz, 2H), 2.76 - 2.65 (m, 2H), 2.45 (d, J = 6, 0 Hz, 2H), 1.32 (d, J= 6.1 Hz, 6H); LCMS: 502.3 [M+H] ⁺ . 65 0 X n^/^n n-^X _ X/ but / YA °YX \χχ _z N~<Z *H NMR (300 MHz, Chloroform-d) δ 8.75 (dd, J = 2.4, 0.8 Hz, 1H), 7.84 (dd, J = 8.1, 2.4 Hz, 1H ), 7.46 - 7.36 (m, 2H), 7.14 (tt, J = 5.2, 5.2, 2.5, 2.5 Hz, ZN), 7.05 - 6.99 (m, 1H), 6.79 (dd, J = 2.1, 0.5 Hz, 1H), 6.40 (dd, J = 7.0, 2.1 Hz, 1H), 4.56 ( d, J = 2.6 Hz, 2H), 4.09 - 3.98 (m, 1H), 3.87 (d, J = 14.9 Hz, 1H), 3.73 3.62 (m, 1H), 3.60 (s, 3H), 3.59 - 3.47 (m, 2H), 3.47 - 3.33 (m, 3H), 3.20 (dd, J = 14.3, 6.4 Hz, 1H), 3.01 - 2.75 (m, 4H), 2.68 - 2.57 (m, 2H); LCMS: 474.2 [M+H] ⁺ .

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Ή NMR (400 MHz, DMSO-d6) δ 8.46 (d, 7= 2.3 Hz, 1H), 7.71 (dd, 7= 8.1, 2.4 Hz, 1H), 7.18 (dd, 7= 8.1, 3.3 Hz, 1H), 7.13 7.06 (m, 3H), 7.03 (dd, 7 = 6.6, 2.4 Hz, 1H), 4 .74 (s, 1H), 4.32 (d, 7= 11.5 Hz, 4H), 3.92 - 3.83 (m, 1H), 3.61 (s, 2H), 3.50 - 3.37 (m, 2H), 3.31 - 3.21 (m, 3H), 3.02 (dd, J = 13.9, 7.2 Hz, 1H), 2.93 2.84 (m , 1H), 2.80 (t, 7 = 5.8, 5.8 Hz, 2H), 2.71 (d, 7 = 6.3 Hz, 2H), 2.44 (d, 7 = 5, 9 Hz, 2H), 2.24 (dt, 7 = 14.3, 7.5, 7.5 Hz, 2H), 1.87 - 1.79 (m, 2H), 1.59 (t, 7 = 6.6, 6.6 Hz, 2H), 1.50 (ddd, 7= 13.6, 9.8, 2.3 Hz, 2H); LCMS: 477.2 [M+H] ⁺ .

'H NMR (400 MHz, DMSO-d6) δ 8.60 (dd, 7 = 2.3, 0.8 Hz, 1H), 8.25 (dd, 7 = 5.4, 0.7 Hz, 1H ), 8.08 (dd, 7= 8.2, 0.9 Hz, 1H), 7.78 (dd, 7= 8.2, 2.3 Hz, 1H), 7.61 (dd, 7 = 5.4, 1.5 Hz, 1H), 7.37 (dd, 7 = 1.5, 0.7 Hz, 1H), 7.12 - 6.99 (m, 4H),

5.29 (p, J = 6.2, 6.2, 6.2, 6.2 Hz,1H),

4.75 (d, 7 = 4.8 Hz, 1H), 4.36 (s, 2H),

3.87 (d, 7 = 6.5 Hz, 1H), 3.60 (s, 2H),

3.46 - 3.36 (m, 2H), 3.31 - 3.16 (m, 3H), 3.04 (dd, 7= 13.9, 7.2 Hz, 1H), 2.79 ( t, J = 5.8, 5.8 Hz, 2H), 2.70 (q, 7 = 5.6, 5.2, 5.2 Hz, 2H), 2.44 (dd, J = 6, 2, 2.8 Hz, 2H), 1.32 (d, 7 = 6.2 Hz, 6H); LCMS: 502.2 [M+H] ⁺ .

Ή NMR (300 MHz, Chloroform-d) δ 8.38 (d, 7= 2.3 Hz, 1H), 7.47 (dd, 7= 8.1, 2.4 Hz, 1H), 7.31 - 7.27 (m, 1H), 7.18 - 7.08 (m, 3H), 7.04 - 6.97 (m, 1H), 4.50 (d, J = 2.6 Hz, 2H ), 4.19 - 4.09 (m, 1H), 4.00 (ddt, 7= 11.6, 4.8, 3.3, 3.3 Hz, 1H), 3.88 - 3.70 (m, 3H), 3.67 - 3.43 (m, 5H), 3.36 (t, 7= 8.2, 8.2 Hz, 2H), 3.18 (dd, 7= 14.3 , 6.5 Hz, 1H), 3.08 (dt, 7 = 12.8, 3.9, 3.9 Hz, 1H), 2.97 - 2.86 (m, 3H), 2.79 - 2.69 (m, 1H), 2.64 - 2.49 (m, 2H), 2.31-2.13 (m, 2H), 2.00 - 1.87 (m, 2H), 1, 62-1.51 (m, 2H); LCMS: 465.2 [M+H] ⁺ .

- 47 046513

Isomer-1

Ή NMR (300 MHz, DMSO-d6) δ 8.62 8.56 (m, 1H), 8.02 (dd, J= 8.1, 0.9 Hz, 1H), 7.82 - 7.73 (m, 2H), 7.13 - 6.99 (m, 5H), 6.91 (dt, J= 7.1, 1.6, 1.6 Hz, 1H), 4.75 (d, J = 4.8 Hz, 1H), 4.35 (s, 2H), 3.87 (s, 1H), 3.60 (s, 2H), 3.46 (d, J = 1.1 Hz, 3H ), 3.45 - 3.39 (m, 2H), 3.32 - 3.24 (m, 3H), 3.23 - 3.15 (m, 2H), 3.03 (dd, J = 13 ,9, 7.3 Hz, 1H), 2.79 (d, J= 5.6 Hz, 2H), 2.47 - 2.39 (m, 2H); LCMS: 474.1 [M+H] ⁺ .

Isomer-1: 'H NMR (300 MHz, Chloroform-d) δ 8.49 - 8.43 (m, 1H), 7.61 (dd, J= 8.0, 2.4 Hz, 1H), 7 .18 - 7.08 (m, 4H), 7.04 - 6.99 (m, 1H), 4.38 (t, J = 2.6, 2.6 Hz, 2H), 4.25 - 4 .11 (m, 1H), 3.99 (ddt, J = 9.9, 7.3, 3.9, 3.9 Hz, 1H), 3.90 - 3.71 (m, 4H), 3.66 - 3.43 (m, 6H), 3.27 - 3.11 (m, 4H), 2.96 - 2.86 (m, 3H), 2.74 (dd, J= 9.9, 5.0 Hz , 1H), 2.65 - 2.48 (m, 2H), 2.33 - 2.16 (m, 2H), 1.72 - 1.61 (m, 2H); LCMS: 465.1 [M+H] ⁺ .

Isomer-2: Ή NMR (300 MHz, Chloroform-d) δ 8.48 - 8.42 (m, 1H), 7.60 (dd, J= 8.0, 2.3 Hz, 1H), 7, 17 - 7.09 (m, 4H), 7.04 - 6.99 (m, 1H), 4.38 (d, J = 2.6 Hz, 2H), 4.26 - 4.16 (m, 1H), 4.03 (ddd, J= 28.5, 11.2, 4.3 Hz, 3H), 3.83 (d, J = 14.9 Hz, 2H), 3.67 - 3.42 (m, 5H), 3.32 - 3.08 (m, 4H), 2.97 - 2.85 (m, 3H), 2.81 - 2.70 (m, 1H), 2.64 - 2 .47 (m, 3H), 2.19-1.85 (m, 2H), 1.78 - 1.49 (m, 2H); LCMS: 465.3 [M+H] ⁺ ,_______________

Ή NMR (400 MHz, Methanol-d4) δ 8.43 - 8.38 (m, 1H), 7.71 (dd, J = 8.1, 2.4 Hz, 1H), 7.35 - 7, 30 (m, 1H), 7.14 - 7.01 (m, 4H), 4.68 (s, 2H), 4.43 (d, J = 2.0 Hz, 2H), 4.36 (s , 2H), 3.75 (s, 2H), 3.61 3.44 (m, 2H), 3.20 (dd, J = 14.2, 7.0 Hz, 2H), 2.90 (d , J= 9.5 Hz, 3H), 2.62 (d, J= 7.3 Hz, 4H), 2.14 (d, .7= 6.7 Hz, 3H), 2.06 - 1, 93 (m, 3H), 1.90 - 1.77 (m, 3H), 4.14 - 4.03 (m, 3H); LCMS: 518.3 [M+H] ⁺ .

- 48 046513

73 O Ν ^Ζ Ύ \_у ^4*55/ ^but G /Gu o Ή NMR (400 MHz, Methanol-d4) δ 8.39 (dd, J - 2.3, 0.8 Hz, 1H), 7.68 (dd, J 8.0, 2.3 Hz, 1H), 7.32 (dd, J= 8.1, 0.8 Hz, 1H), 7.12 - 7.06 (m, 3H), 7.02 (dd, J = 7.5, 2.3 Hz, 1H), 4.68 (d, J= 6.2 Hz, 1H), 4.35 (s, 3H), 4.05 (tt, J= 7.0, 7.0, 4.7, 4, 7 Hz, 1H), 3.73 (s, 2H), 3.55 - 3.45 (m, 2H), 3.45 - 3.35 (m, 2H), 3.27 - 3.10 (m , 4H), 2.88 (dd, J - 20.3, 5.5 Hz, 4H), 2.59 (dd, J = 6.0, 3.5 Hz, 2H), 2.13 (s, 3H), 2.04 - 1.74 (m, 7H); LCMS: 518.3 [M+H] ⁺ . 74 O ^A^ ^but G YAs Ή NMR (600 MHz, DMSO-d6) δ 8.37 (d, J= 2.0 Hz, 1H), 7.56 (dt, J= 8.2, 1.9, 1.9 Hz, 1H) , 7.43 (d, J= 8.1 Hz, 1H), 7.14 7.00 (m, 4H), 4.74 (dd, J = 4.9, 1.6 Hz, 1H), 4 ,32 - 4.24 (m, 4H), 3.86 (h, J= 5.8, 5.8, 5.8, 5.6, 5.6 Hz, 1H), 3.59 (s, 2H), 3.43 - 3.36 (m, 2H), 3.27 (ddd, J= 13.8, 4.1, 1.6 Hz, 1H), 3.18 - 3.10 (m, 2H), 3.08 - 2.98 (m, 2H), 2.79 (t, J= 6.0, 6.0 Hz, 2H), 2.70 (tq, J= 11.3, 11, 3, 6.0, 5.3, 5.3 Hz, 2H), 2.43 (pd, J = 6.5, 6.1, 6.1, 6.1, 1.6 Hz, 2H), 2.14 (dddd, J = 18.4, 9.1, 7.3, 4.0 Hz, 4H), 1.63 (qt, J = 7.7, 7.7, 7.7, 4, 7, 4.7 Hz, 2H), 1.45 (qd, J = 6.7, 6.7, 6.5, 1.7 Hz, 2H); LCMS: 477.0 [M+H] ⁺ . 75 o /==/ V- ^J he V/ Ή NMR (300 MHz, DMSO- _d6 ) δ: 8.27 (d, 1H), 7.48 (d, 1H), 7.25 (d, 1H), 7.14 6.97 (m, 4H ), 4.72 (d, 1H), 4.21 (s, 2H), 3.84 (d, 1H), 3.59 (t, 2H), 3.45 - 3.37 (m, 1H) , 3.33 - 3.22 (m, 1H), 3.11 (t, 2H), 3.06 - 2.94 (m, 1H), 2.79 (t, 2H), 2.75 2, 66 (m, 2H), 2.42 (d, 2H), 2.08 - 2.02 (m, 1H), 1.80 - 1.72 (m, 1H), 1.02 - 0.77 ( m, 4H). LCMS [M+H] + 407.4. 76 Oh ^y:Aoo 1H NMR (300 MHz, DMSO-d6) δ: 8.328.24 (m, 1H), 7.49 (dd,lH), 7.24 (dd,lH), 7.15-6.96 (m, 4H ), 4.88 (d, 1H), 4.52 (s, 2H), 4.07 (s, 1H), 3.70-3.42 (m, 3H), 3.04 (dd, 1H) , 2.83-2.61 (m, 6H), 2.13-1.99 (m, 1H), 1.32 (d, 6H), 0.97-0.78 (m, 4H). LCMS [M+H] +.

Primer-Sh. Synthesis of 1-(^)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((5(tetrahydro-2H-pyran-3-yl)pyride in-2- yl)methyl)imidazolidin-2-one.

Connection-77

Stage-a. Synthesis of 1 -(^)-2-((tert-butyldimethylsilyl)oxy)-3 -(3,4-dihydroisoquinolin-2(1H)yl)propyl)-3-((5-(tetrahydro-2H-pyran-3 -yl)pyridin-2-yl)methyl)imidazolidin-2-one.

^)-1-((5-bromopyridin-2-yl)methyl)-3-(2-((tertbutyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl) was added to the stoppered test tube. propyl)imidazolidin-2-one (intermediate-2) (0.4 g, 0.714 mmol), DMA (10 ml), 3-bromotetrahydro-2H-pyran (0.141 g, 0.857 mmol), NiI2 (0.022 g, 0 .0714 mmol), Mn powder (0.078 g, 1.429 mmol), MgCl ₂ (0.068 g, 0.714 mmol), 4,41-di-tert-butyl-2,21-bipyridyl (0.019 g, 0.0714 mmol), 4-methylpyridine (0.066 g, 0.714 mmol) and the reaction mixture were degassed with argon gas for 10 minutes and the reaction mixture was stirred for 16 hours at 70°C. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was diluted with cold water and extracted with ethyl acetate, and the combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ , 1-2% MeOH in DCM) to give (0.02 g, 4.96%) 1-(^)-2-((tert-butyldimethylsilyl)oxy)-3-(3 ,4-dihydroisoquinolin-2(1H)-yl)propyl)-3-((5-(tetrahydro-2H-pyran-3yl)pyridin-2-yl)methyl)imidazolidin-2-one. LCMS: 565.5 [M+H]+.

Stage-b. Synthesis of 1-(^)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((5-(tetrahydro- 49 046513

2H-pyran-3-yl)pyridin-2-yl)methyl)imidazolidin-2-one.

To a stirred solution of 1-(^)-2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin2(1H)-yl)propyl)-3-((5-(tetrahydro-2H-pyran- 3-yl)pyridin-2-yl)methyl)imidazolidin-2-one (0.02 g, 0.0354 mmol) in 10.0 ml THF was added TBAF (1 M solution in THF) (0.07 ml, 0 .0798 mmol) at 0°C and the reaction mixture was stirred for 12 hours at room temperature. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by the method of Rev. purification: column: XBRIDGE C18 [(21.2 mm x 500 mm), 5 μ], mobile phase: (A): 0.1% ammonia in water; (B): acetonitrile; flow: 15 ml/min; time/% B: 0/25, 2/30, 9/45 to obtain (0.010 g, 62.89%) 1-(^)-3-(3,4-dihydroisoquinolin-2(III)-yl)- 2hydroxypropyl)-3-((5-(tetrahydro-2H-pyran-3-yl)pyridin-2-yl)methyl)imidazolidin-2-one).

1H NMR (400 MHz, methanol^) δ 8.41 - 8.38 (m, 1H), 7.74 (dd, J=8.1, 2.4 Hz, 1H), 7.33 (dd, J =8.0, 0.7 Hz, 1H), 7.11 - 7.06 (m, 3H), 7.05 - 7.01 (m, 1H), 4.43 (s, 2H), 4, 07 (tt, J=7.3, 4.6 Hz, 1H), 3.98 - 3.86 (m, 2H), 3.73 (d, J=1.5 Hz, 2H), 3.58 - 3.43 (m, 4H), 3.38 -3.32 (m, 3H), 3.24 - 3.17 (m, 1H), 2.91 (q, J=5.0 Hz, 4H ), 2.87 - 2.81 (m, 2H), 2.65 - 2.54 (m, 2H), 2.00 (d, J=2.1 Hz, 1H), 1.87 - 1, 70 (m, 3H); LCMS: 451.4 [M+H]+.

The connections shown in the table below. 3 was prepared by a procedure similar to that described in Example-III with appropriate variations in reagents, amounts of reagents, introduction and deprotection, solvents and reaction conditions. The characteristics of the compounds are shown in the table below.

Table 3

Connection no. Structure Characteristics 78 8 8 XX 1-0 *H NMR (400 MHz, Methanol-d4) δ 8.49 - 8.45 (m, 1H), 7.99 (dd, J= 8.3, 2.4 Hz, 1H), 7.43 (d , J = 8.3 Hz, 1H), 7.12 - 7.07 (m, 3H), 7.04 - 6.99 (m, 1H), 5.10 (dd, J = 8.3, 6 ,1 Hz, 2H), 4.72 (t, J = 6.3 Hz, 2H), 4.47 (s, 2H), 4.37 4.26 (m, 1H), 4.07 (tt, J= 7.2, 4.5 Hz, 1H), 3.72 (s, 2H), 3.62 - 3.50 (m, 2H), 3.41 - 3.32 (m, 2H), 3 .26 - 3.17 (m, 2H), 2.90 (d, J = 5.7 Hz, 2H), 2.88 - 79 O N=Z U-J OH W 'H NMR (400 MHz, Methanol-d4) δ 8.33 (d, J= 2.2 Hz, 1H), 7.77 (dd, J = 8.2, 2.4 Hz, 1H), 7, 30 - 7.26 (m, 1H), 6.99 - 6.94 (tn, 3H), 6.92 - 6.86 (m, 1H), 4.49 (td, J = 7.9, 7 ,5, 4.4 Hz, 1H), 4.33 (s, 2H), 4.31 - 4.24 (m, 1H), 4.12 (dd, J = 8.5, 5.6 Hz, 1H), 3.95 (tt, J = 7.2, 4.5 Hz, 1H), 3.89 - 3.78 (m, 3H), 3.62 (s, 2H), 3.48 - 3 .38 (m, 2H), 3.26 - 3.19 (m, 3H), 3.13 - 3.05 (m, 1H), 2.83 - 2.70 (tn, 4H), 2.56 - 2.42 (m, 2H), 2.05 (tn, 1 H), 1.78 (s, 3H); LCMS: 464.4 [M+H] ⁺ .

- 50 046513

Ή NMR (400 MHz, DMSO-d6) δ 8.46 (dd, J= 9.6, 2.4 Hz, 1H), 7.72 (ddd, J = 10.8, 8.1, 2.4 Hz, 1H), 7.23 (dd, .7 = 8.1, 5.5 Hz, 1H), 7.12 - 7.06 (m, 3H), 7.05 6.99 (m, 1H) , 4.74 (d, J = 4.8 Hz, 1H), 4.33 (d, J = 1.6 Hz, 2H), 3.93 - 3.80 (m, 2H), 3.65 - 3.56 (m, 3H), 3.55 3.38 (m, 4H), 3.29 - 3.22 (m, 2H), 3.21 - 3.12 (m, 2H), 3.02 (dd, J= 13.8, 7.2 Hz, 1H), 2.80 (t, J= 5.9 Hz, 2H), 2.71 (q, J = 5.4 Hz, 2H), 2 .44 (dd, J = 6.1, 3.6 Hz, 1H), 1.96 (d, J = 4.9 Hz, 3H), 1.54 (d, J = 15.4 Hz, 3H) ; LCMS: 478.4 [M+H] ⁺ .

Example-IV. Synthesis

1-((5-(4-acetylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-(8-fluoro-3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) imidazolidin-2-one. Connection-81

Stage-a. Synthesis of tert-butyl(2-(((5-bromopyridin-2-yl)methyl)amino)ethyl)carbamate.

To a stirred solution of 5-bromopicolinaldehyde (20.0 g, 107.5 mmol) in 500 ml methanol, tert-butyl(2-aminoethyl)carbamate (17.22 g, 107.5 mmol) was added and the reaction mixture was stirred for 30 min. at room temperature. The reaction mixture was cooled to 0°C, Na(O)Ac) ₃ B11 (68.35 g, 322.5 mmol) was added to this reaction mixture and stirred for 12 hours at room temperature. After completion reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 25.0 g of tert-butyl (2-(((5-bromopyridin2-yl)methyl)amino)ethyl)carbamate. LCMS: 330.2 [M+]; 332.2 [M+2].

Stage-b. Synthesis of 1-((5-bromopyridin-2-yl)methyl)imidazolidin-2-one.

Potassium tert-butoxide (4, 1 g, 36.46 mmol) and stirred for 2 hours at 60°C. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was diluted with 5% MeOH in DCM and washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was triturated with ether and dried to obtain 4.75 g of 1-((5-bromopyridin-2yl)methyl)imidazolidin-2-one as a yellow solid. LCMS: 256.2 [M ⁺ ]; 258.2 [M+2].

Stage-s. Synthesis of 1-((5-bromopyridin-2-yl)methyl)-3-(oxiran-2-ylmethyl)imidazolidin-2-one.

NaH (0.6 g, 14.7 mmol) at 0°C and stirred for 30 min at the same temperature, epibromohydrin (2.0 g, 14.7 mmol) was added to this reaction mixture and left to stir for 12 h at room temperature. After completion of the reaction ( observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was quenched with water and extracted with ethyl acetate. The combined extracts were washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ , 3% MeOH in DCM) to give (1.7 g, 55.73%) 1-((5-bromopyridin-2-yl)methyl)-3-(oxiran-2ylmethyl )imidazolidin-2-one in the form of a yellow viscous liquid. LCMS: LCMS: 312.2 [M+]; 314.2 [M+2].

Stage-d. Synthesis of 1-((5-bromopyridin-2-yl)methyl)-3-(3-(8-fluoro-3,4-dihydroisoquinolin-2(III)-yl)-2hydroxypropyl)imidazolidin-2-one.

1-((5-bromopyridin-2-yl)methyl)-3-(oxiran-2ylmethyl)imidazolidin-2-one (0.5 g, 1.60 mmol), 8-fluoro-1,2 ,3,4-tetrahydroisoquinoline (0.29 g, 1.92 mmol), DIPEA (0.621 g, 4.81 mmol) and IPA (10 ml) and stirred for 12 h at 100°C. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was distilled and the resulting residue was purified by combined flash column chromatography

- 51 046513 (SiO2, 2-3% MeOH in DCM) to give (0.1 g, 14.8%) 1-((5-bromopyridin-2-yl)methyl)-3-(3-(8- fluoro-3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)imidazolidin-2-one. LCMS: 463.3 [M+]; 465.3 [M+2].

Stage-e. Synthesis of 1-((5-(4-acetylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-(8-fluoro-3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )imidazolidin-2-one.

1-((5-bromopyridin-2-yl)methyl)-3-(3-(8-fluoro-3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)imidazolidin-2-one was added to the stoppered test tube (0.1 g, 0.216 mmol), toluene (10 ml), the reaction mixture was degassed with argon gas for 10 min. To this reaction mixture was added 1-(piperazin-1-yl)ethan-1-one (0.033 g, 2.59 mmol), sodium tert-butoxide (0.031 g, 0.324 mmol), Pd ₂ (dba) ₃ (0.004 g , 0.0043 mmol) and BINAP (0.008 g, 0.013 mmol) and stirred for 12 hours at 100°C. After completion of the reaction (observed by TLC, eluent: 5% methanol in CHCl ₃ ), the reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified on preparative TLC plates eluting with 5% MeOH in DCM to give (0.02 g, 17.69%) 1-((5-(4-acetylpiperazin-1-yl)pyridin-2-yl)methyl) -3(3-(8-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)imidazolidin-2-one.

1H NMR (400 MHz, methanol^) δ 8.18 (d, J=2.9 Hz, 1H), 7.42 (dd, J=8.7, 3.0 Hz, 1H), 7.26 ( d, J=8.7 Hz, 1H), 7.18 - 7.08 (m, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.85 (t, J=9 ,0 Hz, 1H), 4.37 (s, 2H), 4.06 (t, J=4.5 Hz, 1H), 3.71 (dt, J =15.5, 5.9 Hz, 5H ), 3.53 (td, J=7.9, 7.5, 2.9 Hz, 3H), 3.42 - 3.33 (m, 3H), 3.28 - 3.12 (m, 5H ), 2.92 (d, J=5.9 Hz, 2H), 2.84 (t, J=5.7 Hz, 2H), 2.63 (dd, J=6.1, 3.4 Hz , 2H), 2.14 (s, 3H); LCMS: 511.4 [M+H] ⁺ .

The connections shown in the table below. 4 was prepared by a procedure similar to that described in Example-IV with appropriate variations in reagents, amounts of reagents, introduction and deprotection, solvents and reaction conditions. The connection characteristics are shown in the table below.

Table 4

Connection no. Structure Characteristics 82 8 h ^O= C b % 'H NMR (600 MHz, DMSO-d6) δ 8.25 - 8.21 (m, 1H), 7.34 (dt, J= 9.0, 2.2 Hz, 1H), 7.26 (dd , J= 5.2, 1.5 Hz, 1H), 7.11 (dd, .1= 8.6, 1.5 Hz, 1H), 6.78 (dd, J = 5.2, 1, 5 Hz, 1H), 4.74 (d, J = 4.5 Hz, 1H), 4.24 (d, J = 1.5 Hz, 2H), 3.87 - 3.80 (m, 1H) , 3.57 (dq, J= 10.9, 7.2, 5.3 Hz, 4H), 3.52 (s, 2H), 3.44 - 3.40 (m, 2H), 3.28 - 3.24 (m, 1H), 3.22 3.17 (m, 4H), 3.15-3.11 (m, 2H), 3.00 (ddd, J= 13.9, 7.2 , 1.5 Hz, 1H), 2.80 2.72 (m, 4H), 2.48 - 2.44 (m, 2H), 2.03 (d, J = 1.5 Hz, ZN); LCMS: 499.4 [M+H] ⁺ . 83 o X _S R - co o 'H NMR (600 MHz, DMSO-d6) δ 8.23 (d, J = 2.8 Hz, 1H), 7.34 (dt, J = 8.6, 2.0 Hz, 1H), 7, 11 (d, J = 8.6 Hz, 1H), 6.57 (dt, J = 2.8, 1.6 Hz, 1H), 5.95 (t, J = 3.0 Hz, 1H), 5.68 (dd, J = 3.3, 1.7 Hz, 1H), 4.78 (s, 1H), 4.25 (s, 2H), 3.89 (td, J = 5.6, 2.1 Hz, 2H), 3.83 (q, J = 6.2 Hz, 1H), 3.63 - 3.54 (m, 6H), 3.41 (q, J = 8.5, 7 ,4 Hz, 2H), 3.27 3.17 (m, 5H), 3.12 (t, J= 5.1 Hz, 2H), 3.04 - 2.97 (m, 1H), 2, 81 (q, J = 5.2 Hz, 2H), 2.42 (td, J = 12.6, 11.6, 5.9 Hz, 2H), 2.04 (d, J = 1.4 Hz , ZN); LCMS: 482.4 [M+H] ⁺ .

- 52 046513

84 0 A _(i ^N ^C ^N LJ%~'NA A> ^H0 HA ζ-N \=/ o 'H NMR (600 MHz, DMSO-d6) δ 8.23 (d, J = 2.9 Hz, 1H), 7.34 (ddd, J = 8.7, 3.0, 1.2 Hz, 1H ), 7.22 (ddt, J = 7.3, 5.0, 2.5 Hz, 2H), 7.20 - 7.15 (m, 2H), 7.12 (d, J = 8.6 Hz, 1H), 4.82 (d, J= 4.4 Hz, 1H), 4.57 (s, 1H), 4.26 (s, 2H), 3.93 3.85 (m, 4H) , 3.81 - 3.76 (m, 1H), 3.57 (dd, J = 6.1, 3.6 Hz, 4H), 3.47 - 3.41 (m, 1H), 3.33 - 3.29 (m, 1H), 3.24 3.16 (m, 4H), 3.13 - 3.10 (m, 2H), 3.00 (ddd, 7= 13.8, 7.4 , 1.2 Hz, 1H), 2.70 2.60 (m, 2H), 2.11 (d, 7= 1.1 Hz, 1H), 2.04 (d, 7= 1.2 Hz, 3H); LCMS: 479.4 [M+H] ⁺ . 85 o N=/ \__J OH A ^N 'N o N—/ °x 'H NMR (400 MHz, Methanol-d4) δ 8.19 (d, 7 = 2.9 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.26 (d, 7 = 8 .6 Hz, 1H), 6.04 (dd, 7= 1.9, 0.9 Hz, 1H), 4.37 (s, 2H), 4.21 - 4.11 (m, 2H), 4 .07 - 3.97 (m, 1H), 3.80 (d, 7= 3.4 Hz, 2H), 3.72 (dq, 7= 15.5, 5.3, 5.1, 5, 1 Hz, 5H), 3.52 (td, 7= 7.9, 7.4, 2.9 Hz, 2H), 3.41 - 3.31 (m, 2H), 3.28 - 3.17 (m, 5H), 3.10 3.03 (m, 2H), 2.67 - 2.58 (m, 2H), 2.14 (s, 3H); LCMS: 483.5 [M+H] ⁺ . 86 0 A/HO H A'N O+U Ή NMR (400 MHz, Methanol-d4) δ 8.07 (dd, 7 = 2.8, 0.7 Hz, 1H), 7.28 (dd, 7 = 8.7, 2.9 Hz, 1H) , 7.22 (dd, 7= 8.6, 0.7 Hz, 1H), 7.17 (dd, 7= 5.4, 3.3 Hz, 2H), 7.13 - 7.05 (m , 2H), 4.35 (s, 2H), 4.18 - 4.12 (m, 2H), 3.90 (ddt, 7= 8.8, 6.8, 5.0, 5.0 Hz , 1H), 3.81 (d, 7= 10.9 Hz, 2H), 3.61 (p, 7= 7.1, 7.1, 7.1, 7.1 Hz, 1H), 3, 57 - 3.44 (m, 4H), 3.40 3.31 (m, 2H), 3.29 - 3.24 (m, 2H), 3.18 (dt, J = 15.8, 6, 9, 6.9 Hz, 2H), 2.83 2.73 (m, 3H), 2.65 (dd, 7 = 12.1, 8.2 Hz, 1H), 2.09 - 1.93 ( m, 4H), 1.48 1.29 (m, 2H); LCMS: 478.8 [M+H] ⁺ . 87 0 A r-x .N^/^N N'-'N^ G GL f Ύ \_/ aAd 7 AU NO Η Ν-^\-=7 G Ή NMR (400 MHz, Methanol-d4) δ 8.06 (d, 7 = 2.6 Hz, 1H), 7.86 (d, 7 = 8.9 Hz, 1H), 7.62 - 7.46 (m, 3H), 7.28 - 7.15 (m, 3H), 6.80 (d, 7 = 9.0 Hz, 1H), 4.36 (s, 2H), 4.15-4, 11 (m, 2H), 4.04 (tdd, 7= 6.6, 6.6, 5.0, 3.7 Hz, 1H), 3.80 (d, 7 -11.0 Hz, 2H) , 3.64 (dd, 7 14.1, 3.8 Hz, 1H), 3.59 - 3.45 (m, 5H), 3.41 - 3.32 (m, 4H), 2.08 - 1.90 (m, 4H); LCMS: 489.3 [M+H] ⁺ .

- 53 046513

Example-V. Synthesis of 1 -(3 -((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-3 -((5-(tetrahydro2H-pyran-4-yl)pyridin-2- yl)methyl)imidazolidin-2-one (compound-88, 89 and 90).

Connection 88

Stage-a. Synthesis of 1 -((5-bromopyridin-2-yl)methyl)-3 -(3-((2,3-dihydro-1 H-inden-2-yl)amino)-2hydroxypropyl)imidazolidin-2-one.

1-((5-bromopyridin-2-yl)methyl)-3-(oxiran-2ylmethyl)imidazolidin-2-one (1.0 g, 3.21 mmol), 2,3-dihydro-1H was added to the stoppered tube -inden-2-amine (0.63 g, 4.8 mmol), DIPEA (2.064 g, 16.0 mmol) and IPA (10 ml), and stirred for 12 h at 100°C. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was distilled and the resulting residue was purified by combi-flash column chromatography (SiO ₂ , 3% MeOH in DCM) to give (1.4 g, 97.28 %) 1-((5-bromopyridin-2-yl)methyl)-3-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2hydroxypropyl)imidazolidin-2-one. LCMS: 445.77 [M+2]; 447.7 [M+2].

Stage-b. Synthesis of 1-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-3-((5-(3,6-dihydro2H-pyran-4-yl)pyridine -2-yl)methyl)imidazolidin-2-one.

1-((5-bromopyridin-2-yl)methyl)-3-(3-((2,3dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)imidazolidin- 2-one (0.5 g, 1.122 mmol), DME/H2O (4:1) (22 ml), the reaction mixture was degassed with argon gas for 10 min. To this reaction mixture was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.282 g, 1.346 mmol), sodium carbonate (0.297 g, 2.805 mmol) and Pd(dppf)Cl ₂ (0.091 g, 0.122 mmol) and stirred for 12 hours at 65°C. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was filtered through a celite pad, and the filtrate was diluted with water and extracted with ethyl acetate, and the combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. . The resulting residue was purified by column chromatography (SiO ₂ , 1.5% MeOH in DCM) to give (0.3 g, 59.64%) 1-(3-((2,3-dihydro-III-indene-2- yl)amino)-2-hydroxypropyl)-3-((5-(3,6-dihydro-2Hpyran-4-yl)pyridin-2-yl)methyl)imidazolidin-2-one. LCMS: 448.8 [M+]; 450.8 [M+2].

Stage-s. Synthesis of 1-(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-3-((5-(tetrahydro2H-pyran-4-yl)pyridin-2-yl )methyl)imidazolidin-2-one.

A mixture of 1-(3-((2,3-dihydro-III-inden-2-yl)amino)-2-hydroxypropyl)-3-((5-(3,6-dihydro-2H-pyran-4yl)pyridine -2-yl)methyl)imidazolidin-2-one (0.3 g, 0.668 mmol) and 10% Pd-C (0.1 g) in 100 ml ethanol were transferred to a Parr mixing vessel and hydrogenated at 60 psi . inch for 24 hours at room temperature. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative purification: column: WATERS XBRTOGE C18 [(150 mmx21.2 m), 5 μ]; mobile phase: (A): 0.02% ammonia in water; (B): acetonitrile; flow: 15 ml/min; gradient program: time/% B: 0/20, 3/30, 10/60 to give (0.15 g, 50.0%) 1-(3-((2,3-dihydro-III-indene-2 -yl)amino)-2-hydroxypropyl)-3-((5-(tetrahydro-2H-pyran-4yl)pyridin-2-yl)methyl)imidazolidin-2-one.

1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J=2.2 Hz, 1H), 7.66 (dd, J=8.1, 2.4 Hz, 1H), 7.22 - 7.13 (m, 3H), 7.13- 7.07 (m, 2H), 4.81 (d, J=4.9 Hz, 1H), 4.32 (s, 2H), 3, 94 (dt, J=11.1, 3.2 Hz, 2H), 3.68 (d, J=5.9 Hz, 1H), 3.54 - 3.36 (m, 6H), 3.26 (dd, J=9.0, 6.8 Hz, 2H), 3.20 - 3.00 (m, 5H), 2.87 - 2.75 (m, 1H), 2.69 - 2.55 (m, 3H), 1.73-1.62 (m, 4H); LCMS: 451.9 [M+H] ⁺ .

Racemic compound-88 was separated by chiral preparative HPLC to obtain compound-89 (isomer-1) and compound-90 (isomer-2).

Method: column: CHIRALPAK IA [(250 mmx10.0 mm), 5 μ]; mobile phase: (A): 0.1% DEA in ethanol; (B): acetonitrile; flow: 8 ml/min; isocratic method: A=50%, B=40%.

Compound-89 (isomer-1)

1H NMR (400 MHz, DMSO-de) δ 8.42 (d, J=2.0 Hz, 1H), 7.66 (dd, J=8.0, 2.4 Hz, 1H), 7.23 - 7.14 (m, 3H), 7.14 - 7.08 (m, 2H), 4.87 (s, 1H), 4.32 (s, 2H), 3.94 (dt, J=11 ,1, 3.1 Hz, 2H), 3.70 (s, 1H), 3.51 (dd, J=9.0, 4.4

- 54 046513

Hz, 1H), 3.47 - 3.37 (m, 4H), 3.31 - 3.23 (m, 2H), 3.19 -3.00 (m, 5H), 2.85 - 2, 75 (m, 1H), 2.71 - 2.57 (m, 4H), 1.74 - 1.62 (m, 4H); LCMS: 451.4 [M+H]+.

Compound-90 (isomer-2)

1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J=2.3 Hz, 1H), 7.66 (dd, J=8.1, 2.4 Hz, 1H), 7.22 - 7.14 (m, 3H), 7.13-7.06 (m, 2H), 4.87 (s, 1H), 4.32 (s, 2H), 3.94 (dt, J=11 ,3, 3.1 Hz, 2H), 3.70 (s, 1H), 3.52 (s, 1H), 3.47 3.38 (m, 4H), 3.26 (t, J=8 ,0 Hz, 3H), 3.19 - 3.01 (m, 4H), 2.80 (p, J=8.3 Hz, 2H), 2.72 - 2.59 (m, 3H), 1 .67 (h, J=4.1 Hz, 4H); LCMS: 451.2 [M+H]+.

The connections shown in the table below. 5 was prepared by a procedure similar to that described in Example-V with appropriate variations in reagents, amounts of reagents, introduction and deprotection, solvents and reaction conditions. The connection characteristics are shown in the table below.

Table 5

Connection no. Structure Characteristics 91 O ^{but 1} \'LS ⁴ /===/^ N \ U -Z z~ ^N IT 'H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 2H), 9.08 - 9.03 (m, 1H), 8.34 - 8.29 (m, 1H), 7.51 - 7.44 (m, 1H), 6.63 (d, J= 16.6 Hz, 2H), 4.74 (d, J = 4.8 Hz, 1H), 4.45 (s, 2H) , 3.93 - 3.84 (m, 2H), 3.69 (d, J= 4.5 Hz, 5H), 3.51 (d, J - 7.5 Hz, 4H), 3.31 - 3.25 (m, 2H), 3.09 - 2.98 (m, 2H), 2.70 (s, 4H), 2.43 (s, 2H); LCMS: 530 [M+H] ⁺ . 92 1 Ar N=/^ OH ^H V >-N N ^Z/ 'H NMR (400 MHz, Methanol-d4) δ 9.25 (s, 2H), 8.93 (dd, J = 2.4, 0.8 Hz, 1H), 8.23 (dd, J = 8 ,2, 2.4 Hz, 1H), 7.57 (d, J= 8.3 Hz, 1H), 7.16 (t, J= 4.3 Hz, 2H), 7.13 - 7.06 (m, 2H), 4.56 (s, 2H), 3.97 - 3.90 (m, 1H), 3.67 - 3.51 (m, 3H), 3.46 (dd, J 9, 3, 7.6 Hz, 2H), 3.20 (dq, J= 15.8, 8.3 Hz, 3H), 2.85 - 2.75 (m, 3H), 2.69 (dd, J = 12.1, 8.1 Hz, 2H); LCMS: 470.8 [M+H] ⁺ .

- 55 046513

93 O Vv /=\ BUT ^ΗΝ '\χ /7 \ 'H NMR (400 MHz, Methanol-d4) δ 8.38 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.1, 2.3 Hz, 1H), 7, 33 (d, J = 8.1 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.62 - 6.58 (m, 1H), 6.49 (dd, J = 8.0, 2.2 Hz, 1H), 4.45 (s, 2H), 4.04 (dt, J = 11.1, 3.1, 3.1 Hz, 2H), 3.97 ( p, J = 5.7, 5.7, 5.6, 5.6 Hz, 1H), 3.55 (ddt, J = 16.4, 10.9, 6.1, 6.1 Hz, 4H ), 3.41 - 3.32 (m, 3H), 3.19 (dd, J = 13.0, 5.3 Hz, 1H), 3.09 (dd, J = 13.0, 6.8 Hz, 1H), 2.88 (dq, J= 10.5, 5.7, 5.7, 5.3 Hz, 1H), 2.78 (dt, J = 11.1, 7.4, 7 .4 Hz, 4H), 2.01 (p, J = 7.4, 7.4, 7.3, 7.3 Hz, 2H), 1.76 (td, J = 9.9, 8.6, 3 ,7 Hz, 4H); LCMS: 451.2 [M+H] ⁺ . 94 o A .N-^/^N //¾ f ^ξ - ¹ ' iAd / As/ HO H \A o^/ Ή NMR (400 MHz, Methanol-d4) δ 8.36 (d, J = 2.2 Hz, 1H), 7.64 - 7.54 (m, 4H), 7.34 - 7.26 (m, 2H), 7.13 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 6.98 (dd, J = 8.8, 2.3 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 4.46 (s, 2H), 4.11 - 3.96 (m, 4H), 3.62 - 3.47 (m, 4H), 3, 42 3.32 (m, 4H), 3.23 (dd, J= 13.1, 6.7 Hz, 1H), 2.80 (td, J= 10.3, 9.9, 4.9 Hz, 1H ), 1.77 - 1.65 (m, 4H), LCMS: 461.8 [M+H] ⁺ .

Example-VI. Synthesis of ^)-1-(6-((3-(3-(3,4-dihydroisoquinolin-2(III)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)pyridin-3-yl) piperidine-4-carboxylic acid.

Connection-95

Stage-a. Synthesis of ^)-1-(6-((3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(III)yl)propyl)-2-oxoimidazolidin-1-yl )methyl)pyridin-3-yl)piperidin-4-carbonitrile.

^)-1-((5-bromopyridin-2-yl)methyl)-3-(2-((tertbutyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl) was added to the stoppered test tube. propyl)imidazolidin-2-one (intermediate-2) (1.0 g, 1.786 mmol), toluene (30 ml), the reaction mixture was degassed with argon gas for 10 min. To this reaction mixture was added piperidine-4-carbonitrile (0.23 g, 2.14 mmol), sodium tert-butoxide (0.25 g, 2.68 mmol), Pd ₂ (dba) ₃ (0.032 g, 0. 0357 mmol) and BINAP (0.066 g, 0.1072 mmol) and stirred for 12 hours at 100°C. After completion of the reaction (observed by TLC, eluent: 7% methanol in DCM), the reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ , 2% MeOH in DCM) to give (0.6 g, 57.12%) (R)-1-(6-((3(2-((tert-butyldimethylsilyl) oxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propyl)-2-oxoimidazolidin-1yl)methyl)pyridin-3-yl)piperidin-4-carbonitrile. LCMS: 589.5 [M+H]+.

Stage-b. Synthesis of ^)-1-(6-((3-(3-(3,4-dihydroisoquinolin-2(III)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)pyridin-3-yl) piperidine-4-carboxylic acid.

To the stirred suspension ^)-1-(6-((3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4

- 56 046513 dihydroisoquinolin-2(1H)-yl)propyl)-2-oxoimidazolidin-1-yl)methyl)pyridin-3-yl)piperidin-4carbonitrile (0.1 g, 0.1698 mmol) in 1,4- dioxane (4.0 ml), 6 N HCl was added and stirred for 12 hours at 100°C. After completion of the reaction (observed by TLC, eluent: 15% methanol in DCM), the reaction mixture was concentrated under reduced pressure. The resulting residue was made alkaline with a solution of NaHCO ₃ and washed with ethyl acetate, and the aqueous layer was acidified with conc. HCl and extracted with 10% MeOH in DCM. The combined organics were washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (0.008 g, 9.63%) ^)-1-(6-((3-(3-(3,4- Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)pyridin-3-yl)piperidin-4-carboxylic acid.

1H NMR (400 MHz, methanol^) δ 8.15 (s, 1H), 7.39 (dd, J=8.7, 2.5 Hz, 1H), 7.27 - 7.14 (m, 4H ), 7.137.08 (m, 1H), 4.36 (s, 2H), 4.18 (t, J=6.6 Hz, 1H), 4.08 (s, 2H), 3.71 (dt , J=12.7, 3.6 Hz, 2H), 2.44 - 2.32 (m, 2H), 3.53 (td, J=7.8, 2.7 Hz, 2H), 3, 28 - 3.18 (m, 4H), 3.04 (d, J=7.0 Hz, 2H), 2.93 (t, J=5.9 Hz, 2H), 2.88 - 2.77 (m, 2H), 1.99 (d, J=12.6 Hz, 2H), 1.86 - 1.71 (m, 2H); LCMS: 494.4 [M+H]+.

Example-VII. Synthesis of (R)-1 -((5-(4-(azetidine-1-carbonyl)piperidin-1-yl)pyridin-2-yl)methyl)-3-(3(3,4-dihydroisoquinoline-2(1H )-yl)-2-hydroxypropyl)imidazolidin-2-one.

Connection-96

To a stirred solution of ^)-1-(6-((3-(3-(3,4-dihydroisoquinolin-2(III)-yl)-2hydroxypropyl)-2-oxoimidazolidin-1-yl)methyl)pyridin-3- yl)piperidine-4-carboxylic acid (0.1 g, 0.202 mmol) in 5 ml DMF was added with DIPEA (0.078 g, 0.607 mmol), HATU (0.115 g, 0.303 mmol) and azetidine hydrochloride (0.022 g, 0.243 mmol) at 0°C and stirred for 12 h at room temperature. After completion of the reaction (observed by TLC, eluent: 10% methanol in DCM), the reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was plate purified by preparative TLC (SiO ₂ , 5% MeOH/DCM) to give (0.012 g, 5.6%) ^)-1-((5-(4-(azetidine-1-carbonyl)piperidine- 1-yl)pyridin-2-yl)methyl)-3-(3(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)imidazolidin-2-one.

1H NMR (400 MHz, methanol^ ₄ ) δ 8.15 (d, J=2.9 Hz, 1H), 7.39 (dd, J=8.7, 2.9 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 7.14 - 7.06 (m, 3H), 7.03 (dd, J=7.5, 2.4 Hz, 1H), 4.35 ( s, 2H), 4.30 (dd, J=8.3, 7.1 Hz, 2H), 4.11 - 3.97 (m, 3H), 3.82 - 3.72 (m, 4H) , 3.57 - 3.47 (m, 2H), 3.38 - 3.32 (m, 2H), 3.22 - 3.16 (m, 2H), 2.91 (d, J=5, 4 Hz, 2H), 2.88 - 2.76 (m, 4H), 2.63 - 2.57 (m, 2H), 2.50 - 2.41 (m, 1H), 2.36 - 2 .26 (m, 2H), 1.78 (h, J=3.7 Hz, 4H); LCMS: 533.6 [M+H]+.

Example-VIII. Synthesis of ^)-1-(6-((3-(3-(3,4-dihydroisoquinolin-2(III)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)pyridin-3-yl) -N^-dimethylpiperidine-4-carboxamide.

Connection-97

Compound-97 was synthesized by the following experimental procedure as in Example-VII.

1H NMR (400 MHz, methanol^) δ 8.17 - 8.14 (m, 1H), 7.40 (dd, J=8.7, 3.0 Hz, 1H), 7.23 (d, J =8.7 Hz,

1H), 7.12 - 7.06 (m, 3H), 7.03 (dd, J=5.5, 2.6 Hz, 1H), 4.36 (s, 2H), 4.13- 4 .02 (m, 1H), 3.79 (d, J=12.5 Hz, 2H),

3.71 (s, 2H), 3.60 - 3.45 (m, 3H), 3.42 - 3.32 (m, 2H), 3.23 - 3.12 (m, 4H), 2, 95 - 2.79 (m, 10 N), 2.63 - 2.53 (m, 2 H), 1.85 - 1.77 (m, 4 H); LCMS: 521.5 [M+H]+.

- 57 046513

Example-IX. Synthesis of (R)-1 -((5-( 1 -((1H-1,2,3-triazol-4-yl)methyl)piperidin-4-yl)pyridin-2yl)methyl)-3-(3- (3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)imidazolidin-2-one.

Connection-98

Stage-a. Synthesis of (R)-1 -(2-((tert-butyldimethylsilyl)oxy)-3 -(3,4-dihydroisoquinolin-2(1H)yl)propyl)-3-((5-(1-(prop-2 -in-1-yl)piperidin-4-yl)pyridin-2-yl)methyl)imidazolidin-2-one.

To a stirred solution ^)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propyl)-3-((5-(piperidin-4- yl)pyridin-2-yl)methyl)imidazolidin-2-one (intermediate-4) (0.25 g, 0.44 mmol) in 10 ml of acetone was added potassium carbonate (0.061 g, 0.443 mmol) and propargyl bromide (0.052 g, 0.443 mmol) and stirred for 12 h at room temperature. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was concentrated under reduced pressure. The resulting residue was purified on preparative TLC plates (SiO ₂ , 2% MeOH in DCM) to give (0.2 g, 75.18%) ^)-1-(2-((tert-butyldimethylsilyl)oxy)-3-( 3,4dihydroisoquinolin-2(1H)-yl)propyl)-3-((5-(1-(prop-2-in-1-yl)piperidin-4-yl)pyridin-2yl)methyl)imidazolidin-2- she. LCMS: 602.6 [M+H]+.

Stage-b. Synthesis of ^)-1-((5-(1-((1H-1,2,3-triazol-4-yl)methyl)piperidin-4-yl)pyridin-2-yl)methyl)3-(2- ((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propyl)imidazolidin-2-one.

To a stirred solution ^)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin2(1 H)-yl)propyl)-3 -((5 -(1 -(prop- 2-yn-1-yl)piperidin-4-yl)pyridin-2-yl)methyl)imidazolidin-2-one (0.12 g, 0.199 mmol) in 10 ml DMF:MeOH (1:1) was added trimethylsilyl azide ( 0.114 g, 0.998 mmol), DIPEA (0.077 g, 0.599 mmol) and CuI (0.0036, 0.018 mmol), and stirred for 12 hours at 100°C. After completion of the reaction (observed by TLC, eluent: 10% methanol in DCM), the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ , 10% MeOH in DCM) to give (0.07 g, 54.68%) (R)-1-((5-(1-((1H-1.2, 3triazol-4-yl)methyl)piperidin-4-yl)pyridin-2-yl)methyl)-3-(2-((tert-butyldimethylsilyl)-oxy)-3-(3,4dihydroisoquinoline-2(1H)- yl)propyl)imidazolidin-2-one. LCMS: 645.6 [M+H] ⁺ .

Stage-s. Synthesis of ^)-1-((5-(1-((1H-1,2,3-triazol-4-yl)methyl)piperidin-4-yl)pyridin-2-yl)methyl)3-(3- (3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)imidazolidin-2-one.

To a stirred solution ^)-1-((5-(1-((1H-1,2,3-triazol-4-yl)methyl)piperidin-4-yl)pyridin2-yl)methyl)-3-(2 -((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)yl)propyl)imidazolidin-2-one (0.07 g, 0.108 mmol) in 10.0 ml THF was added TBAF ( 1 M solution in THF) (0.35 ml, 0.325 mmol) at 0°C and stirred for 12 h at room temperature. After completion of the reaction (observed by TLC, eluent: 10% methanol in DCM), the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative purification: column: KINTEX EVO C18 [(21.2 mmx500 mm), 5 μ]; mobile phase: (A): 0.02% ammonia in water; (B): acetonitrile; flow: 18 ml/min; time/% B: 0/10, 2/15, 10/40 to obtain (0.02 g, 35.08%) (R)1-((5-(1-((1H-1,2,3 -triazol-4-yl)methyl)piperidin-4-yl)pyridin-2-yl)methyl)-3-(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)imidazolidin-2- she.

1H NMR (400 MHz, methanol^) δ 8.42 (s, 1H), 8.04 (s, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.41 - 7, 24 (m, 4H), 7.20 (d, J=6.6 Hz, 1H), 4.54 (s, 2H), 4.46 (d, J=1.5 Hz, 2H), 4, 33 (dq, J=9.6, 4.9 Hz, 1H), 3.69 (d, J=12.1 Hz, 2H), 3.56 (ddd, J=29.8, 8.8, 7.5 Hz, 2H), 3.39 (t, J=8.4 Hz, 2H), 3.27 - 3.18 (m, 5H), 2.99 (d, J=10.0 Hz, 1H), 2.19 -2.08 (m, 2H), 1.99 (s, 2H), 1.65 (ddd, J=11.9, 10.0, 6.2 Hz, 4H), 1 .41 (h, J=7.4 Hz, 3H); LCMS: 531.5 [M+H]+.

Example-X. Synthesis of ^)-1-((5-(1-((2H-tetrazol-5-yl)methyl)piperidin-4-yl)pyridin-2-yl)methyl)-3(3-(3,4-dihydroisoquinoline) -2(III)-yl)-2-hydroxypropyl)imidazolidin-2-one.

Connection-99

Stage-a. Synthesis of ^)-2-(4-(6-((3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin2(1H)-yl)propyl)-2-oxoimidazolidin- 1 -yl)methyl)pyridin-3-yl)piperidin-1-yl)acetonitrile.

- 58 046513

To a stirred solution ^)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin2(1H)-yl)propyl)-3-((5-(piperidin-4-yl) pyridin-2-yl)methyl)imidazolidin-2-one (intermediate-4) (0.4 g, 0.709 mmol) in 10 ml of acetonitrile was added potassium carbonate (0.061 g, 0.443 mmol) and 2-chloroacetonitrile (0.064 g, 0.851 mmol) at 0°C and stirred for 12 h at RT. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was diluted with water and extracted with ethyl acetate and the combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ , 4% MeOH in DCM) to give (0.32 g, 70.25%) ^)-2-(4-(6-((3-(2-((tert -butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)yl)propyl)-2-oxoimidazolidin-1 -yl)methyl)pyridin-3-yl)piperidin-1 -yl)acetonitrile. LCMS: 603.5 [M+H]+.

Stage-b. Synthesis of ^)-2-(4-(6-((3-(3-(3,4-dihydroisoquinolin-2(III)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)pyridin-3 -yl)piperidin-1-yl)acetonitrile.

To a stirred solution of ^)-2-(4-(6-((3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4dihydroisoquinolin-2(1H)-yl)propyl)-2-oxoimidazolidine -1-yl)methyl)pyridin-3-yl)piperidin-1yl)acetonitrile (0.32 g, 0.53 mmol) in 15.0 ml THF was added TBAF (1 M solution in THF) (1.6 ml, 1.592 mmol) at 0°C and stirred for 12 h at room temperature. After completion of the reaction (observed by TLC, eluent: 10% methanol in DCM), the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography (SiO ₂ , 3-4% MeOH in DCM) to give (0.21 g, 81.78%) ^)-2-(4-(6-((3-(3-(3,4-dihydroisoquinoline-2( 1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)pyridin-3-yl)piperidin-1-yl)acetonitrile. LCMS: 489.6 [M+H] ⁺ .

Stage-s. Synthesis of ^)-1-((5-(1-((2H-tetrazol-5-yl)methyl)piperidin-4-yl)pyridin-2-yl)methyl)-3-(3(3,4-dihydroisoquinoline -2(1H)-yl)-2-hydroxypropyl)imidazolidin-2-one.

To a stirred solution ^)-1-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin2(1 H)-yl)propyl)-3 -((5 -(1 -(prop- 2-yn-1-yl)piperidin-4-yl)pyridin-2-yl)methyl)imidazolidin-2-one (0.06 g, 0.122 mmol) in 10 ml of 1,4-dioxane was added trimethylsilyl azide (0.141 g, 1.227 mmol), dibutyltin oxide (0.015 g, 0.0613 mmol) and stirred for 12 hours at 100°C. After completion of the reaction [observed by TLC, eluent: methanol:n-butanol:DCM (4:1:20)], the reaction mixture was concentrated under reduced pressure. The resulting residue was purified on preparative TLC plates [SiO ₂ , methanol:n-butanol:DCM (4:1:20)] to give (0.02 g, 31.25%) (R)-1-((5-( 1((2H-tetrazol-5-yl)methyl)piperidin-4-yl)pyridin-2-yl)methyl)-3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)2-hydroxypropyl )imidazolidin-2-one as a sticky solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (d, J=2.2 Hz, 1H), 7.62 (dd, J=8.0, 2.4 Hz, 1H), 7, 20 (d, J=8.1 Hz, 1H), 7.13 - 6.99 (m, 4H), 5.35 - 5.28 (m, 1H), 4.79 (s, 1H), 4 .31 (s, 2H), 4.13 (s, 2H), 3.89 (s, 1H), 3.65 (s, 2H), 3.45 (d, J=8.3 Hz, 2H) , 3.25 (t, J=7.6, 7.6 Hz, 5H), 3.02 (dd, J=14.0, 7.2 Hz, 1H), 2.86 - 2.71 (m , 4H), 2.69 - 2.63 (m, 3H), 2.35 - 2.30 (m, 2H), 2.08 - 1.92 (m, 1H), 1.88 - 1.69 (m, 3H); LCMS: 532.7 [M+H]+.

Example-XI. Synthesis of ^)-6'-((3-(3-(3,4-dihydroisoquinolin-2(III)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)-2-oxo-2H-[ 1,3'-bipyridine]-4-carbonitrile.

Connection-100

Stage-a. Synthesis of ^)-6'-((3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(III)yl)propyl)-2-oxoimidazolidin-1-yl)methyl )-2-oxo-2H-[1,3'-bipyridine]-4-carbonitrile.

^)-1-((5-bromopyridin-2-yl)methyl)-3-(2-((tertbutyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinoline-2(1H)- yl)propyl)imidazolidin-2-one (intermediate-2) (02 g, 0.357 mmol), dmso (5 ml), 2-oxo-1,2-dihydropyridin-4-carbonitrile (0.068 g, 0.536 mmol), CuI (0.07 g, 0.0357 mmol) 1,10-phenanthroline (0.013 g, 0.071 mmol) and K ₃ PO ₄ (0.227 g, 1.072 mmol) and the reaction mixture was degassed with argon gas for 10 min and stirred for 2 hours at 145°C with microwave irradiation. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was filtered through a celite pad and the filtrate was washed with water, brine, anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified on plates by preparative TLC (SiO ₂ , 5% MeOH in DCM) to obtain 0.04 g ^)-6'-((3-(2-((tert-butyldimethylsilyl)oxy)3-(3, 4-dihydroisoquinolin-2(1H)-yl)propyl)-2-oxoimidazolidin-1-yl)methyl)-2-oxo-2H-[1,3'bipyridin]-4-carbonitrile. LCMS: 598.8 [M+H]+.

Stage-b. Synthesis of ^)-6'-((3-(3-(3,4-dihydroisoquinolin-2(III)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)-2-oxo-2H-[ 1,3'-bipyridine]-4-carbonitrile.

- 59 046513

To a stirred solution ^)-6'-((3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4dihydroisoquinolin-2(1H)-yl)propyl)-2-oxoimidazolidin-1 -yl )methyl)-2-oxo-2H-[1,3'-bipyridine]-4carbonitrile (0.04 g, 0.066 mmol) in 2.0 ml THF was added TBAF (1 M solution in THF) (0.2 ml, 0.20 mmol) at 0°C and stirred for 12 hours at room temperature. After completion of the reaction (observed by TLC, eluent: 10% methanol in DCM), the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by the method of the rep. purification: column: GEMINI NX C18 [(21.2 mmx500 mm), 5 μ]; mobile phase: (A): 0.01% TFA in water; (B): acetonitrile; flow: 18 ml/min; time/%B: 0/10, 2/15, 7/45 to obtain (0.01 g, 40.0%) ^)-6'-((3-(3-(3,4-dihydroisoquinoline-2 (III)-yl)-2hydroxypropyl)-2-oxoimidazolidin-1-yl)methyl)-2-oxo-2H-[1,3'-bipyridine]-4-carbonitrile.

1H NMR (400 MHz, chloroform-d) δ 8.54 (dd, J=2.5, 0.7 Hz, 1H), 7.77 (dd, J=8.4, 2.6 Hz, 1H) , 7.51 (dd, J=8.4, 0.7 Hz, 1H), 7.44 (dd, J=7.1, 0.8 Hz, 1H), 7.19 - 7.08 (m , 3H), 7.05 - 6.98 (m, 2H), 6.42 (dd, J=7.1, 1.8 Hz, 1H), 4.58 (d, J=3.9 Hz, 2H), 4.01 (ddt, J=9.9, 7.2, 3.7, 3.7 Hz, 1H), 3.83 (d, J=14.9 Hz, 1H), 3.68 - 3 .38 (m, 6H), 3.19 (dd, J=14.3, 6.6 Hz, 1H), 2.99 - 2.88 (m, 3H), 2.75 (dd, J=9 ,6, 6.2 Hz, 1H), 2.65 - 2.52 (m, 2H); LCMS: 485.8 [M+H]+.

Example-XII. Synthesis of ^)-6'-((3-(3-(3,4-dihydroisoquinolin-2(III)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)-2H-[1,3' -bipyridine]-2-ona.

Connection-101

Compound-101 was prepared by the same experimental procedure as Example-XL.

1H NMR (300 MHz, Chloroform-d) δ 8.56 (d, J=2.4 Hz, 1H), 7.80 (dd, J=8.4, 2.6 Hz, 1H), 7.51 - 7.38 (m, 2H), 7.31 (dd, J=6.8, 2.1 Hz, 1H), 7.19 - 7.07 (m, 3H), 7.07 - 6.99 (m, 1H), 6.71 - 6.63 (m, 1H), 6.30 (td, J=6.7, 6.7, 1.4 Hz, 1H), 4.57 (d, J =1.7 Hz, 2H), 4.01 (s, 1H), 3.84 (d, J=14.8 Hz, 1H), 3.69 - 3.49 (m, 3H), 3.48 - 3.35 (m, 3H), 3.20 (dd, J=14.3, 6.4 Hz, 1H), 2.92 (d, J=3.3 Hz, 3H), 2.76 ( t, J=7.4, 7.4 Hz, 1H), 2.66 - 2.54 (m, 2H); LCMS: 460.2 [M+H]+.

Example-XIII. Synthesis of ^)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((5-(2(pyrrolidin-1-carbonyl)pyrimidin-5-yl) pyridin-2-yl)methyl)imidazolidin-2-one.

Compound-102

Stage-a. Synthesis of ^)-5-(6-((3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)yl)propyl)-2-oxoimidazolidin-1-yl )methyl)pyridin-3-yl)pyrimidin-2-carbonitrile.

^)-1-((5-bromopyridin-2-yl)methyl)-3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl) was added to the stoppered test tube. propyl)imidazolidin-2-one (3.5 g, 6.254 mmol), DME/H2O (4:1) (70 ml), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)pyrimidin-2carbonitrile (1.589 g, 6.879 mmol), sodium carbonate (1.657 g, 15.635 mmol) and Pd(dppf)Cl ₂ (0.51 g, 0.625 mmol) and the reaction mixture was degassed with argon gas for 10 min, and stirred for 12 hours at 70°C. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was filtered through a celite pad and the filtrate was diluted with water and extracted with ethyl acetate, and the combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ , 2-3% MeOH in DCM) to give (2.0 g, 54.77%) ^)-5-(6-((3-(2-((tert- butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(1H)yl)propyl)-2-oxoimidazolidin-1-yl)methyl)pyridin-3-yl)pyrimidin-2-carbonitrile. LCMS: 281.3 [M+H]+.

Stage-b. Synthesis of methyl^)-5-(6-((3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)pyridin-3-yl )pyrimidine-2-carboxylate.

To a stirred solution ^)-5-(6-((3-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4dihydroisoquinolin-2(1H)-yl)propyl)-2-oxoimidazolidin-1- yl)methyl)pyridin-3-yl)pyrimidin-2carbonitrile (1.6 g, 2.74 mmol) in (30 ml) methanol was added methanolic HCl (2 M solution) (8.3 ml) at 0°C and stirred for 12 hours at 60°C. After completion of the reaction (observed

- 60 046513 using TLC, eluent: 5% methanol in DCM) the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 0.65 g of methyl A)-5-(6-((3-(3-(3,4-dihydroisoquinolin2(1H)-yl) -2-hydroxypropyl)-2-oxoimidazolidin-1-yl)methyl)pyridin-3-yl)pyrimidin-2-carboxylate. LCMS: 547.2 [M+H]+.

Stage-s. Synthesis of A)-5-(6-((3-(3-(3,4-dihydroisoquinolin-2(III)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)pyridin-3-yl) pyrimidine-2-carboxylic acid with lithium salt.

To a stirred solution of methyl A)-5-(6-((3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2hydroxypropyl)-2-oxoimidazolidin-1-yl)methyl)pyridin-3- yl)pyrimidine-2-carboxylate (0.2 g, 0.398 mmol) in THF:H ₂ O (4:1) (10 ml) was added lithium hydroxide (0.033 g, 0.796 mmol) at 0°C and stirred for 12 h at RT. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was concentrated under reduced pressure to obtain 0.25 g of lithium salt (R)-5-(6-((3- (3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-oxoimidazolidin-1 yl)methyl)pyridin-3-yl)pyrimidin-2-carboxylic acid. LCMS: 547.2 [M+H] ⁺ .

Stage-d. Synthesis of Sh)-1-(3-(3,4-dihydroisoquinolin-2(Sh)-yl)-2-hydroxypropyl)-3-((5-(2(pyrrolidin-1-carbonyl)pyrimidin-5-yl) pyridin-2-yl)methyl)imidazolidin-2-one.

To a stirred solution Sh)-5-(6-((3-(3-(3,4-dihydroisoquinolin-2(III)-yl)-2hydroxypropyl)-2-oxoimidazolidium-1-yl)methyl)pyridin-3- yl)pyrimidine-2-carboxylic acid with lithium salt (0.25 g, 0.505 mmol) in 15 ml DMF was added DIPEA (0.391 g, 3.032 mmol), HATU (0.288 g, 0.758 mmol) and pyrrolidine (0.053 g, 0.758 mmol ) at 0°C and stirred for 12 hours at RT. After completion of the reaction (observed by TLC, eluent: 5% methanol in DCM), the reaction mixture was diluted with water and extracted with ethyl acetate, and the combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by the method of Rev. purification: column: WATERS XBRTDGE C18 [(21.2 mmx150 mm), 5 μ]; mobile phase: (A): 0.02% ammonia in water; (B): acetonitrile; flow: 15 ml/min; time/% V: 0/10, 3/15, 10/45 to obtain 0.015 μ)-1-(3-(3,4-dihydroisoquinolin-2(III)-yl)-2hydroxypropyl)-3-((5 -(2-(pyrrolidin-1-carbonyl)pyrimidin-5-yl)pyridin-2-yl)methyl)imidazolidin2-one.

^1H NMR (400 MHz, methanol^) δ 9.21 (s, 2H), 8.91 (dd, J=2.4, 0.8 Hz, 1H), 8.22 (dd, J=8, 2, 2.4 Hz, 1H), 7.56 (dd, J=8.2, 0.8 Hz, 1H), 7.14 - 7.08 (m, 3H), 7.04 (dd, J =5.0, 2.5 Hz, 1H), 4.56 (s, 2H), 4.10 (tt, J=7.2, 4.5 Hz, 1H), 3.78 (d, J= 1.7 Hz, 2H), 3.67 (dd, J=7.4, 6.0 Hz, 2H), 3.64 - 3.57 (m, 3H), 3.47 - 3.35 (m , 3H), 3.27 3.16 (m, 2H), 2.98 - 2.87 (m, 4H), 2.72 - 2.62 (m, 2H), 2.05 - 1.93 ( m, 4H); LCMS: 542.4 [M+H] ⁺ .

Example-XIV. Synthesis of Sh)-1-(3-(3,4-dihydroisoquinolin-2(Sh)-yl)-2-hydroxypropyl)-3-((6-(2(pyrrolidin-1-carbonyl)pyrimidin-5-yl) pyridin-3-yl)methyl)imidazolidin-2-one.

Compound-103

Compound-103 was prepared by the same experimental procedure as described in Example-XIn.

1H NMR (400 MHz, methanol^) δ 9.49 (s, 2H), 8.69 (d, J=2.2 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H) , 7.91 (dd, J=8.2, 2.3 Hz, 1H), 7.14 - 6.99 (m, 4H), 4.47 (s, 2H), 4.13 - 4.05 (m, 3H), 3.77 (s, 2H), 3.71 - 3.52 (m, 5H), 3.39 3.34 (m, 2H), 3.22 (dd, J=14, 2, 7.0 Hz, 1H), 2.92 (s, 4H), 2.64 (s, 2H), 2.05 - 1.93 (m, 4H); LCMS: 542.4 [M+H] ⁺ .

Example-XV. Synthesis of Sh)-1-(3-(3,4-dihydroisoquinolin-2(Sh)-yl)-2-methoxypropyl)-3-((5(tetrahydro-2H-pyran-4-yl)pyridin-2-yl )methyl)imidazolidin-2-one.

Compound-104

To a stirred solution Sh)-1-(3-(3,4-dihydroisoquinolin-2(Sh)-yl)-2-hydroxypropyl)-3-((5(tetrahydro-2H-pyran-4-yl)pyridin-2 -yl)methyl)imidazolidin-2-one (0.03 g, 0.0665 mmol) in 2 ml THF, NaH (0.0039 g, 0.0998 mmol) was added at 0°C and stirred for 30 min at that At the same temperature, MeI (0.0043 g, 0.0798 mmol) was added to this reaction mixture and stirred for 20 hours at room temperature. After completion of the reaction (observed by TLC, eluent: 5% meta

- 61 046513 nol in DCM) the reaction mixture was diluted with water and extracted with ethyl acetate and the combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was plate purified by preparative TLC (SiO2, 5% MeOH in DCM) to give (0.006 g, 19%) ^)-1-(3-(3,4-dihydroisoquinolin-2(III)yl)-2- methoxypropyl)-3-((5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)methyl)imidazolidin-2-one.

1H NMR (300 MHz, Chloroform-d) δ 8.41 (d, J=2.3 Hz, 1H), 7.51 (dd, J=8.1, 2.4 Hz, 1H), 7.27 (d, J=9.0 Hz, 1H), 7.10 (dd, J=5.9, 3.7 Hz, 3H), 7.05 - 6.98 (m, 1H), 5.34 ( t, J=4.7 Hz, 1H), 4.48 (s, 2H), 4.13- 4.01 (m, 2H), 3.70 (s, 2H), 3.68 - 3.60 (m, 1H), 3.60 - 3.51 (m, 3H), 3.30 (ddd, J=11.1, 8.9, 5.8 Hz, 4H), 2.89 (d, J =5.8 Hz, 2H), 2.79 (dd, J=10.9, 5.2 Hz, 3H), 2.72 - 2.57 (m, 2H), 2.22 (t, J= 7.6 Hz, 1H), 2.00 (t, J=6.8 Hz, 2H), 1.88 1.72 (m, 5H); LCMS: 465.4 [M+H]+.

TR-FRET-based PRMT5 inhibition assay.

Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes mono- and symmetric demethylation of arginine residues of histone or non-histone proteins in the presence of S-adenosylmethionine (AdoMet or SAM), a cofactor responsible for methyl group transfer. PRMT5 has been reported to be overexpressed in several human cancers. A TR-FRET based assay was developed to identify compounds that inhibit PRMT 5 and reduce its activity. Time-resolved fluorescence inductive resonance energy transfer (TR-FRET) HTS assays are homogeneous proximity assays in which the interaction of two dye-labeled binding partners is detected through energy transfer between donor and acceptor dyes and subsequent emission of light from the acceptor dye. PRMT5 catalyzes the peptide histone H4 [1–16], which is biotin tagged with the amino acid lysine at the carboxyl terminus, in the presence of S-adenosyl-l-methionine (SAM) to methylate the peptide. An antibody specific for monomethylated H4 peptide (H4R3) with an Ig conjugate binds to the methylated peptide by indirectly binding to the lanthanide europium. SureLight's allophycocyanin-streptavidin binds to the biotin tag of the peptide, thereby accepting the energy transferred from the europium lanthanide. This energy transfer between europium and SureLight allophycocyanin is a direct measure of PRMT5 enzyme activity/inhibition.

Reagents and equipment.

Reagents/equipment Provider Catalog no. Bitsin Sigma B8660 Sodium chloride Sigma S9888 Bovine serum albumin Sigma 5470 Tween-20 Sigma P1379 DMSO Rankem D0178 DL-dithiothreitol Sigma D0632 SGRGKGGKGLGKGGA-K(6hothh) AnaSpec SGA-1129201-QUNNS Complex PRMT5/MEP50 Reaction Biology HMT-22-148 8-(5'-adenosyl)-B-methionine chloride dihydrochloride Sigma A7007 Goat anti-rabbit IgG polyclonal antibody (europium) Abeam abl87910 Rabbit polyclonal antibody against histone H4 (monomethyl R3) Abeam ab!7339 Allophycocyanin SureLight-streptavidin Perkin Elmer CR-130-100 Potassium fluoride Sigma 449148 384-well polystyrene microplates with F-shaped bottom, white, Med Binding Greiner 781075 Victor-3 (Wallac) Perkin Elmer - GraphPad Prism 7 GraphPad Software, Inc. - Micropipettes Eppendorf -

Assay buffer: 20 mM BICINE (pH 7.6), 25 mM NaCl, 2 mM DTT, 0.01% Tween-20 and 0.01%

B.S.A.

- 62 046513

Preparation of reagents.

Reagent Initial concentration Work concentration Final analytical concentration DMSO 100% 7.50% 1% Histone-H4 peptide 5 µM 250 nM 50 nM SAM 300 µM 3 µM 1 µM Complex PRMT5:MEP50 8.7 µM 96 nM 32 nM Revealing mixture AB against H4R3 6.6 µM 60 nM 3 nM Anti-IgG europium antibody 6.6 µM 60 nM 3 nM Streptavidin SAPC 6.35 µM 60 nM 3 nM Potassium fluoride 2M 2M 200 mM

Compounds were prepared as 7.5% DMSO stock solutions in assay buffer. To 2 µl (7.5x) of the test compound, 5 µl of PRMT5 enzyme prepared in assay buffer (final concentration 32 nM in a reaction volume of 15 µl) was added and pre-incubated for 30 min in a white polystyrene 384-well plate at room temperature . A total of 8 μl of a substrate mixture solution containing biotinylated H4 peptide SGRGKGGKGLGKGGA-K (Biotin, 3 μl) and S-adenosylmethionine (5 μl) was added to each well to initiate the reaction at a final concentration of 50 nM and 1 μM, respectively. Reaction mixtures were incubated for 90 min at room temperature and then quenched with 5 μl of detection mixture per well (resulting in a final volume of 20 μl of solution per well). The plates were then read on a Victor-3 with excitation at 340 nM and emission collected at 615 and 665 nM using the TR-FRET protocol. The following calculations were performed.

1. Folding activity: signal at F665/F615x 10000 positive control/signal at F665/F615x 10000 substrate control.

2. Inhibition percentage: 100 - {signal at F665/F615x1000 NCE/signal at F665/F615x 10000 positive control} x 100.

Percent inhibition was plotted against test compound concentration using Graphpad Prism to calculate IC ₅₀ . For IC ₅₀ concentrations, a 1:3 dilution of the compound in 100% DMSO was prepared depending on the potency expected from the screen, followed by dilution with buffer for each concentration. The results are presented in table. 6.

Table 6

IC ₅₀ of compounds according to the present invention with respect to PRMT 5 inhibition

Connection no. IC50 PRMT5 (µM) 28 0.05 29 0.163 thirty 0.092 31 0.059 32 0.022 33 0.014 34 0.047 35 0.014 36 0.013 37 0.053 38 0.069 39 0.026 40 0.163 41 0.025 42 0.012 43 0.01 44 0.011 45 0.018 46 0.012 47 0.085 48 0.03 49 0.043 50 0.024 51 0.066 52 0.017 53 0.018

Connection no. IC50 PRMT5 (µM) 1 0.042 2 0.041 3 0.02 4 0.026 5 0.05 6 0.009 7 0.048 8 0.03 9 0.058 10 0.052 12 0.036 13 0.017 14 0.116 15 0.012 16 0.015 17 0.012 18 0.025 19 0.037 20 0.031 21 0.037 22 0.031 23 0.032 24 0.234 25 0.036 26 0.097 27 0.02

- 63 046513

Z138 cell proliferation assay.

Z138 cells were seeded in a 96-well round bottom plate and treated with various concentrations of the compound. The final DMSO concentration was maintained at 0.05%. Selected compounds of the present invention were screened in a 9-point dose response format starting at 10 µM and a 1/3 serial dilution. On day 4, the cells were centrifuged and the medium was replaced, maintaining the original concentration of compound in each well. At the end of day 7, the cells were centrifuged and the medium was aspirated. 50 μl of medium containing XTT was added to the wells. The plates were read using an M3 spectrophotometer at 465 nm. _GI50 values were calculated by fitting dose response data to an empirical sigmoidal curve equation using GraphPad Prism V7 software. The results are shown in table. 7.

Compounds were screened in the above analytical procedures to determine _IC50 and GI50 values for PRMT5 inhibition. The results for selected compounds are given in table. 6, wherein A refers to a GI50 value below 0.1 μM, B refers to a GI50 value from 0.1 μM to 0.3 μM (both inclusive), and C refers to a GI50 value above 0.3 μM.

- 64 046513

Table 7

GI ₅₀ of compounds according to the present invention with respect to PRMT5 inhibition

Connection no. GI50 Z138 (µM) 1 A 2 WITH 3 A 4 IN 5 WITH 6 A 7 WITH 8 IN 9 A 10 IN 12 IN 13 IN 14 With 15 V 16 V 17 V 18 V 19 A 20 A 21 IN 22 A 23 A 24 WITH 25 A 26 IN 27 WITH 28 IN 29 V thirty A 31 A 32 A 33 A 34 A 35 A 36 A 37 WITH 38 A 39 A 40 WITH 41 A 42 V 43 A 44 A 99 WITH 100 IN 101 IN

Claims (29)

1. Compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof; wherein X1, X2 and X3 are each independently CR5 or N; ring A is (C ₃ -C ₁₀ )cycloalkyl, (C ₆ -C ₁₄ )aryl, 3-15 membered heterocycloalkyl or 5-10 membered heteroaryl; R represents hydrogen, (C ₁ -C ₆ )alkyl or halogen; R ₁ represents R2 represents hydrogen or (C1- _C6 )alkyl; or R1 and R2 together with the nitrogen atom to which they are attached form a 9-12 membered bicycle - 65 046513 ical heterocyclyl ring, optionally containing from 1 to 3 additional heteroatoms selected from N, O and S; wherein the bicyclic heterocyclyl ring is optionally substituted with one or more R6; R ₃ represents hydrogen or (C1-C ₆ )alkyl; R ₄ is in each case independently hydrogen, halogen, halogen(C1- _C6 )alkyl, cyano, (C1- _C6 )alkyl, hydroxy, (C1- _C6 )alkoxy, -C(O) _R7 , - (C1- _C6 )alkyl-C(O^ ₇ , -S(O) _2R7 ; said alkyl is optionally substituted with a 5-10 membered heteroaryl; or two R4 on the same atom together form an oxo (=O) group; R5 is in each instance independently hydrogen, (C1- _C6 )alkyl, halogen, halogen( _C1C6 )alkyl or (C1- _C6 )alkoxy; R6 is (C1- _C6 )alkyl, (C1- _C6 )alkoxy, hydroxy, cyano, halogen or halo(C1C6)alkyl; R ₇ is (C1- _C6 )alkyl, hydroxy, (C1- _C6 )alkoxy, -NReRf, ( _C3 - _C10 )cycloalkyl _, ( _C6C14 )aryl, 3-15 membered heterocycloalkyl or 5 -10-membered heteroaryl; wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is further optionally substituted with one or more R6; R _a and R _b are each independently hydrogen or (C1-C ₆ )alkyl; Rc and Rd are each independently hydrogen or (C1- _C6 )alkyl; or Rc and Rd together represent an oxo (=O) group; Re and Rf are each independently hydrogen or (C1- _C6 )alkyl; or R _e and Rf, together with the nitrogen atom to which they are attached, form an optionally substituted 3-7 membered heterocyclic ring with 1-2 additional heteroatoms selected from N, O and S; wherein the additional substituent is one or more R6; m is an integer from 1 to 3; and n is 0 or 1; wherein each 3-15 membered heterocycloalkyl contains at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O) ₂ , NH or C(O), and each 5-10 membered heteroaryl contains from 1 to 4 heteroatoms selected from N, O and S. 2. A compound according to claim 1, which is a compound of formula (IA) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. 3. A compound according to claim 1, which is a compound of formula (IB) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. 4. A compound according to claim 1, which is a compound of formula (IC) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. 5. A compound according to claim 1, which is a compound of formula (ID) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. 6. A compound according to claim 1, which is a compound of formula (IE) - 66 046513 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. 7. A compound according to claim 1, which is a compound of formula (IF) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. 8. A compound according to claim 1, which is a compound of formula (IG) or (IH) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. 9. A compound according to claim 1, which is a compound of formula (IJ) or (IK) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. 10. A compound according to claim 1, which is a compound of formula (IL) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. 11. The connection according to claim 1, where the ring is 12. The compound according to claim 1, where ring A is - 67 046513 where represents the junction with the ring containing X1, X2 and _X3 . 13. The connection according to claim 1, wherein X1, X2 and _X3 are each CR5; or X1 represents N; X2 and _X3 represent CR5; or X2 represents N; X1 and X ₃ represent CR5; or X1 is CR5; X2 and _X3 represent N; or X2 is CR5; X1 and X3 represent N; or X ₃ is CR ₅ ; X ₁ and X ₂ represent N. 14. The connection according to claim 1, where the group ^R2 represents 15. A compound according to claim 1, wherein R ₃ , Ra, Rb, Rc and Rd are hydrogen. 16. A compound according to claim 1, selected from: - 68 046513 Connection no. Name ShRAS 1 (R)-l -(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((5-(4(pyrrolid in-1 -carbonyl)piperidin-1 -yl )pyr idin-2yl)methyl)imide azolide in-2-one; 2 (R)-1 -((5 -(4-acetylpiperazin-1 -yl)pyrazin-2-yl)methyl)-3 -(3 -(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) imidazolidin-2-one; 3 (R)-1 -((5 -(4-acetylpiperazin-1 -yl)pyrid in-2-yl)methyl)-3 -(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )imidazolidin-2-one; 4 ^)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((5morpholinopyridin-2-yl)methyl)imide azolide in-2-one; 5 (R)-1 -((5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)methyl)-3 -(3 (3,4-dihydroisoquinoline-2(1H )-yl)-2-hydroxypropyl)imidazolidin-2-one; 6 (R)-1 -((5 -(4-(cyclopropanecarbonyl)piperazin-1 -yl)pyride in-2-yl)methyl)3 -(3 -(3,4-d ihydroisoquinoline-2(1H)- yl)-2-hydroxypropyl)imidazolide in2-one; 7 (R)-1 -((5 -(4-acetylpiperidin-1 -yl)pyrazin-2-yl)methyl)-3 -(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) imidazolidin-2-one; 8 (R)-1 -((5 -(4-(cyclopropanecarbonyl)piperazin-1 -yl)pyrazin-2-yl)methyl)3 -(3 -(3,4-d ihydroisoquinolin-2(1H)-yl )-2-hydroxypropyl)imidazolide in2-one; 9 (R)-1 -(6-((3 -(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimid azolide in-1 -yl)methyl)pyride in-3 -yl)piperidin-4-carbonitrile; 10 (R)-1 -(5-((3 -(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimid azolide in-1-yl)methyl)pyrazin-2- yl)piperidine-4-carbonitryl; AND (R)-1 -((5 -(4-acetylpiperidin-1 -yl)pyridin-2-yl)methyl)-3 -(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) imidazolidin-2-one; 12 (R)-1 -((5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)methyl)-3-(3(3,4-dihydroisoquinoline-2 (1H)-yl)-2-hydroxypropyl)imidazolidin-2-one; 13 ethyl(K)-2-( 1 -(6-((3 -(3 -(3,4-d ihydroisoquinolin-2( 1 H)-yl)-2hydroxypropyl)-2-oxoimid azolidin-1-yl)methyl )pyridin-3yl)piperidin-4-yl)-2-methylpropanoate; 14 (R)-2-( 1 -(6-((3 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimid azolide in-1 -yl)methyl)pyride in-3 -yl)piperidin-4-yl)-2methylpropanoic acid; 15 (R)-1 -(6-((3 -(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)pyr idin-3 - ηπ )-N, N-d and methyl piperid and n-4sulfonamide; 16 (R)-1 -(5-((3 -(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)pyridin-2-yl) -G4,T4-dimethylpiperidine-4sulfonamide; 17 ^)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((6-(4(pyrrolid in-1-carbonyl)piperidin-1-yl) pir idin-3 - yl)methyl)imide azolide in-2-one; 18 1-((5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)methyl)-3-((K)-3(3,4-dihydroisoquinoline-2 (1H)-yl)-2-hydroxypropyl)imide azolide in-2-one; 19 1-((5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)methyl)-3-(^)-3(3,4-dihydroisoquinoline-2( 1H)-yl)-2-hydroxypropyl)imide azolide in-2-one; - 69 046513 20 1-((5-((3K,58)-4-acetyl-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)methyl)3 -((R)-3 -(3,4-dihydroisoquinoline -2( 1 H)-yl)-2- hydroxypropyl)imidazolidin-2-one; 21 1 -((5 -(4-acetyl-2-methylpiperazin-1 -yl)pyridin-2-yl)methyl)-3 -((R)-3 -(3,4dihydroisoquinolin-2(1H)-yl)- 2-hydroxypropyl)imidazolidin-2-one; 22 1 -((5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methyl)-3 -((R)-3 (3,4-dihydroisoquinoline-2 (1H)-yl)-2-hydroxypropyl)imide azolide in-2-one; 23 1 -((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)methyl)-3 -((R)-3 (3,4-dihydroisoquinoline- 2(1H)-yl)-2-hydroxypropyl)imide azolide in-2-one; 24 1-((5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrazin-2-yl)methyl)-3-((K)-3(3,4-dihydroisoquinoline-2 (1H)-yl)-2-hydroxypropyl)imidazolidin-2-one; 25 1-((6-(3,3-difluoro-8-azabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)methyl)-3((R)-3 -(3,4-dihydroisoquinoline -2(1H)-yl)-2hydroxypropyl)imidazolidin-2-one; 26 1 -(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzyl)-3 -((R)-3 -(3,4dihydroisoquinolin-2(1H)-yl)-2 -hydroxypropyl)imidazolidin-2-one; 27 1 -((6-(3 -oxa-6-azabicyclo[3.1.1] heptan-6-yl)pyridin-3 -yl)methyl)-3 -((R)3 -(3,4-dihydroisoquinoline-2 (1H)-yl)-2-hydroxypropyl)imidazolidin-2one; 28 1 -(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzyl)-3 -((R)-3 -(3,4dihydroisoquinolin-2(1H)-yl )-2-hydroxypropyl)imidazolidin-2-one; 29 1-((5-(3-oxa-6-azabicyclo[3.1.1] heptan-6-yl)pyridin-2-yl)methyl)-3 -((R)3 -(3,4-dihydroisoquinoline-2 (1H)-yl)-2-hydroxypropyl)imidazolidin-2one; thirty 1-((5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-fluoropyridin-2-yl)methyl)- 3 -((R)-3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2hydroxypropyl)imidazolidin-2-one; 31 1 -(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-fluorobenzyl)-3 -((R)-3 -(3,4dihydroisoquinolin-2(1H)-yl )-2-hydroxypropyl)imidazolidin-2-one; 32 (R)-1 -((6-( 1 -acetylpiperidin-4-yl)pyridin-3 -yl)methyl)-3 -(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) imidazolidin-2-one; 33 (R)-1 -((5-( 1 -acetylpiperidin-4-yl)pyridin-2-yl)methyl)-3 -(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) imidazolidin-2-one; 34 (R)-1 -((5-( 1 -acetylpiperidin-4-yl)pyrazin-2-yl)methyl)-3 -(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) imidazolidin-2-one; 35 (R)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((5(tetrahydro-2H-pyran-4-yl)pyridin-2-yl )methyl)imidazolidin-2-one; 36 (R)-1 -((5 -(1 -(cyclopropanecarbonyl)piperide in-4-yl)pyridin-2-yl)methyl)3 -(3 -(3,4-d ihydroisoquinoline-2(1H)- yl)-2-hydroxypropyl)imidazolide in2-one; 37 ^)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((5(pyridin-3-yl)pyrazin-2-yl)methyl)imidazolidin- 2-on; 38 (R)-1 -((6-( 1 -acetylpiperidin-4-yl)pyridazin-3 -yl)methyl)-3 -(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) imidazolidin-2-one; 39 1 -((5-(1-acetylpiperidin-4-yl)pyridin-2-yl)methyl)-3 -(3 -(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,4dimethylimidazolidine -2-on; 40 (R)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((5(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl )methyl)imidazolidin-2-one; - 70 046513 41 (R)-1 -((5-( 1 -(cyclopropanecarbonyl)piperidin-4-yl)pyrazin-2-yl)methyl)3 -(3 -(3,4-d ihydroisoquinolin-2(1H)-yl )-2-hydroxypropyl)imidazolide in2-one; 42 (R)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((5(pyrimidin-5-yl)pyridin-2-yl)methyl)imidazolidine -2-on; 43 (R)-1 -(3 -(3,4-dihydroisoquinolin-2( 1 H)-yl)-2-hydroxypropyl)-3 -((5-( 1 (methylsulfonyl)piperidin-4-yl)pyridin-2 -yl)methyl)imidazolidin-2one; 44 (R)-1 -(3 -(3,4-dihydroisoquinolin-2( 1 H)-yl)-2-hydroxypropyl)-3 -((5-( 1 propionylpiperidin-4-yl)pyridin-2-yl) methyl)imidazolidin-2-one; 45 (S)-l-((5-(l -acetylpiperide in-4-yl)pyridin-2-yl)methyl)-3 -(3-(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )imidazolidin-2-one; 46 1-((5-(1-acetylpiperide in-3-yl)pyrid in-2-yl)methyl)-3-(^)-3-(3,4dihydroisoquinolin-2(1H)-yl)-2- hydroxypropyl)imidazolidin-2-one; 47 (R)-1 -(3 -(3,4-dihydroisoquinolin-2( 1 H)-yl)-2-hydroxypropyl)-3 -((5-( 1 methylpiperidin-4-yl)pyridin-2-yl) methyl)imidazolidin-2-one; 48 ^)-1-((G-acetyl-G,2',3',6'-tetrahydro-[3,4'-bipyridin]-6-yl)methyl)-3-(3(3,4-dihydroisoquinoline -2(1H)-yl)-2-hydroxypropyl)imidazolidin-2-one; 49 (R)-1 -((5 -(3,6-d ihydro-2H-pyran-4-yl)pyridin-2-yl)methyl)-3 -(3 -(3,4dihydroisoquinoline-2(1H)- yl)-2-hydroxypropyl)imidazolidin-2-one; 50 (R)-5 -(6-((3 -(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimid azolide in-1 -yl)methyl)pyride in-3 -yl)pyrimide in-2-carbonitrile; 51 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((6(tetrahydro-2H-pyran-4-yl)pyridazin-3- yl)methyl)imidazolidin-2-one; 52 ^)-6'-((3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1-yl)methyl)-1-methyl-[3,3 '-bipyridine]-6(1H)-one; 53 (R)-1 -(3-(3,4-dihydroisoquinolin-2(1 H)-yl)-2-hydroxypropyl)-3 -((5 -(1 -(3 methyloxetane-3-carbonyl)piperidin-4 -yl)pyridin-2- yl)methyl)imide azolide in-2-one; 54 (R)-5 -(2-((3 -(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimid azolide in-1-yl)methyl)pyride in- 4-yl)pyrimidin-2-carbonitrile; 55 (R)-5 -(6-((3 -(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimid azolide in-1-yl)methyl)pyride in- 2-yl)pyrimidin-2-carbonitrile; 56 ^)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((2'hydroxy-[3,4'-bipyridin]-6-yl)methyl )imidazolidin-2-one; 57 (R)-1 -((6-( 1 -(cyclopropanecarbonyl)piper id in-4-yl)pyr idin-3 -yl)methyl)3 -(3 -(3,4-d ihydroisoquinoline-2( 1 H )-yl)-2-hydroxypropyl)imidazolide in2-one; 58 (R)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((2'methoxy-[2,4'-bipyridine]-5 -yl )methyl)imidazolidin-2-one; 59 ^)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((2'methoxy-[3,4'-bipyridine]-5-yl) methyl)imidazolidin-2-one; 60 ^)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((6'methoxy-[2,3'-bipyridin]-5-yl)methyl )imidazolidin-2-one; 61 ^)-6'-((3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimid azolide in-1 -yl)methyl)- [3,3'- bipyr idin]-6(1H)-one; 62 (R)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((6'methoxy-[3,3'-bipyridin]-6-yl) methyl)imidazolidin-2-one; 63 ^)-5-((3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimide azolide in-1-yl)methyl)-[2,3'-bipyridine ]-6'(GN)-on; - 71 046513 64 (R)-l -(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((2'isopropoxy-[3,4'-bipyridin]-6-yl )methyl)imidazolidin-2-one; 65 (R)-6-((3 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1 -yl)methyl)-1 '-methyl-[3, 4'-bipyridine]-2'(1'H)-one; 66 1 -((5-(8-oxabicyclo[3.2.1 ]octan-3 -yl)pyridin-2-yl)methyl)-3 -((R)-3 -(3,4dihydroisoquinolin-2(1H)-yl )-2-hydroxypropyl)imidazolidin-2-one; 67 (R)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((2'isopropoxy-[2,4'-bipyridin]-5-yl) methyl)imide azolide in-2-one; 68 1 -((R)-3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 -((5-(3 methyltetrahydro-2H-pyran-4-yl)pyridin- 2-yl)methyl)imidazolidin-2-one; 69 (K)-5-((3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1 -yl)methyl)-1 '-methyl-[2, 4'-bipyridine]-2'(1'H)-one; 70 1 -((R)-3 -(3,4-dihydroisoquinolin-2( 1 H)-yl)-2-hydroxypropyl)-3 -((6-(3 methyltetrahydro-2H-pyran-4-yl)pyridin- 3-yl)methyl)imidazolidin-2-one; 71 1 -((R)-3 -(3,4-dihydroisoquinolin-2( 1 H)-yl)-2-hydroxypropyl)-3 -((6-(3 methyltetrahydro-2H-pyran-4-yl)pyridin- 3-yl)methyl)imidazolidin-2-one; 72 1-((5-(8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)methyl)-3((R)-3 -(3,4-dihydroisoquinoline-2 (1H)-yl)-2hydroxypropyl)imidazolidin-2-one; 73 1-((6-(8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)methyl)-3((R)-3 -(3,4-dihydroisoquinoline-2 (1H)-yl)-2hydroxypropyl)imidazolidin-2-one; 74 1 -((6-(8-oxabicyclo[3.2.1]octan-3 -yl)pyridin-3 -yl)methyl)-3 -((R)-3 -(3,4dihydroisoquinoline-2(1H)- yl)-2-hydroxypropyl)imidazolidin-2-one; 75 1 -((6-cyclopropylpyrid in-3 -yl)methyl)-3 -(3 -(3,4-dihydroisoquinolin2(1H)-yl)-2-hydroxypropyl)imide azolide in-2-one; 76 3 -((6-cyclopropylpyridin-3-yl)methyl)-1 -(3 -(3,4-d ihydroisoquinolin2(1H)-yl)-2-hydroxypropyl)-5,5-dimethylimidazolidine-2,4- dione; 77 1-((K)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((5(tetrahydro-2H-pyran-3-yl)pyridin-2-yl )methyl)imidazolidin-2-one; 78 (R)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((5(oxetan-3-yl)pyridin-2-yl)methyl)imidazolidine -2-on; 79 (R)-1 -((5-( 1 -acetyl azetide in-3 -yl)pyrid in-2-yl)methyl)-3 -(3 -(3,4dihydroisoquinolin-2(1H)-yl)-2- hydroxypropyl)imidazolidin-2-one; 80 1 -((5-(1-acetylpyrrolidin-3-yl)pyrid in-2-yl)methyl)-3 -((R)-3 -(3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )imidazolidin-2-one; 81 1 -((5 -(4-acetylpiperazin-1 -yl)pyridin-2-yl)methyl)-3 -(3 -(8-fluoro-3,4dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) imidazolidin-2-one; 82 1 -((5 -(4-acetylpiperazin-1 -yl)pyridin-2-yl)methyl)-3 -(3-(6,7dihydrothieno[3,2-c]pyridin-5(4H)-yl)- 2-hydroxypropyl)imide azolide in2-one; 83 1 -((5 -(4-acetylpiperazin-1 -yl)pyridin-2-yl)methyl)-3 -(3-(3,4dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)- 2- hydroxypropyl)imidazolidin-2-one; 84 1 -((5 -(4-acetylpiperazin-1 -yl)pyridin-2-yl)methyl)-3 -(2-hydroxy-3 (isoindolin-2-yl)propyl)imidazolidin-2-one; 85 1-((5-(4-acetylpiperazin-1-yl)pyridin-2-yl)methyl)-3-(3-(6,7dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)- 2- hydroxypropyl)imidazolidin-2-one; - 72 046513 86 1-((5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)methyl)-3-(3((2,3-dihydro-1H-inden- 2-yl)amino)-2-hydroxypropyl)imidazolidin-2one; 87 1-((5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)methyl)-3-(2hydroxy-3-(quinolin-2-ylamino)propyl) imidazolidin-2-one; 88 1 -(3 -((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-3 -((5 (tetrahydro-2H-pyran-4-yl)pyridin-2- yl)methyl)imidazolidin-2-one; 89 (R)-l -(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-3-((5(tetrahydro-2H-pyran-4-yl)pyridine -2-yl)methyl)imidazolidin-2-one; 90 (S)-1 -(3 -((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-3 -((5 (tetrahydro-2H-pyran-4-yl) pyridin-2-yl)methyl)imidazolidin-2-one; 91 5-(6-((3-(3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2hydroxypropyl)-2-oxoimid azolidin-1-yl)methyl)pyr idin- 3 yl)pyrimidine-2-carbonitrile; 92 5 -(6-((3 -(3-((2,3-dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2oxoimid azolide in-1-yl)methyl)pyride in- 3 -yl)pyrimide in-2-carbonitrile; 93 1 -(3 -((2,3-dihydro-1H-inden-5-yl)amino)-2-hydroxypropyl)-3 -((5 (tetrahydro-2H-pyran-4-yl)pyridin-2- yl)methyl)imidazolidin-2-one; 94 1-(2-hydroxy-3-(naphthalene-2-ylamino)propyl)-3-((5-(tetrahydro-2Hpyran-4-yl)pyridin-2-yl)methyl)imidazolidin-2-one; 95 (R)-1 -(6-((3 -(3 -(3,4-d ihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimid azolide in-1 -yl)methyl)pyridine -3-yl)piperidine-4-carboxylic acid; 96 (R)-1 -((5 -(4-(azetide in-1-carbonyl)piperidin-1-yl)pyridin-2-yl)methyl)3 -(3 -(3,4-d ihydroisoquinoline-2( 1 H)-yl)-2-hydroxypropyl)imidazolide in2-one; 97 (R)-1 -(6-((3 -(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimidazolidin-1 -yl )methyl)pyr idin-3 -yl )-M,N-dimethylpiper idine-4carboxamide; 98 (R)-1 -((5 -(1 -((1 Η-1,2,3-triazol-4-yl)methyl)piperidin-4-yl)pyridin-2yl)methyl)-3 -(3 - (3,4-d ihydroisoquinolin-2(1H)-yl)-2- hydroxypropyl)imidazolidin-2-one; 99 (R)-1 -((5-(1-((2H-tetrazol-5-yl)methyl)piperidin-4-yl)pyridin-2yl)methyl)-3-(3-(3,4-dihydroisoquinoline- 2(1H)-yl)-2- hydroxypropyl)imidazolidin-2-one; 100 ^)-6'-((3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimid azolide in-1 -yl)methyl)-2-oxo-2H- [1,3'-bipyridine]-4carbonitrile; 101 ^)-6'-((3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2oxoimid azolide in-1-yl)methyl)-2H-[ 1,3 '-bipyr idin]-2-one; 102 (R)-l-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxopropyl)-3-((5-(2(pyrrolidin-1-carbonyl)pyrimidin-5-yl) pyride in-2- yl)methyl)imide azolide in-2-one; 103 ^)-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((6-(2(pyrrolidin-1-carbonyl)pyrimidin-5-yl)pyridine -3- yl)methyl)imidazolidin-2-one; And 104 (R)-1 -(3 -(3,4-dihydroisoquinolin-2(1H)-yl)-2-methoxypropyl)-3 -((5(tetrahydro-2H-pyran-4-yl)pyridin-2- yl)methyl)imidazolidin-2-one; or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. 17. A pharmaceutical composition containing a compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof and at least one pharmaceutically acceptable carrier or excipient. 18. A method of treating or preventing diseases or disorders mediated by PRMT5, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to claim 1. 19. The method of claim 18, wherein the disease or disorder mediated by PRMT5 is a cancer, a blood disorder, an inflammatory disorder, an autoimmune disease, a metabolic disorder, an inherited disease, a hormone-related disease, an immunodeficiency disorder, a condition associated with cell death , bone destructive disorder, thrombin-induced platelet aggregation, liver disease or cardiovascular disorder. 20. The method of claim 19, wherein the disease or disorder mediated by PRMT5 is a cancer, a blood disorder, a metabolic disorder, inflammation, an autoimmune disease, or a hemoglobinopathy. 21. The method according to claim 19, wherein the cancer is a solid tumor, benign or malignant tumor, carcinoma of the brain, kidney, lung, liver, stomach, vagina, ovary, esophagus, tumors of the stomach, breast, bladder, colon , prostate, pancreas, lung, cervix, testicle, skin, bone or thyroid; sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck and head tumor, epidermal hyperproliferation, psoriasis, prostate hyperplasia, neoplasia, adenoma, adenocarcinoma, rectal adenocarcinoma, colon adenocarcinoma - 73 046513 colon, lung adenocarcinoma, keratoacanthoma, epidermoid carcinoma, hepatocellular carcinoma, large cell carcinoma, renal cell carcinoma, oligodendroglioma, ovarian clear cell carcinoma, ovarian serous cystadenocarcinoma, non-small cell lung carcinoma, lymphomas, Hodgkin's lymphoma and non-Hodgkin's lymphoma, breast carcinoma, follicular carcinoma, papillary carcinoma, seminoma, melanoma; hematopoietic carcinoma, hematologic malignancies selected from leukemia, diffuse large B-cell lymphoma (DLBCL), activated B-cell derived DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia (WM), splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma and multiple myeloma. 22. The method of claim 19, wherein the blood disorder is sickle cell anemia or beta thalassemia. 23. The method according to claim 19, wherein the metabolic disorder is diabetes mellitus or obesity. 24. The compound according to claim 5, where R _a and Rb represent hydrogen. 25. The compound according to claim 5, where the group ^R 2 represents ''CO/OE/OE.....ko 26. A compound according to claim 5, wherein ring A is cycloalkyl, aryl, 3-5 membered heterocycloalkyl or 3-10 membered heteroaryl. 27. The compound according to claim 5, wherein ring A is 28. The compound according to claim 5, in which R4 in each case independently represents hydrogen, cyano, (C ₁ -C ₆ )alkyl, hydroxy, (C ₁ -C ₆ )alkoxy, -C(O)R ₇ , (C ₁ -C ₆ )alkyl-C(O)R ₇ , -S(O) ₂ R ₇ , where said alkyl is optionally substituted with a 5-10 membered heteroaryl. 29. The connection according to claim 5, in which R _a and Rb represent hydrogen; represents a ring A represents R4 is in each case independently hydrogen, cyano, (C1- _C6 )alkyl, hydroxy, ( _C1C6 )alkoxy, -C(O) _R7 , -( _C1 - _C6 )alkyl-C(O)R ₇ , -S(O) ₂ R ₇ , wherein said alkyl is optionally substituted with a 510-membered heteroaryl; - 74 046513 R7 is (C1- _C6 )alkyl, hydroxy, (C1- _C6 )alkoxy, -NReRf, ( _C3 - _C10 )cycloalkyl, ( _C6C .'| ₄ )aryl, 3-15 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein each of alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is further optionally substituted with one or more R ₆ ; Re and Rf are each independently hydrogen or (C ₁ -C ₆ )alkyl; or Re and Rf, together with the nitrogen to which they are attached, form an optionally substituted 3-7 membered heterocyclic ring with 1-2 additional heteroatoms selected from N, O and S, the optional substituent being one or more R ₆ ; R ₆ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, hydroxy, cyano, halogen or halogen^O ₆ )alkyl; and m represents 1, 2 or 3.